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1.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200765

RESUMO

BacSp222 is a multifunctional peptide produced by Staphylococcus pseudintermedius 222. This 50-amino acid long peptide belongs to subclass IId of bacteriocins and forms a four-helix bundle molecule. In addition to bactericidal functions, BacSp222 possesses also features of a virulence factor, manifested in immunomodulatory and cytotoxic activities toward eukaryotic cells. In the present study, we demonstrate that BacSp222 is produced in several post-translationally modified forms, succinylated at the ε-amino group of lysine residues. Such modifications have not been previously described for any bacteriocins. NMR and circular dichroism spectroscopy studies have shown that the modifications do not alter the spatial structure of the peptide. At the same time, succinylation significantly diminishes its bactericidal and cytotoxic potential. We demonstrate that the modification of the bacteriocin is an effect of non-enzymatic reaction with a highly reactive intracellular metabolite, i.e., succinyl-coenzyme A. The production of succinylated forms of the bacteriocin depends on environmental factors and on the access of bacteria to nutrients. Our study indicates that the production of succinylated forms of bacteriocin occurs in response to the changing environment, protects producer cells against the autotoxicity of the excreted peptide, and limits the pathogenicity of the strain.


Assuntos
Bacteriocinas/química , Bacteriocinas/farmacologia , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Staphylococcus/fisiologia , Acil Coenzima A/metabolismo , Animais , Antibacterianos/farmacologia , Humanos , Lisina/química , Lisina/metabolismo , Macrófagos/patologia , Camundongos , Neutrófilos/patologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Processamento de Proteína Pós-Traducional
2.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199293

RESUMO

Metabolic syndrome (MetS) represents a cluster of disorders that increase the risk of a plethora of conditions, in particular type two diabetes, cardiovascular diseases, and certain types of cancers. MetS is a complex entity characterized by a chronic inflammatory state that implies dysregulations of adipokins and proinflammatory cytokins together with hormonal and growth factors imbalances. Of great interest is the implication of microRNA (miRNA, miR), non-coding RNA, in cancer genesis, progression, and metastasis. The adipose tissue serves as an important source of miRs, which represent a novel class of adipokines, that play a crucial role in carcinogenesis. Altered miRs secretion in the adipose tissue, in the context of MetS, might explain their implication in the oncogenesis. The interplay between miRs expressed in adipose tissue, their dysregulation and cancer pathogenesis are still intriguing, taking into consideration the fact that miRNAs show both carcinogenic and tumor suppressor effects. The aim of our review was to discuss the latest publications concerning the implication of miRs dysregulation in MetS and their significance in tumoral signaling pathways. Furthermore, we emphasized the role of miRNAs as potential target therapies and their implication in cancer progression and metastasis.


Assuntos
Carcinogênese/genética , Síndrome Metabólica/genética , MicroRNAs/metabolismo , Animais , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , MicroRNAs/genética , Transdução de Sinais/genética
3.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199409

RESUMO

Diabetic nephropathy (DN) is characterized by albuminuria, loss of renal function, renal fibrosis and infiltration of macrophages originating from peripheral monocytes inside kidneys. DN is also associated with intrarenal overactivation of the renin-angiotensin system (RAS), an enzymatic cascade which is expressed and controlled at the cell and/or tissue levels. All members of the RAS are present in the kidneys and most of them are also expressed in monocytes/macrophages. This review focuses on the control of monocyte recruitment and the modulation of macrophage polarization by the RAS in the context of DN. The local RAS favors the adhesion of monocytes on renal endothelial cells and increases the production of monocyte chemotactic protein-1 and of osteopontin in tubular cells, driving monocytes into the kidneys. There, proinflammatory cytokines and the RAS promote the differentiation of macrophages into the M1 proinflammatory phenotype, largely contributing to renal lesions of DN. Finally, resolution of the inflammatory process is associated with a phenotype switch of macrophages into the M2 anti-inflammatory subset, which protects against DN. The pharmacologic interruption of the RAS reduces albuminuria, improves the trajectory of the renal function, decreases macrophage infiltration in the kidneys and promotes the switch of the macrophage phenotype from M1 to M2.


Assuntos
Quimiocina CCL2/genética , Nefropatias Diabéticas/genética , Osteopontina/genética , Sistema Renina-Angiotensina/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Macrófagos/patologia , Monócitos/metabolismo , Monócitos/patologia
4.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208396

RESUMO

Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer death worldwide. Recently, targeting molecules whose functions are associated with tumorigenesis has become a game changing adjunct to standard anti-cancer therapy. As evidenced by the results of preclinical and clinical investigations, whole-body irradiations (WBI) with X-rays at less than 0.1-0.2 Gy per fraction can induce remissions of various neoplasms without inciting adverse side effects of conventional chemo- and radiotherapy. In the present study, a murine model of human NSCLC was employed to evaluate for the first time the anti-neoplastic efficacy of WBI combined with inactivation of CTLA-4, PD-1, and/or HSP90. The results indicate that WBI alone and in conjunction with the inhibition of the function of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed death-1 (PD-1) receptor immune checkpoints (ICs) and/or heat shock protein 90 (HSP90) markedly reduced tumorigenesis in mice implanted by three different routes with the syngeneic Lewis lung cancer cells and suppressed clonogenic potential of Lewis lung carcinoma (LLC1) cells in vitro. These results were associated with the relevant changes in the profile of pro- and anti-neoplastic immune cells recruited to the growing tumors and the circulating anti- and pro-inflammatory cytokines. In contrast, inhibition of the tested molecular targets used either separately or in combination with each other did not exert notable anti-neoplastic effects. Moreover, no significant synergistic effects were detected when the inhibitors were applied concurrently with WBI. The obtained results supplemented with further mechanistic explanations provided by future investigations will help design the effective strategies of treatment of lung and other cancers based on inactivation of the immune checkpoint and/or heat shock molecules combined with low-dose radiotherapy.


Assuntos
Proteínas de Choque Térmico/metabolismo , Proteínas de Checkpoint Imunológico/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia , Transplante de Neoplasias , Dosagem Radioterapêutica , Irradiação Corporal Total , Animais , Células Clonais , Pulmão/patologia , Contagem de Linfócitos , Linfócitos do Interstício Tumoral , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Ensaio Tumoral de Célula-Tronco
5.
Cell Commun Signal ; 19(1): 73, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238338

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has become an ongoing pandemic. Understanding the respiratory immune microenvironment which is composed of multiple cell types, together with cell communication based on ligand-receptor interactions is important for developing vaccines, probing COVID-19 pathogenesis, and improving pandemic control measures. METHODS: A total of 102 consecutive hospitalized patients with confirmed COVID-19 were enrolled in this study. Clinical information, routine laboratory tests, and flow cytometry analysis data with different conditions were collected and assessed for predictive value in COVID-19 patients. Next, we analyzed public single-cell RNA-sequencing (scRNA-seq) data from bronchoalveolar lavage fluid, which offers the closest available view of immune cell heterogeneity as encountered in patients with varying severity of COVID-19. A weighting algorithm was used to calculate ligand-receptor interactions, revealing the communication potentially associated with outcomes across cell types. Finally, serum cytokines including IL6, IL1ß, IL10, CXCL10, TNFα, GALECTIN-1, and IGF1 derived from patients were measured. RESULTS: Of the 102 COVID-19 patients, 42 cases (41.2%) were categorized as severe. Multivariate logistic regression analysis demonstrated that AST, D-dimer, BUN, and WBC were considered as independent risk factors for the severity of COVID-19. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe disease group were significantly lower than those in the moderate disease group. The risk model containing the above mentioned inflammatory damage parameters, and the counts of T cells, with AUROCs ranged from 0.78 to 0.87. To investigate the molecular mechanism at the cellular level, we analyzed the published scRNA-seq data and found that macrophages displayed specific functional diversity after SARS-Cov-2 infection, and the metabolic pathway activities in the identified macrophage subtypes were influenced by hypoxia status. Importantly, we described ligand-receptor interactions that are related to COVID-19 serverity involving macrophages and T cell subsets by communication analysis. CONCLUSIONS: Our study showed that macrophages driving ligand-receptor crosstalk contributed to the reduction and exhaustion of CD8+ T cells. The identified crucial cytokine panel, including IL6, IL1ß, IL10, CXCL10, IGF1, and GALECTIN-1, may offer the selective targets to improve the efficacy of COVID-19 therapy. TRIAL REGISTRATION: This is a retrospective observational study without a trial registration number. Video Abstract.


Assuntos
COVID-19/imunologia , COVID-19/patologia , Comunicação Celular , Macrófagos/imunologia , Análise de Célula Única , Idoso , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , COVID-19/epidemiologia , COVID-19/fisiopatologia , China/epidemiologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Receptores de Citocinas , Estudos Retrospectivos , Análise de Sequência de RNA , Índice de Gravidade de Doença
6.
Front Immunol ; 12: 577517, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084158

RESUMO

Background: Extracellular traps (ETs) and tumor-infiltrating immune cells can contribute to disease progression. The clinical significance of tumor-infiltrating neutrophils and macrophages and related extracellular traps in pancreatic neuroendocrine tumors (pNETs) has not been fully elucidated. This study aimed to explore the prognostic value of tumor infiltration and ET formation by neutrophils and macrophages in pNETs. Methods: A total of 135 patients with radical resection of nonfunctional pNETs were analyzed retrospectively. Immunohistochemistry and immunofluorescence were utilized to stain tumor tissue sections. The recurrence-free survival (RFS) of subgroups determined by Kaplan-Meier analysis was compared with the log-rank test. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. A nomogram was established to predict 3-year RFS. Results: Patients with high tumor-infiltrating neutrophils or macrophages or positive expression of neutrophils ETs or macrophage ETs displayed worse RFS (all p<0.05). Moreover, univariate and multivariate Cox regression analyses showed that neutrophil and macrophage infiltration and ETs were independent prognostic factors for RFS (all p<0.05). A combined parameter including WHO grade, TNM stage, tumor-infiltrating neutrophils and macrophages, and neutrophil and macrophage ETs had the highest C-index (0.866) and lowest Akaike information criteria (326.557). The calibration plot of nomogram composed of the combined parameter exhibited excellent prognostic values for 3-year RFS. Conclusions: Infiltration and ETs by neutrophils and macrophages can be used as biological indicators of patient prognosis, suggesting the treatment potential for targeting those in nonfunctional pNETs.


Assuntos
Armadilhas Extracelulares/imunologia , Macrófagos/imunologia , Tumores Neuroendócrinos/imunologia , Infiltração de Neutrófilos/imunologia , Neoplasias Pancreáticas/imunologia , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Nomogramas , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos
7.
Nat Commun ; 12(1): 3931, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34168143

RESUMO

STAT1α is a key transcription factor driving pro-inflammatory responses in macrophages. We found that the interferon gamma (IFNγ)-regulated transcriptional program in macrophages is controlled by ADP-ribosylation (ADPRylation) of STAT1α, a post-translational modification resulting in the site-specific covalent attachment of ADP-ribose moieties. PARP-1, the major nuclear poly(ADP-ribose) polymerase (PARP), supports IFNγ-stimulated enhancer formation by regulating the genome-wide binding and IFNγ-dependent transcriptional activation of STAT1α. It does so by ADPRylating STAT1α on specific residues in its DNA-binding domain (DBD) and transcription activation (TA) domain. ADPRylation of the DBD controls STAT1α binding to its cognate DNA elements, whereas ADPRylation of the TA domain regulates enhancer activation by modulating STAT1α phosphorylation and p300 acetyltransferase activity. Loss of ADPRylation at either site leads to diminished IFNγ-dependent transcription and downstream pro-inflammatory responses. We conclude that PARP-1-mediated ADPRylation of STAT1α drives distinct enhancer activation mechanisms and is a critical regulator of inflammatory responses in macrophages.


Assuntos
ADP-Ribosilação , Interferon gama/metabolismo , Macrófagos/fisiologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Animais , Sítios de Ligação , DNA/metabolismo , Elementos Facilitadores Genéticos , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Fator de Transcrição STAT1/química , Ativação Transcricional
8.
Aging (Albany NY) ; 13(11): 15511-15522, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34111028

RESUMO

Propofol (Pro) confers protection against renal ischemia/reperfusion (rI/R) injury through incompletely characterized mechanisms. Since Pro has shown net anti-inflammatory properties as part of its beneficial effects, we examined the potential role of Pro in the modulation of macrophage polarization status during both rI/R injury in vivo and exposure of cultured peritoneal macrophages (PMs) to hypoxia/reoxygenation (H/R). Rats were subjected to 45-min r/IR surgery or a sham procedure and administered PBS (vehicle) or Pro during the ischemia stage. Pro administration attenuated rI/R-induced kidney damage and renal TNF-α, IL-6, and CXCL-10 expression. Enhanced macrophage M2 polarization, evidenced by reduced iNOS and increased Arg1 and Mrc1 mRNA levels, was further detected after Pro treatment both in the kidney, after rI/R in vivo, and in H/R-treated PMs. Pro administration also repressed phosphorylated signal transducer and activator of transcription 1 (p-STAT1) and increased p-STAT3, p-STAT6, and peroxisome proliferator-activated receptor-γ (PPARγ) mRNA levels in H/R-exposed PMs. Importantly, siRNA-mediated PPARγ silencing repressed Pro-mediated STAT3 activation in PMs and restored proinflammatory cytokine levels and prevented macrophage M2 marker expression in both rI/R-treated rats and cultured PMs. These findings suggest that Pro confers renoprotection against rI/R by stimulating PPARγ/STAT3-dependent macrophage conversion to the M2 phenotype.


Assuntos
Polaridade Celular , Macrófagos/patologia , PPAR gama/metabolismo , Propofol/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Animais , Polaridade Celular/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Inflamação/patologia , Rim/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Propofol/farmacologia , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley
9.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068595

RESUMO

Systemic inflammation, from gut translocation of organismal molecules, might worsen uremic complications in acute kidney injury (AKI). The monitoring of gut permeability integrity and/or organismal molecules in AKI might be clinically beneficial. Due to the less prominence of Candida albicans in human intestine compared with mouse gut, C. albicans were orally administered in bilateral nephrectomy (BiN) mice. Gut dysbiosis, using microbiome analysis, and gut permeability defect (gut leakage), which was determined by fluorescein isothiocyanate-dextran and intestinal tight-junction immunofluorescent staining, in mice with BiN-Candida was more severe than BiN without Candida. Additionally, profound gut leakage in BiN-Candida also resulted in gut translocation of lipopolysaccharide (LPS) and (1→3)-ß-D-glucan (BG), the organismal components from gut contents, that induced more severe systemic inflammation than BiN without Candida. The co-presentation of LPS and BG in mouse serum enhanced inflammatory responses. As such, LPS with Whole Glucan Particle (WGP, a representative BG) induced more severe macrophage responses than LPS alone as determined by supernatant cytokines and gene expression of downstream signals (NFκB, Malt-1 and Syk). Meanwhile, WGP alone did not induced the responses. In parallel, WGP (with or without LPS), but not LPS alone, accelerated macrophage ATP production (extracellular flux analysis) through the upregulation of genes in mitochondria and glycolysis pathway (using RNA sequencing analysis), without the induction of cell activities. These data indicated a WGP pre-conditioning effect on cell energy augmentation. In conclusion, Candida in BiN mice accelerated gut translocation of BG that augmented cell energy status and enhanced pro-inflammatory macrophage responses. Hence, gut fungi and BG were associated with the enhanced systemic inflammation in acute uremia.


Assuntos
Injúria Renal Aguda/metabolismo , Candida albicans/metabolismo , Inflamação/sangue , Proteoglicanas/sangue , Injúria Renal Aguda/genética , Injúria Renal Aguda/microbiologia , Animais , Candida/metabolismo , Candida albicans/patogenicidade , Disbiose/sangue , Metabolismo Energético , Humanos , Inflamação/microbiologia , Inflamação/patologia , Inflamação/cirurgia , Lipopolissacarídeos/sangue , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Microbiota/genética , Nefrectomia/efeitos adversos
10.
Molecules ; 26(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067016

RESUMO

Shanxi-aged vinegar, a traditional Chinese grain-fermented food that is rich in polyphenols, has been shown to have therapeutic effects on a variety of diseases. However, there has been no comprehensive evaluation of the anti-inflammatory activity of polyphenols extracted from Shanxi-aged vinegar (SAVEP) to date. The anti-inflammatory activities of SAVEP, both in RAW 264.7 macrophages and mice, were extensively investigated for the potential application of SAVEP as a novel anti-inflammatory agent. In order to confirm the notion that polyphenols could improve inflammatory symptoms, SAVEP was firstly detected by gas chromatography mass spectrometry (GC-MS). In total, 19 polyphenols were detected, including 12 phenolic acids. The study further investigated the protective effect of SAVEP on lipopolysaccharide-induced inflammation in RAW264.7 macrophages and ICR mice. The results showed that compared with those of the model group, SAVEP could remarkably recover the inflammation of macrophage RAW264.7 and ICR mice. SAVEP can normalise the expression of related proteins via the suppression of MAPK/NF-κB pathway activation, inhibiting the expression of iNOS and COX-2 proteins, and consequently the production of inflammatory factors, thus alleviating inflammatory stress. These results suggest that SAVEP may have a potential function against inflammation.


Assuntos
Ácido Acético/química , Inflamação/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/patologia , NF-kappa B/metabolismo , Polifenóis/isolamento & purificação , Polifenóis/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Forma do Núcleo Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Células RAW 264.7
11.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070749

RESUMO

Atherosclerosis and nonalcoholic fatty liver disease are leading causes of morbidity and mortality in the Western countries. The renin-angiotensin system (RAS) with its two main opposing effectors, i.e., angiotensin II (Ang II) and Ang-(1-7), is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1-7) and thus favors Ang-(1-7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator, diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE-/- mice fed a high-fat diet (HFD). We have shown that DIZE stabilized atherosclerotic lesions and attenuated hepatic steatosis in apoE-/- mice fed an HFD. Such effects were associated with decreased total macrophages content and increased α-smooth muscle actin levels in atherosclerotic plaques. Moreover, DIZE changed polarization of macrophages towards increased amount of anti-inflammatory M2 macrophages in the atherosclerotic lesions. Interestingly, the anti-steatotic action of DIZE in the liver was related to the elevated levels of HDL in the plasma, decreased levels of triglycerides, and increased biosynthesis and concentration of taurine in the liver of apoE-/- mice. However, exact molecular mechanisms of both anti-atherosclerotic and anti-steatotic actions of DIZE require further investigations.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Aterosclerose/tratamento farmacológico , Diminazena/análogos & derivados , Fígado Gorduroso/tratamento farmacológico , Placa Aterosclerótica/tratamento farmacológico , Taurina/biossíntese , Angiotensina I/genética , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Dieta Hiperlipídica , Diminazena/farmacologia , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Ativação de Macrófagos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Células THP-1 , Taurina/agonistas
12.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072818

RESUMO

The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12-/-). SM-CXCL12-/- mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12-/- mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12-/- mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling. Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.


Assuntos
Cardiomegalia/genética , Quimiocina CXCL12/genética , Infarto do Miocárdio/genética , Receptores CXCR/genética , Técnicas de Ablação , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/terapia , Vasos Coronários , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Músculo Liso/metabolismo , Músculo Liso/patologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Miocárdio/metabolismo , Miocárdio/patologia
13.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071306

RESUMO

The complex interaction between glioblastoma and its microenvironment has been recognized for decades. Among various immune profiles, the major population is tumor-associated macrophage, with microglia as its localized homolog. The present definition of such myeloid cells is based on a series of cell markers. These good sentinel cells experience significant changes, facilitating glioblastoma development and protecting it from therapeutic treatments. Huge, complicated mechanisms are involved during the overall processes. A lot of effort has been dedicated to crack the mysterious codes in macrophage/microglia recruiting, activating, reprogramming, and functioning. We have made our path. With more and more key factors identified, a lot of new therapeutic methods could be explored to break the ominous loop, to enhance tumor sensitivity to treatments, and to improve the prognosis of glioblastoma patients. However, it might be a synergistic system rather than a series of clear, stepwise events. There are still significant challenges before the light of truth can shine onto the field. Here, we summarize recent advances in this field, reviewing the path we have been on and where we are now.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Macrófagos/imunologia , Microglia/imunologia , Microambiente Tumoral/imunologia , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Macrófagos/patologia , Microglia/patologia , Células Mieloides/imunologia , Células Mieloides/patologia , Prognóstico , Transdução de Sinais/imunologia
14.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066450

RESUMO

Macrophages were discovered in the 19th century by Ukrainian biologist Élie Metchnikoff who worked in Ukraine, Russia, and France [...].


Assuntos
Doença , Homeostase , Macrófagos/patologia , Monócitos/patologia , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Estresse Oxidativo
15.
Aging (Albany NY) ; 13(12): 16124-16143, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34133325

RESUMO

The interaction between RNA binding protein (RBP) and circular RNA (circRNA) is important for the regulation of tumor progression. This study aimed to identify the RBP-circRNA network in hepatocellular carcinoma (HCC). 22 differentially expressed (DE) circRNAs in HCC were screened out from Gene Expression Omnibus (GEO) database and their binding RBPs were predicted by Circular RNA Interactome. Among them, 17 DERBPs, which were commonly dysregulated in HCC from The Clinical Proteomic Tumor Analysis Consortium (CPTAC), The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) projects, were utilized to construct the RBP-circRNA network. Through survival analysis, we found TARDBP was the only prognostic RBP for HCC in CPTAC, TCGA and ICGC projects. High expression of TARDBP was correlated with high grade, advanced stage and low macrophage infiltration of HCC. Additionally, gene set enrichment analysis showed that dysregulated TARDBP might be involved in some pathways related to the HCC pathogenesis. Therefore, a hub RBP-circRNA network was generated based on TARDBP. RNA immunoprecipitation and RNA pull-down confirmed that hsa_circ_0004913 binds to TARDBP. These findings indicated certain RBP-circRNA regulatory network potentially involved in the pathogenesis of HCC, which provides novel insights into the mechanism study and biomarker identification for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Redes Reguladoras de Genes , Neoplasias Hepáticas/genética , RNA Circular/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Prognóstico , Ligação Proteica , RNA Circular/genética
16.
Aging (Albany NY) ; 13(11): 15638-15658, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34077394

RESUMO

Dendritic cell-derived exosomes have been proven to be efficient adjuvant options for anti-tumor vaccines in cancer immunotherapy. However, their potency in atherosclerosis remains unclear. Here we summarize the association of microRNA-203-3p (miR-203-3p) with dendritic cell-derived exosomes and atherosclerosis. Firstly, dendritic cell-derived exosomes and bone marrow-derived macrophages were isolated, after which expression of miR-203-3p and cathepsin S was determined. After the establishment of atherosclerosis mouse models, gain- and loss-of-function experiments were conducted for the analysis of effects of miR-203-3p and cathepsin S on foam-cell formation, lipid accumulation, collagen deposition and serum total cholesterol. The results found high expression of cathepsin S in atherosclerosis mice and downregulation of miR-203-3p in the serum of atherosclerosis patients and ox-LDL-simulated bone marrow-derived macrophages. Cathepsin S was the target gene of miR-203-3p. miR-203-3p transporting from exosomes to bone marrow-derived macrophages resulted in inhibition of cathepsin S expression and atherosclerosis-related phenotypes in bone marrow-derived macrophages, thus alleviating atherosclerosis in mice, and this process was found to involve the p38/MAPK signaling pathway. These findings provided evidence that the transfer of miR-203-3p by dendritic cell-derived exosomes targeted cathepsin S in bone marrow-derived macrophages to attenuate atherosclerosis progression in mice, serving as a promising clinical target for atherosclerosis.


Assuntos
Aterosclerose/genética , Catepsinas/genética , Células Dendríticas/metabolismo , Regulação para Baixo/genética , Exossomos/genética , Macrófagos/metabolismo , MicroRNAs/metabolismo , Animais , Sequência de Bases , Catepsinas/metabolismo , Movimento Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Inativação Gênica , Humanos , Lipoproteínas LDL/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pessoa de Meia-Idade , Modelos Biológicos , Fenótipo , Transporte de RNA/efeitos dos fármacos , Reprodutibilidade dos Testes
17.
Aging (Albany NY) ; 13(11): 15479-15490, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099590

RESUMO

Sirtuin 1 (SIRT1) is a class III histone deacetylase that exerts an anti-inflammatory effect in airway diseases. Activated macrophages play an important role in asthma. However, the roles of SIRT1 on allergic airway inflammation in macrophages remain largely unexplored. In this study, we aimed to determine the roles of SIRT1 on allergic airway inflammation in macrophages. The effect of myeloid-specific SIRT1 deletion (Sirt1fl/fl-LysMcre) on airway inflammation was assessed by using in vivo models of asthma following allergen exposure and in vitro culture of primary bone marrow-derived macrophages (BMDMs) exposed to house dust mite (HDM). We observed that Sirt1fl/fl-LysMcre mice substantially enhanced airway inflammation and mucus production in response to allergen exposure. Expression of chemokine ligand (CXCL) 2, interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α were reduced in BMDMs with myeloid-specific deletion of Sirt1 after stimulation of HDM. Moreover, SIRT1 suppressed the inflammatory cytokines expression in BMDMs partially via the ERK/p38 MAPK pathways. Our study demonstrated that SIRT1 suppresses the allergic airway inflammation in macrophages, and suggested that activation of SIRT1 in macrophages may represent therapeutic strategy for asthma.


Assuntos
Asma/patologia , Deleção de Genes , Hipersensibilidade/patologia , Inflamação/patologia , Pulmão/patologia , Células Mieloides/metabolismo , Sirtuína 1/metabolismo , Alérgenos/efeitos adversos , Animais , Asma/complicações , Citocinas/metabolismo , Modelos Animais de Doenças , Hipersensibilidade/complicações , Inflamação/complicações , Integrases/metabolismo , Sistema de Sinalização das MAP Quinases , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Transgênicos , Pyroglyphidae
18.
Scand J Clin Lab Invest ; 81(4): 255-263, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34032527

RESUMO

Coronaviruses belonging to the Coronaviridae family are single-stranded RNA viruses. The entry of SARS-CoV-2 is accomplished via ACE-2 receptors. SARS-CoV-2 infection coactivates both innate and adaptive immune responses. Although SARS-CoV-2 stimulates antibody production with a typical pattern of IgM/IgG, cellular immunity is also impaired. In severe cases, low CD4 + and CD8 + T cell counts are associated with impaired immune functions, and high neutrophil/lymphocyte ratios accompanying low lymphocyte subsets have been demonstrated. Recently, high IFN -α/γ ratios with impaired T cell responses, and increased IL-1, IL-6, TNF-α, MCP-1, IP-10, IL-4, IL-10 have been reported in COVID-19 infection. Increased proinflammatory cytokines and chemokines in patients with severe COVID-19 may cause the suppression of CD4 + and CD8 + T cells and regulatory T cells, causing excessive inflammatory responses and fatal cytokine storm with tissue and organ damage. Consequently, novel therapeutics to be developed against host immune system, including blockade of cytokines (IL-6, IL-1, IFN) themselves, their receptors or signaling pathways- JAK inhibitors- could be effective as potential therapeutics.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/fisiopatologia , Corticosteroides/uso terapêutico , Animais , Antivirais/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Imunoterapia/métodos , Macrófagos/imunologia , Macrófagos/patologia , Macrófagos/virologia
19.
Life Sci ; 278: 119658, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34048809

RESUMO

AIMS: Maslinic acid (MA) is a naturally occurring pentacyclic triterpene known to exert cardioprotective effects. This study aims to investigate the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) for MA-mediated anti-inflammatory effects in atheroma pathogenesis in vitro, including evaluation of tumor necrosis factor-alpha (TNF-α)-induced monocyte recruitment, oxidized low-density lipoprotein (oxLDL)-induced scavenger receptors expression, and nuclear factor-kappa B (NF-ĸB) activity in human umbilical vein endothelial cells (HUVECS) and human acute monocytic leukemia cell line (THP-1) macrophages. MATERIALS AND METHODS: An in vitro monocyte recruitment model utilizing THP-1 and HUVECs was developed to evaluate TNF-α-induced monocyte adhesion and trans-endothelial migration. To study the role of Nrf2 for MA-mediated anti-inflammatory effects, Nrf2 inhibitor ML385 was used as the pharmacological inhibitor. The expression of Nrf2, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 36 (CD36), and scavenger receptor type A (SR-A) in HUVECs and THP-1 macrophages were investigated using RT-qPCR and Western blotting. The NF-κB activity was determined using NF-κB (p65) Transcription Factor Assay Kit. KEY FINDINGS: The results showed opposing effects of MA on Nrf2 expression in HUVECs and THP-1 macrophages. MA suppressed TNF-α-induced Nrf2 expression in HUVECs, but enhanced its expression in THP-1 macrophages. Combined effects of MA and ML385 suppressed MCP-1, VCAM-1, and SR-A expressions. Intriguingly, at the protein level, ML385 selectively inhibited SR-A but enhanced CD36 expression. Meanwhile, ML385 further enhanced MA-mediated inhibition of NF-κB activity in HUVECs. This effect, however, was not observed in THP-1 macrophages. SIGNIFICANCE: MA attenuated foam cell formation by suppressing VCAM-1, MCP-1, and SR-A expression, as well as NF-κB activity, possibly through Nrf2 inhibition. The involvement of Nrf2 for MA-mediated anti-inflammatory effects however differs between HUVECs and macrophages. Future investigations are warranted for a detailed evaluation of the contributing roles of Nrf2 in foam cells formation.


Assuntos
Anti-Inflamatórios/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Placa Aterosclerótica/metabolismo , Triterpenos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/patologia , Fator 2 Relacionado a NF-E2/análise , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/patologia , Células THP-1 , Fator de Necrose Tumoral alfa/análise
20.
Life Sci ; 279: 119660, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34052292

RESUMO

Hyperglycemia has been shown to aggravate ischemic brain damage, in which the inflammatory reaction induced by hyperglycemia is involved in the worsening of cerebral ischemia-reperfusion injury. However, the role of microglial polarization in hyperglycemia-aggravating cerebral ischemia-reperfusion injury remains unknown. The present study investigated whether diabetic hyperglycemia inhibited or activated microglia, as well as microglial subtypes 1 and 2. Rats were used to establish the diabetic hyperglycemia and middle cerebral artery occlusion (MCAO) model. The markers CD11b, CD16, CD32, CD86, CD206, and Arg1 were used to show M1 or M2 microglia. The results revealed increased neurological deficits, infarct volume, and neural apoptosis in rats with hyperglycemia subjected to MCAO for 30 min and reperfused at 1, 3, and 7 days compared with the normoglycemic rats. Microglia and astrocyte activation and proliferation were inhibited in hyperglycemic rats. Furthermore, M1 microglia polarization was promoted, while that of M2 microglia was inhibited in hyperglycemic rats. These findings suggested that the polarization of M1 and M2 microglia is activated and inhibited, respectively, in hyperglycemic rats and may be involved in the aggravated brain damage caused by ischemia-reperfusion in diabetic hyperglycemia.


Assuntos
Isquemia Encefálica/complicações , Hiperglicemia/patologia , Inflamação/patologia , Macrófagos/imunologia , Microglia/imunologia , Traumatismo por Reperfusão/complicações , Animais , Apoptose , Modelos Animais de Doenças , Hiperglicemia/etiologia , Infarto da Artéria Cerebral Média/fisiopatologia , Inflamação/etiologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Microglia/metabolismo , Microglia/patologia , Ratos , Ratos Sprague-Dawley
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