The terms 'antioxidant', 'oxidative stress' and 'oxidative damage' are widely used but rarely defined. This brief review attempts to define them and to examine the ways in which oxidative stress and oxidative damage can affect cell behaviour both in vivo and in cell culture, using cancer as an example.

Biochemistry of oxidative stress

Liver fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSC), which proliferate during fibrotic liver injury. We have studied a model of spontaneous recovery from liver fibrosis to determine the biological mechanisms mediating resolution. Livers were harvested from rats at 0, 3, 7, and 28 d of spontaneous recovery from liver fibrosis induced by 4 wk of twice weekly intraperitoneal injections with CCl4. Hydroxyproline analysis and histology of liver sections indicated that the advanced septal fibrosis observed at time 0 (peak fibrosis) was remodeled over 28 d of recovery to levels close to control (untreated liver). alpha-Smooth muscle actin staining of liver sections demonstrated a 12-fold reduction in the number of activated HSC over the same time period with evidence of HSC apoptosis. Ribonuclease protection analysis of liver RNA extracted at each recovery time point demonstrated a rapid decrease in expression of the collagenase inhibitors TIMP-1 and TIMP-2, whereas collagenase mRNA expression remained at levels comparable to peak fibrosis. Collagenase activity in liver homogenates increased through recovery. We suggest that apoptosis of activated HSC may vitally contribute to resolution of fibrosis by acting as a mechanism for removing the cell population responsible for both producing fibrotic neomatrix and protecting this matrix from degradation via their production of TIMPs.

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Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.

The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of the extracellular matrix. The MMPs have been implicated in the processes of tumor growth, invasion, and metastasis; are frequently overexpressed in malignant tumors; and have been associated with an aggressive malignant phenotype and adverse prognosis in patients with cancer. A number of MMP inhibitors are being developed for the treatment of cancer. The most extensively studied class of MMP inhibitors includes collagen peptidomimetics and nonpeptidomimetic inhibitors of the MMP active site, tetracycline derivatives, and bisphosphonates. The hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat, which bind covalently to the zinc atom at the MMP-active site, were the first MMP inhibitors to be studied in detail. Marimastat is currently being studied in randomized clinical trials. The nonpeptidic MMP inhibitors were synthesized in an attempt to improve the oral bioavailability and pharmaceutical properties of the peptidic inhibitors. Several members of this class of compounds are undergoing evaluation in phase III clinical trials. The tetracyclines and, particularly, the nonantibiotic chemically modified tetracyclines, interfere with several aspects of MMP expression and activation and inhibit tumor growth and metastases in preclinical models. A representative agent of this class, Col-3, is currently undergoing phase I clinical trials. The development of the MMP inhibitors, like that of other targeted and predominantly antiproliferative compounds, poses a challenge because the paradigms that have governed the design of clinical oncology trials may not be relevant to this new class of agents. The anticipated need for long-term administration of these drugs, together with their cytostatic mechanism of action, will require novel clinical trial design strategies.

https://www.hemonc.theclinics.com/article/S0889-8588(02)00044-8/pdf

Development of Matrix Metalloproteinase Inhibitors in Cancer Therapy

Almost 25 centuries ago, Hippocrates, the father of medicine, proclaimed “Let food be thy medicine and medicine be thy food.” Exploring the association between diet and health continues today. For example, we now know that as many as 35% of all cancers can be prevented by dietary changes. Carcinogenesis is a multistep process involving the transformation, survival, proliferation, invasion, angiogenesis, and metastasis of the tumor and may take up to 30 years. The pathways associated with this process have been linked to chronic inflammation, a major mediator of tumor progression. The human body consists of about 13 trillion cells, almost all of which are turned over within 100 days, indicating that 70,000 cells undergo apoptosis every minute. Thus, apoptosis/cell death is a normal physiological process, and it is rare that a lack of apoptosis kills the patient. Almost 90% of all deaths due to cancer are linked to metastasis of the tumor. How our diet can prevent cancer is the focus of this review. Specifically, we will discuss how nutraceuticals, such as allicin, apigenin, berberine, butein, caffeic acid, capsaicin, catechin gallate, celastrol, curcumin, epigallocatechin gallate, fisetin, flavopiridol, gambogic acid, genistein, plumbagin, quercetin, resveratrol, sanguinarine, silibinin, sulforaphane, taxol, γ-tocotrienol, and zerumbone, derived from spices, legumes, fruits, nuts, and vegetables, can modulate inflammatory pathways and thus affect the survival, proliferation, invasion, angiogenesis, and metastasis of the tumor. Various cell signaling pathways that are modulated by these agents will also be discussed.

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Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals

Theory of maternal recognition of pregnancy in swine based on estrogen controlled endocrine versus exocrine secretion of prostaglandin F2alpha by the uterine endometrium.

Neuroprotective Effect of Silymarin in a MPTP Mouse Model of Parkinson's Disease

Morbid obesity has been shown to increase the risk to develop hepatic steatosis, also referred to as non-alcoholic fatty liver disease (NAFLD) Emerging evidence suggests that the severity of NAFLD may associate with increased serum levels of inflammatory markers as well as decreased concentration of mediators with anti-inflammatory actions, such as tumor necrosis factor alpha (TNF-α) and interleukin (IL) 10, respectively We thus examined the serum levels of TNF-α and IL-10 in 102 morbidly obese women and men (body mass index > 40 kg/m2), exhibiting different grades of NAFLD Blood glucose, glycated hemoglobin, insulin, the homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol, triglycerides, high- and low-density lipoproteins, parameters of liver function, TNF-α, and IL-10 were measured in each subject The stage of NAFLD was estimated by abdominal ultrasound imaging In comparison with morbidly obese subjects without steatosis, morbidly obese patients with NAFLD showed increased age (3923 ± 980 years), HOMA-IR (674 ± 162), total cholesterol (2197 ± 958 mg/dl), aspartate aminotransferase (3625 ± 324 UI/l), gamma-glutamyl transpeptidase (3712 ± 341 UI/l), and TNF-α (3741 ± 172 pg/ml) as well as decreased serum levels of IL-10 (6105 ± 243 pg/ml) Interestingly, the systemic levels of TNF-α increased, while IL-10 decreased in accordance with the severity of NAFLD, which supports a role for systemic inflammatory mediators in promoting steatosis progression Further clinical prospective studies need to be addressed to elucidate the role of TNF-α and IL-10 in the development of NAFLD while also establishing their clinical utility in the assessment of morbidly obese patients at higher risk to develop severe steatosis

Severity of non-alcoholic fatty liver disease is associated with high systemic levels of tumor necrosis factor alpha and low serum interleukin 10 in morbidly obese patients.

Collagenolytic activity in experimental cirrhosis of the liver

In this study we examined the production of gelatinases A and B (MMP-2 and MMP-9), and their natural inhibitors TIMP-1 and TIMP-2 in cell lines derived from different histologic types of lung cancer. Gelatinolytic activity was measured by zymography and radiolabeled gelatin degradation. Immunocytochemistry and Western blot analysis were performed to corroborate the presence of immunoreactive MMP-2, MMP-9, TIMP-1 and TIMP-2 proteins. The highest gelatinolytic activity was identified in the cell extracts from a small-cell carcinoma cell line. MMP-9 was observed in all samples as a proenzyme, while MMP-2 was present as zymogen in the squamous-cell and in the small-cell carcinomas, and in its active form in one squamous-cell carcinoma cell line. TIMPs were also present in the neoplastic lung cell lines. TIMP-1 was observed in the media of all cells as a 21-kD band, and as TIMP-1 polymers with the exception of the small-cell carcinoma samples. TIMP-2 was found as higher-order molecular immunoreactive complexes that may correspond to proMMP-2/TIMP-2 complexes. These results demonstrate that lung neoplastic cells produce both MMP-2 and MMP-9 and their inhibitors, with the small-cell carcinoma cell extracts showing the highest enzymatic activity. This gelatinolytic activity fits well with the clinical metastatic behavior of this type of lung cancer.

Ruy Pérez-Tamayo

Papers

Neuroprotective Effect of Silymarin in a MPTP Mouse Model of Parkinson's Disease

Severity of non-alcoholic fatty liver disease is associated with high systemic levels of tumor necrosis factor alpha and low serum interleukin 10 in morbidly obese patients.

Collagenolytic activity in experimental cirrhosis of the liver

72-kD (MMP-2) and 92-kD (MMP-9) Type IV Collagenase Production and Activity in Different Histologic Types of Lung Cancer Cells

Hepatocyte production of modulators of extracellular liver matrix in normal and cirrhotic rat liver.