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Melatonin is a key intracellular neuroimmune-endocrine regulator and coordinator of multiple complex and interrelated biological processes. The main functions of melatonin include the regulation of neuroendocrine and antioxidant system activity, blood pressure, rhythms of the sleep-wake cycle, the retardation of ageing processes, as well as reseting and optimizing mitochondria and thereby the cells of the immune system. Melatonin and its agonists have therefore been mooted as a treatment option across a wide array of medical disorders. This article reviews the role of melatonin in the regulation of respiratory system functions under normal and pathological conditions. Melatonin can normalize the structural and functional organization of damaged lung tissues, by a number of mechanisms, including the regulation of signaling molecules, oxidant status, lipid raft function, optimized mitochondrial function and reseting of the immune response over the circadian rhythm. Consequently, melatonin has potential clinical utility for bronchial asthma, chronic obstructive pulmonary disease, lung cancer, lung vascular diseases, as well as pulmonary and viral infections. The integration of melatonin's effects with the alpha 7 nicotinic receptor and the aryl hydrocarbon receptor in the regulation of mitochondrial function are proposed as a wider framework for understanding the role of melatonin across a wide array of diverse pulmonary disorders.

An endogenous molecular clockwork drives various cellular pathways including metabolism and the cell cycle. Its dysregulation is able to prompt pathological phenotypes including cancer. Besides dramatic metabolic alterations, cancer cells display severe changes in the clock phenotype with likely consequences in tumor progression and treatment response. In this study, we use a comprehensive systems-driven approach to investigate the effect of clock disruption on metabolic pathways and its impact on drug response in a cellular model of colon cancer progression. We identified distinctive time-related transcriptomic and metabolic features of a primary tumor and its metastatic counterpart. A mapping of the expression data to a comprehensive genome-scale reconstruction of human metabolism allowed for the in-depth functional characterization of 24 h-oscillating transcripts and pointed to a clock-driven metabolic reprogramming in tumorigenesis. In particular, we identified a set of five clock–regulated glycolysis genes, ALDH3A2, ALDOC, HKDC1, PCK2, and PDHB with differential temporal expression patterns. These findings were validated in organoids and in primary fibroblasts isolated from normal colon and colon adenocarcinoma from the same patient. We further identified a reciprocal connection of HKDC1 to the clock in the primary tumor, which is lost in the metastatic cells. Interestingly, a disruption of the core-clock gene BMAL1 impacts on HKDC1 and leads to a time-dependent rewiring of metabolism, namely an increase in glycolytic activity, as well as changes in treatment response. This work provides novel evidence regarding the complex interplay between the circadian clock and metabolic alterations in carcinogenesis and identifies new connections between both systems with pivotal roles in cancer progression and response to therapy. Keywords: Circadian clock, Colorectal cancer, Metabolic rewiring, Tumor progression, High-throughput circadian data, Metabolic network reconstruction, Circadian regulation of metabolism, Treatment response, Glycolysis