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1.
Anticancer Res ; 41(9): 4185-4202, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475038

RESUMO

Gastric cancer is one of the leading types of cancer with an annual death toll of 700,000 worldwide. Despite the fact that several agents are approved for its treatment, high percentage of recurrence and intractability of metastatic disease remain a major problem. The identification of new targets and modalities for treatment are therefore of high priority. We have searched the literature for microRNAs down-regulated in gastric cancer with efficacy in gastric cancer-related murine xenograft models after reconstitution therapy. Among the identified miRs were 25 miRs targeting transcription factors, seven of them regulating cell-cycle and apotosis-related targets, and five of them regulating GTPase-related targets such as GAPs and GEFs. According to criteria such as prognostic impact, functional data, and tractability, miR-133 b/a (MCL1) and miR-518 (MDM2) are suggested as potentially valuable targets for further evaluation and possible treatment of gastric cancer.


Assuntos
Regulação para Baixo , MicroRNAs/genética , Neoplasias Gástricas/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Humanos , Terapia de Alvo Molecular , Neoplasias Gástricas/tratamento farmacológico
2.
Anticancer Res ; 41(9): 4215-4228, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475041

RESUMO

BACKGROUND/AIM: Tyrosine kinase inhibitors (TKIs) are used for the treatment of both wild type and mutant non-small cell lung cancer (NSCLC); however, acquired resistance is a major clinical challenge. Herein, we aimed to investigate the effects of telmisartan (Tel), CFM 4.16 and sorafenib combination in rociletinib resistant NSCLC tumors. MATERIALS AND METHODS: 3D spheroid cultures and western blotting were used for evaluating cytotoxic effects and protein expression. An in vivo rociletinib resistant H1975 xenograft model of NSCLC was developed by subcutaneous injection of rociletinib resistant H1975 cells into nude mice. RESULTS: Tel, CFM 4.16 and sorafenib combination displayed superior anti-cancer effects in 3D spheroid cultures and a rociletinib resistant H1975 xenograft model of NSCLC by decreasing the protein expression of oncogenic and cancer stem cell markers (Nanog, Sox2 and Oct4). CONCLUSION: Tel facilitates effective penetration of CFM 4.16 and sorafenib in rociletinib resistant H1975 models of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Esferoides Celulares/citologia , Compostos de Espiro/administração & dosagem , Telmisartan/administração & dosagem , Tiadiazóis/administração & dosagem , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Esferoides Celulares/efeitos dos fármacos , Compostos de Espiro/farmacologia , Telmisartan/farmacologia , Tiadiazóis/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 41(9): 4321-4331, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475052

RESUMO

BACKGROUND/AIM: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are key drugs in cancer treatment due to their minor adverse effects and outstanding anticancer effects. However, drugs for overcoming EGFR-TKI resistance are not in clinical use so far. Therefore, to overcome resistance, we focused on lurasidone, a new antipsychotic drug, due to its mild adverse effect profile from the viewpoint of drug repositioning. MATERIALS AND METHODS: We explored the effects of lurasidone alone or in combination with EGFR-TKI on the growth of osimertinib-resistant cancer cells the anti-apoptotic marker expression such as survivin, and autophagy levels by LC-3B expression. RESULTS: Within a non-toxic concentration range in normal cells, lurasidone and osimertinib combination therapy showed a growth-inhibitory effect in osimertinib-resistant cancer cells in vitro and in vivo. Furthermore, lurasidone decreased survivin expression and mildly induced autophagy. CONCLUSION: Lurasidone may increase the sensitivity to osimertinib in osimertinib-resistant cancer cells in drug repurposing.


Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Cloridrato de Lurasidona/administração & dosagem , Survivina/metabolismo , Células A549 , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Cloridrato de Lurasidona/farmacologia , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Anticancer Res ; 41(9): 4353-4364, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475055

RESUMO

BACKGROUND/AIM: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anti-tumor agent. However, resistance to TRAIL has been reported in a number of clinical trials. In this study, we investigated the molecular mechanisms by which a novel histone deacetylase (HDAC) inhibitor, CBUD-1001, sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. MATERIALS AND METHODS: Apoptotic cell death induced by CBUD-1001 and/or TRAIL was assessed on human CRC cells using the MTT assay, FACS analysis and nuclei staining. The involved molecular mechanisms were explored through western blotting analysis. RESULTS: We demonstrated that combined with CBUD-1001, TRAIL significantly enhanced TRAIL-induced apoptosis in CRC cells via mitochondria-mediated pathways. We also found that hyper-acetylation of histone by CBUD-1001 treatment leads to up-regulation of death receptor (DR) 5 in a dose- and time-dependent manner. Furthermore, we identified that enhanced sensitivity to TRAIL by combination with CBUD-1001 depends on the MAPK/CHOP axis, being a key mediator of DR5. CONCLUSION: A novel HDAC inhibitor CBUD-1001 sensitizes TRAIL-induced apoptosis via up-regulation of DR5, and that CBUD-1001 and TRAIL combination treatment offers an effective strategy to overcome TRAIL resistance in CRC cells.


Assuntos
Neoplasias Colorretais/metabolismo , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Regulação para Baixo , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos
5.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445491

RESUMO

In this study we assessed the effects of antigen exposure in mice pre-sensitized with allergen following viral infection on changes in lung function, cellular responses and tight junction expression. Female BALB/c mice were sensitized to ovalbumin and infected with influenza A before receiving a second ovalbumin sensitization and challenge with saline, ovalbumin (OVA) or house dust mite (HDM). Fifteen days post-infection, bronchoalveolar inflammation, serum antibodies, responsiveness to methacholine and barrier integrity were assessed. There was no effect of infection alone on bronchoalveolar lavage cellular inflammation 15 days post-infection; however, OVA or HDM challenge resulted in increased bronchoalveolar inflammation dominated by eosinophils/neutrophils or neutrophils, respectively. Previously infected mice had higher serum OVA-specific IgE compared with uninfected mice. Mice previously infected, sensitized and challenged with OVA were most responsive to methacholine with respect to airway resistance, while HDM challenge caused significant increases in both tissue damping and tissue elastance regardless of previous infection status. Previous influenza infection was associated with decreased claudin-1 expression in all groups and decreased occludin expression in OVA or HDM-challenged mice. This study demonstrates the importance of the respiratory epithelium in pre-sensitized individuals, where influenza-infection-induced barrier disruption resulted in increased systemic OVA sensitization and downstream effects on lung function.


Assuntos
Hiper-Reatividade Brônquica/tratamento farmacológico , Cloreto de Metacolina/administração & dosagem , Infecções por Orthomyxoviridae/complicações , Ovalbumina/imunologia , Pyroglyphidae/imunologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Hiper-Reatividade Brônquica/etiologia , Claudina-1/metabolismo , Regulação para Baixo , Feminino , Vírus da Influenza A/patogenicidade , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/imunologia , Ovalbumina/administração & dosagem , Resultado do Tratamento
6.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445502

RESUMO

Trace amine-associated receptors (TAAR) recognize organic compounds, including primary, secondary, and tertiary amines. The TAAR5 receptor is known to be involved in the olfactory sensing of innate socially relevant odors encoded by volatile amines. However, emerging data point to the involvement of TAAR5 in brain functions, particularly in the emotional behaviors mediated by the limbic system which suggests its potential contribution to the pathogenesis of neuropsychiatric diseases. TAAR5 expression was explored in datasets available in the Gene Expression Omnibus, Allen Brain Atlas, and Human Protein Atlas databases. Transcriptomic data demonstrate ubiquitous low TAAR5 expression in the cortical and limbic brain areas, the amygdala and the hippocampus, the nucleus accumbens, the thalamus, the hypothalamus, the basal ganglia, the cerebellum, the substantia nigra, and the white matter. Altered TAAR5 expression is identified in Down syndrome, major depressive disorder, or HIV-associated encephalitis. Taken together, these data indicate that TAAR5 in humans is expressed not only in the olfactory system but also in certain brain structures, including the limbic regions receiving olfactory input and involved in critical brain functions. Thus, TAAR5 can potentially be involved in the pathogenesis of brain disorders and represents a valuable novel target for neuropsychopharmacology.


Assuntos
Encéfalo/metabolismo , Transtorno Depressivo Maior/genética , Síndrome de Down/genética , Regulação para Baixo , Encefalite Viral/genética , Infecções por HIV/complicações , Receptores Acoplados a Proteínas G/genética , Bases de Dados Genéticas , Encefalite Viral/etiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Infecções por HIV/genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Sequência de RNA , Distribuição Tecidual
7.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445504

RESUMO

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Leprdb/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.


Assuntos
Diabetes Mellitus Experimental/complicações , Perda Auditiva/fisiopatologia , Mitocôndrias/ultraestrutura , Receptores para Leptina/genética , Animais , Apoptose , Biomarcadores/metabolismo , Cóclea/irrigação sanguínea , Cóclea/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Regulação para Baixo , Perda Auditiva/etiologia , Perda Auditiva/genética , Perda Auditiva/metabolismo , Humanos , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo
8.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445513

RESUMO

The activation of signal transducer and activator of transcription 3 (STAT3), as well as up-regulation of cytokines and growth factors to promote STAT3 activation, have been found in the epidermis of psoriatic lesions. Recently, a series of synthetic compounds possessing the Michael acceptor have been reported as STAT3 inhibitors by covalently binding to cysteine of STAT3. We synthesized a Michael acceptor analog, SKSI-0412, and confirmed the binding affinity between STAT3 and SKSI-0412. We hypothesized that the SKSI-0412 can inhibit interleukin (IL)-17A-induced inflammation in keratinocytes. The introduction of IL-17A increased the phosphorylation of STAT3 in keratinocytes, whereas the inactivation of STAT3 by SKSI-0412 reduced IL-17A-induced STAT3 phosphorylation and IκBζ expression. In addition, human ß defensin-2 and S100A7, which are regulated by IκBζ, were significantly decreased with SKSI-0412 administration. We also confirmed that SKSI-0412 regulates cell proliferation, which is the major phenotype of psoriasis. Based on these results, we suggest targeting STAT3 with SKSI-0412 as a novel therapeutic strategy to regulate IL-17A-induced psoriatic inflammation in keratinocytes.


Assuntos
Anti-Inflamatórios/farmacologia , Interleucina-17/efeitos adversos , Queratinócitos/citologia , Fator de Transcrição STAT3/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Fator de Transcrição STAT3/química , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
9.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445514

RESUMO

Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb mixture composed of Aconitum carmichaelii, Angelica gigas, and Zingiber officinale. Its anti-tumor effect has been reported; however, the efficacy of JI017 against oxaliplatin-induced allodynia has never been explored. Single oxaliplatin injection [6 mg/kg, intraperitoneal, (i.p.)] induced both cold and mechanical allodynia, and oral administration of JI017 (500 mg/kg) alleviated cold but not mechanical allodynia in mice. Real-time polymerase chain reaction (PCR) analysis demonstrated that the upregulation of mRNA of spinal transient receptor potential vanilloid 1 (TRPV1) and astrocytes following oxaliplatin injection was downregulated after JI017 treatment. Moreover, TRPV1 expression and the activation of astrocytes were intensely increased in the superficial area of the spinal dorsal horn after oxaliplatin treatment, whereas JI017 suppressed both. The administration of TRPV1 antagonist [capsazepine, intrathecal (i.t.), 10 µg] attenuated the activation of astrocytes in the dorsal horn, demonstrating that the functions of spinal TRPV1 and astrocytes are closely related in oxaliplatin-induced neuropathic pain. Altogether, these results suggest that JI017 may be a potent candidate for the management of oxaliplatin-induced neuropathy as it decreases pain, spinal TRPV1, and astrocyte activation.


Assuntos
Astrócitos/metabolismo , Hiperalgesia/tratamento farmacológico , Oxaliplatina/efeitos adversos , Compostos Fitoquímicos/administração & dosagem , Canais de Cátion TRPV/metabolismo , Aconitum/química , Administração Oral , Angelica/química , Animais , Astrócitos/efeitos dos fármacos , Temperatura Baixa , Modelos Animais de Doenças , Regulação para Baixo , Gengibre/química , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Hiperalgesia/metabolismo , Camundongos , Compostos Fitoquímicos/farmacologia , Coluna Vertebral/metabolismo , Canais de Cátion TRPV/genética
10.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360957

RESUMO

In recent years, the "non-autonomous motor neuron death" hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1G93A mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1G93A protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1G93A toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , GTP Fosfo-Hidrolases/metabolismo , Mitocôndrias/metabolismo , Superóxido Dismutase-1/genética , Glândulas Suprarrenais/citologia , Esclerose Amiotrófica Lateral/metabolismo , Animais , Células Cultivadas , Células Cromafins/metabolismo , Regulação para Baixo , GTP Fosfo-Hidrolases/genética , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/ultraestrutura , Mutação de Sentido Incorreto , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1/metabolismo
11.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445397

RESUMO

Tumor necrosis factor-alpha (TNFα) can bind two distinct receptors (TNFR1/2). The transmembrane form (tmTNFα) preferentially binds to TNFR2. Upon tmTNFα cleavage by the TNF-alpha-converting enzyme (TACE), its soluble (sTNFα) form is released with higher affinity for TNFR1. This assortment empowers TNFα with a plethora of opposing roles in the processes of tumor cell survival (and apoptosis) and anti-tumor immune stimulation (and suppression), in addition to angiogenesis and metastases. Its functions and biomarker potential to predict cancer progression and response to immunotherapy are reviewed here, with a focus on lung cancer. By mining existing sequencing data, we further demonstrate that the expression levels of TNF and TACE are significantly decreased in lung adenocarcinoma patients, while the TNFR1/TNFR2 balance are increased. We conclude that the biomarker potential of TNFα alone will most likely not provide conclusive findings, but that TACE could have a key role along with the delicate balance of sTNFα/tmTNFα as well as TNFR1/TNFR2, hence stressing the importance of more research into the potential of rationalized treatments that combine TNFα pathway modulators with immunotherapy for lung cancer patients.


Assuntos
Regulação para Baixo , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/genética , Fator de Necrose Tumoral alfa/genética , Proteína ADAM17/genética , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
12.
J Hematol Oncol ; 14(1): 123, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399825

RESUMO

Thromboembolism is a frequent cause of severity and mortality in COVID-19. However, the etiology of this phenomenon is not well understood. A cohort of 1186 subjects, from the GEN-COVID consortium, infected by SARS-CoV-2 with different severity was stratified by sex and adjusted by age. Then, common coding variants from whole exome sequencing were mined by LASSO logistic regression. The homozygosity of the cell adhesion molecule P-selectin gene (SELP) rs6127 (c.1807G > A; p.Asp603Asn) which has been already associated with thrombotic risk is found to be associated with severity in the male subcohort of 513 subjects (odds ratio = 2.27, 95% Confidence Interval 1.54-3.36). As the SELP gene is downregulated by testosterone, the odd ratio is increased in males older than 50 (OR 2.42, 95% CI 1.53-3.82). Asn/Asn homozygotes have increased D-dimers values especially when associated with poly Q ≥ 23 in the androgen receptor (OR 3.26, 95% CI 1.41-7.52). These results provide a rationale for the repurposing of antibodies against P-selectin as adjuvant therapy in rs6127 male homozygotes especially if older than 50 or with an impaired androgen receptor.


Assuntos
COVID-19/genética , Selectina-P/genética , Trombose/genética , COVID-19/complicações , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual , SARS-CoV-2/isolamento & purificação , Trombose/etiologia
13.
J Environ Sci (China) ; 107: 160-170, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34412779

RESUMO

Elevated temperature could influence the sex differentiation by altering the expression of sex-related genes in fish. However, the underlying mechanisms by which the gene expression is altered remain poorly understood. Here, we aimed to explore the role of DNA methylation in sex differentiation of zebrafish (Danio rerio) in response to elevated temperature. The results showed that high temperature (33°C) exposure of fish from 20 to 30 days post fertilization (dpf), compared to normal temperature (28°C), resulted in male-biased sex ratio and decreased expression of female-related genes including cyp19a1a, sox9b and esr1. Meanwhile, the expressions of DNA methyltransferases dnmt3a1 and dnmt3a2, and the DNA methylation levels in sox9b and esr1 promoter were significantly increased by high temperature, strongly implying that DNA methylation is involved in high temperature-induced masculinization of zebrafish. Co-treatment with 5-aza-2'-deoxycytidine (a DNA methylation inhibitor) attenuated the high temperature-induced masculinizing effect, recovered the expression of esr1 and sox9b, suppressed the transcription of dnmt3a1 and dnmt3a2, and decreased the methylation of esr1 and sox9b promoter, further confirming that DNA methylation plays an important role in high temperature-induced masculinization of zebrafish. Furthermore, the methylation of sox9b promoter decreased the enrichment of transcription factor CREB (cAMP-responsive element binding proteins). Overall, these findings suggest that high temperature induce masculinization of zebrafish by down-regulation of female-related genes via DNA methylation, providing a new insight in understanding the epigenetic mechanism of thermal-mediated sex differentiation in fish.


Assuntos
Metilação de DNA , Receptor alfa de Estrogênio/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra , Animais , Regulação para Baixo , Epigênese Genética , Feminino , Masculino , Fatores de Transcrição SOX9/genética , Temperatura , Peixe-Zebra/genética
14.
Adipocyte ; 10(1): 408-411, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34402717

RESUMO

Angiotensin converting enzyme-2 (ACE2) is the cell-surface receptor enabling cellular entry of SARS-CoV-2. ACE2 is highly expressed in adipose tissue (AT), rendering AT a potential SARS-CoV-2 reservoir contributing to massive viral spread in COVID-19 patients with obesity. Although rodent and cell studies suggest that the polyphenol resveratrol alters ACE2, human studies are lacking. Here, we investigated the effects of 30-days resveratrol supplementation on RAS components in AT and skeletal muscle in men with obesity in a placebo-controlled cross-over study. Resveratrol markedly decreased ACE2 (~40%) and leptin (~30%), but did neither alter angiotensinogen, ACE and AT1R expression in AT nor skeletal muscle RAS components. These findings demonstrate that resveratrol supplementation reduces ACE2 in AT, which might dampen SARS-CoV-2 spread in COVID-19.


Assuntos
Tecido Adiposo/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Resveratrol/administração & dosagem , Tecido Adiposo/citologia , Enzima de Conversão de Angiotensina 2/genética , COVID-19/patologia , COVID-19/virologia , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Regulação para Baixo/efeitos dos fármacos , Humanos , Leptina/genética , Leptina/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/patologia , Efeito Placebo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Resveratrol/farmacologia , SARS-CoV-2/isolamento & purificação
15.
Sci Rep ; 11(1): 16843, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413390

RESUMO

Elevated angiotensin-converting enzyme 2 (ACE2) expression in organs that are potential targets of severe acute respiratory syndrome coronavirus 2 may increase the risk of coronavirus disease 2019 (COVID-19) infection. Previous reports show that ACE2 alter its tissue-specific expression patterns under various pathological conditions, including renal diseases. Here, we examined changes in pulmonary ACE2 expression in two mouse chronic kidney disease (CKD) models: adenine-induced (adenine mice) and aristolochic acid-induced (AA mice). We also investigated changes in pulmonary ACE2 expression due to renin-angiotensin system (RAS) blocker (olmesartan) treatment in these mice. Adenine mice showed significant renal functional decline and elevated blood pressure, compared with controls. AA mice also showed significant renal functional decline, compared with vehicles; blood pressure did not differ between groups. Renal ACE2 expression was significantly reduced in adenine mice and AA mice; pulmonary expression was unaffected. Olmesartan attenuated urinary albumin excretion in adenine mice, but did not affect renal or pulmonary ACE2 expression levels. The results suggest that the risk of COVID-19 infection may not be elevated in patients with CKD because of their stable pulmonary ACE2 expression. Moreover, RAS blockers can be used safely in treatment of COVID-19 patients with CKD.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , SARS-CoV-2/fisiologia , Adenina , Enzima de Conversão de Angiotensina 2/genética , Animais , Ácidos Aristolóquicos , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Imidazóis/administração & dosagem , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Tetrazóis/administração & dosagem
16.
FASEB J ; 35(9): e21870, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34436790

RESUMO

COVID-19 is often characterized by dysregulated inflammatory and immune responses. It has been shown that the Traditional Chinese Medicine formulation Qing-Fei-Pai-Du decoction (QFPDD) is effective in the treatment of the disease, especially for patients in the early stage. Our network pharmacology analyses indicated that many inflammation and immune-related molecules were the targets of the active components of QFPDD, which propelled us to examine the effects of the decoction on inflammation. We found in the present study that QFPDD effectively alleviated dextran sulfate sodium-induced intestinal inflammation in mice. It inhibited the production of pro-inflammatory cytokines IL-6 and TNFα, and promoted the expression of anti-inflammatory cytokine IL-10 by macrophagic cells. Further investigations found that QFPDD and one of its active components wogonoside markedly reduced LPS-stimulated phosphorylation of transcription factor ATF2, an important regulator of multiple cytokines expression. Our data revealed that both QFPDD and wogonoside decreased the half-life of ATF2 and promoted its proteasomal degradation. Of note, QFPDD and wogonoside down-regulated deubiquitinating enzyme USP14 along with inducing ATF2 degradation. Inhibition of USP14 with the small molecular inhibitor IU1 also led to the decrease of ATF2 in the cells, indicating that QFPDD and wogonoside may act through regulating USP14 to promote ATF2 degradation. To further assess the importance of ubiquitination in regulating ATF2, we generated mice that were intestinal-specific KLHL5 deficiency, a CUL3-interacting protein participating in substrate recognition of E3s. In these mice, QFPDD mitigated inflammatory reaction in the spleen, but not intestinal inflammation, suggesting CUL3-KLHL5 may function as an E3 for ATF2 degradation.


Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Flavanonas/farmacologia , Glucosídeos/farmacologia , Inflamação/tratamento farmacológico , Proteólise/efeitos dos fármacos , Ubiquitina Tiolesterase/deficiência , Animais , Linhagem Celular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Proteínas Culina/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Sulfato de Dextrana/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Flavanonas/uso terapêutico , Glucosídeos/uso terapêutico , Inflamação/induzido quimicamente , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Pirróis/farmacologia , Pirrolidinas/farmacologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitinação
17.
J Med Food ; 24(8): 852-859, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34382871

RESUMO

CYJ-27, a synthetic analog of decursin, prevents the generation of proinflammatory cytokines and oxidative stress. In this study, the effects of CYJ-27 on the regulation of inducible nitric oxide synthase (iNOS), heme oxygenase (HO)-1, and cyclooxygenase (COX-)2 were characterized in lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs). In addition, the effects of CYJ-27 on the production of iNOS and representative proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, were tested in the lung tissues of LPS-treated mice. CYJ-27 promoted the expression of HO-1, suppressed NF-κB-luciferase activity, and reduced COX-2/PGE2 and iNOS/NO, resulting in a diminution in phosphorylated-STAT-1. Furthermore, CYJ-27 promoted the nuclear translocation of Nrf2, enhanced the combination of Nrf2 to antioxidant response elements, and diminished IL-1ß production in LPS-activated HUVECs. CYJ-27-downregulated iNOS/NO expression was rescued after the RNAi suppression of HO-1. In LPS-treated mice, CYJ-27 significantly diminished iNOS production in the lung tissues and TNF-α expression in the bronchoalveolar lavage fluid. These findings indicate that CYJ-27 exerts anti-inflammatory activities by regulating iNOS through downregulation of both NF-κB activation and phosphorylated-STAT-1. Hence, it can act as a template for the development of novel substances to treat inflammatory diseases.


Assuntos
Inflamação , NF-kappa B , Animais , Benzopiranos , Butiratos , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Lipopolissacarídeos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo
18.
Nat Commun ; 12(1): 4852, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381028

RESUMO

Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Ubiquitina Tiolesterase/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiocinas/metabolismo , Regulação para Baixo , Humanos , Tolerância Imunológica , Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Proteína Fosfatase 2C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores
19.
Nat Commun ; 12(1): 5066, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417456

RESUMO

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.


Assuntos
Colesterol/biossíntese , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Esqualeno Mono-Oxigenase/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Animais , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular , Estudos de Coortes , Simulação por Computador , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Esqualeno Mono-Oxigenase/genética , Esqualeno Mono-Oxigenase/metabolismo , Terbinafina/farmacologia , Ativação Transcricional/genética
20.
Infect Genet Evol ; 94: 105020, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34343725

RESUMO

Nowadays, the coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a major global health problem. Intensive efforts are being employed to better understand this pathology and develop strategies enabling its early diagnosis and efficient treatment. In this study, we compared the signature of circulating miRNAs in plasma of COVID-19 patients versus healthy donors. MiRCURY LNA miRNA miRNome qPCR Panels were performed for miRNA signature characterization. Individual quantitative real-time PCR (qRT-PCR) was carried out to validate miRNome qPCR results. Receiver-operator characteristic (ROC) curve analysis was applied to assess the diagnostic accuracy of the most significantly deregulated miRNA(s) as potential diagnostic biomarker(s). Eight miRNAs were identified to be differentially expressed with miR-17-5p and miR-142-5p being down-regulated whilst miR-15a-5p, miR-19a-3p, miR-19b-3p, miR-23a-3p, miR-92a-3p and miR-320a being up-regulated in SARS-CoV-2-infected patients. ROC curve analyses revealed an AUC (Areas Under the ROC Curve) of 0.815 (P = 0.031), 0.875 (P = 0.012), and 0.850 (P = 0.025) for miR-19a-3p, miR-19b-3p, and miR-92a-3p, respectively. Combined ROC analyses using these 3 miRNAs showed a greater AUC of 0.917 (P = 0.0001) indicating a robust diagnostic value of these 3 miRNAs. These results suggest that plasma miR-19a-3p, miR-19b-3p, and miR-92a-3p expression levels could serve as potential diagnostic biomarker and/or a putative therapeutic target during SARS-CoV-2-infection.


Assuntos
COVID-19/sangue , MicroRNA Circulante/sangue , Adulto , Biomarcadores/sangue , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/fisiopatologia , MicroRNA Circulante/genética , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
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