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David E. Fisher - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Proliferation-Survival Decisions during Tumor Cell Hypoxia
Molecular and cellular biology, 1998Co-Authors: Cornelius Schmaltz, Patricia H. Hardenbergh, Audrey M. Wells, David E. FisherAbstract:One of the hallmarks of cancer treatment is the frequent ability to achieve remission which is inevitably followed by relapse. This behavior is typical of nearly every common human cancer and strongly implies that within an individual patient, tumor Cells are not homogeneous in their treatment sensitivities. Numerous mechanisms of resistance have been demonstrated, including the presence of drug resistance transporters, mutated or amplified drug targets, altered drug metabolism, altered DNA repair, overexpression of antiapoptotic genes, inactivity of proapoptotic gene products, and nonCell autonomous features of tumor growth in vivo, such as the presence of Hypoxia in solid tumors (36). Disordered tumor Cell perfusion and resulting Hypoxia may be particularly important as features conferring tumor inhomogeneity which may contribute to relapse following tumor shrinkage during therapy. Studies of solid tumor Cells have suggested that through induction of apoptosis, Hypoxia may select for Cells with defective apoptotic regulators such as p53 (19). Through understanding the behavior of such hypoxic tumor Cells, strategies which better target this potentially dangerous cancer Cell population may be devised. Hypoxic regions are a common feature of solid tumors (32, 37, 54). The primary features of tumor physiology that lead to Hypoxia are limited arteriolar supply and arteriolar deoxygenation (8), relatively low vascular density and disorderly vascular architecture (46), oxygen consumption rates that are out of balance with oxygen supply (47), and an unstable blood supply (29). Cells in hypoxic regions constitute a clinically relevant problem, because they are more resistant than their normoxic counterparts to the effects of radiotherapy and many conventional chemotherapeutic agents (16, 53; for a review, see reference 52) and are thought to contribute importantly to disease relapse. The presence of Hypoxia may also be involved in the development of a more aggressive phenotype and contribute to metastasis (6, 45). Despite the treatment resistance which it may confer, Hypoxia is also directly toxic to most Cell types. In recent years, Hypoxia has been shown to produce a G0/G1 checkpoint as well as accumulation of p53, although p53 seems not to be required for the Cell cycle arrest (20). Hypoxia may also induce apoptosis in tumor Cells (49, 58) and has recently been implicated in the selection for p53-deficient tumor Cells with a diminished apoptotic potential in central (hypoxic) areas of solid tumors (19). Thus, two seemingly opposing effects of Hypoxia exist, one protective and the other directly toxic. The protective effect of Hypoxia in conjunction with radiation has long been explored and has led to the development of a model according to which DNA radicals generated by radiation react with oxygen to form organic peroxides that “fix” the radiation damage (oxygen fixation hypothesis). To achieve the same biological effect in hypoxic tissues as in aerated tissues, a 2.5- to 3-fold higher dose of radiation has to be used, a factor known as the oxygen enhancement ratio (22). In contrast to the protective effects of Hypoxia, less is known about underlying mechanisms through which Hypoxia under certain conditions is toxic or growth suppressive. Potential triggers of tumor Cell apoptosis include DNA damage (e.g., radiation or chemotherapy) as well as alternative stress-inducing, but non- DNA-damaging, treatments such as growth factor starvation (11), microtubule poisoning (55, 57), heat (10, 51), and Hypoxia (49, 58). p53 protein, a central regulator in tumor Cell apoptosis, has been shown to accumulate following exposure of cultured Cells to Hypoxia (20), displaying increased DNA binding and transactivation capacity. The mechanism for p53 induction by Hypoxia remains unclear. The transcription factor Hypoxia-inducible factor acts as a global transcriptional regulator for a number of Hypoxia-induced genes, including those for erythropoietin, vascular endothelial growth factor, and many of the glycolytic enzymes (reviewed in reference 13). The Cellular oxygen-sensing system that in turn regulates Hypoxia-inducible factor remains to be elucidated, but preliminary evidence suggests the involvement of a hemoprotein (reviewed in reference 21). A clear mechanistic link between Hypoxia and initiation of the apoptotic pathway, however, has not yet been established. To examine the mechanism underlying apoptosis in hypoxic tumor Cells, we have compared genetically related transformed and untransformed rodent fibroblast Cells in vitro for Cell cycle, proliferation, survival, clonogenicity, and p53 expression under conditions of Hypoxia. Hypoxia induced a G0/G1 checkpoint in primary fibroblasts but induced apoptotic death in their oncogene-transformed derivative lines. However, the mechanism of apoptosis was seen to require metabolic acidosis. The direct effect of Hypoxia under nonacidotic conditions was unique to transformed Cells in that they override the hypoxic G0/G1 checkpoint seen in primary Cells. Moreover, when uncoupled from acidosis, Hypoxia enhanced tumor Cell viability and clonogenicity relative to normoxia. p53 was correspondingly upregulated in response to Hypoxia-induced acidosis but was greatly downregulated under conditions of Hypoxia without acidosis.
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regulation of proliferation survival decisions during tumor Cell Hypoxia
Molecular and Cellular Biology, 1998Co-Authors: Cornelius Schmaltz, Patricia H. Hardenbergh, Audrey M. Wells, David E. FisherAbstract:Hypoxia may influence tumor biology in paradoxically opposing ways: it is lethal as a direct stress trigger, yet hypoxic zones in solid tumors harbor viable Cells which are particularly resistant to treatment and contribute importantly to disease relapse. To examine mechanisms underlying growth-survival decisions during Hypoxia, we have compared genetically related transformed and untransformed fibroblast Cells in vitro for proliferation, survival, clonogenicity, Cell cycle, and p53 expression. Hypoxia induces G0/G1 arrest in primary fibroblasts but triggers apoptosis in oncogene-transformed derivatives. Unexpectedly, the mechanism of apoptosis is seen to require accumulated acidosis and is rescued by enhanced buffering. The direct effect of Hypoxia under nonacidotic conditions is unique to transformed Cells in that they override the hypoxic G0/G1 arrest of primary Cells. Moreover, when uncoupled from acidosis, Hypoxia enhances tumor Cell viability and clonogenicity relative to normoxia. p53 is correspondingly upregulated in response to Hypoxia-induced acidosis but downregulated during Hypoxia without acidosis. Hypoxia may thus produce both treatment resistance and a growth advantage. Given strong evidence that hypoxic regions in solid tumors are often nonacidotic (G. Helmlinger, F. Yuan, M. Dellian, and R. K. Jain, Nat. Med. 3:177-182, 1997), this behavior may influence relapse and implicates such Cells as potentially important therapeutic targets.
Junping Kou - One of the best experts on this subject based on the ideXlab platform.
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yiqifumai powder injection attenuates coronary artery ligation induced heart failure through improving mitochondrial function via regulating ros generation and camkii signaling pathways
Frontiers in Pharmacology, 2019Co-Authors: Yu Zhang, Ling Zhang, Yan Zhang, Xiaoxue Fan, Weiwei Yang, Junping KouAbstract:The YiQiFuMai powder injection (YQFM), a traditional Chinese medicine (TCM) prescription re-developed based on Sheng-Mai-San, is widely applied for the treatment of cardiovascular diseases. However, its potential molecular mechanism remains obscure. The present study was designed to observe the effects of YQFM and underlying mechanisms on coronary artery ligation (CAL)-induced heart failure (HF) and Cell Hypoxia of 24 h oxygen-glucose deprivation (OGD) in neonatal rat ventricular myocytes (NRVMs). HF was induced by permanent CAL for 2 weeks in ICR mice. The results demonstrated that YQFM significantly attenuated CAL-induced HF via improving the cardiac function, cardiac systolic function, cardiac structure impairment, cardiac histological features and fibrosis. YQFM markedly attenuated mitochondrial dysfunction through improving mitochondrial morphology, increasing mitochondria membrane potential (Δψm), mitochondrial ROS generation and expression of Mitofusin-2 (Mfn2), meanwhile, decreasing phosphorylation of dynamin-related protein 1 (p-Drp1). Mechanistically, YQFM could significantly decrease the expression of isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NADPH oxidase 2 (NOX2), p67phox and NADPH oxidase 4 (NOX4), ultimately reducing reactive oxygen species (ROS) generation. In addition, YQFM could down-regulate expression of calcium voltage-gated channel subunit α1C (CACNA1C) and phosphorylation of calmodulin dependent protein kinase II (p-CaMKII). These results suggest that YQFM ameliorates mitochondrial function in HF mice, partially through inhibiting ROS generation and CaMKII signaling pathways. Therefore, the present study provided scientific evidence for the underlying mechanism of YQFM.
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Data_Sheet_1_YiQiFuMai Powder Injection Attenuates Coronary Artery Ligation-Induced Heart Failure Through Improving Mitochondrial Function via Regulating ROS Generation and CaMKII Signaling Pathways.docx
2019Co-Authors: Yu Zhang, Ling Zhang, Yan Zhang, Xiaoxue Fan, Weiwei Yang, Junping KouAbstract:The YiQiFuMai powder injection (YQFM), a traditional Chinese medicine (TCM) prescription re-developed based on Sheng-Mai-San, is widely applied for the treatment of cardiovascular diseases. However, its potential molecular mechanism remains obscure. The present study was designed to observe the effects of YQFM and underlying mechanisms on coronary artery ligation (CAL)-induced heart failure (HF) and Cell Hypoxia of 24 h oxygen-glucose deprivation (OGD) in neonatal rat ventricular myocytes (NRVMs). HF was induced by permanent CAL for 2 weeks in ICR mice. The results demonstrated that YQFM significantly attenuated CAL-induced HF via improving the cardiac function, cardiac systolic function, cardiac structure impairment, cardiac histological features and fibrosis. YQFM markedly attenuated mitochondrial dysfunction through improving mitochondrial morphology, increasing mitochondria membrane potential (Δψm), mitochondrial ROS generation and expression of Mitofusin-2 (Mfn2), meanwhile, decreasing phosphorylation of dynamin-related protein 1 (p-Drp1). Mechanistically, YQFM could significantly decrease the expression of isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NADPH oxidase 2 (NOX2), p67phox and NADPH oxidase 4 (NOX4), ultimately reducing reactive oxygen species (ROS) generation. In addition, YQFM could down-regulate expression of calcium voltage-gated channel subunit α1C (CACNA1C) and phosphorylation of calmodulin dependent protein kinase II (p-CaMKII). These results suggest that YQFM ameliorates mitochondrial function in HF mice, partially through inhibiting ROS generation and CaMKII signaling pathways. Therefore, the present study provided scientific evidence for the underlying mechanism of YQFM.
David N Cornfield - One of the best experts on this subject based on the ideXlab platform.
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loss of smooth muscle Cell Hypoxia inducible factor 1α underlies increased vascular contractility in pulmonary hypertension
The FASEB Journal, 2017Co-Authors: Elizabeth A Barnes, Chihhsin Chen, Oshra Sedan, David N CornfieldAbstract:Pulmonary arterial hypertension (PAH) is an often fatal disease with limited treatment options. Whereas current data support the notion that, in pulmonary artery endothelial Cells (PAECs), expression of transcription factor Hypoxia inducible factor-1α (HIF-1α) is increased, the role of HIF-1α in pulmonary artery smooth muscle Cells (PASMCs) remains controversial. This study investigates the hypothesis that, in PASMCs from patients with PAH, decreases in HIF-1α expression and activity underlie augmented pulmonary vascular contractility. PASMCs and tissues were isolated from nonhypertensive control patients and patients with PAH. Compared with controls, HIF-1α and Kv1.5 protein expression were decreased in PAH smooth muscle Cells (primary culture). Myosin light chain (MLC) phosphorylation and MLC kinase (MLCK) activity-major determinants of vascular tone-were increased in patients with PAH. Cofactors involved in prolyl hydroxylase domain activity were increased in PAH smooth muscle Cells. Functionally, PASMC contractility was inversely correlated with HIF-1α activity. In PASMCs derived from patients with PAH, HIF-1α expression is decreased, and MLCK activity, MLC phosphorylation, and Cell contraction are increased. We conclude that compromised PASMC HIF-1α expression may contribute to the increased tone that characterizes pulmonary hypertension.-Barnes, E. A., Chen, C.-H., Sedan, O., Cornfield, D. N. Loss of smooth muscle Cell Hypoxia inducible factor-1α underlies increased vascular contractility in pulmonary hypertension.
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loss of smooth muscle Cell Hypoxia inducible factor 1α underlies increased vascular contractility in pulmonary hypertension
The FASEB Journal, 2017Co-Authors: Elizabeth A Barnes, Chihhsin Chen, Oshra Sedan, David N CornfieldAbstract:Pulmonary arterial hypertension (PAH) is an often fatal disease with limited treatment options. Whereas current data support the notion that, in pulmonary artery endothelial Cells (PAECs), expressi...
Yu Zhang - One of the best experts on this subject based on the ideXlab platform.
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yiqifumai powder injection attenuates coronary artery ligation induced heart failure through improving mitochondrial function via regulating ros generation and camkii signaling pathways
Frontiers in Pharmacology, 2019Co-Authors: Yu Zhang, Ling Zhang, Yan Zhang, Xiaoxue Fan, Weiwei Yang, Junping KouAbstract:The YiQiFuMai powder injection (YQFM), a traditional Chinese medicine (TCM) prescription re-developed based on Sheng-Mai-San, is widely applied for the treatment of cardiovascular diseases. However, its potential molecular mechanism remains obscure. The present study was designed to observe the effects of YQFM and underlying mechanisms on coronary artery ligation (CAL)-induced heart failure (HF) and Cell Hypoxia of 24 h oxygen-glucose deprivation (OGD) in neonatal rat ventricular myocytes (NRVMs). HF was induced by permanent CAL for 2 weeks in ICR mice. The results demonstrated that YQFM significantly attenuated CAL-induced HF via improving the cardiac function, cardiac systolic function, cardiac structure impairment, cardiac histological features and fibrosis. YQFM markedly attenuated mitochondrial dysfunction through improving mitochondrial morphology, increasing mitochondria membrane potential (Δψm), mitochondrial ROS generation and expression of Mitofusin-2 (Mfn2), meanwhile, decreasing phosphorylation of dynamin-related protein 1 (p-Drp1). Mechanistically, YQFM could significantly decrease the expression of isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NADPH oxidase 2 (NOX2), p67phox and NADPH oxidase 4 (NOX4), ultimately reducing reactive oxygen species (ROS) generation. In addition, YQFM could down-regulate expression of calcium voltage-gated channel subunit α1C (CACNA1C) and phosphorylation of calmodulin dependent protein kinase II (p-CaMKII). These results suggest that YQFM ameliorates mitochondrial function in HF mice, partially through inhibiting ROS generation and CaMKII signaling pathways. Therefore, the present study provided scientific evidence for the underlying mechanism of YQFM.
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Data_Sheet_1_YiQiFuMai Powder Injection Attenuates Coronary Artery Ligation-Induced Heart Failure Through Improving Mitochondrial Function via Regulating ROS Generation and CaMKII Signaling Pathways.docx
2019Co-Authors: Yu Zhang, Ling Zhang, Yan Zhang, Xiaoxue Fan, Weiwei Yang, Junping KouAbstract:The YiQiFuMai powder injection (YQFM), a traditional Chinese medicine (TCM) prescription re-developed based on Sheng-Mai-San, is widely applied for the treatment of cardiovascular diseases. However, its potential molecular mechanism remains obscure. The present study was designed to observe the effects of YQFM and underlying mechanisms on coronary artery ligation (CAL)-induced heart failure (HF) and Cell Hypoxia of 24 h oxygen-glucose deprivation (OGD) in neonatal rat ventricular myocytes (NRVMs). HF was induced by permanent CAL for 2 weeks in ICR mice. The results demonstrated that YQFM significantly attenuated CAL-induced HF via improving the cardiac function, cardiac systolic function, cardiac structure impairment, cardiac histological features and fibrosis. YQFM markedly attenuated mitochondrial dysfunction through improving mitochondrial morphology, increasing mitochondria membrane potential (Δψm), mitochondrial ROS generation and expression of Mitofusin-2 (Mfn2), meanwhile, decreasing phosphorylation of dynamin-related protein 1 (p-Drp1). Mechanistically, YQFM could significantly decrease the expression of isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NADPH oxidase 2 (NOX2), p67phox and NADPH oxidase 4 (NOX4), ultimately reducing reactive oxygen species (ROS) generation. In addition, YQFM could down-regulate expression of calcium voltage-gated channel subunit α1C (CACNA1C) and phosphorylation of calmodulin dependent protein kinase II (p-CaMKII). These results suggest that YQFM ameliorates mitochondrial function in HF mice, partially through inhibiting ROS generation and CaMKII signaling pathways. Therefore, the present study provided scientific evidence for the underlying mechanism of YQFM.
Johan Bussink - One of the best experts on this subject based on the ideXlab platform.
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Correlation of [18F]FMISO autoradiography and pimonodazole immunohistochemistry in human head and neck carcinoma xenografts.
European journal of nuclear medicine and molecular imaging, 2008Co-Authors: Esther G.c. Troost, Peter Laverman, Marielle E.p. Philippens, Jasper Lok, Albert J. Van Der Kogel, Wim J.g. Oyen, Otto C. Boerman, Johannes H.a.m. Kaanders, Johan BussinkAbstract:Purpose Tumour Cell Hypoxia is a common feature in solid tumours adversely affecting radiosensitivity and chemosensitivity in head and neck squamous Cell carcinomas. Positron emission tomography (PET) using the tracer [18F]fluoromisonidazole ([18F]FMISO) is most frequently used for non-invasive evaluation of Hypoxia in human tumours. A series of ten human head and neck xenograft tumour lines was used to validate [18F]FMISO as Hypoxia marker at the microregional level.
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tumor Hypoxia at the micro regional level clinical relevance and predictive value of exogenous and endogenous hypoxic Cell markers
Radiotherapy and Oncology, 2003Co-Authors: Johan Bussink, Johannes H.a.m. Kaanders, Albert J. Van Der KogelAbstract:Abstract Background and purpose : Tumor oxygenation is recognized as an important determinant of the outcome of radiotherapy and possibly also of other treatment modalities in a number of tumor types and in particular in squamous Cell carcinomas. The hypoxic status of various solid tumors has been related to a poor prognosis due to tumor progression towards a more malignant phenotype, with increased metastatic potential, and an increased resistance to treatment. It has been demonstrated in head and neck cancer that hypoxic radioresistance can be successfully counteracted by Hypoxia modifying approaches. The microregional distribution and the level of tumor Hypoxia depend on oxygen consumption and temporal and spatial variations in blood supply. It is unclear if severely hypoxic Cells can resume clonogenicity when O 2 and nutrients become available again as a result of (treatment related) changes in the tumor microenvironment. Non-terminally differentiated hypoxic Cells that are capable of proliferation are important for outcome because of their resistance to radiotherapy and possibly other cytotoxic treatments. Various exogenous and endogenous markers for Hypoxia are currently available and can be studied in relation to each other, the tumor architecture and the tumor microenvironment. Use of nitroimidazole markers with immunohistochemical detection allows studying tumor Cell Hypoxia at the microscopic level. Co-registration with other microenvironmental parameters, such as vascular architecture (vascular density), blood perfusion, tumor Cell proliferation and apoptosis, offers the possibility to obtain a comprehensive functional image of tumor patho-physiology and to study the effects of different modalities of cancer treatment. Conclusion : A number of functional microregional parameters have emerged that are good candidates for future use as indicators of tumor aggressiveness and treatment response. The key question is whether these parameters can be used as tools for selection of treatment strategies for individual patients. This requires testing of these markers in prospective randomized clinical trials comparing standard treatment against experimental treatments targeting the relevant microregional constituent.