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BACKGROUND: Splenomegaly can exacerbate liver cirrhosis and portal hypertension. We have previously demonstrated that cyclooxygenase-2 (COX-2) inhibitor can attenuate cirrhotic splenomegaly. However, the mechanism of cirrhotic splenomegaly remains unclear, thus becoming the focus of the present study. MATERIALS AND METHODS: Thioacetamide (TAA) intraperitoneal injection was used to induce cirrhotic splenomegaly. Rats were randomized into the control, TAA and TAA + celecoxib groups. Histological analysis and high-throughput RNA sequencing of the spleen were conducted. Splenic collagen III, α-SMA, Ki-67, and VEGF were quantified. RESULTS: A total of 1461 differentially expressed genes (DEGs) were identified in the spleens of the TAA group compared to the control group. The immune response and immune cell activation might be the major signaling pathways involved in the pathogenesis of cirrhotic splenomegaly. With its immunoregulatory effect, celecoxib presents to ameliorate cirrhotic splenomegaly and liver cirrhosis. Furthermore, 304 coexisting DEGs were obtained between TAA vs. control and TAA + celecoxib vs. TAA. Gene ontology (GO) and KEGG analyses collectively indicated that celecoxib may attenuate cirrhotic splenomegaly through the suppression of splenic immune cell proliferation, inflammation, immune regulation, and fibrogenesis. The impacts on these factors were subsequently validated by the decreased splenic Ki-67-positive cells, macrophages, fibrotic areas, and mRNA levels of collagen III and α-SMA. CONCLUSIONS: Celecoxib attenuates cirrhotic splenomegaly by inhibiting splenic immune cell proliferation, inflammation, and fibrogenesis. The current study sheds light on the therapeutic strategy of liver cirrhosis by targeting splenic abnormalities and provides COX-2 inhibitors as a novel medical treatment for cirrhotic splenomegaly.
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Cirrose Hepática , Esplenomegalia , Ratos , Animais , Celecoxib/farmacologia , Esplenomegalia/tratamento farmacológico , Esplenomegalia/etiologia , Esplenomegalia/patologia , Antígeno Ki-67 , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Colágeno , Inflamação/tratamento farmacológico , Perfilação da Expressão GênicaRESUMO
AIMS: To map the existing literature describing medical device-related pressure injuries in patients during surgery, including investigation of the incidence, types of medical devices, risk factors and strategies for preventing medical device-related pressure injuries. DESIGN: A scoping review. DATA SOURCES: In April 2023, three databases were searched. Studies about adult patients undergoing surgery, from 2014 onwards, in English and Chinese were included. Data were extracted about study characteristics and data related to research questions. The Patterns, Advances, Gaps, Evidence for practice and Research recommendations framework were used to synthesize findings. RESULTS: Two different types of evidence were included in this review; 14 research studies and two quality improvement studies. The incidence of medical device-related pressure injuries in the operating room was 0.56%-24.5% and respiratory devices were the most common medical devices investigated. Length of surgery, age and BMI were risk factors for medical device-related pressure injuries in a few studies. The application of a prophylactic dressing and dressing maintenance was the most common prevention strategy. CONCLUSION: Ongoing research is needed to confirm the incidence of, and risk factors for, medical device-related pressure injuries in the operating room. Additionally, more high-quality evidence is needed to underpin current prevention strategies. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Operating room nurses need to be aware of the risks of medical device-related pressure injuries and assess and plan prevention strategies accordingly. Once more high-quality evidence is available, operating room nurses could implement prevention strategies like prophylactic dressings. REPORTING METHOD: Scoping Reviews (PRISMA-ScR) checklist. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.
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PURPOSE: To compare the clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) creation versus portal vein stent placement (PVS) in patients with noncirrhotic cavernous transformation of the portal vein (CTPV). MATERIALS AND METHODS: In this retrospective study, clinical data from patients with noncirrhotic CTPV who underwent TIPS creation or PVS were compared. A total of 54 patients (mean age, 43.8 years ± 15.8; 31 men and 23 women) were included from January 2013 to January 2021; 29 patients underwent TIPS creation, and 25 patients underwent PVS. Stent occlusion, variceal rebleeding, survival, and postprocedural complications were compared between the 2 groups. RESULTS: The mean follow-up time was 40.2 months ± 26.2 in the TIPS group and 35.3 months ± 21.1 in the PVS group. The stent occlusion rate in the PVS group (16%, 4 of 25) was significantly lower than that in the TIPS group (41.4%, 12 of 29) during the follow-up (P = .042). The cumulative variceal rebleeding rates in the TIPS group were significantly higher than those in the PVS group (28% vs 4%; P = .027). The procedural success rate was 69% in the TIPS group and 86% in the PVS group (P = .156). There was a higher number of severe adverse events after TIPS than after PVS (0% vs 24%; P = .012). CONCLUSIONS: Portal vein recanalization with PVS may be a preferable alternative to TIPS creation in the treatment of noncirrhotic CTPV because of higher stent patency rates, lower risk of variceal rebleeding, and fewer adverse events.
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Varizes Esofágicas e Gástricas , Derivação Portossistêmica Transjugular Intra-Hepática , Masculino , Humanos , Feminino , Adulto , Veia Porta/diagnóstico por imagem , Veia Porta/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Estudos Retrospectivos , Stents/efeitos adversos , Resultado do Tratamento , Hemorragia Gastrointestinal/diagnóstico por imagem , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Varizes Esofágicas e Gástricas/diagnóstico por imagem , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/cirurgiaRESUMO
This study aims to explore the mechanism of Yanghe Decoction(YHD) against subcutaneous tumor in pulmonary metastasis from breast cancer, which is expected to lay a basis for the treatment of breast carcinoma with YHD. The chemical components of medicinals in YHD, and the targets of the components were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and SwissTargetPrediction. The disease-related targets were searched from GeneCards and Online Mendelian Inheritance in Man(OMIM). Excel was employed to screen the common targets and plot the Venn diagram. The protein-protein interaction network was constructed. R language was used for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. A total of 53 female SPF Bablc/6 mice were randomized into normal group(same volume of normal saline, ig), model group(same volume of normal saline, ig), and low-dose and high-dose YHD groups(YHD, ig, 30 days), with 8 mice in normal group and 15 mice in each of the other groups. Body weight and tumor size was measured every day. Curves for body weight variation and growth of tumor in situ were plotted. In the end, the subcutaneous tumor sample was collected and observed based on hematoxylin and eosin(HE) staining. The mRNA and protein levels of hypoxia inducible factor-1α(HIF-1α), pyruvate kinase M2(PKM2), lactate dehydrogenase A(LDHA), and glucose transporter type 1(GLUT1) were detected by PCR and Western blot. A total of 213 active components of YHD and 185 targets against the disease were screened out. The hypothesis that YHD may regulate glycolysis through HIF-1α signaling pathway to intervene in breast cancer was proposed. Animal experiment confirmed that the mRNA and protein levels of HIF-1α, PKM2, LDHA, and GLUT1 in the high-and low-dose YHD groups were lower than those in the model group. YHD has certain inhibitory effect on subcutaneous tumor in pulmonary metastasis from breast cancer in the early stage, which may intervene pulmonary metastasis from breast cancer by regulating glycolysis through HIF-1α signaling pathway.
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Experimentação Animal , Medicamentos de Ervas Chinesas , Neoplasias , Feminino , Camundongos , Animais , Transportador de Glucose Tipo 1/genética , Farmacologia em Rede , Solução Salina , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Transdução de Sinais , Glicólise , RNA Mensageiro , Neoplasias/tratamento farmacológico , Simulação de Acoplamento MolecularRESUMO
The intestinal barrier dysfunction is crucial for the development of liver fibrosis but can be disturbed by intestinal chronic inflammation characterized with cyclooxygenase-2 (COX-2) expression. This study focused on the unknown mechanism by which COX-2 regulates intestinal epithelial homeostasis in liver fibrosis. The animal models of liver fibrosis induced with TAA were established in rats and in intestinal epithelial-specific COX-2 knockout mice. The impacts of COX-2 on intestinal epithelial homeostasis via suppressing ß-catenin signalling pathway were verified pharmacologically and genetically in vivo. A similar assumption was tested in Ls174T cells with goblet cell phenotype in vitro. Firstly, disruption of intestinal epithelial homeostasis in cirrhotic rats was ameliorated by celecoxib, a selective COX-2 inhibitor. Then, ß-catenin signalling pathway in cirrhotic rats was associated with the activation of COX-2. Furthermore, intestinal epithelial-specific COX-2 knockout could suppress ß-catenin signalling pathway and restore the disruption of ileal epithelial homeostasis in cirrhotic mice. Moreover, the effect of COX-2/PGE2 was dependent on the ß-catenin signalling pathway in Ls174T cells. Therefore, inhibition of COX-2 may enhance intestinal epithelial homeostasis via suppression of the ß-catenin signalling pathway in liver fibrosis.
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Celecoxib/farmacologia , Ciclo-Oxigenase 2/química , Homeostase , Inflamação/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , beta Catenina/metabolismo , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , beta Catenina/genéticaRESUMO
Despite the development in hepatocellular carcinoma (HCC) treatment in recent years, the therapeutic outcome of HCC remains unfavourable. This study examines the prognosis of HCC from a genetic level using clinical databases and single-cell data to identify genes with a high prognostic value. Three up-regulated genes (UBE2S, PTTG1, and CDC20) and two down-regulated genes (SOCS2 and DNASE1L3) in HCC tissues were identified. Various analyses confirmed its correlation with tumour stage (p < 0.01) and patient survival time (log-rank p < 0.001). Immune analysis, single-cell analysis, and gene set enrichment analysis (GSEA) were employed to provide insight on how they affect cancer progression, and we observed a close relation between these genes and tumour immune infiltration. Eventually, we constructed a risk score system that risk score = (0.0465) × UBE2S + (0.1851) × CDC20 + (-0.0461) × DNASE1L3 + (-0.2279) × SOCS2 (5-year area under curve = 0.706). The risk score system may serve as an effective novel prognostic system for HCC patients. This study might provide novel ideas for prognostic or therapeutic biomarkers for HCC.
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Biomarcadores Tumorais , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Biologia Computacional , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Microambiente Tumoral , Carcinoma Hepatocelular/patologia , Bases de Dados Genéticas , Suscetibilidade a Doenças/imunologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Análise de Célula Única , Transcriptoma , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase-2 (COX-2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX-2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX-2 overexpression by COX-2-dependent PGE2-EP2-ERK1/2-NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX-2-independent LKB1-AMPK-NRF2-HO-1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX-2-dependent and COX-2-independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.
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Celecoxib/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Celecoxib/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Gerenciamento Clínico , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Hemodinâmica/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Humanos , Hipertensão Portal/diagnóstico , Hipertensão Portal/etiologia , Masculino , Modelos Biológicos , Óxido Nítrico/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: In liver cirrhosis, intestinal mucus barrier is rarely studied. AIMS: This study aimed to investigate whether mucus barrier in ileum is altered in cirrhotic rats and its underlying mechanisms. METHODS: Thioacetamide was injected to induce liver cirrhosis in rats. Serum from portal vein blood, and ileum and liver tissues were obtained for further analysis. Goblet cell-like Ls174T cells were cultured for in vitro experiments. RESULTS: The ileal mucus was thin, loose, and porous with small bubbles in cirrhotic rats. mRNA expressions of Muc2 and TFF3 were also down-regulated in cirrhotic rats. Bacteria located near to crypts and LPS were increased in the serum from portal vein in cirrhotic rats. Smaller theca area and few goblet cells were found in cirrhotic rats compared with control. Increased proliferation of ileal epithelia was observed in cirrhotic rats. Notch1, Dll1, and Hes1 expressions were enhanced, and KLF4 expression was suppressed in ileum of cirrhotic rats. In Ls174T cells, EDTA and NICD plasmid induced NICD and Hes1 expression and suppressed KLF4 concomitantly, and mucus expression almost vanished in these cells. NICD plasmid induced more proliferation in Ls174T cells. Oppositely, after DBZ treatment, NICD and Hes1 were inhibited along with augmentation of KLF4 and increased mucous expression in Ls174T cells, while proliferation of the cells was suppressed. CONCLUSIONS: In cirrhotic rats, mucus barrier was impaired. This might be attributed to increased proliferation and decreased differentiation of epithelia, which might be mediated by Notch1-Hes1-KLF4 signaling.
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Homeostase/fisiologia , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Cirrose Hepática/metabolismo , Receptor Notch1/biossíntese , Animais , Linhagem Celular Tumoral , Homeostase/efeitos dos fármacos , Humanos , Íleo/efeitos dos fármacos , Íleo/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Fator 4 Semelhante a Kruppel , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Tioacetamida/toxicidadeAssuntos
Encefalopatia Hepática , Derivação Portossistêmica Transjugular Intra-Hepática , Humanos , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Cirrose Hepática/complicações , Encefalopatia Hepática/etiologia , Próteses e Implantes/efeitos adversos , Dor Abdominal/diagnóstico , Dor Abdominal/etiologiaAssuntos
Varizes Esofágicas e Gástricas/diagnóstico , Veia Porta/anormalidades , Veia Esplênica/anormalidades , Malformações Vasculares/diagnóstico por imagem , Varizes Esofágicas e Gástricas/etiologia , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Veia Porta/diagnóstico por imagem , Veia Esplênica/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Malformações Vasculares/complicaçõesRESUMO
Inflammatory transport through the gut-liver axis may facilitate liver cirrhosis. Cyclooxygenase-2 (COX-2) has been considered as one of the important molecules that regulates intestinal epithelial barrier function. This study was aimed to test the hypothesis that inhibition of COX-2 by celecoxib might alleviate liver cirrhosis via reduction of intestinal inflammatory transport in thiacetamide (TAA) rat model. COX-2/prostaglandin E2 (PGE2)/EP-2/p-ERK integrated signal pathways regulated the expressions of intestinal zonula occludens-1 (ZO-1) and E-cadherin, which maintain the function of intestinal epithelial barrier. Celecoxib not only decreased the intestinal permeability to a 4-kDa FITC-dextran but also significantly increased expressions of ZO-1 and E-cadherin. When celecoxib greatly decreased intestinal levels of LPS, TNF-α, and IL-6, it significantly enhanced T cell subsets reduced by TAA. As a result, liver fibrosis induced by TAA was significantly alleviated in the celecoxib group. These data indicated that celecoxib improved the integrity of intestinal epithelial barrier, blocked inflammatory transport through the dysfunctional gut-liver axis, and ameliorated the progress of liver cirrhosis.
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Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Jejuno/metabolismo , Cirrose Hepática/tratamento farmacológico , Fígado/metabolismo , Animais , Células CACO-2 , Caderinas/metabolismo , Celecoxib/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Dinoprostona/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Interleucina-6/metabolismo , Absorção Intestinal , Jejuno/efeitos dos fármacos , Fígado/efeitos dos fármacos , Cirrose Hepática/metabolismo , Ratos , Ratos Sprague-Dawley , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Proteína da Zônula de Oclusão-1/metabolismoAssuntos
Tuberculose , Doenças Vasculares , Abdome , Constrição Patológica , Humanos , Veia Porta/diagnóstico por imagemRESUMO
Organolead halide perovskites exhibit superior photoelectric properties, which have given rise to the perovskite-based solar cells whose power conversion efficiency has rapidly reached above 20% in the past few years. However, perovskite-based solar cells have also encountered problems such as current-voltage hysteresis and degradation under practical working conditions. Yet investigations into the intrinsic chemical nature of the perovskite material and its role on the performance of the solar cells are relatively rare. In this work, Raman spectroscopy is employed together with CASTEP calculations to investigate the organic-inorganic interactions in CH3NH3PbI3 and CH3NH3PbBr3-xClx perovskite single crystals with comparison to those having ammonic acid as the cations. For Raman measurements of CH3NH3PbI3, a low energy line of 1030 nm is used to avoid excitation of strong photoluminescence of CH3NH3PbI3. Raman spectra covering a wide range of wavenumbers are obtained, and the restricted rotation modes of CH3-NH3(+) embedded in CH3NH3PbBr3 (325 cm(-1)) are overwhelmingly stronger over the other vibrational bands of the cations. However, the band intensity diminishes dramatically in CH3NH3PbBr3-xClx and most of the bands shift towards high frequency, indicating the interaction with the halides. The details of such an interaction are further revealed by inspecting the band shift of the restricted rotation mode as well as the C-N, NH3(+) and CH3 stretching of the CH3NH3(+) as a function of Cl composition and length of the cationic ammonic acids. The results show that the CH3NH3(+) interacts with the PbX3(-) octahedral framework via the NH3(+) end through N(+)-HX hydrogen bonding whose strength can be tuned by the composition of halides but is insensitive to the size of the organic cations. Moreover, an increase of the Cl content strengthens the hydrogen bonding and thus blueshifts the C-N stretching bands. This is due to the fact that Cl is more electronegative than Br and an increase of the Cl content decreases the lattice constant of the perovskite. The findings of the present work are valuable in understanding the role of cations and halides in the performance of MAPbX3-based perovskite solar cells.
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OBJECTIVE: Coronary artery calcification (CAC) is a well-established risk predictor of coronary heart disease events and is recognized as an indicator of subclinical atherosclerosis. METHODS: A cross-sectional study consisting of 2999 participants aged â40 years from the Jidong community of Tangshan City, an industrial and modern city of China, was conducted between 2013 and 2014 to examine the association between the ideal cardiovascular health (CVH) metrics and CAC. The ideal CVH metrics were determined based on the definition of the American Heart Association (AHA). The participants were then grouped into 4 categories according to the quartiles of their CVH metric scores as follows: first quartile (0-2), second quartile (3), third quartile (4), and fourth quartile (5-7). CAC was assessed by using high-pitch dual-source CT, and patients were identified based on thresholds of 0, 10, 100, or 400 Agatston units, as per common practice. RESULTS: The prevalence of subclinical atherosclerosis was 15.92%, 13.85%, 6.76%, and 1.93%, determined by using the CAC scores at thresholds of 0, 10, 100, and 400 Agatston units, respectively. Compared with the group in the first quartile, the other three CVH groups had a lower odds ratio of CAC >0 after adjusting for age, sex, income level, education level, and alcohol use in the logistic regression analysis. The odds ratios in these groups were 0.86 [95% confidence interval (CI), 0.63-1.17; P<0.05], 0.75 (95% CI, 0.55-1.02; P<0.05), and 0.49 (95% CI, 0.35-0.69; P<0.05), respectively. These associations of CAC with the CVH metrics were consistent when different CAC cutoff scores were used (0, 10, 100, or 400). CONCLUSION: The participants with more-ideal cardiovascular metrics had a lower prevalence of subclinical atherosclerosis determined according to CAC score. Maintaining an ideal cardiovascular health may be valuable in the prevention of atherosclerosis in the general population.
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Aterosclerose/epidemiologia , Aterosclerose/patologia , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/patologia , Adulto , Fenômenos Fisiológicos Cardiovasculares , China/epidemiologia , Estudos Transversais , Feminino , Comportamentos Relacionados com a Saúde , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/epidemiologia , Fatores de Risco , Calcificação Vascular/patologiaRESUMO
We report here on the application of laser-based single molecule total internal reflection fluorescence microscopy (TIRFM) to study the penetration of molecules through the skin. Penetration of topically applied drug molecules is often observed to be limited by the size of the respective drug. However, the molecular mechanisms which govern the penetration of molecules through the outermost layer of the skin are still largely unknown. As a model compound we have chosen a larger amphiphilic molecule (fluorescent dye ATTO-Oxa12) with a molecular weight >700 Da that was applied to excised human skin. ATTO-Oxa12 penetrated through the stratum corneum (SC) into the viable epidermis as revealed by TIRFM of cryosections. Single particle tracking of ATTO-Oxa12 within SC sheets obtained by tape stripping allowed us to gain information on the localization as well as the lateral diffusion dynamics of these molecules. ATTO-Oxa12 appeared to be highly confined in the SC lipid region between (intercellular space) or close to the envelope of the corneocytes. Three main distinct confinement sizes of 52 ± 6, 118 ± 4, and 205 ± 5 nm were determined. We conclude that for this amphiphilic model compound several pathways through the skin exist.
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Epiderme/metabolismo , Corantes Fluorescentes/farmacocinética , Humanos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Absorção CutâneaAssuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Fístula Esofágica/etiologia , Hemorragia Gastrointestinal/etiologia , Veias Pulmonares , Fístula Vascular/etiologia , Endoscopia do Sistema Digestório , Fístula Esofágica/diagnóstico por imagem , Fístula Esofágica/cirurgia , Hemorragia Gastrointestinal/diagnóstico por imagem , Hemorragia Gastrointestinal/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Toracotomia , Tomografia Computadorizada por Raios X , Fístula Vascular/diagnóstico por imagem , Fístula Vascular/cirurgiaRESUMO
Arrestins are regulatory molecules for G-protein coupled receptor function. In visual rhodopsin, selective binding of arrestin to the cytoplasmic side of light-activated, phosphorylated rhodopsin (P-Rh*) terminates signaling via the G-protein transducin. While the "phosphate-sensor" of arrestin for the recognition of receptor-attached phosphates is identified, the molecular mechanism of arrestin binding and the involvement of receptor conformations in this process are still largely hypothetic. Here we used fluorescence pump-probe and time-resolved fluorescence depolarization measurements to investigate the kinetics of arrestin conformational changes and the corresponding nanosecond dynamical changes at the receptor surface. We show that at least two sequential conformational changes of arrestin occur upon interaction with P-Rh*, thus providing a kinetic proof for the suggested multistep nature of arrestin binding. At the cytoplasmic surface of P-Rh*, the structural dynamics of the amphipathic helix 8 (H8), connecting transmembrane helix 7 and the phosphorylated C-terminal tail, depends on the arrestin interaction state. We find that a high mobility of H8 is required in the low-affinity (prebinding) but not in the high-affinity binding state. High-affinity arrestin binding is inhibited when a bulky, inflexible group is bound to H8, indicating close interaction. We further show that this close steric interaction of H8 with arrestin is mandatory for the transition from prebinding to high-affinity binding; i.e., for arrestin activation. This finding implies a regulatory role for H8 in activation of visual arrestin, which shows high selectivity to P-Rh* in contrast to the broad receptor specificity displayed by the two nonvisual arrestins.
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Arrestina/química , Receptores Acoplados a Proteínas G/química , Rodopsina/química , Animais , Anisotropia , Bovinos , Cristalografia por Raios X/métodos , Cinética , Microscopia de Fluorescência/métodos , Conformação Molecular , Fosforilação , Ligação Proteica , Conformação Proteica , Estrutura Terciária de Proteína , Retina/metabolismo , Transdução de Sinais , Espectrofotometria/métodosRESUMO
BACKGROUND: Chylous ascites is caused by disruption of the lymphatic system, which is characterized by the accumulation of a turbid fluid containing high levels of triglycerides within the abdominal cavity. The two most common causes are cirrhosis and tuberculosis, and colon signer ring cell carcinoma (SRCC) due to the use of immunosuppressants is extremely rare in cirrhotic patients after liver transplantation, making it prone to misdiagnosis and missed diagnosis. CASE SUMMARY: A 52-year-old man who underwent liver transplantation and was administered with immunosuppressants for 8 months was admitted with a 3-month history of progressive abdominal distention. Initially, based on lymphoscintigraphy and lymphangiography, lymphatic obstruction was considered, and cystellar chyli decompression with band lysis and external membrane stripping of the lymphatic duct was performed. However, his abdominal distention was persistent without resolution. Abdominal paracentesis revealed allogenic cells in the ascites, and immunohistochemistry analysis revealed adenocarcinoma cells with phenotypic features suggestive of a gastrointestinal origin. Gastrointestinal endoscopy was performed, and biopsy showed atypical signet ring cells in the ileocecal valve. The patient eventually died after a three-month follow-up due to progression of the tumor. CONCLUSION: Colon SRCC, caused by immunosuppressants, is an unusual but un-neglected cause of chylous ascites.