Vitamin K2 Modulates Organelle Damage and Tauopathy Induced by Streptozotocin and Menadione in SH-SY5Y Cells

Shandilya, Shruti; Kesari, Kavindra Kumar; Ruokolainen, Janne

doi:10.3390/antiox10060983

Cited by 7 publications

(5 citation statements)

References 69 publications

(90 reference statements)

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“…Vitamin K2 (VK2) is commonly produced by gut bacteria and is fat-soluble, allowing it to be easily transferred into the host intestinal cells (14). Recently, in vitro studies have shown that VK2 has potential beneficial effects on chronic aging diseases, such as cardiovascular disease (15), Alzheimer's disease (16,17), cancer (18), osteoporosis (19,20), and Parkinson's disease (21). VK2 has also been supplied to patients with diabetes and obesity to evaluate its pharmacological activity (22), and the association between VK2 and T2DM, obesity, and fat mass are becoming more clear (23,24).…”

Section: Introductionmentioning

confidence: 99%

Vitamin K2 Enhances Fat Degradation to Improve the Survival of C. elegans

Zhang

Huang

et al. 2022

Front. Nutr.

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The beneficial effects of vitamin K (VK) on various chronic age-related syndromes have generally been considered dependent on its antioxidant effects. However, due to the distinct bioavailability and biological activities of VKs, exactly which of these activities and by what mechanisms they might act still need to be elucidated. In this study, we found that VK2 can extend the lifespan of C. elegans and improve the resistance to pathogen infection, heat stress and H2O2-induced inner oxidative stress. Importantly, the roles of VK2 on aging and stress resistance were shown to be dependent on enhanced fat metabolism and not due to its antioxidant effects. Moreover, the genes related to fat metabolism that were up-regulated following VK2 treatment play key roles in improving survival. Obesity is a leading risk factor for developing T2DM, and taking VKs has been previously considered to improve the insulin sensitivity associated with obesity and T2DM risk. However, our results showed that VK2 can significantly influence the expression of genes related to fat metabolism, including those that regulate fatty acid elongation, desaturation, and synthesis of fatty acid-CoA. VK2 enhanced the fatty acid β-oxidation activity in peroxisome to degrade and digest fatty acid-CoA. Our study implies that VK2 can enhance fat degradation and digestion to improve survival, supporting the effectiveness of VK2-based medical treatments. VK2 is mainly produced by gut bacteria, suggesting that VK2 might facilitate communication between the gut microbiota and the host intestinal cells to influence fat metabolism.

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Section: Introductionmentioning

confidence: 99%

Vitamin K2 Enhances Fat Degradation to Improve the Survival of C. elegans

Zhang

Huang

et al. 2022

Front. Nutr.

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“…In astroglioma C6 cells, vitamin K2 also helps cells resist Aβ-induced toxicity [ 27 ]. Moreover, vitamin K2 can reduce cytotoxicity of SH-SY5Y cells induced by rotenone [ 19 ] and regulate neuronal cell death by inhibiting endoplasmic reticulum stress and total tau protein expression [ 28 ]. This indicates that vitamin K2 exerts anti-apoptotic and neuroprotective effects in neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Vitamin K2 Modulates Mitochondrial Dysfunction Induced by 6-Hydroxydopamine in SH-SY5Y Cells via Mitochondrial Quality-Control Loop

et al. 2022

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Vitamin K2, a natural fat-soluble vitamin, is a potent neuroprotective molecule, owing to its antioxidant effect, but its mechanism has not been fully elucidated. Therefore, we stimulated SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) in a proper dose-dependent manner, followed by a treatment of vitamin K2. In the presence of 6-OHDA, cell viability was reduced, the mitochondrial membrane potential was decreased, and the accumulation of reactive oxygen species (ROS) was increased. Moreover, the treatment of 6-OHDA promoted mitochondria-mediated apoptosis and abnormal mitochondrial fission and fusion. However, vitamin K2 significantly suppressed 6-OHDA-induced changes. Vitamin K2 played a significant part in apoptosis by upregulating and downregulating Bcl-2 and Bax protein expressions, respectively, which inhibited mitochondrial depolarization, and ROS accumulation to maintain mitochondrial structure and functional stabilities. Additionally, vitamin K2 significantly inhibited the 6-OHDA-induced downregulation of the MFN1/2 level and upregulation of the DRP1 level, respectively, and this enabled cells to maintain the dynamic balance of mitochondrial fusion and fission. Furthermore, vitamin K2 treatments downregulated the expression level of p62 and upregulated the expression level of LC3A in 6-OHDA-treated cells via the PINK1/Parkin signaling pathway, thereby promoting mitophagy. Moreover, it induced mitochondrial biogenesis in 6-OHDA damaged cells by promoting the expression of PGC-1α, NRF1, and TFAM. These indicated that vitamin K2 can release mitochondrial damage, and that this effect is related to the participation of vitamin K2 in the regulation of the mitochondrial quality-control loop, through the maintenance of the mitochondrial quality-control system, and repair mitochondrial dysfunction, thereby alleviating neuronal cell death mediated by mitochondrial damage.

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“…This includes HDAC class I and II inhibitors like Vorinostat (Richon et al 2006) and Trichostatin A (Kim M et al 2019). The cluster also shows small molecules with known effects on mitochondrial function, namely, Menadione (Shandilya et al 2021), FCCP (Grasmick et al 2018) and Decitabine (Shin et al 2012). Incorporating BMD-associated significance and concentration-dependent directionality allowed for the distinction of features that were consistently conserved across chemotypes and those features that distinguish toxicants from one another (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

Applying Cell Painting in Non-Tumorigenic Breast Cells to Understand Impacts of Common Chemical Exposures

Tapaswi,

Cemalovic,

Polemi

et al. 2024

Preprint

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There are a substantial number of chemicals to which individuals in the general population are exposed which have putative, but still poorly understood, links to breast cancer. Cell Painting is a high-content imaging-based in vitro assay that allows for rapid and unbiased measurements of the concentration-dependent effects of chemical exposures on cellular morphology. We optimized the Cell Painting assay and measured the effect of exposure to 16 human exposure relevant chemicals, along with 21 small molecules with known mechanisms of action, for 48 hours in non-tumorigenic mammary epithelial cells, the MCF10A cell line. Through unbiased imaging analyses using CellProfiler, we quantified 3042 morphological features across approximately 1.2 million cells. We used benchmark concentration modeling to quantify significance and dose-dependent directionality to identify morphological features conserved across chemicals and find features that differentiate the effects of toxicants from one another. Benchmark concentrations were compared to chemical exposure biomarker concentration measurements from the National Health and Nutrition Examination Survey to assess which chemicals induce morphological alterations at human-relevant concentrations. Morphometric fingerprint analysis revealed similar phenotypes between small molecules and prioritized NHANES-toxicants guiding further investigation. A comparison of feature fingerprints via hypergeometric analysis revealed significant feature overlaps between chemicals when stratified by compartment and stain. One such example was the similarities between a metabolite of the organochlorine pesticide DDT (p,p-DDE) and an activator of canonical Wnt signaling CHIR99201. As CHIR99201 is a known Wnt pathway activator and its role in beta-catenin translocation is well studied, we studied the translocation of ꞵ-catenin following p,p-DDE exposure in an orthogonal high-content imaging assay. Consistent with activation of Wnt signaling, low dose p,p-DDE (25nM) significantly enhances the nuclear translocation of beta-catenin. Overall, these findings highlight the ability of Cell Painting to enhance mode-of-action studies for toxicants which are common exposures in our environment but have previously been incompletely characterized with respect to breast cancer risk.

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Vitamin K2 Modulates Organelle Damage and Tauopathy Induced by Streptozotocin and Menadione in SH-SY5Y Cells

Cited by 7 publications

References 69 publications

Vitamin K2 Enhances Fat Degradation to Improve the Survival of C. elegans

Vitamin K2 Enhances Fat Degradation to Improve the Survival of C. elegans

Vitamin K2 Modulates Mitochondrial Dysfunction Induced by 6-Hydroxydopamine in SH-SY5Y Cells via Mitochondrial Quality-Control Loop

Applying Cell Painting in Non-Tumorigenic Breast Cells to Understand Impacts of Common Chemical Exposures

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