Functional characterization of nutraceuticals using spectral clustering: Centrality of caveolae-mediated endocytosis for management of nitric oxide and vitamin D deficiencies and atherosclerosis.

It is well recognized that redox imbalance, nitric oxide (NO), and vitamin D deficiencies increase risk of cardiovascular, metabolic, and infectious diseases. However, clinical studies assessing efficacy of NO and vitamin D supplementation have failed to produce unambiguous efficacy outcomes suggesting that the understanding of the pharmacologies involved is incomplete. This raises the need for using systems pharmacology tools to better understand cause-effect relationships at biological systems levels. We describe the use of spectral clustering methodology to analyze protein network interactions affected by a complex nutraceutical, Cardio Miracle (CM), that contains arginine, citrulline, vitamin D, and antioxidants. This examination revealed that interactions between protein networks affected by these substances modulate functions of a network of protein complexes regulating caveolae-mediated endocytosis (CME), TGF beta activity, vitamin D efficacy and host defense systems. Identification of this regulatory scheme and the working of embedded reciprocal feedback loops has significant implications for treatment of vitamin D deficiencies, atherosclerosis, metabolic and infectious diseases such as COVID-19.