RESUMO
BACKGROUND: The formation of scar tissue in the wound healing process is associated with fibroblasts that are produced during the proliferation phase (3-14 days after surgery/injury). One of the strategies to suppress the formation of excessive scar tissue is to use wound care material. The use of herbal extracts is currently being investigated by researchers, as it allows avoiding the side effects of synthetic drugs. The Hydnophytum formicarum extract has antioxidant and anti-inflammatory potential. OBJECTIVES: The aim of the study was to analyze the effects of the Hydnophytum formicarum plant extract on collagen density, angiogenesis, wound length, and re-epithelialization in wound healing. MATERIAL AND METHODS: Twenty-four Sprague-Dawley rats were divided into 2 groups: the control group; and the treatment group. Skin wounds were made on the dorsum of the rats, using the biopsy punch technique. Four rats from each group were sacrificed on days 4, 7 and 14 after injury. Collagen density, angiogenesis, wound length, and re-epithelialization were analyzed using hematoxylin and eosin (H&E) staining and Masson's trichrome staining. RESULTS: There were significant differences in the results of the angiogenesis analysis, wound length and re-epithelialization between the treatment and control groups. When considering angiogenesis, there were fewer vessels in the treatment group, but they were more mature as compared to the control group. There was also a meaningful interaction between the application of the Hydnophytum formicarum extract and the necropsy day with regard to collagen density and the re-epithelialization rate. No secondary infection was found in either group. CONCLUSIONS: The topical use of the Hydnophytum formicarum extract affected the formation of scar tissue, as indicated by the positive area of collagen, the extent of angiogenesis, wound length, and the re-epithelialization rate in the early, middle and final granulation phases. The inhibition of angiogenesis through the application of Hydnophytum formicarum was probably related to the formation of scar tissue in the wound.
Assuntos
Extratos Vegetais , Reepitelização , Moduladores da Angiogênese , Animais , Colágeno/metabolismo , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , CicatrizaçãoRESUMO
The chick embryo chorioallantoic membrane (CAM) is a rich vascularized extraembryonic membrane that is commonly used as an in vivo experimental model to study molecules with angiogenic and anti-angiogenic activity, tumor growth and metastasis. Among other applications of the CAM assay, more recently this assay has been used for the study of acellular scaffolds and of organoids, and of their angiogenic capacity. The aim of this review article is to summarize the literature data concerning these two new applications of the CAM assay and to underline the advantages of this assay.
Assuntos
Bioensaio , Membrana Corioalantoide/irrigação sanguínea , Neoplasias/irrigação sanguínea , Neovascularização Patológica , Neovascularização Fisiológica , Medicina Regenerativa , Alicerces Teciduais , Moduladores da Angiogênese/farmacologia , Animais , Metástase Neoplásica , Neoplasias/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Organoides , Carga TumoralRESUMO
The prevalence of peripheral arterial disease (PAD) in the United States exceeds 10 million people, and PAD is a significant cause of morbidity and mortality across the globe. PAD is typically caused by atherosclerotic obstructions in the large arteries to the leg(s). The most common clinical consequences of PAD include pain on walking (claudication), impaired functional capacity, pain at rest, and loss of tissue integrity in the distal limbs that may lead to lower extremity amputation. Patients with PAD also have higher than expected rates of myocardial infarction, stroke, and cardiovascular death. Despite advances in surgical and endovascular procedures, revascularization procedures may be suboptimal in relieving symptoms, and some patients with PAD cannot be treated because of comorbid conditions. In some cases, relieving obstructive disease in the large conduit arteries does not assure complete limb salvage because of severe microvascular disease. Despite several decades of investigational efforts, medical therapies to improve perfusion to the distal limb are of limited benefit. Whereas recent studies of anticoagulant (eg, rivaroxaban) and intensive lipid lowering (such as PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors) have reduced major cardiovascular and limb events in PAD populations, chronic ischemia of the limb remains largely resistant to medical therapy. Experimental approaches to improve limb outcomes have included the administration of angiogenic cytokines (either as recombinant protein or as gene therapy) as well as cell therapy. Although early angiogenesis and cell therapy studies were promising, these studies lacked sufficient control groups and larger randomized clinical trials have yet to achieve significant benefit. This review will focus on what has been learned to advance medical revascularization for PAD and how that information might lead to novel approaches for therapeutic angiogenesis and arteriogenesis for PAD.
Assuntos
Indutores da Angiogênese/uso terapêutico , Doença Arterial Periférica/terapia , Células-Tronco Adultas/transplante , Amputação Cirúrgica , Moduladores da Angiogênese/uso terapêutico , Animais , Anticoagulantes/uso terapêutico , Aterosclerose/complicações , Endotélio Vascular/metabolismo , Procedimentos Endovasculares , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Claudicação Intermitente/etiologia , Salvamento de Membro , Extremidade Inferior/irrigação sanguínea , Extremidade Inferior/cirurgia , Camundongos , Microcirculação , Infarto do Miocárdio/epidemiologia , Neovascularização Fisiológica/fisiologia , Doença Arterial Periférica/epidemiologia , Prevalência , Pró-Proteína Convertase 9 , RNA não Traduzido/uso terapêutico , Acidente Vascular Cerebral/epidemiologiaRESUMO
The goal of this study was to mechanistically analyze the effects of pre-treatment or post-treatment melatonin on the metastatic spread in a mice model. Consequently, the effects on the tumor growth, angiogenesis and metastasis were evaluated with immunohistochemical and western blot analysis. 8-10 weeks-old female BALB/c mice (n = 60, 10/group) were used. Liver metastatic cells (4TLM) from 4T1 murine breast carcinoma were previously isolated. Melatonin was administrated either before or after the injection of 4TLM cells into the mammary pad. Tumor and vehicle (%6 ethanol) injections were given to vehicle groups. Tumor group consisted of the mice injected with only 4TLM cells injected to tumor group and no intervention to control group. Necropsies were performed 27 days after injection of 4TLM. Primary tumors and metastatic tissues were removed. Furthermore, changes in lung and liver metastasis and primary tumor growth and angiogenesis were evaluated. In our study neutrophil levels were noted to be increased in peripheral blood of the tumor-bearing mice. Melatonin exerted inhibitory effects on the 4TLM-induced leukocytosis. Melatonin significantly decreased lung and liver metastasis, primary tumor growth and angiogenesis. The results demonstrated that melatonin might have a therapeutic role through reducing systemic inflammatory responses, metastasis, tumor growth and angiogenesis.
Assuntos
Moduladores da Angiogênese , Linhagem Celular Tumoral/efeitos dos fármacos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/fisiopatologia , Melatonina/farmacologia , Melatonina/uso terapêutico , Metástase Neoplásica/tratamento farmacológico , Animais , Células Cultivadas/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Semaphorins, the neuronal guidance cues, were shown to have broad influences on pathophysiological processes such as bone remodeling, immune responses, and angiogenesis. In particular, Class-3 Semaphorins (SEMA3) is considered a vital regulator involved in angiogenesis. Scientific evidence has pointed to the role of angiogenesis in many diseases, and numerous efforts have been made to explore the possibilities of curing those diseases by targeting angiogenesis. Nevertheless, the efficacies are limited owing to the complex mechanisms of angiogenesis. Hence, investigating the mechanisms of SEMA3 in angiogenesis may contribute to novel therapeutics for diseases. Previous reviews mainly focused on the various functions of semaphorins in one particular disease, and the specific angiogenesis mechanism of SEMA3 in diverse diseases has not been well elucidated. Additionally, the role of SEMA3 in angiogenesis remains elusive, as contradicting results have been found in different disease types. Some evidence from recent studies implies that, while most SEMA3 molecules inhibit pathological angiogenesis in different diseases, occasionally SEMA3 may also promote angiogenesis. This review summarizes the specific role of SEMA3 in a variety of angiogenesis-associated diseases, and documents SEMA3 may be a promising therapeutic target for treating angiogenesis-associated diseases.
Assuntos
Moduladores da Angiogênese , Neovascularização Patológica/genética , Semaforinas/genética , Indutores da Angiogênese/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Humanos , Transdução de SinaisRESUMO
Tumor angiogenesis plays a vital role in carcinogenesis, cancer progression, and metastasis. Lipoxin A4 (LXA4) is an endogenously-produced family of effective anti-inflammatory with a potent inhibitory effect on angiogenesis. However, BML-111, a LXA4 agonist, its governing tumor-derived endothelial cells (Td-EC) mechanisms remain unknown. In the present study, we utilized VEGF or CoCl2 to mimic tumor microenvironment in vitro to study the effect of BML-111 on angiogenesis and permeability of Td-EC, and preliminarily explore its specific mechanism. Data suggested that BML-111 inhibited viability, migration and angiogenesis in VEGF or CoCl2-treated Td-EC by modulating MMP2/9-TIMP1, and decreasing the production of HIF-1α and COX-2 level. In addition, we observed that BML-111 inhibited Td-EC permeability induced by VEGF or CoCl2, through the stabilization of VE-cadherin/ß-catenin-dependent adherens junctions and TRPC1 pathway. Nevertheless, these effects could be blocked by BOC-2 which was the specific inhibitor of FPR2/ALX (the receptor of LXA4).These results suggest that BML-111 may have inhibitory effects on VEGF or CoCl2-induced migration, angiogenesis and permeability in tumor-derived endothelial cells.
Assuntos
Moduladores da Angiogênese/farmacologia , Endotélio Vascular/fisiologia , Ácidos Heptanoicos/farmacologia , Lipoxinas/agonistas , Neoplasias/tratamento farmacológico , Junções Aderentes/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Cobalto/metabolismo , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica , Transdução de Sinais , Canais de Cátion TRPC/metabolismo , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Angiogenesis, involving the formation of new blood vessels from preexisting vessels, caters an important biological phenomenon for the growth and development of bodily structures in the human body. Regulation of angiogenesis in non-pathological conditions takes place through a well-defined balanced angiogenic-switch, which upon exposure to various pathological conditions may get altered. This makes the cells change their normal behavior resulting in uncontrolled division and angiogenesis. METHODS: The current review tries to present a brief framework of angiogenesis and tumor progression phenomenon along with the latest therapeutic interventions against VEGFR-2 and its future directions. RESULTS: The tumor angiogenic pathways functioning in diverse mechanisms via sprouting angiogenesis, intussusceptive angiogenesis, vascular co-option, vascular mimicry, and glomeruloid angiogenesis are normally activated by varied angiogenic stimulators and their receptors are interrelated to give rise to specialized signaling pathways. Amongst these receptors, VEGFR-2 is found as one of the key, critical mediators in tumor angiogenesis and is seen as a major therapeutic target for combating angiogenesis. Though a number of anti-angiogenic drugs like Ramucirumab, Sunitinib, Axitinib, Sorafenib, etc. showing good survival rates have been developed and approved by FDA against VEGFR-2, but these have also been found to be associated with serious health effects and adverse reactions. CONCLUSION: An improved or alternative treatment is needed shortly that has a higher survival rate with the least side effects. Innovative strategies, including personalized medicine, nano-medicine, and cancer immunotherapy have also been outlined as an alternative treatment with a discussion on advancements and improvements required for their implementation methods.
Assuntos
Inibidores da Angiogênese/farmacologia , Moduladores da Angiogênese/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Angiogênicas/metabolismo , Animais , Humanos , Neoplasias , Transdução de SinaisRESUMO
Angiogenesis and lymphangiogenesis are key processes during embryogenesis as well as under physiological and pathological conditions. Vascular endothelial growth factor C (VEGFC), the ligand for both VEGFR2 and VEGFR3, is a central lymphangiogenic regulator that also drives angiogenesis. Here, we report that members of the highly conserved BACH (BTB and CNC homology) family of transcription factors regulate VEGFC expression, through direct binding to its promoter. Accordingly, down-regulation of bach2a hinders blood vessel formation and impairs lymphatic sprouting in a Vegfc-dependent manner during zebrafish embryonic development. In contrast, BACH1 overexpression enhances intratumoral blood vessel density and peritumoral lymphatic vessel diameter in ovarian and lung mouse tumor models. The effects on the vascular compartment correlate spatially and temporally with BACH1 transcriptional regulation of VEGFC expression. Altogether, our results uncover a novel role for the BACH/VEGFC signaling axis in lymphatic formation during embryogenesis and cancer, providing a novel potential target for therapeutic interventions.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Neovascularização Fisiológica/fisiologia , Fator C de Crescimento do Endotélio Vascular/genética , Proteínas de Peixe-Zebra/genética , Moduladores da Angiogênese/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linhagem Celular Tumoral , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Linfangiogênese/fisiologia , Vasos Linfáticos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Morfogênese , Transdução de Sinais , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/genética , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/metabolismoRESUMO
Microbes have developed mechanisms to resist the host immune defenses and some elicit antitumor immune responses. About 6 million people are infected with Trypanosoma cruzi, the protozoan agent of Chagas' disease, the sixth neglected tropical disease worldwide. Eighty years ago, G. Roskin and N. Klyuyeva proposed that T. cruzi infection mediates an anti-cancer activity. This observation has been reproduced by several other laboratories, but no molecular basis has been proposed. We have shown that the highly pleiotropic chaperone calreticulin (TcCalr, formerly known as TcCRT), translocates from the parasite ER to the exterior, where it mediates infection. Similar to its human counterpart HuCALR (formerly known as HuCRT), TcCalr inhibits C1 in its capacity to initiate the classical pathway of complement activation. We have also proposed that TcCalr inhibits angiogenesis and it is a likely mediator of antitumor effects. We have generated several in silico structural TcCalr models to delimit a peptide (VC-TcCalr) at the TcCalr N-domain. Chemically synthesized VC-TcCalr did bind to C1q and was anti-angiogenic in Gallus gallus chorioallantoic membrane assays. These properties were associated with structural features, as determined in silico. VC-TcCalr, a strong dipole, interacts with charged proteins such as collagen-like tails and scavenger receptors. Comparatively, HuCALR has less polarity and spatial stability, probably due to at least substitutions of Gln for Gly, Arg for Lys, Arg for Asp and Ser for Arg that hinder protein-protein interactions. These differences can explain, at least in part, how TcCalr inhibits the complement activation pathway and has higher efficiency as an antiangiogenic and antitumor agent than HuCALR.
Assuntos
Moduladores da Angiogênese/metabolismo , Antineoplásicos/metabolismo , Calreticulina/metabolismo , Doença de Chagas/imunologia , Complemento C1q/metabolismo , Proteínas de Protozoários/metabolismo , Trypanosoma cruzi/fisiologia , Moduladores da Angiogênese/química , Animais , Antineoplásicos/química , Calreticulina/química , Células Cultivadas , Doença de Chagas/parasitologia , Embrião de Galinha , Ativação do Complemento , Interações Hospedeiro-Parasita , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Domínios e Motivos de Interação entre Proteínas , Proteínas de Protozoários/química , Alinhamento de SequênciaRESUMO
OBJECTIVE: In this study, the molecular mechanism by which EPO regulates the angiogenesis after cerebral ischemia through AMPK-KLF2 signaling pathway was investigated. METHODS: Sixty healthy, male, C57BL/6 mice were randomly divided into three groups of 20 mice: a sham group, the middle cerebral artery occlusion (MCAO) group, and a MCAO+EPO treatment group. The MCAO model was established using a modified ZeaLonga method. Mice in the EPO treatment group were injected with EPO immediately after reperfusion (5000 IU/kg), and EPO was injected the following day. The number of mouse deaths and neurologic function scores were recorded during the experiment. On day 7 after cerebral ischemia, brain tissue proteins were extracted. The following proteins expressions were detected by western blot assay: EPO, vascular endothelial growth factor (VEGE), vascular endothelial growth factor receptor (KDR), adenosine activated protein kinase (AMPK), and alpha HIF-1α alpha (HIF-1α), KLF2 and nitric oxide synthase (eNOS). RESULTS: Compared with the MCAO group, the survival rate of mice in the EPO group was significantly improved and neurological function was significantly improved (P < 0.01). Western blot results showed that the content of EPO in brain tissue in MCAO group significantly increased compared with sham group. The content of EPO in the brain tissue of mice in the MCAO+EPO treatment group was significantly higher than in that of the MCAO group, which indicates that EPO increased the content of EPO in mouse brain tissue. Compared with the sham group, the protein expression of vascular endothelial growth factor (VEGE) and its receptor (KDR) in brain tissue of the MCAO group significantly decreased. However, the protein expression of VEGE and its receptor KDR in brain tissue of rats treated with MCAO+EPO was significantly higher than in that of the MCAO group. Thus, in this study, EPO was associated with vascular endothelial differentiation after cerebral ischemia in mice. The results of AMPK and KLF2 showed that the expression levels of AMPK and KLF2 in brain tissues of MCAO group mice significantly decreased compared with the sham group. However, the expression levels of AMPK and KLF2 in brain tissues of mice treated with MCAO+EPO were significantly higher than those in the MCAO group. Thus, EPO can activate AMPK and upregulate the expression of the transcription factor KLF2. The protein expression of HIF-1α in the brain tissue of mice in the MCAO group significantly increased compared with the sham group. However, the expression of HIF-1α in mice brain tissues in the MCAO+EPO treatment group was significantly lower than in that of the MCAO group, indicating that EPO was involved in regulating HIF-1α expression. The eNOS results showed that, compared with Sham group, the protein expression of eNOS in brain tissue of MCAO group mice significantly decreased. In the MCAO+EPO treatment group, the protein expression of eNOS was significantly higher in the brain tissue of the mice than in that of the MCAO group, indicating that EPO was involved in the synthesis of NO and promoted the angiogenesis. CONCLUSION: EPO promotes VEGE and its receptor (KDR) expression and participates in the regulation of HIF-1α and eNOS protein expression through the activation of AMPK-KLF2 signaling pathways to promote new vascular development after cerebral ischemia.
Assuntos
Isquemia Encefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Eritropoetina/farmacologia , Neovascularização Patológica , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Moduladores da Angiogênese/farmacologia , Moduladores da Angiogênese/uso terapêutico , Animais , Encéfalo/fisiopatologia , Isquemia Encefálica/tratamento farmacológico , Eritropoetina/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição AleatóriaRESUMO
The quotient of concentrations concerning the key proangiogenic factor, that is, the vascular endothelial growth factor (VEGF-A) and the angiogenesis inhibitor, namely, its soluble receptors (sVEGFR-1 or sVEGFR-2), seems to reflect increased hypoxia and intensity of compensation angiogenesis. Therefore, it can be an ischemic and endothelial dysfunction marker reflected in intermittent claudication (IC) or critical limb ischemia (CLI) in patients with symptomatic peripheral arterial disease (PAD). The main objective of this study was to evaluate the levels of VEGF-A/sVEGFR-1 and VEGF-A/sVEGFR-2-presented using a novelty acronym VASCULAR-1 and VASCULAR-2-in patients with IC and CLI, as well as displayed in 4 classes of severity of PAD. VASCULAR-1 and VASCULAR-2 were calculated using the plasma of venous blood sampled from 80 patients with IC (n = 65) and CLI (n = 15) and the control group (n = 30). Patients with CLI were reported to have a slightly higher index of VASCULAR-1 and double VASCULAR-2 levels as compared to patients with IC (P = nonsignificant), and these markers were significantly higher than controls (P < .01 and P < .01, respectively). VASCULAR-2 levels were observed to have an increasing tendency in the subsequent degrees of PAD severity according to the Fontaine classification (P = .02). In view of the need to consider the role of the proangiogenic and antiangiogenic factor in the assessment of the so-called "angiogenic potential," VASCULAR-1 ratio and VASCULAR-2 ratio may be a new useful biomarker of limb ischemia in patients with IC and CLI. However, this requires further studies and evidence on a very large group of patients with PAD.
Assuntos
Moduladores da Angiogênese/sangue , Endotélio/fisiopatologia , Doença Arterial Periférica/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Idoso , Biomarcadores/sangue , Extremidades/patologia , Feminino , Humanos , Claudicação Intermitente/sangue , Isquemia/sangue , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/patologia , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Von Willebrand disease (VWD), a blood coagulation disorder, is also known to cause angiodysplasia. Hitherto, no animal model has been found with angiodysplasia that can be studied in vivo. In addition, VWD patients tend to have a higher incidence of miscarriages for reasons unknown. Thus, we aimed to examine the influence of von Willebrand factor (VWF) on the female reproductive tract histology and the expression and distribution of angiogenic factors in a porcine model for VWD types 1 and 3. The disease-causing tandem duplication within the VWF gene occurred naturally in these pigs, making them a rare and valuable model. Reproductive organs of 6 animals (2 of each mutant genotype and 2 wildtype (WT) animals) were harvested. Genotype plus phenotype were confirmed. Several angiogenic factors were chosen for possible connections to VWF and analyzed alongside VWF by immunohistochemistry and quantitative gene expression studies. VWD type 3 animals showed angiodysplasia in the uterus and shifting of integrin αVß3 from the apical membrane of uterine epithelium to the cytoplasm accompanied by increased vascular endothelial growth factor (VEGF) expression. Varying staining patterns for angiopoietin (Ang)-2 were observed among the genotypes. As compared with WT, the ovaries of the VWD type 3 animals showed decreased gene expression of ANG2 and increased gene expression of TIE (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) 2, with some differences in the ANG/TIE-system among the mutant genotypes. In conclusion, severely reduced VWF seems to evoke angiodysplasia in the porcine uterus. Varying distribution and expression of angiogenic factors suggest that this large animal model is promising for investigation of influence of VWF on angiogenesis in larger groups.
Assuntos
Modelos Animais de Doenças , Suínos/genética , Doenças de von Willebrand/genética , Moduladores da Angiogênese/farmacologia , Animais , Genótipo , Humanos , Fenótipo , Receptor de TIE-1 , Receptor TIE-2 , Fator de von WillebrandRESUMO
BACKGROUND: Molecular targeted therapy increased overall and disease-free survival in a wide range of malignancies. Although generally well tolerated compared to chemotherapy, molecular targeted therapy may be associated with adverse events requiring ICU admission. Informing clinicians about clinical features of these toxic events might maintain awareness and favor early recognition, prompt diagnosis and treatment. METHODS: We performed a systematic review of published case reports of molecular targeted therapy-related life-threatening toxicity that led to ICU admission. The search used the Pubmed database using medical subject heading (Mesh) terms, including all FDA-approved molecular targeted therapy (TT), up to March 2019. No language restriction was applied. All cases reports of patients admitted to the ICU for molecular targeted therapy-related toxicity were included. Non-FDA-approved combinations of treatments or hormonal therapy were not included. RESULTS: Two hundred and fifty-three cases were identified. Nearly half of them (n = 102; 40.3%) were related to anti-angiogenic agents, mostly for gastrointestinal and cardiovascular complications. Other molecules responsible for adverse events were chiefly immune checkpoint inhibitors (n = 85, 33.6%), EGFR inhibitors (n = 33; 13.0%), and anti-HER2 (n = 10; 4.0%). They were associated with adverse events such as respiratory or hypersensitivity events. Management and outcomes associated with these life-threatening complications are reported. CONCLUSIONS: Based on the vast number of treated patients, only 253 cases of molecular therapy-related severe toxicity are reported in cancer patients. Symptoms and biomarkers that depict these events need to be better identified as to allow appropriate reporting and improving dose and schedule of the treatment adapted to each patient.
Assuntos
Unidades de Terapia Intensiva , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Moduladores da Angiogênese/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/terapia , Hipersensibilidade a Drogas/terapia , Receptores ErbB/antagonistas & inibidores , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/terapia , Humanos , Fatores Imunológicos/efeitos adversos , Receptor ErbB-2/antagonistas & inibidores , Doenças Respiratórias/induzido quimicamente , Doenças Respiratórias/terapia , Índice de Gravidade de DoençaRESUMO
Epilepsy is accompanied by angiogenesis and blood-brain barrier (BBB) disruption. The transforming growth factor-ß1 (TGF-ß1)/phosphorylated small mothers against decapentaplegic 2 and 3 (pSmad2/3)/vascular endothelial growth factor (VEGF) pathway, activated by thrombospondin-1 (TSP-1), which is further regulated by Y type P2 purinergic receptor activity, may participate in angiogenesis. We sought to investigate the relationship between the P2R/TSP-1/TGF-ß1/pSmad2/3/VEGF pathway, angiogenesis, and BBB damage in a kainic acid (KA) model of acute generalized seizure. Our results demonstrated that KA-induced seizures were accompanied by angiogenesis and BBB damage. In addition, expression of TSP-1, TGF-ß1, and pSmad2/3 was increased. Rats treated with pyridoxal phosphate-6-azophenyl-2', 4'-disulfonic acid, a broad P2 receptor antagonist, or Reactive Blue 2, a potent P2Y4 receptor antagonist, showed significant attenuation of TSP-1 expression and Smad2/3 phosphorylation levels. Furthermore, angiogenesis, BBB damage, and acute seizure severity were also reduced. The inhibition of TSP-1 expression by siRNA or TGF-ß1 activation by Leu-Ser-Lys-Leu (LSKL) treatment prevented KA-induced phosphorylation of Smad2/3, angiogenesis, BBB damage, and acute seizures. Our results strongly indicate that the P2Y4/TSP-1/TGF-ß1/pSmad2/3/VEGF pathway plays an essential role in seizure pathophysiology and angiogenesis. Therapeutic interventions targeting this pathway may offer new treatment options for acute seizures.
Assuntos
Neovascularização Fisiológica/fisiologia , Receptores Purinérgicos P2/metabolismo , Convulsões/metabolismo , Moduladores da Angiogênese/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Células Cultivadas , Epilepsia/fisiopatologia , Ácido Caínico/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2/fisiologia , Convulsões/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Trombospondina 1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND Hypoxia is an important feature of solid tumors and related to a perturbed blood supply in pathophysiologies. The aim of our research was to analyze the hypoxia response and elaborate its potential functions in colorectal cancer. MATERIAL AND METHODS The lncRNAs and mRNAs expression profile were analyzed in colorectal cancer cell line SW480 by RNA sequencing, and the functions and pathways of differentially expressed genes were screened by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. RESULTS In this study, 77 lncRNAs and 1327 mRNAs were identified as differentially expressed. We discovered several novel lncRNAs, such as RP11-126K1.2, RP3-438O4.4, LINC01119, CTB-22K21.2, RP11-798M19.6, and RP11-2B6.3, which had not been previously reported in regulation by hypoxia. KEGG and GO analyses identified that the differentially expressed changes in mRNAs were mainly related to regulation of basic metabolic processes and gene transcription processes and were involved in several classical pathways which were linked to cancer. CONCLUSIONS Taken together, the present findings elucidate a set of differentially expressed lncRNAs and mRNAs involved in the hypoxia response process of colorectal cancer, which may serve as a candidate diagnostic biomarker and help to explain the mechanism of initial event in colorectal carcinogenesis in colorectal cancer.
Assuntos
Neoplasias Colorretais/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Moduladores da Angiogênese/metabolismo , Linhagem Celular Tumoral , China , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Ontologia Genética , Humanos , Hipóxia/genética , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante/análise , RNA Longo não Codificante/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Análise de Sequência de RNA/métodos , Transcriptoma/genética , Hipóxia Tumoral/genéticaRESUMO
A fraction of patients affected by Duchenne Muscular Dystrophy (DMD) shows mental disability as a consequence of neuronal and metabolic alteration. In this study, we evaluated the effect of α-methyl-prednisolone (PDN) on the expression of the angiogenic marker HIF1α, VEGFA and VEGFR-2 (FLK1) in correlation with PKC expression in the brain of mdx mouse, an experimental model of DMD. We demonstrated that HIF1α, VEGFA and FLK1 are overexpressed in the brain of dystrophic mdx mice in parallel with an increase of PKC expression and reduction of the tight junctions Occludin leading to altered angiogenesis. Moreover, we demonstrated that PDN treatment induces a significant reduction in the HIF1α, VEGF, FLK1, and PKC mRNA and proteins levels and restores Occludin expression reducing its phosphorylation pattern. Our results suggest a new mechanism of action of PDN that through PKC suppression normalizes the angiogenesis in dystrophic mdx brains.
Assuntos
Metilprednisolona/farmacologia , Distrofia Muscular de Duchenne/metabolismo , Proteína Quinase C/metabolismo , Moduladores da Angiogênese/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Metilprednisolona/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Neovascularização Patológica , Neurônios/metabolismo , Ocludina/metabolismo , Fosforilação , Proteína Quinase C/fisiologia , Junções Íntimas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Obesity is the main determinant of type 2 diabetes. Some adipocytokines play important roles in diabetic complications. Lipid transport is an important aspect of lipid metabolism in cancer. Present study aimed to evaluate the effect of some adipocytokines, inflammatory, epigenetic instability & angiogenesis biomarkers in type 2 diabetic Egyptian women with breast cancer. Study Design was performed on eighty females divided into 20 healthy subjects (Group I), 20 patients with type 2 diabetes (Group II), 20 patients with breast cancer (Group III) & 20 patients with diabetes and breast cancer (Group IV). Demographic data & body mass index have been collected. Biochemical analysis included fasting & postprandial blood glucose, lipid profile, fatty acid-binding proteins-4 (FABP-4), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), 8-hydroxy-2'-deoxyguanosine (8-OHdG) & thioredoxin reductase (TrxR) activity. Results revealed significant increase in FABP-4, TNF-α, VEGF, 8-OHdG and significant decreased TrxR activity in diabetic patients with breast cancer in comparison with other groups. These changes were evident in breast cancer subjects than diabetic and healthy cases and in diabetic than healthy cases. Conclusion: This study confirmed the role of FABP-4 in pathogenesis of type 2 diabetes & breast cancer via enhancing angiogenesis, inflammatory and epigenetic instability biomarkers.
Assuntos
Adipocinas/sangue , Moduladores da Angiogênese/metabolismo , Biomarcadores/análise , Neoplasias da Mama/etiologia , Diabetes Mellitus Tipo 2/complicações , Epigênese Genética , Mediadores da Inflamação/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/genética , Egito , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Seguimentos , Instabilidade Genômica , Humanos , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Obesidade/patologia , Prognóstico , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
RNA binding proteins (RBPs) and microRNAs have emerged as crucial post-transcriptional regulators of gene expression. Although the role of Fragile X mental retardation protein (FMRP) has been well studied in the brain, the function of FMRP in endothelial cells remains unknown. In our study, we showed that FMRP controlled human umbilical vein endothelial cells (HUVECs) proliferation and angiogenesis via the miR-181a-mediated calmodulin (CaM)/CaMKII pathway. The knockdown of FMRP induced miR-181a expression and contributed to endothelial cell proliferation and angiogenesis. Furthermore, we identified CaM as a downstream target of miR-181a in endothelial cells. Additionally, tumor necrosis factor-É (TNF-É) treatment specifically decreased the activity of the CaM/CaMKII pathway through the dephosphorylation of FMRP and upregulation of miR-181a. Finally, the overexpression of constitutively phosphorylated FMRP rescued the TNF-É-impaired endothelial cell proliferation and angiogenesis by activating the CaM/CaMKII pathway and downregulating miR-181a, which suggested there was a pivotal role of FMRP in vascular integrity in response to inflammatory stimuli. Thus, our study supports a novel function and mechanism involving FMRP and the miR-181a-CaM-CaMKII pathway may be a therapeutic target for protecting against inflammation-induced vascular diseases.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Calmodulina/metabolismo , Células Endoteliais/citologia , Proteína do X Frágil da Deficiência Intelectual/metabolismo , MicroRNAs/metabolismo , Moduladores da Angiogênese , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Calmodulina/genética , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Células Endoteliais/metabolismo , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at a post-transcriptional level via either the degradation or translational repression of a target mRNA. They play an irreplaceable role in angiogenesis by regulating the proliferation, differentiation, apoptosis, migration and tube formation of angiogenesis-related cells, which are indispensable for multitudinous physiological and pathological processes, especially for the occurrence and development of vascular diseases. Imbalance between the regulation of miRNAs and angiogenesis may cause many diseases such as cancer, cardiovascular disease, aneurysm, Kawasaki disease, aortic dissection, phlebothrombosis and diabetic microvascular complication. Therefore, it is important to explore the essential role of miRNAs in angiogenesis, which might help to uncover new and effective therapeutic strategies for vascular diseases. This review focuses on the interactions between miRNAs and angiogenesis, and miRNA-based biomarkers in the diagnosis, treatment and prognosis of angiogenesis-related diseases, providing an update on the understanding of the clinical value of miRNAs in targeting angiogenesis.
Assuntos
Doenças Cardiovasculares/genética , Células Endoteliais/metabolismo , MicroRNAs/genética , Terapia de Alvo Molecular/métodos , Neovascularização Patológica/genética , RNA Mensageiro/genética , Moduladores da Angiogênese/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Diferenciação Celular , Movimento Celular , Proliferação de Células , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Regulação da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , RNA Mensageiro/metabolismo , Transdução de SinaisRESUMO
The control of the different angiogenic process is an important point in osteochondral regeneration. Angiogenesis is a prerequisite for osteogenesis in vivo; insufficient neovascularization of bone constructs after scaffold implantation resulted in hypoxia and cellular necrosis. Otherwise, angiogenesis must be avoided in chondrogenesis; vascularization of the cartilage contributes to structural damage and pain. Finding a balance between these processes is important to design a successful treatment for osteochondral regeneration. This chapter shows the most important advances in the control of angiogenic process for the treatment of osteochondral diseases focused on the administration of pro- or anti-angiogenic factor and the design of the scaffold.