RESUMO
Airway remodeling is a major pathological characteristic of chronic obstructive pulmonary disease (COPD). This study aimed to investigate the effect of Abhd2 deficiency on ovalbumin (OVA)-induced airway remodeling and inflammation in vivo. Abhd2-deficient mice were used to establish an OVA-induced asthma model. Lung tissues were analyzed using hematoxylin and eosin (HE) staining, Masson staining, immunohistochemistry, quantitative reverse transcription- polymerase chain reaction (qRT-PCR), and western blotting were used to determine the role of Abhd2 in the regulation of OVA-induced airway remodeling and inflammation. Our findings revealed that the RNA expression of inflammatory factors, including IL-1ß, IL-6, IL-4, and IL-13, was significantly increased in OVA-induced Abhd2 Gt/Gt asthmatic mice. The expression of IFN-γ was decreased significantly in OVA-induced Abhd2 Gt/Gt asthmatic mice. The protein expression of airway remodeling factors, including α-SMA, type I collagen, and Ki67, was also increased in OVA-induced Abhd2 Gt/Gt asthmatic mice compared to that in OVA-induced wild-type (WT) mice. Additionally, Abhd2 deficiency promoted the expression of p-Akt in tissues of the asthma model. These results suggest that Abhd2 deficiency exacerbates airway remodeling and inflammation through the PI3K/Akt pathway in chronic asthma.
Assuntos
Asma , Animais , Camundongos , Remodelação das Vias Aéreas , Asma/induzido quimicamente , Asma/genética , Asma/veterinária , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/veterinária , Pulmão , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Ovalbumina/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
OBJECTIVE: To investigate the relationship between antiviral restriction factor Sterile Alpha Motif and Histidine-Aspartic acid domain-containing protein 1 (SAMHD1) expression and T cell activation, furthermore, identifying objective indexes of lung-spleen deficiency symptom pattern. METHODS: We assessed the profile of T lymphocyte subsets, characteristics of SAMHD1 and human leukocyte antigen DR (HLA-DR) expression in lung-spleen deficiency patients. At the same time, people living with human immunodeficiency virus / acquired immune deficiency syndrome (HIV/AIDS) (PLWHA) without obvious clinical symptoms and healthy donors in this area were used as controls. RESULTS: Immunohematologic indexes lower CD4 count, lower CD4/CD8 ratio and higher SAMHD1 level were found in lung-spleen deficiency patients. Furthermore, we demonstrated a positive relationship between SAMHD1 and HLA-DR level as well as with interferon factor in lung-spleen deficiency syndrome and patients without obvious clinical signs and symptoms groups. CONCLUSIONS: These data indicated the positive relationship between SAMHD1 and T cell activation which further elucidated the role of SAMHD1 in cellular immune response. Furthermore, combination of T lymphocyte subsets counts and SAMHD1 level may be used as clinical and biological reference basis for the differentiation and diagnosis of HIV / AIDS traditional Chinese medicine syndromes.
Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Ácido Aspártico , HIV/metabolismo , Infecções por HIV/complicações , Infecções por HIV/genética , Histidina , Humanos , Pulmão/metabolismo , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Baço/metabolismo , Motivo Estéril alfa , Linfócitos TRESUMO
AIMS: Gulf War Illness (GWI), a chronic debilitating disorder characterized by fatigue, joint pain, cognitive, gastrointestinal, respiratory, and skin problems, is currently diagnosed by self-reported symptoms. The Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) is the collaborative effort of expert Gulf War Illness (GWI) researchers who are creating objective diagnostic and pathobiological markers and recommend common data elements for GWI research. MAIN METHODS: BBRAIN is recruiting 300 GWI cases and 200 GW veteran controls for the prospective study. Key data and biological samples from prior GWI studies are being merged and combined into retrospective datasets. They will be made available for data mining by the BBRAIN network and the GWI research community. Prospective questionnaire data include general health and chronic symptoms, demographics, measures of pain, fatigue, medical conditions, deployment and exposure histories. Available repository biospecimens include blood, plasma, serum, saliva, stool, urine, human induced pluripotent stem cells and cerebrospinal fluid. KEY FINDINGS: To date, multiple datasets have been merged and combined from 15 participating study sites. These data and samples have been collated and an online request form for repository requests as well as recommended common data elements have been created. Data and biospecimen sample requests are reviewed by the BBRAIN steering committee members for approval as they are received. SIGNIFICANCE: The BBRAIN repository network serves as a much needed resource for GWI researchers to utilize for identification and validation of objective diagnostic and pathobiological markers of the illness.
Assuntos
Síndrome do Golfo Pérsico/patologia , Boston , Humanos , Disseminação de Informação , Imageamento por Ressonância Magnética , Síndrome do Golfo Pérsico/sangue , Tomografia por Emissão de Pósitrons , Saliva/metabolismoRESUMO
Eight terpenoids(1-8) were isolated from the ethyl acetate soluble fraction of 80% ethanol extract of leaf of Toona sinensis through various column chromatographies on silica gel, Sephadex LH-20, MCI and ODS. Their structures were elucidated as 8ß-hydroxypimar-15-en-19-oic acid methyl ester(1), cedrodorol B(2), 11ß-acetoxyobacunol(3), toonayunnanin D(4), toonaciliatone D(5), toonaciliatone A(6), cedrelone(7), and 11ß-hydroxygedunin(8) based on their chemical and physicochemical methods and spectroscopic data. Compound 1 was a new pimaradienediterpenoid and terpenoid 2-7 were isolated and identified from this plant for the first time. Compound 1 was tested in vitro for cytotoxic potential by employing MTT method and radical scavenging potential using DPPH test. As a result, 1 exhibited weak cytotoxic activity against three tested tumor cell lines(SMMC-7721, A549 and MCF-7) with IC_(50) values less than 40 µmol·L~(-1) and moderate radical scavenging activities with IC_(50) values of 74.3 µmol·L~(-1).
Assuntos
Extratos Vegetais , Terpenos , Linhagem Celular Tumoral , Folhas de Planta , Terpenos/farmacologiaRESUMO
OBJECTIVE: Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM), but the pathophysiology of DN is complex and not fully understood. Renal tubal epithelial-mesenchymal transition (EMT) has been shown to be the critical mechanism of glomerulosclerosis and tubulointerstitial fibrosis. However, the precise mechanisms underlying EMT are not clear. MALAT1 was found induced by hyperglycemia in kidney but whether MALAT1 is involved in renal tubal EMT remains unknown. The objective of our study is to explore the role of MALAT1 in hyperglycemia-induced EMT and fibrosis. PATIENTS AND METHODS: We used db/db mouse and high glucose (HG)-stimulated HK-2 cells as in vivo and in vitro model of DN, respectively. qRT-PCR was used to measure levels of MALAT1 and miR-145. In addition, we validated interactions of MALAT1-miR-145 and miR-145-ZEB2 by dual luciferase reporter assays. Western blot was used to examine expressions of proteins involved in EMT and fibrosis. RESULTS: MALAT1 was upregulated while miR-145 was downregulated in renal tissues of db/db mice. Consistently, hyperglycemia significantly increased the level of MALAT1 but decreased miR-145 expression in a time-dependent manner in HK-2 cells. Furthermore, miR-145 binds to both MALAT1 and ZEB2. Knockdown MALAT1 or ZEB2 inhibited HG-induced EMT and fibrosis, similar to miR-145 overexpression. CONCLUSIONS: Our study is the first to show that MALAT1 and miR-145 regulate HG-induced EMT and fibrosis. Mechanistically, MALAT1 functions as a sponge RNA for miR-145 to derepress the expression of target gene ZEB2, thereby inducing EMT and fibrosis. These results provide a novel potential target for DN therapy in the future.
Assuntos
Nefropatias Diabéticas/genética , Rim/patologia , MicroRNAs/genética , RNA Longo não Codificante/metabolismo , Animais , Glicemia/metabolismo , Linhagem Celular , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Regulação para Baixo , Transição Epitelial-Mesenquimal/genética , Fibrose , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Rim/citologia , Masculino , Camundongos , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética , Regulação para Cima , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genéticaRESUMO
E-cadherin is a cell adhesion molecule best known for its function in suppressing tumor progression and metastasis. Here we show that E-cadherin promotes nucleotide excision repair through positively regulating the expression of xeroderma pigmentosum complementation group C (XPC) and DNA damage-binding protein 1 (DDB1). Loss of E-cadherin activates the E2F4 and p130/107 transcription repressor complexes to suppress the transcription of both XPC and DDB1 through activating the transforming growth factor-ß (TGF-ß) pathway. Adding XPC or DDB1, or inhibiting the TGF-ß pathway, increases the repair of ultraviolet (UV)-induced DNA damage in E-cadherin-inhibited cells. In the mouse skin and skin tumors, UVB radiation downregulates E-cadherin. In sun-associated premalignant and malignant skin neoplasia, E-cadherin is downregulated in association with reduced XPC and DDB1 levels. These findings demonstrate a crucial role of E-cadherin in efficient DNA repair of UV-induced DNA damage, identify a new link between epithelial adhesion and DNA repair and suggest a mechanistic link of early E-cadherin loss in tumor initiation.
Assuntos
Caderinas/metabolismo , Reparo do DNA , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Animais , Sequência de Bases , Western Blotting , Caderinas/genética , Linhagem Celular , Células Cultivadas , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Células HEK293 , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Camundongos Pelados , Microscopia de Fluorescência , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência do Ácido NucleicoRESUMO
OBJECTIVE: To study the treatmaient of non-small cell lung cancer, we established the HU-Prim allograft transplantation tumor model. METHODS: The fresh tumor samples were transplanted in the right scapular subcutaneous layer of the severe combined immunodeficient Non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The pathological features of the tumors were observed. Nonnecrotic tissue was inoculated subcutaneously into the right axillary. When the tumor in burdened rat grew approximately 100 mm3, according to the tumor size all the animals were divided into the following four groups, eight rats in each group:solvent control group, gefitinib group (100 mg/kg), erlotinib group (50 mg/kg), afatinib group (20 mg/kg). Aniamals were treated with drugs by intragastric (i.g.) administrated, once daily, for consecutively 14 days. Measure the tumor size 2-3 times every week. RESULTS: HuPrime1-NSCLC mutant sensitive xenograft model research data showed that reversible tyrosine kinase inhibitors gefitinib, erlotinib and irreversible tyrosine kinase inhibitor afatinib could effectively inhibit tumor growth in EGFR positive NSCLC allografts model. The pharmacodynamic activity of irreversible inhibitor was better than that of the reversible inhibitor. Specimens from clinical anthropogenic tumor retain characteristics of the human primary malignancy, histopathology, biological characteristics, and tumor markers, etc., which can more accurately reflect the characteristics of the tumor and the impact of interventions. CONCLUSIONS: The model is not only a good antitumor drug experimental platform, but also a new evaluation tool of individualized medication.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Afatinib , Animais , Linhagem Celular Tumoral , Cloridrato de Erlotinib/farmacologia , Gefitinibe , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Quinazolinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIM: This study aims to investigate and evaluate the efficacy and safety of early enteral nutrition (EN) in maintaining and improving the postoperative nutritional status in patients undergoing esophagectomy. METHODS: A randomized, controlled clinical trial was conducted in 120 adult patients with esophageal cancer and undergoing esophagectomy. Patients were randomly divided into two groups receiving either EN (N.=64) or parenteral nutrition (PN) (N.=56) postoperatively. The nutritional intake was isonitrogenic and isocalorie for both groups. Nutritional status was evaluated preoperatively as well as on postoperative day I and day 8. Daily nitrogen balance was measured and 7-day cumulative nitrogen balance was calculated. The levels of serum markers including d-lactate, diamine oxidase (DAO), and endotoxin were determined on 1st, 4th and 8th postoperative day for analyzing intestinal barrier function. Postoperative infection rate and the incidence of nutrition support-related complications were examined. RESULTS: The concentrations of serum albumin and prealbumin in patients of EN group were significantly higher than those in PN group and the concentrations of blood glucose, γ-GT, AKP, TB, and DB were significantly lower compared to those in the PN group (P<0.05). Both daily nitrogen balance and cumulative nitrogen balance of EN group were better than those of PN group since postoperative day III. The serum levels of d-lactate, DAO, and endotoxin of EN group were significantly lower than those of PN group on postoperative day VIII (P<0.01). The incidence of postoperative infections in blood, lung, and intestinal tract in EN group was lower compared to PN group (P<0.05). No severe complications associated with nutritional support occurred in EN group. The time to flatus passage in EN group was significantly shorter, and the cost of nutritional support was significantly less compared to PN group (P<0.05). CONCLUSION: Postoperative early enteral nutrition was safe and feasible for patients undergoing esophagectomy. Compared to PN, EN more efficiently ameliorated postoperational nutritional status of the patients undergoing esophagectomy, played an important role in restoring intestinal barrier function postoperatively, reduced the incidence of postoperative infection, and decreased the cost of hospital stay.
Assuntos
Nutrição Enteral , Esofagectomia/métodos , Esofagoplastia/métodos , Desnutrição/prevenção & controle , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias/prevenção & controle , Idoso , Amina Oxidase (contendo Cobre)/sangue , Infecções Bacterianas/epidemiologia , Biomarcadores , Endotoxemia/epidemiologia , Endotoxemia/etiologia , Ingestão de Energia , Neoplasias Esofágicas/cirurgia , Feminino , Humanos , Mucosa Intestinal/fisiopatologia , Lactatos/sangue , Masculino , Pessoa de Meia-Idade , Micoses/epidemiologia , Nitrogênio/metabolismo , Nutrição Parenteral , Complicações Pós-Operatórias/epidemiologia , Recuperação de Função Fisiológica , Albumina Sérica/análiseRESUMO
Skin cancer is the most common cancer in the United States, while DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor. Reducing skin cancer incidence is becoming an urgent issue. The energy-sensing enzyme 5'-AMP-activated protein kinase (AMPK) has a key role in the regulation of cellular lipid and protein metabolism in response to stimuli such as exercise and changes in fuel availability. However, the role of AMPK in the response of skin cells to UVB damage and in skin cancer prevention remains unknown. Here we show that AMPK activation is reduced in human and mouse squamous cell carcinoma as compared with normal skin, and by UVB irradiation, suggesting that AMPK is a tumor suppressor. At the molecular level, AMPK deletion reduced the expression of the DNA repair protein xeroderma pigmentosum C (XPC) and UVB-induced DNA repair. AMPK activation by its activators AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) and metformin (N',N'-dimethylbiguanide), the most widely used antidiabetic drug, increased the expression of XPC and UVB-induced DNA repair in mouse skin, normal human epidermal keratinocytes, and AMPK wild-type (WT) cells but not in AMPK-deficient cells, indicating an AMPK-dependent mechanism. Topical treatment with AICAR and metformin not only delayed onset of UVB-induced skin tumorigenesis but also reduced tumor multiplicity. Furthermore, AMPK deletion increased extracellular signal-regulated kinase (ERK) activation and cell proliferation, whereas AICAR and metformin inhibited ERK activation and cell proliferation in keratinocytes, mouse skin, AMPK WT and AMPK-deficient cells, suggesting an AMPK-independent mechanism. Finally, in UVB-damaged tumor-bearing mice, both topical and systemic metformin prevented the formation of new tumors and suppressed growth of established tumors. Our findings not only suggest that AMPK is a tumor suppressor in the skin by promoting DNA repair and controlling cell proliferation, but also demonstrate previously unknown mechanisms by which the AMPK activators prevent UVB-induced skin tumorigenesis.
Assuntos
Proliferação de Células/efeitos da radiação , Dano ao DNA , Reparo do DNA/efeitos da radiação , Proteínas Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Raios Ultravioleta/efeitos adversos , Quinases Proteína-Quinases Ativadas por AMP , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Linhagem Celular Tumoral , Reparo do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Ativadores de Enzimas/farmacologia , Feminino , Humanos , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Quinases/genética , Ribonucleotídeos/farmacologia , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/agonistas , Proteínas Supressoras de Tumor/genéticaRESUMO
Biofouling and tissue inflammation present major challenges toward the realization of long-term implantable glucose sensors. Following sensor implantation, proteins and cells adsorb on sensor surfaces to not only inhibit glucose flux but also signal a cascade of inflammatory events that eventually lead to permeability-reducing fibrotic encapsulation. The use of drug-eluting hydrogels as outer sensor coatings has shown considerable promise to mitigate these problems via the localized delivery of tissue response modifiers to suppress inflammation and fibrosis, along with reducing protein and cell absorption. Biodegradable poly (lactic-co-glycolic) acid (PLGA) microspheres, encapsulated within a poly (vinyl alcohol) (PVA) hydrogel matrix, present a model coating where the localized delivery of the potent anti-inflammatory drug dexamethasone has been shown to suppress inflammation over a period of 1-3 months. Here, it is shown that the degradation of the PLGA microspheres provides an auxiliary venue to offset the negative effects of protein adsorption. This was realized by: (1) the creation of fresh porosity within the PVA hydrogel following microsphere degradation (which is sustained until the complete microsphere degradation) and (2) rigidification of the PVA hydrogel to prevent its complete collapse onto the newly created void space. Incubation of the coated sensors in phosphate buffered saline (PBS) led to a monotonic increase in glucose permeability (50%), with a corresponding enhancement in sensor sensitivity over a 1 month period. Incubation in serum resulted in biofouling and consequent clogging of the hydrogel microporosity. This, however, was partially offset by the generated macroscopic porosity following microsphere degradation. As a result of this, a 2-fold recovery in sensor sensitivity for devices with microsphere/hydrogel composite coatings was observed as opposed to similar devices with blank hydrogel coatings. These findings suggest that the use of macroscopic porosity can reduce sensitivity drifts resulting from biofouling, and this can be achieved synergistically with current efforts to mitigate negative tissue responses through localized and sustained drug delivery.
Assuntos
Anti-Inflamatórios/administração & dosagem , Incrustação Biológica/prevenção & controle , Técnicas Biossensoriais/instrumentação , Preparações de Ação Retardada/metabolismo , Dexametasona/administração & dosagem , Glucose/análise , Preparações de Ação Retardada/química , Glucose/metabolismo , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Hidrogel de Polietilenoglicol-Dimetacrilato/metabolismo , Ácido Láctico/metabolismo , Microesferas , Permeabilidade , Ácido Poliglicólico/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Álcool de Polivinil/química , Álcool de Polivinil/metabolismo , Porosidade , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Sjögren's syndrome (SS) is a chronic autoimmune disorder of unknown cause. Recent studies have shown that antimuscarinic acetylcholine type 3 receptor (M3R) antibodies can be detected in patients with Sjögren's syndrome (SS), but little is known about the diagnostic value of this antibody. OBJECTIVES: To assess the clinical correlations of anti-M3R (muscarinic acetylcholine receptor type 3) polypeptide (M3RP205-220) antibodies in saliva from patients of primary Sjögren's syndrome (pSS). METHODS: Serum samples and unstimulated mixed saliva from 100 patients with SS were collected and examined. Their mean (SD) age was 54.2 (13.4) years, and the mean (SD) disease duration was 6.2 (3.8) years. Serum samples from 40 patients with systemic lupus erythematosus (SLE), 40 with rheumatoid arthritis (RA), and 60 healthy subjects were analysed as controls. All the patients with SS were carefully evaluated according to European and American criteria. A circular M3RP205-220 peptide sequence was synthesized using solid-phase techniques on an applied biosytems peptide synthesizer. The correlation between anti-M3RP205-220 antibodies and clinical manifestations of pSS was analysed. RESULTS: The IgG of anti-M3RP205-220 antibodies was present in 69% of patients with pSS, 27.5% with SLE, 22.5% with RA, and 23.3% of normal saliva donors. The prevalence of anti-M3RP205-220 antibodies in pSS was significantly higher than in SLE, RA, and normal controls. The specificity of anti-M3RP205-220 antibodies in pSS was 75%. The salivary flow rate in the group positive for anti-M3RP205-220 was 436 µl/10 min, compared to a rate of 658 µl/10 min for the negative group (p<0.05). CONCLUSIONS: The anti-M3RP205-220 antibody was detected in most patients with pSS. The presence of the antibody was closely associated with the salivary flow rate. This indicated that it may act as an autoantigen, with a role in the pathogenesis of pSS.
Assuntos
Autoanticorpos/imunologia , Receptores Muscarínicos/imunologia , Síndrome de Sjogren/imunologia , Adulto , Idoso , Motivos de Aminoácidos/imunologia , Sequência de Aminoácidos , Especificidade de Anticorpos , Autoanticorpos/metabolismo , Feminino , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Receptores Muscarínicos/genética , Saliva/imunologia , Saliva/metabolismoRESUMO
Hypoxia induces the expansion of glioblastoma stem cells (GSCs), but the mechanism underlying it is still unclear. Here, we supply evidence that hypoxia-inducible factor-1α (HIF-1α) induced activation of Notch pathway is essential for hypoxia-mediated maintenance of GSC. Either depletion of HIF-1α or inactivation of Notch signaling partly inhibits the hypoxia-mediated maintenance of GSC. Further data suggest a role for HIF-1α in the interaction and stabilization of intracellular domain of Notch (NICD), and activation of Notch signaling. The mRNA level of HIF-1α and Notch target gene FABP7 was elevated in GSC. And the STAT3 pathway responsible for the HIF-1α gene transcription, the phosphatidylinositol 3-kinase-Akt and ERK1/2, both of which are contributed to HIF-1α protein translation, are also preferentially activated in GSC. Inhibition of these pathways partly reduces the hypoxia-induced activation of the Notch pathway and subsequent GSC maintenance. Taken together, our findings suggest that HIF-1α requires Notch pathway to drive the maintenance of GSC. The activated regulation of HIF-1α makes GSC more sensitive to hypoxia-mediated maintenance. These findings enhance our understanding of mechanism of hypoxia-mediated GSC expansion and provide HIF-1α as an attractive target for glioblastoma therapy.
Assuntos
Glioblastoma/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Neoplásicas/patologia , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia Celular , Glioblastoma/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Receptores Notch/química , Fator de Transcrição STAT3/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Transcrição Gênica , Células Tumorais CultivadasRESUMO
In renal transplantation, hypothermic machine perfusion optimizes preservation of marginal grafts, assesses their quality prior to transplantation, improves outcome, and may contribute to an increased number of transplantations. Recently, hypothermic machine perfusion has become increasingly popular given the organ shortage and the "obligatory" utilization of marginal organs. Increasing mortality on the liver transplantation waiting list makes it urgent to develop machine perfusion systems for livers, trying to better preserve marginal livers and perhaps to recover currently discarded livers are for clinical transplantation without an increased risk of graft nonfunction. However, data on machine perfusion of livers and perfusion parameters capable of predicting viability are scarce. The aim of this study was to determine the baseline hemodynamic and metabolic profiles and morphology of livers during hypothermic machine perfusion in a porcine model. We used protocol similar to hypothermic machine perfusion of kidneys. Hemodynamic analysis revealed higher vascular resistance in the hepatic artery versus the portal vein. The arterial resistance gradually decreased during perfusion (similar to kidneys), suggesting progressive relaxation of the arterial vasculature, and perhaps better penetration of the microcirculation by the perfusion solution. During hypothermic machine perfusion, transaminases were gradually (but modestly) released, and livers displayed unequivocal signs of aerobic and anaerobic metabolism. After 24 hours, livers appeared morphologically well preserved. In conclusion, this study showed that hypothermic machine perfusion was feasible. During hypothermic machine perfusion, was easily assessed hemodynamic, biochemical, and morphological parameters.
Assuntos
Hemodinâmica/fisiologia , Hipotermia Induzida/métodos , Fígado/fisiologia , Preservação de Órgãos/métodos , Animais , Desenho de Equipamento , Hipotermia/fisiopatologia , Hipotermia Induzida/instrumentação , Fígado/citologia , Modelos Animais , Preservação de Órgãos/instrumentação , SuínosRESUMO
A series of potent and selective inhibitors of h-MCH-R1 has been developed based on the piperidine glycineamide compounds I and II. These structurally more rigid tetrahydroisoquinolines (III and IV) showed better pharmacokinetics. The highly potent compounds 12d and 12g displayed excellent rat pk.
Assuntos
Receptores de Somatostatina/antagonistas & inibidores , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologia , Animais , Benzimidazóis/química , Humanos , Estrutura Molecular , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacocinéticaRESUMO
PURPOSE: We evaluated the efficiency of early endoscopic realignment as primary therapy for bulbar urethral disruption after straddle injury. MATERIALS AND METHODS: From 1990 to 1999 we treated 16 men who had bulbar urethral disruption with endoscopic realignment. Followup included uroflowmetry and urethroscopy at 39 to 85 months. RESULTS: All 16 cases were successfully treated at a single session without intraoperative or postoperative complications. Only 2 patients required intermittent self-dilation once weekly and all were potent during followup. CONCLUSIONS: The results of this minimally invasive procedure are comparable to those of open surgery. It may be performed on an outpatient basis using only local anesthesia. Our results imply that this cost-effective therapy should be done as the initial step in most patients with bulbar urethral disruption.
Assuntos
Uretra/lesões , Uretra/cirurgia , Procedimentos Cirúrgicos Urológicos , Adolescente , Adulto , Endoscopia , Feminino , Humanos , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos , Resultado do Tratamento , Procedimentos Cirúrgicos Urológicos/métodosRESUMO
OBJECTIVE: To study the origin of HIV blood spread in China. METHODS: Markers of HBV and HCV in 62 HIV - infections sera (27 blood donors and 35 i.v. drug users) were detected by EIA. RESULTS: The results show that the total HBV infection was 53.2% (33/62) and anti - HCV positive 95.2% (59/62). Super - infection of HIV, HBV, HCV was 51.6% (32/60) and super - infection of HIV, HCV and HIV, HBV were 27.4% (17/62) and 1.6% (1/62). Comparing the markers of HBV and anti - HCV between blood donors and i.v. drug users, there was no statistical significant difference (P > 0.05). The super - infection of HIV, HBV, HCV and HIV, HCV and HIV, HBV were also no statistical differences (P > 0.05) between two groups. CONCLUSION: Results indicated that a common infection mechanism might exist between Chinese HIV - infection blood donors and i.v. drug users.
Assuntos
Doadores de Sangue , Infecções por HIV/transmissão , Abuso de Substâncias por Via Intravenosa/complicações , Hepatite B/transmissão , Hepatite C/transmissão , HumanosRESUMO
A polymerase chain reaction (PCR) based method for the identification of beef by amplification of bovine 1.709 satellite DNA was established. The method not only was able to amplify raw beef DNA, but also cooked or autoclaved meat DNA. The sequence selected for amplification consisted of a 218 bp DNA fragment lying in the 1.709 satellite DNA of bovine. A pair of synthetic oligonucleotides flanking this sequence were used as printers, and genomic DNA extracted from beef samples employed as templates. Each batch of reaction mix contained Taq DNA polymerase, a buffer component, deoxynucleotide triphosphates, genomic DNA template and a pair of bovine oligodeoxynucleotide primers in a final volume of 50 µl. The amplification of bovine DNA was performed by using 33 cycles of denaturation at 94°C (40 s), annealing at 53.5°C (50 s) and extension at 72°C (60 s), with a 7 min extension at 72°C in the last cycles. The amplified products were subjected to rapid electrophoresis in 3% agarose gel and visualized under ultraviolet illumination after ethidium bromide staining. A Hae Ш restriction endonuclease test was done to verify the specificity of the PCR amplification, and the expected DNA fragments were produced. The specificity test demonstrated that this method was positive for bovine, buffalo and yak meat DNA, but negative for equine, sheep, goat, camel, swine, deer and mouse meat DNA, etc. At least 33.6 fg of DNA from raw beef samples and 0.32 pg of DNA from cooked or autoclaved beef samples were detected, respectively, by PCR. We tested 103 beef samples by PCR and obtained 100% correct identification. The method needed only 6 h for detection of meat products of all kinds. The results showed that the PCR method was sensitive, specific, convenient and rapid, so it may be suitable for rapid identification of beef.
RESUMO
The purpose of the present study was to examine the regulation of levels of apolipoprotein B (apoB) mRNA and its protein by cytokines in HepG2 cells. A dose-dependent increase in apoB mRNA levels was observed in the presence of either interleukin-1beta (IL-1beta) or IL-6 alone. This increase occurred as early as 1 h after IL-1beta or IL-6 stimulation. Exogenous addition of IL-1beta (5 ng/ml) and IL-6 (50 ng/ml) induced 2.8- and 2.1-fold increases as a result of 18 h of culture, respectively. Co-stimulation with IL-1beta and IL-6 significantly enhanced the increase in apoB mRNA levels stimulated with either cytokine alone. Treatment with cycloheximide prevented the induction of apoB mRNA by IL-1beta, but not by IL-6. These findings suggest that enhancement of apoB mRNA levels by these cytokines is mediated through different pathways. Conversely, IL-1beta and IL-6 lowered the accumulation of apoB protein levels in the culture medium. The pulse-chase study showed that addition of N-acetyl leucyl leucyl norleucinal to the medium induced a decrease in newly synthesized apoB in the cell lysate in response to IL-1beta (P < 0.05) or IL-6 (not to a significant extent) compared with control. These findings demonstrated that the lower level of apoB in the medium was caused by the enhanced intracellular degradation. In addition, IL-1beta increased LDL receptor mRNA levels as well as protein activity, although IL-6 did not, suggesting that the more marked decrease in apoB accumulation in the medium induced by IL-1beta compared with that induced by IL-6 may reflect an increased uptake of apoB from the medium by IL-1beta. The present study demonstrates that a cytokine network may be involved in the metabolism of apoB under certain conditions such as inflammation.