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1.
J Sport Rehabil ; 33(1): 27-32, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37917973

RESUMO

CONTEXT: Nordic hamstring strength (NH strength) and single leg bridge test (SLBT) scores are used to predict the risk of hamstring strain injury. Although NH strength and SLBT scores may be related, the relationship between NH strength and SLBT score remains unknown. OBJECTIVES: This study investigated the relationship between NH strength and SLBT scores in university soccer players. DESIGN: Cross-sectional study. SETTING: Research laboratory. PARTICIPANTS: 38 male university soccer players. MAIN OUTCOME MEASURES: NH strength and SLBT scores. INTERVENTIONS: A participant was instructed to lean forward gradually at the slowest possible speed from a kneeling posture with the knee joint flexed 90° for the NH strength measurement. Participants in the SLBT crossed their arms over their chests, pushed down from their heels, and lifted their hips off the ground as many times as they could until they failed. We investigated the relationship between NH strength and SLBT scores in the left and right sides using Spearman rank correlation coefficient. Additionally, we calculated the percentage of left-right asymmetry in NH strength and SLBT scores and investigated the relationship between these variables using Pearson correlation coefficient. RESULTS: There were no significant correlations between NH strength and SLBT scores in the right (rs = .239, P = .16) and left (rs = .311, P = .065) legs. Furthermore, there was no significant relationship between NH strength and SLBT between-limb asymmetry (r = .073, P = .671). CONCLUSIONS: NH strength and SLBT scores could be different indexes, indicating either maximal muscle strength or muscle endurance. Thus, the findings suggested that when assessing risk factors for hamstring strain injury, both NH strength and SLBT scores should be measured.


Assuntos
Músculos Isquiossurais , Futebol , Humanos , Masculino , Futebol/lesões , Perna (Membro) , Estudos Transversais , Universidades , Músculos Isquiossurais/fisiologia , Força Muscular/fisiologia
2.
Cancer Sci ; 114(7): 2939-2950, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36939028

RESUMO

Small extracellular vesicles (sEV) contain various microRNAs (miRNAs) and play crucial roles in the tumor metastatic process. Although miR-29b levels in peritoneal exosomes were markedly reduced in patients with peritoneal metastases (PM), their role has not been fully clarified. In this study, we asked whether the replacement of miR-29b can affect the development of PM in a murine model. UE6E7T-12, human bone marrow-derived mesenchymal stem cells (BMSCs), were transfected with miR-29b-integrating recombinant lentiviral vector and sEV were isolated from culture supernatants using ultracentrifugation. The sEV contained markedly increased amounts of miR-29b compared with negative controls. Treatment with transforming growth factor-ß1 decreased the expression of E-cadherin and calretinin with increased expression of vimentin and fibronectin on human omental tissue-derived mesothelial cells (HPMCs). However, the effects were totally abrogated by adding miR-29b-rich sEV. The sEV inhibited proliferation and migration of HPMCs by 15% (p < 0.005, n = 6) and 70% (p < 0.005, n = 6), respectively, and inhibited adhesion of NUGC-4 and MKN45 to HPMCs by 90% (p < 0.0001, n = 5) and 77% (p < 0.0001, n = 5), respectively. MicroRNA-29b-rich murine sEV were similarly obtained using mouse BMSCs and examined for in vivo effects with a syngeneic murine model using YTN16P, a highly metastatic clone of gastric cancer cell. Intraperitoneal (IP) transfer of the sEV every 3 days markedly reduced the number of PM from YTN16P in the mesentery (p < 0.05, n = 6) and the omentum (p < 0.05, n = 6). Bone marrow mesenchymal stem cell-derived sEV are a useful carrier for IP administration of miR-29b, which can suppress the development of PM of gastric cancer.


Assuntos
Exossomos , Vesículas Extracelulares , MicroRNAs , Neoplasias Peritoneais , Neoplasias Gástricas , Animais , Humanos , Camundongos , Modelos Animais de Doenças , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Neoplasias Gástricas/patologia
3.
Gan To Kagaku Ryoho ; 50(13): 1435-1437, 2023 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-38303299

RESUMO

Although miR-29b levels in peritoneal exosomes was markedly reduced in patients with peritoneal metastases(PM), their role has not been fully clarified. Bone marrow derived mesenchymal stem cells(BMSC)were transfected with miR-29b- integrating lentivirus and exosomes isolated from culture supernatants using ultracentrifugation. The effects of the exosomes on human peritoneal mesothelial cells(HPMC)were examined in vitro. The in vivo effect of murine BMSC-derived exosomes was examined with a syngeneic PM model. Culture of HPMC with TGF-ß1 decreased expression of E-cadherin and calretinin with increased expression of vimentin, totally restored by adding miR-29b-rich exosomes. The exosomes inhibited proliferation and migration of HPMC, and inhibited adhesion of gastric cancer cells to HPMC. Intraperitoneal(IP)transfer of miR- 29b-rich exosomes every 3 days markedly reduced the number of PM of a murine gastric cancer cell, YTN16P, on the mesentery of C57/BL6 mice. IP administration of miR-29b-containing exosome suppresses the development of PM of gastric cancer.


Assuntos
Exossomos , MicroRNAs , Neoplasias Peritoneais , Neoplasias Gástricas , Animais , Humanos , Camundongos , MicroRNAs/genética , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Peritônio/patologia , Neoplasias Gástricas/patologia
4.
Gan To Kagaku Ryoho ; 50(13): 1884-1886, 2023 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-38303240

RESUMO

A 72-year-old man visited his local doctor for gastric discomfort. Esophagogastroduodenoscopy revealed a type 3 tumor on the gastric antrum, and histopathological examination revealed a moderately differentiated adenocarcinoma(tub2). The patient was referred to our hospital and CT scan revealed wall thickening with contrast effect in the gastric angle but no enlarged lymph nodes in the region. The patient was diagnosed as cT3N0M0, Stage ⅡB gastric cancer and underwent open distal gastrectomy and D2 lymph node dissection. No peritoneal dissemination was observed, but intraoperative laparoscopic cytology showed Class Ⅴ. The patient was diagnosed as CY1 Stage Ⅳ gastric cancer, and treated with S-1 plus Tmab therapy starting 1 month after surgery. One year postoperative follow-up CT revealed recurrence of peritoneal disseminations, and the patient was treated with nab-PTX as a second-line therapy. Tumor shrinkage was achieved steadily, and the peritoneal disseminations disappeared at the CT after 12 courses, resulting in cCR. Thereafter, cCR continued and treatment was terminated at the 17th course. Seven years have passed since the end of chemotherapy, and the patient is still alive without recurrence.


Assuntos
Gastrectomia , Neoplasias Gástricas , Idoso , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gastrectomia/efeitos adversos , Laparoscopia , Excisão de Linfonodo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia
5.
Gan To Kagaku Ryoho ; 50(13): 1895-1896, 2023 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-38303244

RESUMO

The patient was an 89-year-old man. He underwent laparoscopic distal gastrectomy for gastric cancer and was diagnosed as T1bN1M0, Stage ⅠB. Eight months after surgery, a CT scan showed an 18 mm-sized hypodense mass in S6 of the liver, and the patient was diagnosed with recurrent liver metastasis. He was treated with 3 courses of CapeOX therapy, and the response was judged as partial response(PR). Laparoscopic partial hepatic S6 resection was performed for the single liver metastasis. The pathological results showed liver metastasis of gastric cancer. Capecitabine was started as adjuvant chemotherapy. Nine months after surgery for liver metastasis, CT scan showed a 12 mm-sized single tumor in S5 and the patient was diagnosed with recurrent liver metastasis. The patient underwent laparoscopic partial hepatectomy after 3 courses of weekly paclitaxel plus ramucirumab therapy. The pathological result showed liver metastasis of gastric cancer. After the surgery, adjuvant chemotherapy was not administered according to the patient's request. Seven years have passed since the resection of the gastric cancer, and 5 years have passed since the resection of the second liver metastasis, and the patient has not had any recurrence.


Assuntos
Gastrectomia , Neoplasias Hepáticas , Idoso de 80 Anos ou mais , Humanos , Masculino , Gastrectomia/efeitos adversos , Hepatectomia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
6.
Colorectal Dis ; 24(10): 1140-1149, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35502766

RESUMO

AIM: The clinical efficacy of chemoradiotherapy (CRT) is largely dependent on host immune status. The aim of this study was to identify possible markers expressed on circulating mononuclear cells to predict tumour response in patients with locally advanced rectal cancer (LARC). METHODS: Peripheral blood samples were obtained from 47 patients diagnosed with LARC before and after CRT. The numbers of lymphocytes and monocyte subsets were analysed using flow cytometry. Based on clinical and pathological findings, patients were classified as high or low responders. RESULTS: Lymphocyte counts were markedly decreased after CRT. Total numbers of lymphocytes (p = 0.030) and CD4(+) T cells (p = 0.041) in post-CRT samples were significantly lower in low responders than in high responders. In contrast, monocyte counts were not reduced and the number of CD14dim (+) CD16(+) nonclassical (patrolling) monocytes were somewhat increased after CRT (p = 0.050). Moreover, the ratios of programmed cell death ligand 1 (PD-L1) (+) cells on patrolling monocytes before and after CRT were significantly higher in low responders than in high responders (p = 0.0046, p = 0.0006). The same trend was observed for classical and intermediate monocytes. The expression of PD-L1 on patrolling monocytes before CRT correlated inversely with the number of T cells and natural killer (NK) cells after CRT. PD-L1(+) ratio in patrolling monocytes was an independent predictor for response to CRT. CONCLUSION: Programmed cell death ligand 1 (PD-L1) expression on patrolling monocytes suppresses cell-mediated immunity in patients receiving CRT which could be related to tumour response, and may be a useful biomarker for decision-making in the management of patients with LARC.


Assuntos
Segunda Neoplasia Primária , Neoplasias Retais , Humanos , Neoplasias Retais/terapia , Terapia Neoadjuvante , Antígeno B7-H1 , Monócitos/metabolismo , Monócitos/patologia , Ligantes , Quimiorradioterapia , Apoptose
7.
Pharm Res ; 38(12): 2109-2118, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34904203

RESUMO

PURPOSE: This study was undertaken to develop novel mucoadhesive formulations of clofazimine (CFZ), a drug candidate for the treatment of cryptosporidiosis, with the aim of strategic delivery to the small intestine, the main site of the disease parasites. METHODS: CFZ-loaded nanoparticles (nCFZ) coated with non-biodegradable anionic polymer (nCFZ/A) and biodegradable anionic protein complex (nCFZ/dA) were prepared by Flash NanoPrecipitation (FNP) and evaluated for their physicochemical and biopharmaceutical properties. RESULTS: The mean diameters of nCFZ/A and nCFZ/dA were ca. 90 and 240 nm, respectively, and they showed narrow size distributions and negative ζ-potentials. Both formulations showed higher solubility of CFZ in aqueous solution than crystalline CFZ. Despite their improved dispersion behaviors, both formulations exhibited significantly lower diffusiveness than crystalline CFZ in a diffusion test using artificial mucus (AM). Quartz crystal microbalance analysis showed that both formulations clearly interacted with mucin, which appeared to be responsible for their reduced diffusiveness in AM. These results suggest the potent mucoadhesion of nCFZ/A and nCFZ/dA. After the oral administration of CFZ samples (10 mg-CFZ/kg) to rats, nCFZ/dA and nCFZ/A exhibited a prolongation in Tmax by 2 and >9 h, respectively, compared with crystalline CFZ. At 24 h after oral doses of nCFZ/A and nCFZ/dA with mucoadhesion, there were marked increases in the intestinal CFZ concentration (4-7 fold) compared with Lamprene®, a commercial CFZ product, indicating enhanced CFZ exposure in the small intestine. CONCLUSION: The use of FNP may produce mucoadhesive CFZ formulations with improved intestinal exposure, possibly offering enhanced anti-cryptosporidium therapy.


Assuntos
Clofazimina/administração & dosagem , Sistemas de Liberação de Fármacos por Nanopartículas/química , Administração Oral , Animais , Clofazimina/farmacocinética , Criptosporidiose/tratamento farmacológico , Liberação Controlada de Fármacos , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Masculino , Modelos Animais , Ratos , Solubilidade
8.
Cell Tissue Res ; 379(3): 473-486, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31788758

RESUMO

An impairment of cellular interactions between the elements of the neurovascular unit contributes to the onset and/or progression of retinal diseases. The present study aims to examine how elements of the neurovascular unit are altered in a rat model of retinopathy of prematurity (ROP). Neonatal rats were treated subcutaneously with the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg) on postnatal day (P) 7 and P8 to induce ROP. Morphological assessments were performed of blood vessels, astrocytes and neuronal cells in the retina. Aggressive angiogenesis, tortuous arteries and enlarged veins were observed in the retinal vasculature of KRN633-treated (ROP) rats from P14 to P28, compared to age-matched control (vehicle-treated) animals. Morphological abnormalities in the retinal vasculature showed a tendency toward spontaneous recovery from P28 to P35 in ROP rats. Immunofluorescence staining for glial fibrillary acidic protein and Pax2 (astrocyte markers) revealed that morphological changes to and a reduction in the number of astrocytes occurred in ROP rats. The developmental cell death was slightly accelerated in ROP rats; however, no visible changes in the morphology of retinal layers were observed on P35. The abnormalities in astrocytes might contribute, at least in part, to the formation of abnormal retinal blood vessels and the pathogenesis of ROP.


Assuntos
Modelos Animais de Doenças , Retina/patologia , Neovascularização Retiniana/patologia , Retinopatia da Prematuridade/patologia , Animais , Feminino , Compostos de Fenilureia/farmacologia , Gravidez , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Neovascularização Retiniana/embriologia , Neovascularização Retiniana/metabolismo , Retinopatia da Prematuridade/embriologia , Retinopatia da Prematuridade/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Chem Pharm Bull (Tokyo) ; 68(4): 332-335, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32023589

RESUMO

Herein, we describe a novel synthetic method for 2,5-disubstituted tetrazoles from 5-substituted tetrazoles using cobalt-catalyzed intermolecular hydroamination reaction of nonactivated olefins. Owing to its mild conditions, the method enabled the use of substrates having acid-labile functional groups, such as silyloxy and methoxymethyloxy groups. By using optically active cobalt complexes, asymmetric intermolecular hydroamination of nonactivated olefins, a longstanding challenge in synthetic organic chemistry, was developed to produce optically active disubstituted tetrazoles.


Assuntos
Alcenos/química , Cobalto/química , Tetrazóis/química , Tetrazóis/síntese química , Aminação , Catálise , Estrutura Molecular
10.
Chem Pharm Bull (Tokyo) ; 68(4): 336-338, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32074521

RESUMO

Ketones are a fundamental functionality found throughout a range of natural and synthetic compounds, making their synthesis essential throughout the chemical disciplines. Herein, we describe a one-pot synthesis of ketones via decatungstate-mediated formal dehydrogenative coupling between aldehydes and non-activated hydrocarbons. A variety of substituted benzaldehydes and cycloalkanes could be used in the optimized reaction to produce the desired ketones in moderate yields. The decatungstate photocatalyst functions in two reactions in this synthesis, catalyzing both the coupling and oxidation steps of the process. Notably, the reaction displays both high atom economy and sustainability, as it uses light and oxygen as key energy sources.


Assuntos
Aldeídos/química , Hidrocarbonetos/química , Cetonas/síntese química , Cetonas/química , Estrutura Molecular
11.
Biol Pharm Bull ; 40(9): 1595-1598, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28867746

RESUMO

Methylmercury (MeHg) results in cell death through endoplasmic reticulum (ER) stress. Previously, we reported that MeHg induces S-mercuration at cysteine 383 or 386 in protein disulfide isomerase (PDI), and this modification induces the loss of enzymatic activity. Because PDI is a key enzyme for the maturation of nascent protein harboring a disulfide bond, the disruption in PDI function by MeHg results in ER stress via the accumulation of misfolded proteins. However, the effects of MeHg on unfolded protein response (UPR) sensors and their signaling remain unclear. In the present study, we show that UPR is regulated by MeHg. We found that MeHg specifically attenuated inositol-requiring enzyme 1α (IRE1α)-x-box binding protein 1 (XBP1) branch, but not the protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activating transcriptional factor 6 (ATF6) branches. Treatment with GSK2606414, a specific PERK inhibitor, significantly inhibited MeHg-induced cell death. These findings suggest that MeHg exquisitely regulates UPR signaling involved in cell death.


Assuntos
Compostos de Metilmercúrio/farmacologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Fator 6 Ativador da Transcrição/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/ultraestrutura , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Proteína Dissulfeto Redutase (Glutationa)/metabolismo , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/metabolismo
12.
Luminescence ; 30(8): 1308-12, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25828634

RESUMO

Poly(p-pyridinium phenylene ethynylene)s (PPyPE) functionalized with alternating donor-acceptor repeat units were synthesized by a Pd-catalyzed Sonogashira coupling reaction between diethynyl monomer and di-iodopyridine for use as a pH-responsive fluorescence chemical sensor. The synthesized PPyPE, containing pyridine units, was characterized by FT-IR, (1)H and (13)C NMR, UV-visible and fluorescence spectroscopies. We investigated the relationship between changes of optical properties and protonation/deprotonation of PPyPE containing pyridine units in solution. Addition of HCl decreased and red-shifted the fluorescence intensity of the conjugated polymers that contained pyridine rings; fluorescence intensity of the polymers increased upon addition of NaOH solution. The synthesized PPyPE was found to be an effective and reusable chemical sensor for pH sensing.


Assuntos
Polímeros/química , Fluorescência , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Polímeros/síntese química , Piridinas/química , Compostos de Piridínio/síntese química , Compostos de Piridínio/química , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier
13.
Chemistry ; 20(1): 272-8, 2014 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-24273103

RESUMO

Cyclohexanone with the pMeOC6H4 and CH2=C(Me) substituents at the C3 and C4-positions was prepared from (+)-ß-pinene and converted to the allylic picolinate by a Masamune-Wittig reaction followed by reduction and esterification. Allylic substitution of this picolinate with Me2CuMgBr·MgBr2 in the presence of ZnI2 proceeded with γ regio- and stereoselectively to afford the quaternary carbon center on the cyclohexane ring with the CH2=CH and Me groups in axial and equatorial positions, respectively. This product was converted to cyclobakuchiol A by demethylation and to cyclobakuchiol C by epoxidation of the CH2=C(Me) group. For the synthesis of cyclobakuchiol B, the enantiomer of the above cyclohexanone derived from (-)-ß-pinene was converted to the cyclohexane-carboxylate, and the derived enolate was subjected to the reaction with CH2=CHSOPh followed by sulfoxide elimination to afford the intermediate with the quaternary carbon center with MeOC(=O) and CH2=CH groups in axial and equatorial positions. The MeOC(=O) group was transformed to the Me group to complete the synthesis of cyclobakuchiol B.


Assuntos
Anti-Inflamatórios/síntese química , Cicloexanos/síntese química , Fenóis/síntese química , Anti-Inflamatórios/química , Monoterpenos Bicíclicos , Compostos Bicíclicos com Pontes/química , Cicloexanos/química , Cicloexanonas/química , Compostos de Epóxi/química , Esterificação , Monoterpenos/química , Fenóis/química , Psoralea/química , Psoralea/metabolismo , Estereoisomerismo
14.
Sci Rep ; 14(1): 7832, 2024 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570542

RESUMO

The vagus nerve is the only pathway for transmitting parasympathetic signals between the brain and thoracoabdominal organs, thereby exhibiting anti-inflammatory functions through the cholinergic anti-inflammatory pathway. Despite often being resected during lymph node dissection in upper gastrointestinal cancer surgery, the impact of vagotomy on postoperative outcomes in gastric cancer patients remains unclear. Sub-diaphragmatic vagotomy was performed on C57BL/6 mice. Three weeks later, syngeneic murine gastric cancer cell line YTN16P was injected into the peritoneal cavity, and the number of peritoneal metastases (PM) on the mesentery and omentum compared with control mice. The phenotypes of immune cells in peritoneal lavage and omental milky spots one day after tumor inoculation were analyzed using flow cytometry and immunohistochemistry. Intraperitoneal transfer of 3 × 105 YTN16P significantly increased the number of metastatic nodules on the mesentery in the vagotomy group compared to the control group. The omental metastasis grade was also significantly higher in the vagotomy group. Phenotypic analysis of immune cells in peritoneal lavage did not reveal significant differences after vagotomy. However, vagotomized mice exhibited a notable increase in milky spot area, with a higher presence of cytokeratin(+) tumor cells, F4/80(+) macrophages, and CD3(+) T cells. Vagus nerve signaling appears to regulate the immune response dynamics within milky spots against disseminated tumor cells and inhibits the development of PM. Preserving the vagus nerve may offer advantages in advanced gastric cancer surgery to reduce peritoneal recurrence.


Assuntos
Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Camundongos , Animais , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/patologia , Camundongos Endogâmicos C57BL , Omento/patologia , Nervo Vago/cirurgia , Nervo Vago/patologia
15.
Sci Rep ; 14(1): 4496, 2024 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-38402307

RESUMO

The spleen is a key source of circulating and tumor-infiltrating immune cells. However, the effect of splenectomy on tumor growth remains unclear. At 3 weeks after splenectomy, we subcutaneously injected LuM1 cells into BALB/c mice and evaluated the growth of primary tumors and lung metastases at 4 weeks after tumor inoculation. In addition, we examined the phenotypes of immune cells in peripheral blood by using flow cytometry and in tumor tissue by using multiplex immunohistochemistry. The growth of primary tumors was reduced in splenectomized mice compared with the sham-operated group. Conversely, splenectomized mice had more lung metastases. Splenectomized mice had fewer CD11b+cells, especially monocytic MDSCs (CD11b+Gr-1neg-lowLy6chigh), and NK cells (CD49b+CD335+). The proportion of NK cells was inversely correlated with the number of lung metastases. In splenectomized mice, the density of CD3+ and granzyme B+ CD8+ T cells was increased, with fewer M2-type macrophages in primary tumors, but NK cells were decreased markedly in lung. Splenectomy concurrently enhances T cell-mediated acquired immunity by reducing the number of monocytic MDSCs and suppresses innate immunity by decreasing the number of NK cells. Splenectomy has opposite effects on primary and metastatic lesions through differential regulation on these two immune systems.


Assuntos
Neoplasias do Colo , Neoplasias Pulmonares , Camundongos , Animais , Esplenectomia , Linfócitos T CD8-Positivos , Células Matadoras Naturais , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias do Colo/patologia
16.
Mol Pharmacol ; 84(6): 824-33, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24043703

RESUMO

Salicylic acid is a classic nonsteroidal anti-inflammatory drug. Although salicylic acid also induces mitochondrial injury, the mechanism of its antimitochondrial activity is not well understood. In this study, by using a one-step affinity purification scheme with salicylic acid-immobilized beads, ferrochelatase (FECH), a homodimeric enzyme involved in heme biosynthesis in mitochondria, was identified as a new molecular target of salicylic acid. Moreover, the cocrystal structure of the FECH-salicylic acid complex was determined. Structural and biochemical studies showed that salicylic acid binds to the dimer interface of FECH in two possible orientations and inhibits its enzymatic activity. Mutational analysis confirmed that Trp301 and Leu311, hydrophobic amino acid residues located at the dimer interface, are directly involved in salicylic acid binding. On a gel filtration column, salicylic acid caused a shift in the elution profile of FECH, indicating that its conformational change is induced by salicylic acid binding. In cultured human cells, salicylic acid treatment or FECH knockdown inhibited heme synthesis, whereas salicylic acid did not exert its inhibitory effect in FECH knockdown cells. Concordantly, salicylic acid treatment or FECH knockdown inhibited heme synthesis in zebrafish embryos. Strikingly, the salicylic acid-induced effect in zebrafish was partially rescued by FECH overexpression. Taken together, these findings illustrate that FECH is responsible for salicylic acid-induced inhibition of heme synthesis, which may contribute to its antimitochondrial and anti-inflammatory function. This study establishes a novel aspect of the complex pharmacological effects of salicylic acid.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Ferroquelatase/antagonistas & inibidores , Heme/antagonistas & inibidores , Mitocôndrias/efeitos dos fármacos , Ácido Salicílico/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Proteínas de Escherichia coli/química , Ferroquelatase/biossíntese , Ferroquelatase/química , Heme/biossíntese , Humanos , Mitocôndrias/metabolismo , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Protoporfirinas/metabolismo , Ácido Salicílico/química , Peixe-Zebra
17.
J Org Chem ; 78(9): 4319-28, 2013 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-23565826

RESUMO

This paper describes a total synthesis of (-)-strictinin, an ellagitannin that is 1-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl (HHDP)-ß-D-glucose. In the study, total efficiency of the synthesis was improved to produce a 78% overall yield in 13 steps from D-glucose. In the synthesis, formation of the 4,6-(S)-HHDP bridge including the 11-membered bislactone ring was a key step, in which intramolecular aryl-aryl coupling was adopted. The coupling was oxidatively induced by CuCl2-n-BuNH2 with perfect control of the axial chirality, and the reaction conditions of this coupling were optimized thoroughly to achieve the quantitative formation of the bridge.


Assuntos
Ácido Gálico/química , Fenóis/síntese química , Técnicas de Química Sintética , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fenóis/química , Fenóis/isolamento & purificação , Folhas de Planta/química , Estereoisomerismo , Traqueófitas/química
18.
J Int Med Res ; 51(7): 3000605231189141, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37522366

RESUMO

The primary symptom of urticarial vasculitis (UV), which is a histopathological leukocytoclastic vasculitis disease, is an eruption that resembles urticaria. Other organs may also experience accompanying symptoms. Lung lesions with UV are mostly obstructive pulmonary disease with smoking. However, the coexistence of eosinophilic pneumonia (EP) and complicated UV remains unclear. We report a man in his 70s with chronic obstructive pulmonary disease who attended our department with ring-shaped erythema, marginal edema, and pigmentation. Additionally, a skin histological analysis showed nuclear dust and perivascular neutrophil infiltration, while a blood sample showed a decrease in C3 and C1q concentrations. Administration of prednisone temporarily improved the eruption. However, he developed a cough and a new UV eruption 1 year later. Computed tomography revealed infiltration in the right upper lobe of the lungs, and a blood sample showed a high eosinophil count. He was finally diagnosed with hypocomplementemic urticarial vasculitis syndrome and idiopathic chronic EP. A previous study showed that serum C1q concentrations in patients with EP were lower when this disease was active. Whether a decline in C1q concentrations can cause EP is unclear. However, our case is unique owing to the co-onset of EP with low complement concentrations and recurrence of UV.


Assuntos
Eosinofilia Pulmonar , Urticária , Vasculite Leucocitoclástica Cutânea , Vasculite , Masculino , Humanos , Complemento C1q , Eosinofilia Pulmonar/diagnóstico , Eosinofilia Pulmonar/diagnóstico por imagem , Vasculite/complicações , Vasculite/diagnóstico , Urticária/complicações , Urticária/tratamento farmacológico , Urticária/diagnóstico , Vasculite Leucocitoclástica Cutânea/complicações , Vasculite Leucocitoclástica Cutânea/tratamento farmacológico
19.
Urol J ; 20(4): 222-228, 2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-36906797

RESUMO

PURPOSE: The extent of effectiveness of upfront androgen receptor-axis-targeted therapies (ARAT) versus total androgen blockade (TAB) in improving prostate cancer-specific survival (CSS) and progression-free survival (PFS) in a real-world sample of Japanese patients with high-volume mHSPC remains unclear. We, therefore, investigated the efficacy and safety of upfront ARAT versus bicalutamide for de novo high-volume mHSPC in Japanese patients. MATERIAL AND METHODS: This was a multicenter retrospective study that analyzed CSS, clinical PFS, and adverse events (AEs) in 170 patients with newly diagnosed high-volume mHSPC. Fifty-six patients were treated with upfront ARAT, and 114 of them were prescribed bicalutamide in addition to ADT between January 2018 and March 2021. The primary and secondary endpoints were CSS and PFS, respectively. A 1:1 nearest neighbor propensity score matching (PSM) with a caliper of 0.2 was performed to match the ARAT group to TAB patients. RESULTS: During the follow-up for a median of 21.5 months, the median CSS was not reached and 37 months in the upfront ARAT and total androgen blockade (TAB) groups, respectively (log-rank test: P = 0.006) by propensity score matching (PSM). Moreover, while the PFS of ARAT was unreached, the median PFS of TAB was 9 months (log-rank test: P < 0.001). Nine patients discontinued ARAT owing to grade ≥ 3 AEs; one patient who was treated with TAB had a grade 3 AE. CONCLUSION: Upfront ARAT significantly prolonged the CSS and PFS of patients with high-volume mHSPC better than TAB, although ARAT was associated with a higher rate of grade ≥ 3 AEs. Upfront ARAT can be more beneficial for patients with de novo high-volume mHSPC than TAB.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Receptores Androgênicos/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Estudos Retrospectivos , Androgênios/uso terapêutico , Neoplasias da Próstata/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
20.
Sci Rep ; 12(1): 7290, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35508498

RESUMO

Although preoperative chemoradiation therapy can down-stage locally advanced rectal cancer (LARC), it has little effect on distant metastases. Metformin exerts an anti-cancer effect partly through the activation of host immunity. LuM1, a highly lung metastatic subclone of colon 26, was injected subcutaneously (sc) in BALB/c mice and treated with metformin and/or local radiation (RT). Lung metastases and the primary tumors were evaluated and the phenotypes of immune cells in the spleen and lung metastases were examined with flow cytometry and immunohistochemistry. Local RT, but not metformin, partially delayed the growth of sc tumor which was augmented with metformin. Lung metastases were unchanged in metformin or RT alone, but significantly reduced in the combined therapy. The ratios of splenic T cells tended to be low in the RT group, which were increased by the addition of metformin. IFN-γ production of the splenic CD4(+) and CD8(+) T cells was enhanced and CD49b (+) CD335(+) activated NK cells was increased after combined treatment group. Density of NK cells infiltrating in lung metastases was increased after combination treatment. Metformin effectively enhances local and abscopal effects of RT though the activation of cell-mediated immunity and might be clinically useful for LARC.


Assuntos
Neoplasias Pulmonares , Metformina , Neoplasias Retais , Animais , Linfócitos T CD8-Positivos , Neoplasias Pulmonares/patologia , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia
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