The three-dimensional structure prediction of human bitter taste receptor using the method of AlphaFold3.

Bitter taste receptors (T2Rs), a subfamily of G protein-coupled receptors, are expressed not only in oral tissues but also in extraoral sites, playing key roles in physiological processes such as the gut-brain axis. However, structural information on T2Rs is limited, with only two human T2Rs, T2R14 and T2R46, experimentally determined to date. This study explores the potential of AlphaFold3 (AF3), an advanced AI-based protein structure prediction tool, to predict the structures of 25 human T2Rs and compares them with those of the earlier AlphaFold2 (AF2).

A New Class of Vitamin K Analogues Containing the Side Chain of Retinoic Acid Have Enhanced Activity for Inducing Neuronal Differentiation.

Vitamin K, primarily known for its roles in coagulation and bone metabolism, has recently been implicated in neuroprotection and neuronal differentiation, particularly via its bioactive form, menaquinone-4 (MK-4). Here, we synthesized 12 vitamin K compounds with retinoic acid-conjugated side chains and methyl ester modifications to enhance neuroactive properties. Among these, compound demonstrated superior stability, robust transcriptional activation via steroid and xenobiotic receptor and retinoic acid receptor, and efficient induction of neuronal differentiation in mouse neural progenitor cells.

Potential of fat-soluble vitamins as a platform for antiviral drug development.

Fat-soluble vitamins, including vitamins A, D, E, and K, exhibit antioxidative, anti-inflammatory, and immunomodulatory effects, making them promising candidates for antiviral drug development. This review highlights their structural features, biological roles, and antiviral potential. Vitamin A derivatives modulate immunity and inhibit viral replication, including SARS-CoV-2.

Acyclic Retinoid Overcomes Vemurafenib Resistance in Melanoma Cells Dual Inhibition of MAPK and PI3K/AKT/mTOR Pathways.

Background/aim: To investigate the effects of acyclic retinoid (ACR) on v-raf murine sarcoma viral oncogene homolog B ( )-mutant melanoma cells and its potential to overcome vemurafenib resistance by targeting the mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase 1 (AKT)/mammalian target of rapamycin (mTOR) pathways.

Materials And Methods: The -mutant melanoma cell lines, A375 and SK-Mel28, were treated with ACR alone or in combination with low-dose vemurafenib. Cell viability was measured and vemurafenib-resistant A375 cells (A375VR) were developed through prolonged exposure to vemurafenib.

Divergent roles of 25-hydroxyvitamin D and 1α,25-dihydroxyvitamin D in neural fate determination: A CYP27B1-dependent neuron formation and VDR-dependent astrocyte development.

Vitamin D plays a crucial role in neural differentiation, yet its precise mechanisms remain unclear. In this study, we investigated the effects of vitamin D metabolites, 25-hydroxyvitamin D (25D) and 1α,25-dihydroxyvitamin D (1α,25D), on neural differentiation using Cyp27b1 and Vdr knockout mice-derived neural stem cells. We found that 1α,25D promotes neuronal differentiation via vitamin D receptor (VDR), whereas some of its effects occur independently of VDR.

Acyclic Retinoid Inhibits the EGFR/AKT Signaling Pathway and Cancels Cisplatin-resistant Cell Characteristics.

Background/aim: Lung cancer is among the most prevalent and lethal malignancies worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Overactivation of the EGFR/AKT signaling pathway contributes significantly to NSCLC progression and metastasis. Cisplatin, a widely used chemotherapeutic agent, faces limitations due to severe side effects and the emergence of resistant cancer cells.

Verification of the interaction between human bitter taste receptor T2R46 and polyphenols; Computational chemistry approach.

Recent studies have indicated that the activation of bitter taste receptors (T2R) expressed in gastrointestinal secretory cells has a regulatory effect on the secretion of gastrointestinal hormones. Polyphenols are known to be ingested at a daily intake of 5 g or more and commonly have a bitter taste. Consequently, the interaction between the bitter taste receptor T2R46 and 490 polyphenols was investigated using simulation techniques.

Azolato-Bridged Dinuclear Platinum(II) Complexes Exhibit Androgen Receptor-Mediated Anti-Prostate Cancer Activity.

Prostate cancer is an androgen-dependent malignancy that presents a marked treatment challenge, particularly after progression to the castration-resistant stage. Traditional treatments such as androgen deprivation therapy often lead to resistance, necessitating novel therapeutic approaches. Previous studies have indicated that some of the azolato-bridged dinuclear platinum(II) complexes (general formula: [{-Pt(NH)}(μ-OH)(μ-azolato)]X, where azolato = pyrazolato, 1,2,3-triazolato, or tetrazolato and X = nitrate or perchlorate) inhibit androgen receptor (AR) signaling.

Exploring 2-methyl-substituted vitamin K derivatives with potent inhibitory activity against the 3CL protease of SARS-CoV-2.

Since the outbreak of the pandemic, various anti-SARS-CoV-2 drugs have been developed. In particular, 3CL protease (3C-like protease, 3CLpro) is an attractive drug target because it is an essential enzyme for viral multiplication and is present only in viruses, not in humans. To date, 3CLpro inhibitors against SARS-CoV-2 such as nirmatrelvir and ensitrelvir have been launched as oral drugs in Japan, but there is still no potent drug against SARS-CoV-2, due to issues of in vivo absorption and stability.

Exploring Novel Vitamin K Derivatives with Anti-SARS-CoV-2 Activity.

From our compound library of vitamin K derivatives, we found that some compounds exhibited anti-SARS-CoV-2 activity in VeroE6/TMPRSS2 cells. The common structure of these compounds was menaquinone-2 (MK-2) with either the -methylphenyl or the 1-naphthyl group introduced at the end of the side chain. Therefore, new vitamin K derivatives having more potent anti-SARS-CoV-2 activity were explored by introducing various functional groups at the ω-position of the side chain.

Activation of transient receptor potential channels is involved in reactive oxygen species (ROS)-dependent regulation of blood flow by (-)-epicatechin tetramer cinnamtannin A2.

Intervention trials confirmed that blood flow-mediated dilatation increases significantly after intake of astringent (-)-epicatechin (EC) oligomers (procyanidins)-rich foods, but the mechanism remains unclear. We have previously found that procyanidins can activate the sympathetic nervous and subsequently increase blood flow. Here, we examined whether procyanidin-derived reactive oxygen species (ROS) activate transient receptor potential (TRP) channels in gastrointestinal sensory nerves and consequently induce sympathoexcitation.

Effect of lonidamine derivatives on the inhibition of transformed cell area expansion.

Expansion of transformed cell area is regulated by the surrounding nontransformed cells. Lonidamine (LND) was recently found to regulate transformed cell area expansion through suppressing the cell motility of nontransformed cells; however, the structure-activity relationship between LND and this inhibitory activity has yet to be elucidated. We synthesized several LND derivatives and evaluated their inhibitory activity against the expansion of transformed cell area and found that the halogenation pattern on the benzene ring moiety, the carboxylic acid moiety, and the overall hydrophobicity of the molecule were correlated with inhibition activity.

Synthesis of new vitamin K derivatives with a ketone group at the C-1' position of the side chain and their conversion to menaquinone-4.

Prior to being utilized in the body, dietary vitamin K homologues are converted to menaquinone-4 (MK-4) by cleavage of the side chain part followed by prenylation. We predicted that the prenylation would occur due to the electron deficiency at the C-1' position of the allyl moiety. Therefore, as an alternative method to make the C-1' position electron-deficient, a new vitamin K derivative was synthesized by introducing a ketone group, and its conversion to MK-4 was investigated.

Naturally occurring UBIAD1 mutations differentially affect menaquinone biosynthesis and vitamin K-dependent carboxylation.

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) is responsible for the biosynthesis of menaquinone-4 (MK-4), a cofactor for extrahepatic carboxylation of vitamin K-dependent (VKD) proteins. Genetic variations of UBIAD1 are mainly associated with Schnyder corneal dystrophy (SCD), a disease characterized by abnormal accumulation of cholesterol in the cornea. Results from in vitro studies demonstrate that SCD-associated UBIAD1 mutations are defective in MK-4 biosynthesis.

A novel vitamin K derived anticoagulant tolerant to genetic variations of vitamin K epoxide reductase.

Background: Vitamin K antagonists (VKAs), such as warfarin, have remained the cornerstone of oral anticoagulation therapy in the prevention and treatment of thromboembolism for more than half a century. They function by impairing the biosynthesis of vitamin K-dependent (VKD) clotting factors through the inhibition of vitamin K epoxide reductase (VKOR). The challenge of VKAs therapy is their narrow therapeutic index and highly variable dosing requirements, which are partially the result of genetic variations of VKOR.

Development of Selective TGR5 Ligands Based on the 5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalene Skeleton.

TGR5, a G-protein-coupled receptor (GPCR), plays an important role in several physiological functions. TGR5 activation through bile acids induces an increase in energy expenditure. Therefore, synthetic TGR5 ligands could be useful for the treatment of obesity or dyslipidemia.

Study on structure-activity relationship of vitamin K derivatives: Conversion of the naphthoquinone part into another aromatic ring and evaluation of their neuronal differentiation-inducing activity.

We synthesized novel vitamin K derivatives by converting the naphthoquinone group to benzene derivatives and benzoquinone. We evaluated their neuronal differentiation activities to investigate the effect of the quinone moiety on this process. We observed that the 1,4-quinone as well as the side chain part play important roles in neuronal differentiation.

Synthesis and In Vitro Evaluation of Novel Liver X Receptor Agonists Based on Naphthoquinone Derivatives.

We aimed to synthesize novel liver X receptor (LXR) agonists with potent agonist activity and subtype selectivity. Our synthetic scheme started with naphthoquinone derivatives, such as menadione and 2,3-dichloro-1,4-naphthoquinone. We introduced different substituents into the naphthoquinone structures, including aniline, piperidine, pyrrolidine, and morpholine, in one or two steps, and thus, we produced 14 target compounds.

Elucidation of the Interaction between Flavan-3-ols and Bovine Serum Albumin and Its Effect on Their In-Vitro Cytotoxicity.

Flavan-3-ols (FLs), specifically catechin and its oligomer B-type procyanidins, are suggested to potently bind to bovine serum albumin (BSA). We examined the interaction between BSA and FLs by fluorescence quenching and found the following order of binding activities to BSA: cinnamtannin A2 (A2; tetramer) > procyanidin C1 (C1; trimer) ≈ procyanidin B2 (B2, dimer) > (-)epicatechin (EC, monomer). Docking simulations between BSA and each compound at the binding site showed that the calculated binding energies were consistent with the results of our experimental assay.

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

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 K (phylloquinone: PK), derived from plants with a phythyl side chain; vitamin K (menaquinone-: MK-), derived from intestinal bacteria with an isoprene side chain; and vitamin K (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.

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

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is a vitamin K 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.

Eldecalcitol is more effective in promoting osteogenesis than alfacalcidol in Cyp27b1-knockout mice.

Calcium (Ca) absorption from the intestinal tract is promoted by active vitamin D (1α,25D3). Vitamin D not only promotes Ca homeostasis, but it also inhibits bone resorption and promotes osteogenesis, thus playing a role in the maintenance of normal bone metabolism. Because 1α,25D3 plays an important role in osteogenesis, vitamin D formulations, such as alfacalcidol (ALF) and eldecalcitol (ELD), are used for treating osteoporosis.

Comparison of the sympathetic stimulatory abilities of B-type procyanidins based on induction of uncoupling protein-1 in brown adipose tissue (BAT) and increased plasma catecholamine (CA) in mice.

Objectives: We previously found that elevated energy expenditure following a single oral dose of flavan 3-ols (FL), a mixture of catechins and B type procyanidins, is caused by sympathetic nerve activation. In the present study, we compared the activity of the FL components (-)-epicatechin (EC; monomer), procyanidin B2 (B2; dimer), procyanidin C1 (C1; trimer), cinnamtannin A2 (A2; tetramer), and more than pentamer fraction (P5).

Methods: Male ICR mice were treated with a single oral dose of FL, EC, B2, C1, A2, or P5.

Synthesis of novel vitamin K derivatives with alkylated phenyl groups introduced at the ω-terminal side chain and evaluation of their neural differentiation activities.

Vitamin K is an essential cofactor of γ-glutamylcarboxylase as related to blood coagulation and bone formation. Menaquinone-4, one of the vitamin K homologues, is biosynthesized in the body and has various biological activities such as being a ligand for steroid and xenobiotic receptors, protection of neuronal cells from oxidative stress, and so on. From this background, we focused on the role of menaquinone in the differentiation activity of progenitor cells into neuronal cells and we synthesized novel vitamin K derivatives with modification of the ω-terminal side chain.

Determination of Menadione by Liquid Chromatography-Tandem Mass Spectrometry Using Pseudo Multiple Reaction Monitoring.

This study aimed to develop a menadione (MD) determination method employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a pseudo multiple reaction monitoring (MRM) technique, wherein two quadrupoles are used to monitor the same ion. Detection limits of 40 and 2 pg were obtained for MD and its deuterium-labeled form, respectively, whereas MD intra- and inter-assay coefficient of variation values were determined as 5.4 - 8.