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1.
Eur J Endocrinol ; 190(4): 296-306, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38561929

RESUMEN

OBJECTIVE: The calcium-sensing receptor (CASR) gene encodes a G protein-coupled receptor crucial for calcium homeostasis. Gain-of-function CASR variants result in hypocalcemia, while loss-of-function variants lead to hypercalcemia. This study aims to assess the functional consequences of the novel nonsense CASR variant [c.2897_2898insCTGA, p.(Gln967*) (Q967*)] identified in adolescent patient with chronic hypocalcemia, a phenotype expected for a gain-of-function variants. DESIGN AND METHODS: To functionally characterize the Q967* mutant receptor, both wild-type (WT) and mutant CASR were transiently transfected into HEK293T cells and calcium-sensing receptor (CaSR) protein expression and functions were comparatively evaluated using multiple read-outs. RESULTS: Western blot analysis revealed that the CaSR mutant protein displayed a lower molecular weight compared with the WT, consistent with the loss of the last 122 amino acids in the intracellular domain. Mitogen-activated protein kinase activation and serum responsive element luciferase assays demonstrated that the mutant receptor had higher baseline activity than the WT. Extracellular-signal-regulated kinase/c-Jun N-terminal kinase phosphorylation, however, remained consistently high in the mutant, without significant modulations following exposure to increasing extracellular calcium (Ca2+o) levels, suggesting that the mutant receptor is more sensitive to Ca2+o compared with the WT. CONCLUSIONS: This study provides functional validation of the pathogenicity of a novel nonsense CASR variant, resulting in an abnormally hyperfunctioning protein consistent with the patient's phenotype. Functional analyses indicate that mutant receptor is constitutively active and poorly sensitive to increasing concentrations of extracellular calcium, suggesting that the cytoplasmic tail may contain elements regulating signal transduction.


Asunto(s)
Hipercalcemia , Hipocalcemia , Adolescente , Humanos , Hipocalcemia/genética , Calcio , Receptores Sensibles al Calcio/genética , Células HEK293 , Hipercalcemia/genética , Mutación/genética
2.
Am J Clin Nutr ; 119(4): 927-948, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38569787

RESUMEN

BACKGROUND: A global move toward consumption of diets from sustainable sources is required to protect planetary health. As this dietary transition will result in greater reliance on plant-based protein sources, the impact on micronutrient (MN) intakes and status is unknown. OBJECTIVE: Evaluate the evidence of effects on intakes and status of selected MNs resulting from changes in dietary intakes to reduce environmental impact. Selected MNs of public health concern were vitamins A, D, and B12, folate, calcium, iron, iodine, and zinc. METHODS: We systematically searched 7 databases from January 2011 to October 2022 and followed the PRISMA guidelines. Eligible studies had to report individual MN intake and/or status data collected in free-living individuals from the year 2000 onward and environmental outcomes. RESULTS: From the 10,965 studies identified, 56 studies were included, mostly from high-income countries (n = 49). Iron (all 56) and iodine (n = 20) were the most and least reported MNs, respectively. There was one randomized controlled trial (RCT) that also provided the only biomarker data, 10 dietary intake studies, and 45 dietary modeling studies, including 29 diet optimization studies. Most studies sought to reduce greenhouse gas emissions or intake of animal-sourced foods. Most results suggested that intakes of zinc, calcium, iodine, and vitamins B12, A, and D would decrease, and total iron and folate would increase in a dietary transition to reduce environmental impacts. Risk of inadequate intakes of zinc, calcium, vitamins A, B12 and D were more likely to increase in the 10 studies that reported nutrient adequacy. Diet optimization (n = 29) demonstrated that meeting nutritional and environmental targets is technically feasible, although acceptability is not guaranteed. CONCLUSIONS: Lower intakes and status of MNs of public health concern are a potential outcome of dietary changes to reduce environmental impacts. Adequate consideration of context and nutritional requirements is required to develop evidence-based recommendations. This study was registered prospectively with PROSPERO (CRD42021239713).


Asunto(s)
Yodo , Micronutrientes , Humanos , Calcio , Calcio de la Dieta , Dieta , Ácido Fólico , Hierro , Vitaminas , Zinc , Ensayos Clínicos Controlados Aleatorios como Asunto
3.
Medicine (Baltimore) ; 103(15): e37804, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38608105

RESUMEN

To investigate the impact of RDW/CA (the ratio of red cell distribution width to calcium) on in-hospital mortality in patients with acute respiratory failure (ARF). This retrospective cohort study analyzed the data of 6981 ARF patients from the Medical Information Mart for Intensive Care (MIMIC-IV) database 2.0. Critically ill participants between 2008 and 2019 at the Beth Israel Deaconess Medical Center in Boston. The primary outcome of interest was in-hospital mortality. A Cox proportional hazards regression model was used to determine whether the RDW/CA ratio independently correlated with in-hospital mortality. The Kaplan-Meier method was used to plot the survival curves of the RDW/CA. Subgroup analyses were performed to measure the mortality across various subgroups. After adjusting for potential covariates, we found that a higher RDW/CA was associated with an increased risk of in-hospital mortality (HR = 1.17, 95% CI: 1.01-1.35, P = .0365) in ARF patients. A nonlinear relationship was observed between RDW/CA and in-hospital mortality, with an inflection point of 1.97. When RDW/CA ≥ 1.97 was positively correlated with in-hospital mortality in patients with ARF (HR = 1.554, 95% CI: 1.183-2.042, P = .0015). The Kaplan-Meier curve indicated the higher survival rates for RDW/CA < 1.97 and the lower for RDW/CA ≥ 1.97 after adjustment for age, gender, body mass index, and ethnicity. RDW/CA is an independent predictor of in-hospital mortality in patients with ARF. Furthermore, a nonlinear relationship was observed between RDW/CA and in-hospital mortality in patients with ARF.


Asunto(s)
Síndrome de Dificultad Respiratoria , Insuficiencia Respiratoria , Humanos , Mortalidad Hospitalaria , Índices de Eritrocitos , Calcio , Estudios Retrospectivos
4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 49(1): 21-28, 2024 Jan 28.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-38615162

RESUMEN

OBJECTIVES: The activation of astrocytes is an important process in the formation of chronic pain. This study aims to observe the activation of A1 reactive astrocytes in the medullary dorsal horn in the rat model of trigeminal neuralgia, and to explore the mechanism of central sensitization caused by A1 reactive astrocyte. METHODS: The adult male rats were randomly divided into a sham group and a chronic constriction injury of infraorbital nerve (ION-CCI) group. The facial mechanical pain threshold and thermal withdrawal latency were measured before the operation and on the 1st, 3rd, 7th, 10th, and 14th day after the operation. After pain behavior observation, the expression of glial fibrillary acidic protein (GFAP) in the medullary dorsal horn was observed by immunohistochemistry and immunofluorescence colocalization of GFAP, complement 3 (C3)/S100A10, and 4', 6-diamidino-2-phenylindole (DAPI) was analyzed. Primary astrocytes were cultured and randomly divided into a naive group and a DHK group. The DHK group was treated with 1 mmol/L of astrocyte activation inhibitor dihydrokainic acid (DHK). Fura-2/AM was used to stain the astrocytes and the calcium wave of the 2 groups under the stimulation of high potassium was recorded and compared. The expression of C3 was detected by Western blotting. RESULTS: The facial mechanical pain threshold and thermal withdrawal latency of the ION-CCI group were significantly lower than those of the sham group (both P<0.05). There were a large number of GFAP positive astrocytes in the medullary dorsal horn of the ION-CCI group. The fluorescence intensity of GFAP in the ION-CCI group was higher than that in the sham group (P<0.05). GFAP and C3/S100A10 were co-expressed in astrocytes. Compared with the sham group, the fluorescence intensity of C3 and the protein expression of C3 in the ION-CCI group were increased (both P<0.05). The expression of C3 in ION-CCI group was significantly increased (P<0.05). Compared with the naive group, the C3 protein expression was significantly decreased in the DHK group (P<0.05). The intensity of calcium fluorescence was increased after high potassium stimulation in both groups. Furthermore, the peak and increase amplitude of calcium fluorescence in the naive group were much higher than those in the DHK group (both P<0.05). CONCLUSIONS: A1 reactive astrocytes in the medullary dorsal horn of trigeminal neuralgia model rats are increased significantly, which may participate in central sensitization of trigeminal neuralgia by impacting astrocyte calcium wave.


Asunto(s)
Dolor Crónico , Neuralgia del Trigémino , Masculino , Animales , Ratas , Astrocitos , Calcio , Potasio
5.
Proc Natl Acad Sci U S A ; 121(17): e2303664121, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38621124

RESUMEN

Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic physiology, as well as mechanisms underlying various neuropsychiatric diseases and their treatment. Despite its clear physiological role and disease relevance, BDNF's function at the presynaptic terminal, a fundamental unit of neurotransmission, remains poorly understood. In this study, we evaluated single synapse dynamics using optical imaging techniques in hippocampal cell cultures. We find that exogenous BDNF selectively increases evoked excitatory neurotransmission without affecting spontaneous neurotransmission. However, acutely blocking endogenous BDNF has no effect on evoked or spontaneous release, demonstrating that different approaches to studying BDNF may yield different results. When we suppressed BDNF-Tropomyosin receptor kinase B (TrkB) activity chronically over a period of days to weeks using a mouse line enabling conditional knockout of TrkB, we found that evoked glutamate release was significantly decreased while spontaneous release remained unchanged. Moreover, chronic blockade of BDNF-TrkB activity selectively downscales evoked calcium transients without affecting spontaneous calcium events. Via pharmacological blockade by voltage-gated calcium channel (VGCC) selective blockers, we found that the changes in evoked calcium transients are mediated by the P/Q subtype of VGCCs. These results suggest that BDNF-TrkB activity increases presynaptic VGCC activity to selectively increase evoked glutamate release.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Calcio , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Calcio/metabolismo , Transmisión Sináptica/fisiología , Sinapsis/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Calcio de la Dieta , Receptor trkB/genética , Receptor trkB/metabolismo , Glutamatos/metabolismo
6.
Ecol Lett ; 27(4): e14414, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38622965

RESUMEN

Animals assimilate macronutrients and mineral nutrients in specific quantities and ratios to maximise fitness. To achieve this, animals must ingest different foods that contain the needed nutrients or facilitate the digestion of those nutrients. We explored how these multidimensional considerations affect the desert isopods (Hemilepistus reaumuri) curious food selection, using field and laboratory experiments. Wild isopods consumed three-fold more macronutrient-poor biological soil crust (BSC) than plant litter. Isopods tightly regulated macronutrient and calcium intake, but not phosphorus when eating the two natural foods and when artificial calcium and phosphorus sources substituted the BSC. Despite the equivalent calcium ingestion, isopods performed better when eating BSC compared to artificial foods. Isopods that consumed BSC sterilised by gamma-radiation ate more but grew slower than isopods that ate live BSC, implying that ingested microorganisms facilitate litter digestion. Our work highlights the need to reveal the multifaceted considerations that affect food-selection when exploring trophic-interactions.


Asunto(s)
Polvo , Isópodos , Animales , Calcio , Dieta/veterinaria , Nutrientes
7.
Radiology ; 311(1): e231852, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38625007

RESUMEN

Background Although favorable outcomes have been reported with radiofrequency ablation (RFA) for secondary hyperparathyroidism (SHPT), the long-term efficacy remains insufficiently investigated. Purpose To evaluate the long-term efficacy and safety of US-guided percutaneous RFA in patients with SHPT undergoing dialysis and to identify possible predictors associated with treatment failure. Materials and Methods This retrospective study included consecutive patients with SHPT with at least one enlarged parathyroid gland accessible for RFA who were undergoing dialysis at seven tertiary centers from May 2013 to July 2022. The primary end point was the proportion of patients with parathyroid hormone (PTH) levels less than or equal to 585 pg/mL at the end of follow-up. Secondary end points were the proportion of patients with normal calcium and phosphorus levels, the technical success rate, procedure-related complications, and improvement in self-rated hyperparathyroidism-related symptoms (0-3 ranking scale). The Wilcoxon signed rank test and generalized estimating equation model were used to evaluate treatment outcomes. Univariable and multivariable regression analyses identified variables associated with treatment failure (recurrent or persistent hyperparathyroidism). Results This study included 165 patients (median age, 51 years [IQR, 44-60 years]; 92 female) and 582 glands. RFA effectively reduced PTH, calcium, and phosphorus levels, with targeted ranges achieved in 78.2% (129 of 165), 72.7% (120 of 165), and 60.0% (99 of 165) of patients, respectively, at the end of follow-up (mean, 51 months). For the RFA sessions, the technical success rate was 100% (214 of 214). Median symptom scores (ostealgia, arthralgia, pruritus) decreased (all P < .001). Regarding complications, only hypocalcemia (45.8%, 98 of 214) was common. Treatment failure occurred in 36 patients (recurrent [n = 5] or persistent [n = 31] hyperparathyroidism). The only potential independent predictor of treatment failure was having less than four treated glands (odds ratio, 17.18; 95% CI: 4.34, 67.95; P < .001). Conclusion US-guided percutaneous RFA was effective and safe in the long term as a nonsurgical alternative for patients with SHPT undergoing dialysis; the only potential independent predictor of treatment failure was a lower number (<4) of treated glands. © RSNA, 2024 Supplemental material is available for this article.


Asunto(s)
Calcio , Hiperparatiroidismo Secundario , Humanos , Femenino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Hiperparatiroidismo Secundario/diagnóstico por imagen , Hiperparatiroidismo Secundario/cirugía , Fósforo
8.
J Environ Manage ; 357: 120800, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38579471

RESUMEN

Calcium carbide residue (CCR), a by-product of the acetylene industry, is generated at a rate of 136 million tonnes per year, posing significant environmental risks. This review examines the potential utilisation of CCR in soil stabilisation, focusing on its stabilisation mechanism, performance in improving mechanical properties, environmental safety, and sustainability. The aim is to identify future research directions for CCR-based stabilisation to promote its broader application, and to provide references for managing similar Ca-rich wastes. CCR-based materials demonstrate promising benefits in enhancing various soil properties, such as uniaxial strength, swelling properties, triaxial shear behaviour, compressibility, and dynamic responses, while also reducing the mobility of contaminants. Compared to conventional stabilisers, CCR-based materials exhibit comparable performance in soil improvement, environmental impact and safety, and economic feasibility. However, further research is required to delve deeper into stabilisation mechanisms, mechanical properties, and stability of contaminants for the soil treated with CCR-based materials under diverse conditions.


Asunto(s)
Acetileno/análogos & derivados , Residuos Industriales , Suelo , Suelo/química , Calcio
9.
J Agric Food Chem ; 72(15): 8569-8580, 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38563891

RESUMEN

Rice protein peptides (RPP) are a potentially valuable source of high-quality calcium chelating properties. However, there is a lack of information regarding the calcium-absorption-promoting effect of RPP and its underlying mechanism. The present study adopted molecular docking methodologies to analyze the 10 most potent peptide segments from RPP. Results revealed that the peptide AHVGMSGEEPE (AHV) displayed optimal calcium binding properties (calcium-chelating capacity 55.69 ± 0.66 mg/g). Quantum chemistry analysis revealed that the AHV peptide effectively binds and forms stable complexes with calcium via the carbonyl oxygen atoms in valine at position 3 and the carbonyl of the C-terminal carboxyl group of glutamate at position 11. The spectral analysis results indicated that AHV may bind to calcium through carboxyl oxygen atoms, resulting in a transition from a smooth surface block-like structure to a dense granular structure. Furthermore, this study demonstrated that the 4 mmol/L AHV-Ca chelate (61.75 ± 13.23 µg/well) significantly increases calcium absorption compared to 1 mM CaCl2 (28.57 ± 8.59 µg/well) in the Caco-2 cell monolayer. In terms of mechanisms, the novel peptide-calcium chelate AHV-Ca derived from RPP exerts a cell-level effect by upregulating the expression of TRPV6 calcium-ion-channel-related genes and proteins (TRPV6 and Calbindin-D9k). This study provides a theoretical basis for developing functional foods with the AHV peptide as ingredients to improve calcium absorption.


Asunto(s)
Calcio , Oryza , Humanos , Calcio/metabolismo , Células CACO-2 , Oryza/metabolismo , Simulación del Acoplamiento Molecular , Calcio de la Dieta/metabolismo , Péptidos/química , Oxígeno
10.
Chemosphere ; 355: 141860, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38565377

RESUMEN

Soil salinization is a major environmental hazard that limits land availability. Human-induced salt pollutants (HISPs) are regularly presented in large quantities on the contaminated site (such as brine leakages and salt-water spills), causing a devastating shock with high salt stress to the ecosystem. For instance, Saskatchewan resulted in a 48% drop in wheat production and a 0.3% decline in provincial GDP. As the calcium-modified biochar can potentially ameliorate the negative effects of HISPs on plants and improve the plant, phytoremediation with calcium-modified biochar can have increased detoxification of hazardous pollutants from sites. Therefore, the objective of our study was to develop a biochar-assisted phytoremediation employing diverse approaches to calcium modification for the sustainable removal of HISPs. The co-pyrolyzed calcium biochar achieved a remarkable removal rate of 18.06%, reducing salinity from 9.44 to 7.81 dS/m. During a 90-day long-term phytoremediation, the overall reduction rate of calcium-modified biochar stimulated the germination and growth of Thinopyrum ponticum. The result of post-treatment further indicated that co-pyrolyzed biochar with Ca transferred salt into the plant compared to Ca-coated biochar, which only immobilized HISPs on its surface. These results offer two different treatment approaches for diverse situations involving HISPs contamination, addressing current in-situ spills and providing a calcium-related biochar technology for further research in desalination.


Asunto(s)
Contaminantes Ambientales , Contaminantes del Suelo , Humanos , Biodegradación Ambiental , Calcio , Ecosistema , Carbón Orgánico , Calcio de la Dieta , Suelo , Plantas
11.
Chemosphere ; 355: 141871, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38570052

RESUMEN

Recycling solid waste for preparing sulfoaluminate cementitious materials (SACM) represents a promising approach for low-carbon development. There are drastic physical-chemical reactions during SACM calcination. However, there is a lack of research on the flue gas pollutants emissions from this process. Condensable particulate matter (CPM) has been found to constitute the majority of the primary PM emitted from various fuel combustion. In this study, the emission characteristics of CPM during the calcination of SACM were determined using tests in both a real-operated kiln and laboratory experiments. The mass concentration of CPM reached 96.6 mg/Nm3 and occupied 87% of total PM emission from the SACM kiln. Additionally, the mass proportion of SO42- in the CPM reached 93.8%, thus indicating that large quantities of sulfuric acid mist or SO3 were emitted. CaSO4 was one key component for the formation of main mineral ye'elimite (3CaO·3Al2O3·CaSO4), and its decomposition probably led to the high SO42- emission. Furthermore, the use of CaSO4 as a calcium source led to SO42- emission factor much higher than conventional calcium sources. Higher calcination temperature and more residence time also increased SO42- emission. The most abundant heavy metal in kiln flue gas and CPM was Zn. However, the total condensation ratio of heavy metals detected was only 40.5%. CPM particles with diameters below 2.5 µm and 4-20 µm were both clearly observed, and components such as Na2SO4 and NaCl were conformed. This work contributes to the understanding of CPM emissions and the establishment of pollutant reduction strategies for waste collaborative disposal in cement industry.


Asunto(s)
Contaminantes Atmosféricos , Contaminantes Ambientales , Metales Pesados , Material Particulado/análisis , Contaminantes Atmosféricos/análisis , Residuos Sólidos , Calcio
12.
PLoS Pathog ; 20(4): e1011750, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38574119

RESUMEN

Rotaviruses infect cells by delivering into the cytosol a transcriptionally active inner capsid particle (a "double-layer particle": DLP). Delivery is the function of a third, outer layer, which drives uptake from the cell surface into small vesicles from which the DLPs escape. In published work, we followed stages of rhesus rotavirus (RRV) entry by live-cell imaging and correlated them with structures from cryogenic electron microscopy and tomography (cryo-EM and cryo-ET). The virus appears to wrap itself in membrane, leading to complete engulfment and loss of Ca2+ from the vesicle produced by the wrapping. One of the outer-layer proteins, VP7, is a Ca2+-stabilized trimer; loss of Ca2+ releases both VP7 and the other outer-layer protein, VP4, from the particle. VP4, activated by cleavage into VP8* and VP5*, is a trimer that undergoes a large-scale conformational rearrangement, reminiscent of the transition that viral fusion proteins undergo to penetrate a membrane. The rearrangement of VP5* thrusts a 250-residue, C-terminal segment of each of the three subunits outward, while allowing the protein to remain attached to the virus particle and to the cell being infected. We proposed that this segment inserts into the membrane of the target cell, enabling Ca2+ to cross. In the work reported here, we show the validity of key aspects of this proposed sequence. By cryo-EM studies of liposome-attached virions ("triple-layer particles": TLPs) and single-particle fluorescence imaging of liposome-attached TLPs, we confirm insertion of the VP4 C-terminal segment into the membrane and ensuing generation of a Ca2+ "leak". The results allow us to formulate a molecular description of early events in entry. We also discuss our observations in the context of other work on double-strand RNA virus entry.


Asunto(s)
Rotavirus , Rotavirus/genética , Proteínas de la Cápside/metabolismo , Cápside/metabolismo , Calcio/metabolismo , Liposomas/análisis , Liposomas/metabolismo
13.
BMC Geriatr ; 24(1): 343, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38622550

RESUMEN

BACKGROUND: The first six months of therapy represents a high-risk period for peritoneal dialysis (PD) failure. The risk of death in the first six months is higher for older patients treated with urgent-start PD (USPD). However, there are still gaps in research on mortality and risk factors for death in this particular group of patients. We aimed to investigate mortality rates and risk factors for death in older patients with end-stage renal disease (ESRD) receiving USPD within and after six months of therapy. METHODS: We retrospectively studied the clinical information of older adults aged ≥ 65 years with ESRD who received USPD between 2013 and 2019 in five Chinese hospitals. Patients were followed up to June 30, 2020. The mortality and risk factors for death in the first six months of USPD treatment and beyond were analyzed. RESULTS: Of the 379 elderly patients in the study, 130 died over the study period. During the follow-up period, the highest number (45, 34.6%) of deaths occurred within the first six months. Cardiovascular disease was the most common cause of death. The baseline New York Heart Association (NYHA) class III-IV cardiac function [hazard ratio (HR) = 2.457, 95% confidence interval (CI): 1.200-5.030, p = 0.014] and higher white blood cell (WBC) count (HR = 1.082, 95% CI: 1.021-1.147, p = 0.008) increased the mortality risk within six months of USPD. The baseline NYHA class III-IV cardiac function (HR = 1.945, 95% CI: 1.149-3.294, p = 0.013), lower WBC count (HR = 0.917, 95% CI: 0.845-0.996, p = 0.040), lower potassium levels (HR = 0.584, 95% CI: 0.429-0.796, p = 0.001), and higher calcium levels (HR = 2.160, 95% CI: 1.025-4.554, p = 0.043) increased the mortality risk after six months of USPD. CONCLUSION: Different risk factors correlated with mortality in older adults with ESRD within and after six months of undergoing USPD, including baseline NYHA class III-IV cardiac function, WBC count, potassium, and calcium levels.


Asunto(s)
Fallo Renal Crónico , Diálisis Peritoneal , Anciano , Humanos , Estudios Retrospectivos , Calcio , Diálisis Peritoneal/efectos adversos , Diálisis Renal , Potasio , Factores de Riesgo
14.
Nat Commun ; 15(1): 3039, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38589390

RESUMEN

Astrocytes are a direct target of neuromodulators and can influence neuronal activity on broad spatial and temporal scales in response to a rise in cytosolic calcium. However, our knowledge about how astrocytes are recruited during different animal behaviors remains limited. To measure astrocyte activity calcium in vivo during normative behaviors, we utilize a high-resolution, long working distance multicore fiber optic imaging system that allows visualization of individual astrocyte calcium transients in the cerebral cortex of freely moving mice. We define the spatiotemporal dynamics of astrocyte calcium changes during diverse behaviors, ranging from sleep-wake cycles to the exploration of novel objects, showing that their activity is more variable and less synchronous than apparent in head-immobilized imaging conditions. In accordance with their molecular diversity, individual astrocytes often exhibit distinct thresholds and activity patterns during explorative behaviors, allowing temporal encoding across the astrocyte network. Astrocyte calcium events were induced by noradrenergic and cholinergic systems and modulated by internal state. The distinct activity patterns exhibited by astrocytes provides a means to vary their neuromodulatory influence in different behavioral contexts and internal states.


Asunto(s)
Astrocitos , Calcio , Ratones , Animales , Astrocitos/metabolismo , Calcio/metabolismo , Neuronas/metabolismo , Diagnóstico por Imagen , Corteza Cerebral/metabolismo , Señalización del Calcio/fisiología
15.
Cochrane Database Syst Rev ; 4: CD003376, 2024 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-38591743

RESUMEN

BACKGROUND: Osteoporosis is an abnormal reduction in bone mass and bone deterioration, leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts - bone cells that break down bone tissue. This is an update of a Cochrane review first published in 2008. For clinical relevance, we investigated etidronate's effects on postmenopausal women stratified by fracture risk (low versus high). OBJECTIVES: To assess the benefits and harms of intermittent/cyclic etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women at lower and higher risk of fracture, respectively. SEARCH METHODS: We searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE, Embase, two clinical trial registers, the websites of drug approval agencies, and the bibliographies of relevant systematic reviews. We identified eligible trials published between 1966 and February 2023. SELECTION CRITERIA: We included randomized controlled trials that assessed the benefits and harms of etidronate in the prevention of fractures for postmenopausal women. Women in the experimental arms must have received at least one year of etidronate, with or without other anti-osteoporotic drugs and concurrent calcium/vitamin D. Eligible comparators were placebo (i.e. no treatment; or calcium, vitamin D, or both) or another anti-osteoporotic drug. Major outcomes were clinical vertebral, non-vertebral, hip, and wrist fractures, withdrawals due to adverse events, and serious adverse events. We classified a study as secondary prevention if its population fulfilled one or more of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, a low bone mineral density T-score (≤ -2.5), or aged 75 years or older. If none of these criteria were met, we considered the study to be primary prevention. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The review has three main comparisons: (1) etidronate 400 mg/day versus placebo; (2) etidronate 200 mg/day versus placebo; (3) etidronate at any dosage versus another anti-osteoporotic agent. We stratified the analyses for each comparison into primary and secondary prevention studies. For major outcomes in the placebo-controlled studies of etidronate 400 mg/day, we followed our original review by defining a greater than 15% relative change as clinically important. For all outcomes of interest, we extracted outcome measurements at the longest time point in the study. MAIN RESULTS: Thirty studies met the review's eligibility criteria. Of these, 26 studies, with a total of 2770 women, reported data that we could extract and quantitatively synthesize. There were nine primary and 17 secondary prevention studies. We had concerns about at least one risk of bias domain in each study. None of the studies described appropriate methods for allocation concealment, although 27% described adequate methods of random sequence generation. We judged that only 8% of the studies avoided performance bias, and provided adequate descriptions of appropriate blinding methods. One-quarter of studies that reported efficacy outcomes were at high risk of attrition bias, whilst 23% of studies reporting safety outcomes were at high risk in this domain. The 30 included studies compared (1) etidronate 400 mg/day to placebo (13 studies: nine primary and four secondary prevention); (2) etidronate 200 mg/day to placebo (three studies, all secondary prevention); or (3) etidronate (both dosing regimens) to another anti-osteoporotic agent (14 studies: one primary and 13 secondary prevention). We discuss only the etidronate 400 mg/day versus placebo comparison here. For primary prevention, we collected moderate- to very low-certainty evidence from nine studies (one to four years in length) including 740 postmenopausal women at lower risk of fractures. Compared to placebo, etidronate 400 mg/day probably results in little to no difference in non-vertebral fractures (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.20 to 1.61); absolute risk reduction (ARR) 4.8% fewer, 95% CI 8.9% fewer to 6.1% more) and serious adverse events (RR 0.90, 95% CI 0.52 to 1.54; ARR 1.1% fewer, 95% CI 4.9% fewer to 5.3% more), based on moderate-certainty evidence. Etidronate 400 mg/day may result in little to no difference in clinical vertebral fractures (RR 3.03, 95% CI 0.32 to 28.44; ARR 0.02% more, 95% CI 0% fewer to 0% more) and withdrawals due to adverse events (RR 1.41, 95% CI 0.81 to 2.47; ARR 2.3% more, 95% CI 1.1% fewer to 8.4% more), based on low-certainty evidence. We do not know the effect of etidronate on hip fractures because the evidence is very uncertain (RR not estimable based on very low-certainty evidence). Wrist fractures were not reported in the included studies. For secondary prevention, four studies (two to four years in length) including 667 postmenopausal women at higher risk of fractures provided the evidence. Compared to placebo, etidronate 400 mg/day may make little or no difference to non-vertebral fractures (RR 1.07, 95% CI 0.72 to 1.58; ARR 0.9% more, 95% CI 3.8% fewer to 8.1% more), based on low-certainty evidence. The evidence is very uncertain about etidronate's effects on hip fractures (RR 0.93, 95% CI 0.17 to 5.19; ARR 0.0% fewer, 95% CI 1.2% fewer to 6.3% more), wrist fractures (RR 0.90, 95% CI 0.13 to 6.04; ARR 0.0% fewer, 95% CI 2.5% fewer to 15.9% more), withdrawals due to adverse events (RR 1.09, 95% CI 0.54 to 2.18; ARR 0.4% more, 95% CI 1.9% fewer to 4.9% more), and serious adverse events (RR not estimable), compared to placebo. Clinical vertebral fractures were not reported in the included studies. AUTHORS' CONCLUSIONS: This update echoes the key findings of our previous review that etidronate probably makes or may make little to no difference to vertebral and non-vertebral fractures for both primary and secondary prevention.


Asunto(s)
Fracturas de Cadera , Osteoporosis , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Fracturas de la Muñeca , Traumatismos de la Muñeca , Humanos , Femenino , Fracturas Osteoporóticas/prevención & control , Fracturas Osteoporóticas/inducido químicamente , Fracturas Osteoporóticas/tratamiento farmacológico , Ácido Etidrónico/uso terapéutico , Prevención Secundaria , Calcio , Posmenopausia , Osteoporosis/tratamiento farmacológico , Fracturas de la Columna Vertebral/prevención & control , Vitamina D , Traumatismos de la Muñeca/inducido químicamente , Traumatismos de la Muñeca/tratamiento farmacológico
16.
Protein Sci ; 33(5): e4982, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38591710

RESUMEN

KSR1, a key scaffold protein for the MAPK pathway, facilitates ERK activation upon growth factor stimulation. We recently demonstrated that KSR1 binds the Ca2+-binding protein calmodulin (CaM), thereby providing an intersection between KSR1-mediated and Ca2+ signaling. In this study, we set out to generate a KSR1 point mutant with reduced Ca2+/CaM binding in order to unravel the functional implications of their interaction. To do so, we solved the structural determinants of complex formation. Using purified fragments of KSR1, we showed that Ca2+/CaM binds to the CA3 domain of KSR1. We then used in silico molecular modeling to predict contact residues for binding. This approach identified two possible modes of interaction: (1) binding of extended Ca2+/CaM to a globular conformation of KSR1-CA3 via electrostatic interactions or (2) binding of collapsed Ca2+/CaM to α-helical KSR1-CA3 via hydrophobic interactions. Experimentally, site-directed mutagenesis of the predicted contact residues for the two binding models favored that where collapsed Ca2+/CaM binds to the α-helical conformation of KSR1-CA3. Importantly, replacing KSR1-Phe355 with Asp reduces Ca2+/CaM binding by 76%. The KSR1-F355D mutation also significantly impairs the ability of EGF to activate ERK, which reveals that Ca2+/CaM binding promotes KSR1-mediated MAPK signaling. This work, by uncovering structural insight into the binding of KSR1 to Ca2+/CaM, identifies a KSR1 single-point mutant as a bioreagent to selectively study the crosstalk between Ca2+ and KSR1-mediated signaling.


Asunto(s)
Señalización del Calcio , Calmodulina , Calmodulina/química , Unión Proteica , Mutación , Mutagénesis Sitio-Dirigida , Calcio/metabolismo
17.
J Cell Mol Med ; 28(8): e18202, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38591872

RESUMEN

Secondary hyperparathyroidism has a significant impact on the overall well-being of the body. Capsiates, known for their antioxidant and metabolic properties, have emerged as a promising alternative treatment for secondary hyperparathyroidism. This study aims to evaluate the effects and mechanisms of capsiates in the treatment of secondary hyperparathyroidism. To achieve our research objectives, we conducted a study on patients' serum and examined changes in metabolic markers using serum metabolomics. We induced secondary hyperparathyroidism in rat through dietary intervention and divided them into four groups. The first group, referred to as the Parathyroid Hormone (PTH) group, received a low-calcium and high-phosphate diet (0.2% calcium, 1.2% phosphorus). The second group served as the control group, receiving a standard phosphate and calcium diet (0.6% calcium, 0.6% phosphorus). The third group, called the capsiates group, consisted of rat from the control group treated with capsiates (intraperitoneal injection of 2 mg/kg capsiates for 2 weeks after 2 weeks of dietary intervention). The fourth group was the capsiates-treated PTH group. Subsequently, we conducted ribose nucleic acid (RNA) sequencing on parathyroid gland cells and evaluated serum thyroxine levels, oxidative stress, expression of proteins associated with vascular neogenesis, measurement of SOD, GSH and 3-nitrotyrosine, micro-CT and histological staining. The serum metabolomic data revealed a significant decrease in capsiate levels in the secondary hyperparathyroidism group. Administration of capsiates to PTH rat resulted in increased calcium levels compared to the PTH group. Additionally, the PTH + Capsiates group showed significantly lower levels of PTH and phosphate compared to the PTH group. The PTH group exhibited a notable increase in the quantity and size of mitochondria compared to the control group. Following capsiates administration to the PTH group, there was a significant reduction in the number of mitochondria and length of microvilli, but an increase in the size of mitochondria compared to the PTH group. Sequencing analysis revealed that vascular endothelial growth factor (VEGF) and Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) play crucial roles in this process. Vascular-related variables and downstream signalling were significantly elevated in hyperthyroidism and were alleviated with capsaicin treatment. Finally, combining capsiates with the PTH group improved bone mineral density, Tb.N, BV.TV, Cs.Th, Tt.Ar, OPG, Ob.TV and Oc.TV, as well as the mineral apposition rate, but significantly decreased Tb.Sp and Receptor Activator for Nuclear Factor-κ B Ligand (RANKL) compared to the PTH group. The findings suggest that capsiates can improve secondary hyperparathyroidism and ameliorated osteoporosis outcomes by inhibiting angiogenesis and reducing oxidative stress.


Asunto(s)
Capsaicina/análogos & derivados , Hiperparatiroidismo Secundario , Resistencia a la Insulina , Humanos , Ratas , Animales , Calcio , 60489 , Factor A de Crecimiento Endotelial Vascular , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/etiología , Hormona Paratiroidea , Fósforo , Fosfatos
18.
FASEB J ; 38(7): e23608, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38593315

RESUMEN

Tooth development is a complex process involving various signaling pathways and genes. Recent findings suggest that ion channels and transporters, including the S100 family of calcium-binding proteins, may be involved in tooth formation. However, our knowledge in this regard is limited. Therefore, this study aimed to investigate the expression of S100 family members and their functions during tooth formation. Tooth germs were extracted from the embryonic and post-natal mice and the expression of S100a6 was examined. Additionally, the effects of S100a6 knockdown and calcium treatment on S100a6 expression and the proliferation of SF2 cells were examined. Microarrays and single-cell RNA-sequencing indicated that S100a6 was highly expressed in ameloblasts. Immunostaining of mouse tooth germs showed that S100a6 was expressed in ameloblasts but not in the undifferentiated dental epithelium. Additionally, S100a6 was localized to the calcification-forming side in enamel-forming ameloblasts. Moreover, siRNA-mediated S100a6 knockdown in ameloblasts reduced intracellular calcium concentration and the expression of ameloblast marker genes, indicating that S100a6 is associated with ameloblast differentiation. Furthermore, S100a6 knockdown inhibited the ERK/PI3K signaling pathway, suppressed ameloblast proliferation, and promoted the differentiation of the dental epithelium toward epidermal lineage. Conclusively, S100a6 knockdown in the dental epithelium suppresses cell proliferation via calcium and intracellular signaling and promotes differentiation of the dental epithelium toward the epidermal lineage.


Asunto(s)
Calcio , Fosfatidilinositol 3-Quinasas , Animales , Ratones , Calcio/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Odontogénesis/genética , Ameloblastos/metabolismo , Células Epiteliales , Diferenciación Celular
19.
Radiat Res ; 201(4): 294-303, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38588381

RESUMEN

Radiation-induced intestinal damage (RIID) is a common side effect of radiotherapy in patients with abdominopelvic malignancies. Gap junctions are special structures consisting of connexins (Cxs). This study aimed to investigate the expression and role of connexins in RIID and underlying mechanism. In this study, a calcein-AM fluorescence probe was used to detect changes in gap junctional intercellular communication in intestinal epithelial IEC-6 cells. Our results show that gap junctional intercellular communication of IEC-6 cells was reduced at 6, 12, 24, and 48 h after irradiation, with the most pronounced effect at 24 h. Western blotting and immunofluorescence results showed that the expression of Cx43, but not other connexins, was reduced in irradiated intestinal epithelial cells. Silencing of Cx43 reduced gap junctional intercellular communication between irradiated intestinal epithelial cells with increased ROS and intracellular Ca2+ levels. Furthermore, knockdown of Cx43 reduced the number of clonal clusters, decreased cell proliferation with increased cytotoxicity and apoptosis. Western blotting results showed that silencing of Cx43 resulted in changed γ-H2AX and PI3K/AKT pathway proteins in irradiated intestinal epithelial cells. Administration of the PI3K/AKT pathway inhibitor LY294002 inhibited the radioprotective effects in Cx43-overexpressing intestinal epithelial cells. Our study demonstrated that Cx43 expression is decreased by ionizing radiation, which facilitates the radioprotection of intestinal epithelial cells.


Asunto(s)
Conexina 43 , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Calcio/metabolismo , Conexinas/metabolismo , Conexinas/farmacología , Transducción de Señal , Uniones Comunicantes , Comunicación Celular
20.
Geobiology ; 22(2): e12596, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38591761

RESUMEN

The formation of intracellular amorphous calcium carbonate (ACC) by various cyanobacteria is a widespread biomineralization process, yet its mechanism and importance in past and modern environments remain to be fully comprehended. This study explores whether calcium (Ca) isotope fractionation, linked to ACC-forming cyanobacteria, can serve as a reliable tracer for detecting these microorganisms in modern and ancient settings. Accordingly, we measured stable Ca isotope fractionation during Ca uptake by the intracellular ACC-forming cyanobacterium Cyanothece sp. PCC 7425. Our results show that Cyanothece sp. PCC 7425 cells are enriched in lighter Ca isotopes relative to the solution. This finding is consistent with the kinetic isotope effects observed in the Ca isotope fractionation during biogenic carbonate formation by marine calcifying organisms. The Ca isotope composition of Cyanothece sp. PCC 7425 was accurately modeled using a Rayleigh fractionation model, resulting in a Ca isotope fractionation factor (Δ44Ca) equal to -0.72 ± 0.05‰. Numerical modeling suggests that Ca uptake by these cyanobacteria is primarily unidirectional, with minimal back reaction observed over the duration of the experiment. Finally, we compared our Δ44Ca values with those of other biotic and abiotic carbonates, revealing similarities with organisms that form biogenic calcite. These similarities raise questions about the effectiveness of using the Ca isotope fractionation factor as a univocal tracer of ACC-forming cyanobacteria in the environment. We propose that the use of Δ44Ca in combination with other proposed tracers of ACC-forming cyanobacteria such as Ba and Sr isotope fractionation factors and/or elevated Ba/Ca and Sr/Ca ratios may provide a more reliable approach.


Asunto(s)
Cianobacterias , Cyanothece , Carbonato de Calcio , Carbonatos , Isótopos de Calcio , Isótopos/análisis , Organismos Acuáticos , Calcio
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