Inhibition of pseudo-allergic reactions by vitamin K3 directly targeting GAB1 in mast cells.

BACKGROUND: Vitamin K3 (VK3), a fat-soluble synthetic analog of the vitamin K family, has coagulant, anti-inflammatory, antibacterial, and anticancer properties. Pseudo allergy is a IgE-independent immune response associated with mast cells. This study investigated the role of VK3 in IgE-independent mast cell activation. METHODS: Substance P (SP) was used to induce LAD2-cell activation in order to analyze the effects of VK3 in vitro. Cutaneous allergy and systemic allergy mouse models were used to analyze the anti-pseudo-allergic effects of VK3. Proteome microarray assays were used to analyze VK3-binding protein. Biolayer interferometry and immunoprecipitation were used to verify interaction between VK3 and its key targets. RNA interference was used to determine the role of GAB1 in LAD2cell activation. RESULTS: VK3 inhibited SP-induced LAD2-cell activation, and resulted in the release of ß-hexosaminidase, histamine and cytokines; VK3 inhibited SP-induced pseudo allergic reactions in mice, and serum histamine and TNF-α levels decreased. Degranulation of skin mast cells was reduced; GAB1 in mast cells was stably bound to VK3. GAB1 participated in SP-induced LAD2-cell activation. GAB1 knockdown in LAD2 cells prevented SP-induced ß-hexosaminidase release, calcium mobilization and cell skeletal remodeling. VK3 directly binds to GAB1 and reduces its expression to inhibited SP-induced LAD2 cell activation. CONCLUSION: The anti-pseudo-allergic activity of VK3 was confirmed in vitro and in vivo. VK3 can inhibit SP-induced mast cell activation by directly targeting GAB1. This study provides new insights on the activity of VK3 and the mechanism of pseudoallergic reaction.

Genetic diversity of macrolides resistant Staphylococcus aureus clinical isolates and the potential synergistic effect of vitamins, C and K3.

BACKGROUND: Macrolide antibiotics have been extensively used for the treatment of Staphylococcus aureus infections. However, the emergence of macrolide-resistant strains of S. aureus has become a major concern for public health. The molecular mechanisms underlying macrolide resistance in S. aureus are complex and diverse, involving both target site modification and efflux pump systems. In this study, we aim to overcome the molecular diversity of macrolide resistance mechanisms in S. aureus by identifying common molecular targets that could be exploited for the development of novel therapeutics. METHODS: About 300 Staphylococcus aureus different isolates were recovered and purified from 921 clinical specimen including urine (88), blood (156), sputum (264), nasal swabs (168), pus (181) and bone (39) collected from different departments in Tanta University Hospital. Macrolide resistant isolates were detected and tested for Multi Drug Resistant (MDR). Gel electrophoresis was performed after the D test and PCR reaction for erm(A), (B), (C), msr(A), and mph(C) genes. Finally, we tried different combinations of Erythromycin or Azithromycin antibiotics with either vitamin K3 or vitamin C. RESULTS: Macrolide resistance S. aureus isolates exhibited 7 major resistance patterns according to number of resistance markers and each pattern included sub patterns or subgroups. The PCR amplified products of different erm genes; analysis recorded different phenotypes of the Staphylococcus aureus isolates according to their different genotypes. In addition, our new tested combinations of Erythromycin and vitamin C, Erythromycin, and vitamin K3, Azithromycin and vitamin C and Azithromycin and vitamin K3 showed significant antibacterial effect when using every antibiotic alone. Our findings provide new insights into the molecular mechanisms of macrolide resistance in S. aureus and offer potential strategies for the development of novel protocols to overcome this emerging public health threat.

Vitamin K3 promotes CCL5 expression to recruit preadipocytes deposition to skeletal muscle.

Intramuscular fat (IMF), also known as ectopic fat deposits in skeletal muscle. Researches of IMF mainly focus on increasing the number and size of intramuscular adipocytes in situ. However, recent studies have shown that chemokines secreted by skeletal muscle recruit adipocytes to increase intramuscular fat content. Chemokine ligand 5 (CCL5), a member of chemokine family, is involved in the regulation of cell migration, inflammatory responses, and energy metabolism. In this study, we determined Vitamin K3 (VK3) enhanced Ccl5 transcription and expression, thus resulting in increased preadipocyte migration. VK3-injected vastus lateralis (VL) was observed an increased CCL5 concentration and IMF deposition, whereas blockade of the CCL5/CCR5 axis decreased IMF deposition.VK3 treatment also increased the body weight and VL ratio in mice. In summary, VK3, which targets CCL5, is expected to be a novel pharmacological regulator for promoting IMF content.

Menadione Contribution to the In Vitro Radical Scavenging Potential of Phytochemicals Naringenin and Lignin.

Vitamin K3 (menadione), classified as a pro-vitamin, is a synthetic form of the fat-soluble family of vitamin K compounds. The combination of the vitamin with other molecules sharing structural and/or functional similarities, such as naturally occurring polyphenols, vitamins, or biopolymers, could potentiate mutual improvement of their antioxidant activity. The aim of the present study was to evaluate the role and contribution of vitamin K3 to the in vitro radical scavenging capacity of double and triple combinations with the phytochemicals naringenin and lignin, as well as assess possible intermolecular interactions between the bioactive compounds. Comparative analyses of the DPPH and ABTS radical scavenging activity of the pure substances vitamin K3, naringenin, and lignin; the two-component systems lignin/vitamin K3 and vitamin K3/naringenin; and the triple combination vitamin K3/flavonoid/lignin were carried out. The experimental results demonstrated increased DPPH and ABTS activities of the vitamin in combination with lignin compared to those of the two pure substances, i.e., a synergistic effect was observed. The registered significant increases in the radical scavenging activity of the triple combination determined via both methods are indicative of a remarkable potentiation effect, i.e., higher antioxidant potential exceeding the additive activity of the three pure substances.

Protective Role of Vitamin K3 on SARS-CoV-2 Structural Protein-Induced Inflammation and Cell Death.

The structure proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), such as nucleocapsid protein (N protein) and envelop protein (E protein), are considered to be the critical pro-inflammatory factors in coronavirus disease 2019 (COVID-19). Vitamin K3 has been reported to exert an anti-inflammatory effect. In this study, we investigated the protective effects of vitamin K3 on SARS-CoV-2 N protein induced-endothelial activation and SARS-CoV-2 E protein induced-cell death in THP-1 cells. The results showed that vitamin K3 reduced N protein-induced monocyte adhesion, suppressed the expression of adhesion molecules, and decreased the mRNA levels of pro-inflammatory cytokines in HLMECs. We confirmed that the effects of vitamin K3 on endothelial activation may be related to the inhibition of the NF-κB signal pathway. In addition, vitamin K3 reversed E protein-induced pyroptosis, inhibited NLRP3/GSDMD signal pathway and reduced the mRNA expression of pro-inflammatory cytokines in THP-1 cells. Our results also showed the protective effects of vitamin K3 on the SARS-CoV-2 structural protein-induced THP-1 cells pyroptosis and endothelial activation via NF-κB signaling pathway. These findings suggested that vitamin K3 potently suppressed the inflammatory response to prevent endothelial activation and monocyte pyroptosis induced by SARS-CoV-2 proteins. This may provide a new strategy for the treatment of COVID-19.

Combined effects of dietary faba bean water extract and vitamin K3 on growth performance, textural quality, intestinal characteristics, oxidative and immune responses in grass carp.

Faba bean water extract (FBW) and vitamin K3 (VK3) have been demonstrated to improve the muscle textural quality of fish. To better apply these two feed additives in commercial aquaculture setting, four experimental diets (control, commercial feed group; 15% FBW, 15% faba bean water extract group; 2.5% VK3, 2.5% vitamin K3 group; combined group, 15% faba bean water extract + 2.5% vitamin K3 group) were formulated to explore their combined effects of FBW and VK3 on the growth, health status, and muscle textural quality of grass carp. The growth performance, textural quality, intestinal characteristics, and oxidative and immune responses were analyzed on days 40, 80 and 120. The results showed that supplementation with higher doses of FBW and VK3 have no influence on growth-related parameters and immune parameters of grass carp. Notably, compared with the control, fish in the combined group had the highest textural qualities (hardness, chewiness and adhesiveness), followed by those in 15% FBW and 2.5% VK3 groups (P < 0.05). Also, FBW and VK3, to some extent, may lower antioxidative ability of grass carp, as illustrated by lower levels of GSH and CAT in 15% FBW, 2.5% VK3, and combined groups on day 120 (P < 0.05). In addition, enhanced lipase activity was observed in the 15% FBW group. Taken together, the combined supplementation of FBW and VK3 was demonstrated to be a more advanced option than their individual supplementation in a commercial setting owing to the resulting combined effects on both the textural quality and health status of grass carp.

Effects of dietary vitamin K3 supplementation on production performance, egg quality, vitamin K-dependent proteins, and antioxidant properties in breeding geese during the laying period.

The aim of this work was to investigate the effects of dietary vitamin K3 (VK3) supplementation on production performance, egg quality, vitamin K-dependent proteins, and antioxidant properties in breeding geese during the laying period. A total of one hundred twenty 82-wk-old Wulong geese with similar body weights were randomly divided into 6 groups with 4 replicates and 5 geese each (1 male and 4 female). The geese in the control group were fed a basal diet, and the geese in the treatment groups were fed diets supplemented with different levels of VK3 (2.5, 5.0, 7.5, 10.0, and 12.5 mg/kg) for 11 wk. Dietary VK3 supplementation linearly and quadratically increased feed intake, egg mass, egg weight, and egg production (P < 0.05). Increasing VK3 levels linearly and quadratically increased albumen height, shell thickness and Haugh unit of eggs (P < 0.05). VK3 reduced osteocalcin (OC) and uncarboxylated osteocalcin (ucOC) levels in the serum. Dietary VK3 addition linearly decreased serum malondialdehyde (MDA) levels (P < 0.01). There was linear and quadratic effect in the activity of serum total superoxide dismutase (T-SOD) (P < 0.01), and linear effect in serum total antioxidant capacity (T-AOC) (P < 0.01). In conclusion, dietary VK3 supplementation enhanced the production performance, egg quality, vitamin K-dependent proteins, and antioxidant properties in breeding geese during the laying period. The optimal dose of dietary VK3 supplementation was 10.0 mg/kg.

Vitamin k3-Loaded Magnetic Nanoparticle-Mediated Synergistic Magnetothermodynamic Therapy Evokes Massive ROS and Immune Modulation for Augmented Antitumor Potential.

Magnetic nanoparticle (MNP)-mediated magnetic hyperthermia (MHT) under an alternating magnetic field (AMF) causes tumor regression via reactive oxygen species (ROS) generation. However, less therapeutic efficacy has been reported due to the generation of low levels of ROS in a hypoxic tumor microenvironment. Therefore, improved treatments are required to generate relatively high levels of ROS to promote irreversible oxidative damage to the tumor cells. Herein, we report a magnetothermodynamic (MTD) therapy, as a robust and versatile approach for cancer treatment, by combining the magnetothermodynamic-related ROS and heat-related immunological effect in order to overcome the aforementioned obstacle. The synergistic therapy was achieved by the development of vitamin k3 (Vk3)-loaded copper zinc ferrite nanoparticles (Vk3@Si@CuZnIONPs) as an efficient MTD agent. The in vitro results unveiled that enhanced ROS production under the influence of AMF is a predominant aspect in yielding an assertive anticancer response. The in vivo antitumor response was assessed in an ectopic tumor model of A549 lung adenocarcinoma by MTD. The tumor inhibition rate of 69% was achieved within 20 days of MTD treatment, exhibiting complete tumor eradication within 30 days. The validation of antitumor response was marked by severe apoptosis (TUNEL, Caspase-3) in the Vk3@Si@CuZnIONPs + AMF-treated group. The higher expression level of heat shock proteins and proinflammatory cytokines (IL-6, TNF-α, IL-1α, IL-1ß) was speculated to play a role in the activation of immune response for faster tumor regression in the MTD-treated group. Therefore, by implementing a dual ROS and heat-mediated immunogenic effect, the antitumor efficiency of future cancer magnetotherapies will be greatly enhanced.

Vitamin K3 (Menadione) is a multifunctional microbicide acting as a photosensitizer and synergizing with blue light to kill drug-resistant bacteria in biofilms.

Cutaneous bacterial wound infections typically involve gram-positive cocci such as Staphylococcus aureus (SA) and usually become biofilm infections. Bacteria in biofilms may be 100-1000-fold more resistant to an antibiotic than the clinical laboratory minimal inhibitory concentration (MIC) for that antibiotic, contributing to antimicrobial resistance (AMR). AMR is a growing global threat to humanity. One pathogen-antibiotic resistant combination, methicillin-resistant SA (MRSA) caused more deaths globally than any other such combination in a recent worldwide statistical review. Many wound infections are accessible to light. Antimicrobial phototherapy, and particularly antimicrobial blue light therapy (aBL) is an innovative non-antibiotic approach often overlooked as a possible alternative or adjunctive therapy to reduce antibiotic use. We therefore focused on aBL treatment of biofilm infections, especially MRSA, focusing on in vitro and ex vivo porcine skin models of bacterial biofilm infections. Since aBL is microbicidal through the generation of reactive oxygen species (ROS), we hypothesized that menadione (Vitamin K3), a multifunctional ROS generator, might enhance aBL. Our studies suggest that menadione can synergize with aBL to increase both ROS and microbicidal effects, acting as a photosensitizer as well as an ROS recycler in the treatment of biofilm infections. Vitamin K3/menadione has been given orally and intravenously worldwide to thousands of patients. We conclude that menadione/Vitamin K3 can be used as an adjunct to antimicrobial blue light therapy, increasing the effectiveness of this modality in the treatment of biofilm infections, thereby presenting a potential alternative to antibiotic therapy, to which biofilm infections are so resistant.

A Potent PDK4 Inhibitor for Treatment of Heart Failure with Reduced Ejection Fraction.

Heart failure with reduced ejection fraction (HFrEF) is characterized not only by reduced left ventricular ejection fraction (EF) but is also combined with symptoms such as dyspnea, fatigue, and edema. Several pharmacological interventions have been established. However, a treatment targeting a novel pathophysiological mechanism is still needed. Evidence indicating that inhibition of pyruvate dehydrogenase kinase 4 (PDK4) may be cardioprotective has been accumulating. Thus, we focused on vitamin K3 and used its framework as a new PDK4 inhibitor skeleton to synthesize new PDK4 inhibitors that show higher activity than the existing PDK4 inhibitor, dichloroacetic acid, and tested their cardioprotective effects on a mouse heart failure model. Among these inhibitors, PDK4 inhibitor 8 improved EF the most, even though it did not reverse cardiac fibrosis or wall thickness. This novel, potent PDK4 inhibitor may improve EF of failing hearts by regulating bioenergetics via activation of the tricarboxylic acid cycle.

Fabrication of vitamin K3-carnosine peptide-loaded spun silk fibroin fibers/collagen bi-layered architecture for bronchopleural fistula tissue repair and regeneration applications.

Bronchial and pleural injuries with persistent air leak pose a threat in the repair and regeneration of pulmonary diseases. The need to arrive at a highly efficient therapy for closure of bronchopleural fistula (BPF) so as to effectively suppress inflammation, infection and repair the damaged pleural space caused by cancer as well as contractile restoration of bronchopleural scars remain a significant clinical challenge. Herein, we have designed and developed potent bioactive vitamin K3 carnosine peptide (VKC)-loaded spun SF fibroin fibers/collagen bi-layered 3D scaffold for bronchopleural fistula tissue engineering applications. The VKC drug showed excellent cell viability in human bronchial epithelial cells (HBECs), in addition to its pronounced higher cytotoxicity against the A549 lung cancer cell line with an IC50 of 5 µg/mL. Furthermore, VKC displayed a strong affinity with the catalytic site of EGFR (PDB ID: 1M17) and VEGFR2 (PDB ID: 4AGD, 4ASD) receptors in molecular docking studies. Following which the spun SF-VKC (primary layer) and collagen film (top layer) constructed bi-layered CSVKC were structurally elucidated and its morphological, physicochemical and biological characterizations were well examined. The bi-layered scaffold showed superior biocompatibility and cell migration ability in HBECs than other scaffolds. Interestingly, the CSVKC revealed rapid HBECs motility towards scratched regions for fast healing in vitro bronchial tissue engineering. In vivo biocompatibility and angiogenesis studies of the prepared scaffolds were evaluated and the results obtained demonstrated excellent new tissue formation and neovascularization in the bi-layered architecture rather than others. Therefore, our results suggest that the potent antibacterial and anticancer therapeutic agent (VKC)-impregnated silk fibroin fibers/collagen bi-layered 3D biomaterial could be useful in treating cancerous BPF and pulmonary diseases in future.

Modulating the Siah2-PHD3-HIF1α axis and/or autophagy potentially retard colon cancer proliferation possibly, due to the damping of colon cancer stem cells.

BACKGROUND: Hypoxic microenvironment of colon cancer is associated with HIF-1α upregulation. HIF-1α response elements are responsible for autophagy induction that promotes tumor proliferation. Moreover, HIF-1α induces tumor cell proliferation via maintaining cancer stem cells (CSCs) survival. Siah2 is E3 ubiquitin ligase that indirectly stabilizes HIF-1α. We hypothesized that dual inhibition of Siah2 as well as autophagy could be a promising approach that may inhibit CSCs growth. AIM OF THE WORK: This study investigated the possible effect of vitamin K3 as a Siah2 inhibitor and hydroxychloroquine as an autophagy inhibitor in colon cancer management. The effect (if any) of these agents on CSCs growth will be also manipulated. METHODS: Colon cancer was induced by dimethylhydrazine. MDA and GSH were selected as oxidative stress markers, Expression of HIF-1α, Caspase-3, VEGF, MMP-9, EpCAM, SCF, and CA19.9 were assayed using immunoassay. The Western blot technique was used to assess LC3Ⅰ, CD44, and CD133 whereas RT-PCR was used to investigate PHD3 and CD44 in colon tissues. Additionally, Ki-67 and Siah2 were detected immunohistochemically. RESULTS: vitamin K3 and hydroxychloroquine either alone or in combination downregulated the expression of Siah2 and HIF-1α through upregulating PHD3 in colon tissues. This combination significantly downregulated MDA, Ki-67, VEGF, and MMP-9 expression and upregulated the expression of GSH and caspase-3. LC3Ⅰ was also upregulated. Interestingly, these therapeutic options were correlated with down-regulation of the cancer stem cell marker such as CD44 and EpCAM. CONCLUSION: Our results suggested that suppression of both Siah2-PHD3-HIF-1α axis and autophagy retard colon cancer proliferation and dampened CSCs.

Vitamin K3 inhibits FtsZ assembly, disrupts the Z-ring in Streptococcus pneumoniae and displays anti-pneumococcal activity.

The respiratory pathogen, Streptococcus pneumoniae has acquired multiple-drug resistance over the years. An attractive strategy to combat pneumococcal infection is to target cell division to inhibit the proliferation of S. pneumoniae. This work presents Vitamin K3 as a potential anti-pneumococcal drug that targets FtsZ, the master coordinator of bacterial cell division. Vitamin K3 strongly inhibited S. pneumoniae proliferation with a minimum inhibitory concentration (MIC) and a minimum bactericidal concentration (MBC) of 6 µg/ml. Vitamin K3 disrupted the Z-ring localization in both S. pneumoniae and Bacillus subtilis within 30 min of treatment, while the membrane integrity and nucleoid segregation remain unchanged. Several complementary experiments showed that Vitamin K3 inhibits the assembly of purified S. pneumoniae FtsZ (SpnFtsZ) and induces conformational changes in the protein. Interestingly, Vitamin K3 interfered with GTP binding onto FtsZ and increased the GTPase activity of FtsZ polymers. The intrinsic tryptophan fluorescence of SpnFtsZ revealed that Vitamin K3 delays the nucleation of FtsZ polymers and reduces the rate of polymerization. In the presence of a non-hydrolyzable analog of GTP, Vitamin K3 did not show inhibition of FtsZ polymerization. These results indicated that Vitamin K3 induces conformational changes in FtsZ that increase GTP hydrolysis and thereby, destabilize the FtsZ polymers. Together, our data provide evidence that Vitamin K3 derives its potent anti-pneumococcal activity by inhibiting FtsZ assembly.

Super-magnetization of Co-pectin/gelatin biocomposite for selective synthesis vitamin K3: Design, fabrication and revealing role of the stabilizers.

High pollution and low productivity of the traditional method for synthesis of vitamin group K require an efficient, low-cost, and environmentally sustainable biocatalyst as a greener process. These have encouraged us to design and fabricate a series of novel Co NPs impregnated pectin-gelatin (Co@PTNC, Co@GTNC & Co@PT0.7GT0.3NC) and grafted pectin-gelatin modified magnetic beads (Co@MPT0.7GT0.3NC) by the in situ reduction-precipitation procedure and chemical application in the selective synthesis of vitamin K3 without any promoters or ligands. The chemical structure and morphological properties were fully characterized. Additionally, the influence of structural parameters (i.e., kind of stabilizer with different ratio (nPT/nGT), amount of Co loading, durability, size, distribution, and Leaching test) and operating parameters (i.e., reaction time, reaction temperature, nature of the solvent, and concentration of oxidant) on the efficacy of the biocatalysts was evaluated in detail. The green synthesis involves several advantages, like the heterogeneous nature of catalysts, environmentally-friendly and mild conditions, high recovery efficiency due to superparamagnetism, high activity, and the sustainable performance of the biocatalyst.

Effect of vitamin K3 supplementation on immunoglobulin G concentration in colostrum of periparturient Holstein dairy cows.

This study was to examine the effects of dietary vitamin K (VK) 3 supplementation on immune-related substances in milk, oxidative stress indices in plasma and VK1, and menaquinone 4 (MK-4) in plasma and milk in periparturient dairy cows. Forty healthy perinatal Holstein-Friesian dairy cows were used in this study. Twenty-one animals were randomly selected and categorized into the VK3 supplemented (50 mg/day/head as VK3) group; the remaining 19 were categorized into the control group. On day 3 after calving, blood and milk were sampled, and their chemical components were determined. The VK3 supplemented group had significantly higher menaquinone 4 levels in plasma and milk on day 3 postpartum than the control group. In addition, there was a significant increase in the immunoglobulin G (IgG) level in milk. VK3 may be absorbed from the gastrointestinal tract and converted to MK-4, the biologically active form of VK, in the mammary gland and other tissues. It was thought that the increase in MK-4 level in plasma and milk induced an increase in the concentration of IgG in milk. VK3 supplementation to periparturient dairy cows may contribute to the production of colostrum with high concentrations of IgG and MK-4.

Effects of dietary vitamin K3 supplementation on vitamin K1 and K2 (menaquinone) dynamics in dairy cows.

The effect of dietary vitamin K3 (VK3) on ruminant animals is not fully investigated. The aim of this study was to examine the effects of dietary VK3 on lactation performance, rumen characteristics, and VK1 and menaquinone (MK, or VK2) dynamics in the rumen, plasma, and milk of dairy cows. Eight Holstein dairy cows in late lactation periods were used in two crossover trials including a control (nontreatment) and a 50 or 200 mg/day (d) VK3 supplementation group. After 14 days, plasma, ruminal fluid, and milk were sampled and their VK1 and MKs contents were measured using fluorescence-high-performance liquid chromatography (HPLC). Milk production was unchanged after feeding 50 mg/day VK3 but marginally decreased after feeding 200 mg/day VK3. The molar ratio of propionate in ruminal fluid was significantly increased on feeding 200 mg/day VK3. Additionally, MK-4 concentrations significantly increased in both plasma and milk after VK3 feeding (50 and 200 mg/day). In ruminal fluid, MK-4 concentrations increased after 200 mg/day VK3 feeding. These results suggest that VK3 may be a good source of MK-4, the biologically active form of VK, in Holstein dairy cows during their late lactation periods. This study provides a basis for understanding the physiological role of VK in dairy cows.

Effects of Menadione on Survival, Feeding, and Tunneling Activity of the Formosan Subterranean Termite.

The Formosan subterranean termite, Coptotermes formosanus Shiraki, is a highly destructive pest and a cosmopolitan invasive species. Sustainable termite management methods have been improving with the search for novel insecticides that are effective, safe, and cost efficient. Menadione, also known as vitamin K3, is a synthetic analogue and biosynthetic precursor of vitamin K with low mammalian toxicity. Menadione has shown insecticidal activity in several insects, presumably due to interference with mitochondrial oxidative phosphorylation. However, little is known about its effectiveness against termites. In this study, we evaluated the toxicity and repellency of menadione in C. formosanus. Our results showed that menadione affected the survival and feeding activity of termites both in filter paper and substrate (sand) treatments, and menadione influenced termite tunneling activity in treated sand. In a no-choice assay, ≥90% mortality after seven days and minimal or no food consumption were recorded when sand was treated with menadione at 6 to 600 ppm. In a two-choice assay with a combination of treated and untreated sand, termites were deterred by menadione at 6 to 600 ppm and exhibited low mortality (≤30%) over seven days, while tunneling activity was prevented with 60 to 600 ppm of menadione treatment. Overall, our study demonstrated dose-dependent toxicity and repellency of menadione in C. formosanus. The potential use of menadione as an alternative termite control agent is discussed.

ROS-Activated homodimeric podophyllotoxin nanomedicine with self-accelerating drug release for efficient cancer eradication.

Although podophyllotoxin (POD) demonstrates high efficiency to inhibit various cancers, its clinic application is limited to poor bioavailability. Nanoparticles derived from homodimeric prodrugs with high drug loading potential are emerging as promising nanomedicines. However, complete intracellular drug release remains a major hindrance to the use of homodimeric prodrugs-based nanomedicine. We sought to develop a reactive oxygen species (ROS) responsive POD dimeric prodrug by incorporating vitamin K3 (VK3) and Pluronic F127 to synthesize a spheroid nanoparticle (PTV-NPs). PTV-NPs with high POD content could release drugs under the ROS enrichment microenvironment in cancer cells. The released VK3 could produce abundant ROS selectively in tumor cells catalyzed by the overexpressed NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme. In turn, the resultant high ROS concentration promoted the conversion of POD dimeric prodrug to POD monomer, thereby achieving the selective killing of cancer cells with weak system toxicity. In vitro and in vivo studies consistently confirmed that PTV-NPs exhibit high drug loading potential and upstanding bioavailability. They are also effectively internalized by tumor cells, induce abundant intracellular ROS generation, and have high tumor-specific cytotoxicity. This ROS-responsive dimeric prodrug nanoplatform characterized by selective self-amplification drug release may hold promise in the field of antitumor drug delivery.

Anharmonicity and Spectra-Structure Correlations in MIR and NIR Spectra of Crystalline Menadione (Vitamin K3).

Mid-infrared (MIR) and near-infrared (NIR) spectra of crystalline menadione (vitamin K3) were measured and analyzed with aid of quantum chemical calculations. The calculations were carried out using the harmonic approach for the periodic model of crystal lattice and the anharmonic DVPT2 calculations applied for the single molecule model. The theoretical spectra accurately reconstructed the experimental ones permitting for reliable assignment of the MIR and NIR bands. For the first time, a detailed analysis of the NIR spectrum of a molecular system based on a naphthoquinone moiety was performed to elucidate the relationship between the chemical structure of menadione and the origin of the overtones and combination bands. In addition, the importance of these bands during interpretation of the MIR spectrum was demonstrated. The overtones and combination bands contribute to 46.4% of the total intensity of menadione in the range of 3600-2600 cm-1. Evidently, these bands play a key role in shaping of the C-H stretching region of MIR spectrum. We have shown also that the spectral regions without fundamentals may provide valuable structural information. For example, the theoretical calculations reliably reconstructed numerous overtones and combination bands in the 4000-3600 and 2800-1800 cm-1 ranges. These results, provide a comprehensive origin of the fundamentals, overtones and combination bands in the NIR and MIR spectra of menadione, and the relationship of these spectral features with the molecular structure.

Apoptotic Effects of a Thioether Analog of Vitamin K3 in a Human Leukemia Cell Line.

Research suggests that thioether analogs of vitamin K3 (VK3) can act to preserve the phosphorylation of epidermal growth factor receptors by blocking enzymes (phosphatases) responsible for their dephosphorylation. Additionally, these derivatives can induce apoptosis via mitogen-activated protein kinase and caspase-3 activation, inducing reactive oxygen species (ROS) production, and apoptosis. However, vitamin K1 exhibits only weak inhibition of phosphatase activity, while the ability of VK3 to cause oxidative DNA damage has raised concerns about carcinogenicity. Hence, in the current study, we designed, synthesized, and screened a number of VK3 analogs for their ability to enhance phosphorylation activity, without inducing off-target effects, such as DNA damage. 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay revealed that each analog produced a different level of cytotoxicity in the Jurkat human leukemia cell line; however, none elicited a cytotoxic effect that differed significantly from that of the control. Of the VK3 analogs, CPD5 exhibited the lowest EC50, and flow cytometry results showed that apoptosis was induced at final concentrations of ≥10 µM; hence, only 0.1, 1, and 10 µM were evaluated in subsequent assays. Furthermore, CPD5 did not cause vitamin K-attributed ROS generation and was found to be associated with a significant increase in caspase 3 expression, indicating that, of the synthesized thioether VK3 analogs, CPD5 was a more potent inducer of apoptosis than VK3. Hence, further elucidation of the apoptosis-inducing effect of CPD5 may reveal its efficacy in other neoplastic cells and its potential as a medication.