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1.
Gastroenterology ; 162(1): 223-237.e11, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599932

RESUMO

BACKGROUND & AIMS: Throughout life, the intestinal epithelium undergoes constant self-renewal from intestinal stem cells. Together with genotoxic stressors and failing DNA repair, this self-renewal causes susceptibility toward malignant transformation. X-box binding protein 1 (XBP1) is a stress sensor involved in the unfolded protein response (UPR). We hypothesized that XBP1 acts as a signaling hub to regulate epithelial DNA damage responses. METHODS: Data from The Cancer Genome Atlas were analyzed for association of XBP1 with colorectal cancer (CRC) survival and molecular interactions between XBP1 and p53 pathway activity. The role of XBP1 in orchestrating p53-driven DNA damage response was tested in vitro in mouse models of chronic intestinal epithelial cell (IEC) DNA damage (Xbp1/H2bfl/fl, Xbp1ΔIEC, H2bΔIEC, H2b/Xbp1ΔIEC) and via orthotopic tumor organoid transplantation. Transcriptome analysis of intestinal organoids was performed to identify molecular targets of Xbp1-mediated DNA damage response. RESULTS: In The Cancer Genome Atlas data set of CRC, low XBP1 expression was significantly associated with poor overall survival and reduced p53 pathway activity. In vivo, H2b/Xbp1ΔIEC mice developed spontaneous intestinal carcinomas. Orthotopic tumor organoid transplantation revealed a metastatic potential of H2b/Xbp1ΔIEC-derived tumors. RNA sequencing of intestinal organoids (H2b/Xbp1fl/fl, H2bΔIEC, H2b/Xbp1ΔIEC, and H2b/p53ΔIEC) identified a transcriptional program downstream of p53, in which XBP1 directs DNA-damage-inducible transcript 4-like (Ddit4l) expression. DDIT4L inhibits mechanistic target of rapamycin-mediated phosphorylation of 4E-binding protein 1. Pharmacologic mechanistic target of rapamycin inhibition suppressed epithelial hyperproliferation via 4E-binding protein 1. CONCLUSIONS: Our data suggest a crucial role for XBP1 in coordinating epithelial DNA damage responses and stem cell function via a p53-DDIT4L-dependent feedback mechanism.


Assuntos
Adenocarcinoma/metabolismo , Adenoma/metabolismo , Transformação Celular Neoplásica/metabolismo , Dano ao DNA , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Neoplasias Intestinais/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenoma/tratamento farmacológico , Adenoma/genética , Adenoma/patologia , Animais , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Bases de Dados Genéticas , Estresse do Retículo Endoplasmático , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Inibidores de MTOR/farmacologia , Camundongos Knockout , Transdução de Sinais , Sirolimo/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína 1 de Ligação a X-Box/genética
2.
World J Crit Care Med ; 12(4): 204-216, 2023 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-37745258

RESUMO

Septic shock treatment remains a major challenge for intensive care units, despite the recent prominent advances in both management and outcomes. Vasopressors serve as a cornerstone of septic shock therapy, but there is still controversy over the timing of administration. Specifically, it remains unclear whether vasopressors should be used early in the course of treatment. Here, we provide a systematic review of the literature on the timing of vasopressor administration. Research was systematically identified through PubMed, Embase and Cochrane searching according to PRISMA guidelines. Fourteen studies met the eligibility criteria and were included in the review. The pathophysiological basis for early vasopressor use was classified, with the exploration on indications for the early administration of mono-vasopressors or their combination with vasopressin or angiotensinII. We found that mortality was 28.1%-47.7% in the early vasopressors group, and 33.6%-54.5% in the control group. We also investigated the issue of vasopressor responsiveness. Furthermore, we acknowledged the subsequent challenge of administration of high-dose norepinephrine via peripheral veins with early vasopressor use. Based on the literature review, we propose a possible protocol for the early initiation of vasopressors in septic shock resuscitation.

3.
Nat Cancer ; 3(1): 60-74, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35121988

RESUMO

Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.


Assuntos
Neoplasias da Mama , Apresentação de Antígeno , Neoplasias da Mama/tratamento farmacológico , Endonucleases/metabolismo , Feminino , Humanos , Proteínas de Membrana/metabolismo , Nuclease do Micrococo/metabolismo , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo
4.
Sci Rep ; 12(1): 3205, 2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35217680

RESUMO

The brown planthopper (BPH), Nilaparvata lugens, is an important pest that affects rice (Oryza sativa) production in Asia. The flavone tricin (5,7,4'-trihydroxy-3',5'-dimethoxy flavone) is a valuable secondary metabolite commonly found in rice plants that can defend rice plants against infestation by BPH. BPH damage can reduce the metabolic level of tricin in rice. Our preliminary transcriptome research results showed that BPH salivary protein 7 (NlSP7), is highly responsive to tricin stimuli. However, the function of NlSP7 in mediating the interaction between the rice plant and the BPH is unknown. In this study, we cloned the NlSP7 gene in N. lugens and found that its mRNA level was greater in the presence of high tricin content than low tricin content, regardless of whether the BPHs were fed a rice plant diet or an artificial diet containing 100 mg/L tricin. Knocking down NlSP7 resulted in BPH individuals spending more time in the non-penetration and pathway phase, and less time feeding on the phloem of rice plants. These changes decreased BPH food intake, feeding behavior, and fitness, as well as the tricin content of the rice plants. These findings demonstrate that the salivary protein 7 of BPH functions as an effector for tricin metabolism in rice.


Assuntos
Flavonoides , Hemípteros , Oryza , Animais , Flavonoides/metabolismo , Hemípteros/genética , Oryza/genética , Oryza/metabolismo , Proteínas e Peptídeos Salivares/metabolismo
5.
Nat Cancer ; 3(1): 43-59, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35121987

RESUMO

Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.


Assuntos
Endonucleases/metabolismo , Proteínas de Membrana/metabolismo , Nuclease do Micrococo , Proteínas de Ligação a RNA/metabolismo , Neoplasias de Mama Triplo Negativas , Animais , Moléculas de Adesão Celular/genética , Humanos , Proteínas de Membrana/genética , Camundongos , Proteínas de Ligação a RNA/genética , Fatores de Transcrição
6.
Cancer Res ; 81(4): 1014-1025, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33239430

RESUMO

Colorectal and lung cancers account for one-third of all cancer-related deaths worldwide. Previous studies suggested that metadherin (MTDH) is involved in the development of colorectal and lung cancers. However, how MTDH regulates the pathogenesis of these cancers remains largely unknown. Using genetically modified mouse models of spontaneous colorectal and lung cancers, we found that MTDH promotes cancer progression by facilitating Wnt activation and by inducing cytotoxic T-cell exhaustion, respectively. Moreover, we developed locked nucleic acid-modified (LNA) MTDH antisense oligonucleotides (ASO) that effectively and specifically suppress MTDH expression in vitro and in vivo. Treatments with MTDH ASOs in mouse models significantly attenuated progression and metastasis of colorectal, lung, and breast cancers. Our study opens a new avenue for developing therapies against colorectal and lung cancers by targeting MTDH using LNA-modified ASO. SIGNIFICANCE: This study provides new insights into the mechanism of MTDH in promoting colorectal and lung cancers, as well as genetic and pharmacologic evidence supporting the development of MTDH-targeting therapeutics.


Assuntos
Adenocarcinoma/terapia , Neoplasias Colorretais/terapia , Neoplasias Pulmonares/terapia , Proteínas de Membrana/antagonistas & inibidores , Oligonucleotídeos Antissenso/uso terapêutico , Proteínas de Ligação a RNA/antagonistas & inibidores , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Terapia Genética/métodos , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular/métodos , Metástase Neoplásica , Oligonucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Oligonucleotídeos Antissenso/farmacologia , Proteínas de Ligação a RNA/genética , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 39(2): 168-73, 2010 03.
Artigo em Zh | MEDLINE | ID: mdl-20387245

RESUMO

OBJECTIVE: To evaluate the feasibility of multi-slice spiral CT scan to localize upper airway stricture in patients with obstructive sleep apnea syndrome (OSAS) during drug-induced sleeping. METHODS: One hundred and fourteen patients diagnosed as OSAS by polysomnography were included in the study. Multi-slice spiral CT scan covering upper airway was performed at the end of inspiration and clear upper airway images were obtained in waking. After injecting 5 mg of midazolam intravenously slowly in 109 patients, CT scan was performed at apnea and clear upper airway images were obtained in sleeping. Cross-section area and minimal diameter of airway were measured and the parameters were compared under those two states. Upper airway was displayed intuitionisticly by using post-processing techniques. RESULTS: One hundred and nine patients with OSAS finished the examination with a success rate of 100 %. Airway obstruction at retropalatal level was observed in 62 patients, among whom 26 were associated with airway obstruction at retroglossal level, 27 with narrower airway at retroglossal level in sleeping compared with that in waking, and 9 with no significant change of the airway at retroglossal level after sleeping. Narrower airway at retropalatal level in sleeping compared with that in waking was observed in 40 patients, among whom 20 were associated with narrower airway at retroglossal level in sleeping compared with that in waking, 10 with complete airway obstruction at retroglossal level in sleeping, and 7 with no significant change of the airway at both retropalatal and retroglossal levels before and after sleeping. Minimal mean cross-section area of airway at retropalatal level was (72.60 +/-45.15)mm(2) in waking and (8.26 +/-18.16)mm(2) in sleeping; and minimal mean cross-section area of airway at retroglossal level was (133.21 +/-120.36)mm(2)in waking and (16.73 +/-30.21)mm(2) in sleeping (P <0.01). Minimal mean diameter of airway at retropalatal level was (6.91 +/-2.23) mm in waking and (1.18 +/-2.14) mm in sleeping; and minimal mean diameter of airway at retroglossal level was (8.68 +/-4.32) mm in waking and (1.68 +/-2.22) mm in sleeping (P <0.01). CONCLUSION: Multi-slice spiral CT with post-processing techniques can display the shape of the upper airway in patients with OSAS in sleeping, and can localize the upper airway stricture and assess its range accurately.


Assuntos
Obstrução das Vias Respiratórias/diagnóstico por imagem , Orofaringe/fisiopatologia , Palato Mole/fisiopatologia , Apneia Obstrutiva do Sono/diagnóstico por imagem , Tomografia Computadorizada Espiral , Adulto , Idoso , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Nat Commun ; 10(1): 527, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30692542

RESUMO

The original version of this Article contained an error in the spelling of the author Daniel D. Liu, which was incorrectly given as Daniel Liu. This has now been corrected in both the PDF and HTML versions of the Article.

9.
Cancer Cell ; 35(1): 64-80.e7, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30612941

RESUMO

Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5ß1, αvß1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways. Moreover, Tinagl1 protein level is associated with good prognosis and reversely correlates with FAK and EGFR activation status in TNBC. Our results suggest Tinagl1 as a candidate therapeutic agent for TNBC by dual inhibition of integrin/FAK and EGFR signaling pathways.


Assuntos
Proteínas da Matriz Extracelular/genética , Integrina alfa5beta1/metabolismo , Lipocalinas/genética , Neoplasias Pulmonares/terapia , Receptores de Vitronectina/metabolismo , Neoplasias de Mama Triplo Negativas/terapia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Receptores ErbB/metabolismo , Proteínas da Matriz Extracelular/administração & dosagem , Proteínas da Matriz Extracelular/metabolismo , Feminino , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Lipocalinas/administração & dosagem , Lipocalinas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Prognóstico , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
10.
Science ; 360(6396)2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29773667

RESUMO

The stem cell niche is a specialized environment that dictates stem cell function during development and homeostasis. We show that Dll1, a Notch pathway ligand, is enriched in mammary gland stem cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche in mouse models. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSC-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feedback loop that promotes the function of Dll1-expressing MaSCs. Together, these findings reveal functionally important cross-talk between MaSCs and their macrophageal niche through Dll1-mediated Notch signaling.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/fisiologia , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Receptores Notch/metabolismo , Nicho de Células-Tronco/fisiologia , Células-Tronco/fisiologia , Animais , Proteínas de Ligação ao Cálcio , Contagem de Células , Feminino , Técnicas de Inativação de Genes , Peptídeos e Proteínas de Sinalização Intercelular/genética , Ligantes , Macrófagos/citologia , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Knockout , Morfogênese , Transdução de Sinais , Células-Tronco/citologia , Células Estromais/citologia , Células Estromais/fisiologia , Proteínas Wnt/metabolismo
11.
Nat Commun ; 9(1): 5005, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30479345

RESUMO

Epithelial-mesenchymal transition (EMT) have been extensively characterized in development and cancer, and its dynamics have been modeled as a non-linear process. However, less is known about how such dynamics may affect its biological impact. Here, we use mathematical modeling and experimental analysis of the TGF-ß-induced EMT to reveal a non-linear hysteretic response of E-cadherin repression tightly controlled by the strength of the miR-200s/ZEBs negative feedback loop. Hysteretic EMT conveys memory state, ensures rapid and robust cellular response and enables EMT to persist long after withdrawal of stimuli. Importantly, while both hysteretic and non-hysteretic EMT confer similar morphological changes and invasive potential of cancer cells, only hysteretic EMT enhances lung metastatic colonization efficiency. Cells that undergo hysteretic EMT differentially express subsets of stem cell and extracellular matrix related genes with significant clinical prognosis value. These findings illustrate distinct biological impact of EMT depending on the dynamics of the transition.


Assuntos
Transição Epitelial-Mesenquimal , Metástase Neoplásica/patologia , Animais , Caderinas/metabolismo , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Retroalimentação Fisiológica , Feminino , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Metástase Neoplásica/genética , Fator de Crescimento Transformador beta/farmacologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
12.
Nat Cell Biol ; 19(6): 711-723, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28530657

RESUMO

Tumour-initiating cells, or cancer stem cells (CSCs), possess stem-cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem-cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER- breast tumours, functionally promotes tumour initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signalling.


Assuntos
Neoplasias da Mama/metabolismo , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Interferons/metabolismo , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/metabolismo , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Diferenciação Celular , Movimento Celular , Autorrenovação Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Glândulas Mamárias Animais/patologia , Glândulas Mamárias Humanas/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , Metástase Neoplásica , Células-Tronco Neoplásicas/patologia , Fenótipo , Proteínas Repressoras/genética , Transdução de Sinais , Fatores de Transcrição/genética , Transfecção , Microambiente Tumoral
13.
Zhonghua Yi Xue Za Zhi ; 86(44): 3128-32, 2006 Nov 28.
Artigo em Zh | MEDLINE | ID: mdl-17313765

RESUMO

OBJECTIVE: To study the effect of insulin on cardiac functional recovery, coronary blood flow (CBF), coronary arterial function and coronary vascular endothelial cell apoptosis following acute myocardial ischemia/reperfusion (MI/R). METHODS: In adult dogs, the left anterior descending coronary artery (LAD) was partially occluded (80% reduction in its blood flow) for 50 min and reperfused for 4 h. Vehicle (0.9% NaCl), GIK (glucose: 250 gxL(-1), insulin: 60 UxL(-1), potassium: 80 mmolxL(-1)), or GK (glucose: 250 gxL(-1), potassium: 80 mmolxL(-1)) were intravenously infused (2 mlxkg(-1)xh(-1)) 5 min before reperfusion, and CBF and left ventricular pressure were monitored. At the end of 4 h reperfusion period, coronary arteries were isolated, and the coronary vascular dysfunction, nitric oxide (NO) production and endothelial apoptosis were determined. RESULTS: During reperfusion, compared with the vehicle, GIK increased CBFLAD (19.2 ml/min +/- 2.2 ml/min) vs (14.6 ml/min +/- 1.8 ml/min) of vehicle at the end of reperfusion, P < 0.05, improved recovery of LVSP and +/- LVdP/dtmax. In vivo ischemia/reperfusion caused significant coronary vascular endothelial dysfunction as evidenced by reduced endothelium dependent vasorelaxation, decreased total NO production, and endothelial cell apoptosis as determined by TUNEL staining. Reperfusion with GIK, but not GK, markedly improved the endothelium-dependent vasorelaxation (80.3% +/- 3.8%) vs. vehicle (28.1% +/- 2.3%, P < 0.01) of coronary artery in response to ACh. GIK significantly increased total NO production (17.19 micromol/L +/- 2.18 micromol/L) versus vehicle (4.74 micromol/L +/- 2.01 micromol/L, P < 0.01) and inhibited apoptosis in coronary arterial endothelial cell (12% +/- 4%) vs vehicle (45% +/- 7%, P < 0.01). GK failed to show any significant vasculoprotection against MI/R-induced coronary vascular injury. CONCLUSION: These results demonstrate that insulin exerts cardioprotective effect by increasing CBF, reducing coronary artery injury and improving cardiac functional recovery during reperfusion, which may be partly attributable to the coronary vasculoprotective effect of insulin. The insulin-induced, NO-mediated anti-endothelial apoptotic effect may play a critical role in the insulin-induced coronary artery protective effect in MI/R.


Assuntos
Circulação Coronária/efeitos dos fármacos , Insulina/farmacologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Doença Aguda , Animais , Apoptose/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Cães , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Glucose/farmacologia , Masculino , Óxido Nítrico/metabolismo , Potássio/farmacologia , Disfunção Ventricular Esquerda/fisiopatologia
14.
Nat Cell Biol ; 16(10): 1004-15, 1-13, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25241036

RESUMO

Emerging evidence suggests that cancer is populated and maintained by tumour-initiating cells (TICs) with stem-like properties similar to those of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signalling. Importantly, Fzd7-dependent enhancement of Wnt signalling by ΔNp63 also governs tumour-initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.


Assuntos
Neoplasias da Mama/metabolismo , Receptores Frizzled/metabolismo , Glândulas Mamárias Humanas/metabolismo , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Via de Sinalização Wnt , Animais , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Receptores Frizzled/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Humanas/citologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Microscopia Confocal , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/citologia , Fatores de Transcrição/genética , Transplante Heterólogo , Proteínas Supressoras de Tumor/genética
15.
Mol Med Rep ; 10(5): 2720-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25201740

RESUMO

Y­box binding protein­1 (YB­1) has been identified as an oncoprotein in various malignancies. The aim of this study was to investigate the biological role of YB­1 and its association with epithelial­to­mesenchymal transition (EMT) in colorectal cancer (CRC). The expression of YB­1 and three EMT­related proteins (E­cadherin, N­cadherin and vimentin) was analyzed in 80 CRC and matched normal tissue samples, by immunohistochemistry. The results indicated that the expression of YB­1 was higher in CRC tissue samples than that in matched normal controls and was significantly correlated with tumor differentiation, tumor invasion, lymph node metastasis and distant metastases. Furthermore, analysis showed that YB­1 expression was negatively correlated with E­cadherin and positively correlated with N­cadherin and vimentin expression. In vitro assays showed that knockdown of YB­1 inhibited the proliferation, apoptosis resistance, invasion and migration of the HT­29 CRC cell line. Of note, following knockdown of YB­1, E­cadherin expression was elevated whereas N­cadherin and vimentin expression was reduced. Taken together, these results suggest that YB­1 promotes the malignant progression of CRC in part through the induction of EMT, and YB­1 may therefore be a potential novel target for CRC treatment.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Proteína 1 de Ligação a Y-Box/genética , Adenocarcinoma/secundário , Apoptose , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal , Feminino , Técnicas de Silenciamento de Genes , Células HT29 , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteína 1 de Ligação a Y-Box/biossíntese
16.
Zhonghua Wei Chang Wai Ke Za Zhi ; 15(8): 814-8, 2012 Aug.
Artigo em Zh | MEDLINE | ID: mdl-22941684

RESUMO

OBJECTIVE: To compare laparoscopic Nissen fundoplication (LNF)and Toupet laparoscopic fundoplication (LTF) with respect to treatment outcomes and postoperative complications. METHODS: PubMed, Medline, Embase and the Cochrane Library were searched. Only randomized controlled trials (RCTs) comparing laparoscopic Nissen and Toupet fundoplication were included. Outcomes evaluation included occurrences of heartburn, reflux, difficulty swallowing, chest pain, abdominal distention, failure to hiccup, diarrhea, and early complications and degree of patient satisfaction at early (three to six months) and later (one to three years) post-operative periods. RESULTS: Of 939 patients in seven RCTs, 478 received LNF and 461 received LTF. For both groups, control of reflux was good and occurrence of heartburn was similar (P>0.05). A lower incidence of postoperative dysphagia for both early and later post-operative periods, but a higher overall complication rate in early post-operative period were observed in the LTF group (P<0.05). Patient satisfaction was similar (P>0.05). CONCLUSIONS: LNF and LTF are both safe and effective. The adoption of procedure should be based on the patient status and surgeon experience.


Assuntos
Fundoplicatura/métodos , Refluxo Gastroesofágico/cirurgia , Laparoscopia/métodos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
J Cardiovasc Pharmacol ; 48(6): 306-13, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17204910

RESUMO

This study was designed to examine whether physiologically tolerable insulin, which maintains lower blood glucose, can protect the myocardium against ischemia/reperfusion (I/R) injury in a preclinical large animal model. Adult dogs were subjected to 50 minutes of myocardial ischemia (80% reduction in coronary blood flow) followed by 4 hours of reperfusion and treated with vehicle, glucose-insulin-potassium (GIK; glucose, 250 g/L; insulin, 60 U/L; potassium, 80 mmol/L), GK, or low-dose insulin (30 U/L) 10 minutes before reperfusion. Treatment with GIK exerted significant cardioprotective effects as evidenced by improved cardiac function, improved coronary blood flow, reduced infarct size, and myocardial apoptosis. In contrast, treatment with GK increased blood glucose level and aggravated myocardial I/R injury. It is interesting that treatment with insulin alone at the dose that reduced blood glucose to a clinically tolerable level exerted significant cardioprotective effects that were comparable to that seen in the GIK-treated group. This low-dose insulin had no effect on coronary blood flow after reperfusion but markedly reduced coronary reactive hyperemia and switched myocardial substrate uptake from fat to carbohydrate. Our results suggest that lower glucose supply to the ischemic myocardium at early reperfusion may create a "metabolic postconditioning" and thus reduce myocardial ischemia/reperfusion injury after prolonged reperfusion.


Assuntos
Insulina/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Glicemia/fisiologia , Circulação Coronária/efeitos dos fármacos , Circulação Coronária/fisiologia , Creatina Quinase/sangue , Cães , Relação Dose-Resposta a Droga , Feminino , Glucose/administração & dosagem , Glucose/uso terapêutico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Marcação In Situ das Extremidades Cortadas , Infusões Intravenosas , Insulina/administração & dosagem , L-Lactato Desidrogenase/sangue , Masculino , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Potássio/administração & dosagem , Potássio/uso terapêutico , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia
18.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 10(4): 340-6, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12513770

RESUMO

Many studies have shown that G-CSF mobilized peripheral blood progenitor cell transplants (PBPCT) manifests faster recovery kinetics than conventional bone marrow transplants. This potential advantage of PBPCT still needs to be balanced against the risk of acute and chronic GVHD associating with the infusion of 10 - 15 fold higher donor lymphocyte number in unmanipulated allogeneic PBPCT than the marrow graft. To evaluate the effect of G-CSF primed bone marrow as a source of stem cells in the HLA-matched sibling transplantation, G-CSF primed with non-primed donor marrow in engraftment and incidence of GVHD for a homogenous group of patients with chronic myeloid leukemia (CML) were compared. Fifty patients with CML underwent bone marrow transplant, thirty-two donors (study group) were given G-CSF 3 - 4 micro g/kg per day for seven days prior to marrow harvest and eighteen donors (control group) had marrow harvest without G-CSF stimulation. Conditioning regimen consisted of total body irradiation and cyclophosphamide (CY), busulfan and CY, or busulfan, total body irradiation and CY. Both groups received same post-grafting GVHD prophylaxis and postgrafting G-CSF treatment. It was found that G-CSF primed donor marrow yielded with significantly higher number of total nucleated cells as well as CD34(+) cells and CFU-GM compared to non-G-CSF primed marrow (P = 0.001). The median engraftment time for absolute neutrophil (ANC > 0.5 x 10(9)/L) was day 15 (range 10 - 22) in the group of G-CSF primed vs day 21 in the non-primed donor group (P = 0.001). The median time for platelets (> 20 x 10(9)/L) was day 17.5 (range 13 - 28) in the group of G-CSF primed vs day 24 in non-primed group (P = 0.001). The incidence of acute GVHD grade II - IV in G-CSF primed donor group was surprisingly as low,as only two cases of thirty-two transplants (6.3%) with acute GVHD grade II limited to the skin. Whereas, five of eighteen patients (27.8%) in the control group developed acute GVHD grade II - IV (P = 0.032). G-CSF primed donors showed reduced CD4(+) and increased CD8(+) cells, resulting in a significant reduction of CD4(+)/CD8(+) ratio as compared with non-primed marrow. The total CD3(+) cell count kept unchanged in G-CSF primed donors. There were not significant differences in the incidence of the chronic GVHD (24% vs 33.3%), relapse rate (12.5% vs 11.1%) and overall survival rate (78.1% vs 66.7%, P = 0.32) during 6 - 50 months of follow-up. In conclusion, G-CSF primed donor marrow accelerates engraftment. Although G-CSF did not change the total CD3(+) cells in bone marrow, it altered the ratio of CD4(+) and CD8(+) cells and significantly reduced the incidence of acute GVHD.


Assuntos
Transplante de Medula Óssea , Fator Estimulador de Colônias de Granulócitos/farmacologia , Teste de Histocompatibilidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Doadores Vivos , Adolescente , Adulto , Criança , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Transplante Homólogo
19.
Biol Blood Marrow Transplant ; 8(5): 261-7, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12064363

RESUMO

To investigate the effect of granulocyte colony-stimulating factor (G-CSF) donor-marrow priming on hematopoietic recovery and clinical outcome after allogeneic hematopoietic stem cell transplantation, we compared HILA-matched related marrow transplantation with and without G-CSF donor priming in a prospective randomized study for a homogeneous group of chronic myelogenous leukemia (CML) patients. Fifty patients (aged 12-41 years) with CML were enrolled in the study. Thirty-two patients (study group) received the marrow grafts primed with G-CSF at 3 to 4 micro/kg per day for 7 days prior to the marrow harvest, and 18 patients (control group) received the marrow grafts without G-CSF priming. All patients received the same graft-versus-host disease (GVHD) prophylaxis (cyclosporine A and methotrexate) and postgraft G-CSF treatment, 3 to 4 micro/kg daily until the absolute neutrophil counts (ANCs) were >10(9)/L. The primary end points were engraftment and incidence of acute GVHD. The secondary end points were the incidence of chronic GVHD, relapse, and overall disease-free survival. The study and control groups were comparable for age, sex, donor selections, conditioning regimens, and disease status. The median times to both neutrophil and platelet engraftment (ANC > 0.5 x 10(9)/L; platelets > 20 x 10(9)/L) were significantly faster in the study group than in the control group, at 15 versus 21 days (P < .001) and 17.5 versus 24 days (P < .001), respectively. G-CSF donor printing yielded significantly higher numbers of total nuclear cells in the marrow grafts compared to the numbers in the control grafts (7.2 versus 2.9 x 10(8)/kg, P < .001). Similar results were seen for CD34+ (6.1versus 2.7 x 10(6)/kg, P < .001) and colony-forming unit-granulocyte/macrophage (CFU-GM) cells (68 versus 16 x 10(4)/kg, P < .001). The incidence of grades II to IV acute GVHD was surprisingly low in the study group: only 2 (6.3%) of 32 transplantation patients in the study group developed grade II acute GVHD, limited to the skin, whereas 5 (27.8%) of 18 patients in the control group developed grades II to IV acute GVHD (P = .032). G-CSF priming did not change the total numbers of CD3+ cells in the marrow grafts but lowered CD4+ cells and increased CD8+ cells, resulting in a significant reduction of CD4:CD8 ratio (P = .018). Six patients in the study group developed chronic GVHD either during or after cyclosporine taper. There were no significant differences in chronic GVHD (24% versus 33.3%), relapse rates (12.5% versus 11.1%), and overall survival rates (78.1% versus 66.7%, P = .32) between the study and control groups during a median follow-up period of 24 months (range, 6-50 months). There was, however, a trend in favor of improved chronic GVHD and disease-free survival in the study group. We conclude that G-CSF donor-marrow priming accelerates both neutrophil and platelet engraftment and is associated with a very low incidence of grades II to IV acute GVHD in CML patients after HLA-matched sibling marrow transplantation.


Assuntos
Transplante de Medula Óssea/métodos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Proteínas Recombinantes/administração & dosagem , Adolescente , Adulto , Criança , Feminino , Seguimentos , Sobrevivência de Enxerto/efeitos dos fármacos , Doença Enxerto-Hospedeiro/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Lenograstim , Masculino , Estudos Prospectivos , Proteínas Recombinantes/farmacologia , Análise de Sobrevida , Transplante Homólogo/métodos , Resultado do Tratamento
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