Ca Homeostasis Research Articles

Renal expression of Ca and P transporters: contrasting responses to dietary Ca and microbial phytase in broilers and growing pigs.

Enhanced dietary Ca intake linearly increases intestinal Ca absorption in pigs, but not in broilers, suggesting potential differences in whole body Ca homeostasis. To determine the role of kidney in Ca homeostasis in these species, we varied in growing pigs in experiment (Exp) 1, the dietary Ca content 2.0 vs. 9.6 g/kg and phytase 0 vs. 500 FTU/kg, in broilers, in Exp 2 the dietary Ca/retainable P from 1.3 to 2.8 and phytase 0 vs. 1000 FTU/kg, and in Exp 3 dietary Ca/P from 0.50 to 1.75. Increasing dietary Ca reduced renal mRNA expression of Ca-related transporters (TRPV5, TRPV6, CaBP-D28k, NCX1) and tight junctions (CLDN-12 and -16) in pigs, indicating Ca reabsorption was reduced to maintain Ca homeostasis. In broilers (Exp 2), high dietary Ca increased renal TRPV6, CaBP-D28k and CLDN-2 mRNA, indicating an increased capacity for Ca reabsorption. Moreover, the effect of dietary Ca was enhanced by inclusion of dietary phytase in pigs but reduced in broilers. Furthermore, increasing dietary Ca upregulated PiT-1 while phytase downregulated XPR1 mRNA expression in pigs; in broilers dietary Ca downregulated renal mRNA expression of NaPi-IIa, PiT-1, PiT-2 and XPR1, while phytase downregulated NaPi-IIa but upregulated PiT-2 and XPR1 mRNA expression. In Exp 3, Ca/P effect on transporter mRNA expression was largely consistent with Exp 2. In conclusion of this study, together with previously measured data about Ca and P homeostasis, in pigs the kidneys play a more regulatory role in Ca homeostasis than in broilers where the intestine is more important for regulation.

The effects of magnitude of calcium decline at the onset of lactation on serotonin dynamics and the serotonin-calcium axis

The onset of lactation is characterized by marked increases in calcium (Ca) metabolism. Recently emphasis was placed on understanding the profile and dynamics of blood Ca and serotonin in the peripartal cow in response to this change using a randomized 2x2 factorial design. The aims of our study were to determine i) how a prepartum dietary cation anion difference (DCAD) diet and the magnitude of Ca decline at the onset of lactation alter circulating blood serotonin and iCa concentrations dynamics in the periparturient cow, and ii) the relationship Ca versus serotonin during the peripartal period. Thirty-two multiparous Holstein cows were blocked by parity (2 vs > 2) to ensure equal parity number across the experiment, previous 305 d milk yield and expected parturition date and randomly allocated to either positive (+120 mEq/kg; +DCAD) or negative (-120 mEq/kg; -DCAD) DCAD diets from 251 d of gestation until parturition (n = 16/diet). Immediately after calving cows were continuously infused for 24 h with i) an intravenous solution of 10% dextrose or ii) calcium gluconate (CaGlc) to maintain blood ionized Ca concentrations at 1.2 mM (normocalcemia); forming the following 4 treatment groups: negative DCAD and CaGlc (NCa), negative DCAD and dextrose (NDex), positive DCAD and CaGlc (PCa), and positive DCAD and dextrose (PDex) (n = 8/treatment). Blood was sampled every 6 h from 102 h before parturition until 96 h post parturition. During the continuous infusion period (the 24 h immediately following parturition) cows were sampled every 30 min. Cows fed a -DCAD diet prepartum had greater circulating serotonin concentrations pre and postpartum. Time series analyses demonstrated that the pooled mean effect size (ES) of the relationship between ionized Ca and serotonin 36 h before parturition was significantly positive (ES = 0.164) prepartum. We also observed that the overall pooled mean ES of the relationship between prepartum blood pH 24 h prior and serotonin was significantly positive (ES = 0.111); however, for individual treatment groups, relationships were identified between blood pH and serotonin 18 and 6 h before only for the NDex group. Our data suggest that serotonin is an important factor in the regulation of Ca homeostasis during the prepartal period and that the mechanism may be integrated with blood pH.

STOP1 regulates CCX1-mediated Ca2+ homeostasis for plant adaptation to Ca2+ deprivation.

Calcium (Ca) is essential for plant growth and stress adaptation, yet its availability is often limited in acidic soils, posing a major threat to crop production. Understanding the intricate mechanisms orchestrating plant adaptation to Ca deficiency remains elusive. Here, we show that the Ca deficiency-enhanced nuclear accumulation of the transcription factor SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) in Arabidopsis thaliana confers tolerance to Ca deprivation, with the global transcriptional responses triggered by Ca deprivation largely impaired in the stop1 mutant. Notably, STOP1 activates the Ca deprivation-induced expression of CATION/Ca2+ EXCHANGER 1 (CCX1) by directly binding to its promoter region, which facilitates Ca2+ efflux from endoplasmic reticulum to cytosol to maintain Ca homeostasis. Consequently, the constitutive expression of CCX1 in the stop1 mutant partially rescues the Ca deficiency phenotype by increasing Ca content in the shoots. These findings uncover the pivotal role of the STOP1-CCX1 axis in plant adaptation to low Ca, offering alternative manipulating strategies to improve plant Ca nutrition in acidic soils and extending our understanding of the multifaceted role of STOP1.

Calcium Deregulation in Neurodegeneration and Neuroinflammation in Parkinson's Disease: Role of Calcium-Storing Organelles and Sodium-Calcium Exchanger.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that lacks effective treatment strategies to halt or delay its progression. The homeostasis of Ca2+ ions is crucial for ensuring optimal cellular functions and survival, especially for neuronal cells. In the context of PD, the systems regulating cellular Ca2+ are compromised, leading to Ca2+-dependent synaptic dysfunction, impaired neuronal plasticity, and ultimately, neuronal loss. Recent research efforts directed toward understanding the pathology of PD have yielded significant insights, particularly highlighting the close relationship between Ca2+ dysregulation, neuroinflammation, and neurodegeneration. However, the precise mechanisms driving the selective loss of dopaminergic neurons in PD remain elusive. The disruption of Ca2+ homeostasis is a key factor, engaging various neurodegenerative and neuroinflammatory pathways and affecting intracellular organelles that store Ca2+. Specifically, impaired functioning of mitochondria, lysosomes, and the endoplasmic reticulum (ER) in Ca2+ metabolism is believed to contribute to the disease's pathophysiology. The Na+-Ca2+ exchanger (NCX) is considered an important key regulator of Ca2+ homeostasis in various cell types, including neurons, astrocytes, and microglia. Alterations in NCX activity are associated with neurodegenerative processes in different models of PD. In this review, we will explore the role of Ca2+ dysregulation and neuroinflammation as primary drivers of PD-related neurodegeneration, with an emphasis on the pivotal role of NCX in the pathology of PD. Consequently, NCXs and their interplay with intracellular organelles may emerge as potentially pivotal players in the mechanisms underlying PD neurodegeneration, providing a promising avenue for therapeutic intervention aimed at halting neurodegeneration.

Cadmium impacts on calcium mineralization of zebrafish skeletal development and behavioral impairment

Cadmium (Cd) poses significant risks to aquatic organisms due to its toxicity and ability to disrupt the cellular processes. Given the similar atomic radius of Cd and calcium (Ca), Cd may potentially affect the Ca homeostasis, which can lead to impaired mineralization of skeletal structures and behavioral abnormalities. The formation of the spinal skeleton involves Ca transport and mineralization. In this study, we conducted an in-depth investigation on the effects of Cd at environmental concentrations on zebrafish (Danio rerio) skeletal development and the underlying molecular mechanisms. As the concentration of Cd increased, the accumulation of Cd in zebrafish larvae also rose, while the Ca content decreased significantly by 3.0 %−57.3 %, and vertebral deformities were observed. Transcriptomics analysis revealed that sixteen genes involved in metal absorption were affected. Exposure to 2 µg/L Cd significantly upregulated the expression of these genes, whereas exposure to 10 µg/L resulted in their downregulation. Consequently, exposure of zebrafish larvae to 10 µg/L of Cd inhibited the body segmentation growth and skeletal mineralization development by 29.1 %−56.7 %. This inhibition was evidenced by the downregulation of mineral absorption genes and decreased Ca accumulation. The findings of this study suggested that the inhibition of skeletal mineralization was likely attributed to the disruption of mineral absorption, thus providing novel insights into the mechanisms by which metal pollutants inhibit the skeletal development of fish.

Chondroitin Sulfate-Modified Hydroxyapatite for Caspase-1 Activated Induced Pyroptosis through Ca Overload/ER Stress/STING/IRF3 Pathway in Colorectal Cancer.

Immune checkpoint inhibitors, are the fourth most common therapeutic tool after surgery, chemotherapy, and radiotherapy for colorectal cancer (CRC). However, only a small proportion (≈5%) of CRC patients, those with "hot" (immuno-activated) tumors, benefit from the therapy. Pyroptosis, an innovative form of programmed cell death, is a potentially effective means to mediate a "cold" to "hot" transformation of the tumor microenvironment (TME). Calcium-releasing hydroxyapatite (HAP) nanoparticles (NPs) trigger calcium overload and pyroptosis in tumor cells. However, current limitations of these nanomedicines, such as poor tumor-targeting capabilities and insufficient calcium (Ca) ion release, limit their application. In this study, chondroitin sulfate (CS) is used to target tumors via binding to CD44 receptors and kaempferol (KAE) is used as a Ca homeostasis disruptor to construct CS-HAP@KAE NPs that function as pyroptosis inducers in CRC cells. CS-HAP@KAE NPs bind to the tumor cell membrane, HAP released Ca in response to the acidic environment of the TME, and kaempferol (KAE) enhances the influx of extracellular Ca, resulting in intracellular Ca overload and pyroptosis. This is associated with excessive endoplasmic reticulum stress triggered activation of the stimulator of interferon genes/interferon regulatory factor 3 pathway, ultimately transforming the TME from "cold" to "hot".

Zinc, Copper, and Calcium: A Triangle in the Synapse for the Pathogenesis of Vascular-Type Senile Dementia.

Zinc (Zn) and copper (Cu) are essential for normal brain functions. In particular, Zn and Cu are released to synaptic clefts during neuronal excitation. Synaptic Zn and Cu regulate neuronal excitability, maintain calcium (Ca) homeostasis, and play central roles in memory formation. However, in pathological conditions such as transient global ischemia, excess Zn is secreted to synaptic clefts, which causes neuronal death and can eventually trigger the pathogenesis of a vascular type of senile dementia. We have previously investigated the characteristics of Zn-induced neurotoxicity and have demonstrated that low concentrations of Cu can exacerbate Zn neurotoxicity. Furthermore, during our pharmacological approaches to clarify the molecular pathways of Cu-enhanced Zn-induced neurotoxicity, we have revealed the involvement of Ca homeostasis disruption. In the present review, we discuss the roles of Zn and Cu in the synapse, as well as the crosstalk between Zn, Cu, and Ca, which our study along with other recent studies suggest may underlie the pathogenesis of vascular-type senile dementia.

Effect of increased CO2 on calcium homeostasis and signaling in a marine diatom

AbstractOcean acidification influences photosynthesis, respiration, and metabolism in marine diatoms, leading to changes in diatom growth performance and shifts in phytoplankton communities. Previous studies have demonstrated that increases in seawater CO2 concentrations affect the uptake of trace metals such as iron, zinc, copper, and cobalt by marine diatoms. However, the influence of increased CO2 on calcium, which plays a vital role as a secondary messenger in various signaling pathways within organisms, has received limited attention so far. This study examined the effect of increased CO2 on Ca homeostasis and signaling in the marine diatom Phaeodactylum tricornutum. While seawater acidification had little effect on the diatom's growth, it significantly changed cell properties (surface topography, adhesion, and surface potential). Elevated CO2 concentrations reduced calcium accumulation P. tricornutum and lowered the rise of cytosolic Ca2+ transients stimulated by toxic aldehyde, phosphorus supplement, and hypo‐osmotic stress. Our results suggest that a continuous rise in atmospheric CO2 may alter diatoms' response to environmental cues.

Periparturient Mineral Metabolism: Implications to Health and Productivity.

Mineral metabolism, in particular Ca, and to a lesser extent phosphorus (P) and magnesium (Mg), is altered with the onset of lactation because of extensive irreversible loss to synthesize colostrum and milk. The transient reduction in the concentration of Ca in blood, particularly when it lasts days, increases the risk of mineral-related disorders such as hypocalcemia and, to a lesser extent, hypophosphatemia. Although the incidence of clinical hypocalcemia can be reduced by prepartum dietary interventions, subclinical hypocalcemia remains prevalent, affecting up to 60% of the dairy cows in the first 3 d postpartum. More importantly, strong associations exist between hypocalcemia and increased susceptibility to other peripartum diseases and impaired reproductive performance. Mechanistic experiments have demonstrated the role of Ca on innate immune response in dairy cows, which presumably predisposes them to other diseases. Hypocalcemia is not related to inadequate Ca intake as prepartum diets marginal to deficient in Ca reduce the risk of the disease. Therefore, the understanding of how Ca homeostasis is regulated, in particular how calciotropic hormones such as parathyroid hormone and 1,25-dihydroxyvitamin D3, affect blood Ca concentrations, gastrointestinal Ca absorption, bone remodeling, and renal excretion of Ca become critical to develop novel strategies to prevent mineral imbalances either by nutritional or pharmacological interventions. A common method to reduce the risk of hypocalcemia is the manipulation of the prepartum dietary cation-anion difference. Feeding acidogenic diets not only improves Ca homeostasis and reduces hypocalcemia, but also reduces the risk of uterine diseases and improves productive performance. Feeding diets that induce a negative Ca balance in the last weeks of gestation also reduce the risk of clinical hypocalcemia, and recent work shows that the incorporation of mineral sequestering agents, presumably by reducing the absorption of P and Ca prepartum, increases blood Ca at calving, although benefits to production and health remain to be shown. Alternative strategies to minimize subclinical hypocalcemia with the use of vitamin D metabolites either fed prepartum or as a pharmacological agent administered immediately after calving have shown promising results in reducing hypocalcemia and altering immune cell function, which might prove efficacious to prevent diseases in early lactation. This review summarizes the current understanding of Ca homeostasis around parturition, the limited knowledge of the exact mechanisms for gastrointestinal Ca absorption in bovine, the implications of hypocalcemia on the health of dairy cows, and discusses the methods to minimize the risk of hypocalcemia and their impacts on productive performance and health in dairy cows.

Emerging concepts on the FGF23 regulation and activity.

Fibroblast growth factor 23 (FGF23) discovery has provided new insights into the regulation of Pi and Ca homeostasis. It is secreted by osteoblasts and osteocytes, and acts mainly in the kidney, parathyroid, heart, and bone. The aim of this review is to highlight the current knowledge on the factors modulating the synthesis of FGF23, the canonical and non-canonical signaling pathways of the hormone, the role of FGF23 in different pathophysiological conditions, and the anti-FGF23 therapy. This is a narrative review based on the search of PubMed database in the range of years 2000-2023 using the keywords local and systemic regulators of FGF23 synthesis, FGF23 receptors, canonical and non-canonical pathways, pathophysiological conditions and FGF23, and anti-FGF23 therapy, focusing the data on the molecular mechanisms. The regulation of FGF23 synthesis is complex and multifactorial. It is regulated by local factors and systemic regulators mainly involved in bone mineralization. The excessive FGF23 production is associated with different congenital diseases and with diseases occurring with a secondary high FGF23 production such as in chronic disease kidney and tumor-induced osteomalacia (TIO). The anti-FGF23 therapy appears to be useful to treat chromosome X-linked hypophosphatemia and TIO, but there are doubts about the handle of excessive FGF23 production in CKD. FGF23 biochemistry and pathophysiology are generating a plethora of knowledge to reduce FGF23 bioactivity at many levels that might be useful for future therapeutics of diseases associated with high-serum FGF23 levels.

Male Lrp5A214V mice maintain high bone mass during dietary calcium restriction by altering the vitamin D endocrine system.

Environmental factors and genetic variation individually impact bone. However, it is not clear how these factors interact to influence peak bone mass accrual. Here we tested whether genetically programmed high bone formation driven by missense mutations in the Lrp5 gene (Lrp5A214V) altered the sensitivity of mice to an environment of inadequate dietary calcium (Ca) intake. Weanling male Lrp5A214V mice and wildtype littermates (control) were fed AIN-93G diets with 0.125%, 0.25%, 0.5% (reference, basal), or 1% Ca from weaning until 12 weeks of age (ie, during bone growth). Urinary Ca, serum Ca, Ca regulatory hormones (PTH, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3)), bone parameters (μCT, ash), and renal/intestinal gene expression were analyzed. As expected, low dietary Ca intake negatively impacted bones and Lrp5A214V mice had higher bone mass and ash content. Although bones of Lrp5A214V mice have more matrix to mineralize, their bones were not more susceptible to low dietary Ca intake. In control mice, low dietary Ca intake exerted expected effects on serum Ca (decreased), PTH (increased), and 1,25(OH)2D3 (increased) as well as their downstream actions (ie, reducing urinary Ca, increasing markers of intestinal Ca absorption). In contrast, Lrp5A214V mice had elevated serum Ca with a normal PTH response but a blunted 1,25(OH)2D3 response to low dietary Ca that was reflected in the renal 1,25(OH)2D3 producing/degrading enzymes, Cyp27b1 and Cyp24a1. Despite elevated serum Ca in Lrp5A214V mice, urinary Ca was not elevated. Despite an abnormal serum 1,25(OH)2D3 response to low dietary Ca, intestinal markers of Ca absorption (Trpv6, S100g mRNA) were elevated in Lrp5A214V mice and responded to low Ca intake. Collectively, our data indicate that the Lrp5A214V mutation induces changes in Ca homeostasis that permit mice to retain more Ca and support their high bone mass phenotype.

Study of the metallome and transcriptome of a degenerating cellular model of the retinal pigment epithelium

Aims/Purpose: To study the changes on the metallome and transcriptome of a cellular model of the retinal pigment epithelium (RPE) during its in vitro degeneration after 4 months in culture.Methods: Primary cultures of human fetal RPE cells were established in P12 transwell inserts and cultured for 4 months. Cell pigmentation and barrier function was followed up using optical microscopy and measurement of the transepithelial electrical resistance (TEER). Samples were collected at 21, 91 and 133 days in culture and analysed for gene expression, metal homeostasis of Ca, Na, P, Mg and P, and extracellular deposit formation through RNA sequencing (RNA‐Seq), elemental mass spectrometry (ICP‐MS) and immunocytochemistry assays, respectively.Results: RPE cells formed a differentiated monolayer at 21 days in culture, expressing specific genes and proteins of RPE and giving increasing TEER values. However, after 133 days in culture, loss of tight junction proteins (i.e. CLDN19 and BEST1) and electrical resistance was seen, together with loss of pigmentation and increase of apolipoprotein E deposition in the extracellular space. Gene expression analysis showed an enrichment on apoptotic processes, biomolecule phosphorylation, and signs of epithelial‐to‐mesenchymal transition (EMT). Degeneration of RPE cells concurred with an increase of Na and P content in the cytosol and decrease of Mg, while a decrease of Mg, P and Cu was determined in the insoluble fraction of cells. Time‐dependent changes of metals were accompanied with the alteration of metal transporters and antioxidant enzymes using metals as cofactors.Conclusions: Degeneration of RPE cells in culture was characterized by depigmentation of cells, improper barrier function, downregulation of antioxidant protection, loss of epithelial phenotype, and changes on the levels of Na, P, Mg and Cu, as well as of the expression of their homeostatic proteins.

Calcium, phosphorus, magnesium levels in frequent respiratory tract infections

Background It was well documented that calcium (Ca), phosphorus (P), and magnesium (Mg) participate in many physiological processes. We aimed to study the changing trend of serum levels of Ca, P, and Mg in frequent respiratory tract infections (FRTI) in children. Methods A retrospective study was performed in our centre. A total of 213 FRTI cases and 33 controls were enrolled in our study. We analyzed the correlation between serum Ca/P/Mg levels and inflammatory indexes by using Spearman correlation analysis. Standard mean difference (SMD) was applied to test the differences of serum Ca/P/Mg levels between FRTI subgroups and controls. In terms of the findings of SMD between Ca/P/Mg status between FRTI subgroups and controls, receiver operating characteristics (ROC) curve analysis was further applied to test the association between serum Ca level and bronchitis, parainfluenza virus infection, influenza B virus infection and cytomegalovirus infection. Results Serum Ca level was significantly associated with white blood cell (WBC), platelet (PLT) and procalcitonin (PCT) (p = 0.006; p < 10−4; p = 0.004). Serum P level was markedly associated with eryhtrocyte sedimentation rate (ESR) and PCT (p = 0.018; p < 10−4). Controls showed significantly lower serum Ca level than that among bronchitis (p = 0.001), parainfluenza virus infection (p = 0.027), influenza B virus infection (p = 0.017), cytomegalovirus infection (p = 0.029), and two pathogens infected (p = 0.020). ROC curve analysis showed that serum Ca level was significantly associated with bronchitis (p = 0.047) and influenza B virus infection (p = 0.049). Conclusions Serum levels of Ca and P may reflect the inflammatory status in children with FRTI. Alteration of serum Ca level may predict the risk of bronchitis and influenza B virus infection. Keeping the homeostasis of Ca, P, and Mg may be important for the prevention and treatment of FRTI.

Regulation of magnesium and calcium homeostasis in citrus seedlings under varying magnesium supply

Magnesium (Mg) and calcium (Ca) are two essential macronutrients in plants; however, the characteristics of Mg and Ca concentrations in organ, subcellular and chemical forms and their relationships in citrus plants, especially under varying Mg supply, are not well understood. In this study, Citrus sinensis seedlings (cv. Xuegan) were cultivated in conditions of Mg deficiency (0 mmol Mg2+ L−1) and Mg sufficiency (2 mmol Mg2+ L−1) to investigate the responses of Mg and Ca homeostasis in different organs and fractions. Compared with Mg sufficiency, Mg deficiency significantly decreased root and shoot growth, with the shoot biomass reduction of branch organs was greater than that of parent organs. In addition to increasing the Ca concentration in the parent stem and lateral root organs, Mg deficiency significantly decreased the concentrations and accumulations of Mg and Ca in citrus seedlings, further altering their distribution in different organs. More than 50% of Ca and Mg were sequestrated in the cell wall and soluble fractions, respectively, with Mg concentration decreasing by 15.4% in roots and 46.9% in leaves under Mg deficiency, while Ca concentration decreased by 27.6% in roots and increased by 23.6% in parent leaves. Approximately 90% of Mg exists in inorganic, water-soluble, and pectate and protein-bound forms, and nearly 90% of Ca exists in water-soluble, pectate and protein-bound, phosphate and oxalate acid forms. Except for the decreased inorganic Mg in roots and water-soluble Mg and Ca in leaves, Mg deficiency increased the proportions of Mg and Ca in all chemical forms. However, Mg deficiency generally increased the Ca/Mg ratio in various organs, subcellular and chemical forms, with negative relationships between Mg concentration and Ca/Mg ratio, and the variations of Mg and Ca were highly separated between Mg supply and organs. In conclusion, our results provide insights into the effects of Mg supply on Mg and Ca homeostasis in citrus plants.

SAT219 Severe Isolated Hypocalcemia With Cetuximab &amp; Irinotecan Chemotherapy

Abstract Disclosure: M. Thomas: None. N. Janakiram: None. J. Leary: None. K.E. Foster-Schubert: None. R.R. Narla: None. Background: Electrolyte disorders are commonly seen with chemotherapy (CTX) agents. Cetuximab is an epidermal growth factor receptor inhibitor and irinotecan is topoisomerase 1 inhibitor. Both agents have been associated with hypomagnesemia which can adversely lead to hypocalcemia (HC). Case: A 66-year-old woman with osteoporosis (last bisphosphonate use was 24 months ago), primary hyperparathyroidism status post parathyroidectomy in 2015 (R inferior and superior glands) and 2017 (L inferior gland) with recent diagnosis of metastatic adenocarcinoma of unknown primary who presented with nausea, tetany, leg cramps and found to have severe HC of corrected calcium (CCa) of 5.7, a week post-chemotherapy. On the day of her CTX, her CCa was 7.0, ionized calcium (iCal) of 1.7 with Magnesium (Mg) of 2.0; she received IV calcium (Ca), then underwent CTX. She was prescribed Ca supplements and reports adherence. She returned endorsing the above symptoms with positive Chvostek and Trousseau sign on exam. Labs were notable for CCa of 5.7, iCal of 1.6, Mg of 1.6, Phosphorus of 4.5, PTH 123 (ULN 65), 25-OH vitamin D of 28.6 and normal eGFR. She was hospitalized and received multiple infusions of IV Ca and CCa improved to 7.5. She was discharged on Ca carbonate 1000 mg TID, Mg oxide 420 mg BID and Vitamin D. Before her second cycle of CTX with same agents, she received IV Ca for CCa of 7.3. She remained on Ca and Mg supplements. One week later, she endorsed paresthesia, diarrhea and was admitted again for HC. She was initiated on calcitriol on this admission and 24-hour urine studies showed low Ca excretion and elevated fractional excretion of magnesium (FeMg). Her CCa was 8.0 and she was discharged on calcitriol 0.25 mg BID. Oncology discontinued this CTX regimen. Her HC resolved and calcitriol and Ca supplements were gradually weaned off. Discussion: After both rounds of cetuximab and irinotecan, our patient developed profound HC without hypomagnesemia. Cetuximab can cause occasional Mg wasting syndrome with inappropriate urinary excretion. However, she was started on Mg since her first hospitalization despite normal serum Mg levels. Interestingly, her 24-hour urine studies revealed FeMg of 6.5% suggestive of renal Mg wasting. In the literature, there is a case report of severe HC with irinotecan but they had speculated germline mutations in Ca metabolism genes. It remains unclear how these CTX agents impact Ca homeostasis. It is difficult to discern if the severe HC in our patient could be attributed to Mg wasting with normal Mg levels. It is evident that her HC was associated with the timing of her CTX regimen. Therapy for HC can be complex, involves short- and long-term interventions, and correction is critical. Serum Ca surveillance before and during CTX management of cancer patients may reveal more instances and provide insight into the exact mechanisms. Presentation: Saturday, June 17, 2023

Circulating parathyroid hormone and serotonin in multiparous cows with differing postparturient serum calcium concentrations

Many multiparous dairy cows experience subclinical hypocalcemia (SCH) in the immediate postpartum period as they adapt to the demands of lactation. Furthermore, differing dynamics of SCH in the days following parturition are associated with varied health and production outcomes, with cows experiencing transient SCH producing more milk and facing fewer negative health events than cows with delayed or persistent SCH. Our objectives were to describe differences in mediators of calcium (Ca) homeostasis between cows experiencing differing Ca dynamics postpartum. A prospective cohort of 89 multiparous Holstein cows from 2 herds in New York were classified into 1 of 4 SCH groups based on mean serum total Ca (tCa) at 1 and 4 d in milk (DIM): normocalcemic (NC; [tCa] >1.89 mmol/L at 1 DIM and >2.25 mmol/L at 4 DIM, n = 30); transient SCH (tSCH; [tCa] ≤1.89 mmol/L at 1 DIM and >2.25 mmol/L at 4 DIM, n = 12); delayed SCH (dSCH; [tCa] >1.89 mmol/L at 1 DIM and ≤2.25 mmol/L at 4 DIM, n = 23); and persistent SCH (pSCH; [tCa] ≤1.89 mmol at 1 DIM and ≤2.25 mmol/L at 4 DIM, n = 24). Blood samples were collected at -5, -1, 1 through 5, 7, and 10 DIM and analyzed for tCa, parathyroid hormone (PTH), and serotonin. Repeated measures ANOVA models were used to analyze differences between SCH groups and changes over time for tCa, PTH, and serotonin. During the prepartum period, tCa was greater in the NC, tSCH, and dSCH cows as compared with the pSCH cows and there was marginal evidence for a difference in PTH between SCH groups. Postpartum tCa varied over time between SCH groups. Mean postpartum (95% confidence interval) tCa for respective SCH groups were NC = 2.32 (2.28, 2.35) mmol/L; tSCH = 2.20 (2.14, 2.25) mmol/L; dSCH = 2.17 (2.13, 2.21) mmol/L; and pSCH = 2.03 (1.99, 2.07) mmol/L. Mean concentrations of PTH in the postpartum period were NC = 70.1 (66.2, 74.4) pmol/L; tSCH = 72.1 (66.1, 79.2); dSCH = 75.8 (70.8, 81.5) pmol/L; and pSCH = 77.7 (72.4, 83.9) pmol/L. Serotonin was similar between SCH groups pre- and postpartum and followed a cyclical pattern from 1 to 10 DIM. Our results agreed with our hypothesis that differences in postpartum PTH might exist between cows experiencing different dynamics of SCH in the early lactation period; however, further studies are needed to confirm this difference. If true, this would suggest that Ca homeostasis may be disrupted in cows with dSCH and pSCH. Gaining a better understanding of these modulatory differences may aid in the prevention, management, and treatment of SCH.

Role of PLC/IP3 /IP3 R axis in excess molybdenum exposure induced apoptosis in duck renal tubular epithelial cells.

Excess molybdenum (Mo) is harmful to animals, but its nephrotoxicity has not been comprehensively explained. To appraise the influences of excess Mo on Ca homeostasis and apoptosis via PLC/IP3 /IP3 R axis, primary duck renal tubular epithelial cells were exposed to 480 μM and 960 μM Mo, and joint of 960 μM Mo and 10 μM 2-APB or 0.125 μM U-73122 for 12 h (U-73122 pretreated for 1 h), respectively. The data revealed that the increment of [Ca2+ ]c induced by Mo mainly originated from intracellular Ca storage. Mo exposure reduced [Ca2+ ]ER , elevated [Ca2+ ]mit , [Ca2+ ]c , and the expression of Ca homeostasis-related factors (Calpain, CaN, CRT, GRP94, GRP78 and CaMKII). 2-APB could effectively reverse subcellular Ca2+ redistribution by inhibiting IP3 R, which confirmed that [Ca2+ ]c overload induced by Mo originated from ER. Additionally, PLC inhibitor U-73122 remarkably mitigated the change, and dramatically reduced the number of apoptotic cells, the expression of Bak-1, Bax, cleaved-Caspase-3/Caspase-3, and notably increased the expression of Bcl-xL, Bcl-2, and Bcl-2/Bax ratio. Overall, the results confirmed that the Ca2+ liberation of ER via PLC/IP3 /IP3 R axis was the main cause of [Ca2+ ]c overload, and then stimulated apoptosis in duck renal tubular epithelial cells.

Perspective: Transient postparturient hypocalcemia—A lactation-induced phenomenon of high-producing dairy cows

Milk fever is one of the most historically relevant diseases of dairy cows. It is caused by tremendous calcium (Ca) expenditure at the initiation of lactation, so severe that cows can no longer stand and, if left untreated, die. Fortunately, through prepartum nutritional improvements, this version of clinical hypocalcemia is rare in the United States. Nonetheless, the opinion that all versions of postpartum hypocalcemia are detrimental remains pervasive, which is particularly significant given that 50% of cows are subclinically hypocalcemic after calving. This has led to a variety of available management and treatment strategies, ranging from prepartum dietary programs to postpartum Ca gels and boluses, targeted at preventing hypocalcemia in dairy cows. Recent research has determined that postpartum dairy cows can experience different types of subclinical hypocalcemia: transient, persistent, or delayed. We now know cows experiencing transient hypocalcemia as part of the homeorhetic adaptation to lactation are the highest milk producers in modern dairy herds, whereas cows with hypocalcemia several days after calving experience disease and losses in milk production. Therefore, it is wrong to assume all postpartum hypocalcemia is detrimental and that treatment of all cases is considered necessary and beneficial. Research indicates that milk synthesis at the onset of lactation contributes to immediate postpartum hypocalcemia, and that the mammary gland is a critical factor in management of Ca homeostasis. However, cows differ in their ability to manage this phenomenon, and it is possible that immediate postpartum influences such as dry matter intake, inflammation, and immune activation affect appropriate Ca regulation in the days following calving.

Calcimimetic AMG-416 induced short-term changes in calcium concentrations and calcium isotope ratios in rats

Calcium (Ca) isotopes (δ44/42Ca) in serum and urine have been suggested as novel sensitive markers of bone calcification. The response of δ44/42Ca to acute changes in Ca homeostasis, has not yet been demonstrated. We measured serum Ca and δ44/42Ca in rats maintained on a standard and a 50% Ca reduced diet for 4 weeks, and after injection of 1 mg/kg of the calcimimetic AMG-416, 24 h prior to sacrifice. AMG-416 decreased serum Ca by a maximum of 0.38 ± 0.10 and 0.53 ± 0.35 mmol/l after 12 and 6 h, respectively, in the standard and low-Ca diet groups (p = 0.0006/0.02), while serum δ44/42Ca did not change over 24 h in both groups. Urinary Ca concentrations were higher 24 h after AMG-416 injection in both groups (p = 0.03/0.06), urine δ44/42Ca was not different compared to the untreated control groups. Our data does not show acute changes in δ44/42Ca in response to a single dose of AMG-416 within 24 h after injection, possibly due to a lack of bone calcification.

Mediators of calcium homeostasis in cows with differing postparturient calcium dynamics

Many multiparous dairy cows experience subclinical hypocal­cemia (SCH) in the immediate postpartum period as they adapt to the demands of lactation. Furthermore, differing dynamics of SCH in the days following parturition are associated with varied health and production outcomes, with cows experienc­ing transient SCH producing more milk and facing fewer nega­tive health events than cows with delayed or persistent SCH. Our objectives were to describe differences in mediators of Ca homeostasis between cows experiencing different dynamics of SCH.