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1.
Cell Physiol Biochem ; 58(2): 156-171, 2024 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-38639213

RESUMO

BACKGROUND/AIMS: The physiological phenotype of individuals can influence and shape real-life phenomena in that it can contribute to the development of specific characteristics that can affect the immune response to specific stimuli. In this study we aimed to understand whether the sphingosine/sphingosine-1-phoshate (S1P) axis can modulate the immunotype of circulating cells. METHODS: To pursue this goal, we performed bioinformatic analyses of public datasets. RESULTS: The transcriptomic profile of healthy subjects of GSE192829 dataset identified two clusters with different transcriptional repertoire. Cluster 1 expressed higher levels of enzymes for S1P formation than cluster 0 which was characterized by enzymes that lead to ceramide formation, which represent the opposite metabolic direction. Inference analysis showed that cluster 1 was higher populated by monocytes, CD4+ T and B cells than cluster 0. Of particular interest was the phenotype of the monocytes in cluster 1 which showed an immunosuppressive nature compared to those in cluster 0. The role of S1P signature in healthy PBMCs was confirmed with other dataset analyses, supporting that circulating monocytes positive to the ceramidase, unlike the negative ones, had an immunosuppressive phenotype characterized by hub immunosuppressive markers (i.e. TYROBP, FCER1G, SYK, SIRPA, CSF1R, AIF1, FCGR2A, CLEC7A, LYN, PLCG2, LILRs, HCK, GAB2). This hub genes well discriminated the immunotype of healthy subjects. CONCLUSION: In conclusion this study highlights that S1P-associated hub markers can be useful to discriminate subjects with pronounced immunosuppression.


Assuntos
Monócitos , Esfingosina , Esfingosina/análogos & derivados , Humanos , Esfingosina/metabolismo , Monócitos/metabolismo , Lisofosfolipídeos/metabolismo , Imunossupressores , Fenótipo
2.
Int Immunopharmacol ; 131: 111832, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38460301

RESUMO

Cigarette smoke is widely known as contributing to chronic inflammation underlying several airway diseases, such as chronic obstructive pulmonary disease (COPD) and lung cancer. In our previous studies we found that the lung of both COPD and cancer patients were characterized by the presence and activation of the AIM2 inflammasome. Here, we wanted to investigate the upstream step during the establishment of chronic lung inflammation after cigarette smoke exposure. We took advantage of a mouse model of smoking exposure and public scRNAseq data. We found that AIM2 mRNA was expressed in both alveolar type II, B cells, T regulatory (Treg) and macrophages detected in the lung of non-smokers (n = 4) and smokers (n = 3). The activation of AIM2 in smoking mice by using PolydA:dT did not alter cigarette-smoke-induced alveoli enlargement and mucus production, rather it induced higher recruitment of immunosuppressive cells, such as non-active dendritic cells (DCs), Arginase I+ macrophages, myeloid-derived suppressor cells (MDSC) and Tregs. In addition, the inflammatory environment after AIM2 activation in smoking mice was characterized by higher levels of IL-1α, IL-1ß, IL-33, TNFα, LDH, IL-10 and TGFß. This scenario was not altered after the pharmacological inhibition of both caspase-1 and STING pathway. In conclusion, these data suggest that chronic inflammation after cigarette smoke exposure is associated with AIM2 activation, which could lead towards cigarette smoke-associated lung diseases.


Assuntos
Fumar Cigarros , Doença Pulmonar Obstrutiva Crônica , Animais , Humanos , Camundongos , Fumar Cigarros/efeitos adversos , Proteínas de Ligação a DNA/genética , Inflamassomos/metabolismo , Inflamação , Pulmão/metabolismo , Camundongos Endogâmicos C57BL
3.
Braz. J. Psychiatry (São Paulo, 1999, Impr.) ; Braz. J. Psychiatry (São Paulo, 1999, Impr.);46: e20233235, 2024. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1564068

RESUMO

Generalized anxiety disorder is a highly prevalent mental disorder. Previous data indicate that more than 18 million Brazilians suffer from this condition. Traditionally, generalized anxiety disorder has been considered a mild mental health disorder, despite its links to lower life expectancy, cardiovascular disease, and suicide. The aim of this article is to combine elements of systematic and critical reviews to produce a synthesis of the best evidence about generalized anxiety disorder treatment. Systematic reviews, meta-analyses, and randomized controlled trials were included. The descriptor used in the search was "generalized anxiety disorder," which resulted in 4,860 articles and seven other studies, of which 59 were selected. Antidepressants and benzodiazepines were indicated, as was pregabalin, and atypical antipsychotics, such as quetiapine, have been studied. Individual cognitive behavior therapy (third wave) has proven effective. There is extensive literature on many effective treatments for generalized anxiety disorder. The present review summarizes the therapeutic possibilities, emphasizing those available in Brazil. Further studies are needed to compare other available medications, assess psychotherapies and new treatments in greater depth, as well as to assess the ideal duration of therapy. Registration number: PROSPERO CRD42021288323.

4.
Braz J Psychiatry ; 2023 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-37956131

RESUMO

OBJECTIVE: To combine elements of a systematic review and critical review to produce best evidence synthesis for the treatament of GAD. METHOD: There was included systematic reviews, metanalysis, and randomized controlled trials. Descriptor used was "generalized anxiety disorder", resulting in 4860 articles and 7 other studies, of which 59 were selected. RESULTS: Antidepressants and benzodiazepines are indicated, as well as pregabalin. From, atypical antipsychotics quetiapine has been studied. Cognitive behavior therapy (third wave of behavioral and cognitive therapies) as well as individual CBT proven to be effective. CONCLUSION: There is extensive literature on many effective treatments for GAD. The present work summarizes the therapeutic possibilities, emphasizing those available in the Brazil. Further studies are still needed to compare other available medications, to assess psychotherapies in more depth, new treatments and specially to assess the ideal time for maintaining therapy.

5.
Int Immunopharmacol ; 124(Pt B): 110990, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37857119

RESUMO

The absent in melanoma 2 (AIM2) inflammasome has been demonstrated as involved in tumor growth. In this study we used human samples of lung adenocarcinoma (LUAD) patients, taking advantage of a mouse model of smoking cessation. Human samples were stratified according to the smoking status, high-risk factor for this type of tumor. Both public transcriptomic and human samples obtained by a clinical trial proved that AIM2 was upregulated either in terms of mRNA or protein, respectively, in the tumor mass according to the TNM stage, but it did not relate to the smoking status, age and sex. The upregulation of AIM2 was correlated to an immunosuppressive environment according to resting/non-active dendritic cells (DCs) and T regulatory cells, as demonstrated in both human samples and by means of an experimental model of smoking mice. Computational analysis showed that AIM2 upregulation was correlated to both an inflammasome profile, responsible for the poor prognosis of non-smoker and smoker LUAD patients, and to a non-inflammasome profile for former smoker. In conclusion, our study demonstrated that AIM2 is involved in lung carcinogenesis either in a canonical and non-canonical manner due to an immunosuppressive microenvironment associated to a dismal prognosis of LUAD patients.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Melanoma , Humanos , Camundongos , Animais , Inflamassomos/metabolismo , Adenocarcinoma de Pulmão/genética , Prognóstico , Neoplasias Pulmonares/genética , Microambiente Tumoral , Proteínas de Ligação a DNA/genética
6.
Biomed Pharmacother ; 168: 115709, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37857253

RESUMO

Several studies have associated platelets (PLTs) to NSCLC prognosis. To understand the role of PLTs in immunotherapy-treated patients, we used blood samples of NSCLC patients at different TNM stage. We found that PLTs count and the expression of PD-L1 (pPD-L1) were significantly higher in NSCLC patients at Stage IV than Stage I-III and healthy subjects. The presence of high pPD-L1 was associated to upregulated genes for the extracellular matrix organization and tumor immunosuppression. When patients' survival was correlated to the levels of pPD-L1, longer survival rate was observed, but not when progression disease occurred. The in vitro stimulation of pPD-L1 with Atezolizumab induced CXCL4 release, accompanied by higher levels of TGFß at the time of drug resistance when the levels of CD16, CD32 and CD64 significantly increased. Leiden-clustering method defined the phenotype of PLTs which showed that the ezrin-radixin-moesin (ERM) family proteins, underlying the PD-L1 signalosome, were involved in high pPD-L1 and higher survival rate. These data imply that Stage IV NSCLC patients characterized by high pPD-L1 are associated with longer progression-free survival rate because the blockade of pPD-L1 by Atezolizumab avoids the exacerbation of a T cell-mediated immune-suppressive environment. pPD-L1 could be an easy-to-use clinical approach to predict ICI responsiveness.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico
7.
Int J Mol Sci ; 24(13)2023 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-37446018

RESUMO

Sex is a biological variable that can reflect clinical outcomes in terms of quality of life, therapy effectiveness, responsiveness and/or toxicity. Sphingosine-1-phosphate (S1P) is a lipidic mediator whose activity can be influenced by sex. To evaluate whether the S1P axis underlies sex 'instructions' in the lung during physiological and oncological lung conditions, sphingosine and S1P were quantified in the blood of healthy (H) volunteers, lung adenocarcinoma (ADK) and squamous cell carcinoma (SCC) patients of both sexes. S1P receptors and their metabolic enzymes were evaluated in the tissues. Circulating levels of S1P were similar among H female and male subjects and female SCC patients. Instead, male and female ADK patients had lower circulating S1P levels. S1P receptor 3 (S1PR3) was physiologically expressed in the lung, but it was overexpressed in male SCC, and female and male ADK, but not in female SCC patients, who showed a significantly reduced ceramide synthase 1 (CERS1) mRNA and an overexpression of the ceramidase (ASAH1) precursor in lung tumor tissues, compared to male SCC and both male and female ADK patients. These findings highlighted sex differences in S1P rheostat in pathological conditions, but not in physiological conditions, identifying S1P as a prognostic mediator depending on lung cancer histotype.


Assuntos
Neoplasias Pulmonares , Esfingosina , Humanos , Masculino , Feminino , Esfingosina/metabolismo , Ceramidases/metabolismo , Caracteres Sexuais , Qualidade de Vida , Lisofosfolipídeos/metabolismo , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo
8.
Int J Mol Sci ; 24(9)2023 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-37176007

RESUMO

The stimulator of interferon genes (STING) is a master regulator of innate immunity, involved in several inflammatory diseases. Our previous data showed that sphingosine-1-phosphate (S1P) is released during inflammatory conditions in the lung. The aim of this study was to understand the interplay between S1P and STING during both physiological and pathological conditions. The mRNA levels of ceramidase (ASAH1), S1P precursor enzyme, and STING were inversely correlated in healthy lung tissues, but positively correlated in tumor tissues. The activation of STING induced higher expression of ASAH1 and was accompanied by IFN-ß and IL-6 release. ASAH1 and sphingosine kinases (SPHK I/II) blockade significantly reduced IL-6, but not IFNß, after STING activation. In support of this, taking advantage of a mouse model, we found that inflamed lungs had higher levels of inactive ASAH1 when STING was inhibited. This confirmed the human data, where higher levels of STING promoted the activation of ASAH1. Lung cancer patients positive to STING and ASAH1 mRNA levels had a dismal prognosis in that the overall survival was reduced compared to STING/ASAH1 negative patients. These data highlight that during physiological conditions, STING and the S1P axis do not interfere, whereas in lung cancer patients their interplay is associated to poor prognosis.


Assuntos
Neoplasias Pulmonares , Esfingosina , Animais , Humanos , Camundongos , Inflamação , Interleucina-6/genética , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Lisofosfolipídeos/metabolismo , Esfingosina/metabolismo
9.
Cells ; 11(16)2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-36010601

RESUMO

Sphingosine-1-phosphate (S1P) is involved in inflammatory signaling/s associated with the development of respiratory disorders, including cancer. However, the underlying mechanism/s are still elusive. The aim of this study was to investigate the role of S1P on circulating blood cells obtained from healthy volunteers and non-small cell lung cancer (NSCLC) patients. To pursue our goal, peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with S1P. We found that the administration of S1P did not induce healthy PBMCs to release pro-inflammatory cytokines. In sharp contrast, S1P significantly increased the levels of TNF-α and IL-6 from lung cancer-derived PBMCs. This effect was S1P receptor 3 (S1PR3)-dependent. The pharmacological blockade of ceramidase and sphingosine kinases (SPHKs), key enzymes for S1P synthesis, completely reduced the release of both TNF-α and IL-6 after S1P addition on lung cancer-derived PBMCs. Interestingly, S1P-induced IL-6, but not TNF-α, release from lung cancer-derived PBMCs was mTOR- and K-Ras-dependent, while NF-κB was not involved. These data identify S1P as a bioactive lipid mediator in a chronic inflammation-driven diseases such as NSCLC. In particular, the higher presence of S1P could orchestrate the cytokine milieu in NSCLC, highlighting S1P as a pro-tumor driver.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Carcinoma Pulmonar de Células não Pequenas/patologia , Citocinas , Humanos , Inflamação/patologia , Interleucina-6 , Leucócitos Mononucleares , Neoplasias Pulmonares/patologia , Lisofosfolipídeos , Pneumonia/patologia , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Fator de Necrose Tumoral alfa
10.
Front Immunol ; 13: 934264, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844548

RESUMO

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), responsible for COVID-19, has caused a global pandemic. Observational studies revealed a condition, herein called as Long-COVID syndrome (PC), that affects both moderately and severely infected patients, reducing quality-of-life. The mechanism/s underlying the onset of fibrotic-like changes in PC are still not well defined. The goal of this study was to understand the involvement of the Absent in melanoma-2 (AIM2) inflammasome in PC-associated lung fibrosis-like changes revealed by chest CT scans. Peripheral blood mononuclear cells (PBMCs) obtained from PC patients who did not develop signs of lung fibrosis were not responsive to AIM2 activation by Poly dA:dT. In sharp contrast, PBMCs from PC patients with signs of lung fibrosis were highly responsive to AIM2 activation, which induced the release of IL-1α, IFN-α and TGF-ß. The recognition of Poly dA:dT was not due to the activation of cyclic GMP-AMP (cGAMP) synthase, a stimulator of interferon response (cGAS-STING) pathways, implying a role for AIM2 in PC conditions. The release of IFN-α was caspase-1- and caspase-4-dependent when AIM2 was triggered. Instead, the release of pro-inflammatory IL-1α and pro-fibrogenic TGF-ß were inflammasome independent because the inhibition of caspase-1 and caspase-4 did not alter the levels of the two cytokines. Moreover, the responsiveness of AIM2 correlated with higher expression of the receptor in circulating CD14+ cells in PBMCs from patients with signs of lung fibrosis.


Assuntos
COVID-19 , Proteínas de Ligação a DNA , Fibrose Pulmonar , COVID-19/sangue , COVID-19/imunologia , COVID-19/patologia , Proteínas de Transporte , Caspase 1/imunologia , Proteínas de Ligação a DNA/sangue , Proteínas de Ligação a DNA/imunologia , Humanos , Inflamassomos/sangue , Inflamassomos/imunologia , Interferon-alfa/metabolismo , Leucócitos Mononucleares/imunologia , Fibrose Pulmonar/sangue , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/virologia , SARS-CoV-2 , Fator de Crescimento Transformador beta/metabolismo , Síndrome de COVID-19 Pós-Aguda
11.
Biomedicines ; 9(12)2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34944747

RESUMO

PURPOSE: SARS-CoV-2 infection induces in some patients a condition called long-COVID-19, herein post-COVID-19 (PC), which persists for longer than the negative oral-pharyngeal swab. One of the complications of PC is pulmonary fibrosis. The purpose of this study was to identify blood biomarkers to predict PC patients undergoing pulmonary fibrosis. PATIENTS AND METHODS: We analyzed blood samples of healthy, anti-SARS-CoV-2 vaccinated (VAX) subjects and PC patients who were stratified according to the severity of the disease and chest computed tomography (CT) scan data. RESULTS: The inflammatory C reactive protein (CRP), complement complex C5b-9, LDH, but not IL-6, were higher in PC patients, independent of the severity of the disease and lung fibrotic areas. Interestingly, PC patients with ground-glass opacities (as revealed by chest CT scan) were characterized by higher plasma levels of IL-1α, CXCL-10, TGF-ß, but not of IFN-ß, compared to healthy and VAX subjects. In particular, 19 out of 23 (82.6%) severe PC and 8 out of 29 (27.6%) moderate PC patients presented signs of lung fibrosis, associated to lower levels of IFN-ß, but higher IL-1α and TGF-ß. CONCLUSIONS: We found that higher IL-1α and TGF-ß and lower plasma levels of IFN-ß could predict an increased relative risk (RR = 2.8) of lung fibrosis-like changes in PC patients.

12.
Cell Physiol Biochem ; 55(5): 539-552, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34473432

RESUMO

BACKGROUND/AIMS: The pleiotropic lipid mediator sphingosine-1-phosphate (S1P) exerts a multitude of effects on respiratory cell physiology and pathology through five S1P receptors (S1PR1-5). Epidemiological studies proved high levels of circulating S1P in non-small cell lung cancer (NSCLC) patients. Studies in literature suggest that high levels of S1P support carcinogenesis but the exact mechanism is still elusive. The aim of this study was to understand the mechanism/s underlying S1P-mediated lung tumor cell proliferation. METHODS: We used human samples of NSCLC, a mouse model of first-hand smoking and of Benzo(a)pyrene (BaP)-induced tumor-bearing mice and A549 lung adenocarcinoma cells. RESULTS: We found that the expression of S1PR3 was also into the nucleus of lung cells in vitro, data that were confirmed in lung tissues of NSCLC patients, smoking and tumor bearing BaP-exposed mice. The intranuclear, but not the membrane, localization of S1PR3 was associated to S1P-mediated proliferation of lung adenocarcinoma cells. Indeed, the inhibition of the membrane S1PR3 did not alter tumor cell proliferation after Toll Like Receptor (TLR) 9 activation. Instead, according to the nuclear localization of sphingosine kinase (SPHK) II, the inhibition of the kinase completely blocked the endogenous S1P-induced tumor cell proliferation. CONCLUSION: These results prove that the nuclear S1PR3/SPHK II axis is involved in lung tumor cell proliferation, highlighting a novel molecular mechanism which could provide differential therapeutic approaches especially in non-responsive lung cancer patients.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Transdução de Sinais , Receptores de Esfingosina-1-Fosfato/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Proteínas de Neoplasias/genética , Receptores de Esfingosina-1-Fosfato/genética
13.
Oncotarget ; 12(11): 1057-1071, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34084280

RESUMO

Cigarette smoking is the leading risk factor for COPD and lung cancer establishment. Epidemiologically, COPD patients are 6.35 times more likely to develop lung cancer. To mimic COPD, we exposed mice to nose-only cigarette smoke and used human samples of lung adenocarcinoma patients according to the smoking and COPD status. Smoking C57Bl/6N mice had higher enlargement of alveoli, deposition of collagen and mucus production, associated to the release of IL-1-like cytokines, such as IL-1α and IL-1ß at early time points and IL-18 at later time points. AIM2 expression was higher in lung recruited dendritic cells and macrophages in smoking mice, associated to the activation of caspase-11, rather than caspase-1. In support,129Sv mice, which are dysfunctional for caspase-11, had lower collagen deposition and mucus production, associated to lower release of IL-1-like and fibrotic TGFß. Interestingly, higher expression of AIM2 in non-cancerous tissue of smoking COPD adenocarcinoma patients was correlated to a higher hazard ratio of poor survival rate than in patients who presented lower levels of AIM2. We found that AIM2 inflammasome is at the crossroad between COPD and lung cancer in that its higher presence is correlated to lower survival rate of smoking COPD adenocarcinoma patients.

14.
Cell Physiol Biochem ; 55(2): 222-234, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33914445

RESUMO

BACKGROUND/AIMS: Sphingosine-1-phosphate (S1P) is a membrane-derived bioactive phospholipid involved in many lung physiological and pathological processes. Higher levels of S1P have been registered in a broad range of respiratory diseases, including inflammatory disorders and cancer. The aim of our study was to understand the role of S1P in healthy versus tumor cells after Toll-Like Receptors (TLRs) activation, well-known modulators of sphingolipid metabolism. METHODS: Lung adenocarcinoma cells and non-pathological human fibroblasts were stimulated with unmethylated Cytosine phosphate Guanosine (CpG), the TLR9 ligand, and S1P-dependent TNF-α release was evaluated by means of ELISA. Immunofluorescence and LC-MS/MS analysis were performed to evaluate/quantify S1P generation following TLR9 activation. RESULTS: We found that S1P was involved in TLR9-induced TNF-α release in that the inhibition of both ceramidase and sphingosine kinase I/II (SPHK I/II) significantly reduced the levels of TNF-α after TLR9 triggering in lung adenocarcinoma cells. These results were not observed in healthy fibroblasts, implying that this pathway was mainly involved in pathological conditions. Moreover, the activation of TLR4 by means of LPS did not have similar effects as in the case of CpG-stimulated TLR9. Importantly, the activation of TLR9 induced S1P generation and allowed it to interact on the outside membrane receptor S1P1 and S1P3 via the efflux through its membrane transporter SPNS2. Indeed, both the blockade of S1P3 and the transporter SPNS2 significantly reduced the activity of S1P on TNF-α release from lung adenocarcinoma cells. CONCLUSION: Our study identifies a novel inflammatory pathway in that TLR9 increases the pro-inflammatory cytokine release, such as TNF-α, via the induction of a ceramide/S1P imbalance in favor of S1P, adding a novel puzzle piece in TLR9-orchestrated inflammatory pathway and shedding more light on the role of the higher levels of S1P during inflammatory conditions.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Receptor Toll-Like 9/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células A549 , Western Blotting , Imunofluorescência , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Esfingosina/metabolismo , Espectrometria de Massas em Tandem
15.
Nat Prod Res ; 35(23): 5360-5363, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32406252

RESUMO

Many herbal agents and medicinal plants have provided clinical interest due to their therapeutic properties, availability and lower side effects. The aim of this study was to understand the anti-bacterial activity of the combination of Pelargonium sidoides (PEL), Justicia adhatoda (ADH) and N-Acetyl-L-Cysteine (NAC) (NAXX). We found that NAXX had strong and long-term bacteriostatic activity, which was related to its anti-oxidant activity. Our data demonstrate that NAXX is an innovative medicinal plant-derived strategy to manage of oxidative stress- and microbial-based diseases.


Assuntos
Justicia , Staphylococcus aureus Resistente à Meticilina , Pelargonium , Acetilcisteína/farmacologia , Escherichia coli , Extratos Vegetais/farmacologia , Staphylococcus aureus
16.
17.
J Immunother Cancer ; 8(2)2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33361405

RESUMO

BACKGROUND: Inhibitors of immune checkpoint programmed cell death protein 1 (PD-1) receptor on T cells have shown remarkable clinical outcomes in metastatic melanoma. However, most patients are resistant to therapy. Production of extracellular adenosine, via CD73-mediated catabolism of AMP, contributes to suppress T-cell-mediated responses against cancer. In this study, we analyzed the expression and activity of soluble CD73 in sera of patients with melanoma undergoing anti-PD-1± cytotoxic T-lymphocyte-associated antigen 4 therapy. METHODS: Soluble CD73 expression and activity were retrospectively analyzed in serum of a total of 546 patients with melanoma from different centers before starting treatment (baseline) with anti-PD-1 agents, nivolumab or pembrolizumab, and compared with those of 96 healthy subjects. The CD73 activity was correlated with therapy response and survival of patients. RESULTS: Patients with melanoma show significantly higher CD73 activity and expression than those observed in healthy donors (p<0.0001). Elevated pretreatment levels of CD73 activity were associated with non-response to therapy with nivolumab or pembrolizumab. During treatment, levels of soluble CD73 activity remain unchanged from baseline and still stratify clinical responders from non-responders. High levels of serum CD73 enzymatic activity associate with reduced overall survival (OS; HR=1.36, 95% CI 1.03 to 1.78; p=0.03) as well as progression-free survival (PFS; HR=1.42, 95% CI 1.13 to 1.79, p=0.003). Further, the multivariate Cox regression analysis indicates that serum CD73 activity is an independent prognostic factor besides serum lactate dehydrogenase levels and the presence of brain metastases for both OS (p=0.009) and PFS (p=0.001). CONCLUSION: Our data indicate the relevance of serum CD73 in patients with advanced melanoma receiving anti-PD-1 therapy and support further investigation on targeting CD73 in combination with anti-PD-1 antibodies.


Assuntos
5'-Nucleotidase/sangue , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Melanoma/sangue , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto Jovem
18.
J Exp Clin Cancer Res ; 39(1): 242, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33187551

RESUMO

BACKGROUND: Therapy/prognosis of Non-Small Cell Lung Cancer (NSCLC) patients are strongly related to gene alteration/s or protein expression. However, more than 50% of NSCLC patients are negative to key drugable biomarkers. METHODS: We used human samples of NSCLC and mouse models of lung adenocarcinoma. RESULTS: We showed that caspase-4 was highly present in the tumor mass compared to non-cancerous human tissues. Interestingly, the orthologue murine caspase-11 promoted lung carcinogenesis in mice. Carcinogen-exposed caspase-11 knockout mice had lower tumor lesions than wild type mice, due to the relevance of caspase-11 in the structural lung cell as demonstrated by bone marrow transplantation and adoptive transfer experiments. Similarly to what observed in mice, caspase-4 was correlated to the stage of lung cancer in humans in that it induced cell proliferation in a K-Ras, c-MyC and IL-1α dependent manner. Caspase-4 positive adenocarcinoma (79.3%) and squamous carcinoma (88.2%) patients had lower median survival than patients who had lower levels of caspase-4. Moreover, PD-L1 expression and gene mutation (i.e. EGFR) were not correlated to caspase-4 expression. Instead, NSCLC patients who had K-Ras or c-MyC gene alteration were positively correlated to higher levels of caspase-4 and lower survival rate. CONCLUSIONS: We identified a subgroup of NSCLC patients as caspase-4 positive among which double and triple positive caspase-4, K-Ras and/or c-MyC patients which prognosis was poor. Because K-Ras and c-MyC are still undrugable, the identification of caspase-4 as a novel oncoprotein could introduce novelty in the clinical yet unmet needs for NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Caspases Iniciadoras/metabolismo , Neoplasias Pulmonares/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Transfecção
19.
Biosci Rep ; 40(11)2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33119061

RESUMO

Lactoferrin (LAT), a multifunctional protein involved in numerous physiological functions, and the medicinal plant Pelargonium sidoides DC (PEL) have been described for their anti-inflammatory properties. Because the main advantage of natural products consists in administering them in combination rather than as single compound, we aimed to understand whether the combination of PEL and LAT, herein PELIRGOSTIM, could still prove beneficial or additive/synergistic activities during inflammatory conditions. To pursue this goal, we used macrophagic cells (J774.1) and treated them with PEL and LAT in a concentration-dependent manner. We found that PELIRGOSTIM was able to reduce the levels of reactive oxygen species (ROS) and nitrite, effects that were correlated to the release of lower levels of IL-1ß after LPS treatment. In addition, the combination of PEL and LAT showed bacteriostatic activities against Staphylococcus aureus and Escherichia coli which had limited growth starting from 5 hours up to 20 hours. This effect was stronger than that observed for penicillin/streptomycin. Our results provide PELIRGOSTIM as an innovative combination of natural products capable to prevent inflammation-, oxidative stress- and microbial-related disorders.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Escherichia coli/efeitos dos fármacos , Lactoferrina/farmacologia , Macrófagos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pelargonium , Extratos Vegetais/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/isolamento & purificação , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antioxidantes/isolamento & purificação , Linhagem Celular , Combinação de Medicamentos , Escherichia coli/crescimento & desenvolvimento , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Camundongos , Nitritos/metabolismo , Pelargonium/química , Extratos Vegetais/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/crescimento & desenvolvimento
20.
Oncotarget ; 11(38): 3515-3525, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-33014287

RESUMO

Lung cancer is by far the leading cause of cancer death. Metabolomic studies have highlighted that both tumor progression and limited curative treatment options are partly due to dysregulated glucose metabolism and its associated signaling pathways. In our previous studies, we identified caspase-4 as a novel diagnostic tool for non-small cell lung cancer (NSCLC). Here, we analyzed the metabolomic profile of both plasma and tumor tissues of NSCLC patients stratified as caspase-4 positive or negative. We found that circulating caspase-4 was correlated to LDH. However, this effect was not observed in caspase-4 positive tumor tissues, where instead, fatty acid biosynthesis was favoured in that the malonic acid and the palmitic acid were higher than in non-cancerous and caspase-4 negative tissues. The glycolytic pathway in caspase-4 positive NSCLC tissues was bypassed by the malonic acid-dependent lipogenesis. On the other hand, the dysregulated glucose metabolism was regulated by a higher presence of succinate dehydrogenase (SDHA) and by the gluconeogenic valine which favoured Krebs' cycle. In conclusion, we found that the recently identified caspase-4 positive subpopulation of NSCLC patients is characterized by a lipidomic profile accompanied by alternative pathways to guarantee glucose metabolism in favour of tumor cell proliferation.

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