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Studies on experimental rickets; And experimental demonstration of the existence of a vitamin which promotes calcium deposition
... The reason for the effectiveness of sunlight and phototherapy in rickets remained a mystery until nutritional studies of the period revealed that in addition to the essential dietary factors (protein, carbohydrate, fat, minerals) considered theretofore, there were also other necessary "accessory factors" or "vital amines" leading to the term "vitamines" that was formally abbreviated to "vitamins" in 1920. That paved the way to identifying the mysterious fat soluble "anti-rachitic factor" of cod fish oil as the fourth vitamin (D) by the American biochemist Elmer McCollum (1879McCollum ( -1967 and his associates in 1922 (DeLuca, 2014;Dent, 1970;McCollum et al., 1922). Simultaneously, it was shown that exposure to ultraviolet light bestowed anti-rachitic properties to certain foods (oils, milk, cereals) that was inherent to their sterol content. ...
... Extensive experimental and clinical studies that ensued then revealed that coincident with the improvement of rickets that followed replacement with vitamin D 3 analogs there was increased intestinal calcium absorption, a rise in the levels of serum calcium and phosphorus, an initial drop followed by a rise of calcium excretion in the urine, and an increase in bone mineralization. As vitamin D 3 metabolites began to be identified it became evident that their effectiveness in increasing calcium absorption and bone mineralization was enhanced by their increased polarity following hydroxylation first to 25(OH)D 3 (calcidol) in the liver and then to its biologically active form 1,25(OH) 2 D 3 (calcitriol) in the kidney (DeLuca, 2014;McCollum et al., 1922). Radioactive fluorescent studies led to the identification of receptors for the active form of vitamin D 3 (VDR) in most tissues of the body, specifically in the intestine, kidney, and parathyroid glands. ...
Long considered an inert supporting framework, bone studies went neglected until the 17th century when they began as descriptive microscopic studies of structure which over time progressed into that of chemistry and physiology. It was in the mid-19th century that studies evolved into an inquisitive discipline which matured into the experimental investigation of bone in health and disease in the 20th century, and ultimately that of molecular studies now deciphering the genetic language of bone biology. These fundamental studies were catalyzed by increasing clinical interest in bone disease. The first bone disease to be identified was rickets in 1645. Its subsequent connection to albuminuric patients reported in 1883 later became renal osteodystrophy in 1942, launching studies that elucidated the functions of vitamin D and parathyroid hormone and their role in the altered calcium and phosphate metabolism of the disease. Studies in osteoporosis and renal osteodystrophy have driven most recent progress benefitting from technological advances in imaging and the precision of evaluating bone turnover, mineralization, and volume. This review exposes the progress of bone biology from a passive support structure to a dynamically regulated organ with vital homeostatic functions whose understanding has undergone more revisions and paradigm shifts than that of any other organ.
... In some areas, there has also been a long-standing folk tradition of using cod liver oil as a powerful preventive agent [3]. In the early twentieth century, the burst in experimentation and controlled studies confirmed the curative effect of both direct sunlight and cod liver oil, and "calcium-depositing vitamin" was discovered as the factor that cured rickets [4][5][6][7]. This "calcium-depositing vitamin" later became known as vitamin D. ...
... Intact vitamin D is first built into mixed micelles(2). The uptake of vitamin D at dietary concentrations is protein-mediated (3), while at higher pharmacological concentrations it is absorbed through passive diffusion as well(4). Chylomicrons containing vitamin D are then secreted into the lymphatic capillaries (5) before reaching systemic circulation(6). ...
Vitamin D has a well-known role in the calcium homeostasis associated with the maintenance of healthy bones. It increases the efficiency of the intestinal absorption of dietary calcium, reduces calcium losses in urine, and mobilizes calcium stored in the skeleton. However, vitamin D receptors are present ubiquitously in the human body and indeed, vitamin D has a plethora of non-calcemic functions. In contrast to most vitamins, sufficient vitamin D can be synthesized in human skin. However, its production can be markedly decreased due to factors such as clothing, sunscreens, intentional avoidance of the direct sunlight, or the high latitude of the residence. Indeed, more than one billion people worldwide are vitamin D deficient, and the deficiency is frequently undiagnosed. The chronic deficiency is not only associated with rickets/osteomalacia/osteoporosis but it is also linked to a higher risk of hypertension, type 1 diabetes, multiple sclerosis, or cancer. Supplementation of vitamin D may be hence beneficial, but the intake of vitamin D should be under the supervision of health professionals because overdosing leads to intoxication with severe health consequences. For monitoring vitamin D, several analytical methods are employed, and their advantages and disadvantages are discussed in detail in this review.
... This year is the 100th anniversary of the first use of the term vitamin D to describe a fat-soluble factor that cured rickets in dogs [1,2]. The 50 years that followed this saw rapid advances in the chemistry of vitamin D that included discovery of the synthesis of vitamin D by the action of ultraviolet light on skin [3], and the subsequent isolation of vitamin D (cholecalciferol) [4] and 25-hydroxvitamin D (25(OH)D) [5], the major circulating form of vitamin D. The last 50 years have witnessed equally remarkable changes in vitamin D research. ...
... How would this fare under 3Rs scrutiny in the 21st century? The in vivo strategy utilised by Mawer et al. was, of course, a throwback to the early studies of McCollum [2] and Mellanby [1] and preceded by a few years the development of competitive protein binding assays [14] and radioimmunoassay technology [15] that would revolutionise not only vitamin D research but also the whole field of endocrinology. ...
This commentary revisits a paper from Clinical Science in 1972 entitled “The distribution and storage of vitamin D and its metabolites in human tissues” by Barbara Mawer, Bill Stanbury and colleagues. The paper continues to be well cited 50 years later, in part because the study it describes – which includes the use of human autopsy tissue – would be difficult to replicate today. However, the paper also has resonance today because the focus of the study – what is the fate of vitamin D in the body? – is still not clear. This commentary discusses why the Mawer et al. study was a major advance when published and why there is still much to be learned from this paper half a century later.
... The reason for the effectiveness of sunlight and phototherapy in rickets remained a mystery until nutritional studies of the period revealed that in addition to the essential dietary factors (protein, carbohydrate, fat, minerals) considered theretofore, there were also other necessary "accessory factors" or "vital amines" leading to the term "vitamines" that was formally abbreviated to "vitamins" in 1920. That paved the way to identifying the mysterious fat soluble "anti-rachitic factor" of cod fish oil as the fourth vitamin (D) by the American biochemist Elmer McCollum (1879McCollum ( -1967 and his associates in 1922 (DeLuca, 2014;Dent, 1970;McCollum et al., 1922). Simultaneously, it was shown that exposure to ultraviolet light bestowed anti-rachitic properties to certain foods (oils, milk, cereals) that was inherent to their sterol content. ...
... Extensive experimental and clinical studies that ensued then revealed that coincident with the improvement of rickets that followed replacement with vitamin D 3 analogs there was increased intestinal calcium absorption, a rise in the levels of serum calcium and phosphorus, an initial drop followed by a rise of calcium excretion in the urine, and an increase in bone mineralization. As vitamin D 3 metabolites began to be identified it became evident that their effectiveness in increasing calcium absorption and bone mineralization was enhanced by their increased polarity following hydroxylation first to 25(OH)D 3 (calcidol) in the liver and then to its biologically active form 1,25(OH) 2 D 3 (calcitriol) in the kidney (DeLuca, 2014;McCollum et al., 1922). Radioactive fluorescent studies led to the identification of receptors for the active form of vitamin D 3 (VDR) in most tissues of the body, specifically in the intestine, kidney, and parathyroid glands. ...
Abnormalities of the renal interstitium were noted early in the course of identifying chronic kidney disease (CKD) in 1827, but interest in glomerular, vascular and tubular lesions distracted from their further study. It was as a complication of scarlet fever that interstitial lesions attracted attention in 1859 and came to be defined as acute interstitial nephritis (AIN) in 1898. Their chronic form was traditionally attributed to pyelonephritis until the advent of kidney biopsy in the 1950s, when interstitial lesions were recognized as an independent primary cause of CKD from studies of analgesic nephropathy and vesico-ureteral reflux. The term tubulointerstitial nephritis (TIN) was introduced in 1963 and promoted to denote the role of the tubules in the pathogenesis and the clinical presentation of TIN as tubular dysfunction. Studies since then have established that fibrotic TIN lesions corelate best with the severity and progression of kidney diseases independent of their etiology.KeywordsInterstitial nephritisParenchymatous nephritisInterstitial fibrosisAcute tubulointerstitial nephritisChronic tubulointerstitial nephritisAcute kidney injuryChronic kidney disease
... It therefore seems probable that the cause of rickets is a diminished intake of an anti-rachitic factor, which is either [McCollum's] fat-soluble factor A, or has a similar distribution to it" [25]. Then in 1922, Elmer McCollum [26] and his colleagues identified an anti-rachitic factor that was not destroyed by oxidation and played an important role in bone formation. They named this factor Vitamin D [26]. ...
... Then in 1922, Elmer McCollum [26] and his colleagues identified an anti-rachitic factor that was not destroyed by oxidation and played an important role in bone formation. They named this factor Vitamin D [26]. ...
... Para probar la existencia de una "vitamina antirraquítica", ManCollum realizó experimentos en los que se hirvieron (entre 12-20 horas) y oxidaron, con corriente de burbujas de aire, sustancias en aceite de hígado de bacalao, del que sabían que bajo estas condiciones perdía la capacidad de aliviar la xeroftalmia por efecto del fat-soluble A (vitamina A). Este aceite tratado y suplementado al 2 % en la dieta de ratas con raquitismo curaba la enfermedad, siempre y cuando existieran suficientes cantidades de calcio y fósforo en la dieta; los periodos de recuperación dependían de la edad del animal y la época del año, menor tiempo en primavera y verano (46). En este momento la vitamina D había sido descubierta y se evidenciada la relación del calcio con esta vitamina. ...
Antecedentes: la nutrición tiene una historia fascinante, conocerla permite entender su origen y la evolución de los conocimientos que la sustentan. Este artículo es una revisión de los procedimientos experimentales, resultados y conclusiones que facilitaron el nacimiento de la ciencia de la nutrición y el descubrimiento de los nutrientes orgánicos. Objetivo: describir los primeros diseños experimentales del descubrimiento de la nutrición y los nutrientes orgánicos mediante una revisión narrativa. Materiales y métodos: revisión bibliográfica en textos científicos, utilizando términos MeSH en inglés relacionados con los primeros experimentos publicados por los autores a los que se les atribuye el descubrimiento de la nutrición y los nutrientes orgánicos. Resultados: Lavoisier encuentra semejanza entre la combustión de los metales y la respiración de los animales, lo que es la base del metabolismo. Los nutrientes fueron descubiertos utilizando como modelos experimentales levaduras y roedores, a quienes se les sometió a dietas de restricción para después identificar por descarte un nuevo nutriente responsable de la enfermedad carencial o asociada con retrasos de crecimiento. Conclusiones: la nutrición es una ciencia reciente y aún en construcción de nuevos conocimientos, por lo que los diseños experimentales aquí descritos pueden ser útiles para motivar el descubrimiento de nuevas funciones de los nutrientes reconocidos y de nuevas moléculas que puedan ser clasificadas como nutrientes.
... In 1919, Sir Edward Mellanby discovered that a component in cod liver oil was crucial for the prevention of rickets in dogs, although he did not identify the exact substance responsible. In 1922, Elmer McCollum and Marguerite Davis discovered vitamin D while conducting experiments on rats [4][5][6][7][8]. Later the same year, Harry Steenbock discovered that the irradiation of food could produce vitamin D and he developed a method of fortifying milk with vitamin D [9,10]. ...
In the last few decades, vitamin D has undeniably been one of the most studied nutrients. Despite our ability to produce vitamin D through sunlight exposure, its presence in several natural food sources and fortified foods, and its widespread availability as a dietary supplement, vitamin D deficiency is a serious public health problem, affecting nearly 50% of the global population. Low serum levels of vitamin D are being associated with increased susceptibility to numerous health conditions, including respiratory infections, mental health, autoimmune diseases, and different cancer types. Although the association between vitamin D status and health is well-established, the exact beneficial effects of vitamin D are still inconclusive and indefinite, especially when considering the prevention and treatment of different health conditions and the determination of an appropriate dosage to exert those beneficial effects in various population groups. Therefore, further research is needed. With constant improvements in our understanding of individual variations in vitamin D metabolism and requirements, in the future, precision nutrition and personalized supplementation plans could prove beneficial.
... No obstante, si el AHB era sometido a un tratamiento térmico, burbujeando aire a 100 °C durante 12 a 20 horas, el efecto antixeroftálmico se perdía, pero el efecto antirraquítico permanecía virtualmente intacto, indicando que un factor liposoluble desconocido, pero diferente de la vitamina A, era el responsable. 35 . Dado que ya se habían descubierto las vitaminas A, B (tiamina) y C, el factor antirraquítico fue llamado vitamina D. Por consiguiente, 1922 se reconoce generalmente como el año del descubrimiento de la vitamina D. ...
El año 2022 marca el primer centenario del descubrimiento de la vitamina D, hallazgo que recompensó la prolongada búsqueda de la causa del raquitismo, su prevención y tratamiento. Al mismo tiempo puso en marcha importantes investigaciones relacionadas con su biotransformación y el mecanismo de su acción antirraquítica, además de estudios sobre diversos efectos biológicos sin relación directa con su papel en la salud ósea. Esta breve revisión se limitará a delinear la prehistoria de la vitamina D y los diversos estudios, básicos y clínicos, que condujeron a su descubrimiento y caracterización química.
... The role of vitamin D for calcium metabolism and, especially, for the treatment of rickets was first identified in 1922 by the American biochemist Elmer McCollum (1879-1967) (1). After his observations, thousands of papers have shed light on its important and multifaceted function for human health, not only regarding the musculoskeletal system (2,3). ...
In recent years vitamin D has been in the spotlight of many researchers for its possible role in various disorders, including autoimmune and infectious diseases. Even if vitamin D deficiency remains a major public health problem, its symptomatic manifestations are less and less common in clinical practice, and pediatric age represents a "gray area" where vitamin D supplementation is often administered in the absence of an effective evaluation of its status. Moreover, a poor knowledge about different definitions of "deficiency," "insufficiency," and similar terms is spread among clinicians, while guidelines are not univocal, especially after the first year of life. The aim of this brief opinion paper is to sum up recent evidence about vitamin D status and its supplementation in pediatrics, in order to better clarify a common definition of its deficiency. The aim of this opinion article is to raise awareness on this topic among clinicians and encourage a discussion on the real need for routine 25-hydroxycholecalciferol serum evaluation and its supplementation.
... Vitamin D is an important vitamin with anti-rachitic activity, and it promotes the absorption of calcium in the intestinal tract and its deposition in bones. 1 Vitamin D is transported by the blood to the liver, where it is hydroxylated at position 25 of the side chain to form 25hydroxyvitamin D (25(OH)D). 25(OH)D is then metabolized to 3epi -25hydroxyvitamin D (3-epi-25(OH) D) or (24R)-24,25-dihydroxyvitamin D (24,25(OH) 2D ). ...
Background & Aims: Serum 25-hydroxyvitamin D (25(OH)D) comprises 25(OH)D3 and 25(OH)D2. Although sex differences in 25(OH)D levels have been reported, it remains unclear whether the difference lies in the profiles of 25(OH)D. We determined serum 25(OH)D3, 25(OH)D2, 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3), and (24R)-24,25-dihydroxyvitamin D3 (24,25(OH)2D3) levels measured by LC-MS/MS in healthy adults not consuming supplements and analyzed their profiles.
Methods: The serum 25(OH)D levels of 5,959 participants were measured by CLEIA. Levels of vitamin D metabolites (25(OH)D3, 25(OH)D2, 3-epi-25(OH)D3, and 24,25(OH)2D3) of 96 participants with no history of osteoporosis, hypertension, cardiac disease, cerebrovascular disease or diabetes and whose alanine transaminase, serum creatinine, total cholesterol, and hemoglobin A1c levels were within the reference ranges were measured.
Results: Serum 25(OH)D, 25(OH)D3, 3-epi-25(OH)D3, and 24,25(OH)2D3 levels were significantly higher in men than those in women, but there was no significant difference in the 25(OH)D2 levels. Strong correlations were observed between 25(OH)D and 25(OH)D3, 3-epi-25(OH)D3, and 24,25(OH)2D3 levels in both sexes. Serum 25(OH)D and 25(OH)D2 levels and serum 25(OH)D3 and 25(OH)D2 levels were not correlated.
Conclusions: Serum 25(OH)D3, 25(OH)D2, 3-epi-25(OH)D3, and 24,25(OH)2D3 profiles were determined for healthy participants not consuming supplements. Sex differences in 25(OH)D levels reflected differences in 25(OH)D3, not 25(OH)D2.
... McCollum used this information and conducted a study where he aerated and heated cod liver oil and demonstrated that it no longer had vitamin A activity but was still capable of healing rickets. This eureka discovery resulted in McCollum naming this new nutrient vitamin D [12]. ...
The discovery of a fat-soluble nutrient that had antirachitic activity and no vitamin A activity by McCollum has had far reaching health benefits for children and adults. He named this nutrient vitamin D. The goal of this review and personal experiences is to give the reader a broad perspective almost from the beginning of time for how vitamin D evolved to became intimately involved in the evolution of land vertebrates. It was the deficiency of sunlight causing the devastating skeletal disease known as English disease and rickets that provided the first insight as to the relationship of sunlight and the cutaneous production of vitamin D3. The initial appreciation that vitamin D could be obtained from ultraviolet exposure of ergosterol in yeast to produce vitamin D2 resulted in the fortification of foods with vitamin D2 and the eradication of rickets. Vitamin D3 and vitamin D2 (represented as D) are equally effective in humans. They undergo sequential metabolism to produce the active form of vitamin D, 1,25-dihydroxyvitamin D. It is now also recognized that essentially every tissue and cell in the body not only has a vitamin D receptor but can produce 1,25-dihydroxyvitamin D. This could explain why vitamin D deficiency has now been related to many acute and chronic illnesses, including COVID-19.
... One-hundred years ago, McCollum et al. introduced the term vitamin D into the scientific literature as an antirachitic substance that is distinct from vitamin A [1]. Rickets, a bone disease that was first mentioned in the 17th century in England, is characterized by impaired bone mineralization, disturbed bone growth and skeletal deformations. ...
One hundred years ago, the role of vitamin D for bone mineralization and the prevention of rickets was discovered. Vitamin D comprises a group of over 50 metabolites with multiple functions that go far beyond calcium homeostasis and bone mineralization. Approximately 50 years ago, first methods for the measurement of 25-hydroxyvitamin D (25(OH)D) in human blood were developed. Over the years, different analytical principals were employed including competitive protein binding assays, high-performance liquid chromatography, various immunoassay and mass spectrometric formats. Until the recent standardization of serum 25(OH)D measurement, agreement between methods was unsatisfactory. Since then, comparability has improved, but substantial variability between methods remains. With the advent of liquid chromatography tandem mass spectrometry (LC-MS/MS), the accurate determination of 25(OH)D and other metabolites, such as 24,25(OH)2D, becomes increasingly accessible for clinical laboratories. Easy access to 25(OH)D testing has triggered extensive clinical research showing that large parts of the population are vitamin D deficient. The variable response of vitamin D deficient individuals to supplementation indicates that assessing patients’ vitamin D stores by measuring 25(OH)D provides limited insight into the metabolic situation. Meanwhile, first evidence has emerged suggesting that the simultaneous measurement of 25(OH)D, 24,25(OH)2D and other metabolites allows a dynamic evaluation of patients’ vitamin D status on metabolic principals. This may help to identify patients with functional vitamin D deficiency from those without. It can be expected that research into the assessment vitamin D status will continue for another 50 years and that this will help rationalizing our approach in clinical practice.
... Vitamin D was first described in the 1920s in attempts to find the cause of rickets that had reached epidemic proportions in industrial cities in Middle and Northern Europe at that time [1][2][3][4]. However, it would take almost another century after this seminal discovery until the key factors regulating vitamin D metabolism were found, and a more complete understanding of the vitamin D hormonal system had evolved. ...
The seminal discoveries that parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are major endocrine regulators of vitamin D metabolism led to a significant improvement in our understanding of the pivotal roles of peptide hormones and small proteohormones in the crosstalk between different organs, regulating vitamin D metabolism. The interaction of vitamin D, FGF23 and PTH in the kidney is essential for maintaining mineral homeostasis. The proteohormone FGF23 is mainly secreted from osteoblasts and osteoclasts in the bone. FGF23 acts on proximal renal tubules to decrease production of the active form of vitamin D (1,25(OH)2D) by downregulating transcription of 1α-hydroxylase (CYP27B1), and by activating transcription of the key enzyme responsible for vitamin D degradation, 24-hydroxylase (CYP24A1). Conversely, the peptide hormone PTH stimulates 1,25(OH)2D renal production by upregulating the expression of 1α-hydroxylase and downregulating that of 24-hydroxylase. The circulating concentration of 1,25(OH)2D is a positive regulator of FGF23 secretion in the bone, and a negative regulator of PTH secretion from the parathyroid gland, forming feedback loops between kidney and bone, and between kidney and parathyroid gland, respectively. In recent years, it has become clear that vitamin D signaling has important functions beyond mineral metabolism. Observation of seasonal variations in blood pressure and the subsequent identification of vitamin D receptor (VDR) and 1α-hydroxylase in non-renal tissues such as cardiomyocytes, endothelial and smooth muscle cells, suggested that vitamin D may play a role in maintaining cardiovascular health. Indeed, observational studies in humans have found an association between vitamin D deficiency and hypertension, left ventricular hypertrophy and heart failure, and experimental studies provided strong evidence for a role of vitamin D signaling in the regulation of cardiovascular function. One of the proposed mechanisms of action of vitamin D is that it functions as a negative regulator of the renin-angiotensin-aldosterone system (RAAS). This finding established a novel link between vitamin D and RAAS that was unexplored until then. During recent years, major progress has been made towards a more complete understanding of the mechanisms by which FGF23, PTH, and RAAS regulate vitamin D metabolism, especially at the genomic level. However, there are still major gaps in our knowledge that need to be filled by future research. The purpose of this review is to highlight our current understanding of the molecular mechanisms underlying the interaction between vitamin D, FGF23, PTH, and RAAS, and to discuss the role of these mechanisms in physiology and pathophysiology.
... The science of the etiology and treatment of rickets advanced rapidly after World War I. Mellanby rendered puppies rachitic, then supplemented their diets with various additives, noting that fats, notably cod liver oil, repaired the bony defects, concluding that "fat-soluble A" was responsible for the antirachitic action [17]. In 1922, McCollum et al. [18] showed that heat and oxygen inactivated the fat-soluble vitamin A in cod liver oil, but not the fat-soluble "calcium-depositing vitamin" (i.e., vitamin D), showing that vitamin A was not responsible for the salutary action of cod liver oil. Also at this time, UV light was successfully used to treat rickets [19,20] (Fig. 1); ...
Rickets was a major public health problem dating from Roman times, and medical descriptions of rickets date from the 17th century. Sniadecki first advocated treatment by exposure to sunshine in 1822; contemporaneously, several British physicians advocated use of cod liver oil. Both approaches were successful. Work in 1924 showed that exposure to UV light endowed fats and other foods with antirachitic properties. Vitamins D2 and D3, the antirachitic agent in cod liver oil, were, respectively, produced by UV radiation of ergosterol and 7-dehydrocholesterol. Calcitriol (1,25[OH]2D3) was identified as the biologically active form of vitamin D in the early 1970s. The vitamin D 25-hydroxylase, 24-hydroxylase, and 1α-hydroxylase were cloned in the 1990s and their genetic defects were soon delineated. The vitamin D receptor was also cloned and its mutations identified in vitamin D-resistant rickets. Work with parathyroid hormone (PTH) began much later, as the parathyroids were not identified until the late 19th century. In 1925, James B. Collip (of insulin fame) identified PTH by its ability to correct tetany in parathyroidectomized dogs, but only in the 1970s was it clear that only a small fragment of PTH conveyed its activity. Congenital hypoparathyroidism with immune defects was described in 1968, eventually linked to microdeletions in chromosome 22q11.2. X-linked hypophosphatemic rickets was reported in 1957, and genetic linkage analysis identified the causative PHEX gene in 1997. Autosomal dominant hypophosphatemic rickets similarly led to the discovery of FGF23, a phosphate-wasting humoral factor made in bone, in 2000, revolutionizing our understanding of phosphorus metabolism.
... Soon after the discovery of Vitamins A, B, and C, McCollum et al. discovered that feeding cod liver, oxidized or not, healed rickets [119]. He also made the observation that developing clinical symptoms of rickets in preparation for disease resolution experiments takes significantly longer in the summer than the winter, one of the first hints that sunlight is important in the mechanism. ...
Mycobacterium avium subspecies paratuberculosis (MAP) is an environmentally hardy pathogen of ruminants that plagues the dairy industry. Hallmark clinical symptoms include granulomatous enteritis, watery diarrhea, and significant loss of body condition. Transition from subclinical to clinical infection is a dynamic process led by MAP which resides in host macrophages. Clinical stage disease is accompanied by dysfunctional immune responses and a reduction in circulating vitamin D3. The immunomodulatory role of vitamin D3 in infectious disease has been well established in humans, particularly in Mycobacterium tuberculosis infection. However, significant species differences exist between the immune system of humans and bovines, including effects induced by vitamin D3. This fact highlights the need for continued study of the relationship between vitamin D3 and bovine immunity, especially during different stages of paratuberculosis.
... "The action of fats in rickets is due to a vitamin or accessory food factor which they contain, probably identical with the fat-soluble vitamin" (Mellanby, 1921). Afterwards, McCollum concluded that this food accessory was vitamin D. After heating cod liver oil, he observed that the oxidised cod liver oil was not able to prevent xerophthalmia, but could prevent rickets which meant that the fat soluble moiety was not vitamin A but another vitamin, named as vitamin D (McCollum, et al., 1922). Additionally, in 1921 Hess and Unger (Hess & Unger, 1921) observed that sunlight could cure rickets as well as cod liver oil. ...
DEDICATION To all ambitious people who know that success is hard working and the determination that whether we win or lose, we have applied the best of ourselves to the task at hand. iii ACKNOWLEDGEMENT Foremost, I'm grateful to my God and Lord for everything.
... The importance of vitamin D (VitD) in health was formally recognized in 1922 when it was determined that cod liver oil and sunlight cured rickets (1,2). Our understanding of the role of VitD has expanded well beyond bone health with the observation that VitD receptors (VDR) are widely expressed on many cell types in many tissues. ...
Vitamin D insufficiency during childhood has been linked to the development of multiple sclerosis (MS), typically an adult-onset inflammatory demyelinating disease of the central nervous system (CNS). Since vitamin D was known to have immunoregulatory properties on both innate and adaptive immunity, it was hypothesized that low vitamin D resulted in aberrant immune responses and the development of MS. However, vitamin D receptors are present on many cell types, including neurons, oligodendrocytes, astrocytes and microglia, and vitamin D has profound effects on development and function of the CNS. This leads to the possibility that low vitamin D may alter the CNS in a manner that makes it vulnerable to inflammation and the development of MS. This review analysis the role of vitamin D in the immune and nervous system, and how vitamin D insufficiency in children may contribute to the development of MS.
... It has been a hundred years since McCollum first used the term 'vitamin D' in 1922 [1]. Since then, vitamin D has been known as a regulator and key molecule of calcium metabolism, serum calcium levels, and bone mineralization in the human body [2][3][4][5]. ...
The aim of our study was to identify whether vitamin-D deficiency (VDD) can alter the geometry of the coronary-resistance-artery system. Male Wistar rats were divided into vitamin-D-deficient (VD−, n = 10) and vitamin-D-supplemented (VD+, n = 8) groups. After eight weeks, branches and segments of the left-anterior-descending-coronary-artery (LAD) network were analyzed by a video-microscopy technique. Segments were divided into 50 μm-long cylindrical ring units. VDD did not increase the number of morphological abnormalities. The number of segments did not differ between the groups (VD−: 210 and VD+: 224; pooled data of 8 networks). A larger lumen area of branches was found in VD+ group, while 1–4-order branches were lengthier in the VD− group. VD− rats had less rich coronary-resistance-artery networks in terms of 50 µm-long units. (VD−: 6365 vs. VD+: 6602; pooled data of 8 networks). VD+ animals were richer in the 100–350 µm outer diameter range, and VD− animals were richer in the 400–550 µm-diameter units. In VD− rats, 150–200 and 300 µm units were almost missing at higher flow distances from the orifice. Serum vitamin-D alterations caused by dietary changes can affect the geometry of the coronary-artery network, which may contribute to vitamin-D-dependent changes in cardiovascular mortality.
... The discovery of the nutritional factor, later termed vitamin D by McCollum (27), came largely as the result of the work of a number of researchers: Mellanby, McCollum, Steenbock and Hart working independently. Sir Edward Mellanby (28) in the UK reasoned that rickets might be due to a dietary deficiency and managed to produce beagle dogs with severe rickets by feeding them oatmeal and then cured their rickets with cod liver oil. ...
Vitamin D has many physiological functions including upregulation of intestinal calcium and phosphate absorption, mobilization of bone resorption, renal reabsorption of calcium as well as actions on a variety of pleiotropic functions. It is believed that many of the hormonal effects of vitamin D involve a 1,25-dihydroxyvitamin D3-vitamin D receptor (VDR)-mediated transcriptional mechanism involving binding to the cellular chromatin and regulating hundreds of genes in many tissues. This comprehensive historical review provides a unique perspective of the many steps of the discovery of vitamin D and its deficiency disease, rickets, stretching from 1650 until the present. The overview is divided into four distinct historical phases which cover the major developments in the field and in the process highlighting the: a) first recognition of rickets or vitamin D deficiency; b) discovery of the nutritional factor, vitamin D and its chemical structure; c) elucidation of vitamin D metabolites including the hormonal form, 1,25-dihydroxyvitamin D3; d) delineation of the vitamin D cellular machinery, functions and vitamin D-related diseases which focused on understanding the mechanism of action of vitamin D in its many target cells.
... We have known since the 19th century that cod liver oil has anti-rachitic activity. In a famous experiment performed 100 years ago, McCollum and coworkers showed that heated, oxidized cod-liver oil, in which vitamin A had been destroyed, lost the capacity to prevent xerophthalmia but could still cure rickets in rats [1,2]. Subsequent work revealed that seco-steroidal vitamin D3 could be produced in skin in the presence of sufficient ultraviolet B irradiation via the photochemical and thermal conversion of the conjugated double bonds of the cholesterol precursor, 7dehydrocholesterol [3]. ...
Vitamin D deficiency, characterized by low circulating levels of calcifediol (25-hydroxyvitamin D, 25D) has been linked to increased risk of infections of bacterial and viral origin. Innate immune cells produce hormonal calcitriol (1,25-dihydroxyvitamin D, 1,25D) locally from circulating calcifediol in response to pathogen threat and an immune-specific cytokine network. Calcitriol regulates gene expression through its binding to the vitamin D receptor (VDR), a ligand-regulated transcription factor. The hormone-bound VDR induces the transcription of genes integral to innate immunity including pattern recognition receptors, cytokines, and most importantly antimicrobial peptides (AMPs). Transcription of the human AMP genes β-defensin 2/defensin-β4 (HBD2/DEFB4) and cathelicidin antimicrobial peptide (CAMP) is stimulated by the VDR bound to promoter-proximal vitamin D response elements. HDB2/DEFB4 and the active form of CAMP, the peptide LL-37, which form amphipathic secondary structures, were initially characterized for their antibacterial actively. Notably, calcitriol signaling induces secretion of antibacterial activity in vitro and in vivo, and low circulating levels of calcifediol are associated with diverse indications characterized by impaired antibacterial immunity such as dental caries and urinary tract infections. However, recent work has also provided evidence that the same AMPs are components of 1,25D-induced antiviral responses, including those against the etiological agent of the COVID-19 pandemic, the SARS-CoV2 coronavirus. This review surveys the evidence for 1,25D-induced antimicrobial activity in vitro and in vivo in humans and presents our current understanding of the potential mechanisms by which CAMP and HBD2/DEFB4 contribute to antiviral immunity.
... De hecho, era una práctica común en las costas de las islas británicas (Islas Hébridas) y de los países escandinavos, utilizar aceite de hígado de pescado para prevenir y curar esa enfermedad deformante de los huesos (7) . Al principio, se pensó que la actividad antirraquítica del aceite de hígado de bacalao podía deberse al efecto de la vitamina A. Sin embargo, cuando su actividad era destruida por el calor y la oxidación, el aceite de hígado de bacalao continuaba conservando su actividad antirraquítica (8) . Como resultado de todas estas observaciones, se concluyó que existía una nueva vitamina liposoluble a la que se llamó vitamina D, puesto que ya se habían descubierto las denominadas A, B y C. ...
Prólogo E l tétanos es una enfermedad aguda infecciosa con reper-cusión en el sistema nervioso, caracterizada por espas-mos, contracciones musculares violentas y rigidez. En 1889, el médico y bacteriólogo japonés Kitasato Shibasaburo logró cultivar por primera vez el agente causal Clostridium tetani, productor de las neurotoxinas que originan la sinto-matología. Por la similitud clínica aunque no etiológica, se acuñó el término de "tetania", para designar a las contracciones musculares de origen no infeccioso. El término "espasmofilia" no está considerado en el dic-cionario de la RAE. Procede del griego spasmos (de spaō: con-traigo y philia: tendencia). Se trata de un neologismo que se acuñó para designar una situación algo más amplia que la tetania, indicativa de hiperirritabilidad neuromuscular, ampliable a otros síntomas como lipotimias, parestesias, trastornos psíquicos e, incluso, convulsiones. Hasta que se relacionó la espasmofilia/tetania con el meta-bolismo del calcio y el raquitismo carencial, tuvieron que pasar muchos años. Esta es su historia. Historia del raquitismo y la vitamina D La referencia inicial que se dispone acerca de la primera vez que apareció impresa la palabra "raquitismo" data de 1634, al figurar en el Documento (Bill) Anual de Mortalidad de la Ciudad de Londres de ese año. Estos documentos regis-traban el número y las causas de muerte en el área de alre-dedor de la Torre de Londres y de la Catedral de San Pablo, una parte situada dentro o cerca de las murallas de la ciudad de Londres. Según O'Riordan, las primeras descripciones indudables de raquitismo se publicaron entre 1645 y 1668 por parte de Whistler, Boote, Glisson y Mayow (1). A media-dos del siglo XVII, se identificó el raquitismo como un pro-blema de salud importante entre los niños pequeños, cuando comenzó el éxodo de las comunidades agrícolas rurales a las áreas urbanas lo que, a su vez, indujo cambios en el estilo de vida que limitaron la exposición a la luz solar. En la historia humana, el papel de la luz solar y la vitamina D se convirtió en significativo al comienzo de la revolución industrial, época en la que la incidencia de esta enfermedad ósea debilitante aumentó drásticamente, especialmente, en el norte de Europa y América del Norte. Los niños diagnosticados de raquitismo se identificaban por deformidades en el esqueleto, incluido el agrandamiento de la cabeza, los extremos de los huesos largos y la caja torá-cica, junto a debilidad muscular generalizada (Figs. 1 y 2).
... Vitamin D has attracted attention because its deficiency underlies the pathogenesis of well-known bone pathological conditions, such as rickets in children and osteomalacia in adults [43][44][45]. ...
Several recent studies have demonstrated that the direct precursor of vitamin D3, the calcifediol [25(OH)D3], through the binding to the nuclear vitamin D receptor (VDR), is able to regulate the expression of many genes involved in several cellular processes. Considering that itself may function as a VDR ligand, although with a lower affinity, respect than the active form of vitamin D, we have assumed that 25(OH)D3 by binding the VDR could have a vitamin’s D3 activity such as activating non-genomic pathways, and in particular we selected mesenchymal stem cells derived from human adipose tissue (hADMSCs) for the in vitro assessment of the intracellular Ca2+ mobilization in response to 25(OH)D3. Our result reveals the ability of 25(OH)D3 to activate rapid, non-genomic pathways, such as an increase of intracellular Ca2+ levels, similar to what observed with the biologically active form of vitamin D3. hADMSCs loaded with Fluo-4 AM exhibited a rapid and sustained increase in intracellular Ca2+ concentration as a result of exposure to 10−5 M of 25(OH)D3. In this work, we show for the first time the in vitro ability of 25(OH)D3 to induce a rapid increase of intracellular Ca2+ levels in hADMSCs. These findings represent an important step to better understand the non-genomic effects of vitamin D3 and its role in endocrine system.
... However, fish oil has a flavor and odor problem, so direct intake has not generally been preferred. Other than cod liver oil, rats studies in the 1920s showed that coconut oil [10], alfalfa, and clover [11] contained an anti-rickets component, but the identity of the component was not unknown. UV irradiation has an anti-rickets effect not only in humans and animals, but also in foods. ...
Vitamins D have various biological activities, as well as intestinal calcium absorption. There has been recent concern about insufficient vitamin D intake. In addition to vitamins D2 and D3, there are lesser-known vitamins D4–D7. We synthesized vitamins D5–D7, which are not commercially available, and then evaluated and compared the mixed micelles-solubilized vitamins D uptake by Caco-2 cells. Except for vitamin D5, the uptake amounts of vitamins D4–D7 by differentiated Caco-2 cells were similar to those of vitamins D2 and D3. The facilitative diffusion rate in the ezetimibe inhibited pathway was approximately 20% for each vitamin D type, suggesting that they would pass through the pathway at a similar rate. Lysophosphatidylcholine enhanced each vitamin D uptake by approximately 2.5-fold. Lysophosphatidylcholine showed an enhancing effect on vitamin D uptake by reducing the intercellular barrier formation of Caco-2 cells by reducing cellular cholesterol, suggesting that increasing the uptakes of vitamins D and/or co-ingesting them with lysophosphatidylcholine, would improve vitamin D insufficiency. The various biological activities in the activated form of vitamins D4–D7 were estimated by Prediction of Activity Spectra for Substances (PASS) online simulation. These may have some biological activities, supporting the potential as nutritional components.
... Vitamin D is a fat soluble vitamin acting as an ingredient for various metabolic and biological processes [1]. Vitamin D deficiency is a worldwide pandemic problem with reported incidence up to 77% [2]. ...
Background
Vitamin D deficiency is a worldwide pandemic problem. With vitamin D having some role in exercise-induced inflammation, skeletal muscle mass and endurance, we studied its effect on functional outcome of athletes’ post-Anterior Cruciate Ligament (ACL) reconstruction.MethodsA total of 153 patients who underwent primary ACL reconstruction were enrolled in the study. All patients were screened for vitamin D levels preoperatively. Patients were divided into 3 groups on basis of vitamin D levels; Group 1 patients had < 20 ng/ml, group 2 patients 20–30 ng/ml and group 3 > 30 ng/ml. All patients were followed up for a minimum of 2 years.ResultsA total of 153 patients were enrolled in study. The average age of the patients was 24.12 ± 2.12 years in group 1, 25.24 ± 3.20 years in group 2 and 24.74 ± 2.86 in group 3. The mean follow-up of patients was 2.8 ± 1.2 years. At 2 years, the mean Lysholm score was 96.12, 96.49 and 97.0, respectively (p = 0.75); mean WOMAC score was 3.33, 3.38 and 3.20, respectively (p = 0.91); mean difference between the pre-injury and post-surgery Tegner level of sports activity at 2 years follow-up was 0.78, 0.78 and 0.85, respectively (P = 0.51) and graft failure rate was 5.88%, 1.96% and 1.96%, respectively (p = 0.43).Conclusion
Vitamin D has no effect on functional outcome and graft rupture rates in patients’ post-primary ACL reconstruction.Level of evidenceProspective Cohort Study (Level III)
Melatonin, a product of tryptophan metabolism via serotonin, is a molecule with an indole backbone that is widely produced by bacteria, unicellular eukaryotic organisms, plants, fungi and all animal taxa. Aside from its role in the regulation of circadian rhythms, it has diverse biological actions including regulation of cytoprotective responses and other functions crucial for survival across different species. The latter properties are also shared by its metabolites including kynuric products generated by reactive oxygen species or phototransfomation induced by ultraviolet radiation. Vitamins D and related photoproducts originate from phototransformation of ∆5,7 sterols, of which 7‐dehydrocholesterol and ergosterol are examples. Their ∆5,7 bonds in the B ring absorb solar ultraviolet radiation [290–315 nm, ultraviolet B (UVB) radiation] resulting in B ring opening to produce previtamin D, also referred to as a secosteroid. Once formed, previtamin D can either undergo thermal‐induced isomerization to vitamin D or absorb UVB radiation to be transformed into photoproducts including lumisterol and tachysterol. Vitamin D, as well as the previtamin D photoproducts lumisterol and tachysterol, are hydroxylated by cyochrome P450 (CYP) enzymes to produce biologically active hydroxyderivatives. The best known of these is 1,25‐dihydroxyvitamin D (1,25(OH) 2 D) for which the major function in vertebrates is regulation of calcium and phosphorus metabolism. Herein we review data on melatonin production and metabolism and discuss their functions in insects. We discuss production of previtamin D and vitamin D, and their photoproducts in fungi, plants and insects, as well as mechanisms for their enzymatic activation and suggest possible biological functions for them in these groups of organisms. For the detection of these secosteroids and their precursors and photoderivatives, as well as melatonin metabolites, we focus on honey produced by bees and on body extracts of Drosophila melanogaster . Common biological functions for melatonin derivatives and secosteroids such as cytoprotective and photoprotective actions in insects are discussed. We provide hypotheses for the photoproduction of other secosteroids and of kynuric metabolites of melatonin, based on the known photobiology of ∆5,7 sterols and of the indole ring, respectively. We also offer possible mechanisms of actions for these unique molecules and summarise differences and similarities of melatoninergic and secosteroidogenic pathways in diverse organisms including insects.
Vitamin D is a natural photoproduct that has many beneficial effects on different organs, including skin. Active forms of vitamin D and its derivatives exert biological effects on skin cells, thus maintaining skin homeostasis. In keratinocytes, they inhibit proliferation and stimulate differentiation, have anti-inflammatory properties, act as antioxidants, inhibit DNA damage and stimulate DNA repair after ultraviolet (UV) exposure. In melanocytes, they also inhibit cell proliferation, inhibit apoptosis and act as antioxidants. In fibroblasts, they inhibit cell proliferation, affect fibrotic processes and collagen production, and promote wound healing and regeneration. On the other hand, skin cells have the ability to activate vitamin D directly. These activities, along with the projected topical application of vitamin D derivatives, are promising for skin care and photo protection and can be used in the prevention or possible reversal of skin aging.
Vitamin D3 (VD) is a secosteroid hormone and shows a pleiotropic effect in brain-related disorders where it regulates redox imbalance, inflammation, apoptosis, energy production, and growth factor synthesis. Vitamin D3’s active metabolic form, 1,25-dihydroxy Vitamin D3 (1,25(OH)2D3 or calcitriol), is a known regulator of several genes involved in neuroplasticity, neuroprotection, neurotropism, and neuroinflammation. Multiple studies suggest that VD deficiency can be proposed as a risk factor for the development of several age-related neurological disorders. The evidence for low serum levels of 25-hydroxy Vitamin D3 (25(OH)D3 or calcidiol), the major circulating form of VD, is associated with an increased risk of Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), dementia, and cognitive impairment. Despite decades of evidence on low VD association with neurological disorders, the precise molecular mechanism behind its beneficial effect remains controversial. Here, we will be delving into the neurobiological importance of VD and discuss its benefits in different neuropsychiatric disorders. The focus will be on AD, PD, and HD as they share some common clinical, pathological, and epidemiological features. The central focus will be on the different attributes of VD in the aspect of its anti-oxidative, anti-inflammatory, anti-apoptotic, anti-cholinesterase activity, and psychotropic effect in different neurodegenerative diseases.
The pro-hormone vitamin D3 is an important modulator of both innate and adaptive immunity since its biologically active metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates via the transcription factor VDR (vitamin D receptor) the epigenome and transcriptome of human immune cells and controls in this way the expression of hundreds of vitamin D target genes. Since the myeloid linage of hematopoiesis is epigenetically programmed by VDR in concert with the pioneer factors PU.1 (purine-rich box 1) and CEBPα (CCAAT/enhancer binding protein α), monocytes, macrophages, and dendritic cells are the most vitamin D-sensitive immune cell types. The central role of the immune system in various aging-related diseases suggests that immunocompetence describes not only the ability of an individual to resist pathogens and parasites but also to contest non-communicative diseases and the process of aging itself. In this review, we argue that the individual-specific responsiveness to vitamin D relates to a person’s immunocompetence via the epigenetic programming function of VDR and its ligand 1,25(OH)2D3 during hematopoiesis as well as in the periphery. This may provide a mechanism explaining how vitamin D protects against major common diseases and, in parallel, promotes healthy aging.
Biofortification was first proposed in the early 1990s as a low-cost, sustainable strategy to enhance the mineral and vitamin contents of staple food crops to address micronutrient malnutrition. Since then, the concept and remit of biofortification has burgeoned beyond staples and solutions for low- and middle-income economies. Here we discuss what biofortification has achieved in its original manifestation and the main factors limiting the ability of biofortified crops to improve micronutrient status. We highlight the case for biofortified crops with key micronutrients, such as provitamin D3/vitamin D3, vitamin B12 and iron, for recognition of new demographics of need. Finally, we examine where and how biofortification can be integrated into the global food system to help overcome hidden hunger, improve nutrition and achieve sustainable agriculture.
Metabolic bone disorders and associated fragility fractures are major causes of disability and mortality worldwide and place an important financial burden on the global health systems. These disorders result from an unbalance between bone anabolic and resorptive processes and are characterized by different pathophysiological mechanisms. Drugs are available to treat bone metabolic pathologies, but they are either poorly effective or associated with undesired side effects that limit their use. The molecular mechanism underlying the most common metabolic bone disorders, and the availability, efficacy, and limitations of therapeutic options currently available are discussed here. A source for the unmet need of novel drugs to treat metabolic bone disorders is marine organisms, which produce natural osteoactive compounds of high pharmaceutical potential. In this review, we have inventoried the marine osteoactive compounds (MOCs) currently identified and spotted the groups of marine organisms with potential for MOC production. Finally, we briefly examine the availability of in vivo screening and validation tools for the study of MOCs.
Rickets and osteomalacia are associated with impaired mineralization in growth plate cartilage and the bone osteoid [...]
Vitamin D3 is a pre-hormone that regulates hundreds of target genes and dozens of physiological functions, including calcium homeostasis and the activity of the immune system, via its metabolite 1,25-dihydroxyvitamin D3, which is a high-affinity ligand for the transcription factor vitamin D receptor. In this study, we took advantage of data from the VitDHiD vitamin D3 intervention trial (25 healthy individuals) indicating that 442 protein-coding genes were significantly (false discovery rate < 0.05) up- or downregulated in peripheral blood mononuclear cells one day after taking a vitamin D3 bolus. Since more than half of the encoded proteins had “signaling” assigned as a primary biological function, we evaluated their involvement in signal transduction cascades included in the KEGG (Kyoto Encyclopedia of Genes and Genomes) database and found 88 of the vitamin D targets contributing to 16 different pathways. Eight of the pathways show an approximately even contribution of up- and downregulated genes, suggesting that the actions of vitamin D stabilize homeostasis of the physiological processes driven by the respective signaling cascades. Interestingly, vitamin D target genes involved in the signaling pathways of hypoxia-inducible factor 1 (HIF1), tumor necrosis factor (TNF), mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NFκB) are primarily downregulated. This supports the observation that the physiological role of vitamin D in healthy individuals is to tone down certain processes rather than activate them. In conclusion, under in vivo conditions, vitamin D either alleviates the homeostasis of immune cells in healthy individuals or counteracts molecular responses to oxygen deprivation (HIF1), microbe infection (TNF), growth stimulation (MAPKs) and inflammation (NFκB).
Vitamin D intervention studies are designed to evaluate the impact of the micronutrient vitamin D3 on health and disease. The appropriate design of studies is essential for their quality, successful execution, and interpretation. Randomized controlled trials (RCTs) are considered the “gold standard” for intervention studies. However, the most recent large-scale (up to 25,000 participants), long-term RCTs involving vitamin D3 did not provide any statistically significant primary results. This may be because they are designed similarly to RCTs of a therapeutic drug but not of a nutritional compound and that only a limited set of parameters per individual were determined. We propose an alternative concept using the segregation of study participants into different groups of responsiveness to vitamin D3 supplementation and in parallel measuring a larger set of genome-wide parameters over multiple time points. This is in accordance with recently developed mechanistic modeling approaches that do not require a large number of study participants, as in the case of statistical modeling of the results of a RCT. Our experience is based on the vitamin D intervention trials VitDmet, VitDbol, and VitDHiD, which allowed us to distinguish the study participants into high, mid, and low vitamin D responders. In particular, investigating the vulnerable group of low vitamin D responders will provide future studies with more conclusive results both on the clinical and molecular benefits of vitamin D3 supplementation. In conclusion, our approach suggests a paradigm shift towards detailed investigations of transcriptome and epigenome-wide parameters of a limited set of individuals, who, due to a longitudinal design, can act as their own controls.
Vitamin D plays an important role in calcium homeostasis and many cellular processes. Although vitamin D supplements are widely recommended for community dwelling adults, definitive data on whether these supplements benefit clinically important skeletal and extra-skeletal outcomes have been conflicting. While observational studies on effects of vitamin D on musculoskeletal and extra-skeletal outcomes may be confounded by reverse causation, randomized controlled studies (RCTs) and Mendelian Randomization (MR) studies can help to elucidate causation. In this review we summarize the recent findings from large RCTs and/or MR studies of vitamin D on bone health and risk of fractures, falls, cancer, and cardiovascular disease, disorders of the immune system, multiple sclerosis, and mortality in community-dwelling adults. The primary analyses indicate that vitamin D supplementation does not decrease bone loss, fractures, falls, cancer incidence, hypertension, or cardiovascular risk in generally healthy populations. Large RCTS and meta-analyses suggest an effect of supplemental vitamin D on cancer mortality. The existence of extra-skeletal benefits of vitamin D supplementations are best documented for the immune system especially in people with poor vitamin D status, autoimmune diseases and multiple sclerosis. Accumulating evidence indicates that vitamin D may reduce all-cause mortality. These findings, in mostly vitamin D replete populations, do not apply to older adults in residential communities or adults with vitamin D deficiency or osteoporosis. The focus of vitamin D supplementation should shift from widespread use in generally healthy populations to targeted vitamin D supplementation in select individuals, good nutritional approaches, and elimination of vitamin D deficiency globally. This article is protected by copyright. All rights reserved.
Despite different lifestyles, humankind has suffered from osteoporosis for thousands of years. A literature review concerning the history of osteoporosis in the following databases: Index Medicus, Medline, PubMed, and PMC Citations was done. In the final analysis, 18 review articles and 31 original papers were included. The works were published during the period 1705-2020. Although there is evidence of the existence of osteoporosis for many centuries, it was first described as a disease at the beginning of the 18th century. It was first perceived as an unavoidable course of aging with no possibility to cure. This approach changed only in the 20th century thanks to sudden diagnostic and therapeutic progress. This paper presents the milestones and most important researchers in osteoporosis history. Rapid progress in diagnostic and therapeutic possibilities sheds new light on osteoporosis’ nature. A comprehensive outlook on its history may help find answers for the still unsolved problems of this disease.
Accumulating evidence supports the potential protective effects of vitamin D against chronic diseases such as Alzheimer’s disease, autoimmune diseases, cancers, cardiovascular disease (ischaemic heart disease and stroke), type 2 diabetes, hypertension, chronic kidney disease, stroke, and infectious diseases such as acute respiratory tract diseases, COVID-19, influenza, and pneumonia, as well as adverse pregnancy outcomes. The respective evidence is based on ecological and observational studies, randomized controlled trials, mechanistic studies, and Mendelian randomization studies. However, randomized controlled trials on vitamin D supplementation have largely failed to show benefits, probably due to poor design and analysis. In this work, we aim to use the best available evidence on the potential beneficial effects of vitamin D to estimate the expected reduction in incidence and mortality rates of vitamin D-related diseases in the Kingdom of Saudi Arabia and the United Arab Emirates if minimum serum 25(OH)D concentrations were to be raised to 30 ng/mL. Estimated reductions by 25% for myocardial infarction incidence, 35% for stroke incidence, 20 to 35% for cardiovascular disease mortality, and 35% for cancer mortality rates depicted a promising potential for raising serum 25(OH)D. Methods to increase serum 25(OH)D concentrations at the population level could include food fortification with vitamin D3, vitamin D supplementation, improved dietary vitamin D intake, and sensible sun exposure.
Vitamin D is one of the four fat-soluble vitamins that have been recognized to possess important biologic functions. The major physiologic effect of vitamin D is on calcium and bone metabolism, by maintaining extracellular concentrations of calcium and phosphorus within the normal range (1–3). During the past three decades, intensive research on vitamin D has revealed that it is a hormone and not a vitamin. Once vitamin D is formed in the skin, it requires two sequential hydroxylation reactions, first in the liver to form 25-hydroxyvitamin D (25-OH-D), and then in the kidneys to form 1,25-dihydroxyvitamin D [1,25(OH)2D]. It is 1,25(OH)2D that is responsible for enhancing the efficiency of intestinal absorption of dietary calcium and phosphorus, as well as the mobilization of calcium and phosphorus stores from bone (1–3). In addition, 1,25(OH)2D has other biologic actions in many tissues or cells that possess the 1,25(OH)2D receptor, including enhancement of cellular differentiation and/or inhibition of cellular proliferation in cultured fibroblasts and keratinocytes (2).
This year we are celebrating 100 years of the naming of vitamin D, but the molecule is, in fact, more than one billion years old [...]
Background: Vitamin D has a significant role in the metabolism of calcium and bone. Therefore, its deficiency leads to rickets in growing children and osteomalacia in adults. The classical functions of Vitamin D in bone metabolism and calciumphosphorus homeostasis is well established. The non-classical functions of Vit D as an immunomodulatory and growth-promoting factor influencing the overall well being in general and respiratory health, in particular, is the subject of current interest. It is reported that vitamin D plays a crucial role in foetal lungs proper growth and maturity.In many children with steroid-resistant asthma, vitamin D supplements may increase the responsiveness to steroids. Vitamin D deficiency states were reported to be associated with an increased risk of acute exacerbations of bronchial Asthma. Our study is conducted to determine serum levels of vitamin D in asthmatic children and association of vit D deficiency with asthma. Aim of The Study:To determine the serum levels of vitamin D in asthmatic children. Objective: To Study the relation between vitamin D levels and 1. The severity of asthma 2. Frequency of asthma exacerbation Study Design:It is cross sectional study. Methods: 100 children who got admitted to the pediatric ward (or) PICU of MIMS, of whom 40 were known asthmatics and 60 age and sex-matched controls were considered to do a comparative study of the variables under consideration. Study of vitamin D levels in relation to bronchial asthma in children has been carried out as an analytical case-control study for 18 months. Results: 60% of the study participants were vitamin D deficient. Whereas 15% had insufficient levels, and sufficient vitamin D levels are observed only in 25% of the participants. A statistically significant difference in vitamin D levels and the severity of illness has been observed among the study participants. Moderate persistent Asthma has been seen more in patients who are deficient in vitamin D. A high statistically significant association has been observed between exacerbations of Asthma and levels of vitamin D. Conclusion: A statistically significant difference in vitamin D levels and the severity of illness among the study participants are observed. Moderate persistent Asthma has been seen more in patients who are deficient in vitamin D. A high statistically significant association has been observed between exacerbations of Asthma and levels of vitamin D.
Poor vitamin D status is a global health problem; insufficiency underpins higher risk of cancer, neurocognitive decline and all-cause mortality. Most foods contain little vitamin D and plants are very poor sources. We have engineered the accumulation of provitamin D3 in tomato by genome editing, modifying a duplicated section of phytosterol biosynthesis in Solanaceous plants, to provide a biofortified food with the added possibility of supplement production from waste material. Vitamin D insufficiency is a major public health problem requiring dietary fortification and supplement solutions. This study produced gene-edited tomato lines that accumulate provitamin D3 in fruits, offering a new dietary source of vitamin D3.
The vitamin D metabolite 1α,25-dihydroxyvitamin D3 is the natural, high-affinity ligand of the transcription factor vitamin D receptor (VDR). In many tissues and cell types, VDR binds in a ligand-dependent fashion to thousands of genomic loci and modulates, via local chromatin changes, the expression of hundreds of primary target genes. Thus, the epigenome and transcriptome of VDR-expressing cells is directly affected by vitamin D. Vitamin D target genes encode for proteins with a large variety of physiological functions, ranging from the control of calcium homeostasis, innate and adaptive immunity, to cellular differentiation. This review will discuss VDR’s binding to genomic DNA, as well as its genome-wide locations and interaction with partner proteins, in the context of chromatin. This information will be integrated into a model of vitamin D signaling, explaining the regulation of vitamin D target genes.
Poor physical function and muscle weakness are associated with higher mortality in chronic kidney disease and end-stage renal disease patients. Studies have tested therapeutic agents to prevent and mitigate muscle wasting with the hope of maintaining or even increasing physical function. Anabolic pathways in muscle largely signal through the insulin-like growth factor-1/PI3K/Akt system. Several therapeutic agents have been found to stimulate this pathway, such as testosterone, growth hormone (GH), and vitamin D. The ubiquitin–proteasome system is the major catabolic pathway in skeletal muscle. This pathway is stimulated by myostatin, which decreases anabolic signaling and induces catabolic signaling. Several therapeutic agents have been developed to counter myostatin action. In this chapter, we review the history, molecular mechanisms, in vitro and in vivo data, and clinical trial data for each of these therapeutic agents: testosterone, GH, vitamin D, and antimyostatin antibodies.
De kat en vitamine A Vitamine A is een essentiële voedingsstof voor de kat. Zowel een tekort als overmaat, gedurende langere tijd, veroorzaakt ernstige aandoeningen. Als zuivere stof is vitamine A zeer oxidatiegevoelig. Derhalve worden bij de productie van kattenvoeders gestabiliseerde preparaten gebruikt. In 1957, 35 jaar na de ontdekking van vitamine A in onderzoek bij ratten (1), werd door Gerschoff et al. (2) gepubliceerd dat het vitamine ook voor de kat een essentiële voedingsstof is. Twee tot drie maanden na verstrekking van een semisynthetisch voeder (Noot 1) zonder vitamine A, hadden jonge katten gewichtsverlies, licht roze tot rode uitvloeiing rond de oogleden en spierzwakte in de achterpoten. Tijdens een congres in 1964 sprak Sumner-Smith, dierenarts te Bristol, over voedingsgerelateerde problemen bij katten (3). Hij zei onder meer dat zijn voedingsadvies voor een kat vaak werd weggewuifd door de eigenaar met de reactie dat haar/zijn kat niets anders wil eten dan lever. In 1965 lieten Seawright et al. (4) zien dat een destijds bekende botaandoening bij katten, die veel runderlever aten, werd veroorzaakt door intoxicatie met vitamine A. Vitamines A en D Na een periode van 10 tot 17 weken op een voeder met varkensvet als enige vetbron stopte de groei van jonge ratten (5, Noot 2). De publicatie uit 1913 toont dat vervanging van varkensvet door een etherextract van boter, eieren of eidooier de groei herstelde, terwijl een etherextract van olijfolie dat niet deed. De groeifactor in boter en eieren werd later vetoplosbaar A genoemd, ter onderscheiding van wateroplosbaar B (cf. 6). Bij ratten beschermde groeifactor A behalve tegen groeivertraging ook tegen gebrekkige calciumafzetting in het bot (rachitis) en uitdroging van het oogbindvlies (xeroftalmie). In 1922 bleek dat de groeifactor uit twee vitamines bestaat (1, Noot 3). Na doorborrelen van groeifactor A met lucht trad groeivertraging en xeroftalmie op, maar geen rachitis. De oxidatiegevoelige en-ongevoelige component zouden als vitamines A en D bekend worden. Vitamine A en caroteen In 1932 werd de structuur van vitamine A opgehelderd (7). Retinol, de belangrijkste vorm van vitamine A in de voeding, bestaat uit 20 koolstofatomen met een ringstructuur aan één uiteinde en een hydroxylgroep aan het andere. Het retinolmolekuul bevat vijf onverzadigde bindingen waardoor het zeer oxidatiegevoelig is. Dit verklaart dat de retinolcomponent van groeifactor A werd geïnactiveerd door lucht. De opname van vitamine A bij de kat leek efficiënter op een vetrijk in plaats van vetarm voeder (2). Deze bevinding wordt verteringsfysiologisch ondersteund. De opname van het vetoplosbare retinol door de darm lift mee met de vertering en absorptie van voedingsvetten.
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