Nicola Gaetano Gatta

Curcumin (Diferulolylmethane) Reduces Transglutaminase 2 Overexpression Induced by Retinoic Acid in Human Nervous Cell Lines.

Objectives: Curcumin, a naturally occurring compound derived from turmeric (Curcuma longa) has long been suggested to have strong therapeutic or preventive potential against human diseases because of its antioxidative, anticancerous, and anti-inflammatory effects. Curcumin is known to exert anti-inflammatory effects by interrupting NF-κB signaling at multiple levels. Many observations indicate that curcumin shows its valuable potential by inhibiting the activity of I-κB kinase. Transglutaminase 2 (TG2) expression is increased in inflammatory diseases. Data in the literature suggest that this enzyme activates the proinflammatory transcriptional factor NF-κB by inducing the polymerization of its inhibitory subunit I-κBα, which in turn results in the dissociation of NF-κB and its translocation to the nucleus, where it is capable of upregulating host inflammatory genes. Interestingly, NF-κB regulatory response elements are also present in the TG2 promoter, suggesting a possible role for this pathway in the mechanism responsible for chronic inflammation. On the basis of these literature data, our objective was to analyze the effects of curcumin on TG2 expression in human nervous cell lines. Methods: Human nervous cell lines were treated with curcumin alone or in association with retinoic acid in order to induce TG2 overexpression. TG2 levels were analyzed by Western blot and real-time PCR analyses. Results: Curcumin was able to downregulate the expression of TG2 in human nervous cell lines, which was also the case after treatment with retinoic acid. Conclusions: These results suggest a possible use of curcumin in reducing TG2 overexpression in human nervous cells.

Possible roles of transglutaminases in molecular mechanisms responsible for cancer and human neurodegenerative diseases

Transglutaminases are a family of Ca2+- dependent enzymes which catalyze posttranslational modifications of proteins. The main activity of these enzymes is the crosslinking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted/ crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for either physiological or pathological processes. In particular, transglutaminase activity has been shown to be responsible for human autoimmune diseases and Celiac Disease is just one of them. Interestingly, cancer and neurodegenerative diseases, such as Alzheimer’s Disease, Parkinson’s Disease, supranuclear palsy and Huntington’s Disease, are characterized in part by aberrant transglutaminase activity and by increased cross-linked proteins in affected tissues. This review describes the possible molecular mechanisms by which these enzymes could be responsible for such diseases and the possible use of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.

Transglutaminase inhibition: possible therapeutic mechanisms to protect cells from death in neurological disorders

Transglutaminases are Ca2+-dependent enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted/crosslinked adducts) or –OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological or pathological processes. In particular, transglutaminase activity has been shown to be responsible for human autoimmune diseases, and Celiac Disease is just one of them. Interestingly, neurodegenerative diseases, such as Alzheimer’s Disease, Parkinson’s Disease, supranuclear palsy, Huntington’s Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. Here we describe the possible molecular mechanisms by which these enzymes could be responsible for such diseases and the possible use of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.

Dr. James Matthew Lipton, 1938-2016

Dr. Jim Lipton died on the 10th of July this year. It was a great loss not only to his family and friends but also to the scientific world. The facts and dates of his life are well expressed in the obituary written by his daughter reprinted above, with permission. Many years ago, when Jim and his buddy, S.M. ‘Don’ McCann were both Professors of Physiology in Dallas, they suggested we start a new NIM journal. I was opposed to the idea, because there were already too many journals proliferating at a dizzying pace. The success of the ISNIM journal proved that they were right and I was wrong. One could not imagine two more disparate personalities, but they always managed to work together harmoniously. Both were geniuses, Jim soft-spoken and modest ... and Don, with an amazing photographic memory, boisterous (Don was first my professor at the University of Pennsylvania, and later, my student and honorary lecturer and awardee of the Novera Spector lectureship). A book needs to be written about Don, but most observers agree that he should have shared at least one Nobel Prize. Both remained my good friends all their lives. At one point I went to an international congress organized by Jim, only to find that he had dedicated this meeting to me! I hope that his friends and especially his wife, Luby, will I have been asked to write an obituary-memoriam for the cofounder of Neuroimmunomodulation (NIM) , who died on the 10th of July this year. Below is an obituary written by Jim’s daughter and reprinted with her permission, followed by some informal remembrances from Luby, his widow, and me.