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1.
Int J Mol Sci ; 23(9)2022 Apr 27.
Article in English | MEDLINE | ID: mdl-35563203

ABSTRACT

Chronic inflammation is a major driver of chronic inflammatory diseases (CIDs), with a tremendous impact worldwide. Besides its function as a pathological calcification inhibitor, vitamin K-dependent protein Gla-rich protein (GRP) was shown to act as an anti-inflammatory agent independently of its gamma-carboxylation status. Although GRP's therapeutic potential has been highlighted, its low solubility at physiological pH still constitutes a major challenge for its biomedical application. In this work, we produced fluorescein-labeled chitosan-tripolyphosphate nanoparticles containing non-carboxylated GRP (ucGRP) (FCNG) via ionotropic gelation, increasing its bioavailability, stability, and anti-inflammatory potential. The results indicate the nanosized nature of FCNG with PDI and a zeta potential suitable for biomedical applications. FCNG's anti-inflammatory activity was studied in macrophage-differentiated THP1 cells, and in primary vascular smooth muscle cells and chondrocytes, inflamed with LPS, TNFα and IL-1ß, respectively. In all these in vitro human cell systems, FCNG treatments resulted in increased intra and extracellular GRP levels, and decreased pro-inflammatory responses of target cells, by decreasing pro-inflammatory cytokines and inflammation mediators. These results suggest the retained anti-inflammatory bioactivity of ucGRP in FCNG, strengthening the potential use of ucGRP as an anti-inflammatory agent with a wide spectrum of application, and opening up perspectives for its therapeutic application in CIDs.


Subject(s)
Calcinosis , Calcinosis/pathology , Chondrocytes/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism , Vitamin K/metabolism
2.
Mar Drugs ; 18(12)2020 Dec 07.
Article in English | MEDLINE | ID: mdl-33297528

ABSTRACT

Osteoarthritis (OA) remains a prevalent chronic disease without effective prevention and treatment. Amentadione (YP), a meroditerpenoid purified from the alga Cystoseira usneoides, has demonstrated anti-inflammatory activity. Here, we investigated the YP anti-osteoarthritic potential, by using a novel OA preclinical drug development pipeline designed to evaluate the anti-inflammatory and anti-mineralizing activities of potential OA-protective compounds. The workflow was based on in vitro primary cell cultures followed by human cartilage explants assays and a new OA co-culture model, combining cartilage explants with synoviocytes under interleukin-1ß (IL-1ß) or hydroxyapatite (HAP) stimulation. A combination of gene expression analysis and measurement of inflammatory mediators showed that the proposed model mimicked early disease stages, while YP counteracted inflammatory responses by downregulation of COX-2 and IL-6, improved cartilage homeostasis by downregulation of MMP3 and the chondrocytes hypertrophic differentiation factors Col10 and Runx2. Importantly, YP downregulated NF-κB gene expression and decreased phosphorylated IkBα/total IkBα ratio in chondrocytes. These results indicate the co-culture as a relevant pre-clinical OA model, and strongly suggest YP as a cartilage protective factor by inhibiting inflammatory, mineralizing, catabolic and differentiation processes during OA development, through inhibition of NF-κB signaling pathways, with high therapeutic potential.


Subject(s)
Antirheumatic Agents/pharmacology , Cyanobacteria/chemistry , Diterpenes/pharmacology , Osteoarthritis/prevention & control , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antirheumatic Agents/chemistry , Calcification, Physiologic/drug effects , Cartilage, Articular/drug effects , Cartilage, Articular/pathology , Chondrocytes/drug effects , Coculture Techniques , Diterpenes/chemistry , Durapatite , Gene Expression/drug effects , Humans , Interleukin-1beta , Osteoarthritis/pathology , Primary Cell Culture , Synoviocytes/drug effects
3.
Int J Mol Sci ; 20(17)2019 Aug 25.
Article in English | MEDLINE | ID: mdl-31450694

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 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.


Subject(s)
Aging/metabolism , Disease Susceptibility/metabolism , Micronutrients/metabolism , Vitamin K/metabolism , Age Factors , Animals , Biomarkers , Humans
4.
Nutrients ; 12(1)2020 Jan 03.
Article in English | MEDLINE | ID: mdl-31947821

ABSTRACT

Vitamin K health benefits have been recently widely shown to extend beyond blood homeostasis and implicated in chronic low-grade inflammatory diseases such as cardiovascular disease, osteoarthritis, dementia, cognitive impairment, mobility disability, and frailty. Novel and more efficient nutritional and therapeutic options are urgently needed to lower the burden and the associated health care costs of these age-related diseases. Naturally occurring vitamin K comprise the phylloquinone (vitamin K1), and a series of menaquinones broadly designated as vitamin K2 that differ in source, absorption rates, tissue distribution, bioavailability, and target activity. Although vitamin K1 and K2 sources are mainly dietary, consumer preference for diet supplements is growing, especially when derived from marine resources. The aim of this review is to update the reader regarding the specific contribution and effect of each K1 and K2 vitamers in human health, identify potential methods for its sustainable and cost-efficient production, and novel natural sources of vitamin K and formulations to improve absorption and bioavailability. This new information will contribute to foster the use of vitamin K as a health-promoting supplement, which meets the increasing consumer demand. Simultaneously, relevant information on the clinical context and direct health consequences of vitamin K deficiency focusing in aging and age-related diseases will be discussed.


Subject(s)
Aging/blood , Dietary Supplements , Vitamin K 1/pharmacokinetics , Vitamin K 2/pharmacokinetics , Vitamin K/administration & dosage , Vitamins/administration & dosage , Adult , Aged , Aged, 80 and over , Biological Availability , Female , Humans , Male , Middle Aged , Vitamin K/blood
5.
Bioorg Med Chem Lett ; 19(7): 2038-43, 2009 Apr 01.
Article in English | MEDLINE | ID: mdl-19251414

ABSTRACT

A novel series of semi-synthetic trioxaquines and synthetic trioxolaquines were prepared, in moderate to good yields. Antimalarial activity was evaluated against both the chloroquine-sensitive 3D7 and resistant K1 strain of Plasmodium falciparum and both series of compounds were shown to be active in the low nanomolar range. For comparison the corresponding 9-amino acridine analogues were also prepared and shown to have low nanomolar activity like their quinoline counterparts.


Subject(s)
Antimalarials/chemical synthesis , Peroxides/chemistry , Plasmodium falciparum/drug effects , Quinolines/chemical synthesis , Aminacrine/chemical synthesis , Aminacrine/chemistry , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Artemisinins/chemical synthesis , Artemisinins/chemistry , Peroxides/chemical synthesis , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship
6.
Aging (Albany NY) ; 11(12): 4274-4299, 2019 06 26.
Article in English | MEDLINE | ID: mdl-31241466

ABSTRACT

Chronic kidney disease (CKD) is one of the most powerful predictors of premature cardiovascular disease (CVD), with heightened susceptibility to vascular intimal and medial calcification associated with a high cardiovascular mortality. Abnormal mineral metabolism of calcium (Ca) and phosphate (P) and underlying (dys)regulated hormonal control in CKD-mineral and bone disorder (MBD) is often accompanied by bone loss and increased vascular calcification (VC). While VC is known to be a multifactorial process and a major risk factor for CVD, the view of primary triggers and molecular mechanisms complexity has been shifting with novel scientific knowledge over the last years. In this review we highlight the importance of calcium-phosphate (CaP) mineral crystals in VC with an integrated view over the complexity of CKD, while discuss past and recent literature aiming to highlight novel horizons on this major health burden. Exacerbated VC in CKD patients might result from several interconnected mechanisms involving abnormal mineral metabolism, dysregulation of endogenous calcification inhibitors and inflammatory pathways, which function in a feedback loop driving disease progression and cardiovascular outcomes. We propose that novel approaches targeting simultaneously VC and inflammation might represent valuable new prognostic tools and targets for therapeutics and management of cardiovascular risk in the CKD population.


Subject(s)
Calcinosis/pathology , Inflammation/pathology , Minerals/metabolism , Renal Insufficiency, Chronic/pathology , Homeostasis , Humans , Renal Insufficiency, Chronic/metabolism
7.
PLoS One ; 12(5): e0177829, 2017.
Article in English | MEDLINE | ID: mdl-28542410

ABSTRACT

Calcification-related chronic inflammatory diseases are multifactorial pathological processes, involving a complex interplay between inflammation and calcification events in a positive feed-back loop driving disease progression. Gla-rich protein (GRP) is a vitamin K dependent protein (VKDP) shown to function as a calcification inhibitor in cardiovascular and articular tissues, and proposed as an anti-inflammatory agent in chondrocytes and synoviocytes, acting as a new crosstalk factor between these two interconnected events in osteoarthritis. However, a possible function of GRP in the immune system has never been studied. Here we focused our investigation in the involvement of GRP in the cell inflammatory response mechanisms, using a combination of freshly isolated human leucocytes and undifferentiated/differentiated THP-1 cell line. Our results demonstrate that VKDPs such as GRP and matrix gla protein (MGP) are synthesized and γ-carboxylated in the majority of human immune system cells either involved in innate or adaptive immune responses. Stimulation of THP-1 monocytes/macrophages with LPS or hydroxyapatite (HA) up-regulated GRP expression, and treatments with GRP or GRP-coated basic calcium phosphate crystals resulted in the down-regulation of mediators of inflammation and inflammatory cytokines, independently of the protein γ-carboxylation status. Moreover, overexpression of GRP in THP-1 cells rescued the inflammation induced by LPS and HA, by down-regulation of the proinflammatory cytokines TNFα, IL-1ß and NFkB. Interestingly, GRP was detected at protein and mRNA levels in extracellular vesicles released by macrophages, which may act as vehicles for extracellular trafficking and release. Our data indicate GRP as an endogenous mediator of inflammatory responses acting as an anti-inflammatory agent in monocytes/macrophages. We propose that in a context of chronic inflammation and calcification-related pathologies, GRP might act as a novel molecular mediator linking inflammation and calcification events, with potential therapeutic application.


Subject(s)
Calcinosis/metabolism , Macrophages/metabolism , Monocytes/metabolism , Proteins/metabolism , Adult , Calcinosis/complications , Calcinosis/immunology , Calcium-Binding Proteins/metabolism , Carboxylic Acids/chemistry , Cell Line , Chronic Disease , Extracellular Matrix Proteins/metabolism , Extracellular Vesicles/drug effects , Extracellular Vesicles/metabolism , Humans , Inflammation/complications , Intercellular Signaling Peptides and Proteins , Intracellular Signaling Peptides and Proteins , Lipopolysaccharides/pharmacology , Macrophages/cytology , Macrophages/drug effects , Monocytes/cytology , Monocytes/drug effects , Proteins/chemistry , Matrix Gla Protein
8.
ChemMedChem ; 8(5): 709-18, 2013 May.
Article in English | MEDLINE | ID: mdl-23495190

ABSTRACT

Greater than the sum of its parts: Artemisinins are currently in phase I-II clinical trials against breast, colorectal and non-small-cell lung cancers. In an attempt to offer increased specificity, a series of hybrid artemisinin-polypyrrole minor groove binder conjugates are described. DNA binding/modelling studies and preliminary biological evaluation give insights into their mechanism of action and the potential of this strategy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/chemical synthesis , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Artemisinins/pharmacology , DNA/drug effects , Plasmodium falciparum/drug effects , Polymers/pharmacology , Pyrroles/pharmacology , Antineoplastic Combined Chemotherapy Protocols/chemistry , Artemisinins/chemistry , Binding Sites/drug effects , Cell Proliferation/drug effects , DNA/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , HT29 Cells , Humans , Models, Molecular , Molecular Conformation , Molecular Dynamics Simulation , Parasitic Sensitivity Tests , Polymers/chemistry , Pyrroles/chemistry , Structure-Activity Relationship , Thermodynamics
10.
J Med Chem ; 53(22): 8202-6, 2010 Nov 25.
Article in English | MEDLINE | ID: mdl-20979352

ABSTRACT

We extend our approach of combination chemotherapy through a single prodrug entity (O'Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target "heme", we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.


Subject(s)
Antimalarials/chemical synthesis , Chalcones/chemical synthesis , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/chemical synthesis , Peroxides/chemical synthesis , Prodrugs/chemical synthesis , Antimalarials/chemistry , Antimalarials/pharmacology , Chalcones/chemistry , Chalcones/pharmacology , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Erythrocytes/drug effects , Erythrocytes/parasitology , Inhibitory Concentration 50 , Models, Molecular , Peroxides/chemistry , Peroxides/pharmacology , Plasmodium falciparum/drug effects , Prodrugs/chemistry , Prodrugs/pharmacology , Structure-Activity Relationship
12.
Bioorg Med Chem Lett ; 16(11): 2991-5, 2006 Jun 01.
Article in English | MEDLINE | ID: mdl-16527481

ABSTRACT

A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.


Subject(s)
Alkanes/chemistry , Alkanes/pharmacology , Alkenes/chemistry , Alkenes/pharmacology , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Oxygen/chemistry , Sulfhydryl Compounds/chemistry , Alkanes/chemical synthesis , Alkenes/chemical synthesis , Animals , Antimalarials/chemistry , Cyclization , Cyclohexenes , Epoxy Compounds/chemistry , Limonene , Molecular Structure , Peroxides/chemistry , Plasmodium berghei/drug effects , Structure-Activity Relationship , Terpenes/chemistry
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