RESUMO
OBJECTIVE: Metformin is a medication used to treat type 2 diabetes by inhibiting hepatic glucose production through adenosine monophosphate-activated protein kinase (AMPK) activation. Autophagy is closely related to the homeostasis and stress mechanisms of the body. In recent years, much research has arisen on therapeutic methods utilizing autophagy mechanisms to treat diagnoses such as metabolic diseases, tumors, and Alzheimer's disease. This study thus aimed to investigate the effects of metformin treatment on the differentiation of osteoclasts and changes in AMPK mechanisms, which play an important role in regulating energy homeostasis, and mTOR, a highly conserved kinase that regulates autophagy. MATERIALS AND METHODS: Experimentation, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, tartrate-resistant acid phosphate (TRAP) staining, pit formation assay, immunofluorescence, western blotting, and real-time polymerase chain reaction (PCR) was performed to investigate the effects of metformin on osteoclast differentiation. Additionally, to investigate its association with AMPK and pathways, the AMPK inhibitor compound C and mammalian targets of rapamycin (mTOR) activator leucine were used to examine the expression of osteoclast- or autophagy-related proteins, genes, and TRAP-positive cells. RESULTS: Metformin showed no cytotoxic effects on mouse osteoblastic cell lines (MC3T3-E1) and murine macrophage cell lines (RAW264.7) but did inhibit osteoclast differentiation. Furthermore, metformin was found to inhibit osteoclast differentiation through AMPK activation and mTOR inhibition. In turn, AMPK inhibition using compound C promoted osteoclast differentiation, and mTOR activation using leucine inhibited autophagy and osteoclast differentiation. CONCLUSIONS: Metformin activates the AMPK pathway while functioning as an activator of mTOR, thereby leading to the inhibition of autophagy and osteoclast differentiation.
Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Animais , Camundongos , Proteínas Quinases Ativadas por AMP , Leucina , Metformina/farmacologia , Osteoclastos , Serina-Treonina Quinases TORRESUMO
OBJECTIVE: It is unclear whether photodocumentation is associated with colorectal neoplasm (CRN) detection at colonoscopy, despite its ability to take more images with the development of affordable digital imaging systems. This study aimed to investigate whether photodocumentation-related factors could affect the detection rate of CRNs in healthy subjects. PATIENTS AND METHODS: A total of 2,637 subjects undergoing screening colonoscopy in routine health check-ups at CHA Bundang Medical from January to September 2016 were enrolled in this study. Only the endoscopic image data for observation purposes during colonoscopy withdrawal was used in this analysis. The number of observation images, observation time and the speed of photodocumentation (SPD) defined as the number of observation images per minute were used as quantity measures of photodocumentation. The presence of documented anatomical landmarks such as appendix orifice (AO), ileocecal valve (ICV), anorectal junction was used as quality measures of photodocumentation. RESULTS: Among subject-related factors, the independent factors for CRN detection in the multivariate analysis were age, male sex, waist circumference, and family history of colorectal cancer. In photo-documentation-related factors, SPD [Odds ratio (OR) 0.800; 95% confidence interval (CI), 0.740 to 0.864], observation time over 6 min (OR 1.671; 95% CI, 1.145 to 2.439), clear documentation of appendix orifice (AO) (OR 5.976; 95% CI, 4.548 to 7.852) and ileocecal valve (ICV) (OR 3.826; 95% CI, 2.985 to 4.904), and endoscopists (p < 0.001) were independently significant factors. However, the number of observation images was not associated with the detection of CRNs. CONCLUSIONS: Lower SPD and clear documentation of cecal landmarks might be associated with an increased detection rate of CRNs.
Assuntos
Colonoscopia , Neoplasias Colorretais , Humanos , Masculino , Neoplasias Colorretais/diagnóstico , Programas de Rastreamento , Razão de ChancesRESUMO
AIM: To investigate the predictive value of integrated 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography/computed tomography (PET/CT) for the prediction of programmed death ligand 1 (PD-L1) expression in solid tumours via a systematic review and meta-analysis. MATERIALS AND METHODS: The PubMed, Cochrane, and EMBASE databases, from the earliest available date of indexing through 31 October 2020, were searched for studies evaluating the diagnostic performance of 18F-FDG PET/CT for prediction of PD-L1 expression in solid tumours other than lung cancer. RESULTS: Across seven studies (473 patients), the pooled sensitivity for 18F-FDG PET/CT was 0.75 (95% confidence interval [CI]: 0.65-0.82) without heterogeneity (I2 = 47.2, p=0.08) and a pooled specificity of 0.73 (95% CI: 0.64-0.81) with heterogeneity (I2 = 53.8, p=0.04). Likelihood ratio (LR) syntheses gave an overall positive likelihood ratio (LR+) of 2.8 (95% CI: 2.1-3.7) and negative likelihood ratio (LR-) of 0.35 (95% CI: 0.26-0.47). The pooled diagnostic odds ratio (DOR) was 8 (95% CI: 5-13). Hierarchical summary receiver operating characteristic (ROC) curve and indicates that the area under the curve was 0.80 (95% CI: 0.77-0.84). CONCLUSION: The current meta-analysis showed a moderate sensitivity and specificity of 18F-FDG PET/CT for the prediction of PD-L1 expression in solid tumours. At present, the literature regarding the use of 18F-FDG PET/CT for the prediction of PD-L1 expression in solid tumours still limited; thus, further large multicentre studies would be necessary to substantiate the diagnostic accuracy of 18F-FDG PET/CT for prediction of PD-L1 expression in solid tumours.
Assuntos
Antígeno B7-H1/genética , Fluordesoxiglucose F18 , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos , Humanos , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
DyeCycle Violet efflux, caused by ATP-binding cassette transporters activity, was analyzed in human colorectal adenocarcinoma cell lines SW480, HT-29, Caco-2 by neans of FACSAria III flow cytometer and ImageStreamX Mk II imaging flow cytometer. Along with similarity of cytometry data obtained on the two instruments, the use of imaging flow cytometry made it possible to characterize the morphology of side population cells, as well as morphology of other cell populations differing in the degree of dye accumulation. The population of cells, which are smaller than the side population cells and practically do not take the dye, is of the special interest. Probably, this population may contribute to the tumor resistance to chemotherapy.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Corantes Fluorescentes , Transportadores de Cassetes de Ligação de ATP/genética , Benzimidazóis , Células CACO-2 , Linhagem Celular Tumoral , Citometria de Fluxo , HumanosRESUMO
BACKGROUND: The purpose of this study was to clarify the anatomy of the superior hypogastric plexus, which would contribute to advancement of nerve-sparing paraaortic lymphadenectomy. MATERIALS AND METHODS: Eighteen cadavers were dissected and morphometrically analysed based on photographic images. Anatomical landmarks such as aortic bifurcation, transitional points of abdominal aorta to bilateral common iliac arteries, and cross point of the right ureter and pelvic brim, and cross point of sigmoid mesentery and pelvic brim were selected as reference points. RESULTS: The left lowest lumbar splanchnic nerve was located more laterally to transitional point of abdominal aorta to in 11/18 specimens, whereas the right lowest lumbar splanchnic nerve passed onto the right transitional point in only one specimen. The lowest lumbar splanchnic nerves or the superior hypogastric plexus covered the aortic bifurcation in 11/18 specimens. The superior hypogastric plexus was separate from the cross point of right ureter and pelvic brim as well as cross point of sigmoid mesentery and pelvic brim. CONCLUSIONS: The superior hypogastric plexus is at risk of injury during paraaortic lymphadenectomy because of its topography. Preservation of the superior hypogastric plexus regarding its anatomic basis during paraaortic lymphadenectomy is required.
Assuntos
Plexo Hipogástrico , Pelve , Cadáver , Humanos , Plexo Hipogástrico/anatomia & histologia , Excisão de Linfonodo , Nervos Esplâncnicos/anatomia & histologiaRESUMO
BACKGROUND: Neutrophils present as major inflammatory cells in refractory chronic rhinosinusitis with nasal polyps (CRSwNP), regardless of the endotype. However, their role in the pathophysiology of CRSwNP remains poorly understood. We investigated factors predicting the surgical outcomes of CRSwNP patients with focus on neutrophilic localization. METHODS: We employed machine-learning methods such as the decision tree and random forest models to predict the surgical outcomes of CRSwNP. Immunofluorescence analysis was conducted to detect human neutrophil elastase (HNE), Bcl-2, and Ki-67 in NP tissues. We counted the immunofluorescence-positive cells and divided them into three groups based on the infiltrated area, namely, epithelial, subepithelial, and perivascular groups. RESULTS: On machine learning, the decision tree algorithm demonstrated that the number of subepithelial HNE-positive cells, Lund-Mackay (LM) scores, and endotype (eosinophilic or non-eosinophilic) were the most important predictors of surgical outcomes in CRSwNP patients. Additionally, the random forest algorithm showed that, after ranking the mean decrease in the Gini index or the accuracy of each factor, the top three ranking factors associated with surgical outcomes were the LM score, age, and number of subepithelial HNE-positive cells. In terms of cellular proliferation, immunofluorescence analysis revealed that Ki-67/HNE-double positive and Bcl-2/HNE-double positive cells were significantly increased in the subepithelial area in refractory CRSwNP. CONCLUSION: Our machine-learning approach and immunofluorescence analysis demonstrated that subepithelial neutrophils in NP tissues had a high expression of Ki-67 and could serve as a cellular biomarker for predicting surgical outcomes in CRSwNP patients.
Assuntos
Pólipos Nasais , Rinite , Doença Crônica , Humanos , Pólipos Nasais/complicações , Pólipos Nasais/cirurgia , Infiltração de Neutrófilos , Neutrófilos , Rinite/complicações , Rinite/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Systemic effects of long-term narrowband ultraviolet B (NB-UVB) phototherapy have not been well studied in vitiligo patients. An 11-year nationwide population-based retrospective cohort study was conducted using the Korean National Health Insurance claims database (2007-2017). OBJECTIVES: To investigate the effects of long-term NB-UVB phototherapy on the risk of cardiovascular and cerebrovascular events in vitiligo patients. METHODS: This study included vitiligo patients with ≥100 phototherapy sessions (phototherapy group, n = 3229) and <3 phototherapy sessions (no phototherapy group, n = 9687), in which covariables with age, sex, insurance type and comorbidities such as diabetes, hypertension and hyperlipidemia were matched by 1 : 3 propensity score matching. The outcomes of interest were cardiovascular (ischaemic heart disease and myocardial infarction) and cerebrovascular events (cerebrovascular infraction and haemorrhage). Cox proportional hazards models were used to assess the associations between NB-UVB phototherapy and each event. RESULTS: The risk of cardiovascular or cerebrovascular events was significantly decreased in the phototherapy group compared with the no phototherapy group [hazard ratio (HR) 0.637, 95% confidence interval (CI) 0.523-0.776]. Subgroup analysis revealed that the risk of cardiovascular (HR: 0.682, 95% CI: 0.495-0.940) and cerebrovascular events (HR: 0.601, 95% CI: 0.470-0.769) were significantly lower in the phototherapy group than the no phototherapy group, respectively. CONCLUSIONS: Our findings suggest that long-term NB-UVB phototherapy could decrease the risk of cardiovascular and cerebrovascular events in patients with vitiligo.
Assuntos
Terapia Ultravioleta , Vitiligo , Humanos , Fototerapia , Pontuação de Propensão , Estudos Retrospectivos , Resultado do Tratamento , Terapia Ultravioleta/efeitos adversos , Vitiligo/radioterapiaRESUMO
Excessive body fat and the related dysmetabolic diseases affect both developed and developing countries. The aim of this study was to investigate the beneficial role of a bacterial culture supernatant (hereafter: BS) of Lactobacillus and Bifidobacterium and their potential mechanisms of action on white-fat browning and lipolysis. For selection of four candidates among 55 Lactic acid producing bacteria (LAB) from human infant faeces, we evaluated by Oil Red O staining and Ucp1 mRNA quantitation in 3T3-L1 preadipocytes. The expression of browning and lipolysis markers was examined along with in vitro assays. The possible mechanism was revealed by molecular and biological experiments including inhibitor and small interfering RNA (siRNA) assays. In a mouse model, physiological, histological, and biochemical parameters and expression of some thermogenesis-related genes were compared among six experimental groups fed a high-fat diet and one normal-diet control group. The results allow us to speculate that BS treatment promotes browning and lipolysis both in vitro and in vivo. Moreover, the BS may activate thermogenic programs via a mechanism involving PKA-CREB signaling in 3T3-L1 cells. According to our data, we can propose that two LAB strains, Bifidobacterium longum DS0956 and Lactobacillus rhamnosus DS0508, may be good candidates for a dietary supplement against obesity and metabolic diseases; however, further research is required for the development as dietary supplements or drugs.
Assuntos
Bifidobacterium longum/metabolismo , Lacticaseibacillus rhamnosus/metabolismo , Obesidade/terapia , Termogênese/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/metabolismo , Meios de Cultivo Condicionados/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Lipólise/efeitos dos fármacos , Lipólise/genética , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Oxirredução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Termogênese/genéticaRESUMO
RATIONALE: The incidence of a unicornuate uterus is 0.2% to 0.3% of the whole population. A unicornuate uterus is closely associated with obstetrical complications such as early miscarriages, ectopic pregnancy, and malpresentation. PATIENT CONCERNS: A 32-year-old patient developed a rare ectopic pregnancy arising at a distal, fimbriated end of the undescended fallopian tube. DIAGNOSES: A transvaginal ultrasound scan revealed hemoperitoneum and no gestational sac in the uterine endometrium. A laparoscopic finding showed that high up in the right abdomen, just below the liver, an ectopic mass could be seen arising at a distal, fimbriated end of the fallopian tube, which was developed adjacent to the undescended right ectopic ovary. INTERVENTIONS: After laparoscopic removal of the right salpinx, we removed it with a bag. OUTCOMES: One day after the operation, she was discharged without problems. Postoperative hysterosalpingography showed the unicornuate uterus with patent left and some right salpinx. Magnetic resonance imaging revealed a unicornuate uterus, right ovary at the right inferior hepatic area, a bilateral normal kidney, and double inferior vena cava. LESSONS: This is the first reported case of its type. It demonstrated that ectopic pregnancy may occur in the upper abdomen, not in the pelvic cavity, in uterine anomaly, and double inferior vena cava; hence, we must thoroughly check the whole abdominal cavity. Additional imaging tests are needed after treatment to see if there are any abnormalities.
Assuntos
Tubas Uterinas/anormalidades , Ovário/anormalidades , Gravidez Ectópica/etiologia , Anormalidades Urogenitais/diagnóstico , Útero/anormalidades , Malformações Vasculares/diagnóstico , Veia Cava Inferior/anormalidades , Adulto , Endossonografia/métodos , Feminino , Procedimentos Cirúrgicos em Ginecologia/métodos , Humanos , Histerossalpingografia , Laparoscopia/métodos , Imageamento por Ressonância Magnética , Gravidez , Gravidez Ectópica/diagnóstico , Gravidez Ectópica/cirurgia , Anormalidades Urogenitais/complicações , Anormalidades Urogenitais/cirurgia , Útero/cirurgia , VaginaRESUMO
Using flow cytometry GD2 ganglioside expression was evaluated both on colorectal adenocarcinoma cell lines and on tumor tissue samples from colorectal cancer patients. The marker was found on EpCAM-positive tumor cells in 6 of 12 patients' samples but not on the HT29 and CaCo-2 cell lines. GD2 expression was not an exceptional feature of cancer stem cells, since its expression level was similar on CD133-positive and CD133-negative tumor cells. Thus, the presence of GD2 ganglioside was revealed on colorectal adenocarcinoma cells for the first time. This finding makes it possible to use targeted therapy to treat this disease.
Assuntos
Adenocarcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Gangliosídeos/metabolismo , Células CACO-2 , Células HT29 , HumanosRESUMO
OBJECTIVES: Currently available interferon (IFN)-γ-release assays (IGRA) cannot discriminate active tuberculosis (TB) from latent TB infection (LTBI), and so have limited clinical utility for diagnosing active TB. Since numbers of tumour necrosis factor (TNF)-α-producing T cells are highly correlated with active TB, we hypothesized that detecting IFN-γ- and/or TNF-α-producing T cells would overcome this limitation of IGRA. This study evaluated the diagnostic performances of the IFN-γ and TNF-α dual release fluorospot assay for active TB. METHODS: Adult patients with suspected TB including recent TB exposers were prospectively enrolled over a 28-month period. In addition to the conventional IGRA test (i.e. QuantiFERON-In-Tube), a fluorospot assay for detecting IFN-γ- and TNF-α-producing T cells was performed. The final diagnoses were classified by clinical category. Patients with confirmed or probable TB were regarded as active TB, and patients with not active TB were further classified as having not active TB with and without LTBI, based on the QuantiFERON-In-Tube results. RESULTS: A total of 153 patients including 45 with active TB and 108 with not active TB (38 LTBI vs. 70 not LTBI) were finally analysed. The sensitivity and specificity of the QuantiFERON-In-Tube assay for active TB were 84% (95% confidence interval (CI), 70-93) and 70% (95% CI 61-79), respectively. The IFN-γ/TNF-α dual release assay by fluorospot had substantially higher diagnostic specificity (94%) for diagnosing active TB than the IFN-γ single release assay (72%, p < 0.001), without compromising sensitivity (84% vs. 89%, p 0.79). CONCLUSIONS: The fluorospot-based IFN-γ/TNF-α dual release assay appears to be a simple and useful test for diagnosing active TB.
Assuntos
Linfócitos T/imunologia , Tuberculose/diagnóstico , Fator de Necrose Tumoral alfa/análise , Adulto , Idoso , Diagnóstico Diferencial , Diagnóstico Precoce , Feminino , Humanos , Testes de Liberação de Interferon-gama , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Teste Tuberculínico , Tuberculose/imunologiaRESUMO
SETTING: The Korea National Health and Nutrition Examination Survey is a national, population-based, cross-sectional surveillance programme.OBJECTIVE: 1) To investigate the prevalence of spontaneously healed pulmonary tuberculosis (SHPTB) on chest radiographs (CXRs) in South Korea, as well as its demographic and clinical associations, and 2) to determine the relationship between SHPTB and smoking.DESIGN: People with normal findings on CXRs (n = 24 190) and those with SHPTB (n = 1863) were compared in univariate, bivariate and multivariate analyses with respect to smoking and demographic and clinical factors.RESULTS: The prevalence of SHPTB was 7.2%. The proportion of patients with SHPTB tended to be higher in males, people of older age, ever smokers, as well as people with low body mass index and low education level. In bivariate analysis, after adjustments for age and sex, SHPTB was found more often among ex-smokers (P = 0.005) and current smokers (P = 0.024) than in non-smokers. Multivariate analyses revealed increased relative odds for SHPTB with increased age (P < 0.001), male sex (P < 0.001) and ex-smoker status (P = 0.016). Passive smoking was also significantly associated with SHPTB (P = 0.022).CONCLUSION: In addition to increasing the risk of active TB and negatively affecting the outcome of TB treatment, smoking is also associated with SHPTB, as detected on CXRs.
Assuntos
Pulmão/diagnóstico por imagem , Radiografia Torácica , Fumar/epidemiologia , Tuberculose Pulmonar/epidemiologia , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Inquéritos Nutricionais , Prevalência , República da Coreia/epidemiologia , Fatores de Risco , Tuberculose Pulmonar/diagnóstico por imagemRESUMO
Stress-related mucosal disease (SRMD), or stress ulceration, is a group of conditions ranging from stress-related superficial gastric mucosal damage to deep gastric ulcers that are primarily correlated with mucosal ischemia, and pharmacologic interventions that optimize tissue perfusion or preserve defensive mucus aim to decrease the occurrence of conditions, such as gastric acidity, or enhance gastric defenses. However, the identification of multifactorial pathogenesis may be effective in preventing SMRD, and the use of stress prophylaxis is generally preferred. Since threonine is a component in the polymerization and synthesis of gastric mucin and possibly enhanced defense actions and lignin may provide structural support for defense and antioxidative function, we hypothesized that dietary intake of threonine and/or lignin can enhance defense against SRMD. The water immersion-restraint stress (WIRS) was used in rats and additional groups were pretreated with threonine alone or the combination of threonine and lignin. Based on gross and microscopic evaluations, threonine alone or the combination of threonine and lignin, a natural antioxidant, significantly reduced the development of SRMD (P < 0.05). According to molecular explorations, the levels of inflammatory mediators, such as interleukin (IL)-8, IL-6, IL-1ß, inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ), all of which are mediators that play a significant role in controlling WIRS, significantly decreased in the groups pretreated with either threonine alone or the combination of threonine and lignin (P < 0.01). WIRS significantly increased apoptosis in the stomach. However, the apoptotic index significantly decreased with threonine pretreatment. According to periodic acid Schiff staining results, the expression of gastric mucin was significantly preserved in groups pretreated with threonine but remarkedly decreased in the WIRS group. The gastric heme oxygenase-1 levels significantly increased in the group treated with threonine. In conclusion, the dietary intake of threonine or the combination of threonine and lignin is effective in preventing SRMD.
Assuntos
Mucosa Gástrica/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Treonina/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Dieta , Mediadores da Inflamação/metabolismo , Lignina/metabolismo , Ratos , Ratos Sprague-Dawley , Estômago/efeitos dos fármacos , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/metabolismoRESUMO
Synthetic hydrogels are investigated extensively in tissue engineering for their tunable physicochemical properties but are bioinert and lack the tissue-specific cues to produce appropriate biological responses. To introduce tissue-specific biochemical cues to these hydrogels, we have developed a modular hydrogel cross-linker, poly(glycolic acid)-poly(ethylene glycol)-poly(glycolic acid)-di(but-2-yne-1,4-dithiol) (PdBT), that can be functionalized with small peptide-based cues and large macromolecular cues simply by mixing PdBT in water with the appropriate biomolecules at room temperature. Cartilage- and bone-specific PdBT macromers were generated by functionalization with a cartilage-associated hydrophobic N-cadherin peptide, a hydrophilic bone morphogenetic protein peptide, and a cartilage-derived glycosaminoglycan, chondroitin sulfate. These biofunctionalized PdBT macromers can spontaneously cross-link polymers such as poly(N-isopropylacrylamide) to produce rapidly cross-linking, highly swollen, cytocompatible, and hydrolytically degradable hydrogels suitable for mesenchymal stem cell encapsulation. These favorable properties, combined with PdBT's modular design and ease of functionalization, establish strong potential for its usage in tissue engineering applications.
Assuntos
Materiais Biocompatíveis/química , Hidrogéis/química , Engenharia Tecidual , Resinas Acrílicas/química , Animais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Peptídeos/química , Polietilenoglicóis/química , Polímeros/química , Coelhos , Alicerces Teciduais/químicaRESUMO
In clinical islet transplantation, hepatic ischemia and insufficient neovascularization of transplanted islets are barriers to islet survival and function. However, hepatocytes have a potency to protect themselves against ischemia. We hypothesized that ischemia/reperfusion preconditioning (IRP) of hepatocytes might beneficially affect islet cells in a coculture system. Primary islets were cocultured with primary hepatocytes, and hepatocyte IRP was conducted by subjecting cells to hypoxic conditions for single 15-minute/30-minute hypoxia, or 2 tandem 15-minute/30-minute hypoxic treatments (hypoxic-normoxic-hypoxic). We show that gene expression levels of insulin-like growth factor 1 (IGF-1), hepatocyte growth factor (HGF), transforming growth factor-α (TGF-α), and TGF-ß1 in hepatocytes were increased by IRP. IRP hepatocytes secreted hepatocyte growth factor and insulin-like growth factor-1. Coculture of islets with IRP hepatocytes enhanced islet insulin secretion in glucose challenge test and expression of the survival-related gene Bcl-2 and the regenerating gene-1α (Reg-1α). Islets cocultured with the 30-minute double-IRP hepatocytes displayed significantly higher viability in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase dUTP nick end labeling stain compared with that of islets subjected to 30 minutes of hypoxia. These results suggest that islet coculture with IRP hepatocytes can improve islet survival and insulin secretion.
Assuntos
Hepatócitos/citologia , Precondicionamento Isquêmico/métodos , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas/citologia , Animais , Sobrevivência Celular , Técnicas de Cocultura , Fator de Crescimento de Hepatócito/metabolismo , Hepatócitos/metabolismo , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismoRESUMO
Repeated bouts of ulcerative colitis featured troublesome course of inflammatory bowel disease leading to fatal colitis-associated cancer, which is strongly associated with oxidative stress and sustained inflammation. Since oligonol, low molecular weighted polyphenol extracted from fruit lychee, showed antioxidative and anti-inflammatory actions, we hypothesized that oligonolcan prevent relapse of colitis. We compared oligonol with current gold standard therapeutics, sulfasalazine in preventive efficacy of relapse. First, dextran sulfate sodium (DSS)-induced colitis were made following pretreatment with oligonol, 10, 50, and 100 mg/kg for 7 days to measure therapeutic effect of oligonol and relapse model via repeated DSS administration was made following with either 50 mg/kg oligonol or 30 mg/kg sulfasalazine to explore relapse preventing action of oligonol in C57BL/6 mice. Detailed changes in colon were measured to explain molecular mechanisms. Pretreatment of 10, 50, 100 mg/kg oligonol (p.o.), significantly reduced DSS-induced colitis; total pathologic scores, colon length, and clinical symptom scores (P < 0.05). Oligonol pretreatment significantly decreased the levels of interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) as well as nuclear factor-κB (NF-κB), c-Fos, and c-Jun in affected colon tissues, but the expression of heme oxygenase-1 (HO-1) and NADH: quinone oxidoreductase-1(NQO-1) as well as total antioxidant concentration (P < 0.005) was significantly increased with oligonol. A relapse model established with repeated DSS administration led to high mortality. However, oligonol significantly ameliorated exacerbations of colitis, while sulfasalazine did not (P < 0.01). Significantly decreased expressions of cyclooxygenase-2 (COX-2), TNF-α, and macrophages inhibition were relapse preventing actions of oligonal, but significant action of oligonol relevant to relapse prevention was either significantly increased expressions of NQO-1 or significantly preserved mucin (P < 0.05). Concerted anti-inflammatory, antioxidative, and host defense enhancing actions of oligonol can be applied during maintenance therapy of IBD to prevent relapse of IBD.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Catequina/análogos & derivados , Colite Ulcerativa/tratamento farmacológico , Fenóis/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Catequina/farmacologia , Catequina/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Citocinas/sangue , Sulfato de Dextrana , Heme Oxigenase-1/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Fenóis/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Prevenção SecundáriaRESUMO
While haemodynamic variability interferes with the assumption of constant flow underlying thermodilution cardiac output calculation, variability in (peripheral) arterial vascular physiology may affect pulse contour cardiac output methods. We compared non-invasive finger arterial pressure-derived continuous cardiac output measurements (Nexfin® ) with cardiac output measured using thermodilution during cardiothoracic surgery and determined the impact of cardiovascular variability on either method. We compared cardiac output derived from non-invasive finger arterial pressure with cardiac output measured by thermodilution at four grades (A-D) of cardiovascular variability. We defined Grade A data as heart rate and mean arterial pressure variability < 5% and the absence of arrhythmias (implying stable flow) and Physiocal® interval (as measure of variability in finger arterial physiology) > 30 beats. Grade B included all levels of heart rate/mean arterial pressure variability and arrhythmias (Physiocal < 30 excluded). Grade C included all Physiocal intervals (heart rate/mean arterial pressure variability > 5% and arrhythmias excluded). Grade D included all data. Comparison results were quantified as percentage errors. We analysed measurements in 27 patients undergoing coronary artery bypass surgery. Before extracorporeal circulation, the percentage error was 23% (n = 14 patients) in grade A, 28% (n = 20) in grade B, 32% (n = 22) in grade C and 37% (n = 26) in grade D, with a significant increase in variance (p = 0.035). Bias did not differ between grades. After extracorporeal circulation (n = 27), percentage errors became larger, but were not different between grades. Variability during cardiothoracic surgery affected the comparison between thermodilution and non-invasive finger arterial pressure-derived cardiac output. When the main sources of variability were included, percentage errors were large. Future cardiac output methodology comparison studies should report haemodynamic variability.
Assuntos
Débito Cardíaco , Procedimentos Cirúrgicos Cardíacos/métodos , Monitorização Intraoperatória/métodos , Pulso Arterial , Procedimentos Cirúrgicos Torácicos/métodos , Idoso , Idoso de 80 Anos ou mais , Pressão Arterial , Ponte de Artéria Coronária , Feminino , Dedos/irrigação sanguínea , Frequência Cardíaca , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional/fisiologia , TermodiluiçãoRESUMO
BACKGROUND: The significance of proinflammatory M1 (classically activated) and profibrotic M2 (alternatively activated) macrophages in antibody-mediated rejection (ABMR) after kidney transplantation has not been investigated. METHODS: Fifty-five biopsy-confirmed ABMR samples were stained with MRP 8/14 (a marker of M1 macrophages) and CD163 (a marker of M2 macrophages), and positive cells were counted in glomeruli and the tubulointerstitium, respectively. Patients were classified into M1 and M2 polarization groups according to the glomerular and tubulointerstitial M1:M2 ratio, and the results were compared with Banff scores, serum creatinine level, estimated glomerular filtration rate (eGFR), and graft survival. RESULTS: The glomerular M2 polarization group showed significantly higher chronic glomerulopathy scores, serum creatinine levels, and lower eGFR at the time of biopsy (P = .019 and P = .015, respectively) and 3-month postbiopsy (P = .016 and P = .032, respectively) than the M1 polarization group. The tubulointerstitial M2 polarization group had significantly lower glomerulitis, arteritis, peritubular capillaritis, and glomerulitis + peritubular capillaritis scores than the M1 polarization group, but there was no significant difference in renal function. Long-term graft survival was not associated with macrophage polarization. CONCLUSION: Glomerular M2 polarization in ABMR biopsy samples is associated with chronic glomerular injury and poorer graft function, but without graft survival.
Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Transplante de Rim/efeitos adversos , Macrófagos/imunologia , Adulto , Feminino , Rejeição de Enxerto/patologia , Humanos , Estimativa de Kaplan-Meier , Transplante de Rim/métodos , Transplante de Rim/mortalidade , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Transplante HomólogoRESUMO
BACKGROUND: Although renal function recovery of living kidney donors has been reported in a number of studies, many patients show poor recovery, and the long-term prognosis of these patients has not been well studied. In this investigation we explored the long-term prognosis of renal function in patients with chronic kidney disease (CKD) at 1 year after nephrectomy. METHODS: Patients who underwent donor nephrectomy during the period from March 2006 to April 2014, with a follow-up creatinine study at 1 year postoperatively and more than 3 years of follow-up, were included in the study. Creatinine and estimated glomerular filtration rate (eGFR, using the Modification of Diet in Renal Disease formula) before and after surgery were studied. Age, sex, history of hypertension or diabetes, body mass index, blood pressure, complete blood count, preoperative routine serum chemistry, and urine study results were reviewed. RESULTS: Among 841 patients who had donor nephrectomy, 362 were included in the study. There were 111 patients (30.6%) with eGFR <60 mL/min/1.73 m2 at 1 year postsurgery, and the median follow-up period was 62.8 months (interquartile range [IQR] 42.0-86.3 months). The maximum eGFR after 3-year follow-up was studied, and 48 patients (43.2%) never recovered eGFR to >60 mL/min/1.73 m2. Age, history of hypertension, preoperative eGFR, and eGFR at 1 year were predictive factors at univariate analysis. Multivariate analysis of these factors was studied, and age (52.5 [IQR 47-55.7] vs 47 [IQR 7-53] years, odds ratio [OR] 1.1, 95% confidence interval [CI] 1.02-1.15, P = .007), history of hypertension (16.7% vs 1.6%, OR 10.0, 95% CI 1.09-92.49, P = .042), and eGFR at 1 year (53.9 [IQR 50.3-56.0] vs 57.0 [IQR 54.2-58.4] mL/min/1.73 m2, OR 0.8, 95% CI 0.72-0.92, P = .002) remained as significant risk factors. CONCLUSION: Of all living donors, 15.7% had CKD after >3 years of follow-up. Close observation is warranted when donors have CKD after 1 year follow-up, as 43.2% fail to recover renal function. Patients who are older, have a history of hypertension, and have low eGFR at 1-year follow-up are especially at risk.
Assuntos
Doadores Vivos , Nefrectomia/efeitos adversos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Adulto , Idoso , Feminino , Seguimentos , Taxa de Filtração Glomerular/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nefrectomia/métodos , Razão de Chances , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Prognóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Smoking is known to result in a decline in renal allograft function and survival of recipients; however, the effect of smoking on living kidney donors remains unknown. In this study we evaluated the impact of cigarette smoking on renal function of kidney donors. METHODS: Among 1056 donors who underwent nephrectomy, 612 completed the 6-month follow-up protocol and were enrolled in the study. The association of smoking status, including pack-years smoking history, and postoperative renal function was evaluated. RESULTS: Among donors, 68.1% had never smoked, 8% were former smokers, and 23.9% were current smokers. Donors who never smoked were older than former and current smokers (42.3 ± 11.8, 41.9 ± 11.1, and 38.3 ± 10.9 years, respectively; P < .001). There was no difference in preoperative renal function between groups; however, postoperative estimated glomerular filtration rate (eGFR) was lower in former and current smokers than in those who never smoked (64.6 ± 13.8, 64.7 ± 12.3, and 67.8 ± 13.1 mL/min/1.73 m2, respectively; P = .023). In former and current smokers, pack-years smoking history was negatively associated with pre- and postoperative eGFR (r = -0.305 and -0.435, P < .001), and correlated with postoperative percent eGFR decline (r = 0.248, P < .001). Smoking history was associated with postoperative development of chronic kidney disease (CKD). Especially in former smokers, a smoking history of more than 12 pack-years was strongly associated with development of CKD (odds ratio = 7.5, P = .003). CONCLUSION: Even if they no longer smoke, donors with a smoking history require close observation due to increased risk of CKD development after kidney donation. A detailed pack-years smoking history should be obtained, and smoking cessation strategies should be implemented in kidney donors.