Publisher Summary This chapter discusses the role of free radicals and catalytic metal ions in human disease. The importance of transition metal ions in mediating oxidant damage naturally leads to the question as to what forms of such ions might be available to catalyze radical reactions in vivo . The chapter discusses the metabolism of transition metals, such as iron and copper. It also discusses the chelation therapy that is an approach to site-specific antioxidant protection. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. A wide range of techniques is available to measure the rate of this process, but none is applicable to all circumstances. The two most popular are the measurement of diene conjugation and the thiobarbituric acid (TBA) test, but they are both subject to pitfalls, especially when applied to human samples. The chapter also discusses the essential principles of the peroxidation process. When discussing lipid peroxidation, it is essential to use clear terminology for the sequence of events involved; an imprecise use of terms such as initiation has caused considerable confusion in the literature. In a completely peroxide-free lipid system, first chain initiation of a peroxidation sequence in a membrane or polyunsaturated fatty acid refers to the attack of any species that has sufficient reactivity to abstract a hydrogen atom from a methylene group.

Role of free radicals and catalytic metal ions in human disease: an overview.

Molecular chaperones, including the heat-shock proteins (Hsps), are a ubiquitous feature of cells in which these proteins cope with stress-induced denaturation of other proteins. Hsps have received the most attention in model organisms undergoing experimental stress in the laboratory, and the function of Hsps at the molecular and cellular level is becoming well understood in this context. A complementary focus is now emerging on the Hsps of both model and nonmodel organisms undergoing stress in nature, on the roles of Hsps in the stress physiology of whole multicellular eukaryotes and the tissues and organs they comprise, and on the ecological and evolutionary correlates of variation in Hsps and the genes that encode them. This focus discloses that (a) expression of Hsps can occur in nature, (b) all species have hsp genes but they vary in the patterns of their expression, (c) Hsp expression can be correlated with resistance to stress, and (d) species' thresholds for Hsp expression are correlated with levels of stress that they naturally undergo. These conclusions are now well established and may require little additional confirmation; many significant questions remain unanswered concerning both the mechanisms of Hsp-mediated stress tolerance at the organismal level and the evolutionary mechanisms that have diversified the hsp genes.

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Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology

Advances in flavonoid research since 1992.

In oncology, the term 'hyperthermia' refers to the treatment of malignant diseases by administering heat in various ways. Hyperthermia is usually applied as an adjunct to an already established treatment modality (especially radiotherapy and chemotherapy), where tumor temperatures in the range of 40-43 degrees C are aspired. In several clinical phase-III trials, an improvement of both local control and survival rates have been demonstrated by adding local/regional hyperthermia to radiotherapy in patients with locally advanced or recurrent superficial and pelvic tumors. In addition, interstitial hyperthermia, hyperthermic chemoperfusion, and whole-body hyperthermia (WBH) are under clinical investigation, and some positive comparative trials have already been completed. In parallel to clinical research, several aspects of heat action have been examined in numerous pre-clinical studies since the 1970s. However, an unequivocal identification of the mechanisms leading to favorable clinical results of hyperthermia have not yet been identified for various reasons. This manuscript deals with discussions concerning the direct cytotoxic effect of heat, heat-induced alterations of the tumor microenvironment, synergism of heat in conjunction with radiation and drugs, as well as, the presumed cellular effects of hyperthermia including the expression of heat-shock proteins (HSP), induction and regulation of apoptosis, signal transduction, and modulation of drug resistance by hyperthermia.

The cellular and molecular basis of hyperthermia.

Molecular mechanisms of resistance and toxicity associated with platinating agents.

Damage to salivary glands after radiotherapeutic treatment of head and neck tumours can severely impair the quality of life of the patients. In the current study we have investigated the early-to-late pathogenesis of the parotid gland after radiation. Also the ability to ameliorate the damage using pretreatment with adrenergic or muscarinic receptor agonists is studied. Rats were locally irradiated with or without i.p. pretreatment with phenylephrine (alpha-adrenoceptor agonist, 5 mg kg(-1)), isoproterenol (beta-adrenoceptor agonist, 5 mg kg(-1)), pilocarpine (4 mg kg(-1)), methacholine (3.75 mg kg(-1)) (muscarinic receptor agonists) or methacholine plus phenylephrine. Parotid salivary flow rate, amylase secretion, the number of cells and gland histology were monitored sequentially up to 240 days postirradiation. The effects were described in 4 distinct phases. The first phase (0-10 days) was characterised by a rapid decline in flow rate without changes in amylase secretion or acinar cell number. The second phase (10-60 days) consists of a decrease in amylase secretion and is paralleled by acinar cell loss. Flow rate, amylase secretion and acinar cell numbers do not change in the third phase (60-120 days). The fourth phase (120-240 days) is determined by a further deterioration of gland function but an increase in acinar cell number, albeit with poor tissue morphology. All drug pretreatments used could reduce radiation effects in phase I and II. The protective effects were lost during phase IV, with the exception of methacholine plus phenylephrine pretreatment. The latter combination of drugs ameliorated radiation-damage throughout the entire follow-up time. The data show that combined pre-irradiation stimulation of muscarinic acetylcholine receptors with methacholine plus alpha-adrenoceptors with phenylephrine can reduce both early and late damage, possibly involving the PLC/PIP2 second messenger pathways. This opens perspectives for the development of clinical applicable methods for long-term sparing of parotid glands subjected to radiotherapy of head and neck cancer patients.

/pdf/early-to-late-sparing-of-radiation-damage-to-the-parotid-35l8d2vbv5.pdf

Early to late sparing of radiation damage to the parotid gland by adrenergic and muscarinic receptor agonists

Liposomes were prepared from phospholipids extracted from biological membranes. A comparison was made between the peroxidation rate in handshake liposomes and in sonicated liposomes. The smaller sonicated liposomes were more vulnerable to peroxidation, probably because of the smaller radius of curvature, which results in a less dense packing of lipid molecules in the bilayer and a facilitated action of water radicals produced by the X-irradiation. High oxygen enhancement ratios were obtained, especially at low dose rates, suggesting the operation of slowly progressing chain reactions initiated by ionizing radiation. Three compounds were tested for their ability to protect the liposomal membranes against lipid peroxidation. The naturally occurring compounds reduced glutathione (GSH) and vitamin E(alpha-T) and the powerful radiation protector cysteamine (MEA). All three molecules could protect the liposomes against peroxidation. The membrane-soluble compound vitamin E was by far the most powerful. About 50 per cent protection was achieved by using 5 X 10(-6) M alpha-T, 10(-4) M GSH and 5 X 10(-4) M MEA. The fatty acid composition of the lipids altered drastically as a result of the irradiation. Arachidonic acid and docosahexanoic acid were the most vulnerable of the fatty acids. Very efficient protection of these polyunsaturated fatty acids could be obtained with relatively low concentrations of vitamin E built into the membranes.

Protection of liposomal lipids against radiation induced oxidative damage.

Cells Overexpressing Hsp27 Show Accelerated Recovery from Heat-Induced Nuclear-Protein Aggregation

Resistance to cisplatin (cDDP) is a major limitation to its clinical effectiveness. Review of literature data indicates that cDDP resistance is a multifactorial phenomenon. This provides an explanation why attempts to reverse or circumvent resistance using cDDP-analogues or combination therapy with modulators of specific resistance mechanisms have had limited success so far. It therefore provides a rationale to use hyperthermia, an agent with pleiotropic effects on cells, in trying to modulate cDDP resistance. In this review the effects of hyperthermia on cDDP cytotoxicity and resistance as well as underlying mechanisms are discussed. Hyperthermia is found to be a powerful modulator of cDDP cytotoxicity, both in sensitive and resistant cells. Relatively high heat doses (60 min 43 degrees C) seem to specifically interfere with cDDP resistance. The mechanism of interaction has not been fully elucidated so far, but seems to consist of multiple (simultaneous) effects on drug accumulation, adduct-formation and -repair. This may explain why hyperthermia seems to be so effective in increasing cDDP cytotoxicity, irrespective of the presence of resistance mechanisms. Therefore, the combination of hyperthermia and cDDP deserves further attention.

https://www.tandfonline.com/doi/pdf/10.3109/02656739709023545

Reduction of cellular cisplatin resistance by hyperthermia—a review

We determined the in vitro cytotoxic activity of the sesquiterpene lactone endoperoxide artemisinin (1) and some chemically prepared derivatives, which have been found to display cytotoxicity to cloned murine Ehrlich ascites tumour (EAT) cells and human HeLa cells and against murine bone marrow using a clonogenic assay for committed progenitor cells of the granulocyte-monocyte lineage (CFU-GM assay). Comparing artemisinin (1) to deoxyartemisinin (2), the endoperoxide group appeared to play a role in cytotoxicity to CFU-GM cells. Dimers of dihydroartemisinin and dihydrodeoxyartemisinin revealed that the stereochemistry of the ether linkage of the dimers was a more important determinant for this cytotoxic activity. The nonsymmetrical dimer of dihydroartemisinin (3) and the corresponding endoperoxide-lacking dimer of dihydrodeoxyartemisinin (5) were equally cytotoxic to CFU-GM cells. Despite the differences between both systems, it may be stated that most compounds displayed higher cytotoxicity to CFU-GM cells than to EAT cells. Dimers of dihydroartemisinin (3, 4) were selected as potential antitumour compounds and subjected to the National Cancer Institute drug-screening programme consisting of about sixty human cancer cell lines derived from nine different tissues. Both compounds displayed the same specific cytotoxicity pattern. Throughout the screen dimer 3 was more active than 4.

Awt Konings

Papers

Early to late sparing of radiation damage to the parotid gland by adrenergic and muscarinic receptor agonists

Protection of liposomal lipids against radiation induced oxidative damage.

Cells Overexpressing Hsp27 Show Accelerated Recovery from Heat-Induced Nuclear-Protein Aggregation

Reduction of cellular cisplatin resistance by hyperthermia—a review

Artemisinin-derived sesquiterpene lactones as potential antitumour compounds: cytotoxic action against bone marrow and tumour cells.