Abstract:Abstract-Vascular endothelial growth factor (VEGF) expression is upregulated by hypoxia-inducible factor-1 (HIF-1) in ischemic tissues and growing tumors. Normally, HIF-1 activity depends on the amount of HIF-1␣ subunit, which is tightly regulated by the oxygen tension. In the myocardium, VEGF expression has been shown to be induced under nonhypoxic conditions by mechanical stresses. However, the cellular mechanism of stress-mediated VEGF induction remains unclear. Therefore, we examined the possible involveme… Show more
“…Hence, when the bladder depletes the energy reserves during the voiding phase, detrusor contraction fails prematurely and the result is a PVR. Also, it is known that HIF-1α in hypoxic tissues regulates the expression of all enzymes in the glycolytic pathway [20][21][22][23][24]. These observations are consistent with the present study, where high expression of HIF-1α was four times more likely in men with UR.…”
Section: Discussionsupporting
confidence: 93%
“…The first subunit is almost undetectable under normal oxygen tension because it is rapidly degraded, while the HIF-1 β subunit is constitutively expressed and controlled in an oxygen-independent manner [21]. HIF-1 α can also be stimulated by other cytokines in normoxic conditions [22], but it can also be activated in response to mechanical stress [23].…”
OBJECTIVETo investigate the tissue distribution of ischaemia in human detrusor in patients with bladder outlet obstruction (BOO) and to correlate the results with clinical variables, as clinical BOO is a common problem in ageing men and ischaemia might be important in detrusor dysfunction.PATIENTS AND METHODSFrom September 2004 to October 2006, 70 patients were recruited, comprising 60 scheduled for surgery to treat benign prostatic hyperplasia (the study group) and 10 as controls. Detrusor tissue was retrieved and stained for hypoxia‐inducible factor (HIF)‐1α, a cellular marker of hypoxia.RESULTSThe mean (sd) total number of cells immunoreactive to HIF‐1α in the study group was 93.3 (48.09), and in the specimens from the control group only few rare cells showed weak immunoreactivity to HIF‐1α (0–2). Positive cells were in different proportions between muscle bundles and submucosa, expressed mainly in stromal cells. The urothelium and detrusor muscle showed no immunoreactivity to HIF‐1α. There was strong immunoreactivity in patients with prolonged BOO (<10 years), declining thereafter, and in those patients with urinary retention.CONCLUSIONSThe urothelium and detrusor seem to be more resistant to hypoxic stress, while stromal cells perceive low oxygen tension. The bladder response to chronic hypoxia through HIF‐1α expression is limited in time and might depend on the functional status of the detrusor.
“…Hence, when the bladder depletes the energy reserves during the voiding phase, detrusor contraction fails prematurely and the result is a PVR. Also, it is known that HIF-1α in hypoxic tissues regulates the expression of all enzymes in the glycolytic pathway [20][21][22][23][24]. These observations are consistent with the present study, where high expression of HIF-1α was four times more likely in men with UR.…”
Section: Discussionsupporting
confidence: 93%
“…The first subunit is almost undetectable under normal oxygen tension because it is rapidly degraded, while the HIF-1 β subunit is constitutively expressed and controlled in an oxygen-independent manner [21]. HIF-1 α can also be stimulated by other cytokines in normoxic conditions [22], but it can also be activated in response to mechanical stress [23].…”
OBJECTIVETo investigate the tissue distribution of ischaemia in human detrusor in patients with bladder outlet obstruction (BOO) and to correlate the results with clinical variables, as clinical BOO is a common problem in ageing men and ischaemia might be important in detrusor dysfunction.PATIENTS AND METHODSFrom September 2004 to October 2006, 70 patients were recruited, comprising 60 scheduled for surgery to treat benign prostatic hyperplasia (the study group) and 10 as controls. Detrusor tissue was retrieved and stained for hypoxia‐inducible factor (HIF)‐1α, a cellular marker of hypoxia.RESULTSThe mean (sd) total number of cells immunoreactive to HIF‐1α in the study group was 93.3 (48.09), and in the specimens from the control group only few rare cells showed weak immunoreactivity to HIF‐1α (0–2). Positive cells were in different proportions between muscle bundles and submucosa, expressed mainly in stromal cells. The urothelium and detrusor muscle showed no immunoreactivity to HIF‐1α. There was strong immunoreactivity in patients with prolonged BOO (<10 years), declining thereafter, and in those patients with urinary retention.CONCLUSIONSThe urothelium and detrusor seem to be more resistant to hypoxic stress, while stromal cells perceive low oxygen tension. The bladder response to chronic hypoxia through HIF‐1α expression is limited in time and might depend on the functional status of the detrusor.
“…In addition, under normoxic conditions, the expression and activity of HIF-1α and the subsequent secreted angiogenic factors in cancer can be abnormally up-regulated by different signaling pathways [34], [35], [36] involving Akt and its downstream effectors [20], [22]. Therefore, we hypothesized that RBP2 regulates HIF-1α through the activation of Akt signaling, and we further sought to detect the signaling mechanisms involved in RBP2-mediated tumor angiogenesis.…”
Section: Resultsmentioning
confidence: 99%
“…Another study demonstrated that RBP2 up-regulates the expression of N-cadherin and snail via the activation of Akt signaling [18]. Moreover, ITGB1 and Akt signaling are significantly correlated with tumor angiogenesis [19], [20], [21], [22]. Taken together, these results suggest an oncogenic role for RBP2 in tumor angiogenesis and progression.…”
BackgroundPathological angiogenesis plays an essential role in tumor aggressiveness and leads to unfavorable prognosis. The aim of this study is to detect the potential role of Retinoblastoma binding protein 2 (RBP2) in the tumor angiogenesis of non-small cell lung cancer (NSCLC).MethodsImmunohistochemical staining was used to detect the expression of RBP2, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and CD34. Two pairs of siRNA sequences and pcDNA3-HA-RBP2 were used to down-regulate and up-regulate RBP2 expression in H1975 and SK-MES-1 cells. An endothelial cell tube formation assay, VEGF enzyme-linked immunosorbent assay, real-time PCR and western blotting were performed to detect the potential mechanisms mediated by RBP2 in tumor angiogenesis.ResultsOf the 102 stage I NSCLC specimens analyzed, high RBP2 protein expression is closely associated with tumor size (P = 0.030), high HIF-1α expression (P = 0.028), high VEGF expression (P = 0.048), increased tumor angiogenesis (P = 0.033) and poor prognosis (P = 0.037); high MVD was associated with high HIF-1α expression (P = 0.034), high VEGF expression (P = 0.001) and poor prognosis (P = 0.040). Multivariate analysis indicated that RBP2 had an independent influence on the survival of patients with stage I NSCLC (P = 0.044). By modulating the expression of RBP2, our findings suggested that RBP2 protein depletion decreased HUVECs tube formation by down-regulating VEGF in a conditioned medium. RBP2 stimulated the up-regulation of VEGF, which was dependent on HIF-1α, and activated the HIF-1α via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Moreover, VEGF increased the activation of Akt regulated by RBP2.ConclusionsThe RBP2 protein may stimulate HIF-1α expression via the activation of the PI3K/Akt signaling pathway under normoxia and then stimulate VEGF expression. These findings indicate that RBP2 may play a critical role in tumor angiogenesis and serve as an attractive therapeutic target against tumor aggressiveness for early-stage NSCLC patients.
“…From a scientific standpoint, this validates our belief that concentrating on late reperfusion events, rather than early ischaemic injury, represents a logical approach to modulating infarct development. For example, VEGF production being under transcriptional control requires hours to develop [28], and therefore VEGF-mediated oedema represents a reasonable interventional target for I/R injury. The same is true for the numerous oedema and inflammatory mediators (such as PAF, cytokines and eicosanoids) generated by activated leucocytes during reperfusion.…”
In the present paper, we review the preclinical development of TG100-115, a PI3K (phosphoinositide 3-kinase) gamma/delta isoform-specific inhibitor currently in clinical trials for the reduction of acute MI (myocardial infarction). An overview is presented outlining the pathogenesis of acute MI and the rationale for clinical use of PI3K gamma/delta-specific inhibitors in this indication. TG100-115's broad anti-inflammatory activities are described, as well as its ability to discriminate between cellular signalling pathways downstream of receptor tyrosine kinase ligands such as vascular endothelial growth factor. Finally, we review TG100-115's potent cardioprotective activities as revealed in rigorous animal models of acute MI, and, based on these data, this compound's potential for clinical utility.
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