The rapid development of such research field as multi-omics and artificial intelligence (AI) has made it possible to acquire and analyze the multi-dimensional big data of human phenomes. Increasing evidence has indicated that phenomics can provide a revolutionary strategy and approach for discovering new risk factors, diagnostic biomarkers and precision therapies of diseases, which holds profound advantages over conventional approaches for realizing precision medicine: first, the big data of patients' phenomes can provide remarkably richer information than that of the genomes; second, phenomic studies on diseases may expose the correlations among cross-scale and multi-dimensional phenomic parameters as well as the mechanisms underlying the correlations; and third, phenomics-based studies are big data-driven studies, which can significantly enhance the possibility and efficiency for generating novel discoveries. However, phenomic studies on human diseases are still in early developmental stage, which are facing multiple major challenges and tasks: first, there is significant deficiency in analytical and modeling approaches for analyzing the multi-dimensional data of human phenomes; second, it is crucial to establish universal standards for acquirement and management of phenomic data of patients; third, new methods and devices for acquirement of phenomic data of patients under clinical settings should be developed; fourth, it is of significance to establish the regulatory and ethical guidelines for phenomic studies on diseases; and fifth, it is important to develop effective international cooperation. It is expected that phenomic studies on diseases would profoundly and comprehensively enhance our capacity in prevention, diagnosis and treatment of diseases.

Significance: Increasing evidence has indicated critical roles of NAD+ in various biological functions. NAD+ deficiency has been found in models of a number of diseases such as cerebral ischemia, myocardial ischemia and diabetes, and in models of aging. Application of NAD+ or other approaches that can restore NAD+ levels are highly protective in these models of diseases and aging. NAD+ produces its beneficial effects by targeting at multiple pathological pathways, including attenuating mitochondrial alterations, DNA damage and oxidative stress by modulating such enzymes as sirtuins, glyceraldehyde-3-phosphate dehydrogenase and AP endonuclease. These findings have suggested great therapeutic and nutritional potential of NAD+ for diseases and senescence. Recent advances: Approaches that can restore NAD+ levels are highly protective in the models of such diseases as glaucoma. The NAD+ deficiency in the diseases and aging results from not only poly(ADP-ribose) polymerase-1 (PARP-1) activation, but also decreased Nicotinamide phosphoribosyltransferase (Nampt) activity and increased CD38 activity. Significant biological effects of extracellular NAD+ have been found. Increasing evidence has suggested that NAD+ deficiency is a common central pathological factor in a number of diseases and aging. Critical Issues and Future Directions: Future studies are required for solidly establishing the concept that ‘NAD+ deficiency is a common central pathological factor in a number of disease and aging’. It is also necessary to further investigate the mechanisms underlying the NAD+ deficiency in the diseases and aging. Preclinical and clinical studies should be conducted to determine the therapeutic potential of NAD+ for the diseases and aging.

Numerous studies have indicated oxidative stress as a key pathological factor in ischemic brain injury. One of the key links between oxidative stress and cell death is excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), which plays an important role in the ischemic brain damage in male animals. Multiple studies have also suggested that NAD+ depletion mediates PARP-1 cytotoxicity, and NAD+ administration can decrease ischemic brain injury. A number of recent studies have provided novel information regarding the mechanisms underlying the roles of oxidative stress and NAD+-dependent enzymes in ischemic brain injury. Of particular interest, there have been exciting progresses regarding the mechanisms underlying the roles of NADPH oxidase and PARP-1 in cerebral ischemia. For examples, it has been suggested that androgen signaling and binding of PARP-1 onto estrogen receptors could account for the intriguing findings that PARP-1 plays remarkably differential roles in the ischemic brain damage of male and female animals; and some studies have suggested casein kinase 2, copper-zinc superoxide dismutase, and estrogen signaling can modulate the expression and activity of NADPH oxidase. This review summarizes these important current advances, and proposes future perspectives for the studies on the roles of oxidative stress and NAD+ in cerebral ischemia. It is increasingly likely that future studies on NAD- and NADP-dependent enzymes, such as NADPH oxidase, PARP-1, and sirtuins, would expose novel mechanisms underlying the roles of oxidative stress in cerebral ischemia, and suggest new therapeutic strategies for treating the debilitating disease.