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Investigative Ophthalmology & Visual... Oct 2020To assess the therapeutic effects of fursultiamine on choroidal neovascularization (CNV) through its modulation of inflammation and metabolic reprogramming in the...
PURPOSE
To assess the therapeutic effects of fursultiamine on choroidal neovascularization (CNV) through its modulation of inflammation and metabolic reprogramming in the retinal pigment epithelium (RPE).
METHODS
The anti-angiogenic effects of fursultiamine were assessed by measuring vascular leakage and CNV lesion size in the laser-induced CNV mouse model. Inflammatory responses were evaluated by quantitative polymerase chain reaction, western blot, and ELISA in both CNV eye tissues and in vitro cell cultures using ARPE-19 cells or primary human RPE (hRPE) cells under lipopolysaccharide (LPS) treatment or hypoxia. Mitochondrial respiration was assessed by measuring oxygen consumption in ARPE-19 cells treated with LPS with or without fursultiamine, and lactate production was measured in ARPE-19 cells subjected to hypoxia with or without fursultiamine.
RESULTS
In laser-induced CNV, fursultiamine significantly decreased vascular leakage and lesion size, as well as the numbers of both choroidal and retinal inflammatory cytokines, including IL-1β, IL-6, IL-8, and TNF-α. In LPS-treated ARPE-19 cells, fursultiamine decreased proinflammatory cytokine secretion and nuclear factor kappa B phosphorylation. Furthermore, fursultiamine suppressed LPS-induced upregulation of IL-6, IL-8, and monocyte chemoattractant protein-1 in a dose-dependent and time-dependent manner in primary hRPE cells. Interestingly, fursultiamine significantly enhanced mitochondrial respiration in the LPS-treated ARPE-19 cells. Additionally, fursultiamine attenuated hypoxia-induced aberrations, including lactate production and inhibitory phosphorylation of pyruvate dehydrogenase. Furthermore, fursultiamine attenuated hypoxia-induced VEGF secretion and mitochondrial fission in primary hRPE cells that were replicated in ARPE-19 cells.
CONCLUSIONS
Our findings show that fursultiamine is a viable putative therapeutic for neovascular age-related macular degeneration by modulating the inflammatory response and metabolic reprogramming by enhancing mitochondrial respiration in the RPE.
Topics: Animals; Blotting, Western; Capillary Permeability; Cell Line; Cellular Reprogramming Techniques; Chemokine CCL2; Choroidal Neovascularization; Choroiditis; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Fursultiamin; Inflammation; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Retinal Pigment Epithelium; Vitamin B Complex
PubMed: 33107903
DOI: 10.1167/iovs.61.12.24 -
Frontiers in Cellular and Infection... 2018Antimicrobial resistance (AMR) in pathogens is the result of indiscriminate use of antibiotics and consequent metabolic/genetic modulation to evolve survival strategies...
Antimicrobial resistance (AMR) in pathogens is the result of indiscriminate use of antibiotics and consequent metabolic/genetic modulation to evolve survival strategies and clonal-selection in AMR strains. As an alternative to antibiotic treatment, antivirulence strategies are being developed, not only to combat bacterial pathogenesis, but also to avoid emerging antibiotic resistance. is a foodborne pathogen that causes gastroenteritis, necrotizing wound infections, and sepsis with a high rate of mortality. Here, we developed an inhibitor-screening reporter platform to target HlyU, a master transcriptional regulator of virulence factors in by assessing transcription under its control. The inhibitor-screening platform includes wild type and Δ mutant strains of harboring the reporter construct P for desired luminescence signal detection and control background luminescence, respectively. Using the inhibitor-screening platform, we identified a small molecule, fursultiamine hydrochloride (FTH), that inhibits the transcription of the highly invasive repeat-in-toxin () and hemolysin () along with other HlyU regulated virulence genes. FTH has no cytotoxic effects on either host cells or pathogen at the tested concentrations. FTH rescues host cells from the necrotic cell-death induced by RtxA1 and decreases the hemolytic activity under conditions. The most important point is that FTH treatment does not induce the antivirulence resistance. Current study validated the antivirulence strategy targeting the HlyU virulence transcription factor and toxin-network of and demonstrated that FTH, exhibits a potential to inhibit the pathogenesis of deadly, opportunistic human pathogen, without inducing AMR.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Fursultiamin; Gene Expression Regulation, Bacterial; HeLa Cells; Hemolysin Proteins; Humans; Transcription Factors; Vibrio vulnificus; Virulence; Virulence Factors
PubMed: 29868508
DOI: 10.3389/fcimb.2018.00152 -
Molecular Pharmacology Mar 2013Anemia of inflammation (AI) is common in patients with infection, autoimmune diseases, cancer, and chronic kidney disease. Unless the underlying condition can be...
Anemia of inflammation (AI) is common in patients with infection, autoimmune diseases, cancer, and chronic kidney disease. Unless the underlying condition can be reversed, treatment options are limited to erythropoiesis-stimulating agents with or without intravenous iron therapy, modalities that are not always effective and can cause serious adverse effects. Hepcidin, the iron regulatory hormone, has been identified as a pathogenic factor in the development of AI. To explore new therapeutic options for AI and other iron-related disorders caused by hepcidin excess, we developed a cell-based screen to identify hepcidin antagonists. Of the 70,000 small molecules in the library, we identified 14 compounds that antagonized the hepcidin effect on ferroportin. One of these was fursultiamine, a Food and Drug Administration (FDA)-approved thiamine derivative. Fursultiamine directly interfered with hepcidin binding to its receptor, ferroportin, by blocking ferroportin C326 thiol residue essential for hepcidin binding. Consequently, fursultiamine prevented hepcidin-induced ferroportin ubiquitination, endocytosis, and degradation in vitro and allowed continuous cellular iron export despite the presence of hepcidin, with IC(50) in the submicromolar range. Thiamine, the fursultiamine metabolite, and benfotiamine, another thiamine derivative, did not interfere with the effect of hepcidin on ferroportin. Other FDA-approved thiol-reactive compounds were at least 1000-fold less potent than fursultiamine in antagonizing hepcidin. In vivo, fursultiamine did not reproducibly antagonize the effect of hepcidin on serum iron, likely because of its rapid conversion to inactive metabolites. Fursultiamine is a unique antagonist of hepcidin in vitro that could serve as a template for the development of drug candidates that inhibit the hepcidin-ferroportin interaction.
Topics: Animals; Antimicrobial Cationic Peptides; Cation Transport Proteins; Cell Line; Endocytosis; Fursultiamin; HEK293 Cells; Hepcidins; High-Throughput Screening Assays; Humans; Iron; Iron Metabolism Disorders; Male; Mice; Mice, Inbred C57BL; Protein Binding; Protein Processing, Post-Translational; Proteolysis; Receptors, LDL; Small Molecule Libraries; Thiamine; Ubiquitination
PubMed: 23292796
DOI: 10.1124/mol.112.083428 -
Nutrients Jun 2018Thiamine, named as vitamin B1, is an important cofactor for the critical enzymes regarding to glucose metabolism, like transketolase, pyruvate dehydrogenase, and...
Thiamine, named as vitamin B1, is an important cofactor for the critical enzymes regarding to glucose metabolism, like transketolase, pyruvate dehydrogenase, and alpha-ketoglutarate dehydrogenase. The thiamine tetrahydrofurfuryl disulfide (TTFD) is a derivative of thiamine with higher bioavailability and solubility than thiamine and has been widely applied to health maintenance and disease therapy. Higher physical activities are associated with higher thiamine supplements for efficient energy metabolism. Furthermore, the effective dose of TTFD, beneficial to exercise physiological adaption and performance, still be further validated and the safety evaluation were also an important issue to be considered for potential application. ICR (Institute of Cancer Research) strain mice were allocated as 0, 50, 100, and 500 mg/kg dose groups and administrated by oral gavage consecutively for 6 weeks. Physical activities including grip strength and aerobic endurance were measured. Various fatigue-associated biochemical variables such as lactate, glucose, blood urine nitrogen (BUN) or creatine kinase (CK), were also assessed. The levels of liver and muscle glycogen were measured as an indicator of energy storage at the end of the experiment. Toxicity assessments for long-term supplementation were also further evaluated for safety consideration. TTFD supplementation significantly increased the endurance and grip strength and demonstrated beneficial effects on lactate production and clearance rate after an acute exercise challenge. The TTFD supplementation significantly mitigated the BUN and CK indexes after extended exercise and elevated the glycogen content in the liver and muscle tissues. According to body composition, biochemical and histopathological data, daily administration of TTFD for over 6 weeks (subacute toxicity) also demonstrated reasonable safety results for long-term and adequate supplementation. The toxicity of TTFD were also considered as safety for long-term supplementation with indicated doses. Furthermore, the TTDF could be applied to not only the health promotion but also improvement of exercise physiological adaption and the TTFD could be further considered as potential ergogenic aids combined with different nutrient strategy.
Topics: Adaptation, Physiological; Administration, Oral; Animals; Biomarkers; Dietary Supplements; Dose-Response Relationship, Drug; Drug Administration Schedule; Energy Metabolism; Exercise Tolerance; Fursultiamin; Glycogen; Liver; Male; Mice, Inbred ICR; Muscle Fatigue; Muscle Strength; Muscle, Skeletal; Physical Conditioning, Animal; Time Factors; Vitamin B Complex
PubMed: 29966293
DOI: 10.3390/nu10070851 -
Biological & Pharmaceutical Bulletin 2011Pantethine and fursultiamine have been evaluated for their clinical usefulness in the treatment and prevention of uncomplicated postoperative adhesive intestinal... (Clinical Trial)
Clinical Trial
Pantethine and fursultiamine have been evaluated for their clinical usefulness in the treatment and prevention of uncomplicated postoperative adhesive intestinal obstruction. In recent years, the actions of drugs used to treat gastrointestinal diseases have been elucidated pharmacologically from the viewpoints of gastrointestinal peptide levels. We examined the effects of pantethine and fursultiamine on plasma levels of calcitonin gene-related peptide (CGRP)-, vasoactive intestinal polypeptide (VIP)-, motilin- and substance P (SP)-like immunoreactive substances (IS) in healthy subjects. An open-labeled study was conducted on five healthy volunteers. Each subject was administered a single oral dose of pantethine, fursultiamine and placebo at intervals of one month. Venous blood samples were collected before and at 20, 40, 60, 90, 120, 180 and 240 min after each administration. Plasma peptide levels were measured using a highly sensitive enzyme immunoassay. A single oral dose of pantethine resulted in significant increases of plasma CGRP- and VIP-IS levels compared to placebo. Furthermore, areas under the plasma concentration-time curves (AUC(0-240)) of CGRP- and VIP-IS were significantly higher after pantethine administration compared with placebo. On the other hand, fursultiamine had no effect on plasma levels and AUC(0-240) of CGRP-, VIP-, motilin- and SP-IS. This study demonstrated the different effects of pantethine and fursultiamine from the viewpoint of plasma gastrointestinal peptide changes. The pharmacological effects of pantethine may be closely related to the changes in plasma CGRP- and VIP-IS levels.
Topics: Adult; Calcitonin Gene-Related Peptide; Drug Administration Schedule; Drug Evaluation, Preclinical; Fursultiamin; Gastrointestinal Tract; Humans; Male; Molecular Targeted Therapy; Motilin; Pantetheine; Substance P; Vasoactive Intestinal Peptide; Vitamin B Complex
PubMed: 21963510
DOI: 10.1248/bpb.34.1640 -
Scientific Reports Jul 2018A physically active lifestyle is associated with better health in body and mind, and it is urgent that supporting agents for such lifestyles be developed. In rodents,...
A physically active lifestyle is associated with better health in body and mind, and it is urgent that supporting agents for such lifestyles be developed. In rodents, voluntary locomotor activity as an active physical behavior may be mediated by dopaminergic neurons (DNs). Thiamine phosphate esters can stimulate DNs, and we thus hypothesized that thiamine tetrahydrofurfuryl disulfide (TTFD), a thiamine derivative, promotes locomotor activity via DNs in rats. Acute i.p. administration of TTFD enhanced rat locomotor activity in a normal cage. In vivo microdialysis revealed that TTFD-enhanced locomotor activity was synchronized with dopamine release in the medial prefrontal cortex (mPFC). Antagonism of the dopamine D1 receptor, but not D2 receptor, in the mPFC fully suppressed TTFD-enhanced locomotor activity. Finally, we found a TTFD dose-dependent increase in voluntary wheel running. Our findings demonstrate that DNs in the mPFC mediates TTFD-enhanced locomotor activity, suggesting the potential of TTFD to induce active physical behavior.
Topics: Animals; Dopamine; Dopaminergic Neurons; Fursultiamin; Locomotion; Motor Activity; Prefrontal Cortex; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 29992990
DOI: 10.1038/s41598-018-28462-2 -
Internal Medicine (Tokyo, Japan) Feb 2020A 48-year-old man was brought to our emergency room with acute abdominal pain and systemic edema, indicating acute circulatory failure with lactic acidosis. Furosemide...
A 48-year-old man was brought to our emergency room with acute abdominal pain and systemic edema, indicating acute circulatory failure with lactic acidosis. Furosemide treatment paradoxically worsened the systemic edema and induced confusion. He had no drinking history but hardly ate legumes or meats containing thiamine. Administration of fursultiamine dramatically improved the symptoms and subsequently caused pulmonary edema. Thiamine deficiency may occur in nondrinkers with an unbalanced diet. In this condition, diuretic therapy can worsen the symptoms before thiamine supplementation by promoting the flushing of water-soluble vitamins but is needed for the management of secondary pulmonary edema after thiamine replenishment.
Topics: Beriberi; Fursultiamin; Humans; Male; Middle Aged; Pulmonary Edema; Thiamine; Thiamine Deficiency; Treatment Outcome; Vitamin B Complex
PubMed: 31534090
DOI: 10.2169/internalmedicine.3585-19 -
Neurotoxicology and Teratology Mar 2012Due to genetic defects or illness some individuals require higher amounts of thiamin than are typically provided by the diet. Lipid-soluble thiamin precursors can...
Due to genetic defects or illness some individuals require higher amounts of thiamin than are typically provided by the diet. Lipid-soluble thiamin precursors can achieve high blood levels of thiamin and result in increased concentrations in the central nervous system. High intakes of thiamin have been reported as beneficial in children with autism and attention deficit/hyperactivity disorder. The current study examined the effect of thiamin tetrahydrofurfuryl disulfide (TTFD), a lipophilic precursor, on behavior in the juvenile male DBA/2J mouse. Mice given by oral gavage deionized water or deionized water providing 100 mg or 340 mg TTFD/kg body weight daily for 17 d, starting at postnatal day 18, were tested for effects on operant learning, social interaction, general activity level, and prepulse inhibition of acoustic startle, as well as effects on growth and select organ weights. Results indicate lower activity and altered social interaction at both treatment levels and decreased acoustic startle at the 100 mg/kg level. Compared to controls, percent weight gain was lower in the TTFD-treatment groups, but percent body length increase was not affected by TTFD treatment. TTFD treatment did not influence percent organ weights as percentage of body weights. TTFD treatment resulted in increased whole brain thiamin concentrations. These results support the concept that lipophilic thiamin precursors provided during early development can affect a number of behavioral parameters. In clinical trials with children with behavior disorders, attention should be given to preventing possible adverse gastrointestinal irritant effects associated with TTFD therapy.
Topics: Administration, Oral; Animals; Behavior, Animal; Body Weight; Brain; Fursultiamin; Male; Mice; Mice, Inbred DBA; Organ Size
PubMed: 21816221
DOI: 10.1016/j.ntt.2011.07.006 -
Journal of Nutritional Science and... 2010Thiamin (vitamin B(1)) is known to activate carbohydrate metabolism in part through activation of pyruvate dehydrogenase. The purpose of this study was to investigate...
Thiamin (vitamin B(1)) is known to activate carbohydrate metabolism in part through activation of pyruvate dehydrogenase. The purpose of this study was to investigate the effect of thiamin tetrahydrofurfuryl disulfide (TTFD), a thiamin derivative, on utilization of exogenous glucose by measuring oxidation of (13)C-glucose at rest and during prolonged exercise in mice under normal dietary conditions. Mice orally ingested TTFD (0.1 mg/g BW [body weight]) and (13)C-glucose (0.8 mg/g BW) or (13)C-lactate (0.1 mg/g BW) plus glucose (0.8 mg/g BW) at rest or before endurance running. The average percent of (13)C atoms in total (12)C+(13)C ((13)C atom%) in expired air after ingestion of (13)C-glucose at rest was significantly lower in the TTFD group than in the control group. No significant difference was found in (13)C atom% in expired air after ingestion of (13)C-glucose and prolonged exercise. In addition, no significant effect of TTFD was found in expired (13)C atom% after ingestion of (13)C-lactate plus glucose at rest. TTFD also had no effect on concentrations of muscle or liver glycogen at rest. These results suggest that TTFD, which is a thiamin derivative, decreases oxidation of exogenous glucose at rest, but not during exercise.
Topics: Animals; Carbon Isotopes; Dietary Sucrose; Fursultiamin; Glucose; Lactic Acid; Male; Mice; Mice, Inbred ICR; Oxidation-Reduction; Physical Endurance; Physical Exertion; Rest
PubMed: 20354340
DOI: 10.3177/jnsv.56.9 -
Internal Medicine (Tokyo, Japan) Jun 2005We report a case of a 58-year-old man with Shoshin beriberi who demonstrated ST-segment elevation and myocardial damage without coronary artery stenosis. The patient...
We report a case of a 58-year-old man with Shoshin beriberi who demonstrated ST-segment elevation and myocardial damage without coronary artery stenosis. The patient subsequently recovered with thiamine treatment. We conclude that it is important to consider Shoshin beriberi as part of the differential diagnosis in patients with shock and ST-segment elevation.
Topics: Beriberi; Cardiac Catheterization; Cardiomyopathies; Coronary Angiography; Diagnosis, Differential; Electrocardiography; Follow-Up Studies; Fursultiamin; Gated Blood-Pool Imaging; Humans; Injections, Intravenous; Male; Middle Aged
PubMed: 16020883
DOI: 10.2169/internalmedicine.44.578