Regulation Of Calcium Metabolism Research Articles

Genetic profile of a large Spanish cohort with hypercalcemia.

The disorders in the metabolism of calcium can present with manifestations that strongly suggest their diagnosis; however, most of the time, the symptoms with which they are expressed are nonspecific or present only as a laboratory finding, usually hypercalcemia. Because many of these disorders have a genetic etiology, in the present study, we sequenced a selection of 55 genes encoding the principal proteins involved in the regulation of calcium metabolism. A cohort of 79 patients with hypercalcemia were analyzed by next-generation sequencing. The 30% of our cohort presented one pathogenic or likely pathogenic variant in genes associated with hypercalcemia. We confirmed the clinical diagnosis of 17 patients with hypocalciuric hypercalcemia (pathogenic or likely pathogenic variants in the CASR and AP2S1 genes), one patient with neonatal hyperparathyroidism (homozygous pathogenic variant in the CASR gene), and another patient with infantile hypercalcemia (two pathogenic variants in compound heterozygous state in the CYP24A1 gene). However, we also found variants in genes associated with primary hyperparathyroidism (GCM2), renal hypophosphatemia with or without rickets (SLC34A1, SLC34A3, SLC9A3R1, VDR, and CYP27B1), DiGeorge syndrome (TBX1 and NEBL), and hypophosphatasia (ALPL). Our genetic study revealed 11 novel variants. Our study demonstrates the importance of genetic analysis through massive sequencing to obtain a clinical diagnosis of certainty. The identification of patients with a genetic cause is important for the appropriate treatment and identification of family members at risk of the disease.

Effects of Dietary Colostrum Basic Protein on Bone Growth and Calcium Absorption in Mice.

Colostrum basic protein (CBP) is a trace protein extracted from bovine colostrum. Previous studies have shown that CBP can promote bone cell differentiation and increase bone density. However, the mechanism by which CBP promotes bone activity remains unclear. This study investigated the mechanism of the effect of CBP on bone growth in mice following dietary supplementation of CBP at doses that included 0.015%, 0.15%, 1.5%, and 5%. Compared with mice fed a normal diet, feeding 5% CBP significantly enhanced bone rigidity and improved the microstructure of bone trabeculae. Five-percent CBP intake triggered significant positive regulation of calcium metabolism in the direction of bone calcium accumulation. The expression levels of paracellular calcium transport proteins CLDN2 and CLDN12 were upregulated nearly 1.5-fold by 5% CBP. We conclude that CBP promotes calcium absorption in mice by upregulating the expression of the calcium-transporting paracellular proteins CLND2 and CLND12, thereby increasing bone density and promoting bone growth. Overall, CBP contributes to bone growth by affecting calcium metabolism.

Renal Endocytic Regulation of Vitamin D Metabolism during Maturation and Aging in Laying Hens

Egg-laying hens undergo a specific and dramatic calcium metabolism to lay eggs with eggshells composed of calcium carbonate. Calcium metabolism is mainly regulated by vitamin D3. Although vitamin D3 metabolism is closely related to the deterioration of eggshell quality associated with aging and heat stress, the details of the mechanisms regulating vitamin D3 metabolism are not clear. In mammals, the vitamin D3 metabolite (25(OH)D3) produced in the liver binds to the vitamin binding protein (DBP), is subsequently taken up by renal proximal tubular cells via the endocytic receptors megalin (Meg) and cubilin (CUB), and is metabolized to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Therefore, the present study aimed to examine the expression and localization of Meg and CUB in the kidneys of immature chicks and mature and aged laying hens to prevent eggshell quality deterioration. As a result, we showed that as circulating 1,25(OH)2D3 concentrations increased from 156.0 ± 13.5 pg/mL to 815.5 ± 61.4 pg/mL with maturation in immature chicks, relative expression levels (arbitrary units; AU) of Meg and CUB mRNA in the kidneys of mature hens significantly increased 1.92- and 2.75-fold, respectively, compared to those in immature chicks. On the other hand, the Meg mRNA expression levels of mature hens did not change with age, while CUB mRNA expression levels (1.03 ± 0.11 AU) were significantly decreased compared to mature hens (2.75 ± 0.24 AU). Immunohistochemical observations showed that Meg and CUB proteins were localized to the apical membrane of renal proximal tubular epithelial cells in immature chicks, mature hens, and aged hens, and that DBP protein was observed as granular endosomes in the cytoplasm of proximal tubular cells from the apical membrane to the cell nucleus. Especially in mature hens, the endosomes were larger and more numerous than those in immature chicks. In contrast, in aged hens, DBP-containing endosomes were smaller and limited to the apical cytoplasm. These results indicate that with maturation, the expression of Meg and CUB is promoted in the renal proximal tubules of laying hens, facilitating the uptake of the 25(OH)D3-DBP complex and its conversion to 1,25(OH)2D3, and regulating calcium metabolism in eggshell formation. On the other hand, it is suggested that the age-related decrease in CUB expression suppresses the uptake of the 25(OH)D3-DBP complex in the kidney, resulting in a deterioration of eggshell quality.

Targeting of Specialized Metabolites Biosynthetic Enzymes to Membranes and Vesicles by Posttranslational Palmitoylation: A Mechanism of Non-Conventional Traffic and Secretion of Fungal Metabolites.

In nature, the formation of specialized (secondary) metabolites is associated with the late stages of fungal development. Enzymes involved in the biosynthesis of secondary metabolites in fungi are located in distinct subcellular compartments including the cytosol, peroxisomes, endosomes, endoplasmic reticulum, different types of vesicles, the plasma membrane and the cell wall space. The enzymes traffic between these subcellular compartments and the secretion through the plasma membrane are still unclear in the biosynthetic processes of most of these metabolites. Recent reports indicate that some of these enzymes initially located in the cytosol are later modified by posttranslational acylation and these modifications may target them to membrane vesicle systems. Many posttranslational modifications play key roles in the enzymatic function of different proteins in the cell. These modifications are very important in the modulation of regulatory proteins, in targeting of proteins, intracellular traffic and metabolites secretion. Particularly interesting are the protein modifications by palmitoylation, prenylation and miristoylation. Palmitoylation is a thiol group-acylation (S-acylation) of proteins by palmitic acid (C16) that is attached to the SH group of a conserved cysteine in proteins. Palmitoylation serves to target acylated proteins to the cytosolic surface of cell membranes, e.g., to the smooth endoplasmic reticulum, whereas the so-called toxisomes are formed in trichothecene biosynthesis. Palmitoylation of the initial enzymes involved in the biosynthesis of melanin serves to target them to endosomes and later to the conidia, whereas other non-palmitoylated laccases are secreted directly by the conventional secretory pathway to the cell wall space where they perform the last step(s) of melanin biosynthesis. Six other enzymes involved in the biosynthesis of endocrosin, gliotoxin and fumitremorgin believed to be cytosolic are also targeted to vesicles, although it is unclear if they are palmitoylated. Bioinformatic analysis suggests that palmitoylation may be frequent in the modification and targeting of polyketide synthetases and non-ribosomal peptide synthetases. The endosomes may integrate other small vesicles with different cargo proteins, forming multivesicular bodies that finally fuse with the plasma membrane during secretion. Another important effect of palmitoylation is that it regulates calcium metabolism by posttranslational modification of the phosphatase calcineurin. Mutants defective in the Akr1 palmitoyl transferase in several fungi are affected in calcium transport and homeostasis, thus impacting on the biosynthesis of calcium-regulated specialized metabolites. The palmitoylation of secondary metabolites biosynthetic enzymes and their temporal distribution respond to the conidiation signaling mechanism. In summary, this posttranslational modification drives the spatial traffic of the biosynthetic enzymes between the subcellular organelles and the plasma membrane. This article reviews the molecular mechanism of palmitoylation and the known fungal palmitoyl transferases. This novel information opens new ways to improve the biosynthesis of the bioactive metabolites and to increase its secretion in fungi.

Specific Subcellular Localization of Phosphoinositide-Specific Phospholipase C enzymes in Different Human Osteosarcoma Cell Lines

The role of signal transduction in cancer progression is well established and actively studied, including in osteosarcoma. The signal transduction pathways involved in the regulation of calcium metabolism are being intensively studied, with particular regard to phosphoinositide-specific phospholipase C (PLC) signaling. This family of enzymes helps to modulate calcium metabolism and is interconnected with additional signaling molecules belonging to different pathways. The expression and subcellular localization of PLCs have been shown to differ in normal cells compared to their neoplastic counterpart in different types of cancer. We now describe the localization of the PLC enzyme family in 4 human osteosarcoma cells different in origin and malignancy (MG63, U2OS, HOS and 143B cell lines). We identified cell line-specific differences and discussed possible meaning and implications.

The Parathyroid Gland: An Overall Review of the Hidden Organ for Radiologists.

Parathyroid glands are small endocrine glands that regulate calcium metabolism by producing parathyroid hormone (PTH). These are located at the back of the thyroid gland. Typically, four glands comprise the parathyroid glands, although their numbers may vary among individuals. Parathyroid diseases are related to parathyroid gland dysfunction and can be caused by problems with the parathyroid gland itself or abnormal serum calcium levels arising from renal disease. In recent years, as comprehensive health checkups have become more common, abnormal serum calcium levels are often found incidentally in blood tests, after which several additional tests, including a PTH test, ultrasonography (US), technetium-99m sestamibi parathyroid scan, single-photon-emission CT (SPECT)/CT, four-dimensional CT (4D-CT), and PET/CT, are performed for further evaluation. However, the parathyroid gland remains an organ less familiar to radiologists. Therefore, the normal anatomy, pathophysiology, imaging, and clinical findings of the parathyroid gland and its associated diseases are discussed here.

Vegetarian diets and global disparities in calcium intake in pregnant women: A systematic review and meta‐analysis

AbstractBackgroundVegetarian diets are currently experiencing increasing popularity and are also becoming more common in pregnant women. Calcium plays a crucial role for skeletal health and for physiologic processes during pregnancy for the mother and foetus.AimsOur study aimed to evaluate calcium intake of vegetarian versus nonvegetarian expectant mothers.Materials and MethodsWe searched PubMed and retrieved seven studies (six prospective cohort and one cross‐sectional) for inclusion in our random‐effects meta‐analysis. We calculated standardised mean differences (SMD).ResultsResults showed a significantly higher calcium intake in vegetarian than nonvegetarian pregnant women [SMD: 0.25; 95% confidence interval (CI): 0.14, 0.36].DiscussionMost studies showed that the recommendations for calcium intake during pregnancy (ranging from 700 to 1200 mg/d) were met. Both vegetarian and nonvegetarian pregnant women showed higher calcium intakes in Europe and North America than in Asia. Serum calcium levels did not differ between vegetarian and nonvegetarian pregnant women (SMD: − 0.15; 95% CI: −0.42, 0.11), confirming that the tight regulation of calcium metabolism is not affected by dietary calcium intake.ConclusionTo prevent inadequate calcium intake potentially associated with adverse gestational outcomes, we recommend adherence to existing recommendations by means of calcium supplementation (1.5–2 g/d), food fortification strategies, or behavioural interventions.

Vitamin D - a key to reducing the risk of suicide?

Introduction: Vitamin D has a major positive impact on human health. Its daily supplementation regulates calcium metabolism, inflammatory and neuromodulatory processes. More importantly, vitamin D may be an important factor in reducing the risk of suicide among psychiatric patients. This review aims to describe the potential positive effect of vitamin D supplementation in preventing suicide attempts. Method: The literature review was conducted by search of articles in English and Polish languages on PubMed, Medline, and Google Scholar, published from 1974 to the 1st of April 2023, following SANRA requirements. The search utilized the following keywords: vitamin D, vitamin D deficiency, vitamin D supplementation, suicide, depression, bipolar disorder, schizophrenia, ADHD, anxiety, and autism. The analysis encompassed original studies, meta-analyses, randomized controlled trials, and review articles. Results: There is a limited number of studies investigating the impact of vitamin D supplementation on suicide risk in individuals with mental illness. Several studies suggest that vitamin D may have a beneficial effect on symptoms of mental illnesses. However, the exact mechanism through which vitamin D exerts its therapeutic effects on mental health remains unclear. Incorporating vitamin D into the treatment of the mental disorders such as depression, schizophrenia, bipolar disease, ADHS, autism spectrum disorder, and anxiety, as well as supplementing it during pregnancy and throughout life, could potentially be an effective therapeutic adjunct for suicide prevention approach. Conclusions: According to all the research and gathered data, there is a correlation between Vitamin D supplementation and a decrease in suicide risk among patients suffering from mental disorders. Several lines of evidence have shown a positive impact on mental health in patients suffering from mental diseases. However, further research is needed to establish the mechanisms of the therapeutic effect of Vitamin D. Keywords: vitamin D, vitamin D supplementation, suicide, psychiatric disorders

Bone calcification rate as a factor of craniofacial transformations in salmonid fish: Insights from an experiment with hormonal treatment of calcium metabolism.

Adaptation to different environments can be achieved by physiological shifts throughout development. Hormonal regulators shape the physiological and morphological traits of the evolving animals making them fit for the particular ecological surroundings. We hypothesized that the artificially induced hypersynthesis of calcitonin and parathyroid hormone mutually influencing calcium metabolism could affect bone formation during early ontogeny in fish imitating the heterochrony in craniofacial ossification in natural adaptive morphs. Conducting an experiment, we found that the long-standing treatment of salmonid juveniles with high doses of both hormones irreversibly shifts the corresponding hormone status for a period well beyond the time scale for total degradation of the injected hormone. The hormones program the ossification of the jaw suspension bones and neurocranial elements in a specific manner affecting the jaws position and pharingo-branchial area stretching. These morphological shifts resemble the adaptive variants found in sympatric pelagic and demersal morphs of salmonids. We conclude that solitary deviations in the regulators of calcium metabolism could determine functional morphological traits via transformations in skeletal development.

Vitamin D deficiency in children and pathology of the digestive system

The review shows the relationship of vitamin D deficiency (VDD) with various forms of pathology of the gastrointestinal tract. The VDD prevalence in Russia has regional and age characteristics and reaches 42%. In addition to the key role as a regulator of calcium metabolism, which ensures the growth and formation of the structure of bone tissue, vitamin D was established to affect the course of various forms of pathology of the gastrointestinal tract. At the same time, it acts as a regulator of innate immunity. In other cases, the effects of vitamin D are aimed at activating anti-inflammatory factors, which determine its positive effect on the course of diseases through antioxidant action. Data on the VDD impact on the formation of various forms of intestinal pathology with an inflammatory and immune mechanism of development are presented. The authors point to the VDD impact in inflammatory bowel diseases. Regardless of the VDD primacy of inflammatory bowel disease, the correction of the VDD has a pronounced positive effect on the course of the disease.

The Role of Soluble α-klotho Protein in Acromegaly

Soluble α-klotho (sαKl) is an isoform of the α-klotho protein that regulates calcium metabolism but also has anti-aging, anti-apoptotic, and tumor suppressor effects. The assumption that sαKl could inhibit the insulin-like growth factor 1 (IGF-1) signaling pathway has increased the interest of its research in acromegaly - a pathology characterized by an excess of growth hormone (GH) and IGF-1. This review aimed to identify the role of sαKl in acromegaly. Most studies have identified higher concentrations of sαKl in acromegaly versus non-GH pituitary adenomas (PAs) or healthy subjects. Also, the sαKl level was higher in active acromegaly versus controlled or cured disease. Moreover, sαKl positively correlated with GH, IGF-1, and GH-secreting PA size. The increased level of sαKl seems to be due to the autonomous secretion of GH, considering their drastic decrease after transsphenoidal surgery. The data regarding the relationship between sαKl, age, and gender in acromegaly are inconsistent. The latest research noted a correlation between sαKl and various parameters for monitoring the quality of life in acromegaly. In conclusion, sαKl could reflect the disease activity. Furthermore, sαKl would represent an alternative for monitoring acromegalic patients with discrepancies between IGF-1 and GH.

The Neurospora crassa PCL-1 cyclin is a PHO85-1 (PGOV) kinase partner that directs the complex to glycogen metabolism and is involved in calcium metabolism regulation.

Cyclins are a family of proteins characterized by possessing a cyclin box domain that mediates binding to cyclin dependent kinases (CDKs) partners. In this study, the search for a partner cyclin of the PHO85-1 CDK retrieved PCL-1 an ortholog of yeast Pcls (for Pho85 cyclins) that performs functions common to Pcls belonging to different cyclin families. We show here that PCL-1, as a typical cyclin, is involved in cell cycle control and cell progression. In addition, PCL-1 regulates glycogen metabolism; Δpcl-1 cells accumulate higher glycogen levels than wild-type cells and the glycogen synthase (GSN) enzyme is less phosphorylated and, therefore, more active in the mutant cells. Together with PHO85-1, PCL-1 phosphorylates in vitro GSN at the Ser636 amino acid residue. Modeling studies identified PHO85-1 and PCL-1 as a CDK/cyclin complex, with a conserved intermolecular region stabilized by hydrophobic and polar interactions. PCL-1 is also involved in calcium and NaCl stress response. Δpcl-1 cells are sensitive to high NaCl concentration; on the contrary, they grow better and overexpress calcium responsive genes under high calcium chloride concentration compared to the wild-type strain. The expression of the calcium-responsive CRZ-1 transcription factor is modulated by PCL-1, and this transcription factor seems to be less phosphorylated in Δpcl-1 cells since exhibits nuclear location in these cells in the absence of calcium. Our results show that PCL-1 locates at different cell regions suggesting that it may determine its activity by controlling its intracellular location and reveal an interesting functional divergence between yeast and filamentous fungus cyclins.

Approach to the Patient: Management of Parathyroid Diseases Across Pregnancy.

Taking care of patients with parathyroid disorders during pregnancy requires consideration of the physiological fundamental changes in bone and mineral metabolism occurring in these women. Diagnostic and therapeutic procedures regarding primary hyperparathyroidism (PHPT) and hypoparathyroidism significantly differ from the nonpregnant population. PHPT should preferably be cured by parathyroidectomy before pregnancy since in women with hypercalcemic PHPT, maternal and fetal pregnancy complications seem to increase according to the degree of hypercalcemia. Parathyroidectomy, if needed during pregnancy, is preferentially performed in the second trimester. Conservative treatment is recommended for milder cases and is mainly restricted to hydration, with only limited evidence regarding drug treatment. Women with hypoparathyroidism can be informed that there are no major concerns regarding disease-associated infertility and that the risk of pregnancy complications is low if the disease is properly managed. Regular active surveillance is recommended, as requirements for calcium and active vitamin D may change during the course of pregnancy in either direction, with an overall trend for rather reduced doses. Any woman suffering from parathyroid disorders during pregnancy requires further surveillance in the postpartum period and during lactation, as there is an increased risk of hypercalcemia after delivery. Newborns of mothers with parathyroid diseases should, depending on disease severity, be carefully monitored for calcium levels in the first days (to weeks) after delivery since intrauterine exposure to hyper- or hypocalcemia may impact their postnatal regulation of calcium metabolism.

Gastrointestinal and renal regulation of calcium metabolism

Calcium is critical to human physiology for the function of excitable tissues (e.g. neuromuscular function) and is also needed for skeletal mineralization. The maintenance of a constant free ionized calcium concentration is biologically important for these functions. Regulation of calcium levels is a pre-requisite for its maintenance. In this article, calcium homeostasis is reviewed in respect to the critical organs involved; gastrointestinal tract, and the kidneys. Also reviewed is the calcium sensing receptor (CaSR) which serve as a calcium regulator (calciostat) in calciotropic tissues and regulates other biological functions in non-calciotropic tissues. The purpose of this review is to discuss the normal regulation of calcium metabolism in order to provide the clinician with basic information for the diagnosis and therapeutic management of calcium metabolism disorders as well as related pathologies.

The structure, biosynthesis, and biological roles of fetuin-A: A review.

Fetuin-A is a heterodimeric plasma glycoprotein containing an A-chain of 282 amino acids and a B-chain of 27 amino acid residues linked by a single inter-disulfide bond. It is predominantly expressed in embryonic cells and adult hepatocytes, and to a lesser extent in adipocytes and monocytes. Fetuin-A binds with a plethora of receptors and exhibits multifaceted physiological and pathological functions. It is involved in the regulation of calcium metabolism, osteogenesis, and the insulin signaling pathway. It also acts as an ectopic calcification inhibitor, protease inhibitor, inflammatory mediator, anti-inflammatory partner, atherogenic factor, and adipogenic factor, among other several moonlighting functions. Fetuin-A has also been demonstrated to play a crucial role in the pathogenesis of several disorders. This review mainly focuses on the structure, synthesis, and biological roles of fetuin-A. Information was gathered manually from various journals via electronic searches using PubMed, Google Scholar, HINARI, and Cochrane Library from inception to 2022. Studies written in English and cohort, case-control, cross-sectional, or experimental studies were considered in the review, otherwise excluded.

Role of Fetuin-A in the Pathogenesis of Psoriasis and Its Potential Clinical Applications.

Fetuin-A is a plasma glycoprotein exhibiting multifaceted physiological and pathological functions. It has been determined to be involved in various essential biological functions, such as regulation of calcium metabolism, osteogenesis, and insulin signaling pathway. It also plays a crucial role in the pathogenesis of several disorders, including psoriasis. Psoriasis is a chronic systemic inflammatory disorder caused by a constellation of environmental, immunogenic, and genetic factors. It has been shown that dysregulation of cytokines mediated immune response is responsible for the development of psoriasis. Several recent publications suggest that dysregulation of fetuin-A correlates with psoriasis disease activities, revealing its putative role in the development of psoriasis. Furthermore, clinical application of fetuin-A as a diagnostic marker, prognostic predictor, and therapeutic target for different clinical conditions is in progress, and some are showing promising outcomes. This review primarily focuses on the current understanding of the role of fetuin-A in the pathogenesis of psoriasis and its potential clinical applications, with a brief highlight of psoriasis epidemiology and burden. The information was gathered systematically from various journals via electronic searches using various search engines: PubMed, Google Scholar, HINARI, and Cochrane Library from inception to 2022. The studies involved were restricted to English language. Conversely, articles written in other languages, studies done on fetuin B, or studies conducted on other dermatological diseases were excluded from the review article.

Age-related changes in eggshell physical properties, ultrastructure, calcium metabolism-related serum indices, and gene expression in eggshell gland during eggshell formation in commercial laying ducks

This study evaluated the changes in eggshell mechanical properties, ultrastructure, calcium metabolism-related serum indices, and gene expression in eggshell gland during eggshell formation between laying ducks in the peak (young duck) and late phase (aged duck) of production. A total of 84 healthy young (31 wk of age) and 84 healthy aged (65 wk of age) Longyan laying ducks were each divided into 6 replicates of 14 birds, and caged individually. All the ducks were fed in one house with the same corn-soybean meal-based diet for 5 wk. The eggshell mechanical properties (shell proportion, thickness, breaking strength, and fracture toughness) and chemical components (matrix proteins, calcium, phosphorus, and magnesium) decreased in aged laying ducks (P < 0.05). Shell structural indices: total thickness, effective thickness and its proportion decreased, whereas mammillary knob width and its proportion increased (P < 0.05). The regulation values of early fusion, cuffing, caps, and total score of mammillary knobs were higher in aged laying ducks relative to the young ducks (P < 0.05). During the initial, growth and terminal stages of eggshell formation, shell thickness and breaking strength (terminal), shell weight, and its proportion (terminal) decreased in aged laying ducks (P < 0.05). Ultrastructural changes during shell formation indicated that the mammillary-knob density and effective thickness decreased (P < 0.05). Decreases occurred in serum content of phosphorus (growth), and estradiol and calcium contents (terminal) (P < 0.05). Relative expression of Ca2+ transporter and HCO3− exchanger, and matrix proteins genes decreased in aged laying ducks (P < 0.05) at all stages of eggshell formation. Collectively, the decreased incidence of early fusion and caps, increased thickness and width of mammillary knobs, and decreased effective thickness are the crucial differences leading to the compromised mechanical properties of eggshell in the late laying period. A disturbed regulation of calcium metabolism and uterine expression of ion transporters, especially for HCO3− exchange of aged laying ducks likely contribute to age-induced ultrastructural deterioration of the eggshell.

Vitamin D Enhances Neutrophil Generation and Function in Zebrafish (Danio rerio)

Vitamin D (VD) is a major regulator of calcium metabolism in many living organisms. In addition, VD plays a key role in regulating innate and adaptive immunity in vertebrates. Neutrophils constitute an important part of the first line of defense against invading microbes; however, the potential effect of VD on neutrophils remains elusive. Thus, in this study zebrafish in different developmental stages were utilized to identify the potential role of VD in the basal homeostasis and functions of neutrophils. Our results showed that addition of exogenous VD₃ promoted granulopoiesis in zebrafish larvae. Reciprocally, neutrophil abundance in the intestine of adult zebrafish with a cyp2r1 mutant, lacking the capacity to 25-hydroxylate VD, was reduced. Moreover, VD-mediated granulopoiesis was still observed in gnotobiotic zebrafish larvae, indicating that VD regulates neutrophil generation independent of the microbiota during early development. In contrast, VD was incapable to influence granulopoiesis in adult zebrafish when the commensal bacteria were depleted by antibiotic treatment, suggesting that VD might modulate neutrophil activity via different mechanisms depending on the developmental stage. In addition, we found that VD₃ augmented the expression of il-8 and neutrophil recruitment to the site of caudal fin amputation. Finally, VD₃ treatment significantly decreased bacterial counts and mortality in zebrafish infected with Edwardsiella tarda (E. tarda) in a neutrophil-dependent manner. Combined, these findings demonstrate that VD regulates granulopoiesis and neutrophil function in zebrafish immunity.

Concomitant familial hypocalciuric hypercalcemia and single parathyroid adenoma: a case report

BackgroundPrimary hyperparathyroidism (PHPT) is a common endocrine disorder and the most frequent benign cause of hypercalcemia. PHPT is characterized by autonomous hypersecretion of parathyroid hormone (PTH), regardless of serum calcium levels. Familial hypocalciuric hypercalcemia (FHH) is a rare, benign syndrome only affecting the regulation of calcium metabolism. FHH is an autosomal-dominant genetic disease with high penetrance, caused by an inactivating variant in the CASR gene encoding the calcium-sensing receptor (CaSR). We present a unique case of concomitant PHPT and FHH without clinically actionable variants in MEN1.Case presentationA 47-year-old Caucasian man with severe hypercalcemia, genetic FHH, and initially normal parathyroid scintigraphy was referred for endocrine evaluation due to nonspecific symptoms. Biochemical evaluation showed elevated serum ionized calcium and PTH. The calcium–creatinine clearance ratio was low. All other biochemical measures were normal, including kidney function. Genetic evaluation was redone and confirmed FHH. A new parathyroid scintigraphy showed a significant single adenoma corresponding to the lower left gland. The patient underwent parathyroidectomy, and a parathyroid adenoma was removed. A reduced level of hypercalcemia persisted due to FHH.ConclusionsThe correct diagnosis of the underlying cause of hypercalcemia is important to ensure the right treatment. Patients with FHH should avoid operative treatment, and PHPT should be differentiated from MEN1 to determine whether surgery should include parathyroidectomy with removal of one adenoma or 3.5 hyperplastic parathyroid glands.

Spatiotemporally controlled calcitonin delivery: Long-term and targeted therapy of skeletal diseases

Bone is a connective tissue that support the entire body and protect the internal organs. However, there are great challenges on curing intractable skeletal diseases such as hypercalcemia, osteoporosis and osteoarthritis. To address these issues, calcitonin (CT) therapy is an effective treatment alternative to regulate calcium metabolism and suppress inflammation response, which are closely related to skeletal diseases. Traditional calcitonin formulation requires frequent administration due to the low bioavailability resulting from the short half-life and abundant calcitonin receptors distributed through the whole body. Therefore, long-term and targeted calcitonin delivery systems (LCDS and TCDS) have been widely explored as the popular strategies to overcome the intrinsic limitations of calcitonin and improve the functions of calcium management and inflammation inhibition in recent years. In this review, we first explain the physiological effects of calcitonin on bone remodeling: (i) inhibitory effects on osteoclasts and (ii) facilitated effects on osteoblasts. Then we summarized four strategies for spatiotemporally controlled delivery of calcitonin: micro−/nanomedicine (e.g. inorganic micro−/nanomedicine, polymeric micro−/nanomedicine and supramolecular assemblies), hydrogels (especially thermosensitive hydrogels), prodrug (PEGylation and targeting design) and hybrid biomaterials. Subsequently, we discussed the application of LCDS and TCDS in treating hypercalcemia, osteoporosis, and arthritis. Understanding and analyzing these advanced calcitonin delivery applications are essential for future development of calcitonin therapies toward skeletal diseases with superior efficacy in clinic.