RESUMO
BACKGROUND: Serratia marcescens is a gram-negative bacterium that is widespread in the environment. S. marcescens bacteremia can be fatal during pregnancy and cause persistent chorioamnionitis. This study reports an outbreak of Serratia marcescens bloodstream infection (BSI) among high-risk pregnant women in an obstetric ward. The purpose of this study is to report our experience with the usefulness of the ATP test in hospital environmental management and to confirm that bloodstream infections of patients with the same strain were correlated by WGS testing. METHODS: This retrospective study collected the data of inpatients with S. marcescens bacteremia in obstetric ward for high-risk pregnant women from August 22, 2021, to October 14, 2021. We performed: an adenosine triphosphate (ATP) bioluminescence test in the environment with a high-contact area; environmental culture; on-site monitoring and staff education; and whole-genome sequencing (WGS) to evaluate genetic relationships among S. marcescens isolates. RESULTS: S. marcescens BSI occurred in four consecutive patients. None of the patients had central venous catheters. An ATP bioluminescence test revealed that high-contact areas and areas for injection preparation were not clean (≥ 1000 relative light units). However, S. marcescens was not identified in the environmental cultures, likely due to intensive environmental cleaning and discarding of potentially contaminated specimens before the culture test. On-site monitoring and education were conducted for 1 month. There were no further reports of BSI until 6 months after the last patient was discharged. WGS performed on three isolates from three patients indicated that the isolated S. marcescens was likely from the same strain. CONCLUSIONS: We controlled an S. marcescens outbreak by improving environmental cleaning as well as education of and behavior changes in healthcare workers. Using the ATP bioluminescence test can provide feedback on environmental cleaning and education. WGS played a role in determining the spread of BSI caused by the same strain.
Assuntos
Bacteriemia , Infecção Hospitalar , Sepse , Infecções por Serratia , Gravidez , Humanos , Feminino , Recém-Nascido , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/microbiologia , Gestantes , Serratia marcescens/genética , Estudos Retrospectivos , Infecções por Serratia/epidemiologia , Infecções por Serratia/microbiologia , Sepse/epidemiologia , Surtos de Doenças , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Hospitais , Trifosfato de Adenosina , Unidades de Terapia Intensiva NeonatalRESUMO
Bcl-2-interacting cell death suppressor (BIS), also called as BAG3, regulates numerous physiological processes, such as apoptosis, protein quality control, and senescence. Whole-body Bis-knockout (KO) mice exhibit early lethality following cardiac and skeletal muscle dysfunction. The first attempt to generate organ-specific knockout mice resulted in constitutive or inducible heart-specific Bis-knockout mice, which exhibited cardiac dilation and underwent premature death. Here, we generated hepatocyte-specific Bis-knockout (Bis-HKO) mice and found no abnormalities in metabolic function and survival. However, depletion of HSPB8 and accumulation of p62 indicated impaired autophagy in Bis-HKO livers. Interestingly, the number of peroxisomes wrapped by phagophore membranes increased as evidenced by transmission electron microscopy analysis, indicating defects in the progression of pexophagy. In addition, increased dihydroethidine intensities and histone H3 K9me3-positive nuclei indicated increased oxidative stress and senescence induction in Bis-HKO livers. Mechanistically, p27 was upregulated in Bis-HKO livers. In SNU368 hepatocellular carcinoma cells, BIS depletion led to p27 upregulation, and increase in histone H3 K9me3 levels and senescence-associated ß-galactosidase staining; therefore, reproducing the in vivo senescence phenotype. Despite the observation of no metabolic abnormalities, BIS depletion led to defective autophagy, increased oxidative stress, and senescence in Bis-HKO livers. Collectively, our results suggest a role for BIS in maintaining liver regeneration potential under pathological conditions.
Assuntos
Histonas , Neoplasias Hepáticas , Animais , Senescência Celular/genética , Hepatócitos/metabolismo , Histonas/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Regeneração Hepática/fisiologia , Camundongos , Camundongos KnockoutRESUMO
Anterior gradient protein 2 homolog (AGR2), an endoplasmic reticulum protein, is secreted in the tumor microenvironment. AGR2 is a member of the disulfide isomerase family, is highly expressed in multiple cancers, and promotes cancer metastasis. In this study, we found that etravirine, which is a non-nucleoside reverse transcriptase inhibitor, could induce AGR2 degradation via autophagy. Moreover, etravirine diminished proliferation, migration, and invasion in vitro. Moreover, in an orthotopic xenograft mouse model, the combination of etravirine and paclitaxel significantly suppressed cancer progression and metastasis. This drug may be a promising therapeutic agent for the treatment of ovarian cancer.
Assuntos
Mucoproteínas/metabolismo , Nitrilas/administração & dosagem , Proteínas Oncogênicas/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Pirimidinas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Mucoproteínas/genética , Metástase Neoplásica , Nitrilas/farmacologia , Proteínas Oncogênicas/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Paclitaxel/farmacologia , Proteólise , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The purpose of the present study is to improve the endothelial progenitor cells (EPC) activation, proliferation, and angiogenesis using enzyme-aided extraction of fucoidan by amyloglucosidase (EAEF-AMG). Enzyme-aided extraction of fucoidan by AMG (EAEF-AMG) significantly increased EPC proliferation by reducing the reactive oxygen species (ROS) and decreasing apoptosis. Notably, EAEF-AMG treated EPCs repressed the colocalization of TSC2/LAMP1 and promoted perinuclear localization of mTOR/LAMP1 and mTOR/Rheb. Moreover, EAEF-AMG enhanced EPC functionalities, including tube formation, cell migration, and wound healing via regulation of AKT/Rheb signaling. Our data provided cell priming protocols to enhance therapeutic applications of EPCs using bioactive compounds for the treatment of CVD.
Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Glucana 1,4-alfa-Glucosidase/metabolismo , Polissacarídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Progenitoras Endoteliais/metabolismo , Humanos , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Cicatrização/efeitos dos fármacosRESUMO
Angiogenesis plays an essential role in embryo development, tissue repair, inflammatory diseases, and tumor growth. In the present study, we showed that endothelial nitric oxide synthase (eNOS) regulates retinal angiogenesis. Mice that lack eNOS showed growth retardation, and retinal vessel development was significantly delayed. In addition, the number of tip cells and filopodia length were significantly reduced in mice lacking eNOS. Retinal endothelial cell proliferation was significantly blocked in mice lacking eNOS, and EMG-2-induced endothelial cell sprouting was significantly reduced in aortic vessels isolated from eNOS-deficient mice. Finally, pericyte recruitment to endothelial cells and vascular smooth muscle cell coverage to blood vessels were attenuated in mice lacking eNOS. Taken together, we suggest that the endothelial cell function and blood vessel maturation are regulated by eNOS during retinal angiogenesis.
RESUMO
During the pathogenesis of atherosclerosis, adhesion of monocytes to vascular endothelium and subsequent migration across the endothelium has been recognized as a key process in the chronic inflammatory response in atherosclerosis. As type 2 diabetes is closely associated with the pathogenesis of atherosclerosis, we investigated whether monocyte adhesion and migration were affected by insulin. We found that insulin activated Akt and induced subsequent migration in THP-1. However, glucose and insulin-like growth factor-1, which is a growth factor that is structurally similar to insulin, were not effective. Insulin-dependent migration of THP-1 was blocked by inhibition of PI3K or Akt and by silencing of Akt1. Insulin-dependent migration of bone marrow-derived monocytic cells (BDMCs) was attenuated by inhibition of PI3K and Akt. In addition, BDMCs from Akt1(-/-) mice showed defects in insulin-dependent migration. Stimulation of THP-1 with insulin caused adhesion with human vein endothelial cells (HUVECs) that was blocked by silencing of Akt1. However, stimulation of HUVECs did not cause adhesion with THP-1. Moreover, BDMCs from Akt1(-/-) mice showed defects in insulin-dependent adhesion with HUVECs. Insulin induced surface expression of Mac-1, and neutralization of Mac-1 blocked insulin-induced adhesion of THP-1 as well as BDMCs. Surface expression of Mac-1 was blocked in THP-1 with silenced Akt1, and in BDMCs isolated from mice lacking Akt1. Finally, trans-endothelial migration of THP-1 and BDMCs was blocked by Mac-1-neutralizing antibody, in THP-1 with silenced Akt1 and in BDMCs from Akt1(-/-) mice. These results suggest that insulin stimulates monocyte trans-endothelial migration through Akt-dependent surface expression of Mac-1, which may be part of the atherogenesis in type 2 diabetes.
Assuntos
Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Insulina/farmacologia , Antígeno de Macrófago 1/metabolismo , Monócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/fisiologia , Animais , Western Blotting , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/citologia , Monócitos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , RNA Interferente Pequeno/genéticaRESUMO
In this study, we investigated the role of Akt1 isoform in phenotypic change of vascular smooth muscle cells (VSMCs) and neointima formation. Laminin-induced conversion of synthetic VSMCs into contractile VSMCs was measured by expression of marker proteins for contractile VSMCs and collagen gel contraction assay. Culture of synthetic VSMCs on laminin-coated plates induced expression of marker proteins for contractile VSMCs and showed contraction in response to angiotensin II (AngII) stimulation. Silencing integrin-linked kinase attenuated activation of Akt and blocked phenotypic conversion of VSMCs resulting in the loss of AngII-dependent contraction. Laminin-induced phenotypic conversion of VSMCs was abrogated by phosphatidylinositol 3-kinase inhibitor or in cells silencing Akt1 but not Akt2. Proliferation of contractile VSMCs on laminin-coated plate was enhanced in cells silencing Akt1 whereas silencing Akt2 did not affect. Promoter activity of myocardin and SM22α was enhanced in contractile phenotype and overexpression of myocardin stimulated promoter activity of SM22α in synthetic phenotype. Promoter activity of myocardin and SM22α was reduced in cells silencing Akt1 and promoter activity of SM22α was restored by overexpression of myocardin in cells silencing Akt1. However, silencing of Akt2 affected neither promoter activity of myocardin nor SM22α. Finally, neointima formation in carotid artery ligation and high fat-diet-induced atherosclerosis was facilitated in mice lacking Akt1. This study demonstrates that Akt1 isoform stimulates laminin-induced phenotypic conversion of synthetic VSMCs by regulating the expression of myocardin. VSMCs become susceptible to shifting from contractile to synthetic phenotype by the loss of Akt1 in pathological conditions.
RESUMO
We investigated a light emission mechanism of blue phosphorescent organic light emitting diodes (PHOLEDs), using a stepwise doping profile of 2, 8, and 14 wt.% within the emitting layer (EML). We fabricated several blue PHOLEDs with phosphorescent blue emitter iridium(III) bis[(4,6-difluorophenyl)-pyridinato-N,C2]picolinate doped in N,N'-dicarbazolyl-3,5-benzene as a p-type host material. A blue PHOLED with the highest doping concentration as part of the EML close to an electron transporting layer showed a maximum luminous efficiency of 20.74 cd/A, and a maximum external quantum efficiency of 10.52%. This can be explained by effective electron injection through a highly doped EML side. Additionally, a white OLED based on the doping profile was fabricated with two thin red EMLs within a blue EML maintaining a thickness of 30 nm for the entire EML. Keywords: Blue Phosphorescent Organic Light Emitting Diodes, Stepwise Doping Structure, Charge Trapping Effect.
Assuntos
Cor , Iluminação/instrumentação , Nanocompostos/química , Compostos Orgânicos/química , Semicondutores , Transferência de Energia , Desenho de Equipamento , Análise de Falha de Equipamento , Teste de Materiais , Nanocompostos/ultraestruturaRESUMO
Bio-based polymer materials from renewable resources have recently become a growing research focus. Herein, a novel thermoplastic elastomer is developed via controlled/living radical polymerization of plant-derived itaconic acid derivatives, which are some of the most abundant renewable acrylic monomers obtained via the fermentation of starch. The reversible addition-fragmentation chain-transfer (RAFT) polymerizations of itaconic acid imides, such as N-phenylitaconimide and N-(p-tolyl)itaconimide, and itaconic acid esters, such as di-n-butyl itaconate and bis(2-ethylhexyl) itaconate, are examined using a series of RAFT agents to afford well-defined polymers. The number-average molecular weights of these polymers increase with the monomer conversion while retaining relatively narrow molecular weight distributions. Based on the successful controlled/living polymerization, sequential block copolymerization is subsequently investigated using mono- and di-functional RAFT agents to produce block copolymers with soft poly(itaconate) and hard poly(itaconimide) segments. The properties of the obtained triblock copolymer are evaluated as bio-based acrylic thermoplastic elastomers.
Assuntos
Acrilatos/síntese química , Elastômeros/química , Succinatos/química , Espectroscopia de Ressonância Magnética , Polimerização , Reprodutibilidade dos TestesRESUMO
Green phosphorescent organic light emitting diodes (PHOLEDs) were developed using a mixed layer system. They were fabricated with 4,4'-N,N'-dicarbazolyl-biphenyl (CBP) and typical charge transporting materials, which are 4,4'-bis[N-(naphthyl)-N-phenylamino]biphenyl (NPB) as a hole transporting material and 1,3,5-tris(N-phenylbenzimidazole-2-yl)benzene (TPBi) as an electron transporting material, mixed at each interface in a stacked organic layer to reduce the hole injection barrier and extend the recombination zone. We introduced a mixed layer for the hole transporting layer side, the electron transporting layer side, and on both sides to make a bulk heterojunction. This reduced the driving voltage, and the luminous efficiency (LE) was increased to 500 cd/m2. The optimized device showed a maximum LE of 59.87 cd/A and a maximum external quantum efficiency of 17.52%.
Assuntos
Substâncias Luminescentes/química , Semicondutores , Compostos de Bifenilo/química , Desenho de Equipamento , Nanotecnologia/instrumentação , Nanotecnologia/métodosRESUMO
We fabricated a flexible bottom-emitting white organic light-emitting diode (BEWOLED) with a structure of PET/Ni/Ag/Ni (3/6/3 nm)/ NPB (50 nm)/mCP (10 nm)/7% FIrpic:mCP (10 nm)/3% Ir(pq)(2) acac:TPBi (5 nm)/7% FIrpic:TPBi (5 nm)/TPBi (10 nm)/Liq (2 nm)/ Al (100 nm). To improve the performance of the BEWOLED, a multilayered metal stack anode of Ni/Ag/Ni treated with oxygen plasma for 60 sec was introduced into the OLED devices. The Ni/Ag/Ni anode effectively enhanced the probability of hole-electron recombination due to an efficient hole injection into and charge balance in an emitting layer. By comparing with a reference WOLED using ITO on glass, it is verified that the flexible BEWOLED showed a similar or better electroluminescence (EL) performance.
Assuntos
Iluminação/instrumentação , Microeletrodos , Nanotecnologia/instrumentação , Nanofios/química , Níquel/química , Semicondutores , Prata/química , Cor , Módulo de Elasticidade , Desenho de Equipamento , Análise de Falha de Equipamento , Nanofios/ultraestrutura , RefratometriaRESUMO
We have demonstrated highly efficient blue phosphorescent organic light-emitting diodes (PHOLEDs) using iridium (III) bis[(4,6-di-fluoropheny)-pyridinato-N,C2] picolinate (Flrpic) doped in three kinds of host materials, such as 9-(4-(triphenylsilyl)phenyl)-9H-carbazole (SPC), N,N'-dicarbazolyl-3,5-benzene (mCP), and 2,2',2"-(1,3,5-benzenetriyl)tris-[1-phenyl-1H-benzimidazole] (TPBi) as triple-emitting layer (T-EML). The properties of device with T-EML using the stepwise structure was found to be superior to the other blue PHOLEDs and exhibited a maximum luminous efficiency of 23.02 cd/A, a maximum external quantum efficiency of 11.09%, and a maximum power efficiency of 14.89 lm/W, respectively. An optimal blue device has improving charge balance and triplet excitons confinement within emitting layers (EMLs) each. Additionally, we also fabricated white PHOLED using a phosphorescent red dopant, bis(2-phenylquinolinato)-acetylacetonate iridium III (Ir(pq)2acac) doped in mCP and TPBi between blue EMLs. The properties of white PHOLED showed a maximum luminous efficiency and a maximum external quantum efficiency of 33.03 cd/A and 16.95%, respectively. It also showed the white emission with CIEx,y coordinates of (x = 0.36, y = 0.39) at 10 V.
RESUMO
AIM: Hormones and inflammation have been implicated in the pathological process of endometriosis; therefore, we investigated the combined effects of 17ß-estradiol (E2) and peritoneal fluid obtained from patients with endometriosis (ePF) or a control peritoneal fluid (cPF) obtained from patients without endometriosis on the release of monocyte chemotactic protein-1 (MCP-1) by monocytes and the role of signaling pathways. METHODS: Monocytes were cultured with ePF and cPF in the presence of E2; the MCP-1 levels in the supernatants were then measured by ELISA. In addition, mitogen activated protein kinase (MAPK) activation was measured by Western blotting of phosphorylated proteins. RESULTS: E2 down-regulated MCP-1 release by lipopolysaccharide- or cPF-treated monocytes, but failed to suppress its release by ePF-treated monocytes. The release of MCP-1 by ePF- and cPF-treated monocytes was efficiently abrogated by p38 mitogen activated protein kinase (MAPK) inhibitors; however, the MCP-1 release by cPF-treated monocytes, but not by ePF-treated monocytes, was blocked by a MAPK kinase inhibitor. In addition, ePF and cPF induced the phosphorylation of extracellular stress regulated kinase (ERK)1/2, p38 MAPK and c-Jun N-terminal kinase (JNK). E2 decreased the phosphorylation of p38 MAPK, but not ERK1/2 in ePF-treated monocytes; however, E2 decreased the phosphorylation of p38 MAPK, ERK1/2 and JNK in cPF-treated monocytes. CONCLUSIONS: The ability of E2 to modulate MCP-1 production is impaired in ePF-treated monocytes, which may be related to regulation of MAPK activity. These findings suggest that the failure of E2 to suppress ePF-treated production of MCP-1 may be involved in the pathogenesis of endometriosis.
Assuntos
Líquido Ascítico/metabolismo , Quimiocina CCL2/metabolismo , Endometriose/metabolismo , Estradiol/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/metabolismo , Doenças Ovarianas/metabolismo , Biomarcadores/metabolismo , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Técnicas In Vitro , Sistema de Sinalização das MAP Quinases , MasculinoRESUMO
RATIONALE: Cervical cancer complicated by irreducible complete uterine prolapse in elderly patients is extremely rare. No standard treatment has been established for these conditions. PATIENT CONCERNS: A 74-year-old woman with a 30-year history of pelvic organ prolapse presented with irreducible complete uterine prolapse and a large exophytic mass involving the cervix and vaginal wall. DIAGNOSIS: Biopsy of the mass was performed at the referring institution and showed invasive verrucous-type squamous cell carcinoma. INTERVENTIONS: A prolapsed uterus with a tumor mass could not be manually reduced. After completion of concurrent chemoradiotherapy, the tumor mass in the prolapsed uterus decreased and could be reduced manually. Subsequently, the patient underwent hysterectomy and intra-abdominal uterosacral ligament suspension. OUTCOMES: At 19âmonths of postoperative follow-up, the patient remained disease-free and had no evidence of vault prolapse. LESSONS: This study has important clinical implications and may provide a therapeutic strategy to address unmet medical needs in combination with locally advanced cervical cancer complicated by irreducible complete uterine prolapse. These conditions were successfully treated using a multidisciplinary approach of chemoradiotherapy followed by radical hysterectomy and uterosacral ligament suspension.
Assuntos
Antineoplásicos/uso terapêutico , Histerectomia , Neoplasias do Colo do Útero/terapia , Prolapso Uterino/complicações , Idoso , Feminino , Humanos , Resultado do Tratamento , Neoplasias do Colo do Útero/complicações , Prolapso Uterino/cirurgia , ÚteroRESUMO
RATIONALE: Transvaginal evisceration of the small bowel is an extremely rare condition after hysterectomy, which requires urgent surgical intervention to prevent serious bowel morbidity and mortality. PATIENT CONCERNS: A 65-year-old woman presented with sudden-onset severe abdominal pain and a mass protruding through the vagina. The past surgical history was significant, with an abdominal hysterectomy for cervical cancer performed 11âweeks prior to presentation. DIAGNOSIS: Pelvic examination revealed prolapsed small-bowel loops (18-20âcm in length). Pelvic computed tomography scan confirmed the presence of transvaginal evisceration of the small bowel. INTERVENTIONS: Bowel reduction and urgent laparotomy were the selected treatment approaches for a detailed inspection and thorough washing of the intrα-abdominal cavity. A Foley catheter was inserted in the emergency room, with the subject in the lithotomy position. The prolapsed bowel loops spontaneously reduced without manual reduction, and the vault defect was repaired transvaginally. OUTCOMES: The patient experienced no postoperative complications and remained disease-free for 9months postoperatively. LESSONS: Transvaginal evisceration of the small bowel should be considered a surgical emergency. A multidisciplinary approach to prompt case management involving clinicians in gynecology, general surgery, and emergency medicine is vital for preventing serious consequences. Hysterectomy is the most frequently performed gynecological surgical procedure, and evisceration occurs most often after hysterectomy. Therefore, patients should be informed about this rare but possible hysterectomy complication.
Assuntos
Neoplasias do Colo do Útero , Dor Abdominal/cirurgia , Idoso , Feminino , Humanos , Histerectomia/efeitos adversos , Histerectomia/métodos , Intestino Delgado/cirurgia , Laparotomia/métodos , Prolapso , Neoplasias do Colo do Útero/cirurgia , Vagina/cirurgiaRESUMO
Oncogenic RhoA GTPase has been investigated as a mediator of pro-inflammatory responses and aggressive carcinogenesis. Among the various targets of RhoA-linked signals, pro-inflammatory prostaglandin E(2) (PGE(2)), a major prostaglandin metabolite, was assessed in epithelial cancer cells. RhoA activation increased PGE(2) levels and gene expression of the rate-limiting PGE(2) producing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase 1 (mPGES-1). In particular, human mPGES-1 was induced by RhoA via transcriptional activation in control and interleukin (IL)-1ß-activated cancer cells. To address the involvement of potent signaling pathways in RhoA-activated mPGES-1 induction, various signaling inhibitors were screened for their effects on mPGES-1 promoter activity. RhoA activation enhanced basal and IL-1ß-mediated phosphorylated nuclear factor-κB and extracellular signal-regulated kinase1/2 proteins, all of which were positively involved in RhoA-induced gene expression of mPGES-1. As one potent down-stream transcription factor of ERK1/2 signals, early growth response gene 1 product also mediated RhoA-induced gene expression of mPGES-1 by enhancing transcriptional activity. Since oncogene-triggered PGE(2) production is a critical modulator of epithelial tumor cells, RhoA-associated mPGES-1 represents a promising chemo-preventive or therapeutic target for epithelial inflammation and its associated cancers.
Assuntos
Adenocarcinoma/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Oxirredutases Intramoleculares/genética , Proteína rhoA de Ligação ao GTP/metabolismo , Adenocarcinoma/genética , Linhagem Celular Tumoral , Dinoprostona/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Prostaglandina-E SintasesRESUMO
Recruitment and adhesion of exogenous endothelial progenitor cells (EPCs) or endogenously mobilized bone marrow mononuclear cells (BM MNCs) to the sites of ischemia is an important focus of cell therapy. This study sought to determine whether cilostazol enhances integrin-dependent homing of progenitor cells both in vitro and in vivo. In the in vitro experiments with human umbilical cord blood (HUCB)-derived EPCs, cilostazol (10 µM) stimulated up-regulation of integrins ß1, α1, and αv as well as 8-pCPT-2'-O-Me-cAMP (100 µM; 8-pCPT, Epac activator). Cilostazol and 8-pCPT significantly enhanced migration and adhesion of HUCB EPCs to a fibronectin-coated plate and endothelial cells, which were inhibited by KT5720 (PKA inhibitor, 1 µM) and GGTI-298 (Rap1 inhibitor, 20 µM). Cilostazol stimulated Epac1 expression and up-regulated the active Rap1, as did 8-pCPT, and they were suppressed by KT5720 (P < 0.001) and GGTI-298 (P < 0.001). 8-pCPT increased p-CREB expression and stimulated PKA activity, which was inhibited by KT5720, Rp-cAMPS, and GGTI-298. In addition, N(6)-benzoyl-cAMP (100 µM) increased Rap1 GTP expression, as did 8-pCPT; they were suppressed by Rp-cAMPS and GGTI-298. The in vivo experiments showed that cilostazol (30 mg/kg/day, orally for 7 days) significantly enhanced the integrin ß1 expression in the molecular layer and up-regulated homing of BM MNCs to the injured molecular layer with increased capillary density in mouse brain subjected to transient forebrain ischemia (n = 6, P < 0.001). In conclusion, cilostazol stimulated integrin expression and enhanced migration and adhesion of progenitor cells through cooperative activation of PKA and Epac signals; such activity may improve the efficacy of cell therapy for ischemic disease.
Assuntos
Quimiotaxia/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Integrina beta1/fisiologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Tetrazóis/farmacologia , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/terapia , Células Cultivadas , Quimiotaxia/fisiologia , Cilostazol , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Modelos Animais de Doenças , Humanos , Recém-Nascido , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Tetrazóis/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
PURPOSE: Chemokines have been implicated in the pathological process of endometriosis. We compared the effects of peritoneal fluid obtained from patients with endometriosis (ePF) and controls without endometriosis (cPF) on the release of monocyte-specific CC chemokines such as monocyte chemotactic protein-1 (MCP-1), regulated upon activation normal T cell expressed and secreted (RANTES), and macrophage inflammatory protein-1α (MIP-1α) by neutrophils, monocytes, and T cells. Moreover, we evaluated the correlation between the levels of chemokines in ePF and their release by these cells. METHODS: Cells were obtained from healthy young volunteers and cultured with ePF (n = 12) or cPF (n = 8). The chemokine levels in the ePF and the supernatants of cultured cells with ePF were then measured by ELISA. RESULTS: There was a positive correlation between the levels of MCP-1 and MIP-1α in ePF. The addition of ePF to the cell cultures failed to increase the release of MCP-1, RANTES, and MIP-1α when compared to cPF, but the levels of RANTES in ePF were positively correlated with the release of RANTES by ePF-treated monocytes and T cells. Moreover, there was a positive correlation between the levels of RANTES and MIP-1α released by neutrophils and between the levels of MCP-1 and MIP-1α released by T cells. Finally, the levels of RANTES released by monocyte-derived macrophages and monocytes cultured with ePF were positively correlated. CONCLUSIONS: These findings suggest that monocytes, neutrophils, and T cells release differential levels of MCP-1, RANTES, and MIP-1α in response to stimulation with ePF.
Assuntos
Líquido Ascítico/imunologia , Quimiocinas CC/metabolismo , Endometriose/imunologia , Leucócitos/imunologia , Monócitos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CCL3/metabolismo , Quimiocina CCL5/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Neutrófilos/imunologia , Estatística como Assunto , Linfócitos T/imunologiaRESUMO
Women and men share similar diseases; however, women have unique issues, including gynecologic diseases and diseases related to menstruation, menopause, and post menopause. In recent decades, scientists paid more attention to natural products and their derivatives because of their good tolerability and effectiveness in disease prevention and treatment. Olive oil is an essential component in the Mediterranean diet, a diet well known for its protective impact on human well-being. Investigation of the active components in olive oil, such as oleuropein and hydroxytyrosol, showed positive effects in various diseases. Their effects have been clarified in many suggested mechanisms and have shown promising results in animal and human studies, especially in breast cancer, ovarian cancer, postmenopausal osteoporosis, and other disorders. This review summarizes the current evidence of the role of olives and olive polyphenols in women's health issues and their potential implications in the treatment and prevention of health problems in women.
Assuntos
Dieta Saudável/métodos , Olea/química , Azeite de Oliva/farmacologia , Substâncias Protetoras/farmacologia , Saúde da Mulher , Animais , Dieta Mediterrânea , Feminino , Humanos , Glucosídeos Iridoides/farmacologia , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Óleos de Plantas/farmacologia , Polifenóis/farmacologiaRESUMO
Cilostazol is known to be a specific type III phosphodiesterase inhibitor, which promotes increased intracellular cAMP levels. We assessed the effect of cilostazol on production of angioneurins and chemokines and recruitment of new endothelial cells for vasculogenesis in a mouse model of transient forebrain ischemia. Pyramidal cell loss was prominently evident 3-28 days postischemia, which was markedly ameliorated by cilostazol treatment. Expression of angioneurins, including endothelial nitric oxide synthase, vascular endothelial growth factor, and brain-derived neurotrophic factor, was up-regulated by cilostazol treatment in the postischemic hippocampus. Cilostazol also increased Sca-1/vascular endothelial growth factor receptor-2 positive cells in the bone marrow and circulating peripheral blood and the number of stromal cell-derived factor-1alpha-positive cells in the molecular layer of the hippocampus, which colocalized with CD31. CXCR4 chemokine receptors were up-regulated by cilostazol in mouse bone marrow-derived endothelial progenitor cells, suggesting that cilostazol may be important in targeting or homing in of bone marrow-derived stem cells to areas of injured tissues. CD31-positive cells were colocalized with almost all bromodeoxyuridine-positive cells in the molecular layer, indicating stimulation of endothelial cell proliferation by cilostazol. These data suggest that cilostazol markedly enhances neovascularization in the hippocampus CA1 area in a mouse model of transient forebrain ischemia, providing a beneficial interface in which both bone marrow-derived endothelial progenitor cells and angioneurins influence neurogenesis in injured tissue. (c) 2010 Wiley-Liss, Inc.