International Journal of Molecular Sciences

Research

13 pages, 2823 KiB

Open AccessArticle

Prodrugs for Skin Delivery of Menahydroquinone-4, an Active Form of Vitamin K₂₍₂₀₎, Could Overcome the Photoinstability and Phototoxicity of Vitamin K₂₍₂₀₎

by Shotaro Goto, Shuichi Setoguchi, Hirofumi Yamakawa, Daisuke Watase, Kazuki Terada, Kazuhisa Matsunaga, Yoshiharu Karube and Jiro Takata

Int. J. Mol. Sci. 2019, 20(10), 2548; https://doi.org/10.3390/ijms20102548 - 24 May 2019

Cited by 12 | Viewed by 4039

Abstract

The effective delivery of menahydroquinone-4 (MKH), an active form of menaquinone-4 (MK-4, vitamin K₂₍₂₀₎), to the skin is beneficial in the treatment of various skin pathologies. However, its delivery through the application of MK-4 to the skin is hampered due to [...] Read more.

The effective delivery of menahydroquinone-4 (MKH), an active form of menaquinone-4 (MK-4, vitamin K₂₍₂₀₎), to the skin is beneficial in the treatment of various skin pathologies. However, its delivery through the application of MK-4 to the skin is hampered due to the photoinstability and phototoxicity of MK-4. This study aimed to evaluate the potential of ester prodrugs of MKH for its delivery into the skin to avoid the abovementioned issues. The ester prodrugs, MKH 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG) and MKH 1,4-bis-hemisuccinate (MKH-SUC), were prepared using our previously reported methods. Photostability was determined under artificial sunlight and multi-wavelength light irradiation, phototoxicity was determined by intracellular ROS formation and cell viability of UVA-irradiated human epidermal keratinocyte cells (HaCaT), and delivery of MKH into HaCaT cells was assessed by measuring menaquinone-4 epoxide (MKO) levels. MKH prodrugs showed higher photostability than MK-4. Although MK-4 induced cellular ROS and reduced cell viability after UVA irradiation, MKH prodrugs did not affect either ROS generation or cell viability. MKH prodrugs enhanced intracellular MKO, indicating effective delivery of MKH and subsequent carboxylation activity. In conclusion, these MKH prodrugs show potential for the delivery of MKH into the skin without photoinstability and phototoxicity. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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10 pages, 1783 KiB

Open AccessArticle

Geranylgeraniol Suppresses the Expression of IRAK1 and TRAF6 to Inhibit NFκB Activation in Lipopolysaccharide-Induced Inflammatory Responses in Human Macrophage-Like Cells

by Puspo E. Giriwono, Hitoshi Shirakawa, Yusuke Ohsaki, Shoko Sato, Yukihide Aoyama, Hsin-Jung Ho, Tomoko Goto and Michio Komai

Int. J. Mol. Sci. 2019, 20(9), 2320; https://doi.org/10.3390/ijms20092320 - 10 May 2019

Cited by 23 | Viewed by 4161

Abstract

Geranylgeraniol (GGOH), a natural isoprenoid found in plants, has anti-inflammatory effects via inhibiting the activation of nuclear factor-kappa B (NFκB). However, its detailed mechanism has not yet been elucidated. Recent studies have revealed that isoprenoids can modulate signaling molecules in innate immune responses. [...] Read more.

Geranylgeraniol (GGOH), a natural isoprenoid found in plants, has anti-inflammatory effects via inhibiting the activation of nuclear factor-kappa B (NFκB). However, its detailed mechanism has not yet been elucidated. Recent studies have revealed that isoprenoids can modulate signaling molecules in innate immune responses. We found that GGOH decreased the expression of lipopolysaccharide (LPS)-induced inflammatory genes in human macrophage-like THP-1 cells. Furthermore, we observed that the suppression of NFκB signaling proteins, in particular interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), occurred in GGOH-treated cells prior to LPS stimulation, suggesting an immunomodulatory effect. These results indicate that GGOH may modulate and help prevent excessive NFκB activation that can lead to numerous diseases. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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14 pages, 1825 KiB

Open AccessArticle

Menaquinone-4 Suppresses Lipopolysaccharide-Induced Inflammation in MG6 Mouse Microglia-Derived Cells by Inhibiting the NF-κB Signaling Pathway

by Wahyu Dwi Saputra, Nao Aoyama, Michio Komai and Hitoshi Shirakawa

Int. J. Mol. Sci. 2019, 20(9), 2317; https://doi.org/10.3390/ijms20092317 - 10 May 2019

Cited by 39 | Viewed by 6844

Abstract

The overactivation of microglia is known to trigger inflammatory reactions in the central nervous system, which ultimately induce neuroinflammatory disorders including Alzheimer’s disease. However, increasing evidence has shown that menaquinone-4 (MK-4), a subtype of vitamin K₂, can attenuate inflammation in the [...] Read more.

The overactivation of microglia is known to trigger inflammatory reactions in the central nervous system, which ultimately induce neuroinflammatory disorders including Alzheimer’s disease. However, increasing evidence has shown that menaquinone-4 (MK-4), a subtype of vitamin K₂, can attenuate inflammation in the peripheral system. Whereas it was also observed at high levels within the brain, its function in this organ has not been well characterized. Therefore, we investigated the effect of MK-4 on microglial activation and clarified the underlying mechanism. Mouse microglia-derived MG6 cells were exposed to lipopolysaccharide (LPS) either with or without MK-4 pretreatment. Cell responses with respect to inflammatory cytokines (Il-1β, Tnf-α, and Il-6) were measured by qRT-PCR. We further analyzed the phosphorylation of TAK1, IKKα/β, and p65 of the NF-κB subunit by Western blotting. We observed that in LPS-induced MG6 cells, MK-4 dose-dependently suppressed the upregulation of inflammatory cytokines at the mRNA level. It also significantly decreased the phosphorylation of p65, but did not affect that TAK1 and IKKα/β. Furthermore, the nuclear translocation of NF-κB in LPS-induced MG6 cells was inhibited by MK-4. These results indicate that MK-4 attenuates microglial inflammation by inhibiting NF-κB signaling. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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10 pages, 1572 KiB

Open AccessArticle

Menaquinone-4 Amplified Glucose-Stimulated Insulin Secretion in Isolated Mouse Pancreatic Islets and INS-1 Rat Insulinoma Cells

by Hsin-Jung Ho, Hitoshi Shirakawa, Keisukei Hirahara, Hideyuki Sone, Shin Kamiyama and Michio Komai

Int. J. Mol. Sci. 2019, 20(8), 1995; https://doi.org/10.3390/ijms20081995 - 23 Apr 2019

Cited by 14 | Viewed by 5042

Abstract

Vitamin K2 is indispensable for blood coagulation and bone metabolism. Menaquinone-4 (MK-4) is the predominant homolog of vitamin K2, which is present in large amounts in the pancreas, although its function is unclear. Meanwhile, β-cell dysfunction following insulin secretion has been found to [...] Read more.

Vitamin K2 is indispensable for blood coagulation and bone metabolism. Menaquinone-4 (MK-4) is the predominant homolog of vitamin K2, which is present in large amounts in the pancreas, although its function is unclear. Meanwhile, β-cell dysfunction following insulin secretion has been found to decrease in patients with type 2 diabetes mellitus. To elucidate the physiological function of MK-4 in pancreatic β-cells, we studied the effects of MK-4 treatment on isolated mouse pancreatic islets and rat INS-1 cells. Glucose-stimulated insulin secretion significantly increased in isolated islets and INS-1 cells treated with MK-4. It was further clarified that MK-4 enhanced cAMP levels, accompanied by the regulation of the exchange protein directly activated by the cAMP 2 (Epac2)-dependent pathway but not the protein kinase A (PKA)-dependent pathway. A novel function of MK-4 on glucose-stimulated insulin secretion was found, suggesting that MK-4 might act as a potent amplifier of the incretin effect. This study therefore presents a novel potential therapeutic approach for impaired insulinotropic effects. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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16 pages, 6822 KiB

Open AccessArticle

UBIAD1 Plays an Essential Role in the Survival of Pancreatic Acinar Cells

by Kimie Nakagawa, Kiyomi Fujiwara, Akihiro Nishimura, Chinami Murakami, Kanaha Kawamoto, Chihiro Ichinose, Yumi Kunitou, Yoshitomo Suhara, Toshio Okano and Hiroshi Hasegawa

Int. J. Mol. Sci. 2019, 20(8), 1971; https://doi.org/10.3390/ijms20081971 - 22 Apr 2019

Cited by 11 | Viewed by 4708

Abstract

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is a vitamin K₂ biosynthetic enzyme. We previously showed the lethality of this enzyme in UBIAD1 knockout mice during the embryonic stage. However, the biological effects of UBIAD1 deficiency after birth remain unclear. In the present [...] Read more.

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is a vitamin K₂ biosynthetic enzyme. We previously showed the lethality of this enzyme in UBIAD1 knockout mice during the embryonic stage. However, the biological effects of UBIAD1 deficiency after birth remain unclear. In the present study, we used a tamoxifen-inducible systemic UBIAD1 knockout mouse model to determine the role of UBIAD1 in adult mice. UBIAD1 knockout resulted in the death of the mice within about 60 days of administration of tamoxifen. The pancreas presented with the most prominent abnormality in the tamoxifen-induced UBIAD1 knockout mice. The pancreas was reduced remarkably in size; furthermore, the pancreatic acinar cells disappeared and were replaced by vacuoles. Further analysis revealed that the vacuoles were adipocytes. UBIAD1 deficiency in the pancreatic acinar cells caused an increase in oxidative stress and autophagy, leading to apoptotic cell death in the tamoxifen-induced UBIAD 1 knockout mice. These results indicate that UBIAD1 is essential for maintaining the survival of pancreatic acinar cells in the pancreas. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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18 pages, 6019 KiB

Open AccessArticle

Inhibitory Effects of Menadione on Helicobacter pylori Growth and Helicobacter pylori-Induced Inflammation via NF-κB Inhibition

by Min Ho Lee, Ji Yeong Yang, Yoonjung Cho, Hyun Jun Woo, Hye Jin Kwon, Do Hyun Kim, Min Park, Cheol Moon, Min Ji Yeon, Hyun Woo Kim, Woo-Duck Seo, Sa-Hyun Kim and Jong-Bae Kim

Int. J. Mol. Sci. 2019, 20(5), 1169; https://doi.org/10.3390/ijms20051169 - 7 Mar 2019

Cited by 29 | Viewed by 6368

Abstract

H. pylori is classified as a group I carcinogen by WHO because of its involvement in gastric cancer development. Several reports have suggested anti-bacterial effects of menadione, although the effect of menadione on major virulence factors of H. pylori and H. pylori-induced [...] Read more.

H. pylori is classified as a group I carcinogen by WHO because of its involvement in gastric cancer development. Several reports have suggested anti-bacterial effects of menadione, although the effect of menadione on major virulence factors of H. pylori and H. pylori-induced inflammation is yet to be elucidated. In this study, therefore, we demonstrated that menadione has anti-H. pylori and anti-inflammatory effects. Menadione inhibited growth of H. pylori reference strains and clinical isolates. Menadione reduced expression of vacA in H. pylori, and translocation of VacA protein into AGS (gastric adenocarcinoma cell) was also decreased by menadione treatment. This result was concordant with decreased apoptosis in AGS cells infected with H. pylori. Moreover, cytotoxin-associated protein A (CagA) translocation into H. pylori-infected AGS cells was also decreased by menadione. Menadione inhibited expression of several type IV secretion system (T4SS) components, including virB2, virB7, virB8, and virB10, that are responsible for translocation of CagA into host cells. In particular, menadione inhibited nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation and thereby reduced expression of the proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α in AGS as well as in THP-1 (monocytic leukemia cell) cell lines. Collectively, these results suggest the anti-bacterial and anti-inflammatory effects of menadione against H. pylori. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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15 pages, 2888 KiB

Open AccessArticle

Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells

by Jinghe Xia, Iwata Ozaki, Sachiko Matsuhashi, Takuya Kuwashiro, Hirokazu Takahashi, Keizo Anzai and Toshihiko Mizuta

Int. J. Mol. Sci. 2019, 20(5), 1022; https://doi.org/10.3390/ijms20051022 - 26 Feb 2019

Cited by 18 | Viewed by 4112

Abstract

Hypoxia-inducible factor 1 (HIF-1) plays important roles in cancer cell biology. HIF-1α is reportedly activated by several factors, including protein kinase C (PKC), in addition to hypoxia. We investigated the role of PKC isoforms and the effects of vitamin K2 (VK2) in the [...] Read more.

Hypoxia-inducible factor 1 (HIF-1) plays important roles in cancer cell biology. HIF-1α is reportedly activated by several factors, including protein kinase C (PKC), in addition to hypoxia. We investigated the role of PKC isoforms and the effects of vitamin K2 (VK2) in the activation process of HIF-1α. Human hepatocellular carcinoma (HCC)-derived Huh7 cells were cultured under normoxic and hypoxic (1% O₂) conditions with or without the PKC stimulator TPA. The expression, transcriptional activity and nuclear translocation of HIF-1α were examined under treatment with PKC inhibitors, siRNAs against each PKC isoform and VK2. Hypoxia increased the expression and activity of HIF-1α. TPA increased the HIF-1α activity several times under both normoxic and hypoxic conditions. PKC-δ siRNA-mediated knockdown, PKC-δ inhibitor (rottlerin) and pan-PKC inhibitor (Ro-31-8425) suppressed the expression and transcriptional activity of HIF-1α. VK2 significantly inhibited the TPA-induced HIF-1α transcriptional activity and suppressed the expression and nuclear translocation of HIF-1α induced by TPA without altering the HIF-1α mRNA levels. These data indicate that PKC-δ enhances the HIF-1α transcriptional activity by increasing the nuclear translocation, and that VK2 might suppress the HIF-1α activation through the inhibition of PKC in HCC cells. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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Review

Jump to: Research, Other

21 pages, 1182 KiB

Open AccessReview

Vitamin K as a Powerful Micronutrient in Aging and Age-Related Diseases: Pros and Cons from Clinical Studies

by Dina C. Simes, Carla S. B. Viegas, Nuna Araújo and Catarina Marreiros

Int. J. Mol. Sci. 2019, 20(17), 4150; https://doi.org/10.3390/ijms20174150 - 25 Aug 2019

Cited by 58 | Viewed by 20450

Abstract

Vitamin K is a multifunctional micronutrient implicated in age-related diseases such as cardiovascular diseases, osteoarthritis and osteoporosis. Although vitamin K-dependent proteins (VKDPs) are described to have a crucial role in the pathogenesis of these diseases, novel roles have emerged for vitamin K, independently [...] Read more.

Vitamin K is a multifunctional micronutrient implicated in age-related diseases such as cardiovascular diseases, osteoarthritis and osteoporosis. Although vitamin K-dependent proteins (VKDPs) are described to have a crucial role in the pathogenesis of these diseases, novel roles have emerged for vitamin K, independently of its role in VKDPs carboxylation. Vitamin K has been shown to act as an anti-inflammatory by suppressing nuclear factor κB (NF-κB) signal transduction and to exert a protective effect against oxidative stress by blocking the generation of reactive oxygen species. Available clinical evidences indicate that a high vitamin K status can exert a protective role in the inflammatory and mineralization processes associated with the onset and progression of age-related diseases. Also, vitamin K involvement as a protective super-micronutrient in aging and ‘inflammaging’ is arising, highlighting its future use in clinical practice. In this review we summarize current knowledge regarding clinical data on vitamin K in skeletal and cardiovascular health, and discuss the potential of vitamin K supplementation as a health benefit. We describe the clinical evidence and explore molecular aspects of vitamin K protective role in aging and age-related diseases, and its involvement as a modulator in the interplay between pathological calcification and inflammation processes. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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11 pages, 1453 KiB

Open AccessReview

New Aspects of Vitamin K Research with Synthetic Ligands: Transcriptional Activity via SXR and Neural Differentiation Activity

by Yoshihisa Hirota and Yoshitomo Suhara

Int. J. Mol. Sci. 2019, 20(12), 3006; https://doi.org/10.3390/ijms20123006 - 20 Jun 2019

Cited by 26 | Viewed by 6249

Abstract

Vitamin K is classified into three homologs depending on the side-chain structure, with 2-methyl-1,4-naphthoqumone as the basic skeleton. These homologs are vitamin K₁ (phylloquinone: PK), derived from plants with a phythyl side chain; vitamin K₂ (menaquinone-n: MK-n), [...] Read more.

Vitamin K is classified into three homologs depending on the side-chain structure, with 2-methyl-1,4-naphthoqumone as the basic skeleton. These homologs are vitamin K₁ (phylloquinone: PK), derived from plants with a phythyl side chain; vitamin K₂ (menaquinone-n: MK-n), derived from intestinal bacteria with an isoprene side chain; and vitamin K₃ (menadione: MD), a synthetic product without a side chain. Vitamin K homologs have physiological effects, including in blood coagulation and in osteogenic activity via γ-glutamyl carboxylase and are used clinically. Recent studies have revealed that vitamin K homologs are converted to MK-4 by the UbiA prenyltransferase domain-containing protein 1 (UBIAD1) in vivo and accumulate in all tissues. Although vitamin K is considered to have important physiological effects, its precise activities and mechanisms largely remain unclear. Recent research on vitamin K has suggested various new roles, such as transcriptional activity as an agonist of steroid and xenobiotic nuclear receptor and differentiation-inducing activity in neural stem cells. In this review, we describe synthetic ligands based on vitamin K and exhibit that the strength of biological activity can be controlled by modification of the side chain part. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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15 pages, 1305 KiB

Open AccessReview

Multiple Modes of Vitamin K Actions in Aging-Related Musculoskeletal Disorders

by Kotaro Azuma and Satoshi Inoue

Int. J. Mol. Sci. 2019, 20(11), 2844; https://doi.org/10.3390/ijms20112844 - 11 Jun 2019

Cited by 52 | Viewed by 9081

Abstract

Vitamin K is a fat-soluble vitamin that was originally found as an essential factor for blood coagulation. With the discovery of its role as a co-factor for γ-glutamyl carboxylase (GGCX), its function for blood coagulation was understood as the activation of several blood [...] Read more.

Vitamin K is a fat-soluble vitamin that was originally found as an essential factor for blood coagulation. With the discovery of its role as a co-factor for γ-glutamyl carboxylase (GGCX), its function for blood coagulation was understood as the activation of several blood coagulation factors by their γ-carboxylation. Over the last two decades, other modes of vitamin K actions have been discovered, such as the regulation of transcription by activating the steroid and xenobiotic receptor (SXR), physical association to 17β-Hydroxysteroid dehydrogenase type 4 (17β-HSD4), covalent modification of Bcl-2 antagonist killer 1 (Bak), and the modulation of protein kinase A (PKA) activity. In addition, several epidemiological studies have revealed that vitamin K status is associated with some aging-related diseases including osteoporosis, osteoarthritis, and sarcopenia. Clinical studies on single nucleotide polymorphisms of GGCX suggested an association between higher GGCX activity and bone protective effect, while recent findings using conditional knockout mice implied that a contribution in protective effect for bone loss by GGCX in osteoblastic lineage was unclear. GGCX in other cell lineages or in other tissues might play a protective role for osteoporosis. Meanwhile, animal experiments by our groups among others revealed that SXR, a putative receptor for vitamin K, could be important in the bone metabolism. In terms of the cartilage protective effect of vitamin K, both GGCX- and SXR-dependent mechanisms have been suggested. In clinical studies on osteoarthritis, the γ-carboxylation of matrix Gla protein (MGP) and gla-rich protein (GRP) may have a protective role for the disease. It is also suggested that SXR signaling has protective role for cartilage by inducing family with sequence similarity 20a (Fam20a) expression in chondrocytes. In the case of sarcopenia, a high vitamin K status in plasma was associated with muscle strength, large muscle mass, and high physical performance in some observational studies. However, the basic studies explaining the effects of vitamin K on muscular tissue are limited. Further research on vitamin K will clarify new biological mechanisms which contribute to human longevity and health through the prevention and treatment of aging-related musculoskeletal disorders. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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19 pages, 1096 KiB

Open AccessReview

The Role of Vitamin K and Its Related Compounds in Mendelian and Acquired Ectopic Mineralization Disorders

by Lukas Nollet, Matthias Van Gils, Shana Verschuere and Olivier Vanakker

Int. J. Mol. Sci. 2019, 20(9), 2142; https://doi.org/10.3390/ijms20092142 - 30 Apr 2019

Cited by 12 | Viewed by 4567

Abstract

Ectopic mineralization disorders comprise a broad spectrum of inherited or acquired diseases characterized by aberrant deposition of calcium crystals in multiple organs, such as the skin, eyes, kidneys, and blood vessels. Although the precise mechanisms leading to ectopic calcification are still incompletely known [...] Read more.

Ectopic mineralization disorders comprise a broad spectrum of inherited or acquired diseases characterized by aberrant deposition of calcium crystals in multiple organs, such as the skin, eyes, kidneys, and blood vessels. Although the precise mechanisms leading to ectopic calcification are still incompletely known to date, various molecular targets leading to a disturbed balance between pro- and anti-mineralizing pathways have been identified in recent years. Vitamin K and its related compounds, mainly those post-translationally activated by vitamin K-dependent carboxylation, may play an important role in the pathogenesis of ectopic mineralization as has been demonstrated in studies on rare Mendelian diseases, but also on highly prevalent disorders, like vascular calcification. This narrative review compiles and summarizes the current knowledge regarding the role of vitamin K, its metabolism, and associated compounds in the pathophysiology of both monogenic ectopic mineralization disorders, like pseudoxanthoma elasticum or Keutel syndrome, as well as acquired multifactorial diseases, like chronic kidney disease. Clinical and molecular aspects of the various disorders are discussed according to the state-of-the-art, followed by a comprehensive literature review regarding the role of vitamin K in molecular pathophysiology and as a therapeutic target in both human and animal models of ectopic mineralization disorders. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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24 pages, 1456 KiB

Open AccessReview

Vitamin K Dependent Proteins in Kidney Disease

by Ciprian N. Silaghi, Tamás Ilyés, Vladimir P. Filip, Marius Farcaș, Adriana J. van Ballegooijen and Alexandra M. Crăciun

Int. J. Mol. Sci. 2019, 20(7), 1571; https://doi.org/10.3390/ijms20071571 - 29 Mar 2019

Cited by 28 | Viewed by 7531

Abstract

Patients with chronic kidney disease (CKD) have an increased risk of developing vascular calcifications, as well as bone dynamics impairment, leading to a poor quality of life and increased mortality. Certain vitamin K dependent proteins (VKDPs) act mainly as calcification inhibitors, but their [...] Read more.

Patients with chronic kidney disease (CKD) have an increased risk of developing vascular calcifications, as well as bone dynamics impairment, leading to a poor quality of life and increased mortality. Certain vitamin K dependent proteins (VKDPs) act mainly as calcification inhibitors, but their involvement in the onset and progression of CKD are not completely elucidated. This review is an update of the current state of knowledge about the relationship between CKD and four extrahepatic VKDPs: matrix Gla protein, osteocalcin, growth-arrest specific protein 6 and Gla-rich protein. Based on published literature in the last ten years, the purpose of this review is to address fundamental aspects about the link between CKD and circulating VKDPs levels as well as to raise new topics about how the interplay between molecular weight and charge could influence the modifications of circulating VKDPs at the glomerular level, or whether distinct renal etiologies have effect on VKDPs. This review is the output of a systematic literature search and may open future research avenues in this niche domain. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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15 pages, 998 KiB

Open AccessReview

Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease

by Maurice Halder, Ploingarm Petsophonsakul, Asim Cengiz Akbulut, Angelina Pavlic, Frode Bohan, Eric Anderson, Katarzyna Maresz, Rafael Kramann and Leon Schurgers

Int. J. Mol. Sci. 2019, 20(4), 896; https://doi.org/10.3390/ijms20040896 - 19 Feb 2019

Cited by 185 | Viewed by 42708

Abstract

Vitamin K is an essential bioactive compound required for optimal body function. Vitamin K can be present in various isoforms, distinguishable by two main structures, namely, phylloquinone (K1) and menaquinones (K2). The difference in structure between K1 and K2 is seen in different [...] Read more.

Vitamin K is an essential bioactive compound required for optimal body function. Vitamin K can be present in various isoforms, distinguishable by two main structures, namely, phylloquinone (K1) and menaquinones (K2). The difference in structure between K1 and K2 is seen in different absorption rates, tissue distribution, and bioavailability. Although differing in structure, both act as cofactor for the enzyme gamma-glutamylcarboxylase, encompassing both hepatic and extrahepatic activity. Only carboxylated proteins are active and promote a health profile like hemostasis. Furthermore, vitamin K2 in the form of MK-7 has been shown to be a bioactive compound in regulating osteoporosis, atherosclerosis, cancer and inflammatory diseases without risk of negative side effects or overdosing. This review is the first to highlight differences between isoforms vitamin K1 and K2 by means of source, function, and extrahepatic activity. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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Other

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10 pages, 978 KiB

Open AccessCase Report

VKORC1 and CYP2C9 Polymorphisms: A Case Report in a Dutch Family with Pulmonary Fibrosis

by Petal Wijnen, Marjolein Drent, Otto Bekers, Johny Verschakelen and Aalt Bast

Int. J. Mol. Sci. 2019, 20(5), 1160; https://doi.org/10.3390/ijms20051160 - 7 Mar 2019

Cited by 5 | Viewed by 4246

Abstract

Here, we describe a Dutch family with idiopathic pulmonary fibrosis (IPF). We hypothesized that there might be an association between the presence of Vitamin K epoxide reductase complex 1 (VKORC1) and/or cytochrome P450 2C9 (CYP2C9) variant alleles and the early onset [...] Read more.

Here, we describe a Dutch family with idiopathic pulmonary fibrosis (IPF). We hypothesized that there might be an association between the presence of Vitamin K epoxide reductase complex 1 (VKORC1) and/or cytochrome P450 2C9 (CYP2C9) variant alleles and the early onset of IPF in the members of this family. VKORC1 (rs9923231 and rs9934438) and CYP2C9 (rs1799853 and rs1057910) were genotyped in this family, which includes a significant number of pulmonary fibrosis patients. In all family members, at least one of the variant alleles tested was present. The presence of the VKORC1 variant alleles in all of the IPF cases and CYP2C9 variants in all but one, which likely leads to a phenotype that is characterized by the early onset and progressive course of IPF. Our findings indicate a role of these allelic variants in (familial) IPF. Therefore, we suggest that the presence of these variants, in association with other pathogenic mutations, should be evaluated during genetic counselling. Our findings might have consequences for the lifestyle of patients with familial IPF in order to prevent the disease from becoming manifest. Full article

(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)

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