Hypoxia-inducible factors and hypoxic cell death in tumour physiology

Hypoxic up-regulation of hypoxia-inducible factors (HIFs) during tumourigenesis presents an interesting paradox with respect to their role in tumour growth. Hypoxia-inducible factor 1 (HIF-1) plays a key role in the adaptive response to hypoxia, trans-activating many genes whose protein products are involved in pathways of angiogenesis, glucose metabolism and cell proliferation, thus facilitating tumour progression. However, it is also emerging that up-regulation of HIF-1 trans-activates anti-proliferative and pro-apoptotic genes (such as BNIP3, NIX     

Nitrite as regulator of hypoxic signaling in mammalian physiology

In this review we consider the effects of endogenous and pharmacological levels of nitrite under conditions of hypoxia. In humans, the nitrite anion has long been considered as metastable intermediate in the oxidation of nitric oxide radicals to the stable metabolite nitrate. This oxidation cascade was thought to be irreversible under physiological conditions. However, a growing body of experimental observations attests that the presence of endogenous nitrite regulates a number of signaling events along the physiological and pathophysiological oxygen gradient. Hypoxic signaling events include vasodilation, modulation of mitochondrial respiration, and cytoprotection following ischemic insult. These phenomena are attributed to the reduction of nitrite anions to nitric oxide if local oxygen levels in tissues decrease. Recent research identified a growing list of enzymatic and nonenzymatic pathways for this endogenous reduction of nitrite. Additional direct signaling events not involving free nitric oxide are proposed. We here discuss the mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue. © 2009 Wiley Periodicals, Inc. Med Res Rev, 29, No. 5, 683–741, 2009     

The physiology of sudden violent death

BACKGROUND AND PURPOSE: The physiology behind sudden violent death is considered in the light of information from a wide variety of clinical, experimental, forensic and veterinary sources. Physiological causes can be classified under the headings of blood loss; asphyxia; electrocution; tissue loss; destruction of brain; disconnection of brain; and poisoning. Death, although sudden, is not necessarily instantaneous; asphyxia and electrocution take some time to kill the subjects. CONCLUSIONS: The chemistry of dying, death and changes post mortem, needs more research in order to design further rational resuscitation procedures.     

Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair

Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.     

Host and tumour factors in cancer metastasis

The process of cancer metastasis is sequential and selective and contains stochastic elements. The growth of metastases represents the endpoint of many lethal events that only few tumour cells survive. Primary tumours contain cells with heterogeneous metastatic properties, and the outcome of metastasis depends on the interplay of tumour cells with various host factors. Collectively, then, our studies and most data reported by others have led us to conclude that metastasis is a highly selective process regulated by a number of mechanisms. This belief is contrary to the once widely accepted notion that neoplastic dissemination is the ultimate expression of cellular anarchy. In fact, suggesting that cancer metastasis is a selective process is a more optimistic view in terms of cancer therapy than the one that contends that tumour dissemination is an entirely random event. A selective biological process is regulated by the interaction of tumour cells with their host, and these complex interactions can be studied and manipulated. A better understanding of the complexity of the processes of tumour evolution, progression, and metastasis should lead to improvements in the treatment of cancer.     

Host and tumour factors in cancer metastasis

Abstract. The process of cancer metastasis is sequential and selective and contains stochastic elements. The growth of metastases represents the endpoint of many lethal events that only few tumour cells survive. Primary tumours contain cells with heterogeneous metastatic properties, and the outcome of metastasis depends on the interplay of tumour cells with various host factors. Collectively, then, our studies and most data reported by others have led us to conclude that metastasis is a highly selective process regulated by a number of mechanisms. This belief is contrary to the once widely accepted notion that neoplastic dissemination is the ultimate expression of cellular anarchy. In fact, suggesting that cancer metastasis is a selective process is a more optimistic view in terms of cancer therapy than the one that contends that tumour dissemination is an entirely random event. A selective biological process is regulated by the interaction of tumour cells with their host, and these complex interactions can be studied and manipulated. A better understanding of the complexity of the processes of tumour evolution, progression, and metastasis should lead to improvements in the treatment of cancer.     

BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha

Hypoxia is a common cause of cell death and is implicated in many disease processes including stroke and chronic degenerative disorders. In response to hypoxia, cells express a variety of genes, which allow adaptation to altered metabolic demands, decreased oxygen demands, and the removal of irreversibly damaged cells. Using polymerase chain reaction-based suppression subtractive hybridization to find genes that are differentially expressed in hypoxia, we identified the BH3-only Bcl-2 family protein Noxa. Noxa is a candidate molecule mediating p53-induced apoptosis. We show that Noxa promoter responds directly to hypoxia via hypoxia-inducible factor (HIF)-1alpha. Suppression of Noxa expression by antisense oligonucleotides rescued cells from hypoxia-induced cell death and decreased infarction volumes in an animal model of ischemia. Further, we show that reactive oxygen species and resultant cytochrome c release participate in Noxa-mediated hypoxic cell death. Altogether, our results show that Noxa is induced by HIF-1alpha and mediates hypoxic cell death.     

乏氧诱导因子预测肺鳞癌放疗敏感性研究

目的 探讨乏氧诱导因子(hypoxia-inducible factor-1α,H1F-1α)预测肺鳞癌放疗敏感性的价值.方法 对数期人肺鳞癌细胞,按放疗照射时间分为24 h组和48 h组,2组分别采用0、2、10 Gy照射剂量单次X线照射24 h和48 h.照射后采用Western blot检测肺鳞癌细胞HIF-1α蛋白表达情况,采用逆转录PCR检测肺鳞癌细胞HIF-1α基因表达情况,比较2组肺鳞癌细胞放疗前、后HIF-1α阳性表达率、微血管密度和细胞凋亡率.结果 48 h组肺鳞癌细胞在照射0、2、10 Gy剂量时HIF-1α mRNA((14±2)％、(37±2)％、(69±3)％)和蛋白表达量((16±1)％、(70±5)％、(97±13)％)均明显高于24h组((10±1)％、(29±5)％、(41±6)％,(13±2)％、(65±4)％、(89±10)％),且10 Gy剂量时高于0、2 Gy剂量,2 Gy剂量高于0 Gy剂量(P＜0.05);放疗前24h组肺鳞癌细胞HIF-1α阳性表达率(12.5％)、微血管密度(40.78±5.25)和细胞凋亡率((2.10±0.43)％)与48 h组(12.5％、42.90±7.54、(2.08±0.39)％)比较差异均无统计学意义(P＞0.05),放疗后48 h组肺鳞癌细胞HIF-1α阳性表达率(87.5％)、微血管密度(83.31±4.67)和细胞凋亡率((4.04±1.22)％)均高于24 h组(62.5％、61.22±9.48、(2.23±0.57)％)(P＜0.05),2组放疗后均较放疗前明显增高(P＜0.05).结论 放射剂量越大、放射时间越长,肺鳞癌中HIF-1α阳性表达量越高,对放疗越不敏感;HIF-1α与微血管密度、细胞凋亡密切相关.     

Targeting cell death

Functional consequences of myocardial or cerebral infarction are the result of excessive cell death. It is patent that preventing cell death is the therapeutic goal in any ischemia-reperfusion setting. Mitochondria amplify apoptotic cascades and have emerged as crucial organelles in ischemia-reperfusion. Changes in mitochondrial inner membrane permeability and in the morphology of the organelle are regulated, perhaps interconnected processes that are starting to emerge as novel therapeutic targets for reducing cell death induced by ischemia-reperfusion.     

Radiation-induced cell death

Elucidation of the molecular mechanism(s) of cell death induced by ionizing radiation is a main topic in the field of radiation biology. Radiation-induced cell death has been classified as interphase death estimated by vital cell counting and reproductive death estimated by colony forming assay. Recently, many modes of cell death, such as apoptosis, autophagy, mitotic catastrophe, senescence-like cell death, etc. have been reported. In this review, (1) classification of modes of cell death induced by ionizing radiation, (2) radiation-induced apoptosis and its molecular mechanism, (3) significance of radiation-induced cell death are summarized. Discussion on radiation-induced cell death will also focus on radiation-induced normal tissue damage and strategies in radiation cancer     

Relationship between intracellular GSH levels and hypoxic cell radiosensitivity

The present studies show the following: (a) The plating density of cells (V79 and GM3877) affects the experimentally determined OER values. (b) Fibroblasts depleted of cysteine and GSH are more sensitive to radiation under hypoxic conditions (under aerobic conditions the absence of cysteine or GSH has no detectable effect on radiation sensitivity). (c) Addition of GEE to V79 cells (previously depleted of GSH) leads to increased intracellular GSH levels and protects the cells against radiation under hypoxic conditions.     

影响重症中暑患者预后因素及其死亡原因分析

目的：探讨影响重症中暑预后的因素及死亡原因,以指导治疗。方法：收集重症中暑患者４４例,将死亡病例与治疗好转病例的临床资料进行比较,并分析死亡原因。结果：死亡组与好转组比较,体温＞４０．５℃者,昏迷程度深者,合并基础疾病、休克、心律失常者,血Ｎａ＋、血细胞比容（Ｈｃｔ）几项指标均有显著性差异（Ｐ均＜０．０１）,血Ｋ＋也有差异（Ｐ＜０．０５）。死亡原因：２４小时内主要为心、脑、循环衰竭与猝死;２４小时后主要为呼吸衰竭。结论：影响重症中暑患者预后的因素主要有体温、昏迷程度、基础疾病、心律失常、休克、低血Ｎａ＋、低血Ｋ＋、血液浓缩。治疗应针对各危险因素,应早期阻断高热引起的恶性循环,及时纠正水、电解质紊乱;防止各主要脏器的衰竭;晚期则主要预防肺部感染等并发症