Untargeted Metabolomics Based Prediction of Therapeutic Potential for Apigenin and Chrysin.

The prominent flavonoids apigenin and chrysin have been demonstrated to have systemic benefits. Our previous work was first to establish the impact of apigenin and chrysin on cellular transcriptome. In the current study, we have revealed the ability of apigenin and chrysin to alter the cellular metabolome based on our untargeted metabolomics. Based on our metabolomics data, both these structurally related flavonoids demonstrate diverging and converging properties. Apigenin demonstrated the potential to possess anti-inflammatory and vasorelaxant properties through the upregulation of intermediate metabolites of alpha-linolenic acid and linoleic acid pathways. Chrysin, on the other hand, exhibited abilities to inhibit protein and pyrimidine synthesis along with downregulation of gluconeogenesis pathways based on the altered metabolites detected. Chrysin-mediated metabolite changes are mostly due to its ability to modulate L-alanine metabolism and the urea cycle. On the other hand, both the flavonoids also demonstrated converging properties. Apigenin and chrysin were able to downregulate metabolites involved in cholesterol biosynthesis and uric acid synthesis, namely 7-dehydrocholesterol and xanthosine, respectively. This work will provide understanding regarding the diverse therapeutic potential of these naturally occurring flavonoids and help us in curbing an array of metabolic complications.

Impact of Glucocorticoids on Cardiovascular System-The Yin Yang Effect.

Glucocorticoids are not only endogenous hormones but are also administered exogenously as an anti-inflammatory and immunosuppressant for their long-term beneficial and lifesaving effects. Because of their potent anti-inflammatory property and ability to curb the cytokines, they are administered as lifesaving steroids. This property is not only made use of in the cardiovascular system but also in other major organ systems and networks. There is a fine line between their use as a protective anti-inflammatory and a steroid that could cause overuse-induced complications in major organ systems including the cardiovascular system. Studies conducted in the cardiovascular system demonstrate that glucocorticoids are required for growth and development and also for offering protection against inflammatory signals. Excess or long-term glucocorticoid administration could alter cardiac metabolism and health. The endogenous dysregulated state due to excess endogenous glucocorticoid release from the adrenals as seen with Cushing's syndrome or excess exogenous glucocorticoid administration leading to Cushing's-like condition show a similar impact on the cardiovascular system. This review highlights the importance of maintaining a glucocorticoid balance whether it is endogenous and exogenous in regulating cardiovascular health.

Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function.

Impairments in macroautophagy/autophagy, which degrades dysfunctional organelles as well as long-lived and aggregate proteins, are associated with several cardiomyopathies; however, the regulation of cardiac autophagy remains insufficiently understood. In this regard, ULK1 and ULK2 are thought to play primarily redundant roles in autophagy initiation, but whether their function is developmentally determined, potentially having an impact on cardiac integrity and function remains unknown. Here, we demonstrate that perinatal loss of ULK1 or ULK2 in cardiomyocytes (cU1-KO and cU2-KO mice, respectively) enhances basal autophagy without altering autophagy machinery content while preserving cardiac function. This increased basal autophagy is dependent on the remaining ULK protein given that perinatal loss of both ULK1 and ULK2 in cU1/2-DKO mice impaired autophagy causing age-related cardiomyopathy and reduced survival. Conversely, adult loss of cardiac ULK1, but not of ULK2 (i.e., icU1-KO and icU2-KO mice, respectively), led to a rapidly developing cardiomyopathy, heart failure and early death. icU1-KO mice had impaired autophagy with robust deficits in mitochondrial respiration and ATP synthesis. Trehalose ameliorated autophagy impairments in icU1-KO hearts but did not delay cardiac dysfunction suggesting that ULK1 plays other critical, autophagy-independent, functions in the adult heart. Collectively, these results indicate that cardiac ULK1 and ULK2 are functionally redundant in the developing heart, while ULK1 assumes a more unique, prominent role in the adult heart.Abbreviations: ATG4: autophagy related 4, cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9: autophagy related 9; ATG13: autophagy related 13; CYCS: Cytochrome C; DNM1L, dynamin 1-like; MAP1LC3A: microtubule-associated protein 1 light chain 3 alpha; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MFN1: mitofusin 1; MFN2: mitofusin 2; MT-CO1: mitochondrially encoded cytochrome c oxidase I; MYH: myosin, heavy polypeptide; NBR1: NBR1 autophagy cargo receptor; NDUFA9: NADH:ubiquinone oxidoreductase subunit A9; OPA1: OPA1, mitochondrial dynamin like GTPase; PPARGC1A, peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; SDHA: succinate dehydrogenase complex, subunit A, flavoprotein (Fp); SQSTM1: sequestosome 1; ULK1: unc-51 like kinase 1; ULK2: unc-51 like kinase 2; UQCRC1: ubiquinol-cytochrome c reductase core protein 1.