Vitamin K2 (MK-7) Intercepts Keap-1/Nrf-2/HO-1 Pathway and Hinders Inflammatory/Apoptotic Signaling and Liver Aging in Naturally Aging Rat

Abstract

Aging is a naturally occurring physiological process with a deleterious impact on various body organs and humans’ well-being. The aging population is increasing worldwide, which imposes the need for the exploration of nutritional options that can intercept the impact of the aging processed on various body organs. Vitamin K2 (VK2) is a fat-soluble vitamin with emerging evidence on its therapeutic merits. In the current study, natural aging induced a significant liver deterioration with a disrupted Keap-1/Nrf-2/HO-1 axis and increased COX-2, iNOS and TNF-α expression and apoptotic and fibrotic changes. VK2 administration, on the other hand, improved the biochemical indices of liver function (total protein, albumin, ALT and AST); the suppressed hepatic expression of Keap-1 and increased the hepatic expression of Nrf-2 with a parallel increase in the hepatic activity of HO-1. Subsequently, the liver content and hepatic expression of TNF-α, COX-2 and iNOS were significantly retracted. In context, the liver content and hepatic expression of the fibrotic biomarkers TGFβ and TIMP significantly retracted as well. Moreover, the TUNEL assay confirmed the retraction of liver apoptotic changes. Of notice, electron transmission microscope examination confirmed the preservation of mitochondrial functions and preservation of the ultra-microscopical structures. In conclusion, the VK2-mediated interception of aging-induced Keap-1/Nrf-2/HO-1 signaling suppressed the hepatic contents of inflammatory and fibrotic biomarkers, as well as apoptotic changes with preservation of the hepatic architectural and functional status. VK2 can be presumed to be an effective nutritional supplement to the aging population to spare the liver, amongst other body organs, against aging-induced deleterious injury.

Links between Vitamin K, Ferroptosis and SARS-CoV-2 Infection

“…The Nrf2 pathway is a cellular defense mechanism that helps protect cells from oxidative stress by upregulating the expression of genes involved in antioxidant defense and detoxification. Vitamin K 2 has been shown to activate this pathway, leading to increased expression of antioxidant enzymes, including glutathione peroxidase [ 130 , 131 , 132 ]. Given the potential role of ferroptosis in COVID-19 pathogenesis and the possible link between vitamin K and ferroptosis, there is interest in exploring the potential therapeutic benefits of vitamin K in COVID-19.…”

NAMPT‑NAD+ is involved in the senescence‑delaying effects of saffron in aging mice

“…Several prior studies have reported that the morphology of the liver ( 26 ), kidneys ( 27 ) and skin ( 28 ) all change with aging, including the development of pycnotic nuclei in the liver, thinner dermal collagen fibers, lower infiltration of inflammatory cytokines in the skin, and less hemorrhaging and ballooning in the kidneys. In the present study, the senescence-delaying effects of saffron were also indicated by amelioration of the pathophysiological changes in the liver, skin and kidneys.…”

Vitamin K2 (MK-7) attenuates LPS-induced acute lung injury via inhibiting inflammation, apoptosis, and ferroptosis

“…Based on our experiment, VK2 could improve LPS-induced ALI. We determined the VK2 intervention dose for this experiment based on previous studies [18,19,25] and on the range of recommended VK2 intakes in each country [26,27].…”

“…The results of this study indicated that VK2 exerted its protective effect on ALI through the upregulation of Bcl-2 and downregulation of Caspase-3 in LPS-induced ALI. Indeed, VK2 administration has been reported to exert anti-apoptotic and anti-inflammatory effects [18,42]. Furthermore, P38 MAPK pathway has been evidenced to mediate apoptosis [43].…”

“…VK2, essential for human metabolism and health is predominantly present in cheese and fermented soybeans (natto) [16]. In recent years, VK2 has become a research hotspot for scientists due to its multiple pharmacological activities, including anti-inflammatory, anti-oxidant, anti-apoptosis, and anti-ferroptosis [17][18][19]. However, whether VK2 has a beneficial effect on LPS-induced ALI has not been investigated.…”