The current COVID-19 pandemic is one of the most devastating events in recent history. The virus causes relatively minor damage to young, healthy populations, imposing life-threatening danger to the elderly and people with diseases of chronic inflammation. Therefore, if we could reduce the risk for vulnerable populations, it would make the COVID-19 pandemic more similar to other typical outbreaks. Children don't suffer from COVID-19 as much as their grandparents and have a much higher melatonin level. Bats are nocturnal animals possessing high levels of melatonin, which may contribute to their high anti-viral resistance. Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. The programmed cell death coronaviruses cause, which can result in significant lung damage, is also inhibited by melatonin. Coronavirus causes inflammation in the lungs which requires inflammasome activity. Melatonin blocks these inflammasomes. General immunity is impaired by anxiety and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks due to oxidative stress, which can be reduced by melatonin. Thus, by using the safe over-the-counter drug melatonin, we may be immediately able to prevent the development of severe disease symptoms in coronavirus patients, reduce the severity of their symptoms, and/or reduce the immuno-pathology of coronavirus infection on patients' health after the active phase of the infection is over. ARTICLE HISTORY

Recent studies highlighted the role of autophagy as a cardinal regulatory system for homeostasis and cancer-related signalling pathways. In this context, the deregulated expression of p62 -Sequestosome1 (p62/SQSTM1)a protein acting both as an autophagy receptor and signalling hub, has been associated with tumour development and chronic inflammation. Multiple clinical studies test drugs targeting autophagy, and even more research is on the way to clinical trials. However, no comparative investigations have been carried out to identify adequate preclinical models to assess p62-based medicine. In veterinary oncology the role of p62 in cancerrelated pathways has been largely ignored. We compared p62 sequences in multiple organisms and found that canine p62 significantly diverges from the humans and from other animals sequences. Then, we chart by immunohistochemistry the expression levels of p62 in canine mammary tumours. A total of 66 tumours and 10 nonneoplastic mammary samples were examined. The expression of p62 was higher in normal tissue and adenomas than carcinomas, with lowest levels of p62 protein detected in high grade carcinomas. In all cases examined the tumour stroma appeared to be p62-negative. Taken together our results would suggest that in dogs the association between p62 expression and cancer cells overturns that reported in human breast carcinoma, where p62 accumulates in malignant cells as compared to normal epithelium. Thus, at least in canine mammary tumours, p62 should be not considered a tumour-rejection antigen for an anti-cancer immunotherapy. K E Y W O R D Sautophagy, dog, gene homology, immunohistochemistry, mammary tumours, p62/SQSTM1

Previously, we reported that the administration of a p62/SQSTM1-encoding plasmid demonstrates high safety and clinical benefits for human cancer patients, having also suppressed tumor growth and metastasis in dogs and mouse models. Here we investigated the mechanistic aspects of these effects. In mammary tumors bearing-dogs, p62 plasmid i.m. injections reduced tumor volumes, and reverted tumor grade to less aggressive lesions in 5 out of 6 animals, with one carcinoma switching to benign adenoma. The treatment increased levels of alpha-SMA in stroma cells and collagen 3 in the extracellular matrix, both of which correlate with a good clinical prognosis. p62 treatment also increased the abundance of intratumoral T-cell. To test the role of adaptive immunity, we compared protective effects of the plasmid against B16 melanoma in wild type C57BL/6J mice and in the corresponding SCID strain lacking lymphocytes. The plasmid was only protective in the wild type strain. Also, p62 plasmid amplified anti-tumor effect of adoptive T-cell transfer from tumor-bearing animals to animals challenged with the same tumors. We conclude that the plasmid acts indirectly via re-modeling of the tumor microenvironment, making it more favorable for increased anti-cancer immunity. Thus, the p62-encoding plasmid might be a new adjuvant for cancer treatments.