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1.
Anticancer Res ; 41(7): 3519-3522, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230147

RESUMO

BACKGROUND/AIM: Electrochemotherapy (ECT) is a predominately palliative treatment for cutaneous metastases where an electric field is used to increase the intracellular accumulation of a chemotherapeutic drug (bleomycin or cisplatin). ECT induces a strong anti-vascular effect and endothelial cells seem especially vulnerable. To date, almost no neurological and/or cerebrovascular complications after ECT treatment have been published. In this paper two such cases are reported. CASE REPORT: A seizure in a man treated with ECT for a basal cell carcinoma in the temporal region and a fatal ischemic stroke in a woman treated for cutaneous metastases in the neck are reported. In both cases a causal relationship to ECT treatment was strongly suspected. CONCLUSION: ECT in the head and neck can potentially cause severe neurological complications. Ultrasound is recommended for ECT treatment in the neck.


Assuntos
Carcinoma Basocelular/tratamento farmacológico , Eletroquimioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Cabeça/patologia , Pescoço/patologia , Doenças do Sistema Nervoso/induzido quimicamente , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Doenças do Sistema Nervoso/patologia , Neoplasias Cutâneas/patologia
2.
Arch Iran Med ; 24(5): 419-426, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196208

RESUMO

BACKGROUND: The pathogenesis of the COVID19 pandemic, that has killed one million nine hundred people and infected more the 90 million until end of 2020, has been studied by many researchers. Here, we try to explain its biological behavior based on our recent autopsy information and review of literature. METHODS: In this study, patients with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result were considered eligible for enrollment. Histopathological examinations were done on 13 people who were hospitalized in Afzalipour hospital, Kerman, Iran. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry and electron microscopy. RESULTS: The most frequent co-morbidity in the patients was cardiovascular disease. The common initial symptoms of COVID-19 infection were dyspnea and cough. In all cases, the number of white blood cells was higher than the normal range. Common histopathological findings were variable degrees of vasculitis as degenerative to necrotic changes of endothelium and trafficking of inflammatory cells in the vessel wall with fibrinoid necrosis. Tissue damage included interstitial acute inflammatory cells reaction with degenerative to necrotic changes of the parenchymal cells. CD34 and Factor VIII immunohistochemistry staining showed endothelial cell degeneration to necrosis at the vessel wall and infiltration by inflammatory cells. Electron microscopic features confirmed the degenerative damages in the endothelial cells. CONCLUSION: Our histopathological studies suggest that the main focus of the viral damage is the endothelial cells (endotheliopathica) in involved organs. Also, our findings suggest that degeneration of leukocytes occurs at the site of inflammation and release of cytokines (leukocytoclastica) resulting in a cytokine storm.


Assuntos
COVID-19/complicações , COVID-19/patologia , Células Endoteliais/patologia , Leucócitos/patologia , Adulto , Idoso , COVID-19/metabolismo , Estudos de Coortes , Citocinas/metabolismo , Feminino , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Pericardite/patologia , Pericardite/virologia , Dermatopatias/patologia , Dermatopatias/virologia
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(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204159

RESUMO

By upregulation of cell adhesion molecules and secretion of proinflammatory cytokines, cells of the neurovascular unit, including pericytes and endothelial cells, actively participate in neuroinflammatory reactions. As previously shown, both cell types can activate inflammasomes, cerebral endothelial cells (CECs) through the canonical pathway, while pericytes only through the noncanonical pathway. Using complex in vitro models, we demonstrate here that the noncanonical inflammasome pathway can be induced in CECs as well, leading to a further increase in the secretion of active interleukin-1ß over that observed in response to activation of the canonical pathway. In parallel, a more pronounced disruption of tight junctions takes place. We also show that CECs respond to inflammatory stimuli coming from both the apical/blood and the basolateral/brain directions. As a result, CECs can detect factors secreted by pericytes in which the noncanonical inflammasome pathway is activated and respond with inflammatory activation and impairment of the barrier properties. In addition, upon sensing inflammatory signals, CECs release inflammatory factors toward both the blood and the brain sides. Consequently, CECs activate pericytes by upregulating their expression of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), an inflammasome-forming pattern recognition receptor. In conclusion, cerebral pericytes and endothelial cells mutually activate each other in inflammation.


Assuntos
Encéfalo/patologia , Comunicação Celular , Células Endoteliais/patologia , Inflamassomos/metabolismo , Pericitos/patologia , Transdução de Sinais , Animais , Inflamação/metabolismo , Inflamação/patologia , Suínos , Junções Íntimas/metabolismo
5.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066474

RESUMO

Corneal endothelial dystrophy is a relevant cause of vision loss and corneal transplantation worldwide. In the present study, we analyzed the effect of mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) in an in vitro model of corneal dystrophy, characterized by endoplasmic reticulum stress. The effects of MSC-EVs were compared with those of serum-derived EVs, reported to display a pro-angiogenic activity. MSC-EVs were able to induce a significant down-regulation of the large majority of endoplasmic reticulum stress-related genes in human corneal endothelial cells after exposure to serum deprivation and tunicamycin. In parallel, they upregulated the Akt pathway and limited caspase-3 activation and apoptosis. At variance, the effect of the serum EVs was mainly limited to Akt phosphorylation, with minimal or absent effects on endoplasmic reticulum stress modulation and apoptosis prevention. The effects of MSC-EVs were correlated to the transfer of numerous endoplasmic reticulum (ER)-stress targeting miRNAs to corneal endothelial cells. These data suggest a potential therapeutic effect of MSC-EVs for corneal endothelial endoplasmic reticulum stress, a major player in corneal endothelial dystrophy.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Células Endoteliais/patologia , Epitélio Posterior/patologia , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Separação Celular , Meios de Cultura Livres de Soro , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Vesículas Extracelulares/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/metabolismo , Fosforilação/efeitos dos fármacos , Tunicamicina/farmacologia
6.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070558

RESUMO

Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with cardiovascular and metabolic dysfunction. However, the mechanisms underlying these morbidities remain poorly delineated. Extracellular vesicles (EVs) mediate intercellular communications, play pivotal roles in a multitude of physiological and pathological processes, and could mediate IH-induced cellular effects. Here, the effects of IH on human primary cells and the release of EVs were examined. Microvascular endothelial cells (HMVEC-d), THP1 monocytes, THP1 macrophages M0, THP1 macrophages M1, THP1 macrophages M2, pre-adipocytes, and differentiated adipocytes (HAd) were exposed to either room air (RA) or IH for 24 h. Secreted EVs were isolated and characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. The effects of each of the cell-derived EVs on endothelial cell (EC) monolayer barrier integrity, on naïve THP1 macrophage polarity, and on adipocyte insulin sensitivity were also evaluated. IH did not alter EVs cell quantal release, but IH-EVs derived from HMVEC-d (p < 0.01), THP1 M0 (p < 0.01) and HAd (p < 0.05) significantly disrupted HMVEC-d monolayer integrity, particularly after H2O2 pre-conditioning. IH-EVs from HMVEC-d and THP1 M0 elicited M2-polarity changes did not alter insulin sensitivity responses. IH induces cell-selective changes in EVs cargo, which primarily seem to target the emergence of endothelial dysfunction. Thus, changes in EVs cargo from selected cell sources in vivo may play causal roles in some of the adverse outcomes associated with OSA.


Assuntos
Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Hipóxia/metabolismo , Apneia Obstrutiva do Sono/metabolismo , Células Endoteliais/patologia , Vesículas Extracelulares/patologia , Humanos , Hipóxia/patologia , Apneia Obstrutiva do Sono/patologia , Células THP-1
7.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070679

RESUMO

Hemolytic uremic syndrome (HUS) is characterized by a triad of symptoms consisting of hemolytic anemia, thrombocytopenia and acute renal failure. The most common form of HUS is caused by an infection with Shiga toxin (Stx) producing Escherichia coli bacteria (STEC-HUS), and the kidneys are the major organs affected. The development of HUS after an infection with Stx occurs most frequently in children under the age of 5 years. However, the cause for the higher incidence of STEC-HUS in children compared to adults is still not well understood. Human glomerular microvascular endothelial cells (HGMVECs) isolated and cultured from pediatric and adult kidney tissue were investigated with respect to Stx binding and different cellular responses. Shiga toxin-1 (Stx-1) inhibited protein synthesis in both pediatric and adult HGMVECs in a dose-dependent manner at basal conditions. The preincubation of pediatric and adult HGMVECs for 24 hrs with TNFα resulted in increased Stx binding to the cell surface and a 20-40% increase in protein synthesis inhibition in both age groups. A decreased proliferation of cells was found when a bromodeoxyuridine (BrdU) assay was performed. A trend towards a delay in endothelial wound closure was visible when pediatric and adult HGMVECs were incubated with Stx-1. Although minor differences between pediatric HGMVECs and adult HGMVECs were found in the assays applied in this study, no significant differences were observed. In conclusion, we have demonstrated that in vitro primary HGMVECs isolated from pediatric and adult kidneys do not significantly differ in their cell biological responses to Stx-1.


Assuntos
Células Endoteliais/metabolismo , Mesângio Glomerular/metabolismo , Microvasos/metabolismo , Toxina Shiga I/toxicidade , Adulto , Células Cultivadas , Pré-Escolar , Relação Dose-Resposta a Droga , Células Endoteliais/patologia , Feminino , Mesângio Glomerular/patologia , Humanos , Masculino , Microvasos/patologia
8.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073212

RESUMO

In the 1900s, researchers established animal models experimentally to induce atherosclerosis by feeding them with a cholesterol-rich diet. It is now accepted that high circulating cholesterol is one of the main causes of atherosclerosis; however, plaque localization cannot be explained solely by hyperlipidemia. A tremendous amount of studies has demonstrated that hemodynamic forces modify endothelial athero-susceptibility phenotypes. Endothelial cells possess mechanosensors on the apical surface to detect a blood stream-induced force on the vessel wall, known as "wall shear stress (WSS)", and induce cellular and molecular responses. Investigations to elucidate the mechanisms of this process are on-going: on the one hand, hemodynamics in complex vessel systems have been described in detail, owing to the recent progress in imaging and computational techniques. On the other hand, investigations using unique in vitro chamber systems with various flow applications have enhanced the understanding of WSS-induced changes in endothelial cell function and the involvement of the glycocalyx, the apical surface layer of endothelial cells, in this process. In the clinical setting, attempts have been made to measure WSS and/or glycocalyx degradation non-invasively, for the purpose of their diagnostic utilization. An increasing body of evidence shows that WSS, as well as serum glycocalyx components, can serve as a predicting factor for atherosclerosis development and, most importantly, for the rupture of plaques in patients with high risk of coronary heart disease.


Assuntos
Doença da Artéria Coronariana , Circulação Coronária , Células Endoteliais , Placa Aterosclerótica , Resistência ao Cisalhamento , Estresse Mecânico , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Placa Aterosclerótica/fisiopatologia , Placa Aterosclerótica/terapia
9.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062897

RESUMO

Cancer is a phenomenon broadly related to ageing in various ways such as cell cycle deregulation, metabolic defects or telomerases dysfunction as principal processes. Although the tumor cell is the main actor in cancer progression, it is not the only element of the disease. Cells and the matrix surrounding the tumor, called the tumor microenvironment (TME), play key roles in cancer progression. Phenotypic changes of the TME are indispensable for disease progression and a few of these transformations are produced by epigenetic changes including miRNA dysregulation. In this study, we found that a specific group of miRNAs in the liver TME produced by colon cancer called geromiRs, which are miRNAs related to the ageing process, are significantly downregulated. The three principal cell types involved in the liver TME, namely, liver sinusoidal endothelial cells, hepatic stellate (Ito) cells and Kupffer cells, were isolated from a murine hepatic metastasis model, and the miRNA and gene expression profiles were studied. From the 115 geromiRs and their associated hallmarks of aging, which we compiled from the literature, 75 were represented in the used microarrays, 26 out of them were downregulated in the TME cells during colon cancer colonization of the liver, and none of them were upregulated. The histone modification hallmark of the downregulated geromiRs is significantly enriched with the geromiRs miR-15a, miR-16, miR-26a, miR-29a, miR-29b and miR-29c. We built a network of all of the geromiRs downregulated in the TME cells and their gene targets from the MirTarBase database, and we analyzed the expression of these geromiR gene targets in the TME. We found that Cercam and Spsb4, identified as prognostic markers in a few cancer types, are associated with downregulated geromiRs and are upregulated in the TME cells.


Assuntos
Neoplasias do Colo/genética , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , MicroRNAs/genética , Animais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica/genética , Células Estreladas do Fígado/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Macrófagos do Fígado/metabolismo , Macrófagos do Fígado/patologia , Fígado/patologia , Camundongos , MicroRNAs/classificação
10.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: covidwho-1227032

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) caused by the betacoronavirus SARS-CoV-2 is now a worldwide challenge for healthcare systems. Although the leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure due to viral pneumonia and acute respiratory distress syndrome, accumulating evidence has shown that the risk of thromboembolism is substantially high in patients with severe COVID-19 and that a thromboembolic event is another major complication contributing to the high morbidity and mortality in patients with COVID-19. Endothelial dysfunction is emerging as one of the main contributors to the pathogenesis of thromboembolic events in COVID-19. Endothelial dysfunction is usually referred to as reduced nitric oxide bioavailability. However, failures of the endothelium to control coagulation, inflammation, or permeability are also instances of endothelial dysfunction. Recent studies have indicated the possibility that SARS-CoV-2 can directly infect endothelial cells via the angiotensin-converting enzyme 2 pathway and that endothelial dysfunction caused by direct virus infection of endothelial cells may contribute to thrombotic complications and severe disease outcomes in patients with COVID-19. In this review, we summarize the current understanding of relationships between SARS-CoV-2 infection, endothelial dysfunction, and pulmonary and extrapulmonary complications in patients with COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/mortalidade , COVID-19/fisiopatologia , Citocinas/metabolismo , Células Endoteliais/virologia , Endotélio Vascular/virologia , Tromboembolia/virologia , COVID-19/complicações , COVID-19/virologia , Células Endoteliais/patologia , Endotélio Vascular/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Pulmão/patologia , Pulmão/virologia , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/patogenicidade , Tromboembolia/complicações
11.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066226

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) caused by the betacoronavirus SARS-CoV-2 is now a worldwide challenge for healthcare systems. Although the leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure due to viral pneumonia and acute respiratory distress syndrome, accumulating evidence has shown that the risk of thromboembolism is substantially high in patients with severe COVID-19 and that a thromboembolic event is another major complication contributing to the high morbidity and mortality in patients with COVID-19. Endothelial dysfunction is emerging as one of the main contributors to the pathogenesis of thromboembolic events in COVID-19. Endothelial dysfunction is usually referred to as reduced nitric oxide bioavailability. However, failures of the endothelium to control coagulation, inflammation, or permeability are also instances of endothelial dysfunction. Recent studies have indicated the possibility that SARS-CoV-2 can directly infect endothelial cells via the angiotensin-converting enzyme 2 pathway and that endothelial dysfunction caused by direct virus infection of endothelial cells may contribute to thrombotic complications and severe disease outcomes in patients with COVID-19. In this review, we summarize the current understanding of relationships between SARS-CoV-2 infection, endothelial dysfunction, and pulmonary and extrapulmonary complications in patients with COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/mortalidade , COVID-19/fisiopatologia , Citocinas/metabolismo , Células Endoteliais/virologia , Endotélio Vascular/virologia , Tromboembolia/virologia , COVID-19/complicações , COVID-19/virologia , Células Endoteliais/patologia , Endotélio Vascular/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Pulmão/patologia , Pulmão/virologia , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/patogenicidade , Tromboembolia/complicações
12.
Int J Mol Sci ; 22(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064331

RESUMO

Metastasis is the process whereby cancer cells migrate from the primary tumour site to colonise the surrounding or distant tissue or organ. Metastasis is the primary cause of cancer-related mortality and approximately half of all cancer patients present at diagnosis with some form of metastasis. Consequently, there is a clear need to better understand metastasis in order to develop new tools to combat this process. MicroRNAs (miRNAs) regulate gene expression and play an important role in cancer development and progression including in the metastatic process. Particularly important are the roles that miRNAs play in the interaction between tumour cells and non-tumoral cells of the tumour microenvironment (TME), a process mediated largely by circulating miRNAs contained primarily in extracellular vesicles (EVs). In this review, we outline the accumulating evidence for the importance of miRNAs in the communication between tumour cells and the cells of the TME in the context of the pre-metastatic and metastatic niche.


Assuntos
MicroRNAs/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , RNA Neoplásico/genética , Microambiente Tumoral/genética , Animais , Comunicação Celular , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , MicroRNAs/classificação , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Precursores de RNA/genética , Precursores de RNA/metabolismo , RNA Neoplásico/metabolismo , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
13.
Int J Mol Sci ; 22(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064508

RESUMO

During tumor growth, angiogenesis is required to ensure oxygen and nutrient transport to the tumor. Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and appears to be a key modulator of the anti-tumor immune response. Indeed, VEGF modulates innate and adaptive immune responses through direct interactions and indirectly by modulating protein expressions on endothelial cells or vascular permeability. The inhibition of the VEGF signaling pathway is clinically approved for the treatment of several cancers. Therapies targeting VEGF can modulate the tumor vasculature and the immune response. In this review, we discuss the roles of VEGF in the anti-tumor immune response. In addition, we summarize therapeutic strategies based on its inhibition, and their clinical approval.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Fatores Imunológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Imunidade Adaptativa/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab/uso terapêutico , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Inata/efeitos dos fármacos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Transdução de Sinais , Sorafenibe/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/imunologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/imunologia
14.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072943

RESUMO

Coronary artery disease remains one of the primary healthcare problems due to the high cost of treatment, increased number of patients, poor clinical outcomes, and lack of effective therapy. Though pharmacological and surgical treatments positively affect symptoms and arrest the disease progression, they generally exhibit a limited effect on the disease outcome. The development of alternative therapeutic approaches towards ischemic disease treatment, especially of decompensated forms, is therefore relevant. Therapeutic angiogenesis, stimulated by various cytokines, chemokines, and growth factors, provides the possibility of restoring functional blood flow in ischemic tissues, thereby ensuring the regeneration of the damaged area. In the current study, based on the clinically approved plasmid vector pVax1, multigenic constructs were developed encoding vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF2), and the DsRed fluorescent protein, integrated via picornaviruses' furin-2A peptide sequences. In vitro experiments demonstrated that genetically modified cells with engineered plasmid constructs expressed the target proteins. Overexpression of VEGF and FGF2 resulted in increased levels of the recombinant proteins. Concomitantly, these did not lead to a significant shift in the general secretory profile of modified HEK293T cells. Simultaneously, the secretome of genetically modified cells showed significant stimulating effects on the formation of capillary-like structures by HUVEC (endothelial cells) in vitro. Our results revealed that when the multicistronic multigene vectors encoding 2A peptide sequences are created, transient transgene co-expression is ensured. The results obtained indicated the mutual synergistic effects of the growth factors VEGF and FGF2 on the proliferation of endothelial cells in vitro. Thus, recombinant multicistronic multigenic constructs might serve as a promising approach for establishing safe and effective systems to treat ischemic diseases.


Assuntos
Doença da Artéria Coronariana/genética , Fator 2 de Crescimento de Fibroblastos/genética , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/genética , Indutores da Angiogênese/farmacologia , Proliferação de Células/genética , Doença da Artéria Coronariana/terapia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Furina/genética , Regulação da Expressão Gênica/genética , Genes/genética , Vetores Genéticos , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Patológica/terapia , Neovascularização Fisiológica/genética , Peptídeos/genética , Peptídeos/farmacologia , Plasmídeos/genética , Plasmídeos/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia
15.
Nat Commun ; 12(1): 3279, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078883

RESUMO

Targeting the molecular pathways underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin (Dox) could reduce the morbidity and mortality associated with these anticancer treatments. Here, we find that vascular endothelial cells (ECs) with persistent DNA damage induced by irradiation and Dox treatment exhibit a fibrotic phenotype (endothelial-mesenchymal transition, EndMT) correlating with the colocalization of L1CAM and persistent DNA damage foci. We demonstrate that treatment with the anti-L1CAM antibody Ab417 decreases L1CAM overexpression and nuclear translocation and persistent DNA damage foci. We show that in whole-heart-irradiated mice, EC-specific p53 deletion increases vascular fibrosis and the colocalization of L1CAM and DNA damage foci, while Ab417 attenuates these effects. We also demonstrate that Ab417 prevents cardiac dysfunction-related decrease in fractional shortening and prolongs survival after whole-heart irradiation or Dox treatment. We show that cardiomyopathy patient-derived cardiovascular ECs with persistent DNA damage show upregulated L1CAM and EndMT, indicating clinical applicability of Ab417. We conclude that controlling vascular DNA damage by inhibiting nuclear L1CAM translocation might effectively prevent anticancer therapy-associated cardiotoxicity.


Assuntos
Anticorpos Neutralizantes/farmacologia , Cardiomiopatias/prevenção & controle , Cardiotoxicidade/prevenção & controle , Doxorrubicina/toxicidade , Raios gama/efeitos adversos , Molécula L1 de Adesão de Célula Nervosa/genética , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Estudos de Casos e Controles , Técnicas de Cocultura , Dano ao DNA , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais/efeitos da radiação , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos da radiação , Molécula L1 de Adesão de Célula Nervosa/antagonistas & inibidores , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
16.
Int J Infect Dis ; 107: 232-233, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-1220255

RESUMO

The ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has been a formidable global challenge. As yet, there are very few drugs to treat this infection and no vaccine is currently available. It has gradually become apparant that coronavirus disease 2019 (COVID-19) is not a simple disease involving a single organ; rather, many vital organs and systems are affected. The endothelium is one target of SARS-CoV-2. Damaged endothelial cells, which break away from organs and enter the bloodstream to form circulating endothelial cells, were recently reported as putative biomarkers for COVID-19. Modulation of the expression level of sphingosine-1 phosphate via sphingosine kinase activation can control endothelial cell proliferation and apoptosis. As such, it may be possible to obtain a sensitive and specific diagnosis of the severity of COVID-19 by assessing the absolute number and the viable/apoptotic ratio of circulating endothelial cells. Furthermore, a focus on the endothelium could help to develop a strategy for COVID-19 treatment from the perspective of endothelial protection and repair.


Assuntos
COVID-19/diagnóstico , Células Endoteliais/patologia , SARS-CoV-2 , Biomarcadores , COVID-19/terapia , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Humanos , Lisofosfolipídeos/análise , Esfingosina/análogos & derivados , Esfingosina/análise
17.
Aging (Albany NY) ; 13(10): 14159-14169, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34015766

RESUMO

Atherosclerosis correlates with ischemic cardio-cerebrovascular diseases such as coronary heart disease. Long non-coding RNAs (lncRNAs) can promote atherosclerosis. We investigated the role of the lncRNA AK136714 in atherosclerosis. Compared with the healthy group, lncRNA AK136714 expression was elevated in the plaque and plasma of the atherosclerosis patients in a GEO dataset. AK136714 silencing inhibited atherosclerosis formation in ApoE-/- mice. AK136714 silencing also protected the endothelial barrier and inhibited endothelial cell inflammation. In vitro assays showed that knockdown of AK136714 suppressed the inflammatory response and apoptosis in human umbilical vein endothelial cells (HUVECs). Moreover, AK136714 was found to bind directly to HuR to increase the mRNA stability of TNF-α, IL-1ß and IL-6 mRNAs. In addition, AK136714 promoted the transcription of Bim. This study expands our understanding of the role of lncRNA AK136714 in atherosclerosis and provides potential drug targets for the treatment of atherosclerosis.


Assuntos
Aterosclerose/genética , Células Endoteliais/patologia , Inativação Gênica , RNA Longo não Codificante/metabolismo , Animais , Apoptose/genética , Aterosclerose/sangue , Proteína Semelhante a ELAV 1/metabolismo , Células Endoteliais/metabolismo , Proteína Forkhead Box O3/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Placa Aterosclerótica/sangue , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Ligação Proteica , RNA Longo não Codificante/genética
18.
Kidney Blood Press Res ; 46(3): 377-386, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34044409

RESUMO

INTRODUCTION: Cardiovascular disease is the most common cause of morbidity and mortality in patients with ESRD. In addition to phosphate overload, oxalate, a common uremic toxin, is also involved in vascular calcification in patients with ESRD. The present study investigated the role and mechanism of hyperoxalemia in vascular calcification in mice with uremia. METHODS: A uremic atherosclerosis (UA) model was established by left renal excision and right renal electrocoagulation in apoE-/- mice to investigate the relationship between oxalate loading and vascular calcification. After 12 weeks, serum and vascular levels of oxalate, vascular calcification, inflammatory factors (TNF-α and IL-6), oxidative stress markers (malondialdehyde [MDA], and advanced oxidation protein products [AOPP]) were assessed in UA mice. The oral oxalate-degrading microbe Oxalobacter formigenes (O. formigenes) was used to evaluate the effect of a reduction in oxalate levels on vascular calcification. The mechanism underlying the effect of oxalate loading on vascular calcification was assessed in cultured human aortic endothelial cells (HAECs) and human aortic smooth muscle cells (HASMCs). RESULTS: Serum oxalate levels were significantly increased in UA mice. Compared to the control mice, UA mice developed more areas of aortic calcification and showed significant increases in aortic oxalate levels and serum levels of oxidative stress markers and inflammatory factors. The correlation analysis showed that serum oxalate levels were positively correlated with the vascular oxalate levels and serum MDA, AOPP, and TNF-α levels, and negatively correlated with superoxide dismutase activity. The O. formigenes intervention decreased serum and vascular oxalate levels, while did not improve vascular calcification significantly. In addition, systemic inflammation and oxidative stress were also improved in the O. formigenes group. In vitro, high concentrations of oxalate dose-dependently increased oxidative stress and inflammatory factor expression in HAECs, but not in HASMCs. CONCLUSIONS: Our results indicated that hyperoxalemia led to the systemic inflammation and the activation of oxidative stress. The reduction in oxalate levels by O. formigenes might be a promising treatment for the prevention of oxalate deposition in calcified areas of patients with ESRD.


Assuntos
Células Endoteliais/patologia , Oxalatos/metabolismo , Estresse Oxidativo , Insuficiência Renal Crônica/patologia , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Linhagem Celular , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Humanos , Masculino , Camundongos , Insuficiência Renal Crônica/metabolismo , Uremia/metabolismo , Uremia/patologia , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia
19.
Int J Infect Dis ; 107: 232-233, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33965598

RESUMO

The ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has been a formidable global challenge. As yet, there are very few drugs to treat this infection and no vaccine is currently available. It has gradually become apparant that coronavirus disease 2019 (COVID-19) is not a simple disease involving a single organ; rather, many vital organs and systems are affected. The endothelium is one target of SARS-CoV-2. Damaged endothelial cells, which break away from organs and enter the bloodstream to form circulating endothelial cells, were recently reported as putative biomarkers for COVID-19. Modulation of the expression level of sphingosine-1 phosphate via sphingosine kinase activation can control endothelial cell proliferation and apoptosis. As such, it may be possible to obtain a sensitive and specific diagnosis of the severity of COVID-19 by assessing the absolute number and the viable/apoptotic ratio of circulating endothelial cells. Furthermore, a focus on the endothelium could help to develop a strategy for COVID-19 treatment from the perspective of endothelial protection and repair.


Assuntos
COVID-19/diagnóstico , Células Endoteliais/patologia , SARS-CoV-2 , Biomarcadores , COVID-19/terapia , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Humanos , Lisofosfolipídeos/análise , Esfingosina/análogos & derivados , Esfingosina/análise
20.
Cell Prolif ; 54(6): e13055, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33987885

RESUMO

OBJECTIVES: We aimed to investigate the underlying mechanism of endothelial cells (ECs) proliferation in anti-Thy-1 nephritis. MATERIALS AND METHODS: We established anti-Thy-1 nephritis and co-culture system to explore the underlying mechanism of ECs proliferation in vivo and in vitro. EdU assay kit was used for measuring cell proliferation. Immunohistochemical staining and immunofluorescence staining were used to detect protein expression. ELISA was used to measure the concentration of protein in serum and medium. RT-qPCR and Western blot were used to qualify the mRNA and protein expression. siRNA was used to knock down specific protein expression. RESULTS: In anti-Thy-1 nephritis, ECs proliferation was associated with mesangial cells (MCs)-derived vascular endothelial growth factor A (VEGFA) and ECs-derived angiopoietin2 (Angpt2). In vitro co-culture system activated MCs-expressed VEGFA to promote vascular endothelial growth factor receptor2 (VEGFR2) activation, Angpt2 expression and ECs proliferation, but inhibit TEK tyrosine kinase (Tie2) phosphorylation. MCs-derived VEGFA stimulated Angpt2 expression in ECs, which inhibited Tie2 phosphorylation and promoted ECs proliferation. And decline of Tie2 phosphorylation induced ECs proliferation. In anti-Thy-1 nephritis, promoting Tie2 phosphorylation could alleviate ECs proliferation. CONCLUSIONS: Our study showed that activated MCs promoted ECs proliferation through VEGFA/VEGFR2 and Angpt2/Tie2 pathway in experimental mesangial proliferative glomerulonephritis (MPGN) and in vitro co-culture system. And enhancing Tie2 phosphorylation could alleviate ECs proliferation, which will provide a new idea for MPGN treatment.


Assuntos
Células Endoteliais/patologia , Glomerulonefrite/patologia , Glomérulos Renais/patologia , Células Mesangiais/patologia , Transdução de Sinais , Antígenos Thy-1/antagonistas & inibidores , Angiopoietina-2/metabolismo , Animais , Anticorpos , Proliferação de Células , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/metabolismo , Glomérulos Renais/metabolismo , Masculino , Células Mesangiais/metabolismo , Ratos , Ratos Wistar , Receptor TIE-2/metabolismo , Antígenos Thy-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
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