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1.
Int J Oncol ; 61(1)2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35543162

RESUMO

Drug repositioning is a strategy for repurposing the approved or investigational drugs that are outside the scope of the original medical indication. Memantine is used as a non­competitive N­methyl­D­aspartate receptor antagonist to prevent glutamate­mediated excitotoxicity in Alzheimer's disease, and is one of the promising agents which is utilized for the purpose of cancer therapy. However, the association between memantine and Golgi glycoprotein 1 (GLG1), an intracellular fibroblast growth factor receptor, in cancers has not yet been clarified. The present study analyzed the expression and location of GLG1 in tumor cells treated with memantine. Memantine was found to suppress the growth of malignant glioma and breast cancer cells in a concentration­dependent manner. The mRNA expression of GLG1 was upregulated in a concentration­dependent manner, and the splicing variant profiles were altered in all cell lines examined. The results of western blot analysis revealed an increase in the full­length and truncated forms of GLG1. Moreover, GLG1 spread in the cytosol of memantine­treated cells, whereas it localized in the Golgi apparatus in control cells. Since GLG1 functions as a decoy FGF receptor, the modulation of GLG1 may prove to be one of the mechanisms underlying the cancer­suppressive effects of memantine.


Assuntos
Doença de Alzheimer , Memantina , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Proteínas de Transporte/metabolismo , Humanos , Memantina/farmacologia , Memantina/uso terapêutico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Sialoglicoproteínas , Transdução de Sinais
2.
Sci Rep ; 12(1): 1377, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-35082348

RESUMO

Muscle wasting is a major problem leading to reduced quality of life and higher risks of mortality and various diseases. Muscle atrophy is caused by multiple conditions in which protein degradation exceeds its synthesis, including disuse, malnutrition, and microgravity. While Vitamin D receptor (VDR) is well known to regulate calcium and phosphate metabolism to maintain bone, recent studies have shown that VDR also plays roles in skeletal muscle development and homeostasis. Moreover, its expression is upregulated in muscle undergoing atrophy as well as after muscle injury. Here we show that VDR regulates simulated microgravity-induced atrophy in C2C12 myotubes in vitro. After 8 h of microgravity simulated using 3D-clinorotation, the VDR-binding motif was associated with chromatin regions closed by the simulated microgravity and enhancer regions inactivated by it, which suggests VDR mediates repression of enhancers. In addition, VDR was induced and translocated into the nuclei in response to simulated microgravity. VDR-deficient C2C12 myotubes showed resistance to simulated microgravity-induced atrophy and reduced induction of FBXO32, an atrophy-associated ubiquitin ligase. These results demonstrate that VDR contributes to the regulation of simulated microgravity-induced atrophy at least in part by controlling expression of atrophy-related genes.


Assuntos
Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Mioblastos Esqueléticos/metabolismo , Receptores de Calcitriol/metabolismo , Transdução de Sinais/genética , Simulação de Ausência de Peso/efeitos adversos , Animais , Linhagem Celular , Técnicas de Inativação de Genes/métodos , Homeostase/genética , Camundongos , Desenvolvimento Muscular/genética , Atrofia Muscular/genética , Receptores de Calcitriol/genética , Transfecção
3.
Neuroradiol J ; 35(2): 260-263, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34379009

RESUMO

Cerebral hyperperfusion syndrome is a rare but severe complication of carotid artery stenting or carotid endarterectomy. Staged angioplasty is reportedly an effective strategy to avoid cerebral hyperperfusion syndrome. We encountered a case of internal carotid artery stenosis with a rare clinical presentation of limb shaking that was successfully improved by staged angioplasty. To our knowledge, there are no reported cases of limb shaking treated with staged angioplasty.A 76-year-old woman presented with continuous chorea in her left lower limb and shoulder. Medical examination revealed a tiny cerebral infarction in the right corona radiata and severe right internal carotid artery stenosis. Angiography showed near occlusion of the right internal carotid artery. Staged angioplasty was performed to avoid the risk of cerebral hyperperfusion syndrome. The first angioplasty resulted in an expanded diameter of 2.5 mm and was followed by definitive carotid artery stenting using a closed-cell stent 3.5 weeks later. Limb shaking improved in a stepwise manner along with an improvement in internal carotid artery stenosis and distal flow state with no signs of cerebral hyperperfusion syndrome. Patients with internal carotid artery stenosis or occlusion presenting with limb shaking have been suggested to have impaired cerebrovascular reactivity, which is also thought to be a risk factor for cerebral hyperperfusion syndrome. The stepwise improvement in limb shaking observed in this case supports the idea that the pathophysiology of limb shaking is related to cerebral haemodynamic impairment. Measures to prevent cerebral hyperperfusion syndrome, including staged angioplasty, should be actively considered in patients with limb shaking because the symptoms themselves suggest severe hypoperfusion.


Assuntos
Estenose das Carótidas , Idoso , Angioplastia/efeitos adversos , Angioplastia/métodos , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/cirurgia , Feminino , Humanos , Stents
4.
Brain Sci ; 11(12)2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34942951

RESUMO

The dura-like membrane (DLM) is an outermost membranous structure arising from the dura mater adjacent to the internal auditory meatus (IAM) that envelops some vestibular schwannomas (VSs). Its recognition is important for the preservation of the facial and cochlear nerves during tumor resection. This study analyzes the histopathological characteristics of the DLM. The expression of CD34 and αSMA was histopathologically analyzed in tumor and DLM tissue of 10 primary VSs with and without a DLM. Tumor volume, resection volume percentage, microvessel density (MVD), and vessel diameter were analyzed. Volumetric analysis revealed that the presence of a DLM was significantly associated with lower tumor resection volume (p < 0.05). Intratumoral vessel diameter was significantly larger in the DLM group than the non-DLM group (p < 0.01). Larger VSs showed a higher intratumoral MVD in the DLM group (p < 0.05). Multilayered αSMA-positive vessels were identified in the DLM, tumor, and border; there tended to be more of these vessels within the tumor in the DLM group compared to the non-DLM group (p = 0.08). These arteriogenic characteristics suggest that the DLM is formed as the tumor induces feeding vessels from the dura mater around the IAM.

5.
Proc Natl Acad Sci U S A ; 118(35)2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34426497

RESUMO

Skeletal muscle atrophy is caused by various conditions, including aging, disuse related to a sedentary lifestyle and lack of physical activity, and cachexia. Our insufficient understanding of the molecular mechanism underlying muscle atrophy limits the targets for the development of effective pharmacologic treatments and preventions. Here, we identified Krüppel-like factor 5 (KLF5), a zinc-finger transcription factor, as a key mediator of the early muscle atrophy program. KLF5 was up-regulated in atrophying myotubes as an early response to dexamethasone or simulated microgravity in vitro. Skeletal muscle-selective deletion of Klf5 significantly attenuated muscle atrophy induced by mechanical unloading in mice. Transcriptome- and genome-wide chromatin accessibility analyses revealed that KLF5 regulates atrophy-related programs, including metabolic changes and E3-ubiquitin ligase-mediated proteolysis, in coordination with Foxo1. The synthetic retinoic acid receptor agonist Am80, a KLF5 inhibitor, suppressed both dexamethasone- and microgravity-induced muscle atrophy in vitro and oral Am80 ameliorated disuse- and dexamethasone-induced atrophy in mice. Moreover, in three independent sets of transcriptomic data from human skeletal muscle, KLF5 expression significantly increased with age and the presence of sarcopenia and correlated positively with the expression of the atrophy-related ubiquitin ligase genes FBXO32 and TRIM63 These findings demonstrate that KLF5 is a key transcriptional regulator mediating muscle atrophy and that pharmacological intervention with Am80 is a potentially preventive treatment.


Assuntos
Benzoatos/farmacologia , Desenvolvimento de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/fisiologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/tratamento farmacológico , Tetra-Hidronaftalenos/farmacologia , Animais , Dexametasona/toxicidade , Glucocorticoides/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Transdução de Sinais , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
6.
Sci Rep ; 11(1): 286, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431898

RESUMO

Osteopontin (OPN) is a multifunctional secreted glycoprotein. We evaluated OPN concentrations in blood and follicular fluid (FF) during the ovarian cycle and their relationship with the production of vascular endothelial growth factor (VEGF), which is involved in the pathophysiology of ovarian hyperstimulation syndrome (OHSS). Twenty-two women undergoing in vitro fertilization (minimal stimulation protocol with clomiphene citrate) were enrolled. Samples were collected (a) on the third day of withdrawal bleeding, (b) 2 days before oocyte retrieval, and (c) on the day of oocyte retrieval. FF was collected during oocyte retrieval. The OPN concentration in each specimen and the VEGF concentration in FF was measured by enzyme-linked immunosorbent assays. Plasma OPN concentrations were (in ng/mL): (a) 416 ± 37.2, (b) 378 ± 35.8, and (c) 390 ± 40.0, with no significant differences between the groups. The OPN concentration in FF was 106 ± 13.4 ng/mL. A positive correlation was found between OPN concentrations in FF and plasma samples. A positive correlation was also found between plasma OPN and FF VEGF concentrations, irrespective of the blood-sampling period. Plasma OPN concentration is suggested to reflect the FF VEGF level at oocyte retrieval and maybe a novel clinical marker for predicting the risk for OHSS.


Assuntos
Líquido Folicular/metabolismo , Ciclo Menstrual/metabolismo , Osteopontina/sangue , Osteopontina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Feminino , Humanos , Síndrome de Hiperestimulação Ovariana/sangue , Síndrome de Hiperestimulação Ovariana/metabolismo
7.
J Nippon Med Sch ; 87(6): 310-317, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-32238732

RESUMO

BACKGROUND: 5-Aminolevulinic Acid (5-ALA) photodiagnosis (PD) is an effective method to detect residual tumors during glioma surgery. However, fluorescence strength differs in malignant gliomas, and false-negative fluorescence may result in tumor residue. We investigated the effect of ultrasound on the intracellular level of protoporphyrin IX (PpIX) and expression level of ATP-binding cassette transporter 2 (ABCG2), which is thought to act as a membrane efflux pump of PpIX from cytosol. METHODS: The malignant glioma cell lines SNB19, U87MG, and T98G were used for in vitro experiments. Cultured cells underwent ultrasound irradiation (1 MHz, 3 W/cm2, duty cycle 10%) after administration of 5-ALA, and morphological changes in tumor cells were observed. PpIX levels and ABCG2 expression were evaluated. RESULTS: The glioma tumor cells showed transient morphological changes and detachment from the culture dish; however, most cells survived and reverted to their original morphology within 6 hours. PpIX expression levels increased in glioma cells after ultrasound irradiation, and the increase was earlier and greater than that for 5-ALA alone. ABCG2 expressions increased after 5-ALA administration but were lower in ultrasound-irradiated glioma cells. CONCLUSIONS: Ultrasound irradiation of malignant gliomas contributes to stronger 5-ALA-induced fluorescence by elevating intracellular PpIX levels. Suppression of ABCG2 expression by ultrasound may contribute to PpIX accumulation in glioma cells.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Fluorescência , Expressão Gênica , Glioma/diagnóstico , Glioma/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ultrassonografia , Ácido Aminolevulínico , Linhagem Celular Tumoral , Glioma/patologia , Humanos , Protoporfirinas/genética , Protoporfirinas/metabolismo
8.
World Neurosurg ; 147: e215-e224, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33316485

RESUMO

BACKGROUND: Lateral ventricular meningioma (LVM) is a rare entity, accounting for 0.5%-5% of all intracranial meningiomas. This type of meningioma arises from meningothelial inclusion bodies in the tela choroidea and/or mesenchymal stroma of the choroid plexus. Although not yet fully characterized, a membranous structure is frequently observed around LVMs. This study analyzed quiescent and activated fibroblast phenotypes in LVMs with focus on the relationship between tumor growth and development of the membranous structure. METHODS: This retrospective study analyzed 9 LVM cases for which gross total removal was achieved. Expression of the ependymal cell marker (Forkhead Box J1 [FoxJ1]) was histopathologically evaluated. The distribution of quiescent and activated fibroblasts was also analyzed using anti-fibroblast-specific protein-1 (FSP1)/S100A4 antibody and anti-α-smooth muscle actin (αSMA) antibody, respectively. The control group was 5 cases with primary convexity meningioma for which Simpson grade I removal was achieved. RESULTS: Small LVMs (≤30 mm) were covered by a FoxJ1-positive(+) ependymal cell monolayer; no αSMA(+) cells were detected in the tumor; and a thick membrane capsule was not observed. None of the convexity meningiomas showed FoxJ1(+) cells. Large LVMs (>30 mm) had thick membrane capsules without an ependymal cell monolayer, which resembled dura mater. The FSP1/S100A4(+) and αSM(+) cells were clearly concentrated in the peripheral area just below the thick dura mater-like membrane capsules. CONCLUSIONS: This study found an association between activated fibroblasts and dura mater-like membrane capsules in LVMs. The characteristics of membranous structure in LVMs may differ depending on tumor size.


Assuntos
Neoplasias do Ventrículo Cerebral/patologia , Neoplasias do Ventrículo Cerebral/cirurgia , Dura-Máter/patologia , Fibroblastos/patologia , Ventrículos Laterais/patologia , Neoplasias Meníngeas/patologia , Meningioma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ventrículo Cerebral/diagnóstico por imagem , Dura-Máter/diagnóstico por imagem , Dura-Máter/cirurgia , Feminino , Humanos , Ventrículos Laterais/diagnóstico por imagem , Ventrículos Laterais/cirurgia , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/cirurgia , Meningioma/diagnóstico por imagem , Meningioma/cirurgia , Pessoa de Meia-Idade , Estudos Retrospectivos
9.
J Biochem ; 169(4): 387-394, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33289521

RESUMO

A set of C43(DE3) and BL21(DE3) Escherichia coli host strains that are auxotrophic for various amino acids is briefly reviewed. These strains require the addition of a defined set of one or more amino acids in the growth medium, and have been specifically designed for overproduction of membrane or water-soluble proteins selectively labelled with stable isotopes, such as 2H, 13C and 15N. The strains described here are available for use and have been deposited into public strain banks. Although they cannot fully eliminate the possibility of isotope dilution and mixing, metabolic scrambling of the different amino acid types can be minimized through a careful consideration of the bacterial metabolic pathways. The use of a suitable auxotrophic expression host strain with an appropriately isotopically labelled growth medium ensures high levels of isotope labelling efficiency as well as selectivity for providing deeper insight into protein structure-function relationships.


Assuntos
Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica , Escherichia coli/genética , Domínios Proteicos , Relação Estrutura-Atividade
10.
Molecules ; 25(19)2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33027981

RESUMO

Tea and coffee are consumed worldwide and epidemiological and clinical studies have shown their health beneficial effects, including anti-cancer effects. Epigallocatechin gallate (EGCG) and chlorogenic acid (CGA) are the major components of green tea polyphenols and coffee polyphenols, respectively, and believed to be responsible for most of these effects. Although a large number of cell-based and animal experiments have provided convincing evidence to support the anti-cancer effects of green tea, coffee, EGCG, and CGA, human studies are still controversial and some studies have suggested even an increased risk for certain types of cancers such as esophageal and gynecological cancers with green tea consumption and bladder and lung cancers with coffee consumption. The reason for these inconsistent results may have been arisen from various confounding factors. Cell-based and animal studies have proposed several mechanisms whereby EGCG and CGA exert their anti-cancer effects. These components appear to share the common mechanisms, among which one related to reactive oxygen species is perhaps the most attractive. Meanwhile, EGCG and CGA have also different target molecules which might explain the site-specific differences of anti-cancer effects found in human studies. Further studies will be necessary to clarify what is the mechanism to cause such differences between green tea and coffee.


Assuntos
Antineoplásicos Fitogênicos , Antioxidantes , Catequina/análogos & derivados , Ácido Clorogênico , Café/química , Neoplasias/tratamento farmacológico , Chá/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/química , Antioxidantes/uso terapêutico , Catequina/química , Catequina/uso terapêutico , Ácido Clorogênico/química , Ácido Clorogênico/uso terapêutico , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
11.
Development ; 147(21)2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32878913

RESUMO

Temple and Kagami-Ogata syndromes are genomic imprinting diseases caused by maternal and paternal duplication of human chromosome 14, respectively. They exhibit different postnatal muscle-related symptoms as well as prenatal placental problems. Using the mouse models for these syndromes, it has been demonstrated that retrotransposon gag like 1 [Rtl1, also known as paternally expressed 11 (Peg11)] located in the mouse orthologous imprinted region is responsible for the prenatal placental problems because it is an essential placental gene for maintenance of fetal capillary network during gestation. However, the causative imprinted gene for the postnatal muscle-related symptoms remains unknown. Here, we demonstrate that Rtl1 also plays an important role in fetal/neonatal skeletal muscle development: its deletion and overproduction in mice lead to neonatal lethality associated with severe but distinct skeletal muscle defects, similar to those of Temple and Kagami-Ogata syndromes, respectively. Thus, it is strongly suggested that RTL1 is the major gene responsible for the muscle defects in addition to the placental defects in these two genomic imprinting diseases. This is the first example of an LTR retrotransposon-derived gene specific to eutherians contributing to eutherian skeletal muscle development.


Assuntos
Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Músculos/anormalidades , Proteínas da Gravidez/deficiência , Animais , Animais Recém-Nascidos , Diferenciação Celular , Proliferação de Células , Desmina/metabolismo , Feminino , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Genéticos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculos/embriologia , Músculos/patologia , Mutação/genética , Proteínas da Gravidez/genética , Proteínas da Gravidez/metabolismo , Células Satélites de Músculo Esquelético/metabolismo , Síndrome , Fatores de Tempo
12.
Proc Natl Acad Sci U S A ; 117(25): 14365-14375, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513690

RESUMO

Proper resolution of inflammation is vital for repair and restoration of homeostasis after tissue damage, and its dysregulation underlies various noncommunicable diseases, such as cardiovascular and metabolic diseases. Macrophages play diverse roles throughout initial inflammation, its resolution, and tissue repair. Differential metabolic reprogramming is reportedly required for induction and support of the various macrophage activation states. Here we show that a long noncoding RNA (lncRNA), lncFAO, contributes to inflammation resolution and tissue repair in mice by promoting fatty acid oxidation (FAO) in macrophages. lncFAO is induced late after lipopolysaccharide (LPS) stimulation of cultured macrophages and in Ly6Chi monocyte-derived macrophages in damaged tissue during the resolution and reparative phases. We found that lncFAO directly interacts with the HADHB subunit of mitochondrial trifunctional protein and activates FAO. lncFAO deletion impairs resolution of inflammation related to endotoxic shock and delays resolution of inflammation and tissue repair in a skin wound. These results demonstrate that by tuning mitochondrial metabolism, lncFAO acts as a node of immunometabolic control in macrophages during the resolution and repair phases of inflammation.


Assuntos
Ácidos Graxos/metabolismo , Inflamação/imunologia , Macrófagos/imunologia , Subunidade beta da Proteína Mitocondrial Trifuncional/genética , RNA Longo não Codificante/metabolismo , Animais , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Lipopolissacarídeos/imunologia , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Masculino , Camundongos , Subunidade beta da Proteína Mitocondrial Trifuncional/metabolismo , Oxirredução , Cultura Primária de Células , RNA Longo não Codificante/genética , Pele/imunologia , Pele/lesões , Cicatrização/imunologia
13.
Brain Tumor Pathol ; 37(3): 105-110, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32556925

RESUMO

Central nervous system (CNS) ganglioneuroblastoma is a rare neuroectodermal neoplasm and little is known about its clinical and biological features. Herein, we report a pediatric case of CNS ganglioneuroblastoma harboring MYO5A-NTRK3 fusion. The patient, a 4-year-old boy, underwent a partial resection of a supratentorial tumor that was histopathologically diagnosed as a CNS ganglioneuroblastoma. Treatment with radiotherapy was started per the St Jude Medulloblastoma 03 (SJMB03) protocol; however, the tumor progressed rapidly and radiotherapy was temporally discontinued. Meanwhile, the patient underwent a second surgery, in which a gross total resection was successfully performed, following which he completed the remaining protocol-based therapy. Although an early focal recurrence was detected for which he received additional radiotherapy and oral temozolomide, the patient remained in complete remission for 14 months after the completion of the treatment. A central pathological review and molecular analysis were performed that revealed a MYO5A-NTRK3 fusion. Interestingly, the MYO5A-NTRK3 fusion has been recurrently detected in melanocytic tumors but not in other types of tumors. Therefore, it can be speculated that our case might partly share tumorigenesis mechanisms with MYO5A-NTRK3-positive melanocytic tumors. In addition, our case may enable an improved understanding of the pathogenesis and clinical features of CNS ganglioneuroblastomas.


Assuntos
Neoplasias Encefálicas/genética , Ganglioneuroblastoma/genética , Fusão Gênica , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Receptor trkC/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Ganglioneuroblastoma/diagnóstico por imagem , Ganglioneuroblastoma/patologia , Humanos , Masculino
14.
Front Cardiovasc Med ; 7: 64, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411724

RESUMO

The close association among cardiovascular, metabolic, and kidney diseases suggests a common pathological basis and significant interaction among these diseases. Metabolic syndrome and cardiorenal syndrome are two examples that exemplify the interlinked development of disease or dysfunction in two or more organs. Recent studies have been sorting out the mechanisms responsible for the crosstalk among the organs comprising the cardiovascular, metabolic, and renal systems, including heart-kidney and adipose-liver signaling, among many others. However, it is also becoming clear that this crosstalk is not limited to just pairs of organs, and in addition to organ-organ crosstalk, there are also organ-system and organ-body interactions. For instance, heart failure broadly impacts various organs and systems, including the kidney, liver, lung, and nervous system. Conversely, systemic dysregulation of metabolism, immunity, and nervous system activity greatly affects heart failure development and prognosis. This is particularly noteworthy, as more and more patients present with two or more coexisting chronic diseases or conditions (multimorbidity) due in part to the aging of society. Advances in treatment also contribute to the increase in multimorbidity, as exemplified by cardiovascular disease in cancer survivors. To understand the mechanisms underlying the increasing burden of multimorbidity, it is vital to elucidate the multilevel crosstalk and communication within the body at the levels of organ systems, tissues, and cells. In this article, we focus on chronic inflammation as a key common pathological basis of cardiovascular and metabolic diseases, and discuss emerging mechanisms that drive chronic inflammation in the context of multimorbidity.

16.
Int J Mol Sci ; 21(8)2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32295185

RESUMO

Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.


Assuntos
Colesterol/metabolismo , Células Espumosas/metabolismo , Metabolismo dos Lipídeos , Transdução de Sinais , Biomarcadores , Suscetibilidade a Doenças , Células Espumosas/patologia , Perfilação da Expressão Gênica , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Modelos Biológicos
18.
BMC Cancer ; 20(1): 196, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164575

RESUMO

BACKGROUND: The expression of vascular endothelial growth factor (VEGF)-A/ VAGF receptors (VEGFRs) signaling plays a pivotal role in the tumor angiogenesis and the development of the immunosuppressive tumor microenvironment in glioblastomas. We have previously conducted exploratory clinical studies investigating VEGFRs peptide vaccination with and without multiple glioma oncoantigens in patients with recurrent high-grade gliomas. Recently, an exploratory clinical investigation of VEGFRs peptide vaccination was conducted in patients with progressive neurofibromatosis type 2. Those studies suggested that cytotoxic T lymphocytes (CTLs) induced by the vaccination can directly kill a wide variety of cells associated with tumor growth, including tumor vessels, tumor cells, and immunosuppressive cells expressing VEGFR1 and/or 2. In the present study, synergistic activity of the combination of VEGFRs peptide vaccination with chemotherapy was evaluated. METHODS: We performed the first clinical trial to assess VEGFR1 and 2 vaccination along with temozolomide (TMZ) -based chemoradiotherapy for the patients with primary glioblastomas. Furthermore, histopathological changes after the vaccination were evaluated using paired pre- and post- vaccination specimens. RESULTS: The disappearance of radiographically enhanced lesion was observed in 2 patients after the vaccination, including one in which the methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was not observed. The histopathological findings of pre- and post-vaccination specimens demonstrated that tumor vessels showed negative or slight VEGFRs expressions after the vaccination and most endothelial cells were covered with PDGFR-ß-positive pericytes. Notably, CTLs induced by VEGFRs peptide vaccination attacked not only tumor vessels but also tumor cells and regulatory T cells expressing VEGFRs even in recurrent tumors. CONCLUSIONS: VEGFR1 and 2 vaccination may have a preliminary synergistic effect when administered with TMZ. The limitation of the present study was the paucity of the number of the samples. Further studies involving more patients are warranted to confirm the findings of this study. TRIAL REGISTRATION: This study was registered as UMIN000013381 (University Hospital Medical Information Network-Clinical Trial Registry: UMIN-CTR) on 5 March, 2014 and with the Japan Registry of Clinical Trials (jRCT) as jRCTs031180170 on 1 March, 2019.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Vacinas Anticâncer/administração & dosagem , Glioblastoma/tratamento farmacológico , Fragmentos de Peptídeos/administração & dosagem , Temozolomida/administração & dosagem , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Vacinas Anticâncer/farmacologia , Sinergismo Farmacológico , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/uso terapêutico , Análise de Sobrevida , Temozolomida/uso terapêutico , Resultado do Tratamento , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química
19.
Exp Mol Pathol ; 114: 104408, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32088190

RESUMO

Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)1 and 2 signaling is a potent activator of tumor angiogenesis. Although the expressions of VEGFR1 and VEGFR2 were initially thought to be limited to the endothelial cells, it is now known that both the receptors are expressed in tumor cells. This is the first study wherein VEGFRs-positive tumor cells are quantitatively evaluated for brain tumors with upregulated VEGF/VEGFR signaling. The percentage of VEGFRs-positive tumor cells was quantitatively evaluated in various brain tumors (10 glioblastomas, 22 neurofibromatosis type 2 [NF2]-related schwannomas, 21 sporadic schwannomas, 27 chordomas, 36 meningiomas, 29 hemangioblastomas, 11 hemangiopericytoma, and 13 ependymomas) using immunohistochemistry. VEGF-A expression was also analyzed using quantitative real-time polymerase chain reaction. Double immunofluorescence staining using anti-PDGFR-ß and anti-CD34 antibody, microvessel density, and vessel diameter were analyzed to evaluate the vascular characteristics. Chordomas demonstrated an extremely higher percentage of VEGFR1 and VEGFR2-positive tumor cells than other tumors. In contrast, meningiomas and hemangiopericytomas showed few VEGFRs-positive tumor cells. The percentage of positive tumor cells in chordomas, hemangioblastomas, and NF2 schwannomas was associated with clinical courses, such as shorter progression free survival, and growth speed. Glioblastomas and NF2 schwannomas showed larger tumor vessels without pericyte coverage. The present study is the first to quantitatively analyze VEGFR1- and VEGFR2- positive tumor cells in various types of refractory brain tumors. This novel parameter significantly correlated with the progressive clinical courses.


Assuntos
Neoplasias Encefálicas/genética , Neovascularização Patológica/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/patologia , Cordoma/genética , Cordoma/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Ependimoma/genética , Ependimoma/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Glioblastoma/patologia , Hemangioblastoma/genética , Hemangioblastoma/patologia , Humanos , Imuno-Histoquímica , Masculino , Meningioma/genética , Meningioma/patologia , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Neurilemoma/genética , Neurilemoma/patologia , Transdução de Sinais/genética , Fator A de Crescimento do Endotélio Vascular/genética
20.
Int J Mol Sci ; 21(3)2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32012706

RESUMO

Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response.


Assuntos
Células Espumosas/metabolismo , Células Espumosas/patologia , Lipoproteínas LDL/metabolismo , Fagocitose , Biomarcadores , Células Espumosas/imunologia , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata , Metabolismo dos Lipídeos , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Oxirredução , Fagocitose/genética , Fagocitose/imunologia , Transdução de Sinais , Transcriptoma
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