Research Focus

Aging is a process accompanied by cellular redox dysregulation and impaired metabolic adaptation to oxidative factors. Redox biochemistry influences many of the cellular signaling processes, and we know that the pathogenesis of aging and age-related diseases is accompanied by changes in redox-active signaling pathways. Apparently, the adaptation to the increased oxidant or reductant status is important to cell survival and the cellular redox homeostasis is essential to maintain a normal long life.

Life requires oxygen. This runs the risk of reactive oxygen species (ROS) forming when oxygen leaks from normal metabolism, which – when too high – triggers disease. Protein oxidative modifications, also known as protein oxidation, result from reactions between protein amino acid residues and reactive oxygen species (ROS) or reactive nitrogen species (RNS). Increased protein oxidation has been associated with functional decline of target proteins, which are generally thought to contribute to normal aging and age-related pathogenesis.

Proteins can be modified by lipids as well as carbohydrates. Glyco-oxidation is a term used for glycation processes involving oxidation, and advanced glyco-oxidation end products (AGEs)  accumulate in tissue where they cross-link with proteins.They may also interact with receptor of AGE (RAGE) and other receptors, which lead to activation of intracellular transduction mechanisms resulting in cytokine release and further tissue damage in many diseases. During oxidative stress, reactive oxygen species also attack to polyunsaturated fatty acids (PUFAs) either in the cell membrane or circulating lipoprotein molecules. This oxidative decomposition of PUFAs initiates chain reactions that lead to the formation of a variety of reactive carbonyl species. Among them is 4-hydroxy-trans-2-nonenal (4-HNE), which is subsequently react by the so-called Michael addition mechanism with cysteine, histidine and lysine residues in proteins, generating relatively stable adducts known as advanced lipid peroxidation end products (advanced lipo-oxidation end products ALEs). Reactive carbonyl compounds (RCCs) may induce “carbonyl stress” characterized by the increased formation of adducts and cross-links on proteins. The growing number of evidence have demonstrated that carbonyl stress associates the promotion of cytotoxic events such as cell growth arrest, mitochondrial dysfunction, early apoptosis, and necrosis by modifying cellular proteins, contributing to the dysfunction and damages in tissues and to the induction and/or progression of age-related diseases such as diabetes mellitus (DM).

In studies conducted under the “Antioxidants, Diabetes-Related Complications (ADIC) Study Group”, we have shown that the treatment of diabetes with certain vitamins, essential fatty acids, natural polyphenolic compounds as cellular redox regulators and carbonyl modifiers, can prevent or restore abnormal tissue biochemistry and functions, maintain physiological survival signal, and inhibit accelerated cell death due to enhanced protein oxidation.

The chronic hyperglycemic condition accounts for most of the complications associated with DM, and the prevalent mechanism proposed is related with the activated polyol pathway and the glyco-oxidation and lipo-oxidation process. Under hyperglycemic conditions, aldose reductase (AR) reduces glucose to sorbitol and fructose by using NADPH as a cofactor, then inducing the oxidative and carbonyl stresses.

Although the neurotoxic mechanisms underlying Alzheimer's disease (AD) have yet to be fully elucidated, hyperglycemia seems to trigger oxidative and inflammatory responses in the brain of afflicted patients. Removal of advanced glyco-lipo-oxidation may reduce the neurotoxic effects of hyperglycemia in AD modelsWe are dealing with the effects of phytochemicals and secondary metabolites, redox active natural substances, some antioxidants and newly synthesized aldose reductase inhibitors that can interact with the endocannabinoid system in neurodegeneration disease models.

The Cellular Stress Response and Signal Transduction Research Laboratory explores the molecular mechanisms that regulate hippocampal identity and function. We are interested in transcriptional control over the differentiation and maturation of hippocampal neurons and regulation of thalamic axon growth and guidance to the cerebral cortex. We work with primary neuron cultures, organotypic cultures and in vivo models. We use a variety of molecular biology, biochemistry, pharmacology and cell biology techniques.

One of our subgroups is to conduct studies at the molecular level in the pathogenesis of osteoarthritis, which is characterized by cartilage damage related to aging and redox active inflammatory mechanisms. We are investigating the effects of potential therapeutics in chondrocytes and synoviocytes isolated from patients with osteoarthritis.

On the other hand, the main purpose of the NutRedOx network we are involved in is to conduct new generation multidisciplinary research in the field of biological redox active food ingredients, to raise awareness about redox regulators in the prevention and treatment of age-related diseases, and to establish relationships with the industry to develop nutraceuticals and drugs that extend life span.