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1.
Front Immunol ; 12: 726283, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34721388

RESUMO

Severe status of coronavirus disease 2019 (COVID-19) is extremely associated to cytokine release. Moreover, it has been suggested that blood group is also associated with the prevalence and severity of this disease. However, the relationship between the cytokine profile and blood group remains unclear in COVID-19 patients. In this sense, we prospectively recruited 108 COVID-19 patients between March and April 2020 and divided according to ABO blood group. For the analysis of 45 cytokines, plasma samples were collected in the time of admission to hospital ward or intensive care unit and at the sixth day after hospital admission. The results show that there was a risk of more than two times lower of mechanical ventilation or death in patients with blood group O (log rank: p = 0.042). At first time, all statistically significant cytokine levels, except from hepatocyte growth factor, were higher in O blood group patients meanwhile the second time showed a significant drop, between 20% and 40%. In contrast, A/B/AB group presented a maintenance of cytokine levels during time. Hepatocyte growth factor showed a significant association with intubation or mortality risk in non-O blood group patients (OR: 4.229, 95% CI (2.064-8.665), p < 0.001) and also was the only one bad prognosis biomarker in O blood group patients (OR: 8.852, 95% CI (1.540-50.878), p = 0.015). Therefore, higher cytokine levels in O blood group are associated with a better outcome than A/B/AB group in COVID-19 patients.


Assuntos
COVID-19/imunologia , Citocinas/sangue , SARS-CoV-2/fisiologia , Sistema ABO de Grupos Sanguíneos , Idoso , Biomarcadores , COVID-19/diagnóstico , COVID-19/mortalidade , Progressão da Doença , Feminino , Fator de Crescimento de Hepatócito/sangue , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Respiração Artificial , Índice de Gravidade de Doença , Análise de Sobrevida
2.
J Clin Neurosci ; 93: 1-5, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34656230

RESUMO

OBJECTIVES: Meningiomas are the most common primary intracranial tumor. Hepatocyte growth factor (HGF) and its receptor, cMet, were shown to be involved in meningioma. This study was aimed to determine the concentration of HGF and soluble cMet (s-cMet) in the serum of patients with different grades of meningioma. METHODS: Ninety serum samples from different grades of meningioma patients (42 cases of grade I, 28 grade II, 20 grade III) and 51 controls were included in this study. The serum total protein concentration (TPC) was measured by a Bio-Rad protein assay and serum concentration of HGF and s-cMet by enzyme linked immunosorbent assay (ELISA). RESULTS: No significant change in the serum TPC of patients was seen as compared to controls. We also showed that serum HGF and s-cMet concentration in meningioma patients was higher than in controls. The results showed that starting from grades I to III meningioma, a significant increase in HGF and s-cMet serum concentration was observed (HGF; 380 ± 57.69, 430.27 ± 48.72, 596.36 ± 104.49 pg/ml, respectively, as compared to controls which was 327.72 ± 49.68 pg/ml and for s-cMet was 274.45 ± 45.05, 314.81 ± 38.71, 433.54 ± 51.81 ng/ml, respectively, as compared to controls which was 213.72 ± 29.13 ng/ml). The results showed that a high concentration of HGF and s-cMet is associated with advanced grades of meningioma. CONCLUSION: It is concluded that HGF and s-cMet serum levels increased in meningioma patients and their concentration was significantly higher in more advanced grades of the disease. It is also suggested that HGF/s-cMet might be involved in the progression of meningioma.


Assuntos
Neoplasias Encefálicas , Neoplasias Meníngeas , Meningioma , Criança , Ensaio de Imunoadsorção Enzimática , Fator de Crescimento de Hepatócito , Humanos
3.
BMC Neurol ; 21(1): 387, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615471

RESUMO

BACKGROUND: Hepatocyte growth factor (HGF) plays a role in neuronal survival and development, and has been implicated in neurodegenerative diseases. We sought to examine the associations of the CSF HGF with Alzheimer's disease (AD) pathology and cognitive function. METHODS: A total of 238 participants (including 90 cognitively normal (CN) and 148 mild cognitive impairment (MCI)) who had measurements of CSF HGF were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Multiple linear regression models were utilized to explore the cross-sectional associations of CSF HGF with AD biomarkers (including Aß42, pTau, and tTau proteins) in non-demented participants. Moreover, linear mixed-effects regression models were utilized to explore the longitudinal associations of HGF subgroups with cognitive function. Mediation analyses were utilized to explore the mediation effects of AD markers. RESULTS: MCI individuals had significantly increased CSF HGF compared with the CN individuals. Results of multiple linear regressions showed significant correlations of CSF HGF with CSF Aß42, pTau, and tTau in non-demented participants. Higher level of baseline CSF HGF was associated with faster cognitive decline. Influences of the baseline CSF HGF on cognition were partially mediated by Aß42, pTau, and tTau pathologies. CONCLUSIONS: High concentrations of HGF in CSF may be related to faster cognitive decline. The cognitive consequences of higher CSF HGF partly stem from AD pathology, which suggests that the CSF HGF may be an attractive biomarker candidate to track AD progression.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Fator de Crescimento de Hepatócito/metabolismo , Peptídeos beta-Amiloides , Biomarcadores , Cognição , Estudos Transversais , Fator de Crescimento de Hepatócito/líquido cefalorraquidiano , Humanos , Fragmentos de Peptídeos , Proteínas tau
4.
Zhonghua Shao Shang Za Zhi ; 37(9): 860-868, 2021 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-34645152

RESUMO

Objective: To investigate the effects and mechanism of hepatocyte growth factor (HGF)-modified human adipose mesenchymal stem cells (ADSCs) on the wound healing of full-thickness skin defects in diabetic rats. Methods: The experimental research method was adopted. The discarded abdominal adipose tissue was collected from a 35-year-old healthy female who underwent abdominal liposuction in the Department of Plastic Surgery of the First Affiliated Hospital of Air Force Medical University in December 2019. The long spindle-shaped primary ADSCs were obtained by collagenase digestion, and the third passage of cells were identified by flow cytometry to positively express ADSCs surface markers CD29 and CD90 and negatively express CD34 and CD45. The third passage of ADSCs were used for the subsequent experiments. ADSCs were transfected with lentivirus-mediated HGF for 4 h (obtaining HGF modified ADSCs) and then routinely cultured for 24 h. The cell morphology was observed under an inverted phase contrast microscope, and the transfection rate was calculated. Eighty-one male Sprague-Dawley rats aged 4 weeks were induced into diabetic rat model by high glucose and high fat diet combined with streptozotocin injection. A full-thickness skin defect wound of 1.5 cm×1.5 cm was made on the back of each rat. The injured rats were divided into phosphate buffer solution (PBS) group, ADSCs alone group, and HGF-modified ADSCs group according to the random number table, with 27 rats in each group. The rats were injected with the same volume of corresponding substances around the wound on post injury day (PID) 1, 3, and 7, respectively. Nine rats in each group were selected according to the random number table, the wound area of whom was measured on PID 0 (immediately), 3, 7, 10, and 14 (after injection on injection day), and the wound healing rates on PID 3, 7, 10, and 14 were calculated. Nine remaining rats in each group were sacrificed after injection on PID 3 and 7, respectively, and the skin tissue around the wound were collected. The mRNA expressions of inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-10 on PID 3 and collagen type Ⅰ and Ⅲ on PID 7 were detected by real-time fluorescent quantitative reverse transcription polymerase chain reaction. The expression level of vascular endothelial growth factor (VEGF) was detected by enzyme-linked immunosorbent assay on PID 7. The protein expression of nuclear factor κb-p65 on PID 3 and phosphorylation level of protein kinase B (Akt) on PID 7 were detected by Western blotting. Data were statistically analyzed with analysis of variance for repeated measurement, one-way analysis of variance, least significant difference t test, and Bonferroni correction. Results: After 24 h of culture, the HGF-transfected human ADSCs showed good morphology, which was not different with the non-transfected ADSCs, and the transfection rate reached 90%. On PID 3, 7, 10, and 14, the wound healing rates of rats in HGF-modified ADSCs group were (31.5±1.0)%, (75.2±2.0)%, (92.2±1.3)%, and (99.1±1.8)%, respectively, being significantly higher than (21.4±1.3)%, (61.4±1.5)%, (80.1±2.1)%, and (92.4±1.8)% in PBS group and (25.1±2.1)%, (67.2±1.3)%, (89.3±1.4)%, and (95.1±2.1)% in ADSCs alone group (t=1.452, 0.393, 0.436, 0.211, 4.982, 3.011, 4.211, 7.503, P<0.05 or P<0.01). On PID 3, compared with those in PBS group and ADSCs alone group, the mRNA expressions of TNF-α and IL-1ß and protein expression of nuclear factor κb-p65 in the skin tissue around the wound of rats in HGF-modified ADSCs group were significantly decreased (t=7.281, 17.700, 9.447, 6.231, 13.083, 7.783, P<0.01), and the mRNA expression of IL-10 in the skin tissue around the wound of rats in HGF-modified ADSCs group was significantly increased (t=-6.644, -6.381, P<0.01). On PID 7, compared with those in PBS group and ADSCs alone group, the mRNA expressions of collagen type Ⅰ and Ⅲ, the expression level of VEGF, and the phosphorylation level of Akt in the skin tissue around the wound of rats in HGF-modified ADSCs group were significantly increased (t=-5.126, -4.347, -5.058, -3.367, -10.694, -19.876, -4.890, -6.819, P<0.05 or P<0.01). Conclusions: HGF-modified human ADSCs can significantly promote the wound healing of full-thickness skin defects in diabetic rats. The mechanism may be related to the inhibition of TNF-α and IL-1ß expression, the promotion of IL-10, collagen type Ⅰ and Ⅲ, and VEGF expression, which could be related to the inhibition of nuclear factor κB signaling pathway, and the promotion of Akt signaling pathway.


Assuntos
Diabetes Mellitus Experimental , Células-Tronco Mesenquimais , Animais , Feminino , Fator de Crescimento de Hepatócito/genética , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular , Cicatrização
5.
J Oral Sci ; 63(4): 341-346, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34526445

RESUMO

PURPOSE: This study aimed to determine expressions of hepatocyte growth factor (HGF) and MET proto-oncogene receptor tyrosine kinase (MET) in palatal periosteum (PP) and to examine the effect of HGF/MET on osteogenic differentiation of human palatal periosteum-derived mesenchymal stem cells (PD-MSCs). METHODS: HGF/MET proteins in human palatal periosteum (n = 3) were localized using immunohistochemistry. PD-MSCs (n = 3) were cultured in serum-free Essential 8 (E8) medium or osteogenic medium with and without Capmatinib, a selective ATP-inhibitor of MET. HGF concentration in vitro was measured with ELISA. Relative gene expression was quantified from PD-MSCs by quantitative reverse transcription real-time polymerase chain reaction. RESULTS: Immunohistochemistry detected co-localization of HGF and MET protein in PP. HGF protein levels were significantly higher (P < 0.05) in osteogenic media (day 21: 12.19 ± 8.36 ng/mL) than in E8 medium (day 21: 0.42 ± 0.72 ng/mL). MET inhibitor had a limited feedback effect on the expression profile of the osteogenic genes tested. Gene expression levels for all but three genes were comparable in serum-free and osteogenic media at all time points. CONCLUSION: HGF/MET present in human PP and HGF is upregulated in vitro during osteogenesis; however the targeted pathways controlled by MET may not involve osteoblast maturation.


Assuntos
Fator de Crescimento de Hepatócito/metabolismo , Células-Tronco Mesenquimais , Osteogênese , Proteínas Proto-Oncogênicas c-met/metabolismo , Diferenciação Celular , Células Cultivadas , Humanos , Periósteo
6.
Anticancer Res ; 41(9): 4377-4385, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475057

RESUMO

BACKGROUND/AIM: Expression of pleckstrin homology-like domain family A member 2 (PHLDA2) has been reported to be suppressed or activated in several cases of malignant tumors. However, its apoptotic regulatory mechanism and role in gastric cancer are not understood. This study examined the role of PHLDA2 in apoptosis in gastric cancer. MATERIALS AND METHODS: We used cell culture, western blotting, semiquantitative reverse transcription polymerase chain reaction, MTT assays, and PHLDA2 knockdown with short hairpin RNA (shRNA). RESULTS: To identify the pathway associated with HGF-induced PHLDA2 up-regulation, the cells were treated with PI3-kinase inhibitor (LY294002), MEK inhibitor (PD098059), or p38 inhibitor (SB203580) and then analyzed by western blotting. HGF-mediated changes in PHLDA2 protein levels were only decreased by LY294002. PHLDA2-shRNA cells showed decreased levels of p53 and increased levels of pAKT. Furthermore, HGF-induced cell proliferation and in vitro invasion were increased in PHLDA2 knockdown cells and HGF-induced cell apoptosis was increased in PHLDA2 knockdown cells. CONCLUSION: PHLDA2 plays a role in gastric cancer tumorigenesis by inhibiting apoptosis through the PI3K/AKT pathway.


Assuntos
Fator de Crescimento de Hepatócito/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Gástricas/metabolismo , Regulação para Cima , Apoptose , Linhagem Celular Tumoral , Cromonas/farmacologia , Flavonoides/farmacologia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Imidazóis , Morfolinas/farmacologia , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Piridinas
7.
Elife ; 102021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34590584

RESUMO

Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that targets Wnt receptors for ubiquitination and lysosomal degradation. Previously, we showed that dephosphorylation of an endocytic tyrosine motif (4Y motif) in ZNRF3 by protein tyrosine phosphatase receptor-type kappa (PTPRK) promotes ZNRF3 internalization and Wnt receptor degradation (Chang et al 2020). However, a responsible protein tyrosine kinase(s) (PTK) phosphorylating the 4Y motif remained elusive. Here we identify the proto-oncogene MET (mesenchymal-epithelial transition factor) as a 4Y kinase. MET binds to ZNRF3 and induces 4Y phosphorylation, stimulated by the MET ligand HGF (hepatocyte growth factor, scatter factor). HGF-MET signaling reduces ZNRF3-dependent Wnt receptor degradation thereby enhancing Wnt/ß-catenin signaling. Conversely, depletion or pharmacological inhibition of MET promotes the internalization of ZNRF3 and Wnt receptor degradation. We conclude that HGF-MET signaling phosphorylates- and PTPRK dephosphorylates ZNRF3 to regulate ZNRF3 internalization, functioning as a rheostat for Wnt signaling that may offer novel opportunities for therapeutic intervention.


Assuntos
Adenocarcinoma de Pulmão/enzimologia , Neoplasias Pulmonares/enzimologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Linhagem Celular Tumoral , Endocitose , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Fosforilação , Transporte Proteico , Proteólise , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Receptores Wnt/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Proteínas Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacos
8.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502141

RESUMO

NK1, a splicing variant of hepatocyte growth factor (HGF), binds to and activates Met receptor by forming an NK1 dimer and 2:2 complex with Met. Although the structural mechanism underlying Met activation by HGF remains incompletely resolved, it has been proposed that the NK1 dimer structure participates in this activation. We investigated the NK1 dimer interface's role in Met activation by HGF. Because N127, V140, and K144 are closely involved in the head-to-tail NK1 dimer formation, mutant NK1 proteins with replacement of these residues by alanine were prepared. In Met tyrosine phosphorylation assays, N127-NK1, V140-NK1, and K144-NK1 showed 8.3%, 23.8%, and 52.2% activity, respectively, compared with wild-type NK1. Although wild-type NK1 promoted cell migration and scattering, N127-NK1, V140-NK1, and K144-NK1 hardly or marginally promoted them, indicating loss of activity of these mutant NK1 proteins to activate Met. In contrast, mutant HGFs (N127-HGF, V140-HGF, and K144-HGF) with the same amino acid replacements as in NK1 induced Met tyrosine phosphorylation and biological responses at levels comparable to those of wild-type HGF. These results indicate that the structural basis responsible for NK1-dependent Met dimer formation and activation differs from, or is at least distinguishable from, the structural basis responsible for HGF-dependent Met activation.


Assuntos
Fator de Crescimento de Hepatócito/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Cães , Células HEK293 , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Células Madin Darby de Rim Canino , Mutação , Ligação Proteica , Multimerização Proteica , Proteínas Proto-Oncogênicas c-met/química , Transdução de Sinais
9.
J Biol Chem ; 297(3): 101079, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34391780

RESUMO

Phosphorylation (activation) and dephosphorylation (deactivation) of the slit diaphragm proteins NEPHRIN and NEPH1 are critical for maintaining the kidney epithelial podocyte actin cytoskeleton and, therefore, proper glomerular filtration. However, the mechanisms underlying these events remain largely unknown. Here we show that NEPHRIN and NEPH1 are novel receptor proteins for hepatocyte growth factor (HGF) and can be phosphorylated independently of the mesenchymal epithelial transition receptor in a ligand-dependent fashion through engagement of their extracellular domains by HGF. Furthermore, we demonstrate SH2 domain-containing protein tyrosine phosphatase-2-dependent dephosphorylation of these proteins. To establish HGF as a ligand, purified baculovirus-expressed NEPHRIN and NEPH1 recombinant proteins were used in surface plasma resonance binding experiments. We report high-affinity interactions of NEPHRIN and NEPH1 with HGF, although NEPHRIN binding was 20-fold higher than that of NEPH1. In addition, using molecular modeling we constructed peptides that were used to map specific HGF-binding regions in the extracellular domains of NEPHRIN and NEPH1. Finally, using an in vitro model of cultured podocytes and an ex vivo model of Drosophila nephrocytes, as well as chemically induced injury models, we demonstrated that HGF-induced phosphorylation of NEPHRIN and NEPH1 is centrally involved in podocyte repair. Taken together, this is the first study demonstrating a receptor-based function for NEPHRIN and NEPH1. This has important biological and clinical implications for the repair of injured podocytes and the maintenance of podocyte integrity.


Assuntos
Fator de Crescimento de Hepatócito/metabolismo , Proteínas de Membrana/metabolismo , Animais , Linhagem Celular , Taxa de Filtração Glomerular/fisiologia , Fator de Crescimento de Hepatócito/fisiologia , Humanos , Junções Intercelulares/metabolismo , Rim/patologia , Glomérulos Renais/metabolismo , Proteínas de Membrana/genética , Camundongos , Peptídeos/metabolismo , Fosforilação , Podócitos/metabolismo , Ligação Proteica/fisiologia , Transdução de Sinais/fisiologia
10.
Front Immunol ; 12: 678661, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335580

RESUMO

Background: Chronic obstructive pulmonary disease (COPD) is associated with increased risk of severe COVID-19, but the mechanisms are unclear. Besides, patients with severe COVID-19 have been reported to have increased levels of several immune mediators. Methods: Ninety-two proteins were quantified in 315 plasma samples from 118 asthmatics, 99 COPD patients and 98 healthy controls (age 40-90 years), who were recruited in Colombia before the COVID-19 pandemic. Protein levels were compared between each disease group and healthy controls. Significant proteins were compared to the gene signatures of SARS-CoV-2 infection reported in the "COVID-19 Drug and Gene Set Library" and with experimentally tested protein biomarkers of severe COVID-19. Results: Forty-one plasma proteins showed differences between patients and controls. Asthmatic patients have increased levels in IL-6 while COPD patients have a broader systemic inflammatory dysregulation driven by HGF, OPG, and several chemokines (CXCL9, CXCL10, CXCL11, CX3CL1, CXCL1, MCP-3, MCP-4, CCL3, CCL4 and CCL11). These proteins are involved in chemokine signaling pathways related with response to viral infections and some, were found up-regulated upon SARS-CoV-2 experimental infection of Calu-3 cells as reported in the COVID-19 Related Gene Sets database. An increase of HPG, CXCL9, CXCL10, IL-6, MCP-3, TNF and EN-RAGE has also been experimentally detected in patients with severe COVID-19. Conclusions: COPD patients have altered levels of plasma proteins that have been reported increased in patients with severe COVID-19. Our study suggests that COPD patients have a systemic dysregulation in chemokine networks (including HGF and CXCL9) that could make them more susceptible to severe COVID-19. Also, that IL-6 levels are increased in some asthmatic patients (especially in females) and this may influence their response to COVID-19. The findings in this study depict a novel panel of inflammatory plasma proteins in COPD patients that may potentially associate with increased susceptibility to severe COVID-19 and might be useful as a biomarker signature after future experimental validation.


Assuntos
Asma/imunologia , COVID-19/imunologia , Mediadores da Inflamação/sangue , Doença Pulmonar Obstrutiva Crônica/imunologia , SARS-CoV-2/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/diagnóstico , Biomarcadores/sangue , COVID-19/diagnóstico , Quimiocina CXCL9/sangue , Feminino , Fator de Crescimento de Hepatócito/sangue , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Índice de Gravidade de Doença , Regulação para Cima
11.
Nat Commun ; 12(1): 4888, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373466

RESUMO

The objective of the present study was to identify biological signatures of severe coronavirus disease 2019 (COVID-19) predictive of admission in the intensive care unit (ICU). Over 170 immunological markers were investigated in a 'discovery' cohort (n = 98 patients) of the Lausanne University Hospital (LUH-1). Here we report that 13 out of 49 cytokines were significantly associated with ICU admission in the three cohorts (P < 0.05 to P < 0.001), while cellular immunological markers lacked power in discriminating between ICU and non-ICU patients. The cytokine results were confirmed in two 'validation' cohorts, i.e. the French COVID-19 Study (FCS; n = 62) and a second LUH-2 cohort (n = 47). The combination of hepatocyte growth factor (HGF) and C-X-C motif chemokine ligand 13 (CXCL13) was the best predictor of ICU admission (positive and negative predictive values ranging from 81.8% to 93.1% and 85.2% to 94.4% in the 3 cohorts) and occurrence of death during patient follow-up (8.8 fold higher likelihood of death when both cytokines were increased). Of note, HGF is a pleiotropic cytokine with anti-inflammatory properties playing a fundamental role in lung tissue repair, and CXCL13, a pro-inflammatory chemokine associated with pulmonary fibrosis and regulating the maturation of B cell response. Up-regulation of HGF reflects the most powerful counter-regulatory mechanism of the host immune response to antagonize the pro-inflammatory cytokines including CXCL13 and to prevent lung fibrosis in COVID-19 patients.


Assuntos
COVID-19/imunologia , COVID-19/mortalidade , Quimiocina CXCL13/imunologia , Citocinas/imunologia , Fator de Crescimento de Hepatócito/imunologia , Biomarcadores/sangue , Linfócitos T CD4-Positivos , COVID-19/sangue , COVID-19/diagnóstico , Quimiocina CXCL13/genética , Citocinas/sangue , Fator de Crescimento de Hepatócito/genética , Hospitalização , Humanos , Unidades de Terapia Intensiva , Fibrose Pulmonar , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
12.
Nat Commun ; 12(1): 5006, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408135

RESUMO

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.


Assuntos
Tecido Adiposo/citologia , Reprogramação Celular , Neoplasias do Colo/fisiopatologia , Células-Tronco Neoplásicas/citologia , Nicho de Células-Tronco , Tecido Adiposo/metabolismo , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica , Células-Tronco/citologia , Células-Tronco/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
13.
Cells ; 10(7)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34359843

RESUMO

Glomerulonephritis are renal inflammatory processes characterized by increased permeability of the Glomerular Filtration Barrier (GFB) with consequent hematuria and proteinuria. Glomerular endothelial cells (GEC) and podocytes are part of the GFB and contribute to the maintenance of its structural and functional integrity through the release of paracrine mediators. Activation of the complement cascade and pro-inflammatory cytokines (CK) such as Tumor Necrosis Factor α (TNF-α) and Interleukin-6 (IL-6) can alter GFB function, causing acute glomerular injury and progression toward chronic kidney disease. Endothelial Progenitor Cells (EPC) are bone-marrow-derived hematopoietic stem cells circulating in peripheral blood and able to induce angiogenesis and to repair injured endothelium by releasing paracrine mediators including Extracellular Vesicles (EVs), microparticles involved in intercellular communication by transferring proteins, lipids, and genetic material (mRNA, microRNA, lncRNA) to target cells. We have previously demonstrated that EPC-derived EVs activate an angiogenic program in quiescent endothelial cells and renoprotection in different experimental models. The aim of the present study was to evaluate in vitro the protective effect of EPC-derived EVs on GECs and podocytes cultured in detrimental conditions with CKs (TNF-α/IL-6) and the complement protein C5a. EVs were internalized in both GECs and podocytes mainly through a L-selectin-based mechanism. In GECs, EVs enhanced the formation of capillary-like structures and cell migration by modulating gene expression and inducing the release of growth factors such as VEGF-A and HGF. In the presence of CKs, and C5a, EPC-derived EVs protected GECs from apoptosis by decreasing oxidative stress and prevented leukocyte adhesion by inhibiting the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin). On podocytes, EVs inhibited apoptosis and prevented nephrin shedding induced by CKs and C5a. In a co-culture model of GECs/podocytes that mimicked GFB, EPC-derived EVs protected cell function and permeselectivity from inflammatory-mediated damage. Moreover, RNase pre-treatment of EVs abrogated their protective effects, suggesting the crucial role of RNA transfer from EVs to damaged glomerular cells. In conclusion, EPC-derived EVs preserved GFB integrity from complement- and cytokine-induced damage, suggesting their potential role as therapeutic agents for drug-resistant glomerulonephritis.


Assuntos
Complemento C5a/farmacologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Interleucina-6/farmacologia , Podócitos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/metabolismo , Vesículas Extracelulares/química , Regulação da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Selectina L/genética , Selectina L/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Comunicação Parácrina/efeitos dos fármacos , Podócitos/citologia , Podócitos/metabolismo , Cultura Primária de Células , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Elife ; 102021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34350830

RESUMO

Acute skeletal muscle injury is followed by an inflammatory response, removal of damaged tissue, and the generation of new muscle fibers by resident muscle stem cells, a process well characterized in murine injury models. Inflammatory cells are needed to remove the debris at the site of injury and provide signals that are beneficial for repair. However, they also release chemokines, reactive oxygen species, as well as enzymes for clearance of damaged cells and fibers, which muscle stem cells have to withstand in order to regenerate the muscle. We show here that MET and CXCR4 cooperate to protect muscle stem cells against the adverse environment encountered during muscle repair. This powerful cyto-protective role was revealed by the genetic ablation of Met and Cxcr4 in muscle stem cells of mice, which resulted in severe apoptosis during early stages of regeneration. TNFα neutralizing antibodies rescued the apoptosis, indicating that TNFα provides crucial cell-death signals during muscle repair that are counteracted by MET and CXCR4. We conclude that muscle stem cells require MET and CXCR4 to protect them against the harsh inflammatory environment encountered in an acute muscle injury.


Assuntos
Fator de Crescimento de Hepatócito/genética , Inflamação/fisiopatologia , Fibras Musculares Esqueléticas/fisiologia , Receptores CXCR4/genética , Regeneração , Células-Tronco/fisiologia , Animais , Fator de Crescimento de Hepatócito/metabolismo , Camundongos , Músculo Esquelético/fisiologia , Receptores CXCR4/metabolismo
15.
Pediatr Surg Int ; 37(12): 1743-1753, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34448078

RESUMO

PURPOSE: Total parental nutrition (TPN) causes gastrointestinal mucosal atrophy. The present study investigated the effects of hepatocyte growth factor (HGF) on the intestinal mucosal atrophy induced by TPN. METHODS: Rats underwent jugular vein catheterization and were divided into four groups: oral feeding (OF), TPN alone (TPN), TPN plus low-dose HGF (0.3 mg/kg/day; TPNLH), and TPN plus high-dose HGF (1.0 mg/kg/day; TPNHH). On day 7, rats were euthanized, and the small intestine was harvested and evaluated histologically. The expression of c-MET, a receptor of HGF, and nutrition transporter protein were evaluated using quantitative polymerase chain reaction. RESULTS: The jejunal villus height (VH) and absorptive mucosal surface area in the TPNHH group were significantly higher than in the TPN group (p < 0.05). The VH in the ileum showed the same trend only in the TPNHH group, albeit without statistical significance. The crypt cell proliferation rate (CCPR) of the jejunum in both HGF-treated groups was significantly higher than in the TPN group (p < 0.01). The expression of c-MET and transporter protein in all TPN-treated groups was decreased compared with that in the OF group. CONCLUSION: HGF attenuated TPN-associated intestinal mucosal atrophy by increasing the villus height, which was associated with an increase in CCPR.


Assuntos
Fator de Crescimento de Hepatócito , Nutrição Parenteral Total , Animais , Atrofia , Mucosa Intestinal/patologia , Jejuno , Nutrição Parenteral Total/efeitos adversos , Ratos
16.
FASEB J ; 35(8): e21775, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245621

RESUMO

Innervation sustains cornea integrity. Pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) regenerated damaged nerves by stimulating the synthesis of a new stereoisomer of Resolvin D6 (RvD6si). Here, we resolved the structure of this lipid isolated from mouse tears after injured corneas were treated with PEDF + DHA. RvD6si synthesis was inhibited by fluvoxamine, a cytochrome P450 inhibitor, but not by 15- or 5-LOX inhibitors, suggesting that the 4- and 17-hydroxy of DHA have an RR- or SR-configuration. The two compounds were chemically synthesized. Using chiral phase HPLC, four peaks of RvD6si1-4 from tears were resolved. The RR-RvD6 standard eluted as a single peak with RvD61 while pure SR-RvD6 eluted with RvD63 . The addition of these pure mediators prompted a trigeminal ganglion transcriptome response in injured corneas and showed that RR-RvD6 was the more potent, increasing cornea sensitivity and nerve regeneration. RR-RvD6 stimulates Rictor and hepatocyte growth factor (hgf) genes specifically as upstream regulators and a gene network involved in axon growth and suppression of neuropathic pain, indicating a novel function of this lipid mediator to maintain cornea integrity and homeostasis after injury.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Regeneração Nervosa , Nervo Trigêmeo/fisiologia , Animais , Fluvoxamina/farmacologia , Fator de Crescimento de Hepatócito/metabolismo , Masculino , Camundongos , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
17.
Nat Commun ; 12(1): 4074, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210960

RESUMO

The c-MET receptor is a receptor tyrosine kinase (RTK) that plays essential roles in normal cell development and motility. Aberrant activation of c-MET can lead to both tumors growth and metastatic progression of cancer cells. C-MET can be activated by either hepatocyte growth factor (HGF), or its natural isoform NK1. Here, we report the cryo-EM structures of c-MET/HGF and c-MET/NK1 complexes in the active state. The c-MET/HGF complex structure reveals that, by utilizing two distinct interfaces, one HGF molecule is sufficient to induce a specific dimerization mode of c-MET for receptor activation. The binding of heparin as well as a second HGF to the 2:1 c-MET:HGF complex further stabilize this active conformation. Distinct to HGF, NK1 forms a stable dimer, and bridges two c-METs in a symmetrical manner for activation. Collectively, our studies provide structural insights into the activation mechanisms of c-MET, and reveal how two isoforms of the same ligand use dramatically different mechanisms to activate the receptor.


Assuntos
Fator de Crescimento de Hepatócito/química , Fator de Crescimento de Hepatócito/metabolismo , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Linhagem Celular , Microscopia Crioeletrônica , Células HEK293 , Heparina/metabolismo , Humanos , Ligantes , Modelos Moleculares , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Isoformas de Proteínas/metabolismo , Receptores da Neurocinina-1/metabolismo
18.
J Oral Biosci ; 63(3): 245-252, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34303825

RESUMO

OBJECTIVES: Periodontitis is a chronic inflammatory process associated with the loss of tooth-supporting tissue. The imbalance of epithelial-mesenchymal signaling is considered to drive disease progression, and hepatocyte growth factor (HGF) is one of the main mediators of this interaction. The aim of this study was to validate the role of HGF in the pathogenesis of periodontitis and to evaluate the effects of anti-HGF neutralizing antibodies. METHODS: Gingival tissues from cynomolgus monkeys, which naturally develop severe periodontitis, were isolated to establish an in vitro periodontitis model. Periodontitis-affected monkeys were treated by gingival injection of anti-HGF neutralizing antibodies. The therapeutic effects were documented by clinical examination (probing depth and bleeding on probing), histological examination of tissue, and reevaluation of gingival fibroblasts in the in vitro model. RESULTS: Periodontitis-affected monkeys contain periodontitis-associated fibroblasts (PAFs) with a pro-inflammatory phenotype that induced pronounced collagen degradation in vitro. This degradation was effectively inhibited by anti-HGF-neutralizing antibodies. Locally administered anti-HGF antibody to monkey gingiva clinically improved the severity of periodontitis. This was also reflected in the tissue histology with lower inflammatory cell infiltrates in treated gingiva than in non-treated gingiva. Moreover, fibroblasts isolated from anti-HGF-treated gingiva demonstrated reduced collagen degradation capacity. CONCLUSIONS: Our study confirmed the central role of HGF in the pathogenesis of severe periodontitis in relevant in vitro and in vivo models. The positive effect of anti-HGF treatment provides a strong rationale for the use of anti-HGF-neutralizing antibodies for the treatment of human periodontitis.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Fator de Crescimento de Hepatócito , Periodontite , Animais , Células Cultivadas , Gengiva , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Macaca fascicularis , Periodontite/tratamento farmacológico
19.
Angew Chem Int Ed Engl ; 60(42): 22745-22752, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34142433

RESUMO

Designing synthetic surrogates of functional proteins is an important, albeit challenging, task in the field of chemistry. A strategy toward the design of synthetic agonists for growth factor or cytokine receptors that elicit a desired signal activity has been in high demand, as such ligands hold great promise as safer and more effective therapeutics. In the present study, we used a DNA aptamer as a building block and described the strategy-guided design of a synthetic receptor agonist with fine-tuned agonism. The developed synthetic partial agonist can regulate therapeutically relevant cellular activities by eliciting fine-tuned receptor signaling.


Assuntos
Aptâmeros de Nucleotídeos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/agonistas , Receptores de Citocinas/agonistas , Células A549 , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Movimento Celular/efeitos dos fármacos , Dimerização , Fator de Crescimento de Hepatócito/agonistas , Fator de Crescimento de Hepatócito/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ligantes , Microscopia de Fluorescência , Ligação Proteica , Proteínas Proto-Oncogênicas c-met/agonistas , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores de Citocinas/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Molecules ; 26(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068164

RESUMO

Astragaloside IV (AS-IV) is one of the major bio-active ingredients of huang qi which is the dried root of Astragalus membranaceus (a traditional Chinese medicinal plant). The pharmacological effects of AS-IV, including anti-oxidative, anti-cancer, and anti-diabetic effects have been actively studied, however, the effects of AS-IV on liver regeneration have not yet been fully described. Thus, the aim of this study was to explore the effects of AS-IV on regenerating liver after 70% partial hepatectomy (PHx) in rats. Differentially expressed mRNAs, proliferative marker and growth factors were analyzed. AS-IV (10 mg/kg) was administrated orally 2 h before surgery. We found 20 core genes showed effects of AS-IV, many of which were involved with functions related to DNA replication during cell division. AS-IV down-regulates MAPK signaling, PI3/Akt signaling, and cell cycle pathway. Hepatocyte growth factor (HGF) and cyclin D1 expression were also decreased by AS-IV administration. Transforming growth factor ß1 (TGFß1, growth regulation signal) was slightly increased. In short, AS-IV down-regulated proliferative signals and genes related to DNA replication. In conclusion, AS-IV showed anti-proliferative activity in regenerating liver tissue after 70% PHx.


Assuntos
Ciclo Celular , Replicação do DNA , Regulação para Baixo , Hepatectomia , Regeneração Hepática/efeitos dos fármacos , Fígado/citologia , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Replicação do DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Fator de Crescimento de Hepatócito/metabolismo , Fígado/efeitos dos fármacos , Fígado/cirurgia , Masculino , Anotação de Sequência Molecular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Saponinas/química , Análise de Sequência de RNA , Fator de Crescimento Transformador beta1/metabolismo , Triterpenos/química
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