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1.
Methods Mol Biol ; 2384: 247-255, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34550579

RESUMO

Primary monkey brain capillary endothelial cell cultures, with rat pericytes and astrocytes, provide an assay system for predicting the ability of oxytocin (OT) to cross the blood-brain barrier (BBB), using a commercially available in vitro BBB kit. The integrity of the in vitro "BBB," which has a high transendothelial electrical resistance (TEER), can be established approximately 4 days after preparations for experiments. Dominant endothelial transport of OT is from the upper (luminal blood side) to lower (abluminal brain side) chambers, dose-dependently. OT is transported by the receptor for advanced glycation end-products (RAGE) in endothelial cells, which is evidenced using the RAGE knockdown system with short hairpin RNA (shRNA) treatment. This in vitro assay system is useful for further assessment of OT transport across the BBB.

2.
Biol Open ; 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34812852

RESUMO

The full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34398301

RESUMO

Chronic inflammation contributes to tumor development by creating a local microenvironment that facilitates neoplastic transformation and potentiates the progression of cancer. Esophageal cancer (EC) is an inflammation-associated malignancy with a poor prognosis. The nature of the switch between chronic inflammation of the esophagus and EC-related immunological changes remains unclear. Here, we examined the dynamic alterations of immune cells at different stages of chronic esophagitis, Barrett's esophagus (BE) and EC using an esophageal spontaneous carcinogenesis rat model. We also investigated the anticancer effects of metformin. To stimulate EC carcinogenesis, chronic gastroduodenal reflux esophagitis via esophagojejunostomy was induced in 120 rats in metformin-treated and non-treated (control) groups. After 40 weeks, BE and EC developed in 96.7% and 63.3% of the control group, and in 66.7% and 23.3% of the metformin-treated group, respectively. Flow cytometric analysis demonstrated that the balance of M1/M2-polarized or phospho-Stat3-positive macrophages, regulatory T, cytotoxic T, natural killer (NK), NK T cells, and Th17 T cells was dynamically changed at each stage of the disease and were resolved by metformin treatment. These findings clarify the immunity in esophageal carcinogenesis and suggest that metformin could suppress this disease by improving the immunosuppressive tumor microenvironment and immune evasion.

5.
Biochem Biophys Res Commun ; 555: 74-80, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33813279

RESUMO

The engagement of the receptor for advanced glycation end-products (receptor for AGEs, RAGE) with diverse ligands could elicit chronic vascular inflammation, such as atherosclerosis. Binding of cytoplasmic tail RAGE (ctRAGE) to diaphanous-related formin 1 (Diaph1) is known to yield RAGE intracellular signal transduction and subsequent cellular responses. However, the effectiveness of an inhibitor of the ctRAGE/Diaph1 interaction in attenuating the development of atherosclerosis is unclear. In this study, using macrophages from Ager+/+ and Ager-/- mice, we validated the effects of an inhibitor on AGEs-RAGE-induced foam cell formation. The inhibitor significantly suppressed AGEs-RAGE-evoked Rac1 activity, cell invasion, and uptake of oxidized low-density lipoprotein, as well as AGEs-induced NF-κB activation and upregulation of proinflammatory gene expression. Moreover, expression of Il-10, an anti-inflammatory gene, was restored by this antagonist. These findings suggest that the RAGE-Diaph1 inhibitor could be a potential therapeutic drug against RAGE-related diseases, such as chronic inflammation and atherosclerosis.


Assuntos
Células Espumosas/metabolismo , Macrófagos Peritoneais/patologia , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Expressão Gênica , Inflamação/genética , Inflamação/patologia , Lipoproteínas LDL/metabolismo , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Neuropeptídeos/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Receptor para Produtos Finais de Glicação Avançada/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismo
6.
Physiol Behav ; 235: 113395, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33757778

RESUMO

Receptor for advanced glycation end-products (RAGE) is a pattern recognition molecule belonging to the immunoglobulin superfamily, and it plays a role in the remodeling of endothelial cells under pathological conditions. Recently, it was shown that RAGE is a binding protein for oxytocin (OT) and a transporter of OT to the brain on neurovascular endothelial cells via blood circulation. Deletion of the mouse RAGE gene, Ager (RAGE KO), induces hyperactivity in male mice. Impairment of pup care by mother RAGE KO mice after stress exposure results in the death of neonates 1-2 days after pup birth. Therefore, to understand the role of RAGE during the postpartum period, this study aims to examine parental behavior in female RAGE KO mice and ultrasonic vocalizations in pups. RAGE KO mothers without stress before delivery raised their pups and displayed hyperactivity at postpartum day (PPD) 3. KO dams showed impaired retrieval or interaction behavior after additional stress, such as body restraint stress or exposure to a novel environment, but such impaired behavior disappeared at PPD 7. Postnatal day 3 pups emitted ultrasonic vocalizations at >60 kHz as a part of the mother-pup relationship, but the number and category of calls by RAGE KO pups were significantly lower than wild-type pups. The results indicate that RAGE is important in the manifestation of normal parental behavior in dams and for receiving maternal care by mouse pups; moreover, brain OT recruited by RAGE plays a role in damping of signals of additional external stress and endogenous stress during the early postpartum period. Thus, RAGE-dependent OT may be critical for initiating and maintaining the normal mother-child relationship.


Assuntos
Células Endoteliais , Mães , Animais , Feminino , Humanos , Masculino , Comportamento Materno , Camundongos , Período Pós-Parto , Receptor para Produtos Finais de Glicação Avançada/genética
7.
J Neuroendocrinol ; 33(3): e12963, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33733541

RESUMO

Oxytocin (OT) is a neuropeptide hormone. Single and repetitive administration of OT increases social interaction and maternal behaviour in humans and mammals. Recently, it was found that the receptor for advanced glycation end-products (RAGE) is an OT-binding protein and plays a critical role in the uptake of OT to the brain after peripheral OT administration. Here, we address some unanswered questions on RAGE-dependent OT transport. First, we found that, after intranasal OT administration, the OT concentration increased in the extracellular space of the medial prefrontal cortex (mPFC) of wild-type male mice, as measured by push-pull microperfusion. No increase of OT in the mPFC was observed in RAGE knockout male mice. Second, in a reconstituted in vitro blood-brain barrier system, inclusion of the soluble form of RAGE (endogenous secretory RAGE [esRAGE]), an alternative splicing variant, in the luminal (blood) side had no effect on the transport of OT to the abluminal (brain) chamber. Third, OT concentrations in the cerebrospinal fluid after i.p. OT injection were slightly higher in male mice overexpressing esRAGE (esRAGE transgenic) compared to those in wild-type male mice, although this did not reach statistical significance. Although more extensive confirmation is necessary because of the small number of experiments in the present study, the reported data support the hypothesis that RAGE may be involved in the transport of OT to the mPFC from the circulation. These results suggest that the soluble form of RAGE in the plasma does not function as a decoy in vitro.

8.
Glycoconj J ; 38(3): 303-310, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33108607

RESUMO

The receptor for advanced glycation end-products (receptor for AGEs, RAGE) is a pattern recognition receptor. The interaction of RAGE with its ligands, such as AGEs, S100 proteins, high mobility group box-1 (HMGB1), and lipopolysaccharides (LPS), is known to play a pivotal role in the propagation of immune responses and inflammatory reactions. The ligand-RAGE interaction elicits cellular responses, for example, in myeloid and lymphoid cells, through distinct pathways by activating NF-κB and Rac1/cdc42, which lead to cytokine production, cell migration, phagocytosis, maturation, and polarization. Recently, oxytocin, a peptide hormone and neuropeptide, was identified as a novel binding molecule for the RAGE; however, it cannot compete with the interaction of RAGE with other ligands or induce RAGE intracellular signaling. The RAGE transports oxytocin from the blood into the brain and regulates brain functions. In this review, we summarize the current understanding of glycation reaction, AGEs, and the RAGE-mediated biological responses as well as the physiological role of RAGE in immunity and social behaviors, particularly, maternal bonding.

9.
Aging Dis ; 11(3): 547-558, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32489701

RESUMO

The receptor for advanced glycation end-products (RAGE) is expressed on human brain endothelial cells (HBEC) and is implicated in neuronal cell death after ischemia. We report that endogenous secretory RAGE (esRAGE) is a splicing variant form of RAGE that functions as a decoy against ischemia-induced neuronal cell damage. This study demonstrated that esRAGE was associated with heparan sulphate proteoglycans on HBEC. The parabiotic experiments between human esRAGE overexpressing transgenic (Tg), RAGE knockout (KO), and wild-type (WT) mice revealed a significant neuronal cell damage in the CA1 region of the WT side of parabiotic WT→WT mice, but not of Tg→WT mice, 7 days after bilateral common carotid artery occlusion. Human esRAGE was detected around the CA1 neurons in the WT side of the parabiotic Tg→WT pair, but not in the KO side of the Tg→KO pair. To elucidate the dynamic transfer of esRAGE into the brain, we used the blood-brain barrier (BBB) system (PharmaCo-Cell) with or without RAGE knockdown in endothelial cells. A RAGE-dependent transfer of esRAGE was demonstrated from the vascular to the brain side. These findings suggested that esRAGE is associated with heparan sulphate proteoglycans and is transferred into the brain via BBB to exert its neuroprotective effects in ischemia.

10.
Cancer Med ; 9(11): 3904-3917, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32253832

RESUMO

BACKGROUND: Aquaporin (AQP) 1 expression has been linked with tumor malignancy but its role in glioblastoma (GBM), a lethal glioma, remains to be clarified. METHODS: AQP1 expression was examined in 33 human GBM specimens by immunohistochemistry. GBM cells (U251 and U87) that stably express AQP1 were established and used for cellular proliferation, migration, invasion, and vascular tube formation assays. The GeneChip assay was used to identify differentially expressed genes in AQP1-expressing cells. RESULTS: AQP1 was expressed only in tumor cells. AQP1 dose-dependently accelerated cell migration and invasion, but not proliferation, in GBM cell lines. AQP1 also upregulated cathepsin B, focal adhesion kinase and activities of matrix metalloproteinase 9. AQP1 in GBM cells induced wall thickness of ECV304, vascular endothelial cells, in a contact-dependent manner. Downregulation of thrombospondin type 1 domain containing 7A (THSD7A) was identified in AQP1-expressing GBM cells in vitro, and was negatively correlated with AQP1 expression in human GBM specimens. CONCLUSION: AQP1 is involved in tumor malignancy by facilitating the migration and invasion of GBM cells, and promoting the formation of vascular beds that are characteristic of GBM by downregulating THSD7A.


Assuntos
Aquaporina 1/metabolismo , Biomarcadores Tumorais/metabolismo , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Glioblastoma/irrigação sanguínea , Neovascularização Patológica/patologia , Trombospondinas/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Aquaporina 1/genética , Biomarcadores Tumorais/genética , Proliferação de Células , Regulação para Baixo , Feminino , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Prognóstico , Taxa de Sobrevida , Trombospondinas/genética , Trombospondinas/metabolismo , Células Tumorais Cultivadas
11.
Cells ; 9(1)2019 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-31881755

RESUMO

Recent studies provide evidence to support that cluster of differentiation 38 (CD38) and CD157 meaningfully act in the brain as neuroregulators. They primarily affect social behaviors. Social behaviors are impaired in Cd38 and Cd157 knockout mice. Single-nucleotide polymorphisms of the CD38 and CD157/BST1 genes are associated with multiple neurological and psychiatric conditions, including autism spectrum disorder, Parkinson's disease, and schizophrenia. In addition, both antigens are related to infectious and immunoregulational processes. The most important clues to demonstrate how these molecules play a role in the brain are oxytocin (OT) and the OT system. OT is axo-dendritically secreted into the brain from OT-containing neurons and causes activation of OT receptors mainly on hypothalamic neurons. Here, we overview the CD38/CD157-dependent OT release mechanism as the initiation step for social behavior. The receptor for advanced glycation end-products (RAGE) is a newly identified molecule as an OT binding protein and serves as a transporter of OT to the brain, crossing over the blood-brain barrier, resulting in the regulation of brain OT levels. We point out new roles of CD38 and CD157 during neuronal development and aging in relation to nicotinamide adenine dinucleotide+ levels in embryonic and adult nervous systems. Finally, we discuss how CD38, CD157, and RAGE are crucial for social recognition and behavior in daily life.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , ADP-Ribosil Ciclase/metabolismo , Antígenos CD/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Comportamento Social , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Biomarcadores , Encéfalo/metabolismo , Sinalização do Cálcio , Ativação Enzimática , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Humanos , Imuno-Histoquímica , Camundongos Knockout , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Ocitocina , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Receptor para Produtos Finais de Glicação Avançada/genética , Canais de Cátion TRPM/metabolismo
12.
Anticancer Res ; 39(10): 5393-5401, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570434

RESUMO

BACKGROUND/AIM: Local recurrence of hepatocellular carcinoma (HCC) after thermal coagulation therapy may be associated with an aggressive phenotypic change. This study focused on the thermal effects on HCC cells and evaluated the heat shock response and phenotypic changes after heat treatment. MATERIALS AND METHODS: HepG2 and HuH7 cells were used. After heat treatment at 37-50°C for 5-30 min, we assessed their survival rate, induction of heat shock protein (HSP)70 promoter, proliferation rate, induction of the epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related markers. RESULTS: Induction of HSP70 promoter per surviving cell was maximized after 10 min of heat treatment at 48°C. Induction of EMT and CSC-related markers was also observed. CONCLUSION: Sub-lethal heat treatment causes large heat shock response to surviving HCC cells and induce EMT-like and CSC-like phenotypic changes that might contribute to increased aggressiveness.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Resposta ao Choque Térmico/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Transição Epitelial-Mesenquimal/genética , Proteínas de Choque Térmico HSP70/genética , Células Hep G2 , Temperatura Alta , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Taxa de Sobrevida
13.
Commun Biol ; 2: 76, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820471

RESUMO

Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bonding behaviours. Mice lacking secreted oxcytocin (Oxt -/-, Cd38 -/-) or its receptor (Oxtr -/-) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt -/- and Cd38 -/-, but not Oxtr -/- mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager -/- male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager -/- mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.


Assuntos
Encéfalo/metabolismo , Comportamento Materno/fisiologia , Apego ao Objeto , Ocitocina/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Comportamento Materno/psicologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptor para Produtos Finais de Glicação Avançada/genética , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo
14.
J Surg Res ; 234: 132-138, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30527465

RESUMO

BACKGROUND: Neutrophil extracellular traps (NETs) play a crucial role in host defense, but excess and prolonged interaction of NETs with platelets can cause severe inflammation and host organ damage. Modification of histone H3 by citrullination is involved in in vitro NET formation. The phosphodiesterase III inhibitor, cilostazol (Ciz), which has a protective effect on liver sinusoidal endothelial cells and inhibits platelet aggregation, may prevent organ damage caused by excess NETosis. In this study, we investigated whether citrullinated histone H3 (H3Cit) could serve as a biomarker for the detection of critical liver damage in sepsis and the efficacy of phosphodiesterase-III inhibition for preventing the liver dysfunction induced by NETosis. MATERIALS AND METHODS: Mice injected with lipopolysaccharide (LPS; 1 mg/kg) were used as a sepsis model with or without treatment with Ciz (200 mg/kg). H3Cit, myeloperoxidase, and neutrophil elastase levels were measured by immunohistochemistry. We evaluated H3Cit-positive neutrophils in the peripheral blood by flow cytometry. RESULTS: Immunohistochemistry revealed that H3Cit-, neutrophil elastase-, and myeloperoxidase-positive cell numbers in the livers peaked at 12 h after LPS administration. However, flow cytometry showed a significant increase in H3Cit-positive neutrophils in the peripheral blood only 4 h after LPS injection. Treatment with Ciz significantly ameliorated all parameters. CONCLUSIONS: H3Cit is a useful biomarker for early detection of NETosis or liver dysfunction, and Ciz may be an effective treatment for septic liver damage.


Assuntos
Armadilhas Extracelulares , Histonas/metabolismo , Hepatopatias/imunologia , Sepse/imunologia , Animais , Biomarcadores/metabolismo , Cilostazol , Citrulinação , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos BALB C
15.
In Vivo ; 32(6): 1409-1417, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30348695

RESUMO

BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, is a form of drug-induced liver injury, the initial morphological changes associated with which occur in liver sinusoidal endothelial cells (LSECs). Recombinant human soluble thrombomodulin (rTM) is reported to have anti-inflammatory and cytoprotective effects. Therefore, we investigated the ability of rTM to protect endothelial cells and enhance their functions in a monocrotaline (MCT)-induced model of SOS. MATERIALS AND METHODS: Human umbilical vein endothelial cells were assessed in vitro following administration of MCT (2-4 mM) with/without rTM (10-100 ng/ml) to investigate the effect of rTM on cell proliferation and apoptosis. In vivo experiments were performed with Crl:CD1 mice divided into three groups: rTM (rTM + MCT), placebo (control diluent + MCT), and control (control diluent only). LSECs [cluster of differentiation (CD) 31+CD34+ vascular endothelial growth factor receptor 3 (VEGFR3)+ cells] from these mice were identified using fluorescence-activated cell sorting and assessed by quantitative real-time polymerase chain reaction (qPCR). RESULTS: In vitro, caspase-3 and -7 activities were significantly lower and cell viability (as assessed by MTT assays) significantly higher in the rTM group than in the placebo group. Moreover, levels of p-AKT increased upon rTM administration. In vivo, damage to LSECs in zone 3 of the hepatic acinus was attenuated and the number of LSECs were maintained in the rTM group, in contrast to the placebo group. Furthermore, expression of Nos3 (encoding endothelial nitric oxide synthase) was higher and that of plasminogen activator inhibitor 1 (Pai1) lower in LSECs from mice in the rTM group than in those from the placebo group. CONCLUSION: rTM can attenuate SOS by protecting LSECs and enhancing their functions.


Assuntos
Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Hepatopatia Veno-Oclusiva/metabolismo , Hepatopatia Veno-Oclusiva/patologia , Proteínas Recombinantes/farmacologia , Trombomodulina/metabolismo , Animais , Biomarcadores , Caspase 3/metabolismo , Citoproteção/efeitos dos fármacos , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunofenotipagem , Camundongos
16.
Cancer Med ; 7(5): 1944-1954, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29573200

RESUMO

Surgical resection is the only treatment for chondrosarcomas, because of their resistance to chemotherapy and radiotherapy; therefore, additional strategies are crucial to treat chondrosarcomas. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor, which has been reported as a possible therapeutic target in certain malignancies including chondrosarcomas. In this study, we demonstrated that a nonsteroidal anti-inflammatory drug, zaltoprofen, could induce PPARγ activation and elicit anti-tumor effects in chondrosarcoma cells. Zaltoprofen was found to induce expressions of PPARγ mRNA and protein in human chondrosarcoma SW1353 and OUMS27 cells, and induce PPARγ-responsible promoter reporter activities. Inhibitory effects of zaltoprofen were observed on cell viability, proliferation, migration, and invasion, and the activity of matrix metalloproteinase-2 (MMP2); these effects were dependent on PPARγ activation and evidenced by silencing PPARγ. Moreover, we showed a case of a patient with cervical chondrosarcoma (grade 2), who was treated with zaltoprofen and has been free from disease progression for more than 2 years. Histopathological findings revealed enhanced expression of PPARγ and reduced expression of MMP2 after administration of zaltoprofen. These findings demonstrate that zaltoprofen could be a promising drug against the malignant phenotypes in chondrosarcomas via activation of PPARγ and inhibition of MMP2 activity.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Benzopiranos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Condrossarcoma/tratamento farmacológico , Metaloproteinase 2 da Matriz/genética , PPAR gama/genética , Propionatos/administração & dosagem , Adulto , Anti-Inflamatórios não Esteroides/farmacologia , Benzopiranos/farmacologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/cirurgia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Condrossarcoma/genética , Condrossarcoma/metabolismo , Condrossarcoma/cirurgia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pescoço , PPAR gama/metabolismo , Regiões Promotoras Genéticas , Propionatos/farmacologia , Resultado do Tratamento
17.
Oncol Lett ; 15(4): 4627-4634, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29541234

RESUMO

Receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in the pathogenesis of certain types of cancer. In the present study, papaverine was identified as a RAGE inhibitor using the conversion to small molecules through optimized-peptide strategy drug design system. Papaverine significantly inhibited RAGE-dependent nuclear factor κ-B activation driven by high mobility group box-1, a RAGE ligand. Using RAGE- or dominant-negative RAGE-expressing HT1080 human fibrosarcoma cells, the present study revealed that papaverine suppressed RAGE-dependent cell proliferation and migration dose-dependently. Furthermore, papaverine significantly inhibited cell invasion. The results of the present study suggested that papaverine could inhibit RAGE, and provided novel insights into the field of RAGE biology, particularly anticancer therapies.

18.
Sci Rep ; 7(1): 7883, 2017 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801574

RESUMO

Plasma oxytocin (OT) originates from secretion from the pituitary gland into the circulation and from absorption of OT in mother's milk into the blood via intestinal permeability. However, the molecular mechanism underlying the absorption of OT remains unclear. Here, we report that plasma OT concentrations increased within 10 min after oral delivery in postnatal day 1-7 mice. However, in Receptors for Advanced Glycation End Products (RAGE) knockout mice after postnatal day 3, an identical OT increase was not observed. In adult mice, plasma OT was also increased in a RAGE-dependent manner after oral delivery or direct administration into the intestinal tract. Mass spectrometry evaluated that OT was absorbed intact. RAGE was abundant in the intestinal epithelial cells in both suckling pups and adults. These data highlight that OT is transmitted via a receptor-mediated process with RAGE and suggest that oral OT supplementation may be advantageous in OT drug development.


Assuntos
Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Ocitocina/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Animais Recém-Nascidos , Feminino , Lactação , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ocitocina/administração & dosagem , Ocitocina/sangue , Permeabilidade , Receptor para Produtos Finais de Glicação Avançada/genética
19.
Mol Med Rep ; 16(1): 403-409, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28534951

RESUMO

Patients with diabetes are vulnerable to delayed bone fracture healing or pseudoarthrosis. Chronic sustained hyperglycemia, reactive intermediate derivatives of glucose metabolism, such as methylglyoxal (MGO), and advanced glycation end­products (AGEs) are implicated in diabetic complications. In the present study, it was examined whether MGO is able to cause disturbed bone healing in diabetes. Diabetes was induced in male mice by injection of streptozotocin (50 mg/kg) for 5 days. A bone defect (1.0­mm diameter) was created in the left distal femur, and bone repair was assessed from an examination of computed tomography scans. ST2 cells were exposed to MGO (0­400 µM) to investigate osteoblastic differentiation, cell viability, and damage. Consequently, blood glucose and hemoglobin A1c levels in diabetic mice were determined to be 493±14.1 mg/dl and 8.0±0.05%, respectively. Compared with non­diabetic control mice, diabetic mice exhibited markedly delayed bone healing, with increased levels of the MGO­derived AGEs, Nε­(carboxymethyl)­lysine and Nδ­(5­hydro­5­methyl­4­imidazolone­2­yl)­ornithine, in the sera and femurs. MGO inhibited the osteoblastic differentiation of ST2 cells in a dose­dependent manner, and markedly decreased cell proliferation through cytotoxicity. In conclusion, MGO has been demonstrated to cause impaired osteoblastic differentiation and delayed bone repair in diabetes. Therefore, detoxification of MGO may be a potentially useful strategy against bone problems in patients with diabetes.


Assuntos
Complicações do Diabetes/metabolismo , Fraturas Ósseas/complicações , Fraturas Ósseas/metabolismo , Aldeído Pirúvico/metabolismo , Cicatrização , Animais , Glicemia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Linhagem Celular , Diabetes Mellitus Experimental , Modelos Animais de Doenças , Fraturas Ósseas/diagnóstico por imagem , Produtos Finais de Glicação Avançada/metabolismo , Masculino , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Aldeído Pirúvico/farmacologia , Fatores de Tempo , Cicatrização/efeitos dos fármacos , Microtomografia por Raio-X
20.
Oncol Rep ; 37(6): 3341-3350, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28440494

RESUMO

Tumor-associated macrophages of the M2 phenotype promote tumor proliferation and are associated with a poor prognosis in patients with various malignancies, including gastric cancer with peritoneal dissemination. The present study assessed whether paclitaxel (PTX) suppresses M2 macrophages, by acting as a Toll-like receptor 4 (TLR4) agonist. Macrophages derived from the THP-1 monocytic cell line and peripheral blood mononuclear cell (PBMC)-derived macrophages were cultured with gastric cancer cells in medium containing PTX, at a concentration that did not affect cell proliferation. The effects of PTX on macrophage expression of CD204, a marker of M2 macrophages and NOS2, a marker of M1 macrophages, was evaluated by western blotting. The ability of PTX to stimulate intranuclear translocation of NF-κB was determined by evaluating the expression of the p65 subunit of NF-κB. In THP-1 macrophages, low-dose PTX (1 and 5 nM) inhibited the expression of CD204, enhanced the expression of NOS2, and significantly suppressed the phosphorylation of Stat3, which is essential for the M2 phenotype. Low-dose PTX also inhibited CD204 expression in primary macrophages derived from PBMCs. PTX treatment of THP-1 macrophages for 1 h induced marked intranuclear translocation of NF-κB p65. Low-dose PTX inhibited the M2 phenotype and induced the M1 phenotype via TLR4 signaling, suggesting that low-dose PTX can alter the macrophage phenotype, whereas clinical doses can kill cancer cells. These results suggest that the anticancer effects of PTX are due both to its cytotoxic and immunomodulatory activities.


Assuntos
Paclitaxel/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Receptor 4 Toll-Like/genética , Fator de Transcrição RelA/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Óxido Nítrico Sintase Tipo II/genética , Fator de Transcrição STAT3/genética , Receptores Depuradores Classe A/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
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