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Patients with eczema with a systemic metal allergy, such as nickel (Ni), cobalt (Co), chromium (Cr), and tin (Sn), should pay attention to symptomatic exacerbation by excessive metal intake in food. However, dietary intervention for systemic metal allergy can be difficult. In this study, we evaluated the effect of dietary intervention by a registered dietitian on clinical symptoms in patients with a systemic metal allergy. Forty-four patients with cutaneous symptoms who were diagnosed with a metal allergy were randomly assigned to the dietary intervention group (DI group, n = 29) by a registered dietitian or the control group (C group, n = 15). The DI group was individually instructed by a registered dietitian how to implement a metal-restricted diet and then evaluated 1 month later. Dermatologists treated skin lesions of patients in both groups. Skin symptoms assessed by the Severity Scoring of Atopic Dermatitis (SCORAD) index, blood tests, and urinary metal excretion were evaluated. The DI group showed decreased Ni, Co, Cr, and Sn intake (all P ≤ 0.05), and an improved total SCORAD score, eczema area, erythema, edema/papulation, oozing/crust, excoriation, lichenization and dryness after 1 month of intervention compared with before the intervention (all P ≤ 0.05). However, the C group showed decreased Ni and Sn intake and an improved oozing/crust score (all P < 0.05). It showed the effective reduction of dietary metal intake controls dermatitis due to a metal allergy. In conclusion, dietary intervention by a registered dietitian is effective in improving skin symptoms with a reduction in metal intake.
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Dermatite Atópica , Eczema , Humanos , Dermatite Atópica/diagnóstico , Dermatite Atópica/patologia , Dermatite Atópica/terapia , DietaRESUMO
BACKGROUND & AIMS: Muscle atrophy is one of the most important and frequent problems for critically ill patients. The purpose of this study was to evaluate the effect of lipid mediators on acute muscle atrophy. Skeletal muscle fiber-specific analysis of lipid mediators in endotoxemic rats was therefore performed. METHODS: Male Wistar rats were intraperitoneally injected with lipopolysaccharide (LPS). Slow-twitch soleus muscle and fast-twitch extensor digitorum longus (EDL) muscle were harvested 0, 6, and 24 h after LPS injection. Lipid mediators were profiled using liquid chromatography-tandem mass spectrometry, and free fatty acid (FFA) concentrations were measured using gas chromatography-mass spectrometry. Muscles were weighed and their cross-sectional areas were evaluated. Expression levels of mRNAs encoding inflammatory cytokines, autophagy-related transcription factors, and members of the ubiquitin-proteasome system were measured using real-time PCR. RESULTS: Before LPS injection, the concentrations of all FFAs, including arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, and all measured lipid mediators were higher in soleus muscle than in EDL muscle, especially those of pro-inflammatory prostaglandin E2 (PGE2) and leukotriene B4. LPS injection, increased PGE2 and D2 and decreased FFAs in soleus muscle but did not change in EDL muscle. The concentrations of specialized pro-resolving mediators E-series hydroxy-eicosapentaenoic acid and D-series hydroxy-docosahexaenoic acid were higher in soleus muscle. Muscle cross-sectional area decreased and the expression level of atrogin-1 was upregulated in EDL muscle, but both were unchanged in soleus muscle. After LPS injection, a discrepancy involving an increased PGE2 concentration and decreased muscle atrophy was identified in this acute muscle atrophy model of critical illness. CONCLUSION: Concentrations of FFAs and lipid mediators were higher in soleus muscle than in EDL muscle, and LPS injection rapidly increased concentrations of pro-inflammatory lipid mediators. However, muscle atrophy with upregulation of autophagy-related transcription factors was observed in EDL muscle but not in soleus muscle.
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Ácidos Docosa-Hexaenoicos , Lipopolissacarídeos , Humanos , Masculino , Ratos , Animais , Ácido Eicosapentaenoico , Ratos Wistar , Atrofia Muscular/induzido quimicamente , Ácidos Graxos não Esterificados , Músculo EsqueléticoRESUMO
BACKGROUND: Despite advances in multidisciplinary treatment, the prognosis of pancreatic cancer remains poor. Since distant metastasis defines prognosis, elucidation of the mechanism of metastasis is important for improving survival. Exosomes are extracellular secretory vesicles and are responsible for intercellular communication. In this study, we investigated whether exosomes secreted by human pancreatic cancer cells are involved in promoting distant metastasis of cancer and the mechanism that underlies the promotion of metastasis. METHODS: Exosomes were isolated from ascites of a patient with pancreatic cancer and a patient with liver cirrhosis as a control. Three days after the administration of exosomes to nude mice, GFP-labeled human pancreatic cancer cells were injected via the spleen or tail vein, and then the liver and lungs were histologically analyzed. To elucidate the mechanism, vascular permeability was estimated using FITC-dextran in place of pancreatic cancer cells in vivo and human umbilical vascular endothelial cells (HUVECs) were used to analyze vascular permeability and the induction of endothelial-mesenchymal transition (EndMT) in vitro. RESULTS: Distant metastasis and vascular permeability were significantly enhanced in mice treated with exosomes from pancreatic cancer patients in comparison to exosomes from a control patient in vivo. In addition, exosomes from pancreatic cancer patients significantly enhanced vascular permeability and the induction of EndMT in HUVECs in vitro. CONCLUSION: Exosomes derived from pancreatic cancer cells form a pre-metastatic niche and promote the extravasation and colonization of pancreatic cancer cells to remote organs, partially through endothelial-mesenchymal transition.
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Exossomos , Neoplasias Pancreáticas , Humanos , Animais , Camundongos , Células Endoteliais/patologia , Ascite/patologia , Camundongos Nus , Neoplasias Pancreáticas/patologia , Linhagem Celular Tumoral , Neoplasias PancreáticasRESUMO
Growing evidence from animal experiments suggests that icing after skeletal muscle injury is harmful to muscle regeneration. However, these previous experimental models yielded massive necrotic myofibers, whereas muscle injury with necrosis in a small myofiber fraction (<10%) frequently occurs in human sports activities. Although macrophages play a proreparative role during muscle regeneration, they exert a cytotoxic effect on muscle cells through an inducible nitric oxide synthase (iNOS)-mediated mechanism. In this study, we established an animal injury model with necrosis limited to a small myofiber fraction and investigated the effect of icing on muscle regeneration with a focus on macrophage-related events. Icing after muscle injury of this model resulted in an enlarged size of regenerating myofibers compared with those in untreated animals. During the regenerative process, icing attenuated the accumulation of iNOS-expressing macrophages, suppressed iNOS expression in the whole damaged muscle, and limited the expansion of the injured myofiber area. In addition, icing increased the ratio of M2 macrophages within the injured site at an earlier time point than that in untreated animals. Following these phenomena in icing-treated muscle regeneration, an early accumulation of activated satellite cells within the damaged/regenerating area occurred. The expression level of myogenic regulatory factors, such as MyoD and myogenin, was not affected by icing. Taken together, our results suggest that icing after muscle injury with necrosis limited to a small fraction of myofibers facilitates muscle regeneration by attenuating iNOS-expressing macrophage invasion, limiting muscle damage expansion, and accelerating the accumulation of myogenic cells which form regenerating myofibers.
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Doenças Musculares , Células Satélites de Músculo Esquelético , Animais , Humanos , Óxido Nítrico Sintase Tipo II , Músculo Esquelético/fisiologia , Regeneração , Necrose , MacrófagosRESUMO
Following skeletal muscle injury, both myogenic and immune cells interact closely during the regenerative process. Although icing is still a common acute treatment for sports-related skeletal muscle injuries, icing after muscle injury has been shown to disrupt macrophage accumulation and impair muscle regeneration in animal models. However, it remains unknown whether icing shortly after injury affects macrophage-related phenomena during the early stages of muscle regeneration. Therefore, we focused on the distribution of M1/M2 macrophages and cytokines expressed predominantly by macrophages during the early stages of muscle regeneration after muscle crush injury. Icing resulted in a decrease, not retardation, in the accumulation of M1 macrophages, but not M2 macrophages, in injured muscles. Consistent with the decrease in M1 macrophage accumulation, icing led to a reduction, instead of delay, in the level of tumor necrosis factor-α (TNF-α) expression. Additionally, at subsequent timepoints, icing decreased the number of myogenic precursor cells in the regenerating area and the size of centrally nucleated regenerating myofibers. Together, our findings suggest that icing after acute muscle damage by crushing disturbs muscle regeneration through hindering tM1 macrophage-related phenomena.
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Doenças Musculares , Fator de Necrose Tumoral alfa , Ratos , Animais , Fator de Necrose Tumoral alfa/metabolismo , Músculo Esquelético/metabolismo , Macrófagos , Doenças Musculares/metabolismo , Citocinas/metabolismoRESUMO
Distant metastasis is a dismal prognostic factor of pancreatic cancer. Metastasis is established in several steps, but the mechanism underlying the very early stages remains unclear. Epithelial-mesenchymal transition (EMT) is involved in these stages. Although signaling molecules have been reported to induce EMT, the mechanism underlying their origin is unclear. In this study, we hypothesized that pancreatic cancer cell-derived exosomes induce EMT in cancer cells themselves, a notion we entertained because we found EMT in in vitro three-dimensional colonies of cancer cells, with vimentin-positive cells observed in some of the budding pancreatic cancer cells and in single cells outside the colony as well. First, we clarified that pancreatic cancer cell-derived exosomes induce EMT in cancer cells themselves. Next, we examined the involvement of transforming growth factor-ß1 (TGF-ß1), and TGF-ß1 knock-down in pancreatic cancer cells with TGF-ß1 siRNA significantly suppressed TGF-ß1 gene expression in cancer cells, and exosomal TGF-ß1 was significantly reduced in the secretory exosomes. Exosomes from TGF-ß1 knock-down cells suppressed EMT induction in cancer cells themselves and TGF-ß1 protein expression in target cells. Taken together, these findings suggest that TGF-ß1 is involved in EMT induction via exosomes, results that may support the production of effective metastasis inhibitors.
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Transição Epitelial-Mesenquimal , Exossomos , Neoplasias Pancreáticas , Fator de Crescimento Transformador beta1 , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Exossomos/metabolismo , Humanos , Neoplasias Pancreáticas/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Neoplasias PancreáticasRESUMO
BACKGROUND/AIM: Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare subtype of renal cell carcinoma and generally considered a low-grade renal epithelial neoplasm. However, MTSCC with distant metastases often shows a poor prognosis. This is the first reported case of cytoreductive nephrectomy after nivolumab plus ipilimumab combination treatment. CASE REPORT: A 26-year-old man had a 72-mm tumor at the left kidney with multiple osteolytic bone metastases. A biopsy of the renal tumor and bone metastases resulted in the diagnosis of MTSCC of the kidney with bone metastases. After nivolumab plus ipilimumab combined treatment, he underwent cytoreductive nephrectomy. The excised specimen showed higher PD-L1 expression in the spindle components than in the tubular components, but CD4- and CD8-positve T-cells showed greater infiltration in the tubular components than the spindle components. CONCLUSION: Combination immunotherapy of nivolumab and ipilimumab may be an effective treatment option for metastatic MTSCC of the kidney.
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Adenocarcinoma Mucinoso , Neoplasias Ósseas/secundário , Ipilimumab/uso terapêutico , Neoplasias Renais , Nivolumabe/uso terapêutico , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/cirurgia , Adulto , Procedimentos Cirúrgicos de Citorredução , Humanos , Rim , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Masculino , NefrectomiaRESUMO
The options available for treating infections with carbapenemase-producing Enterobacteriaceae (CPE) are limited; with the increasing threat of these infections, new treatments are urgently needed. Biapenem (BIPM) is a carbapenem, and limited data confirming its in vitro killing effect against CPE are available. In this study, we examined the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of BIPM for 14 IMP-1-producing Enterobacteriaceae strains isolated from the Okayama region in Japan. The MICs against almost all the isolates were lower than 0.5 µg ml-1, indicating susceptibility to BIPM, while approximately half of the isolates were confirmed to be bacteriostatic to BIPM. However, initial killing to a 99.9â% reduction was observed in seven out of eight strains in a time-kill assay. Despite the small data set, we concluded that the in vitro efficacy of BIPM suggests that the drug could be a new therapeutic option against infection with IMP-producing CPE.
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Antibacterianos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Tienamicinas/farmacologia , beta-Lactamases/metabolismo , Farmacorresistência Bacteriana , Enterobacteriaceae/enzimologia , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND & AIMS: Muscle atrophy is a public health issue and inflammation is a major cause of muscle atrophy. While docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are typical ω-3 polyunsaturated fatty acids, are reported to have anti-inflammatory effects on endotoxin-induced inflammatory responses, their effects on inflammatory muscle atrophy have not been clarified. In this study, we aimed to investigate the effects of DHA and EPA on inflammatory muscle atrophy. METHODS: DHA or EPA was added to C2C12 myotubes at a concentration of 25, 50, or 100 µM, and 1 h later, lipopolysaccharide (LPS) was added at a concentration of 1 µg/mL. Two hours after the first LPS addition, mRNA expression of atrogin-1 and Murf-1 in C2C12 myotubes was measured. The second LPS addition was performed 24 h after the first LPS addition, and myotube diameter, myofibrillar protein, and cell viability were measured. One-way ANOVA and Tukey's multiple comparison test were used for statistical processing of the results, and the significance level was set to less than 5 %. RESULTS: The LPS-added group significantly decreased the myotube diameter and the myofibrillar protein content compared to the control group. The myotube diameter was significantly higher in the 25 µM, 50 µM DHA and 25 µM EPA-added groups compared to the LPS group. In the 25 µM DHA and EPA-added groups, the myofibrillar protein content was significantly higher than that in the LPS group. The mRNA expression levels of atrogin-1 and murf-1 were significantly suppressed in the 25 µM DHA and EPA-added groups compared to the LPS group. The cell viability did not change by the addition of LPS, DHA, and EPA. CONCLUSIONS: The addition of DHA or EPA suppressed the decrease in myotube diameter and myofibrillar protein content and suppressed the increase in atrogin-1 and murf-1 induced by LPS. This study showed the preventive effect of DHA and EPA on endotoxin-induced muscle atrophy.
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Ácido Eicosapentaenoico , Ácidos Graxos Ômega-3 , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Endotoxinas , Humanos , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/prevenção & controleRESUMO
The degradation characteristics of InGaN/GaN multiple quantum well (MQW) photodetectors (PDs) stressed at 100 and 200 mA over 480 h are investigated. We have observed that the luminescence intensity, short circuit current density, and open circuit voltage decrease strongly, whereas the leakage current increases intensely due to the constant current stress. The strong activity of the Mg dopant and trap-assisted tunneling under the direct current stress are critical factors in the degradation of InGaN/GaN MQW PDs. Further, the photocurrent spectroscopy results reveal that for 100 mA stress current, the peak value of relative external quantum efficiency (EQE) slightly increases due to the widening of the space-charge region while, for the 200 mA of stress current, the peak value of EQE decreases (â¼15.4%) due to some permanent damages in the active region and/or the metal/semiconductor interface, and the associated resistive effects.
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Icing is still one of the most common treatments to acute skeletal muscle damage in sports medicine. However, previous studies using rodents reported the detrimental effect of icing on muscle regeneration following injury. This study aimed to elucidate the critical factors governing the impairment of muscle regeneration by icing with a murine model of eccentric contraction-induced muscle damage by electrical stimulation. Because of icing after muscle injury, the infiltration of polynuclear and mononuclear cells into necrotic muscle fibers was retarded and attenuated, leading to the persistent presence of necrotic cellular debris. These phenomena coincided with the delayed emergence and sustained accumulation of Pax7+ myogenic cells within the regenerating area. In addition, due to icing, delayed and/or sustained infiltration of M1 macrophages was noted in accordance with the perturbed expression patterns of inflammation-related factors, including tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10). The key myogenic regulatory factors (i.e., MyoD and myogenin) involved in the activation/proliferation and differentiation of myogenic precursor cells were not altered by icing during the regenerative process. A detailed analysis of regenerating myofibers by size distribution at day 14 after muscle damage showed that the ratio of small regenerating fibers to total regenerating fibers was higher in icing-treated animals than in untreated animals. These findings suggest that icing following muscle damage blunts the efficiency of muscle regeneration by perturbing the removal of necrotic myofibers and phenotypic dynamics of macrophages rather than affecting myogenic factors.NEW & NOTEWORTHY Icing blunted the muscle regeneration by perturbing the infiltration of polynuclear and mononuclear cells into necrotic myofibers and the phenotypic dynamics of macrophages rather than affecting the myogenic regulatory factors. Because of icing, the disappearance of necrotic muscle debris was retarded, coinciding with the delayed emergence and sustained accumulation of Pax7+ cells within the regenerating area. The expression patterns of TNF-α and IL-10 were altered by icing consistent with the perturbation of the macrophage phenotype.
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Músculo Esquelético , Regeneração , Animais , Macrófagos , Camundongos , Fibras Musculares Esqueléticas , Miogenina , FenótipoRESUMO
Hemodialysis patients often develop constipation. We analyzed the advantage of synbiotics over prebiotics based on the stool form due to the intestinal environment in hemodialysis patients. Patients received either synbiotics or prebiotics for four weeks. The synbiotics group was treated with partially hydrolyzed guar gum containing Bifidobacterium longum BB536, while the prebiotics group was treated with the same fiber alone. The defecation status was assessed using the Bristol Stool Form Scale and abdominal bloating was evaluated using a visual analog scale. The fecal microbiota, measured by a terminal restriction fragment length polymorphism analysis, and the fecal short-chain fatty acid concentrations, measured by gas chromatography, were compared between the two groups. Synbiotics ingestion improved the individual stool form and abdominal bloating, and increased Bifidobacterium, which produces short-chain fatty acid, 13.9-fold after ingestion. In particular, acetic acid increased 2.5-fold in the synbiotics group. On the other hand, butyric acid increased 3.0-fold in the prebiotics group. Synbiotics improved the stool form in hemodialysis patients due to the composition of the intestinal microbiota and short-chain fatty acid concentrations.
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Microbioma Gastrointestinal , Simbióticos , Ácidos Graxos Voláteis , Fezes , Humanos , Diálise RenalRESUMO
Hemodialysis patients often become constipated. We analyzed the effect of prebiotics on the defecation status due to the intestinal environment in hemodialysis patients. Fifteen patients received prebiotics as partially hydrolyzed guar gum for four weeks. The defecation status was assessed using both the Bristol Stool Form Scale and the Japanese version of the Constipation Assessment Scale. The fecal status, microbiota measured by a terminal restriction fragment length polymorphism analysis, and fecal short-chain fatty acid concentrations by gas chromatography were compared before and after prebiotics ingestion. Prebiotics ingestion improved the individual stool form and decreased the constipation score from 5.1 to 3.0. The ratio of short-chain fatty acid-producing microbiota, such as Bifidobacterium and Bacteroides, increased after ingestion (2.35- and 3.17-fold, respectively). Furthermore, the concentration of short-chain fatty acids significantly increased (1.58-fold). The individual dendrogram distribution after ingestion was changed in 8 participants (53.3% of the subjects). In 5 participants (33.3% of the subjects), the clusters were even more noticeably different. Prebiotics improved the defecation status in hemodialysis patients due in part to the composition of intestinal microbiota and short-chain fatty acid concentrations.
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Constipação Intestinal/dietoterapia , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/fisiologia , Prebióticos , Diálise Renal/efeitos adversos , Adulto , Idoso , Biomarcadores/metabolismo , Cromatografia Gasosa , Constipação Intestinal/etiologia , Constipação Intestinal/metabolismo , Constipação Intestinal/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
After skeletal muscle injury, unloading disturbs the regenerative process of injured myofibers, in a manner highly attributed to impairment of macrophage functions. However, the effect of unloading on the spatiotemporal context of proinflammatory macrophage recruitment and satellite cell accumulation within the damaged area remains unclear. This study focused on macrophages expressing inducible nitric oxide synthase (iNOS) that synthesize nitric oxide, a key regulator of muscle regeneration, and compared the continuous hindlimb unloading (HU) by tail suspension versus weight-bearing (WB) after skeletal muscle crush injury in rats. We found that in the WB group, the recruitment of iNOS+ proinflammatory macrophages into the injured site gradually increased until their peak number at 48 h post-injury. In the HU group, the accumulation of iNOS+ macrophages until 48 h after injury was significantly less than that in the WB group and continued to increase at 72 h. In accordance with attenuated and/or delayed iNOS+ macrophage recruitment, whole iNOS expression at 24 and 48 h after injury was weakened by unloading. Additionally, in the HU group, satellite cell content of dystrophin-positive non-injured areas diminished at 48 h after injury, and the numbers of activated satellite cells within the regenerating area at 72 and 96 h post-injury were significantly smaller than those in the WB group. These findings suggest that muscle regeneration under unloading conditions results in attenuated and/or delayed recruitment of iNOS+ macrophages and lower iNOS expression in the early phase after muscle injury, leading to perturbed satellite cell accumulation and muscle regeneration.
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Elevação dos Membros Posteriores , Macrófagos/enzimologia , Músculo Esquelético/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Regeneração , Células Satélites de Músculo Esquelético/metabolismo , Animais , Macrófagos/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Eicosanoid modulation by butyrate has been reported in various cells and conditions. Recently, comprehensive analyses of lipid mediators using liquid chromatography/tandem mass spectrometry has been reported. We hypothesized that tributyrin, a prodrug of butyrate, may attenuate LPS-induced liver injury in rats by suppressing the production of pro-inflammatory lipid mediators and/or by inducing anti-inflammatory specialized proresolving mediators. To test this, groups of Wistar rats were orally administered tributyrin (1 g/kg body weight) or vehicle 1 h before intraperitoneal injection of LPS. The livers were collected at 0, 1.5, 6, and 24 h later and analyzed: lipid mediators were profiled by liquid chromatography/tandem mass spectrometry; expression of cyclooxygenase-2, 5-lipoxygenase (LOX), 12/15-LOX, and leukotriene (LT) A4 hydrolase, and nuclear translocation of 5-LOX were evaluated by western blot analysis; and induction of liver injury was assessed by immunostaining for 8-hydroxy-2'-deoxyguanosine, an indicator of oxidative DNA damage. We found that tributyrin treatment attenuated LPS-induced production of pro-inflammatory LTB4 (p < 0.05) and decreased oxidative stress levels in the liver. Tributyrin also attenuated the nuclear translocation of 5-LOX in response to LPS, suggesting a possible mechanism for the LTB4 reduction. LPS-induced changes in other lipid mediators were not significantly affected by tributyrin treatment up to 24 h after LPS injection. Our results suggest that oral tributyrin administration protects against endotoxemia-associated liver damage by reducing production of the pro-inflammatory eicosanoid LTB4.
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Endotoxinas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Triglicerídeos/administração & dosagem , Animais , Cromatografia Líquida , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/farmacologia , Endotoxinas/metabolismo , Epóxido Hidrolases , Lipidômica , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/efeitos adversos , Fígado/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas em Tandem , Triglicerídeos/uso terapêuticoRESUMO
OBJECTIVES: Most patient-derived pancreatic ductal adenocarcinoma (PDAC) xenografts have been established from surgical specimens of patients who have not received chemotherapy. However, xenografts have rarely been established from chemotherapy-resistant, advanced PDACs, because such cases are usually inoperable. The purpose of this study is to establish patient-derived xenografts using PDAC cells refractory to chemotherapy. METHODS: Clinical PDAC cells obtained from ascites of patients who had received continuous chemotherapy were implanted into the flanks of immunocompromised mice. Growth and histological features of the xenografts with and without gemcitabine treatment were then analyzed. RESULTS: Ascites-derived PDAC cells were successfully expanded through serial xenograft passage without changes in histological appearance. While treatment with gemcitabine substantially inhibited the growth of all PDAC xenografts tested, the tumor volume gradually increased, and the tumors showed marked regrowth even under continued gemcitabine treatment. These findings are consistent with the actual clinical course of the corresponding patients for each xenograft. CONCLUSIONS: Ascites-derived xenograft models represent a valuable experimental system for testing the efficacy of currently available therapeutic compounds on chemotherapy-resistant PDAC cells and for elucidation of the mechanisms underlying chemotherapy resistance.
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Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Idoso de 80 Anos ou mais , Animais , Ascite , Carcinoma Ductal Pancreático/patologia , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , GencitabinaRESUMO
Objective: Dermal fibroproliferative disorders impair patients' quality of life. Although several therapeutic approaches exist for treatment of dermal scars, the development of effective ointments with few adverse effects could improve these therapeutic methods. Short-chain and ω-3 polyunsaturated fatty acids are reported to be immunomodulators with anti-inflammatory properties. Our aim was to evaluate anti-inflammatory and antifibrogenic effects of these fatty acids in human dermal fibroblasts. Methods: Cells were incubated with short-chain fatty acids (butyrate or propionate; 0-16 mM) and/or ω-3 polyunsaturated fatty acids (docosahexaenoic acid or eicosapentaenoic acid; 0-100 µM) for 24 hours to evaluate antifibrogenic effects and for 3 or 48 hours to evaluate anti-inflammatory effects after stimulation with lipopolysaccharide or without stimulation. Expression levels of α-smooth muscle actin, collagen I, collagen III, and IL-6 were evaluated, as were cell proliferation, stress fiber formation, and histone acetylation. Results: In the lipopolysaccharide-unstimulated group, butyrate inhibited mRNA expression of α-smooth muscle actin and collagen III more effectively than propionate and increased histone acetylation. Docosahexaenoic acid inhibited mRNA expression of α-smooth muscle actin and collagen III, whereas eicosapentaenoic acid did not. Combining butyrate with docosahexaenoic acid had stronger effects, downregulating α-smooth muscle actin, collagen I, and collagen III mRNA. As for cell proliferation and stress fiber formation, butyrate acted as a stronger inhibitor than docosahexaenoic acid and the combined administration had stronger effects. In the lipopolysaccharide-stimulated group, butyrate and docosahexaenoic acid attenuated IL-6 mRNA upregulation by lipopolysaccharide. Conclusion: Butyrate and docosahexaenoic acid may be a novel therapeutic approach to treatment of dermal fibroproliferative disorders.
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A hypervalent iodine(III) reagent mediated oxidative skeletal rearrangement reaction of secondary amines is reported. The transformation, which uses PhI(OAc)2 in CF3CH2OH, was found to be highly efficient at inducing the direct 1,2-C-to-N migration of secondary amines. This method offers facile and divergent access to polycyclic and macrocyclic indole-fused compounds. The synthetic potential of the method is also demonstrated through its application to several substrates, including secondary as well as primary amines.
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AIM: To evaluate the antifibrogenic effects of butyrate or phenylbutyrate, a chemical derivative of butyrate, in human pterygium fibroblasts. METHODS: Human pterygium fibroblasts obtained from patient pterygium tissue were treated with butyrate or phenylbutyrate for 48h. Expression of α-smooth muscle actin, collagen I, collagen III and matrix metalloproteinase-1 mRNA was measured by quantitative real-time reverse transcription polymerase chain reaction, and acetylated histone was evaluated by Western blotting. RESULTS: Butyrate inhibited α-smooth muscle actin, type III collagen and matrix metalloproteinase-1 expressions, and phenylbutyrate inhibited types I and III collagen and matrix metalloproteinase-1 expressions without changing cell viability as well as both of these increased histone acetylation. These results suggested that butyrate and phenylbutyrate suppress fibrosis through a mechanism involving histone deacetylase inhibitor. CONCLUSION: This indicates that butyrate or phenylbutyrate have antifibrogenic effects in human pterygium fibroblasts and could be novel types of prophylactic and/or therapeutic drugs for pterygium, especially phenylbutyrate, which does not have the unpleasant smell associated with butyrate.
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OBJECTIVE: Serum diamine oxidase (DAO) activity varies to a greater extent in women than in men. DAO activity during the luteal phase was higher than that during the follicular phase in healthy women. Recent reports have indicated that duodenal lipid infusion increased DAO activity in the intestinal lymph in rats. The aim of this study was to elucidate the effect of dietary nutrient intake on serum DAO activity in healthy women. METHODS: Thirty-four healthy Japanese women were recruited. Food surveys were performed using dietary records for 3 d during both the follicular and luteal phases. Nutrient intake was calculated and expressed as the energy intake ratio. The correlation between DAO activity and nutrient intake was analyzed. RESULTS: Serum DAO activity in both phases was positively correlated with intake of long-chain fatty acids, saturated fatty acids, and monounsaturated fatty acids (P < 0.05). Intake of phosphorus, calcium, zinc, magnesium, iron, and vitamin B12 during the luteal phase was positively correlated with serum DAO activity (P < 0.05). CONCLUSION: In healthy women, serum DAO activity was influenced by dietary fatty acid and micronutrient intake.