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CROSSTALK BETWEEN VITAMIN B AND IMMUNITY
Abstract
Vitamin B1 (thiamin) is considered to be the oldest vitamin and in 1936 R.R. Williams and colleagues determined its chemical structure and were able to synthesize this vitamin. Vitamin B1 influences pro-apoptotic proteins, mitochondrial membrane potential, cytochrome C release, protein kinases, p38-MAPK, suppresses oxidative stress-induced NF-kappaB and has anti-inflammatory properties. Deficiency of vitamin B1 may cause beriberi, dysfunction of the nervous system, neuroinflammation, T cell infiltration, chemokine CCL2 activation, over expression of proinflammatory cytokines, such as IL-1, TNF, IL-6, and arachidonic acid products, and induces expression of CD40 by the microglia and CD40L by astrocytes which provoke the death of neurons. Here we report the relationship between vitamin B complex and immunity.
... La tiamina (B 1 ) la cual se encuentra principalmente en cereales integrales, pescado, carnes rojas, aves, leche y productos lácteos. Es antiinflamatoria, activa las proteínas apoptóticas y provoca la liberación de citocromo C. Su deficiencia se denomina beriberi, lo que implica la infiltración de células T y la activación del estado inflamatorio con la liberación de citocinas proinflamatorias como la IL-1, TNF e IL-6 (Spinas et al., 2015). ...
The relationship between nutrition and immunity is very complex, because each phase of the immune response can be affected by the lack of essential nutrients such as vitamins and minerals. In addition, it has been described that the most prevalent non-communicable diseases worldwide, such as metabolic syndrome, diabetes mellitus, cardiovascular diseases and cancer, underlie the activation of inflammatory mechanisms, which can compromise immune functions, often caused or accompanied by alterations in nutritional patterns and intestinal microbiota. In this context, it is clear that diet is a key modulator of the immune system and much interest is emerging in the area of nutrition as a means of treatment and prevention. The Mediterranean diet has been widely described as positively influencing and is proposed not only as a potential tool in the clinical management of different diseases, but also for global health promotion. Therefore, the aim of this review is to address the current knowledge on the regulatory role of the nutritional components present in the Mediterranean diet on the immune system and the intestinal microbiota.
... Vitamin B1 has an impact on antiinflammatory characteristics, cytochrome C release, mitochondrial membranes, oxidative stress-induced, NF-kappaβ and protein kinases and P38-MAPK. Deficiency of vitamin B1 leads to over expression of proinflammation cytokines like TNF, IL-1, IL-6, and arachidonic acid products, nervous system malfunction, Tcycle infiltration, neuroinflammation, expression CD40 by the microglia and CD40L, causing the loss of astrocytes, beriberi, CL2 chemokine over expression (Spinas et al., 2015). Vitamin B6, in addition to its role as a cofactor for many enzymes involved in macromolecular metabolism, exerts a protective effect against chronic diseases such as cardiovascular diseases (CVD) and diabetes by suppressing inflammation, inflammasomes, oxidative stress and carbonyl stress (Zhang and Liu, 2020). ...
... For instance, vitamin B1 influences mitochondrial membrane potential, apoptotic proteins, and protein kinases [p38 mitogen-activated protein kinases (p38-MAPK)]; suppresses NF-B-induced oxidative stress; and exhibits anti-inflammatory properties. Vitamin B1 deficiency can cause T cell infiltration and chemokine (C-C motif) ligand 2 activation, as well as the overexpression of proinflammatory molecules, such as IL-1, TNF, IL-6, and arachidonic acid derivatives (Spinas et al., 2015). ...
Dietary supplementation with nutraceuticals can promote optimal immune system activation, modulating different pathways that enhance immune defenses. Therefore, the immunity-boosting effects of nutraceuticals encompass not only immunomodulatory but also antioxidant, antitumor, antiviral, antibacterial, and antifungal properties, with therapeutic effects against diverse pathological conditions. However, the complexity of the pathways that regulate the immune system, numerous mechanisms of action, and heterogeneity of the immunodeficiencies, and subjects treated make their application in the clinical field difficult. Some nutraceuticals appear to safely improve immune system function, particularly by preventing viral and bacterial infections in specific groups, such as children, the elderly, and athletes, as well as in frail patients, such as those affected by autoimmune diseases, chronic diseases, or cancer. Several nutraceuticals, such as vitamins, mineral salts, polyunsaturated omega-3 fatty acids, many types of phytocompounds, and probiotic strains, have the most consolidated evidence in humans. In most cases, further large and long-term randomized clinical trials are needed to confirm the available preliminary positive data.
... Their concentration in AM varies, and they are crucial to cell metabolism. While working on macrophages, vitamin B1 may have an anti-inflammatory impact and reduce NF-κB activation induced by oxidative stress (Spinas et al., 2015). It significantly contributes to the eradication of SARS-CoV-2 by fostering humoral and cell-mediated immunity in COVID-19 patients (Shakoor et al., 2021). ...
The global pandemic of COVID‐19 is considered one of the most catastrophic events on earth. During the pandemic, food ingredients may play crucial roles in preventing infectious diseases and sustaining people's general health and well‐being. Animal milk acts as a super food since it has the capacity to minimize the occurrence of viral infections due to inherent antiviral properties of its ingredients. SARS‐CoV‐2 virus infection can be prevented by immune‐enhancing and antiviral properties of caseins, α‐lactalbumin, β‐lactoglobulin, mucin, lactoferrin, lysozyme, lactoperoxidase, oligosaccharides, glycosaminoglycans, and glycerol monolaurate. Some of the milk proteins (i.e., lactoferrin) may work synergistically with antiviral medications (e.g., remdesivir), and enhance the effectiveness of treatment in this disease. Cytokine storm during COVID‐19 can be managed by casein hydrolyzates, lactoferrin, lysozyme, and lactoperoxidase. Thrombus formation can be prevented by casoplatelins as these can inhibit human platelet aggregation. Milk vitamins (i.e., A, D, E, and B complexes) and minerals (i.e., Ca, P, Mg, Zn, and Se) can have significantly positive effects on boosting the immunity and health status of individuals. In addition, certain vitamins and minerals can also act as antioxidants, anti‐inflammatory, and antivirals. Thus, the overall effect of milk might be a result of synergistic antiviral effects and host immunomodulator activities from multiple components. Due to multiple overlapping functions of milk ingredients, they can play vital and synergistic roles in prevention as well as supportive agents during principle therapy of COVID‐19.
Thiamine (thiamin, B1) is a vitamin necessary for proper cell function. It exists in a free form as a thiamine, or as a mono-, di- or triphosphate. Thiamine plays a special role in the body as a coenzyme necessary for the metabolism of carbohydrates, fats and proteins. In addition, it participates in the cellular respiration and oxidation of fatty acids: in malnourished people, high doses of glucose result in acute thiamine deficiency. It also participates in energy production in the mitochondria and protein synthesis. In addition, it is also needed to ensure the proper functioning of the central and peripheral nervous system, where it is involved in neurotransmitter synthesis. Its deficiency leads to mitochondrial dysfunction, lactate and pyruvate accumulation, and consequently to focal thalamic degeneration, manifested as Wernicke's encephalopathy or Wernicke-Korsakoff syndrome. It can also lead to severe or even fatal neurologic and cardiovascular complications, including heart failure, neuropathy leading to ataxia and paralysis, confusion, or delirium. The most common risk factor for thiamine deficiency is alcohol abuse. This paper presents current knowledge of the biological functions of thiamine, its antioxidant properties, and the effects of its deficiency in the body.
Coronavirus 2019 (COVID-19), an epidemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), has spread worldwide since it was first identified in Wuhan, China, in December 2019, leading to outbreaks of epidemics. Due to the increasing spread of this disease, definitive treatment and approved vaccines have not been found for it. In this study, we reviewed recent articles on the effect of vitamins (including vitamins A, B, and E) for treating coronavirus. This result suggests that some dietary supplements such as vitamins (A, B, C, D, E, etc.) have antiviral, antioxidant, and anti-inflammatory effects. Dietary supplements consisting of vitamins and individual dietary habits can therefore be used as adjunctive therapy along with antiviral drugs in the treatment of COVID-19 disease.
Non-communicable diseases, such as cardiovascular disease, cancer, diabetes, obesity, and hypertension, represent the cause of 60% of all deaths around the globe. With proper diet and natural dietary antioxidant supplements, these diseases can be prevented by up to 40% according to the British Nutrition Foundation.
This book provides a comprehensive overview of the literature on the health benefits of natural dietary antioxidant supplements. It presents state-of-the-art research and information as well as the global regulations, labelling, and health claims of natural dietary antioxidant supplements.
Written by expert authors, the wealth of research is arranged by disease type rather than by supplement type making it much more useful to the reader. Filling a gap in the literature, the book is aimed at researchers and professionals working in food chemistry, nutrition, and health benefits.
Background
Inflammation and cytokine storm have been reported to be the main cause of acute symptoms of coronavirus disease (COVID-19). Diet-induced inflammation may affect the condition of patients with COVID-19. Therefore, this study aimed to investigate the relationship between disease severity, inflammatory and immune system biomarkers, and the dietary inflammatory index (DII) in patients with COVID-19.
Methods
This cross-sectional study was conducted on 500 adult patients with COVID-19. Patients were divided into mild, moderate, and severe conditions based on clinical and laboratory evidence. A validated food frequency questionnaire (FFQ) was used to determine DII and energy-adjusted DII (E-DII) scores. The serum C-reactive protein (CRP) level and blood cell count were measured for all patients. Multiple linear regression was used to explore the association between DII and E-DII and CRP, blood cell counts, and hospitalization in patients with COVID-19.
Results
Coronavirus disease (COVID-19) patients with higher DII had higher consumption of fat and carbohydrate and lower intakes of protein, anti-inflammatory nutrients, garlic, caffeine, tea, onion, and fiber ( P < 0.05). There was a positive association between DII and CRP (β = 1.024, P < 0.001), hospitalization (β = 1.062, P < 0.001), WBC count (β = 0.486, P < 0.009), neutrophil count (β = 0.565, P < 0.001), and neutrophil-to-lymphocyte ratio (β = 0.538, P < 0.001) and a negative association between DII and the lymphocyte count (β = −0.569, P < 0.001). There was a positive association between E-DII and hospitalization (β = 1.645, P < 0.001), WBC count (β = 0.417, P < 0.02), and neutrophil-to-lymphocyte ratio (β = 0.35, P < 0.03).
Conclusion
There is a positive correlation between DII and inflammation, immune hyperactivation, and length of hospital stay in patients with COVID-19. Further longitudinal studies are necessary.
The aim of this study was to evaluate the potential of micronutrients and feed additives to modulate intestinal microbiota and systemic and mucosal immune responses in weaned pigs infected with Salmonella. At weaning, 32 litters of 12 piglets each were allocated to four dietary treatments: 1) control diet (CTRL), 2) CTRL supplemented with chlortetracycline (ATB), 3) CTRL supplemented with a cocktail of feed additives (CKTL); and 4) CKTL diet containing bovine colostrum in replacement of spray-dry animal plasma (CKTL+COL). The CKTL supplement included cranberry extract, encapsulated carvacrol and yeast-derived products and an enriched selenium and vitamin premix. Three weeks after weaning, four pigs per litter were orally inoculated with Salmonella Typhimurium DT104. Half of them were euthanized 3 days post-infection (dpi) and the other half, 7 dpi. The expression of IL6, TNF, IL8, monocyte chemoattractant protein 1 (MCP1), IFNG, cyclooxygenase 2 (COX2), glutathione peroxidase 2 (GPX2) and β-defensin 2 (DEFB2) showed a peaked response at 3 dpi (P < 0.05). Results also revealed that DEFB2 expression was higher at 3 dpi in CTRL and CKTL groups than in ATB (P=0.01 and 0.06, respectively) while GPX2 gene was markedly increased at 3 and 7 dpi in pigs fed CKTL or CKTL+COL diet compared to CTRL pigs (P<0.05). In piglets fed CKTL or CKTL+COL diet, intestinal changes in microbial communities were less pronounced after exposure to Salmonella compared to CTRL and progressed faster toward the status before Salmonella challenge (AMOVA P<0.01). Furthermore, the relative abundance of several families was either up- or down-regulated in pigs fed CKTL or CKTL+COL diet after Salmonella challenge. In conclusion, weaning diet enriched with bovine colostrum, vitamins and mixture of feed additives mitigated the influence of Salmonella infection on intestinal microbial populations and modulate systemic and intestinal immune defences.
Multiple sclerosis (MS) is a complex multifactorial disease that results from the interplay between environmental factors and a susceptible genetic background. Experimental autoimmune encephalomyelitis (EAE) has been widely used to investigate the mechanisms underlying MS pathogenesis. Chemokines, such as CCL2, are involved in the development of EAE. We have previously shown that thiamine deficiency (TD) induced CCL2 in neurons. We hypothesized that TD may affect the pathogenesis of EAE. In this study, EAE was induced in C57BL/6J mice by the injection of myelin oligodendroglial glycoprotein (MOG) peptides 35-55 with or without TD. TD aggravated the development of EAE, which was indicated by clinical scores and pathologic alterations in the spinal cord. TD also accelerated the development of EAE in an adoptive transfer EAE model. TD caused microglial activation and a drastic increase (up 140%) in leukocyte infiltration in the spinal cord of the EAE mice; specifically, TD increased Th1 and Th17 cells. TD upregulated the expression of CCL2 and its receptor CCR2 in the spinal cord of EAE mice. Cells in peripheral lymph node and spleen isolated from MOG-primed TD mice showed much stronger proliferative responses to MOG. CCL2 stimulated the proliferation and migration of T lymphocytes in vitro. Our results suggested that TD exacerbated the development of EAE through activating CCL2 and inducing pathologic inflammation.
Incomplete β-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and long-chain acylcarnitines (by-products of incomplete β-oxidation) are elevated in type 2 diabetes and insulin resistance. In a previous study, we reported that mixed D, L isomers of C12- or C14-carnitine induced an NFκB-luciferase reporter gene in RAW 264.7 cells suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant L-acylcarnitines activate classical pro-inflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of COX-2 in a chain length dependent manner in RAW 264.7 cells. L-C14 carnitine (5-25μM), used as a representative acylcarnitine, stimulated the expression and secretion of pro-inflammatory cytokines in a dose-dependent manner. Furthermore, L-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many pro-inflammatory signaling pathways including PRRs. Knockdown of MyD88, a key co-factor in PRR signaling and inflammation, blunted the pro-inflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, L-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking TLR2 and TLR4, and did not activate reporter constructs in TLR-overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified.
Virtual Histology Intravascular Ultrasound (VH-IVUS) may be used to detect early signs of unstable coronary artery disease. Monocyte Chemoattractant Protein-1 (MCP-1) is linked with coronary atherosclerosis and plaque instability and could potentially be modified by folic acid treatment.
In a randomized, prospective study, 102 patients with stable angina pectoris (SAP) received percutaneous coronary intervention and established medical treatment as well as either homocysteine-lowering folic acid/vitamin B12 (±B6) or placebo (±B6) for 1 year before VH-IVUS was performed. The presence of VH-Thin-Cap Fibroatheroma (VH-TCFA) in non-intervened coronary vessels was registered and serum levels of MCP-1 were measured. The patients were subsequently followed for incident myocardial infarction (MI).
Patients treated with folic acid/vitamin B12 had a geometric mean (SD) MCP-1 level of 79.95 (1.49) versus 86.00 (1.43) pg/mL for patients receiving placebo (p-value 0.34). VH-TCFA lesions were present in 7.8% of patients and did not differ between intervention arms (p-value 0.47). Serum levels of MCP-1 were 1.46 (95% CI 1.12 to 1.92) times higher in patients with VH-TCFA lesions than in those without (p-value 0.005). Afterwards, patients were followed for median 2.1 years and 3.8% experienced a myocardial infarction (MI), which in post-hoc Cox regression analyses was independently predicted by both MCP-1 (P-value 0.006) and VH-TCFA (p-value 0.01).
In patients with SAP receiving established medical treatment, folic acid supplementation is not associated with either presence of VH-TCFA or levels of MCP-1. MCP-1 is however associated with VH-TCFA, a finding corroborated by increased risk for future MI. ClinicalTrials.gov Identifier: NCT00354081.
Several emerging lines of evidence support an anti-inflammatory role for nicotinic acid (niacin); however, its role in the regulation of leukocyte migration in response to inflammatory stimuli has not been elucidated until now. Herein, we have examined the effect of nicotinic acid on neutrophil recruitment in experimentally induced inflammation. We demonstrated that nicotinic acid treatment inhibited interleukin (IL)-8-induced, leukotriene (LT)B4-induced, and carrageenan-induced neutrophil migration into the pleural cavity of BALB/c mice and reduced neutrophil rolling and adherence in a mouse cremaster muscle preparation. Surprisingly, nicotinic acid treatment increased the level of the neutrophil chemoattractant KC in response to carrageenan. These results suggest that nicotinic acid plays an important role in the regulation of inflammation due to its ability to inhibit the actions of the neutrophil chemoattractants IL-8 and LTB4. Further inhibition of chemoattractants leads to impairment of leukocyte rolling and adherence to the vascular endothelium in the microcirculation of inflamed tissues.
Background In vitro, vitamin B12 acts as a natural inhibitor of hepatitis C virus (HCV) replication.
Objective To assess the effect of vitamin B12 on virological response in patients with chronic HCV hepatitis naïve to antiviral therapy.
Methods Ninety-four patients with chronic HCV hepatitis were randomly assigned to receive pegylated interferon α plus ribavirin (standard-of-care; SOC) or SOC plus vitamin B12 (SOC+B12). Viral response—namely, undetectable serum HCV-RNA, was evaluated 4 weeks after starting treatment (rapid viral response), 12 weeks after starting treatment (complete early viral response) and 24 or 48 weeks after starting treatment (end-of-treatment viral response) and 24 weeks after completing treatment (sustained viral response (SVR)). Genotyping for the interleukin (IL)-28B polymorphism was performed a posteriori in a subset (42/64) of HCV genotype 1 carriers.
Results Overall, rapid viral response did not differ between the two groups, whereas the rates of complete early viral response (p=0.03), end-of-treatment viral response (p=0.03) and SVR (p=0.001) were significantly higher in SOC+B12 patients than in SOC patients. In SOC+B12 patients, the SVR rate was also significantly higher in carriers of a difficult-to-treat genotype (p=0.002) and in patients with a high baseline viral load (p=0.002). Distribution of genotype IL-28B did not differ between the two groups. At multivariate analysis, only easy-to-treat HCV genotypes (OR=9.00; 95% CI 2.5 to 37.5; p=0.001) and vitamin B12 supplementation (OR=6.9; 95% CI 2.0 to 23.6; p=0.002) were independently associated with SVR.
Conclusion Vitamin B12 supplementation significantly improves SVR rates in HCV-infected patients naïve to antiviral therapy.
Liver is a vital organ for the detoxification of toxic substances present in the body and hepatic injury is associated with excessive exposure to toxicants. The present study was designed to evaluate the possible hepatoprotective effects of riboflavin against carbon tetrachloride (CCl4) induced hepatic injury in rats. Rats were divided into six groups. Hepatotoxicity was induced by the administration of a single intraperitoneal dose of CCl4 in experimental rats. Riboflavin was administered at 30 and 100mg/kg by oral gavage to test its protective effect on hepatic injury biochemically and histopathologically in the blood/liver and liver respectively. The administration of CCl4 resulted in marked alteration in serum hepatic enzymes (like AST, ALT and ALP), oxidant parameters (like GSH and MDA) and pro-inflammatory cytokine TNF-α release from blood leukocytes indicative of hepatic injury. Changes in serum hepatic enzymes, oxidant parameters and TNF-α production induced by CCl4 were reversed by riboflavin treatment in a dose dependent manner. Treatment with standard drug, silymarin also reversed CCl4 induced changes in biomarkers of liver function, oxidant parameters and inflammation. The biochemical observations were paralleled by histopathological findings in rat liver both in the case of CCl4 and treatment groups. In conclusion, riboflavin produced a protective effect against CCl4-induced liver damage. Our study suggests that riboflavin may be used as a hepato-protective agent against toxic effects caused by CCl4 and other chemical agents in the liver.
Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder. Severe folate deficiency in HFM can result in immunodeficiency. We describe a female infant with HFM who acquired severe Pneumocystis pneumonia. The objective of the present study was to elucidate her immunological phenotype and to examine the time course of immune recovery following parenteral folate therapy. The patient demonstrated a combined immunodeficiency with an impaired T cell proliferation response, pan-hypogammaglobulinemia, and an imbalanced pro-inflammatory cytokine profile. She had a normal white blood cell count, normal lymphocyte subsets, and normal complement levels. Two novel mutations were identified within the SLC46A1 gene to produce a compound heterozygote. We confirmed full recovery of her immunological and neurophysiological status with parenteral folate replacement. The time course of recovery of her immunological profile varied widely, however. HFM should be recognized as a unique form of immunodeficiency.
It is known that cobalamin (Cbl) deficiency damages myelin by increasing tumor necrosis factor (TNF)-α and decreasing epidermal growth factor (EGF) levels in rat central nervous system (CNS), and affects the peripheral nervous system (PNS) morphologically and functionally. It is also known that some polyneuropathies not due to Cbl deficiency are connected with increased TNF-α levels, and that various cytokines (including TNF-α) and growth factors regulate the in vitro synthesis of normal prions (PrP(C)s). Given that there is extensive evidence that PrP(C)s play a key role in the maintenance of CNS and PNS myelin, we investigated whether the PrP(C) octapeptide repeat (OR) region is involved in the pathogenesis of rat Cbl-deficient (Cbl-D) polyneuropathy. After intracerebroventricularly administering antibodies (Abs) against the OR-region (OR-Abs) to Cbl-D rats to prevent myelin damage and maximum nerve conduction velocity (MNCV) abnormalities, and PrP(C)s to otherwise normal rats to reproduce PNS Cbl-D-like lesions, we measured PrP(C) levels and MNCV of the sciatic and tibial nerves. PrP(C) and TNF-α levels were increased in sciatic and tibial nerves of Cbl-D and saline-treated rats, and the OR-Abs normalized the myelin ultrastructure, TNF-α levels, and MNCV values of the sciatic and tibial nerves of Cbl-D rats. The same peripheral nerves of the otherwise normal PrP(C)-treated rats showed typical Cbl-D myelin lesions, significantly increased TNF-α levels, and significantly decreased MNCV values. These findings demonstrate that Cbl deficiency induces excess PrP(C)s and thereby excess OR regions, which seem to be responsible for the PNS myelin damage, as has recently been found in the case of CNS myelin damage (Scalabrino et al., 2012). Furthermore, excess TNF-α is also involved in the pathogenesis of Cbl-D polyneuropathy. In conclusion, we have extended the list of prion diseases by adding one caused by excess PrP(C)s and the polyneuropathies related to excess TNF-α.
The influence of riboflavin (vitamin B(2) ) upon growth, invasion, and migration in non-small cell lung cancer cell lines was evaluated. Riboflavin at 1, 10, 25, 50, 100, 200, or 400 μmol/L was added into A549, H3255, or Calu-6 cells. The effects of this compound upon level and/or expression of reactive oxygen species (ROS), inflammatory cytokines, intercellular adhesion molecule (ICAM)-1, fibronectin, matrix metalloproteinase (MMP)-9, MMP-2, focal adhesion kinase (FAK), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) were examined. Results showed that riboflavin at test doses did not affect the level of ROS and glutathione. Riboflavin at 200 and 400 μmol/L significantly enhanced cell growth in test lung cancer cell lines, and at 400 μmol/L significantly increased the release of interleukin-6, tumor necrosis factor-alpha, and vascular endothelial growth factor. This agent at 200 and 400 μmol/L also upregulated protein production of ICAM-1, fibronectin, MMP-9, MMP-2, NF-κB p50, p-p38 MAPK, and FAK; and at 400 μmol/L enhanced invasion and migration in test cell lines. These findings suggested that riboflavin at high doses might promote lung cancer progression.