Iron is necessary for the production of hemoglobin, a protein in red blood cells that carries oxygen from the lungs to the body's tissues.

Iron plays a key role in energy metabolism and is essential for the synthesis of ATP, the body's primary source of cellular energy.

Iron is involved in the production of white blood cells and antibodies, which support the body's immune system.

Riboflavin plays a key role in energy production. It helps break down proteins, fats, and carbohydrates.

Riboflavin is necessary for maintaining good eye health and may prevent certain eye conditions like cataracts.

Riboflavin plays a vital role in maintaining healthy skin and hair. It is often used in treatments for skin disorders, including acne and dermatitis.

Niacin has been shown to lower LDL cholesterol levels, which may help reduce the risk of heart disease and stroke.

Niacin can help increase HDL cholesterol levels, improving the overall cholesterol profile and supporting heart health.

Niacin plays a vital role in the production of various neurotransmitters, supporting cognitive function and mental health.

Some research suggests that niacin may help improve blood sugar control in people with type 2 diabetes by enhancing insulin sensitivity.

Niacin has anti-inflammatory properties and can help improve skin health by reducing redness, inflammation, and symptoms of certain skin conditions.

Vegetarian

Dairy-Free

Milk Allergy

Kosher (Kashrut)

Slow Carb

Cream of Wheat

Water

Energy

Energy (by joule)

Protein

Total lipid (fat)

Carbohydrate, by difference

Fiber, total dietary

Sugars, total including NLEA

Sucrose

Calcium, Ca

Iron, Fe

Magnesium, Mg

Phosphorus, P

Potassium, K

Sodium, Na

Zinc, Zn

Copper, Cu

Selenium, Se

Thiamin

Riboflavin

Niacin

Pantothenic acid

Vitamin B-6

Folate, total

Folic acid

Folate, food

Folate, DFE

Choline, total

Vitamin A, RAE

Retinol

Vitamin A, IU

Lutein + zeaxanthin

Vitamin E (alpha-tocopherol)

Vitamin K (phylloquinone)

Fatty acids, total saturated

SFA 14:0

SFA 16:0

SFA 18:0

Fatty acids, total monounsaturated

MUFA 16:1

MUFA 18:1

Fatty acids, total polyunsaturated

PUFA 18:2

PUFA 18:3

Tryptophan

Threonine

Isoleucine

Leucine

Lysine

Methionine

Cystine

Phenylalanine

Tyrosine

Valine

Arginine

Histidine

Alanine

Aspartic acid

Glutamic acid

Glycine

Proline

Serine

Ferroptosis is an iron-dependent cell death pathway and participates in various diseases. Current evidence suggests that ferroptosis can obviously affect the function of blood cells. This paper aims to elaborate the role of ferroptosis in blood cells and related diseases. First, abnormal ferroptosis damages the developing red blood cells by breaking systemic iron homeostasis, leading to erythropoiesis suppression and anaemia. Ferroptosis mediates neutrophils recruitment and neutrophil extracellular trap formation (NETosis). In T-cells, ferroptosis induces a novel point of synergy between immunotherapy and radiotherapy. Additionally, ferroptosis may mediate B cells differentiation, antibody responses and lymphoma. Nevertheless, increased ferroptosis can ameliorate acute myeloid leukaemia and T-cell leukaemia/lymphoma by inducing iron-dependent cancer cells death. Besides, ferroptosis activates platelets by increasing P-selectin, thus causing thromboembolism. Ferroptosis mediates virus infection and parasite infection by driving T-cell death and preventing T-cell immunity. Interestingly, ferroptosis is also considered as a critical player in COVID-19 infections, while targetting ferroptosis may also improve thromboembolism and prognosis in patients with COVID-19 infection. Overall, the crucial role of ferroptosis in blood cells will show a new therapeutic potential in blood cell-related diseases.HighlightsFerroptosis shows a new therapeutic potential for blood cell-related diseases.Ferroptosis damages erythropoiesis and thus induces anaemia.Ferroptosis induces platelet activation and leads to thromboembolism.Ferroptosis regulates T-cell and B-cell immunity, which participant in infectious diseases.Inversely, ferroptosis ameliorates acute myeloid leukaemia and T-cell leukaemia.

Targetting ferroptosis for blood cell-related diseases.

Iron is an essential micronutrient for virtually all living cells. In infectious diseases, both invading pathogens and mammalian cells including those of the immune system require iron to sustain their function, metabolism and proliferation. On the one hand, microbial iron uptake is linked to the virulence of most human pathogens. On the other hand, the sequestration of iron from bacteria and other microorganisms is an efficient strategy of host defense in line with the principles of 'nutritional immunity'. In an acute infection, host-driven iron withdrawal inhibits the growth of pathogens. Chronic immune activation due to persistent infection, autoimmune disease or malignancy however, sequesters iron not only from infectious agents, autoreactive lymphocytes and neoplastic cells but also from erythroid progenitors. This is one of the key mechanisms which collectively result in the anemia of chronic inflammation. In this review, we highlight the most important interconnections between iron metabolism and immunity, focusing on host defense against relevant infections and on the clinical consequences of anemia of inflammation.

Iron in infection and immunity.

Anemia is common in elective surgery and is an independent risk factor for morbidity and mortality. Historical management of anemia has focused on the use of allogeneic blood transfusion but this in itself is not without risk. It too has been independently associated with morbidity and mortality, let alone the costs and relative shortage of this resource. In recognition of this, patient blood management (PBM) shifts the focus from the product to the patient and views the patient's own blood as a resource that should be conserved and managed appropriately as a standard of care. It consists of 3 pillars: the optimization of red blood cell mass; reduction of blood loss and bleeding; and optimization of the patient's physiological tolerance toward anemia. Integration of these 3 pillars in the form of multimodal care bundles and strategies into perioperative pathways should improve care processes and patient outcome. Preoperative anemia is most commonly caused by functional iron deficiency and should be treated with oral iron, intravenous iron, and/or recombinant erythropoietin. An individualized assessment of the thrombotic risk of discontinuing anticoagulant and antiplatelet medication should be balanced against the risk of perioperative bleeding. Neuraxial anesthetic techniques should be considered and minimally invasive surgery undertaken where appropriate. Cell salvage should be used if significant blood loss is anticipated and pharmacological treatments such as tranexamic acid and fibrin sealants have been shown to reduce blood loss. Point of care tests can guide the perioperative management of dynamic coagulopathy. Blood testing sampling should be performed only when indicated and when taken, sample volume and waste should be minimized. Restrictive blood transfusion thresholds and reassessment after single unit transfusion should be incorporated into clinical practice where appropriate. For PBM to become standard practice in routine surgical care, national health care quality change initiatives must set the agenda for change but the patient-centered approach to PBM should be delivered in a way that is also hospital centered. Characterization of the current practice of PBM at each hospital is crucial to facilitate the benchmarking of performance. Barriers to effective implementation such as lack of knowledge should be identified and acted on. Continuous audit of practice with a focus on transfusion rates and patient outcomes can identify areas in need of improvement and provide iterative feedback to motivate and inspire the main stakeholders.

Perioperative Patient Blood Management to Improve Outcomes.

Metals are essential components in all forms of life required for the function of nearly half of all enzymes and are critically involved in virtually all fundamental biological processes. Especially, the transition metals iron (Fe), zinc (Zn), manganese (Mn), nickel (Ni), copper (Cu) and cobalt (Co) are crucial micronutrients known to play vital roles in metabolism as well due to their unique redox properties. Metals carry out three major functions within metalloproteins: to provide structural support, to serve as enzymatic cofactors, and to mediate electron transportation. Metal ions are also involved in the immune system from metal allergies to nutritional immunity. Within the past decade, much attention has been drawn to the roles of metal ions in the immune system, since increasing evidence has mounted to suggest that metals are critically implicated in regulating both the innate immune sensing of and the host defense against invading pathogens. The importance of ions in immunity is also evidenced by the identification of various immunodeficiencies in patients with mutations in ion channels and transporters. In addition, cancer immunotherapy has recently been conclusively demonstrated to be effective and important for future tumor treatment, although only a small percentage of cancer patients respond to immunotherapy because of inadequate immune activation. Importantly, metal ion-activated immunotherapy is becoming an effective and potential way in tumor therapy for better clinical application. Nevertheless, we are still in a primary stage of discovering the diverse immunological functions of ions and mechanistically understanding the roles of these ions in immune regulation. This review summarizes recent advances in the understanding of metal-controlled immunity. Particular emphasis is put on the mechanisms of innate immune stimulation and T cell activation by the essential metal ions like calcium (Ca2+), zinc (Zn2+), manganese (Mn2+), iron (Fe2+/Fe3+), and potassium (K+), followed by a few unessential metals, in order to draw a general diagram of metalloimmunology.

Metalloimmunology: The metal ion-controlled immunity.

Iron overload causes progressive organ damage and is associated with arthritis, liver damage, and heart failure. Elevated iron levels are present in 1%-5% of individuals; however, iron overload is undermonitored and underdiagnosed. Genetic factors affecting iron homeostasis are emerging. Individuals with hereditary xerocytosis, a rare disorder with gain-of-function (GOF) mutations in mechanosensitive PIEZO1 ion channel, develop age-onset iron overload. We show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. We further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, we find that E756del, a mild GOF PIEZO1 allele present in one-third of individuals of African descent, is strongly associated with increased plasma iron. Our study links macrophage mechanotransduction to iron metabolism and identifies a genetic risk factor for increased iron levels in African Americans.

A role of PIEZO1 in iron metabolism in mice and humans.

Ferroptosis, a type of cell death involving iron and lipid peroxidation, has been found to be closely associated with the development of many diseases. Mitochondria are vital components of eukaryotic cells, serving important functions in energy production, cellular metabolism, and apoptosis regulation. Presently, the precise relationship between mitochondria and ferroptosis remains unclear. In this study, we aim to systematically elucidate the mechanisms via which mitochondria regulate ferroptosis from multiple perspectives to provide novel insights into mitochondrial functions in ferroptosis. Additionally, we present a comprehensive overview of how mitochondria contribute to ferroptosis in different conditions, including cancer, cardiovascular disease, inflammatory disease, mitochondrial DNA depletion syndrome, and novel coronavirus pneumonia. Gaining a comprehensive understanding of the involvement of mitochondria in ferroptosis could lead to more effective approaches for both basic cell biology studies and medical treatments.

Mitochondria-mediated Ferroptosis in Diseases Therapy: From Molecular Mechanisms to Implications.

Complex I (NADH:ubiquinone oxidoreductase) is crucial for respiration in many aerobic organisms. In mitochondria, it oxidizes NADH from the tricarboxylic acid cycle and β-oxidation, reduces ubiquinone, and transports protons across the inner membrane, contributing to the proton-motive force. It is also a major contributor to cellular production of reactive oxygen species. The redox reaction of complex I is catalyzed in the hydrophilic domain; it comprises NADH oxidation by a flavin mononucleotide, intramolecular electron transfer along a chain of iron-sulfur clusters, and ubiquinone reduction. Redox-coupled proton translocation in the membrane domain requires long-range energy transfer through the protein complex, and the molecular mechanisms that couple the redox and proton-transfer half-reactions are currently unknown. This review evaluates extant data on the mechanisms of energy transduction and superoxide production by complex I, discusses contemporary mechanistic models, and explores how mechanistic studies may contribute to understanding the roles of complex I dysfunctions in human diseases.

Mitochondrial complex I.

Optimising nutrition intake is a key component for supporting athletic performance and supporting adaption to training. Athletes often use micronutrient supplements in order to correct vitamin and mineral deficiencies, improve immune function, enhance recovery and or to optimise their performance. The aim of this review was to investigate the recent literature regarding micronutrients (specifically iron, vitamin C, vitamin E, vitamin D, calcium) and their effects on physical performance. Over the past ten years, several studies have investigated the impacts of these micronutrients on aspects of athletic performance, and several reviews have aimed to provide an overview of current use and effectiveness. Currently the balance of the literature suggests that micronutrient supplementation in well-nourished athletes does not enhance physical performance. Excessive intake of dietary supplements may impair the body's physiological responses to exercise that supports adaptation to training stress. In some cases, micronutrient supplementation is warranted, for example, with a diagnosed deficiency, when energy intake is compromised, or when training and competing at altitude, however these micronutrients should be prescribed by a medical professional. Athletes are encouraged to obtain adequate micronutrients from a wellbalanced and varied dietary intake.

Micronutrients and athletic performance: A review.

Meat represents an important source of high-quality dietary protein for a large proportion of the global population. In addition, red meat, in particular, significantly contributes to the intake of a wide range of micronutrients, including iron, zinc, selenium, vitamin D and vitamin B12. While these nutrients can be supplied in sufficient amounts by consumption of a range of fruit and vegetables, in many developing countries, where the availability of such foods may be limited, access to meat often protects against malnutrition and improves child cognitive development. Excessive consumption of meat and meat products is often associated with overconsumption of energy and fat, resulting in excess weight, obesity and an increased risk of chronic diseases, such as cardiovascular disease and type 2 diabetes. In addition, certain components of fresh and processed red meat may further increase the risk of these diseases and predispose the consumer to cancer, particularly colorectal cancer. In the face of population growth and global warming, there is increasing concern about the sustainability of farm animal production. Thus, while a modest intake of meat represents an important strategy to avoid essential nutrient deficiencies, limiting its intake can reduce the development of a range of chronic diseases and could have significant beneficial effects on global food security.

The effects of meat consumption on global health.

Iron plays a crucial role in the biochemistry and development of nearly all living organisms. Iron starvation of pathogens during infection is a striking feature utilized by a host to quell infection. In mammals and some other animals, iron is essentially obtained from diet and recycled from erythrocytes. Free iron is cytotoxic and is readily available to invading pathogens. During infection, most pathogens utilize host iron for their survival. Therefore, to ensure limited free iron, the host's natural system denies this metal in a process termed nutritional immunity. In this fierce battle for iron, hosts win over some pathogens, but others have evolved mechanisms to overdrive the host barriers. Production of siderophores, heme iron thievery, and direct binding of transferrin and lactoferrin to bacterial receptors are some of the pathogens' successful strategies which are highlighted in this review. The intricate interplay between hosts and pathogens in iron alteration systems is crucial for understanding host defense mechanisms and pathogen virulence. This review aims to elucidate the current understanding of host and pathogen iron alteration systems and propose future research directions to enhance our knowledge in this field.

Key players in the regulation of iron homeostasis at the host-pathogen interface.

Understanding of ferritin biology has traditionally centered on its role in iron storage and homeostasis, with low ferritin levels indicative of deficiency and high levels indicative of primary or secondary hemochromatosis. However, further work has shown that iron, redox biology and inflammation are inexorably linked. During infection, increased ferritin levels represent an important host defense mechanism that deprives bacterial growth of iron and protects immune cell function. It may also be protective, limiting the production of free radicals and mediating immunomodulation. Additionally, hyperferritinemia is a key acute-phase reactants, used by clinicians as an indication for therapeutic intervention, aimed at controlling inflammation in high-risk patients. One school of thought maintains that hyperferritinemia is an 'innocent bystander' biomarker of uncontrolled inflammation that can be used to gauge effectiveness of intervention. Other schools of thought maintain that ferritin induction could be a protective negative regulatory loop. Others maintain that ferritin is a key mediator of immune dysregulation, especially in extreme hyperferritinemia, via direct immune-suppressive and pro-inflammatory effects. There is a clear need for further investigation of the role of ferritin in uncontrolled inflammatory conditions both as a biomarker and mediator of disease because its occurrence identifies patients with high mortality risk and its resolution predicts their improved survival.

Hyperferritinemia and inflammation.

Iron is vital for many physiological functions, including energy production, and dysregulated iron homeostasis underlies a number of pathologies. Ferroptosis is a recently recognized form of regulated cell death that is characterized by iron dependency and lipid peroxidation, and this process has been reported to be involved in multiple diseases. The mechanisms underlying ferroptosis are complex, and involve both well-described pathways (including the iron-induced Fenton reaction, impaired antioxidant capacity, and mitochondrial dysfunction) and novel interactions linked to cellular energy production. In this review, we examine the contribution of iron to diverse metabolic activities and their relationship to ferroptosis. There is an emphasis on the role of iron in driving energy production and its link to ferroptosis under both physiological and pathological conditions. In conclusion, excess reactive oxygen species production driven by disordered iron metabolism, which induces Fenton reaction and/or impairs mitochondrial function and energy metabolism, is a key inducer of ferroptosis.

Double-edge sword roles of iron in driving energy production versus instigating ferroptosis.

The role of iron in the formation and functioning of erythrocytes, and to a lesser degree of white blood cells, is well established, but the relationship between iron and platelets is less documented. Physiologically, iron plays an important role in hematopoiesis, including thrombopoiesis; iron levels direct, together with genetic factors, the lineage commitment of megakaryocytic/erythroid progenitors toward either megakaryocyte or erythroid progenitors. Megakaryocytic iron contributes to cellular machinery, especially energy production in platelet mitochondria. Thrombocytosis, possibly favoring vascular thrombosis, is a classical feature observed with abnormally low total body iron stores (mainly due to blood losses or decreased duodenal iron intake), but thrombocytopenia can also occur in severe iron deficiency anemia. Iron sequestration, as seen in inflammatory conditions, can be associated with early thrombocytopenia due to platelet consumption and followed by reactive replenishment of the platelet pool with possibility of thrombocytosis. Iron overload of genetic origin (hemochromatosis), despite expected mitochondrial damage related to ferroptosis, has not been reported to cause thrombocytopenia (except in case of high degree of hepatic fibrosis), and iron-related alteration of platelet function is still a matter of debate. In acquired iron overload (of transfusional and/or dyserythropoiesis origin), quantitative or qualitative platelet changes are difficult to attribute to iron alone due to the interference of the underlying hematological conditions; likewise, hematological improvement, including increased blood platelet counts, observed under iron oral chelation is likely to reflect mechanisms other than the sole beneficial impact of iron depletion.

Iron and platelets: A subtle, under-recognized relationship.

Thiamin.

Starting with a brief history of beriberi and the discovery that thiamin deficiency is its cause, the symptoms and signs are reviewed. None are pathognomonic. The disease has a low mortality and a long morbidity. The appearance of the patient can be deceptive, often being mistaken for psychosomatic disease in the early stages. The chemistry of thiamin and the laboratory methodology for depicting its deficiency are outlined. The diseases associated with thiamin deficiency, apart from malnutrition, include a number of genetically determined conditions where mutations, either in the cofactor relationship or a transporter, provide the etiology. It is emphasized that such mutations are often epigenetically responsive to megadoses of thiamin or one of its derivatives. The use of thiamin in clinical practice requires a high index of suspicion on the part of the clinician since it has a part to play in eating disorders, diabetes, neurodegenerative disease, and cancer. A high rate of critical illness and postsurgery thiamin deficiency have been reported, particularly those associated with gastrointestinal bypass. Emphasis is placed on thiamin deficiency as a major cause of asymmetric dysautonomia, because of the high degree of sensitivity to thiamin deficiency in the brainstem, cerebellum, and hypothalamus. The relationship of thiamin with regional pain syndrome, eosinophilic esophagitis, its analgesic capacity, and its preventive use in obstetrics is raised as a potential issue. The role of thiamin in SIDS and autism is outlined. It is emphasized that megadose thiamin is being used as a drug, either in stimulating the damaged cofactor/enzyme combination, or mitochondria.

Thiamin is a hydrosoluble vitamin that plays a role in several biological processes, mainly in glucose metabolism. There are several risk factors for developing thiamin deficiency, such as malnutrition, refeeding syndrome, gastrointestinal surgery, and alcoholism. Recently, the role of thiamin in critically ill patients has gained prominence, and the prevalence of thiamin deficiency was found to be increased in patients with severe burns, major surgery, septic shock, end-stage renal disease, and heart failure. In adults, thiamin deficiency presents as encephalopathy, dry beriberi (with neurological signs and symptoms), or wet beriberi (with cardiovascular signs and symptoms). Thiamin deficiency can be diagnosed clinically, and all clinicians should be aware of this disease, especially in patients with risk factors for thiamin deficiency. Thiamin supplementation should be started as early as possible in patients suspected to have thiamin deficiency. Treatment is safe, inexpensive, simple, and life-saving. Diagnosis is confirmed on a positive response to treatment.

Role of Thiamin in Health and Disease.

Thiamin is essential for human health. While plants are the ultimate source of thiamin in most human diets, staple foods like white rice have low thiamin content. Therefore, populations whose diets are mainly based on low-thiamin staple crops suffer from thiamin deficiency. Biofortification of rice grain by engineering the thiamin biosynthesis pathway has recently been attempted, with up to 5-fold increase in thiamin content in unpolished seeds. However, polished seeds that retain only the starchy endosperm had similar thiamin content than that of non-engineered plants. Various factors such as limited supply of precursors, limited activity of thiamin biosynthetic enzymes, dependence on maternal tissues to supply thiamin, or lack of thiamin stabilizing proteins may have hindered thiamin increase in the endosperm.

Thiamin biofortification of crops.

Thiamin is a water-soluble vitamin also known as vitamin B1. Its biologically active form, thiamin pyrophosphate (TPP), is a cofactor in macronutrient metabolism. In addition to its coenzyme roles, TPP plays a role in nerve structure and function as well as brain metabolism. Signs and symptoms of thiamin deficiency (TD) include lactic acidosis, peripheral neuropathy, ataxia, and ocular changes (eg, nystagmus). More advanced symptoms include confabulation and memory loss and/or psychosis, resulting in Wernicke's encephalopathy and/or Wernicke's Korsakoff syndrome, respectively. The nutrition support clinician should be aware of patients who may be at risk for TD. Risk factors include those patients with malnutrition due to 1 or more nutrition-related etiologies: decreased nutrient intake, increased nutrient losses, or impaired nutrient absorption. Clinical scenarios such as unexplained heart failure or lactic acidosis, renal failure with dialysis, alcoholism, starvation, hyperemesis gravidarum, or bariatric surgery may increase the risk for TD. Patients who are critically ill and require nutrition support may also be at risk for TD, especially those who are given intravenous dextrose void of thiamin repletion. Furthermore, understanding thiamin's role as a potential therapeutic agent for diabetes, some inborn errors of metabolism, and neurodegenerative diseases warrants further research. This tutorial describes the absorption, digestion, and metabolism of thiamin. Issues pertaining to thiamin in clinical practice will be described, and evidence-based practice suggestions for the prevention and treatment of TD will be discussed.

Thiamin in Clinical Practice.

Corneal crosslinking (CXL) is used in keratoconus to strengthen and stabilize the cornea and to prevent further progression with subsequent visual loss and the possible need for keratoplasty. Correct treatment indications is crucial in this context. Since the introduction of the initial Dresden protocol, other modified CXL protocols have been proposed to optimize treatment success.

[Treatment indications for corneal crosslinking and clinical results of new corneal crosslinking techniques].

Bacterial luciferase is a flavin-dependent monooxygenase which is remarkable for its distinctive feature in transforming chemical energy to photons of visible light. The bacterial luciferase catalyzes bioluminescent reaction using reduced flavin mononucleotide, long-chain aldehyde and oxygen to yield oxidized flavin, corresponding acid, water and light at λmax around 490nm. The enzyme comprises of two non-identical α and β subunits, where α subunit is a catalytic center and β subunit is crucially required for maintaining catalytic function of the α subunit. The crystal structure with FMN bound and mutagenesis studies have assigned a number of amino acid residues that are important in coordinating critical reactions and stabilizing intermediates to attain optimum reaction efficiency. The enzyme achieves monooxygenation by generating C4a-hydroperoxyflavin intermediate that later changes its protonation status to become C4a-peroxyflavin, which is necessary for the nucleophilic attacking with aldehyde substrate. The decomposing of C4a-peroxyhemiacetal produces excited C4a-hydroxyflavin and acid product. The chemical basis regrading bioluminophore generation in Lux reaction remains an inconclusive issue. However, current data can, at least, demonstrate the involvement of electron transfer to create radical molecules which is the key step in this mechanism. Lux is a self-sufficient bioluminescent system in which all substrates can be recycled and produced by a group of enzymes from the lux operon. This makes Lux distinctively advantageous over other luciferases for reporter enzyme application. The progression of understanding of Lux catalysis is beneficial to improve light emitting efficiency in order to expand the robustness of Lux application.

Bacterial luciferase: Molecular mechanisms and applications.

To resolve the growing problem of drug resistance in the treatment of bacterial and fungal pathogens, specific cellular targets and pathways can be used as targets for new antimicrobial agents. Endogenous riboflavin biosynthesis is a conserved pathway that exists in most bacteria and fungi. In this review, the roles of endogenous and exogenous riboflavin in infectious disease as well as several antibacterial agents, which act as analogues of the riboflavin biosynthesis pathway, are summarized. In addition, the effects of exogenous riboflavin on immune cells, cytokines, and heat shock proteins are described. Moreover, the immune response of endogenous riboflavin metabolites in infectious diseases, recognized by MHC-related protein-1, and then presented to mucosal associated invariant T cells, is highlighted. This information will provide a strategy to identify novel drug targets as well as highlight the possible clinical use of riboflavin.

The promise of endogenous and exogenous riboflavin in anti-infection.

Riboflavin.

Riboflavin (vitamin B2) is an essential nutrient for humans and animals that must be obtained from the diet. To ensure an optimal supply, riboflavin is used on a large scale as additive in the food and feed industries. Here, we describe a historical overview of the industrial process of riboflavin production starting from its discovery and the need to produce the vitamin in bulk at prices that would allow for their use in human and animal nutrition. Riboflavin was produced industrially by chemical synthesis for many decades. At present, the development of economical and eco-efficient fermentation processes, which are mainly based on Bacillus subtilis and Ashbya gossypii strains, has replaced the synthetic process at industrial scale. A detailed account is given of the development of the riboflavin overproducer strains as well as future prospects for its improvement.

Bioproduction of riboflavin: a bright yellow history.

Interest in utilizing an alternative to animal method for toxicological evaluation has received considerable attention due to cost effectiveness and the ethical issues involving animal experimentation. Alternative methods for phototoxicity evaluation are significant because of growing concern over increasing health effects due to stratospheric ozone depletion resulting in an increasing penetration of ultraviolet light-B radiation (UVB, 290-320 nm) which contributes to activation of chemical and biological molecules to potential phototoxic agents. The classic rabbit eye-irritancy test referred to as Draize test has been the subject of severe criticism by animal welfare groups. Dermal toxicity test using guinea pigs and mouse tail phototoxicity test is time consuming and requires a large number of laboratory animals. In photohaemolysis assay some of the phototoxic agents (such as riboflavin) react with the membrane proteins of the erythrocyte. However, in vitro test system using protozoa offers a promising alternative means of phototoxicity evaluation. Our previous studies have demonstrated that synergistic action of photochemically reactive agents and sunlight produces lethal effects to Paramecium but the protozoan has not received serious consideration for use as an alternative model for phototoxicity evaluation. In the present communication we have described the potential application of Tetrahymena as an alternative model to study the radiation-induced changes both in the presence or absence of photoreactive chemical agents. This model is likely to provide scope for studying the biological effects of environmental UVB radiation, DNA damage and defence against oxidative stress.

Phototoxicity evaluation--Tetrahymena thermophila as an alternative model.

As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported in nutritional surveys and population studies, even in non-developing countries with abundant sources of riboflavin-rich dietary products. A latent subclinical riboflavin deficiency can result in a significant clinical phenotype when combined with inborn genetic disturbances or environmental and physiological factors like infections, exercise, diet, aging and pregnancy. Riboflavin, and more importantly its derivatives, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), play a crucial role in essential cellular processes including mitochondrial energy metabolism, stress responses, vitamin and cofactor biogenesis, where they function as cofactors to ensure the catalytic activity and folding/stability of flavoenzymes. Numerous inborn errors of flavin metabolism and flavoenzyme function have been described, and supplementation with riboflavin has in many cases been shown to be lifesaving or to mitigate symptoms. This review discusses the environmental, physiological and genetic factors that affect cellular riboflavin status. We describe the crucial role of riboflavin for general human health, and the clear benefits of riboflavin treatment in patients with inborn errors of metabolism.

Riboflavin Deficiency-Implications for General Human Health and Inborn Errors of Metabolism.

Expressed sequence tag (EST) analysis was performed on un-normalized, unamplified cDNA libraries constructed from adult human retina to examine the expression profile of the tissue and to contribute resources for functional genomics studies.

Expressed sequence tag analysis of human retina for the NEIBank Project: retbindin, an abundant, novel retinal cDNA and alternative splicing of other retina-preferred gene transcripts.

Riboflavin is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), coenzymes required for the activity of flavoenzymes involved in the transfer of electrons in oxidation-reduction reactions. Flavins are light sensitive and rapidly degrade when exposed to light in the near ultraviolet and visible wavelengths. Some of the byproducts of flavin photodegradation are toxic. A quantitative survey of flavins in rabbit ocular tissues is reported. Adult male Dutch-Belt Rabbits were fed purified diets containing 3, 30, or 300 mg riboflavin/kg for 1 month. A method of aqueous extraction and high-performance liquid chromatography with fluorescence detection was used to measure riboflavin, FMN, and FAD in cornea, lens cortex, lens nucleus, retina, and blood. The retina contained the highest flavin concentration. In all tissues, the primary flavin was FAD followed by FMN and riboflavin. The highest concentration of riboflavin occurred in the cornea followed by the retina, lens cortex, and lens nucleus. A trend toward increasing concentrations of riboflavin occurred in the retina and blood in response to excess dietary riboflavin, but the concentration changes were not statistically significant. The highest concentration of FAD and FMN occurred in the retina followed by the cornea and the lens cortex and nucleus. The relative contribution of riboflavin, FMN, and FAD to the total flavin pool was markedly different in the various tissues of the eye. The proportion of tissue flavins present as riboflavin decreased from anterior to posterior. It was highest in the cornea followed by lens and retina. The pattern of distribution for FMN was: cornea greater than retina greater than lens cortex and nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of flavins in ocular tissues of the rabbit.

Riboflavin and its cofactors are essential for cellular energy generation, responses to oxidative stress, and overall homeostasis. Retbindin is a novel retina-specific riboflavin binding protein essential for the maintenance of retinal flavin levels, but its function remains poorly understood. To further elucidate the function of retbindin in retinal health and disease, we evaluated its role in retinal degeneration in a cone-rod dystrophy model associated with the R172W mutation in the photoreceptor tetraspanin Prph2.

Elimination of a Retinal Riboflavin Binding Protein Exacerbates Degeneration in a Model of Cone-Rod Dystrophy.

Corneal collagen cross-linking (CXL) with riboflavin and ultraviolet A (UVA) radiation is the first therapeutic modality that appears to arrest the progression of keratoconus and other corneal ectasias. Riboflavin is central to the process, acting as a photosensitizer for the production of oxygen singlets and riboflavin triplets. These free radicals drive the CXL process within the proteins of the corneal stroma, altering its biomechanical properties. Riboflavin also absorbs the majority of the UVA radiation, which is potentially cytotoxic and mutagenic, within the anterior stroma, preventing damage to internal ocular structures, such as the corneal endothelium, lens and retina. Clinical studies report cessation of ectatic progression in over 90% of cases and the majority document significant improvements in visual, keratometric and topographic parameters. Clinical follow-up is limited to 5-10 years, but suggests sustained stability and enhancement in corneal shape. Sight-threatening complications are rare. The optimal stromal riboflavin dosage for CXL is as yet undetermined.

Riboflavin for corneal cross-linking.

To generate a prognostic model to predict keratoconus progression to corneal crosslinking (CXL).

Personalized Model to Predict Keratoconus Progression From Demographic, Topographic, and Genetic Data.

Riboflavin, or vitamin B2, is indispensable for poultry, profoundly impacting their metabolic equilibrium, growth, and overall health. In a climate of increasing demand for poultry products and heightened production intensity, grasping the multifaceted roles of riboflavin in domestic fowl nutrition becomes paramount. This essential vitamin serves as a precursor to two vital coenzymes, flavin mononucleotide and flavin adenine dinucleotide, integral players in pivotal redox reactions and energy metabolism. Inadequate riboflavin levels translate into stunted growth, skeletal deformities, and compromised feed conversion efficiency, thereby adversely affecting poultry performance and bottom-line profitability. Riboflavin goes beyond its fundamental role, ameliorating nutrient utilization, facilitating protein synthesis, and augmenting enzyme activity, rightfully earning its epithet as the "growth-promoting vitamin". Poultry's reproductive success intricately hinges on riboflavin levels, dictating egg production and hatchability. It is imperative to note that riboflavin requirements exhibit variations among poultry species and distinct production phases, emphasizing the importance of judicious and balanced supplementation strategies. Aligning dietary recommendations with genetic advancements holds the promise of fostering sustainable growth within the poultry sector. Exploring the multifaceted aspects of riboflavin empowers researchers, nutritionists, and producers to elevate poultry nutrition and overall well-being, harmonizing with the industry's evolving demands.

From Metabolism to Vitality: Uncovering Riboflavin's Importance in Poultry Nutrition.

Migraine headache is a relatively common, debilitating condition that costs our healthcare system over 78 billion dollars per year. Riboflavin has been advocated as a safe, effective prophylactic therapy for the prevention of migraines. The purpose of this study was to provide a systematic review of the current role of riboflavin in the prophylaxis of migraine headache.

Prophylaxis of migraine headaches with riboflavin: A systematic review.

Mitochondrial diseases are a group of rare multisystem disorders characterized by genetic heterogeneity and pleomorphic clinical manifestations. The clinical burden may be heavy for patients and their caregivers. There are no therapies of proven efficacy until now and a multidisciplinary supportive care is therefore necessary. Since the common pathogenic mechanism is the insufficient energy production by defective mitochondria, nutrition may play a crucial role. However, no guidelines are still available. The article reports the current evidence, highlighting nutrition both as support and as therapy. The estimate of nutritional status, energy needs and nutritional behaviors are firstly discussed. Then, we go in-depth on the scientific rationale and the clinical evidence of the use of anti-oxidants and enzyme-cofactors in the clinical practice. In particular, we analyze the role of Coenzyme Q10, Creatine monohydrate, α-lipoic acid, riboflavin, arginine and citrulline, folinic acid, carnitine, vitamin C, K, and E. Every attempt at nutritional intervention should be made knowing patient's disease and focusing on his/her energy and nutrients' requirements. For this reason, clinicians expert in mitochondrial medicine and clinical nutritionists should work together to ameliorate care in these fragile patients.

Nutritional support in mitochondrial diseases: the state of the art.

Riboflavin (RF) is a water-soluble member of the B-vitamin family. Sufficient dietary and supplemental RF intake appears to have a protective effect on various medical conditions such as sepsis, ischemia etc., while it also contributes to the reduction in the risk of some forms of cancer in humans. These biological effects of RF have been widely studied for their anti-oxidant, anti-aging, anti-inflammatory, anti-nociceptive and anti-cancer properties. Moreover, the combination of RF and other compounds or drugs can have a wide variety of effects and protective properties, and diminish the toxic effect of drugs in several treatments. Research has been done in order to review the latest findings about the link between RF and different clinical aberrations. Since further studies have been published in this field, it is appropriate to consider a re-evaluation of the importance of RF in terms of its beneficial properties.

Riboflavin: The Health Benefits of a Forgotten Natural Vitamin.

Familial hypercholesterolemia is a common, inherited disorder of cholesterol metabolism that leads to early cardiovascular morbidity and mortality. It is underdiagnosed and undertreated. Statins, ezetimibe, bile acid sequestrants, niacin, lomitapide, mipomersen, and low-density lipoprotein (LDL) apheresis are treatments that can lower LDL cholesterol levels. Early treatment can lead to substantial reduction of cardiovascular events and death in patients with familial hypercholesterolemia. It is important to increase awareness of this disorder in physicians and patients to reduce the burden of this disorder.

Familial hypercholesterolemia.

Niacin (also known as "vitamin B₃" or "vitamin PP") includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for oxidative reactions crucial for energy production, but they are also substrates for enzymes involved in non-redox signaling pathways, thus regulating biological functions, including gene expression, cell cycle progression, DNA repair and cell death. In the central nervous system, vitamin B₃ has long been recognized as a key mediator of neuronal development and survival. Here, we will overview available literature data on the neuroprotective role of niacin and its derivatives, especially focusing especially on its involvement in neurodegenerative diseases (Alzheimer's, Parkinson's, and Huntington's diseases), as well as in other neuropathological conditions (ischemic and traumatic injuries, headache and psychiatric disorders).

Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications.

Diabetic dyslipidemia is characterized by elevated fasting and postprandial triglycerides, low HDL-cholesterol, elevated LDL-cholesterol and the predominance of small dense LDL particles. These lipid changes represent the major link between diabetes and the increased cardiovascular risk of diabetic patients. The underlying pathophysiology is only partially understood. Alterations of insulin sensitive pathways, increased concentrations of free fatty acids and low grade inflammation all play a role and result in an overproduction and decreased catabolism of triglyceride rich lipoproteins of intestinal and hepatic origin. The observed changes in HDL and LDL are mostly sequence to this. Lifestyle modification and glucose control may improve the lipid profile but statin therapy mediates the biggest benefit with respect to cardiovascular risk reduction. Therefore most diabetic patients should receive statin therapy. The role of other lipid lowering drugs, such as ezetimibe, fibrates, omega-3 fatty acids, niacin and bile acid sequestrants is less well defined as they are characterized by largely negative outcome trials. This review examines the pathophysiology of diabetic dyslipidemia and its relationship to cardiovascular diseases. Management approaches will also be discussed.

Diabetic dyslipidemia.

Niacin (vitamin B3) is an essential nutrient that treats pellagra, and prior to the advent of statins, niacin was commonly used to counter dyslipidemia. Recent evidence has posited niacin as a promising therapeutic for several neurological disorders. In this review, we discuss the biochemistry of niacin, including its homeostatic roles in NAD+ supplementation and metabolism. Niacin also has roles outside of metabolism, largely through engaging hydroxycarboxylic acid receptor 2 (Hcar2). These receptor-mediated activities of niacin include regulation of immune responses, phagocytosis of myelin debris after demyelination or of amyloid beta in models of Alzheimer's disease, and cholesterol efflux from cells. We describe the neurological disorders in which niacin has been investigated or has been proposed as a candidate medication. These are multiple sclerosis, Alzheimer's disease, Parkinson's disease, glioblastoma and amyotrophic lateral sclerosis. Finally, we explore the proposed mechanisms through which niacin may ameliorate neuropathology. While several questions remain, the prospect of niacin as a therapeutic to alleviate neurological impairment is promising.

The Promise of Niacin in Neurology.

Although a change in life-style is often the method of first choice for lipid lowering, lipid-lowering drugs, in general, help to control elevated levels of different forms of lipids in patients with hyperlipidemia. While one group of drugs, statins, lowers cholesterol, the other group, fibrates, is known to take care of fatty acids and triglycerides. In addition, other drugs, such as ezetimibe, colesevelam, torcetrapib, avasimibe, implitapide, and niacin are also being considered to manage hyperlipidemia. As lipids are very critical for cardiovascular diseases, these drugs reduce fatal and nonfatal cardiovascular abnormalities in the general population. However, a number of recent studies indicate that apart from their lipid-lowering activities, statins and fibrates exhibit multiple functions to modulate intracellular signaling pathways, inhibit inflammation, suppress the production of reactive oxygen species, and modulate T cell activity. Therefore, nowadays, these drugs are being considered as possible therapeutics for several forms of human disorders including cancer, autoimmunity, inflammation, and neurodegeneration. Here I discuss these applications in the light of newly discovered modes of action of these drugs.

Lipid-lowering drugs.

The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain.

Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis.

Nicotinic acid and nicotinamide, collectively referred to as niacin, are nutritional precursors of the bioactive molecules nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP are important cofactors for most cellular redox reactions, and as such are essential to maintain cellular metabolism and respiration. NAD also serves as a cosubstrate for a large number of ADP-ribosylation enzymes with varied functions. Among the NAD-consuming enzymes identified to date are important genetic and epigenetic regulators, e.g., poly(ADP-ribose)polymerases and sirtuins. There is rapidly growing knowledge of the close connection between dietary niacin intake, NAD(P) availability, and the activity of NAD(P)-dependent epigenetic regulator enzymes. It points to an exciting role of dietary niacin intake as a central regulator of physiological processes, e.g., maintenance of genetic stability, and of epigenetic control mechanisms modulating metabolism and aging. Insight into the role of niacin and various NAD-related diseases ranging from cancer, aging, and metabolic diseases to cardiovascular problems has shifted our view of niacin as a vitamin to current views that explore its potential as a therapeutic.

Niacin.

Statins are effective drugs for lowering low-density lipoprotein cholesterol, and their use has been associated with a significant decrease in cardiovascular morbidity and mortality. However, statins are ineffective in lowering plasma triglycerides and lipoprotein(a), or increasing low high-density lipoprotein cholesterol (HDL-C) plasma levels, which are independent risk factors for coronary heart disease. Niacin, on the other hand, is the most potent drug available for lowering plasma levels of triglycerides and lipoprotein(a) and raising HDL-C levels. It follows, then, that a combination of niacin with a statin might be an effective combination in improving all components of the lipid profile. Previous studies have shown that the use of long-acting niacin with a statin, in dose combinations of niacin-ER/lovastatin 1,000/20 mg or 2,000/40 mg once daily, has been effective in favorably modifying low-density lipoprotein cholesterol, triglycerides, lipoprotein(a), and HDL-C plasma levels. Dyslipidemias often predate the onset of hypertension, and HDL-C has been found to be inversely related to the incidence of hypertension. Normalization of lipid components, including the total cholesterol/HDL-C ratio, is important in the management of hypertensive individuals and patients with the metabolic syndrome or diabetes. Thus, the long-term treatment of dyslipidemias with these two agents may help to modify risk and reduce cardiovascular morbidity and mortality in these patients over and above benefits achieved by lowering blood pressure.

Niacin-ER/statin combination for the treatment of dyslipidemia: focus on low high-density lipoprotein cholesterol.

Although the phenomenon of attenuated niacin response (ANR) has been widely replicated in some patients with first-episode psychosis (FEP), its relevance to the negative symptoms (NS) of psychosis remains unclear. Total of 240 patients with drug-naïve FEP and 101 healthy controls (HCs) were recruited, and 209 were followed up for 1 year. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and niacin-induced responses were measured using laser Doppler flowmetry. We calculated the log-transform EC50 [concentration of methyl nicotinate required to elicit a half-maximal blood flow (MBF) response] and MBF values. Core-NS was generated by factor analysis of the PANSS-NS subscale and cluster analysis to produce subtypes. Significant differences were found in the log10 (EC50) values between the FEP and HC groups (p < 0.001), supporting the ANR in patients with FEP. A higher NS severity was found in the ANR subgroup than that in other patients. Factor analysis determined that a two-dimensional model included core NS and rigidity of thinking. The log10 (EC50) value was significantly associated with only the core NS. Cluster analysis revealed three subtypes-36.7% (cluster-1, n = 88), 16.7% (cluster-2, n = 40), and 46.7% (cluster-3, n = 112). Cluster-2 characterized by extensive NS appeared to have a more remarkable ANR and less symptomatic improvement than those with other clusters during follow-up. No significant changes were found in the niacin response trajectories between the baseline and follow-up. Our findings indicate a significant correlation between ANR and core NS in patients with FEP. ANR may be a potential biomarker for certain subtypes with NS-dominated characteristics and poor symptomatic remission.

Attenuated niacin response is associated with a subtype of first-episode drug-naïve psychosis characterized as serious negative symptoms.

The mechanisms of migraine pathogenesis are not completely clear, but 31P-nuclear magnetic resonance studies revealed brain energy deficit in migraineurs. As glycolysis is the main process of energy production in the brain, mitochondria may play an important role in migraine pathogenesis. Nutrition is an important aspect of migraine pathogenesis, as many migraineurs report food-related products as migraine triggers. Apart from approved anti-migraine drugs, many vitamins and supplements are considered in migraine prevention and therapy, but without strong supportive evidence. In this review, we summarize and update information about nutrients that may be important for mitochondrial functions, energy production, oxidative stress, and that are related to migraine. Additionally, we present a brief overview of caffeine and alcohol, as they are often reported to have ambiguous effects in migraineurs. The nutrients that can be considered to supplement the diet to prevent and/or ameliorate migraine are riboflavin, thiamine, magnesium ions, niacin, carnitine, coenzyme Q10, melatonin, lipoic acid, pyridoxine, folate, and cobalamin. They can supplement a normal, healthy diet, which should be adjusted to individual needs determined mainly by the physiological constitution of an organism. The intake of caffeine and alcohol should be fine-tuned to the history of their use, as withdrawal of these agents in regular users may become a migraine trigger.

Nutrients to Improve Mitochondrial Function to Reduce Brain Energy Deficit and Oxidative Stress in Migraine.

Niacinamide (aka nicotinamide) and Niacin (aka nicotinic acid) are heterocyclic aromatic compounds which function in cosmetics primarily as hair and skin conditioning agents. Niacinamide is used in around 30 cosmetic formulations including shampoos, hair tonics, skin moisturizers, and cleansing formulations. Niacin is used in a few similar product types. The concentration of use of Niacinamide varies from a low of 0.0001% in night preparations to a high of 3% in body and hand creams, lotions, powders and sprays. Niacin concentrations of use range from 0.01% in body and hand creams, lotions, powders and sprays to 0.1% in paste masks (mud packs). Both ingredients are accepted for use in cosmetics in Japan and the European Union. Both are GRAS direct food additives and nutrient and/or dietary supplements. Niacinamide may be used in clinical treatment of hypercholesteremia and Niacin in prevention of pellegra and treatment of certain psychological disorders. Both ingredients are readily absorbed from skin, blood, and the intestines and widely distribute throughout the body. Metabolites include N1-methylnicotinamide and N1-methyl-4-pyridone-3-carboxamide. Excretion is primarily through the urinary tract. While Niacinamide is more toxic than Niacin in acute toxicity studies, both are relatively non-toxic. Short-term oral, parenteral, or dermal toxicity studies did not identify significant irreversible effects. Niacinamide, evaluated in an in vitro test to predict ocular irritation, was not an acute ocular hazard. Animal testing of Niacinamide in rabbits in actual formulations produced mostly non-irritant reactions, with only some marginally irritating responses. Skin irritation tests of up to 2.5% Niacinamide in rabbits produced only marginal irritation. Skin sensitization tests of Niacinamide at 5% during induction and 20% during challenge were negative in guinea pigs. Neither cosmetic ingredient was mutagenic in Ames tests, with or without metabolic activation. Niacinamide and Niacin at 2 mg/ml were negative in a chromosome aberration test in Chinese hamster ovary cells, but did produce large structural chromosome aberrations at 3 mg/ml. Niacinamide induced sister chromatid exchanges in Chinese hamster ovary cells, but Niacin did not. Under certain circumstances, Niacinamide can cause an increase in unscheduled DNA synthesis in human lymphocytes treated with UV or a nitrosoguanidine compound. Niacinamide itself was not carcinogenic when administered (1%) in the drinking water of mice. No data on the carcinogenic effect of Niacin were available. Niacinamide can moderate the induction of tumors by established carcinogens. Niacinamide in combination with streptozotocin (a nitrosourea compound) or with heliotrine (a pyrrolizidine alkaloid), produced pancreatic islet tumors. On the other hand, Niacinamide reduced the renal adenomas produced by streptozotocin; and intestinal and bladder tumors induced by a preparation of bracken fern. Niacinamide evaluated in in vitro test systems did affect development, but Niacinamide reduced the reproductive/developmental toxicity of 2-aminonicotinamide-amino-1,3,4-thiadiazole hydrochloride and urethane. Clinical testing of Niacinamide produced no stinging sensation at concentrations up to 10%, use tests produced no irritation at concentrations up to 5%, and a 21-day cumulative irritation test at concentrations up to 5% resulted in no irritancy. Niacinamide was not a sensitizer, nor was it a photosensitizer. The CIR Expert Panel considered that Niacinamide and Niacin are sufficiently similar from a toxicologic standpoint to combine the available data and reach a conclusion on the safety of both as cosmetic ingredients. Overall, these ingredients are non-toxic at levels considerably higher than would be experienced in cosmetic products. Clinical testing confirms that these ingredients are not significant skin irritants, sensitizers or photosensitizers. While certain formulations were marginal to slight ocular irritants, other formulations were not. Niacinamide, while not carcinogenic alone, can modulate the induction of tumors by certain established carcinogens. The Panel noted that the doses in these studies are high relative to the low concentrations at which Niacinamide is used in cosmetic formulations. In neither case (tumor protection or tumor promotion) are these findings considered relevant to the use of Niacinamide at its current low concentrations of use in cosmetics. Both ingredients were considered safe as used in cosmetics.

Final report of the safety assessment of niacinamide and niacin.

This is a description of some unknown skin disorders found by a physician inmate in a concentration camp, 1958 to 1962. After prolonged semistarvation and ultraheavy physical labor, skin lesions developed among the inmates including cutaneous pigmentation overlying bony prominence, buccal membrane pigmentation, palmoplantar keratoderma with fissures, palmar crease clefts, nail layering, intra-nail hemorrhage, and so on. These lesions responded dramatically to nutrition therapy, including dietary improvement, yeast administration, or thiamin injection. Thiamin deficiency was confirmed to be one of major etiologic factors, whereas the deficiency of niacin or riboflavin also played a part. In the pediatric case with palmar crease clefts, both thiamin and niacin were dramatically effective. No laboratory data could be provided.

Personal observation of skin disorders in malnutrition.

Type 2 diabetes mellitus and the closely related metabolic syndrome markedly increase the risk of cardiovascular disease a major contributor is the dyslipidemia. Recent studies and new national guidelines suggest these very high risk patients with cardiovascular disease achieve optional low density lipoprotein cholesterol (LDL-C) level of less than 70 mg/dl. In addition there may be no threshold to begin therapeutic lifestyle change and pharmacologic therapy to reduce LDL-C by 30-40%. Although randomized controlled trials with statins indicate that LDL reduction clearly reduces cardiovascular risk in these patients, the typical dyslipidemia of type 2 diabetes mellitus is also characterized by low high density lipoprotein cholesterol (HDL-C) levels, increased triglyceride-rich lipoproteins and small dense LDL, as well as increased postprandial lipemia. The later lipoproteins increase non-HDL-C levels. In order to address these abnormalities it may be necessary to utilize combined approaches with a fibrate or nicotinic acid, or other agents with statins to help reduce risk beyond statins. In addition, supervised, therapeutic life-style change is often underutilized therapy in patients with established coronary artery disease. This review will focus on maximizing the treatment of dyslipidemia in type 2 diabetes and the metabolic syndrome and discuss the evidence based studies and new developments in the management in these very high risk patients.

Cardiovascular disease risk of type 2 diabetes mellitus and metabolic syndrome: focus on aggressive management of dyslipidemia.

Lipoprotein(a) (Lp[a]) is a low-density lipoprotein (LDL) cholesterol-like particle bound to apolipoprotein(a). This novel marker of cardiovascular disease acts through induction of vascular inflammation, atherogenesis, calcification, and thrombosis. While an absolute risk threshold remains to be universally accepted, an estimated 20% to 25% of the global population have Lp(a) levels of 50 mg/dL or higher, a level noted by the European Atherosclerosis Society to confer increased cardiovascular risk.

Lipoprotein(a) and its Significance in Cardiovascular Disease: A Review.

The cholesterol concentrations of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) have traditionally served as risk factors for cardiovascular disease. As such, novel therapeutic interventions aiming to raise HDL cholesterol have been tested in the clinical setting. However, most trials led to a significant increase in HDL cholesterol with no improvement in cardiovascular events. The complexity of the HDL particle, which exerts multiple physiological functions and is comprised of a number of subclasses, has raised the question as to whether there should be more focus on HDL subclass and function rather than cholesterol quantity. We review current data regarding HDL subclasses and subclass-specific functionality and highlight how current lipid modifying drugs such as statins, cholesteryl ester transfer protein inhibitors, fibrates and niacin often increase cholesterol concentrations of specific HDL subclasses. In addition this review sets out arguments suggesting that the HDL3 subclass may provide better protective effects than HDL2.

Pharmacological Intervention to Modulate HDL: What Do We Target?

Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.

Residual macrovascular risk in 2013: what have we learned?

Increased dietary intake of niacin has been correlated with reduced risk of Alzheimer's disease (AD). Niacin serves as a high-affinity ligand for the receptor HCAR2 (GPR109A). In the brain, HCAR2 is expressed selectively by microglia and is robustly induced by amyloid pathology in AD. The genetic inactivation of Hcar2 in 5xFAD mice, a model of AD, results in impairment of the microglial response to amyloid deposition, including deficits in gene expression, proliferation, envelopment of amyloid plaques, and uptake of amyloid-β (Aβ), ultimately leading to exacerbation of amyloid burden, neuronal loss, and cognitive deficits. In contrast, activation of HCAR2 with an FDA-approved formulation of niacin (Niaspan) in 5xFAD mice leads to reduced plaque burden and neuronal dystrophy, attenuation of neuronal loss, and rescue of working memory deficits. These data provide direct evidence that HCAR2 is required for an efficient and neuroprotective response of microglia to amyloid pathology. Administration of Niaspan potentiates the HCAR2-mediated microglial protective response and consequently attenuates amyloid-induced pathology, suggesting that its use may be a promising therapeutic approach to AD that specifically targets the neuroimmune response.

The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer's disease.

Apples and their products exemplify the recently reemphasized link between dietary fruit intake and the alleviation of human disease. Their consumption does indeed improve human health due to their high phytochemical content. To identify potentially relevant articles from clinical trials, some epidemiological studies and meta-analyses, and in vitro and in vivo studies (cell cultures and animal models), PubMed was searched from January 1, 2012, to May 15, 2022. This review summarized the potential effects of apple and apple products (juices, puree, pomace, dried apples, extracts rich in apple bioactives and single apple bioactives) on health. Apples and apple products have protective effects against cardiovascular diseases, cancer, as well as mild cognitive impairment and promote hair growth, healing of burn wounds, improve the oral environment, prevent niacin-induced skin flushing, promote the relief of UV-induced skin pigmentation, and improve the symptoms of atopic dermatitis as well as cedar hay fever among others. These effects are associated with various mechanisms, such as vascular endothelial protection, blood lipids lowering, anti-inflammatory, antioxidant, antiapoptotic, anti-invasion, and antimetastatic effects. Meanwhile, it has provided an important reference for the application and development of medicine, nutrition, and other fields.

Does an apple a day keep away diseases? Evidence and mechanism of action.

Elevated triglyceride (TG) levels are prevalent among the US population, often occurring in persons who are overweight or obese, or who have type 2 diabetes or the metabolic syndrome. There is evidence that elevated TG levels may be a significant independent risk factor for coronary heart disease (CHD), particularly in women.

Hypertriglyceridemia and cardiovascular risk reduction.

Familial hypercholesterolemia (FH) is a common, inherited disorder of cholesterol metabolism. This pathology is usually an autosomal dominant disorder and is caused by inherited mutations in the APOB, LDLR, and PCSK9 genes. Patients can have a homozygous or a heterozygous genotype, which determines the severity of the disease and the onset age of cardiovascular disease (CVD) manifestations. The incidence of heterozygous FH is 1: 200-250, whereas that of homozygous FH is 1: 100.000-160.000. Unfortunately, FH is often diagnosed too late and after the occurrence of a major coronary event. FH may be suspected in patients with elevated blood low-density lipoprotein cholesterol (LDL-C) levels. Moreover, there are other criteria that help to diagnose FH. For instance, the Dutch Lipid Clinical Criteria are a helpful diagnostic tool that is used to diagnose FH. FH often leads to the development of early cardiovascular disease and increases the risk of sudden cardiac death. Therefore, early diagnosis and treatment of this disease is very important. Statins, ezetimibe, bile acid sequestrants, niacin, PCSK9 inhibitors (evolocumab and alirocumab), small-interfering-RNA-based therapeutics (inclisiran), lomitapide, mipomersen, and LDL apheresis are several of the available treatment possibilities that lower LDL-C levels. It is important to say that the timeous lowering of LDL-C levels can reduce the risk of cardiovascular events and mortality in patients with FH. Therefore, it is essential to increase awareness of FH in order to reduce the burden of acute coronary syndrome (ACS).

Familial Hypercholesterolemia and Its Current Diagnostics and Treatment Possibilities: A Literature Analysis.

In patients with established cardiovascular disease, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein (LDL) cholesterol levels with statin therapy. It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein (HDL) cholesterol is superior to simvastatin alone in reducing such residual risk.

Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.

The B-vitamins comprise a group of eight water soluble vitamins that perform essential, closely inter-related roles in cellular functioning, acting as co-enzymes in a vast array of catabolic and anabolic enzymatic reactions. Their collective effects are particularly prevalent to numerous aspects of brain function, including energy production, DNA/RNA synthesis/repair, genomic and non-genomic methylation, and the synthesis of numerous neurochemicals and signaling molecules. However, human epidemiological and controlled trial investigations, and the resultant scientific commentary, have focused almost exclusively on the small sub-set of vitamins (B9/B12/B6) that are the most prominent (but not the exclusive) B-vitamins involved in homocysteine metabolism. Scant regard has been paid to the other B vitamins. This review describes the closely inter-related functions of the eight B-vitamins and marshals evidence suggesting that adequate levels of all members of this group of micronutrients are essential for optimal physiological and neurological functioning. Furthermore, evidence from human research clearly shows both that a significant proportion of the populations of developed countries suffer from deficiencies or insufficiencies in one or more of this group of vitamins, and that, in the absence of an optimal diet, administration of the entire B-vitamin group, rather than a small sub-set, at doses greatly in excess of the current governmental recommendations, would be a rational approach for preserving brain health.

B Vitamins and the Brain: Mechanisms, Dose and Efficacy--A Review.

The latest recommended goals for blood lipid levels may require multiple lipid drugs. Lower doses in combination may render more efficacy and safety than highest doses of single agents. Except for isolated hypoalphalipoproteinemia (a low level of high-density lipoprotein cholesterol), therapies will start with a statin. All marketed statins are acceptable. The choice may be based on dose- efficacy and patient's tolerability. High-potency statins (eg, atorvastatin, simvastatin, or rosuvastatin) are often chosen. Currently, generic statins, such as simvastatin, lovastatin, pravastatin, and fluvastatin, offer cost benefits. The choice of added agent depends on the "residual lipoprotein abnormalities" after statin therapy, efficacy, compliance issues, and cost. Approved "combined" preparations improve cost and compliance. To further lower low-density lipoprotein cholesterol, ezetimibe is a safe, efficacious choice, pending resolution of a controversial trial's results. Colesevelam is moderately effective and the best tolerated bile acids sequestrant. In combined dyslipidemias, extended-release niacin is the best tolerated niacin preparation; other quality-controlled immediate-release preparations have similar safety and efficacy but produce more flushing of the skin. Niacin or fenofibrate is effective in normalizing high-density lipoprotein and triglyceride levels persisting after statin therapy. Agents approved by the US Food and Drug Administration and the latest guidelines of the National Cholesterol Education Program, American Heart Association/American College of Cardiology provide choices and indications of drug combinations.

What combination therapy with a statin, if any, would you recommend?

High-density lipoprotein cholesterol (HDL-C) has been shown in epidemiologic studies to be associated with cardiovascular (CV) risk and thus significant efforts have been focused on HDL-C modulation. Multiple pharmaceutical agents have been developed with the goal of increasing HDL-C. Niacin, the most widely used medication to raise HDL-C, increases HDL-C by up to 25 % and was shown in multiple surrogate end point studies to reduce CV risk. However, two large randomized controlled trials of niacin, AIM-HIGH and HPS2-THRIVE, have shown that despite its effects on HDL-C, niacin does not decrease the incidence of CV events and may have significant adverse effects. Studies of other classes of agents such as cholesteryl ester transfer protein (CETP) inhibitors have also shown that even dramatic increases in HDL-C do not necessarily translate to reduction in clinical events. While these findings have cast doubt upon the importance of HDL-C modulation on CV risk, it is becoming increasingly clear that HDL function-related measures may be better targets for CV risk reduction. Increasing ApoA-I, the primary apolipoprotein associated with HDL, correlates with reduced risk of events, and HDL particle concentration (HDL-P) inversely associates with incident CV events adjusted for HDL-C and LDL particle measures. Cholesterol efflux, the mechanism by which macrophages in vessel walls secrete cholesterol outside cells, correlates with both surrogate end points and clinical events. The effects of niacin on these alternate measures of HDL have been conflicting. Further studies should determine if modulation of these HDL function markers translates to clinical benefits. Although the HDL cholesterol hypothesis may be defunct, the HDL function hypothesis is now poised to be rigorously tested.

Niacin Therapy, HDL Cholesterol, and Cardiovascular Disease: Is the HDL Hypothesis Defunct?

Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity despite notable advances in its treatment. Many of the complications of nephrotic syndrome, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidaemia. These abnormalities include elevated plasma levels of cholesterol, triglycerides and the apolipoprotein B-containing lipoproteins VLDL and IDL; decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased hepatic lipase activity; and increased levels of the enzyme PCSK9. In addition, there is an increase in the plasma levels of immature HDL particles and reduced cholesterol efflux. Studies from the past few years have markedly improved our understanding of the molecular pathogenesis of nephrotic syndrome-associated dyslipidaemia, and also heightened our awareness of the associated exacerbated risks of cardiovascular complications, progressive kidney disease and thromboembolism. Despite the absence of clear guidelines regarding treatment, various strategies are being increasingly utilized, including statins, bile acid sequestrants, fibrates, nicotinic acid and ezetimibe, as well as lipid apheresis, which seem to also induce partial or complete clinical remission of nephrotic syndrome in a substantial percentage of patients. Future potential treatments will likely also include inhibition of PCSK9 using recently-developed anti-PCSK9 monoclonal antibodies and small inhibitory RNAs, as well as targeting newly identified molecular regulators of lipid metabolism that are dysregulated in nephrotic syndrome.

Dyslipidaemia in nephrotic syndrome: mechanisms and treatment.

Niacin extended-release (ER)/simvastatin is a once-daily, fixed-dose combination of the HMG-CoA reductase inhibitor simvastatin and an ER formulation of niacin (a B-complex vitamin). In healthy volunteers who were given niacin ER/simvastatin 2000 mg/40 mg, niacin exposure was similar to that with niacin ER 2000 mg, while simvastatin exposure was increased compared to that with simvastatin 40 mg. In patients with elevated non-high-density lipoprotein cholesterol (non-HDL-C) but with low-density lipoprotein cholesterol (LDL-C) at or below the National Cholesterol Education Program (NCEP) goal after a > or = 2-week simvastatin 20 mg/day run-in period (SEACOAST I), 24 weeks of niacin ER/simvastatin 1000 mg/20 mg or 2000 mg/20 mg per day reduced median plasma non-HDL-C levels to a significantly greater extent than simvastatin 20 mg/day. In patients with elevated non-HDL-C and LDL-C at any level after a > or = 2-week simvastatin 40 mg/day run-in period (SEACOAST II), 24 weeks of niacin ER/simvastatin 1000 mg/40 mg or 2000 mg/40 mg per day was noninferior to simvastatin 80 mg/day in reducing median plasma non-HDL-C levels. Compared with simvastatin monotherapy, there was no significant difference in reduction in plasma LDL-C levels with niacin ER/simvastatin in SEACOAST I, and the noninferiority criterion for LDL-C was not met in SEACOAST II. However, plasma HDL-C levels increased more and triglyceride levels were lowered more than with simvastatin monotherapy (SEACOAST I and II). Niacin ER/simvastatin was generally well tolerated, with flushing being the most common adverse reaction.

Niacin extended-release/simvastatin.

Vitamin B6 is an ensemble of six interconvertible vitamers: pyridoxine (PN), pyridoxamine (PM), pyridoxal (PL), and their 5'-phosphate derivatives, PNP, PMP, and PLP. Pyridoxal 5'-phosphate is a coenzyme in a variety of enzyme reactions concerning transformations of amino and amino acid compounds. This review summarizes all known and putative PLP-binding proteins found in the Escherichia coli MG1655 proteome. PLP can have toxic effects since it contains a very reactive aldehyde group at its 4' position that easily forms aldimines with primary and secondary amines and reacts with thiols. Most PLP is bound either to the enzymes that use it as a cofactor or to PLP carrier proteins, protected from the cellular environment but at the same time readily transferable to PLP-dependent apoenzymes. E. coli and its relatives synthesize PLP through the seven-step deoxyxylulose-5-phosphate (DXP)-dependent pathway. Other bacteria synthesize PLP in a single step, through a so-called DXP-independent pathway. Although the DXP-dependent pathway was the first to be revealed, the discovery of the widespread DXP-independent pathway determined a decline of interest in E. coli vitamin B6 metabolism. In E. coli, as in most organisms, PLP can also be obtained from PL, PN, and PM, imported from the environment or recycled from protein turnover, via a salvage pathway. Our review deals with all aspects of vitamin B6 metabolism in E. coli, from transcriptional to posttranslational regulation. A critical interpretation of results is presented, in particular, concerning the most obscure aspects of PLP homeostasis and delivery to PLP-dependent enzymes.

Knowns and Unknowns of Vitamin B6 Metabolism in Escherichia coli.

Vitamin B-6 in the form of pyridoxine (PN) is commonly used by the general population. The use of PN-containing supplements has gained lots of attention over the past years as they have been related to the development of peripheral neuropathy. In light of this, the number of reported cases of adverse health effects due to the use of vitamin B-6 have increased. Despite a long history of study, the pathogenic mechanisms associated with PN toxicity remain elusive. Therefore, the present review is focused on investigating the mechanistic link between PN supplementation and sensory peripheral neuropathy. Excessive PN intake induces neuropathy through the preferential injury of sensory neurons. Recent reports on hereditary neuropathy due to pyridoxal kinase (PDXK) mutations may provide some insight into the mechanism, as genetic deficiencies in PDXK lead to the development of axonal sensory neuropathy. High circulating concentrations of PN may lead to a similar condition via the inhibition of PDXK. The mechanism behind PDXK-induced neuropathy is unknown; however, there is reason to believe that it may be related to γ-aminobutyric acid (GABA) neurotransmission. Compounds that inhibit PDXK lead to convulsions and reductions in GABA biosynthesis. The absence of central nervous system-related symptoms in PDXK deficiency could be due to differences in the regulation of PDXK, where PDXK activity is preserved in the brain but not in peripheral tissues. As PN is relatively impermeable to the blood-brain barrier, PDXK inhibition would similarly be confined to the peripheries and, as a result, GABA signaling may be perturbed within peripheral tissues, such as sensory neurons. Perturbed GABA signaling within sensory neurons may lead to excitotoxicity, neurodegeneration, and ultimately, the development of peripheral neuropathy. For several reasons, we conclude that PDXK inhibition and consequently disrupted GABA neurotransmission is the most plausible mechanism of toxicity.

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