TRAF6

Aging and related diseases are associated with alterations in oxidative status and low-grade inflammation, as well as a decreased endoplasmic reticulum (ER) unfolded protein response (UPR). UPR is a functional mechanism by which cells attempt to protect themselves against ER stress. Researchers analyzed these proteins in peripheral blood mononuclear cells of elderly subjects and used computer simulation to predict the key proteins associated with these biomolecules underlying physiological adaptations to exercise. They collected blood samples about five to six days before and after the training period and analyzed various oxidative stress biomarkers in peripheral blood mononuclear cells. The study takes research one step further in helping to elucidate the benefits of exercise in this population. Aging involves a balance between oxidants and antioxidants, low-grade inflammation and a protein response that occurs at the cellular level, which is responsible for many health disorders. Exercise has been shown to regulate the inflammatory response, balance oxidants such as free radicals that build up in the cells and damage DNA; and ameliorate the process by which cells protect themselves against these stressors. Furthermore, resistance training in older adults is recommended to help maintain muscle, flexibility and balance. Aging and related diseases are associated with alterations in oxidative status and low-grade inflammation, as well as a decreased endoplasmic reticulum (ER) unfolded protein response (UPR). UPR is a functional mechanism by which cells attempt to protect themselves against ER stress, resulting from the accumulation of the unfolded/misfolded proteins. One group of proteins associated with the aging process is the mitochondrial heat shock protein 60 (HSP60), which has been demonstrated to play a protective role in the ability for cells to remain active and healthy. Currently, there is limited research investigating the effects of resistance training in older adults on the expression of HSP60 and Klotho, a gene involved in the aging process in mammals. A new study by researchers at Florida Atlantic University, in collaboration with the University of León in Spain, examined whether an eight-week resistance training program would modulate the oxidative status, the UPR activation and key inflammatory pathways as well as their relationships with HSP60 and Klotho proteins. For the study, researchers analyzed these proteins in peripheral blood mononuclear cells of elderly subjects. In addition, they utilized computer simulation to predict the key proteins associated with these biomolecules underlying physiological adaptations to exercise. They collected blood samples approximately five to six days before and after the training period and just before training intervention in young subjects who were included for basal assessments. Researchers also analyzed various oxidative stress biomarkers in peripheral blood mononuclear cells. Results of the study, published in the journal Antioxidants, demonstrated that the levels of the inflammatory proteins (pIRAK1, TLR4, and TRAF6), as well as different markers of the redox balance (catalase, GSH, LP, NRF2, PC, ROS, SOD1, and SOD2) remained unchanged with training. Importantly, untrained elderly subjects showed a significant reduction in pIRE1/IRE1 ratio when compared to trained elderly subjects. Such a finding was further confirmed by a gene ontology analysis, showing that endoplasmic reticulum stress is a key mechanism modulated by IRE1. Additionally, analysis did not show the training effect on the expression of HSP60 and Klotho or their relationships with other outcome variables. Although elderly male and female subjects were included in the training program, researchers did not find any sex effects in the study. These findings might partially support the modulatory effect of resistance training on the endoplasmic reticulum in the elderly. "Regular physical activity is suggested to be an effective intervention in improving age-related diseases such as osteoporosis, sarcopenia or muscle loss and dynapenia or loss of muscle strength, cardiovascular diseases, and type 2 diabetes," said Chun-Jung "Phil" Huang, Ph.D., co-author and a professor in the Department of Exercise Science and Health Promotion within FAU's Charles E. Schmidt College of Science. "Although the beneficial effects of regular physical exercise to alleviate inflammation and oxidative stress are well-established, the processes of these physiological adaptations with regard to protein folding or UPR remains to be explored. That is why we used a systems biology approach for our study." The resistance training protocol for the study consisted of 16 sessions over eight weeks (two sessions per week), with a minimum of 48 hours between sessions. The participants started with a 10-minute warm-up on a cycle ergometer. Subsequently, eight different resistance exercises (leg press, ankle extension, bench press, leg extension, bicep curl, pec deck, high pulley traction, and dumbbell lateral lift) were performed using the exercise device. For each exercise, participants performed three sets of 12-8-12 repetitions. There was a two-to-three-minute rest between each repetition and a three-minute rest between each exercise. "We know how very important physical activity is for older adults and our study takes research one step further in helping to elucidate the benefits of exercise in this population," said Huang. Study co-authors are senior author Brisamar Estébanez, Ph.D.; Marta Rivera-Viloria; and José A. de Paz, M.D., all with the University of León; José E. Vargas, Ph.D., Universidad Federal do Paraná, Curtiba; and Nishant P. Visavadiay, Ph.D.; and Andy V. Kahmoui, Ph.D., both with FAU's Department of Exercise Science and Health Promotion.

Prostate cancer is a common form of cancer. Researchers have now discovered a faster and easier way to determine who has an aggressive form of cancer, and who has not. Prostate cancer is the most common form of cancer in male in Sweden. Researchers at Umeå University in Sweden have now discovered a faster and easier way to determine who has an aggressive form of cancer, and who has not. "This may have great implications on precision medicine when treating prostate cancer, and on more cancer groups alike," says Maréne Landström, Professor of Pathology at Umeå University. Over 10,000 men are annually diagnosed with prostate cancer in Sweden. Out of those, 2,300 of these lives cannot be saved, whereas many others can be cured or actually carry harmless tumours. The medical services are struggling with a balancing act between detecting as many cancers as possible in good time to start treatments early, and avoiding to diagnose men with cancer when the tumour is harmless as this causes unnecessary anxiety and negatively impacts the quality of life. Consequently, intense work is carried out at research institutes to improve the methods distinguishing cancers that require treatment from cancers that should be left untouched, or preferably should not even be detected. The research group of Professor Maréne Landström at the Department of Medical Biosciences is busy studying just that. In this project, they have also collaborated with a research group at Uppsala University. The Umeå researchers have now discovered a new function in specific proteins in the transforming growth factor beta (TGF-β) signalling pathway, which is a significant path that affects how cancer cells grow and spread. This may have huge implications on the treatment of cancer since the discovery makes it possible to identify the men who are at risk of developing aggressive and life-threatening prostate cancer more easily, faster and early in the course of disease. "We have found a new, previously unknown, function of the TGF-β type I receptor (TbRI), which is an important signalling protein in cancer cells. Previous studies have shown that TGF-β signalling is important in the development of several cancer forms," says Maréne Landström, Professor of Pathology at the Department of Medical Biosciences at Umeå University, continuing: "But with the use of this new discovery, we can put the men with prostate cancer whose prognosis is promising at ease, and those with high-risk prostate cancer can be offered treatment sooner. Our findings and the publication is significant for a large group of patients with prostate cancer, and there is reason to believe that further patient groups will benefit from this. Jie Song, first author of the publication in EBioMedicine is tremendously pleased: "Our discovery is a breakthrough in cancer research in the field of TGF-β signalling," she says whilst explaining the finding in more detail: "We have discovered that AURKB, which is a kinase usually overexpressed in cancer cells, interacts with TβRI during cell division of both prostate cancer cells and neuroblastoma cells, which is a form of cancer common in children. We have also shown that TRAF6 -- an enzyme which causes so-called K63-linked polyubiquitination -- ubiquitinates AURKB on two amino acids and thereby contributes to the kinase activity of AURKB when cancer cells proliferate. By in situ PLA technique, we show that K63-linked polyubiquitination of AURKB is present in lung adenocarcinoma, prostate cancer and clear cell renal cell carcinoma in patient tissue sections. Moreover, the AURKB-TβRI complex is correlated with the malignancy of prostate cancer. Our results suggest that the AURKB-TβRI complex may be a useful biomarker for early detection of advanced prostate cancer, which may be of huge clinical benefit in the development of precision drugs for treating prostate cancer," she says. This finding is so unique that the researchers have applied for a patent through the pharmaceutical development company, MetaCurUm Biotech AB, as well as recruited further members to the research group. "We wish to really reach out with these news to the medical services as we think it can be of great use to patients with cancer, and to the medical services in general," says Maréne Landström. "We will apply for funding from innovation agencies such as Vinnova and others to develop a method that the medical services can use. We estimate that it will take us two to three years to develop a test based on our findings," says Maréne Landström. What happens next? "We are now investigating the molecular mechanisms for how these proteins can affect the activity of one another. This takes place in a research project in collaboration with Professor Magnus Wolf-Watz at the Department of Chemistry at Umeå University, and through studies of clinical samples from patients together with our clinical partners from the medical service.