Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.

Hypoxia — a key regulatory factor in tumour growth

This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

▪ Abstract The prostaglandin endoperoxide H synthases-1 and 2 (PGHS-1 and PGHS-2; also cyclooxygenases-1 and 2, COX-1 and COX-2) catalyze the committed step in prostaglandin synthesis. PGHS-1 and 2 are of particular interest because they are the major targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, and the new COX-2 inhibitors. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. In this review, we examine how the structures of these enzymes relate mechanistically to cyclooxygenase and peroxidase catalysis, and how differences in the structure of PGHS-2 confer on this isozyme differential sensitivity to COX-2 inhibitors. We further examine the evidence for independent signaling by PGHS-1 and PGHS-2, and the complex mechanisms for regulation of PGHS-2 gene expression.

Cyclooxygenases: Structural, cellular, and molecular biology

Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R- containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17 R -hydroxy-containing di- and tri-hydroxy-docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17 R -hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17 R -HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA‐derived 17 R -hydroxy-DHA into two sets of novel diand trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC 50 � 50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40‐80% leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17 R -hydroxy series of docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status.

https://rupress.org/jem/article-pdf/196/8/1025/1142248/jem19681025.pdf

Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.

Atherosclerosis is a process with inflammatory features and selective
cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects
by virtue of inhibiting inflammation. However, by decreasing vasodilatory
and antiaggregatory prostacyclin production, COX-2 antagonists may lead to
increased prothrombotic activity. To define the cardiovascular effects of
COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients
without coronary artery disease, we performed a MEDLINE search to identify
all English-language articles on use of COX-2 inhibitors published between
1998 and February 2001. We also reviewed relevant submissions to the US Food
and Drug Administration by pharmaceutical companies.Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal
Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term
Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials
with approximately 1000 patients each. The results from VIGOR showed that
the relative risk of developing a confirmed adjudicated thrombotic cardiovascular
event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated
cardiac arrest, sudden or unexplained death, ischemic stroke, and transient
ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38
(95% confidence interval, 1.39-4.00; P = .002). There
was no significant difference in cardiovascular event (myocardial infarction,
stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory
agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors
in both VIGOR and CLASS were significantly higher than that in the placebo
group of a recent meta-analysis of 23 407 patients in primary prevention
trials (0.52%): 0.74% with rofecoxib (P = .04 compared
with the placebo group of the meta-analysis) and 0.80% with celecoxib (P = .02 compared with the placebo group of the meta-analysis).The available data raise a cautionary flag about the risk of cardiovascular
events with COX-2 inhibitors. Further prospective trial evaluation may characterize
and determine the magnitude of the risk.

/pdf/risk-of-cardiovascular-events-associated-with-selective-cox-1b98pd2lb1.pdf

Risk of cardiovascular events associated with selective COX-2 inhibitors.

Hypoxia Induces Cyclooxygenase-2 via the NF-κB p65 Transcription Factor in Human Vascular Endothelial Cells

Evidence of Hypoxia-Inducible Factor-1 in Vascular Endothelial and Smooth Muscle Cells

pH is critical to the regulation of expression of the β2-adrenergic receptor gene in hypoxia

Hypoxia can cause basement membrane (BM) degradation in tissues. Matrix metalloproteinase 9 (MMP-9) is involved in various human cancers as well as BM degradation by downregulating type IV collagen (COL4). This study investigated the role of MMP-9 in hypoxia-mediated BM degradation in rat bone marrow based on its regulation of collagen type IV alpha 1 chain (COL4A1). Eighty male rats were randomly divided into four groups based on exposure to hypoxic conditions at a simulated altitude of 7,000 m, control (normoxia) and 3, 7, and 10 days of hypoxia exposure. BM degradation in bone marrow was determined by transmission electron microscopy. MMP-9 levels were assessed by western blot and real-time PCR, and COL4A1 levels were assessed by western blot and immunohistochemistry. Microvessels BMs in bone marrow exposed to acute hypoxia were observed by electron microscopy. MMP-9 expression increased, COL4A1 protein expression decreased, and BM degradation occurred in the 10-, 7-, and 3-day hypoxia groups compared with that in the control group (all P < 0.05). Hypoxia increased MMP-9 levels, which in turn downregulated COL4A1, thereby increasing BM degradation. MMP-9 upregulation significantly promoted BM degradation and COL4A1 downregulation. Our results suggest that MMP-9 is related to acute hypoxia-induced BM degradation in bone marrow by regulating COL4A1.

/pdf/hypoxia-induced-upregulation-of-matrix-metalloproteinase-9-q1xfzwqm.pdf

W. L. Liu

Papers

Hypoxia Induces Cyclooxygenase-2 via the NF-κB p65 Transcription Factor in Human Vascular Endothelial Cells

Evidence of Hypoxia-Inducible Factor-1 in Vascular Endothelial and Smooth Muscle Cells

pH is critical to the regulation of expression of the β2-adrenergic receptor gene in hypoxia

Hypoxia-induced upregulation of matrix metalloproteinase 9 increases basement membrane degradation by downregulating collagen type IV alpha 1 chain.