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1.
Nat Commun ; 12(1): 5311, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493724

RESUMO

Although some effective therapies have been available for cancer, it still poses a great threat to human health and life due to its drug resistance and low response in patients. Here, we develop a ferroptosis-based therapy by combining iron nanoparticles and cancer-specific gene interference. The expression of two iron metabolic genes (FPN and LCN2) was selectively knocked down in cancer cells by Cas13a or microRNA controlled by a NF-κB-specific promoter. Cells were simultaneously treated by iron nanoparticles. As a result, a significant ferroptosis was induced in a wide variety of cancer cells. However, the same treatment had little effect on normal cells. By transferring genes with adeno-associated virus and iron nanoparticles, the significant tumor growth inhibition and durable cure were obtained in mice with the therapy. In this work, we thus show a cancer therapy based on gene interference-enhanced ferroptosis.


Assuntos
Proteínas de Transporte de Cátions/antagonistas & inibidores , Ferroptose/genética , Ferro/metabolismo , Lipocalina-2/antagonistas & inibidores , Neoplasias/terapia , Interferência de RNA , Espécies Reativas de Oxigênio/agonistas , Animais , Proteínas Associadas a CRISPR/genética , Proteínas Associadas a CRISPR/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular Tumoral , Dependovirus/genética , Dependovirus/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Lipocalina-2/genética , Lipocalina-2/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Nanopartículas/administração & dosagem , Nanopartículas/química , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Regiões Promotoras Genéticas , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Baço/metabolismo , Baço/patologia , Análise de Sobrevida , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Immunol ; 22(9): 1118-1126, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34326534

RESUMO

Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD.


Assuntos
Proteínas de Ligação a DNA/genética , Doenças Hereditárias Autoinflamatórias/genética , Doenças Inflamatórias Intestinais/genética , Macrófagos/imunologia , Fatores de Transcrição/genética , Animais , Calgranulina A/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Lipocalina-2/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th17/imunologia , Transcrição Genética/genética , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo
3.
Int J Nanomedicine ; 16: 4335-4349, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234429

RESUMO

Purpose: Selenium nanoparticles (SeNPs) have recently gained much attention in nanomedicine applications owing to their unique biological properties. Biosynthesis of SeNPs using nutraceuticals as lycopene (LYC) maximizes their stability and bioactivities. In this context, this study aimed to elucidate the renoprotective activity of SeNPs coated with LYC (LYC-SeNPs) in the acute kidney injury (AKI) model. Methods: Rats were divided into six groups: control, AKI (glycerol-treated), AKI+sodium selenite (Na2SeO3; 0.5 mg/kg), AKI+LYC (10 mg/kg), AKI+LYC-SeNPs (0.5 mg/kg) and treated for 14 days. Results: Glycerol treatment evoked significant increases in rhabdomyolysis-related markers (creatine kinase and LDH). Furthermore, relative kidney weight, Kim-1, neutrophil gelatinase-associated lipocalin (NGAL), serum urea, and creatinine in the AKI group were elevated. Glycerol-injected rats displayed declines in reduced glutathione level, and superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities, paralleled with downregulations in Nfe2l2 and Hmox-1 expressions and high renal MDA and NO contents. Glycerol-induced renal inflammation was evident by rises in TNF-α, IL-1ß, IL-6, and upregulated Nos2 expression. Also, apoptotic (elevated caspase-3, Bax, and cytochrome-c with lowered Bcl-2) and necroptotic (elevated Pipk3 expression) changes were reported in damaged renal tissue. Co-treatment with Na2SeO3, LYC, or LYC-SeNPs restored the biochemical, molecular, and histological alterations in AKI. In comparison with Na2SeO3 or LYC treatment, LYC-SeNPs had the best nephroprotective profile. Conclusion: Our findings authentically revealed that LYC-SeNPs co-administration could be a prospective candidate against AKI-mediated renal damage via antioxidant, anti-inflammatory, anti-apoptotic and anti-necroptotic activities.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Glicerol/efeitos adversos , Licopeno/química , Nanopartículas/química , Selênio/química , Selênio/farmacologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Antioxidantes/metabolismo , Creatinina/sangue , Química Verde , Lipocalina-2/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Selênio/uso terapêutico
4.
Int J Mol Sci ; 22(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205319

RESUMO

Recent studies indicate that Acanthamoeba spp. may play a significant role in kidney dysfunction. The aim of the study was to examine the levels of kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemotactic protein 1 (MCP-1), as well as an activity of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9, respectively) in the kidneys of immunocompetent and immunosuppressed mice infected with Acanthamoeba spp. The levels of KIM-1, NGAL, and MCP-1 were analyzed by enzyme-linked immunosorbent assay (ELISA), and the activity of MMPs was determined by gelatin zymography. The elevated KIM-1 level was found in the kidneys of immunocompetent mice at the beginning of Acanthamoeba spp. infection. In the immunosuppressed mice, the KIM-1 level was statistically different. The statistically decreased NGAL level was found in the kidneys of immunocompetent mice compared to the uninfected mice. In the immunocompromised mice, we found statistically significant differences in MCP-1 levels between the uninfected and infected groups. There was an increase in the expression of both MMP-2 and MMP-9 in the kidneys of immunocompetent and immunosuppressed mice infected with Acanthamoeba spp. compared to the uninfected mice. The results indicate that KIM-1, NGAL, MCP-1, MMP-2, MMP-9, and MMP-9/NGAL might be promising biomarkers of renal acanthamoebiasis.


Assuntos
Acanthamoeba , Amebíase/metabolismo , Biomarcadores/metabolismo , Nefropatias/metabolismo , Amebíase/diagnóstico , Amebíase/parasitologia , Animais , Quimiocina CCL2/metabolismo , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Nefropatias/diagnóstico , Nefropatias/parasitologia , Lipocalina-2/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos BALB C
5.
Int J Cancer ; 149(7): 1495-1511, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34146401

RESUMO

Lipocalin 2 is a siderophore-binding protein that regulates iron homeostasis. Lipocalin 2 expression is elevated in multiple tumor types; however, the mechanisms that drive tumor progression upon Lipocalin 2 expression remain unclear. When Lipocalin 2 is over-expressed, it leads to resistance to 5-fluorouracil in colon cancer cell lines in vitro and in vivo by inhibiting ferroptosis. Lipocalin 2 inhibits ferroptosis by decreasing intracellular iron levels and stimulating the expression of glutathione peroxidase4 and a component of the cysteine glutamate antiporter, xCT. The increase in xCT levels is dependent on increased levels of ETS1 in Lipocalin 2 over-expressing cells. Inhibiting Lipocalin 2 function with a monoclonal antibody leads to a decrease in chemo-resistance and transformation in vitro, and a decrease in tumor progression and chemo-resistance in xenograft mouse models. Lipocalin 2 and xCT levels exhibit a positive correlation in human tumor samples suggesting that the pathway we have identified in cell lines is operative in human tumor samples. These results indicate that Lipocalin 2 is a potential therapeutic target and that the monoclonal antibody described in our study can serve as the basis for a potential therapeutic in patients who do not respond to chemotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lipocalina-2/metabolismo , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Lipocalina-2/genética , Camundongos , Camundongos Nus , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Aging (Albany NY) ; 13(10): 13859-13875, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34029211

RESUMO

Atherosclerosis (AS) is a chronic progressive inflammatory disease and a leading cause of death worldwide. Being a novel adipokine, chemerin is reported to be positively correlated with the severity of AS, yet its underlying mechanisms in AS remains elusive. It is well-known that AS development is significantly attributed to abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). Therefore, we investigated the role of the chemerin / chemokine-like receptor 1 (CMKLR1, chemerin receptor) signaling, and the potential therapeutic effect of curcumin in VSMCs proliferation and migration during AS by establishing a high fat diet (HFD) mouse model. We found that CMKLR1 was highly expressed in HFD-induced AS tissues and that its expression level was positively correlated with aortic proliferation. Knockdown of CMKLR1 significantly inhibited VSMCs proliferation and migration, as evidenced by the EdU-incorporation assay, wound healing assay, and the induction of proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-9 (MMP-9) expression. Furthermore, we discovered that Lipocalin-2 (LCN2) acts as a key factor involved in CMKLR1-mediated VSMCs proliferation and migration via the p38 / MAPK and Wnt / ß-catenin signaling pathways, and we demonstrated that curcumin inhibits VSMCs proliferation and migration by inhibiting chemerin / CMKLR1 / LCN2, thereby reducing AS progression. Our findings suggest that chemerin / CMKLR1 activation promotes the development of AS; hence, targeting the chemerin / CMKLR1 / LCN2 signaling pathway may be a reasonable treatment modality for AS.


Assuntos
Movimento Celular/efeitos dos fármacos , Quimiocinas/metabolismo , Curcumina/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lipocalina-2/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Receptores de Quimiocinas/metabolismo , Transdução de Sinais , Animais , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Dieta Hiperlipídica , Técnicas de Silenciamento de Genes , Masculino , Camundongos Knockout , Miócitos de Músculo Liso/efeitos dos fármacos , Placa Aterosclerótica/patologia , Transdução de Sinais/efeitos dos fármacos
7.
Med Sci Monit ; 27: e929115, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33927176

RESUMO

BACKGROUND Hydration remains the mainstay of contrast-induced nephropathy (CIN) prevention, and new biomarkers of cystatin C (Cys C) and neutrophil gelatinase-associated lipocalin (NGAL) have been suggested. This study aimed to explore whether hydration is essential in patients with very low-risk profiles of CIN who are undergoing coronary angiography. MATERIAL AND METHODS A total of 150 patients were enrolled and randomly distributed to 3 groups: the Preventive Group (n=50, saline hydration was given 6 h before the procedure until 12 h after the procedure), the Remedial Group (n=50, saline hydration was given after procedure for 12 h), and the No Hydration (NH) group (n=50, saline was only given during the procedure). Serum creatinine (Cr), Cys C, and urinary NGAL were tested 3 times at different times. RESULTS Six patients were excluded because of Mehran risk score >2. There was no CIN among 144 individuals. At 24 h and at 72 h after the procedure, we found no significant differences in the levels of Cr and Cys C (0.72±0.11 mg/L for the Preventive Group, 0.67±0.14 mg/L for the Remedial Group, and 0.70±0.1 6 mg/L for the NH Group) among the 3 groups. Urinary NGAL also did not differ significantly among the 3 groups at 6 h or at 48 h (6.31±6.60 ng/ml for the Preventive Group, 5.00±5.86 ng/ml for the Remedial Group, and 6.97±6.37 ng/ml for the NH Group) after the procedure. Subgroup analysis in patients who underwent percutaneous coronary intervention (PCI) showed that there was no significant difference in serum Cr, Cys C, or urinary NGAL at different time points among the 3 groups. CONCLUSIONS Saline hydration during the perioperative period might be unnecessary in patients with very low-risk profiles of CIN.


Assuntos
Meios de Contraste/efeitos adversos , Nefropatias/induzido quimicamente , Biomarcadores/sangue , Angiografia Coronária/métodos , Creatinina/sangue , Feminino , Humanos , Nefropatias/sangue , Nefropatias/metabolismo , Lipocalina-2/metabolismo , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/métodos , Estudos Prospectivos , Fatores de Risco
8.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799862

RESUMO

Excess calorie intake and a sedentary lifestyle have made non-alcoholic fatty liver disease (NAFLD) one of the fastest growing forms of liver disease of the modern world. It is characterized by abnormal accumulation of fat in the liver and can range from simple steatosis and non-alcoholic steatohepatitis (NASH) to cirrhosis as well as development of hepatocellular carcinoma (HCC). Biopsy is the golden standard for the diagnosis and differentiation of all NAFLD stages, but its invasiveness poses a risk for patients, which is why new, non-invasive ways of diagnostics ought to be discovered. Lipocalin-2 (LCN2), which is a part of the lipocalin transport protein family, is a protein formally known for its role in iron transport and in inflammatory response. However, in recent years, its implication in the pathogenesis of NAFLD has become apparent. LCN2 shows significant upregulation in several benign and malignant liver diseases, making it a good candidate for the NAFLD biomarker or even a therapeutic target. What makes LCN2 more interesting to study is the fact that it is overexpressed in HCC development induced by chronic NASH, which is one of the primary causes of cancer-related deaths. However, to this day, neither its role as a biomarker for NAFLD nor the molecular mechanisms of its implication in NAFLD pathogenesis have been completely elucidated. This review aims to gather and closely dissect the current knowledge about, sometimes conflicting, evidence on LCN2 as a biomarker for NAFLD, its involvement in NAFLD, and NAFLD-HCC related pathogenesis, while comparing it to the findings in similar pathologies.


Assuntos
Biomarcadores/metabolismo , Carcinoma Hepatocelular/metabolismo , Lipocalina-2/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Biópsia , Carcinoma Hepatocelular/patologia , Humanos , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia
9.
Nat Commun ; 12(1): 2057, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824339

RESUMO

Lipocalin 2 (LCN2) was recently identified as an endogenous ligand of the type 4 melanocortin receptor (MC4R), a critical regulator of appetite. However, it remains unknown if this molecule influences appetite during cancer cachexia, a devastating clinical entity characterized by decreased nutrition and progressive wasting. We demonstrate that LCN2 is robustly upregulated in murine models of pancreatic cancer, its expression is associated with reduced food consumption, and Lcn2 deletion is protective from cachexia-anorexia. Consistent with LCN2's proposed MC4R-dependent role in cancer-induced anorexia, pharmacologic MC4R antagonism mitigates cachexia-anorexia, while restoration of Lcn2 expression in the bone marrow is sufficient in restoring the anorexia feature of cachexia. Finally, we observe that LCN2 levels correlate with fat and lean mass wasting and is associated with increased mortality in patients with pancreatic cancer. Taken together, these findings implicate LCN2 as a pathologic mediator of appetite suppression during pancreatic cancer cachexia.


Assuntos
Apetite , Caquexia/complicações , Lipocalina-2/metabolismo , Neoplasias Pancreáticas/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anorexia/sangue , Anorexia/complicações , Barreira Hematoencefálica/patologia , Medula Óssea/patologia , Caquexia/sangue , Linhagem Celular Tumoral , Modelos Animais de Doenças , Comportamento Alimentar , Feminino , Deleção de Genes , Humanos , Lipocalina-2/sangue , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Modelos Biológicos , Músculos/patologia , Neutrófilos/patologia , Tamanho do Órgão , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/metabolismo , Regulação para Cima
10.
Medicine (Baltimore) ; 100(14): e25411, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832138

RESUMO

ABSTRACT: This study is to investigate the role of neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC) and creatinine in the diagnosis of acute kidney injury (AKI) secondary to liver cirrhosis.A total of 825 patients (including 540 liver cirrhosis patients and 285 healthy controls) were enrolled. Liver cirrhosis patients were further subdivided into AKI secondary to liver cirrhosis group (AKI group, 210 patients) and simple liver cirrhosis group (LC group, 330 patients). Serum NGAL/urine NGAL (sNGAL/uNGAL), and serum creatinine (sCr) levels as well as estimated glomerular filtration rates were measured. The diagnostic performances of these indicators in AKI secondary to liver cirrhosis were evaluated.The levels of sNGAL, uNGAL, CysC and sCr in the AKI group were significantly higher than those of LC and healthy control groups. However, the eGFR and c-aGFR of AKI group were significantly lower. With the progression of AKI (AKI-S1→AKI-S2→AKI-S3), the levels of sNGAL, uNGAL, CysC and sCr increased gradually, while the levels of c-aGFR and eGFR decreased gradually. The sNGAL, uNGAL and CysC were positively correlated with sCr (r = 0.638, 0.635, and 0.650), but negatively correlated with c-aGFR (r = -0.617, -0.606 and -0.655). However, eGFR had a negative correlation with sCr (r = -0.711), but a positive correlation with c-aGFR (r = 0.736). ROC curve analysis showed that the area under the curve for uNGAL was the largest (0.976), followed by sNGAL (0.967). The diagnostic efficacy of uNGAL and sNGAL in AKI group were 0.907 and 0.870, and the risk degrees were OR = 54.524 and 5.115, respectively.NGAL might perform better than sCr and CysC in the diagnosis of AKI secondary to liver cirrhosis, while uNGAL might be a better indicator than sNGAL in AKI diagnosis.


Assuntos
Injúria Renal Aguda/diagnóstico , Creatinina/metabolismo , Cistatina C/metabolismo , Lipocalina-2/metabolismo , Cirrose Hepática/complicações , Injúria Renal Aguda/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Taxa de Filtração Glomerular , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade
11.
Nat Commun ; 12(1): 2366, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888692

RESUMO

Aptamers are single-stranded nucleic acid ligands that bind to target molecules with high affinity and specificity. They are typically discovered by searching large libraries for sequences with desirable binding properties. These libraries, however, are practically constrained to a fraction of the theoretical sequence space. Machine learning provides an opportunity to intelligently navigate this space to identify high-performing aptamers. Here, we propose an approach that employs particle display (PD) to partition a library of aptamers by affinity, and uses such data to train machine learning models to predict affinity in silico. Our model predicted high-affinity DNA aptamers from experimental candidates at a rate 11-fold higher than random perturbation and generated novel, high-affinity aptamers at a greater rate than observed by PD alone. Our approach also facilitated the design of truncated aptamers 70% shorter and with higher binding affinity (1.5 nM) than the best experimental candidate. This work demonstrates how combining machine learning and physical approaches can be used to expedite the discovery of better diagnostic and therapeutic agents.


Assuntos
Aptâmeros de Nucleotídeos/metabolismo , Aprendizado de Máquina , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Simulação por Computador , Descoberta de Drogas/métodos , Biblioteca Gênica , Ligantes , Lipocalina-2/química , Lipocalina-2/genética , Lipocalina-2/metabolismo , Modelos Químicos , Ligação Proteica
12.
PLoS Pathog ; 17(4): e1009487, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33905460

RESUMO

Lipocalin 2 (LCN2) is a secreted glycoprotein with roles in multiple biological processes. It contributes to host defense by interference with bacterial iron uptake and exerts immunomodulatory functions in various diseases. Here, we aimed to characterize the function of LCN2 in lung macrophages and dendritic cells (DCs) using Lcn2-/- mice. Transcriptome analysis revealed strong LCN2-related effects in CD103+ DCs during homeostasis, with differential regulation of antigen processing and presentation and antiviral immunity pathways. We next validated the relevance of LCN2 in a mouse model of influenza infection, wherein LCN2 protected from excessive weight loss and improved survival. LCN2-deficiency was associated with enlarged mediastinal lymph nodes and increased lung T cell numbers, indicating a dysregulated immune response to influenza infection. Depletion of CD8+ T cells equalized weight loss between WT and Lcn2-/- mice, proving that LCN2 protects from excessive disease morbidity by dampening CD8+ T cell responses. In vivo T cell chimerism and in vitro T cell proliferation assays indicated that improved antigen processing by CD103+ DCs, rather than T cell intrinsic effects of LCN2, contribute to the exacerbated T cell response. Considering the antibacterial potential of LCN2 and that commensal microbes can modulate antiviral immune responses, we speculated that LCN2 might cause the observed influenza phenotype via the microbiome. Comparing the lung and gut microbiome of WT and Lcn2-/- mice by 16S rRNA gene sequencing, we observed profound effects of LCN2 on gut microbial composition. Interestingly, antibiotic treatment or co-housing of WT and Lcn2-/- mice prior to influenza infection equalized lung CD8+ T cell counts, suggesting that the LCN2-related effects are mediated by the microbiome. In summary, our results highlight a novel regulatory function of LCN2 in the modulation of antiviral immunity.


Assuntos
Influenza Humana/imunologia , Lipocalina-2/metabolismo , Microbiota/imunologia , Transcriptoma , Animais , Apresentação do Antígeno , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Feminino , Microbioma Gastrointestinal , Homeostase , Humanos , Imunidade , Influenza Humana/virologia , Lipocalina-2/genética , Pulmão/imunologia , Pulmão/virologia , Ativação Linfocitária , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Organismos Livres de Patógenos Específicos
13.
Biomed Pharmacother ; 139: 111624, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33915503

RESUMO

Acute kidney injury (AKI) is a sudden insult of the kidney that happens within a short period of time, which is associated with poor prognosis in diabetic patients with myocardial infarction (MI). Subclinical AKI is a condition in which tubular damage biomarkers [Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1(KIM-1)] are positive even in the absence of elevated serum creatinine. Recent studies reported that SGLT-2 inhibitors could protect against subclinical AKI in diabetic patients by elevating the level of ß-Hydroxybutyric acid (ßOHB). This study aims to examine the reno-protective potential of empagliflozin (EMPA) against MI associated AKI in diabetic rats. Eighty Albino Wistar rats were divided into: (1) nondiabetic sham group (CS), (2) nondiabetic + myocardial infarction group (CM), (3) diabetic + myocardial infarction group (DM) and (4) diabetic + myocardial infarction + empagliflozin group (DME). At the end of the experiment, blood samples and kidneys were collected for biochemical analysis, histopathological, and immunohistochemical studies. After induction of myocardial infarction, there was a significant decrease in serum creatinine and NGAL levels in DME. After EMPA administration, mesangial matrix index and glomerular area were lowered in DME if compared to DM group. As a marker for tubular injury, we used anti-NGAL and anti-KIM-1 immunohistochemistry. Strong positive reaction was noticed in DM group if compared to DME group which showed weak positive reaction. Levels of renal mRNAs [NGAL; KIM-1; Nox-2,4; TLR-2,4; MyD88; TNF- α and IL-1 ß, 18] in DME group were reduced significantly compared to DM group. In conclusion, empagliflozin can protect against subclinical acute kidney injury in diabetic albino Wistar rats after myocardial infarction induction, which could improve the clinical outcome of SGLT-2 inhibitors in diabetic patients.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Infarto do Miocárdio/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Animais , Moléculas de Adesão Celular/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Eletrocardiografia , Rim/patologia , Lipocalina-2/metabolismo , Masculino , Infarto do Miocárdio/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar
14.
Korean J Radiol ; 22(5): 801-810, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33660455

RESUMO

OBJECTIVE: To investigate imaging biomarkers of microperfusion in contrast-induced nephropathy (CIN) using contrast-enhanced ultrasound (CEUS). MATERIALS AND METHODS: The CIN model was fabricated by administering indomethacin (10 mg/kg), L-NAME (15 mg/kg), and iopamidol (10 mL/kg) to Sprague-Dawley rats. After 24 hours, CEUS was performed on CIN (n = 6) and control (n = 6) rats with sulphur hexafluoride microbubbles (SonoVue). From time-intensity curves obtained from the kidney arriving time (AT), acceleration time (AC), time to peak (TTP), and peak enhancement (PE) were measured and compared between the groups. After CEUS, the rats were sacrificed, and cell apoptosis markers were evaluated to confirm the development of CIN. RESULTS: Among CEUS parameters, AT (7.8 ± 1.6 vs. 4.2 ± 0.5 s, p = 0.002), AC (4.7 ± 1.4 vs. 2.0 ± 0.4 s, p = 0.002), and TTP (12.5 ± 2.9 vs. 6.2 ± 0.6 s, p = 0.002) were significantly prolonged in the CIN group compared to controls. PE was significantly higher in the control group than in the CIN group (17.1 ± 1.9 vs. 12.2 ± 2.0 dB, p = 0.004). In kidney tissue, mRNA and protein levels of the apoptotic makers were significantly higher in the CIN group than in the control group (p = 0.003 and p = 0.002). CONCLUSION: CEUS parameters can be used as imaging biomarkers for microperfusion in CIN. In rats with CIN, AT, AC, and TTP were significantly prolonged, while PE was significantly lower compared to controls.


Assuntos
Injúria Renal Aguda/etiologia , Fosfolipídeos/efeitos adversos , Hexafluoreto de Enxofre/efeitos adversos , Ultrassonografia , Injúria Renal Aguda/diagnóstico , Animais , Modelos Animais de Doenças , Interleucina-18/genética , Interleucina-18/metabolismo , Rim/metabolismo , Rim/patologia , Testes de Função Renal , Lipocalina-2/genética , Lipocalina-2/metabolismo , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
15.
Cell Death Dis ; 12(2): 221, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637683

RESUMO

Gastric mucosal injury is a less well known complication of obesity. Its mechanism remains to be further elucidated. Here, we explored the protective role of lipocalin 2 (LCN2) against endoplasmic reticulum stress and cell apoptosis in gastric mucosa in patients and mice with obesity. Through molecular and genetic analyses in clinical species, LCN2 secreted by parietal cells expression is elevated in obese. Immunofluorescence, TUNEL, and colorimetry results show that a more significant upregulation of pro-inflammatory factors and increased amount of apoptotic cells in gastric tissue sections in obese groups. Loss- and gain-of-function experiments in gastric epithelial cells demonstrate that increased LCN2 protected against obesity associated gastric injury by inhibiting apoptosis and improving inflammatory state. In addition, this protective effect was mediated by repressing ER stress. Our findings identify LCN2 as a gastric hormone could be a compensatory protective factor against gastric injury in obese.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Mucosa Gástrica/metabolismo , Lipocalina-2/metabolismo , Obesidade/metabolismo , Úlcera Gástrica/prevenção & controle , Animais , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Etanol , Mucosa Gástrica/patologia , Humanos , Indometacina , Lipocalina-2/genética , Masculino , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/patologia , Estresse Oxidativo , Transdução de Sinais , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , Regulação para Cima
16.
Am J Physiol Renal Physiol ; 320(4): F608-F616, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33615891

RESUMO

Stimulator of interferon genes (STING) is an important adaptor in cytosolic DNA-sensing pathways. A recent study found that the deletion of STING ameliorated cisplatin-induced acute kidney injury (AKI), suggesting that STING could serve as a potential target for AKI therapy. Up to now, a series of small-molecule STING inhibitors/antagonists have been identified. However, none of the research was performed to explore the role of human STING inhibitors in AKI. Here, we investigated the effect of a newly generated covalent antagonist, H151, which targets both human and murine STING, in cisplatin-induced AKI. We found that H151 treatment significantly ameliorated cisplatin-induced kidney injury as shown by the improvement of renal function, kidney morphology, and renal inflammation. In addition, tubular cell apoptosis and increased renal tubular injury marker neutrophil gelatinase-associated lipocalin induced by cisplatin were also effectively attenuated in H151-treated mice. Moreover, the mitochondrial injury caused by cisplatin was also reversed as evidenced by improved mitochondrial morphology, restored mitochondrial DNA content, and reversed mitochondrial gene expression. Finally, we observed enhanced mitochondrial DNA levels in the plasma of patients receiving platinum-based chemotherapy compared with healthy controls, which could potentially activate STING signaling. Taken together, these findings suggested that H151 could be a potential therapeutic agent for treating AKI possibly through inhibiting STING-mediated inflammation and mitochondrial injury.NEW & NOTEWORTHY Although various stimulator of interferon genes (STING) inhibitors have been identified, no research was performed to investigate the role of human STING inhibitors in AKI. Here, we evaluated the effect of H151 targeting both human and murine STING on cisplatin-induced AKI and observed a protection against renal injury possibly through ameliorating inflammation and mitochondrial dysfunction.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Cisplatino/farmacologia , Lipocalina-2/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Injúria Renal Aguda/metabolismo , Animais , Apoptose/efeitos dos fármacos , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Lipocalina-2/metabolismo , Camundongos , Mitocôndrias/metabolismo , Nefrite/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Vet Surg ; 50(3): 641-649, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33522003

RESUMO

OBJECTIVE: To investigate neutrophil gelatinase-associated lipocalin (NGAL) concentrations in serum and synovial fluid (SF) from horses with joint inflammation. STUDY DESIGN: Experimental studies and retrospective clinical study. SAMPLE POPULATION: Serum and SF samples were available from healthy horses (n = 19), clinical cases, and horses with experimental joint inflammation. Clinical cases included horses with (n = 10) or without (n = 10) septic arthritis. Experimental intra-articular inflammation was induced by lipopolysaccharide (LPS; n = 7, severe inflammation), lidocaine (n = 6, moderate inflammation), or mepivacaine (n = 6, mild inflammation). METHODS: Availability of samples was based on approval from the local ethical committee and from the Danish Animal Experiments Inspectorate. Neutrophil gelatinase-associated lipocalin was measured with a previously validated enzyme-linked immunosorbent assay. Repeated-measurements one- and two-way analysis of variance and correlation analysis were used to analyze NGAL concentrations and white blood cell counts (WBC). RESULTS: After injection of LPS or lidocaine, SF NGAL concentrations increased 343- (P = .0035) and 60-fold (P = .0038) relative to baseline, respectively. Serum NGAL also increased in both groups (P < .05) but to lower concentrations than in SF. Concentrations were higher after injection of lidocaine SF NGAL than after injection of mepivacaine (P < .05) at 6 and 12 hours. Synovial fluid concentrations of NGAL were higher in horses with septic arthritis than in the nonseptic group (P = .0070) and in healthy controls (P = .0071). Concentrations of NGAL correlated with WBC in SF (P < .0001, R2 = 0.49) and in blood (P = .0051, R2 = 0.27). CONCLUSION: Neutrophil gelatinase-associated lipocalin concentrations increased in SF in response to experimentally induced and naturally occurring joint inflammation. Synovial fluid NGAL concentration correlated with WBC and, thus, seems to reflect intensity of joint inflammation. CLINICAL SIGNIFICANCE: Neutrophil gelatinase-associated lipocalin may prove to be a useful biomarker of joint inflammation and infection in horses.


Assuntos
Doenças dos Cavalos/metabolismo , Inflamação/veterinária , Artropatias/veterinária , Lipocalina-2/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Doenças dos Cavalos/induzido quimicamente , Cavalos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Artropatias/induzido quimicamente , Artropatias/metabolismo , Lidocaína/efeitos adversos , Lipocalina-2/sangue , Lipocalina-2/líquido cefalorraquidiano , Lipopolissacarídeos/efeitos adversos , Masculino , Mepivacaína/efeitos adversos , Estudos Retrospectivos
18.
Nat Commun ; 12(1): 474, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33473115

RESUMO

Smoking has a profound impact on tumor immunity, and nicotine, which is the major addictive component of smoke, is known to promote tumor progression despite being a non-carcinogen. In this study, we demonstrate that chronic exposure of nicotine plays a critical role in the formation of pre-metastatic niche within the lungs by recruiting pro-tumor N2-neutrophils. This pre-metastatic niche promotes the release of STAT3-activated lipocalin 2 (LCN2), a secretory glycoprotein from the N2-neutrophils, and induces mesenchymal-epithelial transition of tumor cells thereby facilitating colonization and metastatic outgrowth. Elevated levels of serum and urine LCN2 is elevated in early-stage breast cancer patients and cancer-free females with smoking history, suggesting that LCN2 serve as a promising prognostic biomarker for predicting increased risk of metastatic disease in female smoker(s). Moreover, natural compound, salidroside effectively abrogates nicotine-induced neutrophil polarization and consequently reduced lung metastasis of hormone receptor-negative breast cancer cells. Our findings suggest a pro-metastatic role of nicotine-induced N2-neutrophils for cancer cell colonization in the lungs and illuminate the therapeutic use of salidroside to enhance the anti-tumor activity of neutrophils in breast cancer patients.


Assuntos
Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmão/metabolismo , Metástase Neoplásica , Neutrófilos/metabolismo , Nicotina/efeitos adversos , Animais , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lipocalina-2/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/patologia , Camundongos , Metástase Neoplásica/genética , Infiltração de Neutrófilos/efeitos dos fármacos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fumar
19.
Sci Rep ; 11(1): 2591, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510370

RESUMO

Neutrophil gelatinase-associated lipocalin (NGAL) is involved in cardiovascular and renal diseases. Gene inactivation of NGAL blunts the pathophysiological consequences of cardiovascular and renal damage. We aimed to design chemical NGAL inhibitors and investigate its effects in experimental models of myocardial infarction (MI) and chronic kidney disease induced by 5/6 nephrectomy (CKD) on respectively 8-12 weeks old C57Bl6/j and FVB/N male mice. Among the 32 NGAL inhibitors tested, GPZ614741 and GPZ058225 fully blocked NGAL-induced inflammatory and profibrotic markers in human cardiac fibroblasts and primary mouse kidney fibroblasts. The administration of GPZ614741 (100 mg/kg/day) for three months, was able to improve cardiac function in MI mice and reduced myocardial fibrosis and inflammation. The administration of GPZ614741 (100 mg/kg/day) for two months resulting to no renal function improvement but prevented the increase in blood pressure, renal tubulointerstitial fibrosis and profibrotic marker expression in CKD mice. In conclusion, we have identified new compounds with potent inhibitory activity on NGAL-profibrotic and pro-inflammatory effects. GPZ614741 prevented interstitial fibrosis and dysfunction associated with MI, as well as tubulointerstitial fibrosis in a CKD model. These inhibitors could be used for other diseases that involve NGAL, such as cancer or metabolic diseases, creating new therapeutic options.


Assuntos
Lipocalina-2/antagonistas & inibidores , Lipocalina-2/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Animais , Modelos Animais de Doenças , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Masculino , Camundongos
20.
Int Immunopharmacol ; 91: 107334, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33412493

RESUMO

Psoriasis is the most prevalent inflammatory skin disorders, affecting 1-3% of the worldwide population. We previously reported that topical application of methyl 4-(adenin-9-yl)-2-hydroxybutanoate (DZ2002), a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, was a viable treatment in murine psoriatic skin inflammation. In current study, we further explored the mechanisms of DZ2002 on keratinocyte dysfunction and skin infiltration, the key pathogenic events in psoriasis. We conducted genome-wide DNA methylation analysis in skin tissue from imiquimod (IMQ)-induced psoriatic and normal mice, demonstrated that topical administration of DZ2002 directly rectified aberrant DNA methylation pattern in epidermis and dermis of psoriatic skin lesion. Especially, DZ2002 differentially regulated DNA methylation of GATA3 and LCN2 promoters, which maintained keratinocytes differentiation and reduced inflammatory infiltration in psoriatic skin respectively. In vitro studies in TNF-α/IFN-γ-elicited HaCaT manifested that DZ2002 treatment rectified compromised keratinocyte differentiation via GATA3 enhancement and abated chemokine expression by reducing LCN2 production under inflammatory stimulation. Chemotaxis assays conducted on dHL-60 cells confirmed that suppression of LCN2 expression by DZ2002 was accompanied by CXCR1 and CXCR2 downregulation, and contributed to the inhibition of CXCL8-driven neutrophils migration. In conclusion, therapeutic benefits of DZ2002 are achieved through differentially regulating DNA methylation of GATA3 and LCN2 promoters in psoriatic skin lesion, which efficiently interrupt the pathogenic interplay between keratinocytes and infiltrating immune cells, thus maintains epidermal keratinocytes differentiation and prevents dermal immune infiltration in psoriatic skin.


Assuntos
Adenina/análogos & derivados , Anti-Inflamatórios/farmacologia , Butiratos/farmacologia , Metilação de DNA/efeitos dos fármacos , Fator de Transcrição GATA3/genética , Queratinócitos/efeitos dos fármacos , Lipocalina-2/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Psoríase/prevenção & controle , Pele/efeitos dos fármacos , Adenina/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fator de Transcrição GATA3/metabolismo , Células HL-60 , Células HaCaT , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Lipocalina-2/metabolismo , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos/efeitos dos fármacos , Psoríase/genética , Psoríase/metabolismo , Psoríase/patologia , Pele/metabolismo , Pele/patologia
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