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1.
Nefrología (Madrid) ; 44(2): 233-240, Mar-Abr. 2024. tab
Artigo em Espanhol | IBECS | ID: ibc-231573

RESUMO

Antecedentes y objetivo: La asociación de hipouricemia e hipercalciuria es poco frecuente. En 1974 se describió un nuevo síndrome nominado Hipouricemia con hipercalciuria y reducción de la densidad ósea. Posteriormente, se publicaron algunos casos con esa asociación en los que la excreción fraccional de urato era superior a 20/100ml FGR. Hemos analizado una serie de niños que fueron diagnosticados de hipouricemia e hipercalciuria y que fueron controlados evolutivamente. El objetivo del trabajo es intentar conocer si nuestros pacientes podrían estar afectos del síndrome antes mencionado o ser portadores de una variante de hipercalciuria idiopática. Pacientes y métodos: Estudio retrospectivo longitudinal en el que se estudiaron las historias clínicas de 8 pacientes (5V y 3M) diagnosticados de hipouricemia e hipercalciuria en la infancia. Se anotaron la clínica al diagnóstico, los hallazgos ecográficos y densitométricos, y determinadas variables bioquímicas, con especial hincapié en el manejo tubular renal del urato. Los resultados se compararon con los de 36 niños afectos de hipercalciuria idiopática sin hipouricemia (14V y 22M). Resultados: En el grupo con hipouricemia los niveles iniciales de uricemia fueron 1,9 (0,3) mg/dl (rango: 1,5-2) y los del cociente calcio/creatinina en primera orina del día, 0,27 (0,05) mg/mg (rango: 0,23-0,31). En todos los casos la excreción fraccional de urato fue inferior a 20ml/100ml FGR. Los valores de z-DMO fueron menores de −1 en 4/8 casos. En el último control, solo en 3 casos persistía el cociente calcio/creatinina elevado, y en todos la uricemia era superior a 2mg/dl. El valor de z-DMO había mejorado en 5 casos y empeorado en otros 3... (AU)


Background and objective: The association of hypouricemia and hypercalciuria is rare. In 1974 a new syndrome named Hypouricemia with hypercalciuria and decreased bone density was described. Afterwards, some cases with such association were published in which the fractional excretion of urate was higher than 20/100ml FGR. We have analyzed a series of children who were diagnosed with hypouricemia and hypercalciuria and who were monitored. The aim of this study was to determine whether our patients could be affected by the aforementioned syndrome or be carriers of a variant of idiopathic hypercalciuria. Patients and methods: Retrospective longitudinal study in which the medical records of eight patients (5V and 3M) diagnosed with hypouricemia and hypercalciuria in childhood. Clinical features at diagnosis, ultrasound and densitometric findings and selected biochemical variables were noted, with special emphasis on renal tubular handling of urate. Results were compared with 36 children with idiopathic hypercalciuria without hypouricemia (14V and 22M). Results: In the hypouricemia group baseline urate levels were 1.9 (0.3)mg/dl (range: 1.5-2) and first day urine calcium/creatinine ratio 0.27 (0.05)mg/mg (range: 0.23-0.31). In all cases fractional urate excretion was less than 20/100ml FGR. The z-DMO values were less than −1 in 4/8 cases. At the last follow-up only three cases still had an elevated calcium/creatinine ratio and in all of them the urates levels was greater than 2mg/dl. The z-DMO value had improved in five cases and worsened in three others. In relation to the group without hypouricemia, no differences were observed between the various parameters studied including the z-DMO value, with the exception of fractional excretion and tubular urate reabsorption although plasmatic uric acid levels were still significantly lower... (AU)


Assuntos
Humanos , Hipercalciúria , Densidade Óssea , Registros Médicos/estatística & dados numéricos , Diagnóstico , Pacientes , Cálcio , Creatinina/urina , Estudos Retrospectivos
3.
Methods Mol Biol ; 2761: 529-557, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427260

RESUMO

Parkinson's disease (PD) is a neurodegenerative condition linked to the deterioration of motor and cognitive performance. It produces degeneration of the dopaminergic neurons along the nigrostriatal pathway in the central nervous system (CNS), which leads to symptoms such as bradykinesias, tremors, rigidity, and postural instability. There are several medications currently approved for the therapy of PD, but a permanent cure for it remains elusive. With the aging population set to increase, a number of PD cases are expected to shoot up in the coming times. Hence, there is a need to look for new molecular targets that could be investigated both preclinically and clinically for PD treatment. Among these, several ion channels and metal ions are being studied for their effects on PD pathology and the functioning of dopaminergic neurons. Ion channels such as N-methyl-D-aspartate (NMDA), γ-aminobutyric acid A (GABAA), voltage-gated calcium channels, potassium channels, HCN channels, Hv1 proton channels, and voltage-gated sodium channels and metal ions such as mercury, zinc, copper, iron, manganese, calcium, and lead showed prominent involvement in PD. Pharmacological agents have been used to target these ion channels and metal ions to prevent or treat PD. Hence, in the present review, we summarize the pathophysiological events linked to PD with an emphasis on the role of ions and ion channels in PD pathology, and pharmacological agents targeting these ion channels have also been listed.


Assuntos
Doença de Parkinson , Humanos , Cálcio/metabolismo , Neurônios Dopaminérgicos/metabolismo , Canais Iônicos/metabolismo , Doença de Parkinson/metabolismo
4.
Glob Chang Biol ; 30(3): e17220, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38433333

RESUMO

Zooplankton community composition of northern lakes is changing due to the interactive effects of climate change and recovery from acidification, yet limited data are available to assess these changes combined. Here, we built a database using archives of temperature, water chemistry and zooplankton data from 60 Scandinavian lakes that represent broad spatial and temporal gradients in key parameters: temperature, calcium (Ca), total phosphorus (TP), total organic carbon (TOC), and pH. Using machine learning techniques, we found that Ca was the most important determinant of the relative abundance of all zooplankton groups studied, while pH was second, and TOC third in importance. Further, we found that Ca is declining in almost all lakes, and we detected a critical Ca threshold in lake water of 1.3 mg L-1 , below which the relative abundance of zooplankton shifts toward dominance of Holopedium gibberum and small cladocerans at the expense of Daphnia and copepods. Our findings suggest that low Ca concentrations may shape zooplankton communities, and that current trajectories of Ca decline could promote widespread changes in pelagic food webs as zooplankton are important trophic links from phytoplankton to fish and different zooplankton species play different roles in this context.


Assuntos
Cálcio , Cladóceros , Animais , Lagos , Zooplâncton , Água
5.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 46(1): 1-10, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38433624

RESUMO

Objective To investigate the impact of Pseudomonas aeruginosa(PA) infection on the function of pulmonary vascular endothelial cells,and explore the mechanism of this bacterium in exacerbating lung inflammation in mice. Methods Two hours after human lung microvascular endothelial cell(HULEC-5a) were infected with the PA strain PAO1,the mRNA levels of autophagy-related gene 5(ATG5),6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3),and calcium adhesion protein 5(CDH5) were determined by reverse transcription real-time fluorescent quantitative PCR(RT-qPCR).The protein levels of ATG5,PFKFB3,and vascular endothelial calcium adhesion protein(VE-cadherin) were detected by immunofluorescence.After the expression of ATG5 and PFKFB3 was respectively knocked down by small interfering RNA(siRNA),RT-qPCR was employed to measure the mRNA levels of ATG5,PFKFB3,and CDH5,and immunofluorescence to detect the protein levels of PFKFB3 and VE-cadherin.In addition,the lactate assay kit was used to determine the level of lactate in the cells.After mice were infected with PAO1,lung inflammation was assessed through histopathological section staining.Confocal microscopy was employed to capture and analyze fluorescence-labeled PFKFB3 and VE-cadherin in endothelial cells. Results Compared with the control group,the HULEC-5a cells infected with PAO1 showed up-regulated mRNA and protein levels of PFKFB3(all P<0.05),down-regulated mRNA level of CDH5(P=0.023),disrupted continuity and down-regulated protein level of VE-cadherin(P<0.001),and elevated lactate level(P=0.017).Compared with PAO1-infected HULEC-5a cells,knocking down PFKFB3 led to the up-regulated mRNA level of CDH5(P=0.043),lowered lactate level(P=0.047),and restored continuity of VE-cadherin;knocking down ATG5 led to up-regulated mRNA and protein levels of PFKFB3(P=0.013 and P=0.003),elevated lactate level(P=0.015),and down-regulated mRNA level of CDH5(P=0.020) and protein level of VE-cadherin(P=0.001).The HE staining results showed obvious red blood cell leakage,inflammatory cell infiltration,alveolar septal widening,and partial detachment of vascular endothelial cells in the alveoli of PA-infected mice.Immunofluorescence staining showed up-regulated expression of PFKFB3 and decreased fluorescence signal of VE-cadherin in endothelial cells of infected mice compared with normal mice. Conclusion PA may regulate the PFKFB3 pathway via AGT5 to disrupt the function of pulmonary vascular endothelial cells,thereby exacerbating the inflammation in the lungs of mice.


Assuntos
Pneumonia , Infecções por Pseudomonas , Humanos , Animais , Camundongos , Células Endoteliais , Pseudomonas aeruginosa , Cálcio , Fatores de Transcrição , Pulmão , Lactatos , RNA Mensageiro
6.
Top Spinal Cord Inj Rehabil ; 30(1): 98-112, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38433741

RESUMO

Background: Osteoporotic fractures occur in almost half of patients with a spinal cord injury (SCI) and are associated with significant morbidity and excess mortality. Paralyzed Veterans Administration (PVA) guidelines suggest that adequate calcium and vitamin D intake is important for skeletal health, however, the association of these supplements with osteoporotic fracture risk is unclear. Objectives: To determine the association of filled prescriptions for calcium and vitamin D with fracture risk in Veterans with an SCI. Methods: The 5897 persons with a traumatic SCI of at least 2 years' duration (96% male; 4% female) included in the VSSC SCI/D Registry in FY2014 were followed from FY2014 to FY2020 for incident upper and lower extremity fractures. Filled daily prescriptions for calcium or vitamin D supplements for ≥6 months with an adherence ≥80% were examined. Results: Filled prescriptions for calcium (hazard ratio [HR] 0.65; 95% CI, 0.54-0.78) and vitamin D (HR 0.33; 95% CI, 0.29-0.38) supplements were associated with a significantly decreased risk for incident fractures. Conclusion: Calcium and vitamin D supplements are associated with decreased risk of fracture, supporting PVA guidelines that calcium and vitamin D intake are important for skeletal health in persons with an SCI.


Assuntos
Fraturas Ósseas , Traumatismos da Medula Espinal , Humanos , Feminino , Masculino , Vitamina D , Cálcio , Traumatismos da Medula Espinal/complicações , Suplementos Nutricionais , Fraturas Ósseas/etiologia
7.
Glob Heart ; 19(1): 25, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38434155

RESUMO

Background: It is unclear whether serum calcium on admission is associated with clinical outcomes in dilated cardiomyopathy (DCM). In this study, we conducted a retrospective study spanning a decade to investigate the prognostic value of baseline calcium in elderly patients with DCM. Methods: A total of 1,089 consecutive elderly patients (age ≥60 years) diagnosed with DCM were retrospectively enrolled from January 2010 to December 2019. Univariate and multivariate analyses were performed to investigate the association of serum calcium with their clinical outcomes. Results: In this study, the average age of the subjects was 68.36 ± 6.31 years. Receiver operating characteristic (ROC) curve analysis showed that serum calcium level had a great sensitivity and specificity for predicting in-hospital death, with an AUC of 0.732. Kaplan-Meier survival analysis showed that patients with a serum calcium >8.62 mg/dL had a better prognosis than those with a serum calcium ≤8.62 mg/dL (log-rank χ2 40.84, p < 0.001). After adjusting for several common risk factors, a serum calcium ≤8.62 mg/dL was related to a higher risk of long-term mortality (HR: 1.449; 95% CI: 1.115~1.882; p = 0.005). Conclusions: Serum calcium level could be served as a simple and affordable tool to evaluate patients' prognosis in DCM.


Assuntos
Cálcio , Cardiomiopatia Dilatada , Idoso , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Cardiomiopatia Dilatada/diagnóstico , Mortalidade Hospitalar
8.
Am J Sports Med ; 52(2): 461-473, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38426316

RESUMO

BACKGROUND: Treatment options for calcific tendinitis (CT) of the shoulder remain controversial. A consensus for an operative indication for this condition is lacking. PURPOSE: To compare nonoperative versus operative treatment for shoulder CT and analyze factors affecting the prognosis after treatment. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 180 patients diagnosed with symptomatic CT between January 2017 and September 2021 were evaluated in this retrospective cohort study. There were 103 patients treated nonoperatively at our institution, which included the use of nonsteroidal anti-inflammatory drugs, acupuncture, steroid injections, extracorporeal shock wave therapy, and ultrasound-guided needle aspiration/percutaneous irrigation. However, 77 patients were treated with arthroscopic surgery after 6 months of failed nonoperative treatment. The visual analog scale (VAS) for pain, the Constant-Murley score, and imaging were used to assess and evaluate outcomes. Descriptive data, functional outcomes, and imaging findings were compared between the operative and nonoperative groups before and after propensity score matching. Additionally, prognostic factors including calcium deposit size, tendon infiltration by calcium deposits, involvement of single or multiple tendons, and occurrence of rotator cuff tears were analyzed by comparing the groups to determine their effect on treatment options and recovery. RESULTS: Magnetic resonance imaging showed that the supraspinatus tendon (66.7%) was most commonly involved, followed by the infraspinatus (42.8%) and subscapularis (21.1%) tendons. Tendon infiltration by calcium deposits was observed in 84.4% of the patients, and rotator cuff tears occurred in 30.0% of the patients. After propensity score matching, there was no significant difference in changes in the Constant-Murley score (48.1 ± 25.4 vs 49.0 ± 22.8, respectively; P = .950) and VAS score (4.9 ± 2.3 vs 4.5 ± 1.9, respectively; P = .860) between the operative and nonoperative groups at the final follow-up. However, for patients with shoulder CT and without rotator cuff tears, there was a significant difference in changes in the Constant-Murley score (52.93 ± 25.18 vs 42.13 ± 22.35, respectively; P = .012) and VAS score (5.21 ± 2.06 vs 3.81 ± 1.98, respectively; P < .001) between the operative and nonoperative groups, but the recovery time in the operative group was longer than that in the nonoperative group (86.92 ± 138.56 vs 30.42 ± 54.97 days, respectively; P = .016). The results also showed that calcium deposit size, involvement of multiple tendons, and tendon infiltration by calcium deposits did not affect the recovery time after treatment. The survival analysis showed that rotator cuff tears affected the complete recovery of shoulder function. CONCLUSION: This study demonstrated no significant difference between nonoperative and operative treatment for patients with shoulder CT, on the whole. However, for patients with shoulder CT and without rotator cuff tears, the effect of operative treatment was better than that of nonoperative treatment; yet, operative treatment was shown to prolong the recovery time. Calcium deposit size, tendon infiltration by calcium deposits, and involvement of multiple tendons did not correlate with recovery time or the recovery of function. A rotator cuff tear was the only factor affecting the complete recovery of shoulder function.


Assuntos
Lesões do Manguito Rotador , Tendinopatia , Humanos , Ombro/cirurgia , Lesões do Manguito Rotador/diagnóstico por imagem , Lesões do Manguito Rotador/cirurgia , Estudos de Coortes , Artroscopia/métodos , Estudos Retrospectivos , Cálcio , Resultado do Tratamento , Imageamento por Ressonância Magnética , Tendinopatia/diagnóstico por imagem , Tendinopatia/terapia
9.
Urolithiasis ; 52(1): 40, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38427040

RESUMO

This retrospective study aims to examine the correlation between calcium oxalate (CaOx) stones and common clinical tests, as well as urine ionic composition. Additionally, we aim to develop and implement a personalized model to assess the accuracy and feasibility of using charts to predict calcium oxalate stones in patients with urinary tract stones. A retrospective analysis was conducted on data from 960 patients who underwent surgery for urinary stones at the First Affiliated Hospital of Soochow University from January 1, 2010, to December 31, 2022. Among these patients, 447 were selected for further analysis based on screening criteria. Multivariate logistic regression analysis was then performed to identify the best predictive features for calcium oxalate stones from the clinical data of the selected patients. A prediction model was developed using these features and presented in the form of a nomogram graph. The performance of the prediction model was assessed using the C-index, calibration curve, and decision curve, which evaluated its discriminative power, calibration, and clinical utility, respectively. The nomogram diagram prediction model developed in this study is effective in predicting calcium oxalate stones which is helpful in screening and early identification of high-risk patients with calcium oxalate urinary tract stones, and may be a guide for urologists in making clinical treatment decisions.


Assuntos
Líquidos Corporais , Cálculos Urinários , Humanos , Oxalato de Cálcio/química , Estudos Retrospectivos , Nomogramas , Cálculos Urinários/diagnóstico , Cálcio/urina
10.
NPJ Syst Biol Appl ; 10(1): 22, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429306

RESUMO

In the initial hours following the application of the calcium channel blocker (CCB) nifedipine to microtissues consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we observe notable variations in the drug's efficacy. Here, we investigate the possibility that these temporal changes in CCB effects are associated with adaptations in the expression of calcium ion channels in cardiomyocyte membranes. To explore this, we employ a recently developed mathematical model that delineates the regulation of calcium ion channel expression by intracellular calcium concentrations. According to the model, a decline in intracellular calcium levels below a certain target level triggers an upregulation of calcium ion channels. Such an upregulation, if instigated by a CCB, would then counteract the drug's inhibitory effect on calcium currents. We assess this hypothesis using time-dependent measurements of hiPSC-CMs dynamics and by refining an existing mathematical model of myocyte action potentials incorporating the dynamic nature of the number of calcium ion channels. The revised model forecasts that the CCB-induced reduction in intracellular calcium concentrations leads to a subsequent increase in calcium ion channel expression, thereby attenuating the drug's overall efficacy. The data and fit models suggest that dynamic changes in cardiac cells in the presence of CCBs may be explainable by induced changes in protein expression, and that this may lead to challenges in understanding calcium based drug effects on the heart unless timings of applications are carefully considered.


Assuntos
Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Humanos , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio , Canais de Cálcio
11.
PLoS One ; 19(3): e0299055, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38466667

RESUMO

The effect of sound waves (SWs) on plant cells can be considered as important as other mechanical stimuli like touch, wind, rain, and gravity, causing certain responses associated with the downstream signaling pathways on the whole plant. The objective of the present study was to elucidate the response of suspension-cultured tobacco cells (Nicotiana tabacum L. cv Burley 21) to SW at different intensities. The sinusoidal SW (1,000 Hz) was produced through a signal generator, amplified, and beamed to the one layer floating tobacco cells inside a soundproof chamber at intensities of 60, 75, and 90 dB at the plate level for 15, 30, 45, and 60 min. Calibration of the applied SW intensities, accuracy, and uniformity of SW was performed by a sound level meter, and the cells were treated. The effect of SW on tobacco cells was monitored by quantitation of cytosolic calcium, redox status, membrane integrity, wall components, and the activity of wall modifying enzymes. Cytosolic calcium ions increased as a function of sound intensity with a maximum level of 90 dB. Exposure to 90 dB was also accompanied by a significant increase of H2O2 and membrane lipid peroxidation rate but the reduction of total antioxidant and radical scavenging capacities. The increase of wall rigidity in these cells was attributed to an increase in wall-bound phenolic acids and lignin and the activities of phenylalanine ammonia-lyase and covalently bound peroxidase. In comparison, in 60- and 75 dB, radical scavenging capacity increased, and the activity of wall stiffening enzymes reduced, but cell viability showed no changes. The outcome of the current study reveals that the impact of SW on plant cells is started by an increase in cytosolic calcium. However, upon calcium signaling, downstream events, including alteration of H2O2 and cell redox status and the activities of wall modifying enzymes, determined the extent of SW effects on tobacco cells.


Assuntos
Cálcio , Cálcio/metabolismo , Peróxido de Hidrogênio/metabolismo , Parede Celular/metabolismo , Cálcio da Dieta/metabolismo , Som
12.
Biochemistry (Mosc) ; 89(1): 116-129, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38467549

RESUMO

Cardiac myosin binding protein C (cMyBP-C) is one of the essential control components of the myosin cross-bridge cycle. The C-terminal part of cMyBP-C is located on the surface of the thick filament, and its N-terminal part interacts with actin, myosin, and tropomyosin, affecting both kinetics of the ATP hydrolysis cycle and lifetime of the cross-bridge, as well as calcium regulation of the actin-myosin interaction, thereby modulating contractile function of myocardium. The role of cMyBP-C in atrial contraction has not been practically studied. We examined effect of the N-terminal C0-C1-m-C2 (C0-C2) fragment of cMyBP-C on actin-myosin interaction using ventricular and atrial myosin in an in vitro motility assay. The C0-C2 fragment of cMyBP-C significantly reduced the maximum sliding velocity of thin filaments on both myosin isoforms and increased the calcium sensitivity of the actin-myosin interaction. The C0-C2 fragment had different effects on the kinetics of ATP and ADP exchange, increasing the affinity of ventricular myosin for ADP and decreasing the affinity of atrial myosin. The effect of the C0-C2 fragment on the activation of the thin filament depended on the myosin isoforms. Atrial myosin activates the thin filament less than ventricular myosin, and the C0-C2 fragment makes these differences in the myosin isoforms more pronounced.


Assuntos
Actinas , Proteína C , Actinas/metabolismo , Proteína C/metabolismo , Proteínas de Transporte/metabolismo , Cálcio/metabolismo , Miosinas Atriais , Miosinas Ventriculares/metabolismo , Miosinas/metabolismo , Miocárdio/metabolismo , Trifosfato de Adenosina/metabolismo , Isoformas de Proteínas/metabolismo , Ligação Proteica
13.
Clin Nutr ESPEN ; 60: 348-355, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38479934

RESUMO

BACKGROUND & AIMS: Patients receiving oncological esophagectomy or gastrectomy are known to be at high risk for vitamin and micronutrient deficiency before, during and after surgery. However, there are no clear guidelines for these cancer patients regarding postoperative vitamin supplementation. METHODS: We conducted a metanalysis consisting of 10 studies regarding vitamin and micronutrient deficiencies after oncological gastric or esophageal resection. 5 databases were searched. RESULTS: Data was sufficient regarding Vitamins B12 and 25-OH D3 as well as calcium. We were able to show deficiencies in 25-OH Vitamin D3 levels (p < 0.001) and lower levels of Vitamin B12 and calcium (bit p < 0.001) when compared to the healthy population. CONCLUSIONS: Patients from these groups are at risk for vitamin deficiencies. A guideline on postoperative supplementation is needed.


Assuntos
Deficiência de Vitaminas , Neoplasias Esofágicas , Desnutrição , Obesidade Mórbida , Neoplasias Gástricas , Humanos , Neoplasias Esofágicas/cirurgia , Neoplasias Gástricas/cirurgia , Cálcio , Obesidade Mórbida/cirurgia , Vitaminas , Desnutrição/complicações , Vitamina B 12
14.
Int J Mol Sci ; 25(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38473847

RESUMO

The normal ageing process affects resistance arteries, leading to various functional and structural changes. Systolic hypertension is a common occurrence in human ageing, and it is associated with large artery stiffening, heightened pulsatility, small artery remodeling, and damage to critical microvascular structures. Starting from young adulthood, a progressive elevation in the mean arterial pressure is evidenced by clinical and epidemiological data as well as findings from animal models. The myogenic response, a protective mechanism for the microcirculation, may face disruptions during ageing. The dysregulation of calcium entry channels (L-type, T-type, and TRP channels), dysfunction in intracellular calcium storage and extrusion mechanisms, altered expression of potassium channels, and a change in smooth muscle calcium sensitization may contribute to the age-related dysregulation of myogenic tone. Flow-mediated vasodilation, a hallmark of endothelial function, is compromised in ageing. This endothelial dysfunction is related to increased oxidative stress, lower nitric oxide bioavailability, and a low-grade inflammatory response, further exacerbating vascular dysfunction. Resistance artery remodeling in ageing emerges as a hypertrophic response of the vessel wall that is typically observed in conjunction with outward remodeling (in normotension), or as inward hypertrophic remodeling (in hypertension). The remodeling process involves oxidative stress, inflammation, reorganization of actin cytoskeletal components, and extracellular matrix fiber proteins. Reactive oxygen species (ROS) signaling and chronic low-grade inflammation play substantial roles in age-related vascular dysfunction. Due to its role in the regulation of vascular tone and structural proteins, the RhoA/Rho-kinase pathway is an important target in age-related vascular dysfunction and diseases. Understanding the intricate interplay of these factors is crucial for developing targeted interventions to mitigate the consequences of ageing on resistance arteries and enhance the overall vascular health.


Assuntos
Hipertensão , Vasoconstrição , Animais , Humanos , Adulto Jovem , Adulto , Cálcio/metabolismo , Proteômica , Artérias/metabolismo , Envelhecimento , Inflamação
15.
Int J Mol Sci ; 25(5)2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38474037

RESUMO

Protein kinase D (PKD) enzymes play important roles in regulating myocardial contraction, hypertrophy, and remodeling. One of the proteins phosphorylated by PKD is titin, which is involved in myofilament function. In this study, we aimed to investigate the role of PKD in cardiomyocyte function under conditions of oxidative stress. To do this, we used mice with a cardiomyocyte-specific knock-out of Prkd1, which encodes PKD1 (Prkd1loxP/loxP; αMHC-Cre; PKD1 cKO), as well as wild type littermate controls (Prkd1loxP/loxP; WT). We isolated permeabilized cardiomyocytes from PKD1 cKO mice and found that they exhibited increased passive stiffness (Fpassive), which was associated with increased oxidation of titin, but showed no change in titin ubiquitination. Additionally, the PKD1 cKO mice showed increased myofilament calcium (Ca2+) sensitivity (pCa50) and reduced maximum Ca2+-activated tension. These changes were accompanied by increased oxidation and reduced phosphorylation of the small myofilament protein cardiac myosin binding protein C (cMyBPC), as well as altered phosphorylation levels at different phosphosites in troponin I (TnI). The increased Fpassive and pCa50, and the reduced maximum Ca2+-activated tension were reversed when we treated the isolated permeabilized cardiomyocytes with reduced glutathione (GSH). This indicated that myofilament protein oxidation contributes to cardiomyocyte dysfunction. Furthermore, the PKD1 cKO mice exhibited increased oxidative stress and increased expression of pro-inflammatory markers interleukin (IL)-6, IL-18, and tumor necrosis factor alpha (TNF-α). Both oxidative stress and inflammation contributed to an increase in microtubule-associated protein 1 light chain 3 (LC3)-II levels and heat shock response by inhibiting the mammalian target of rapamycin (mTOR) in the PKD1 cKO mouse myocytes. These findings revealed a previously unknown role for PKD1 in regulating diastolic passive properties, myofilament Ca2+ sensitivity, and maximum Ca2+-activated tension under conditions of oxidative stress. Finally, we emphasized the importance of PKD1 in maintaining the balance of oxidative stress and inflammation in the context of autophagy, as well as cardiomyocyte function.


Assuntos
Miofibrilas , Proteína Quinase C , Processamento de Proteína Pós-Traducional , Camundongos , Animais , Conectina/metabolismo , Miofibrilas/metabolismo , Miócitos Cardíacos/metabolismo , Fosforilação , Proteínas dos Microfilamentos/metabolismo , Homeostase , Inflamação/metabolismo , Cálcio/metabolismo , Mamíferos/metabolismo
16.
Int J Mol Sci ; 25(5)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38474244

RESUMO

Adrenaline has recently been found to trigger phosphatidylserine (PS) exposure on blood platelets, resulting in amplification of the coagulation process, but the mechanism is only fragmentarily established. Using a panel of platelet receptors' antagonists and modulators of signaling pathways, we evaluated the importance of these in adrenaline-evoked PS exposure by flow cytometry. Calcium and sodium ion influx into platelet cytosol, after adrenaline treatment, was examined by fluorimetric measurements. We found a strong reduction in PS exposure after blocking of sodium and calcium ion influx via Na+/H+ exchanger (NHE) and Na+/Ca2+ exchanger (NCX), respectively. ADP receptor antagonists produced a moderate inhibitory effect. Substantial limitation of PS exposure was observed in the presence of GPIIb/IIIa antagonist, phosphoinositide-3 kinase (PI3-K) inhibitors, or prostaglandin E1, a cyclic adenosine monophosphate (cAMP)-elevating agent. We demonstrated that adrenaline may develop a procoagulant response in human platelets with the substantial role of ion exchangers (NHE and NCX), secreted ADP, GPIIb/IIIa-dependent outside-in signaling, and PI3-K. Inhibition of the above mechanisms and increasing cytosolic cAMP seem to be the most efficient procedures to control adrenaline-evoked PS exposure in human platelets.


Assuntos
Plaquetas , Ativação Plaquetária , Humanos , Plaquetas/metabolismo , Cálcio/metabolismo , Epinefrina/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Sódio/metabolismo , Trombina/metabolismo
17.
Int J Mol Sci ; 25(5)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38474263

RESUMO

Dexmedetomidine is widely used to induce sedation in the perioperative period. This study examined the effect of hypothermia (33 and 25 °C) on dexmedetomidine-induced contraction in an endothelium-intact aorta with or without the nitric oxide synthase inhibitor NW-nitro-L-arginine methyl ester (L-NAME). In addition, the effect of hypothermia on the contraction induced by dexmedetomidine in an endothelium-denuded aorta with or without a calcium-free Krebs solution was examined. The effects of hypothermia on the protein kinase C (PKC), myosin light chain (MLC20) phosphorylation, and Rho-kinase membrane translocation induced by dexmedetomidine were examined. Hypothermia inhibited dexmedetomidine-induced contraction in the endothelium-intact aorta with L-NAME or endothelium-denuded aorta. Hypothermia had almost no effect on the dexmedetomidine-induced contraction in the endothelium-denuded aorta with the calcium-free Krebs solution; however, the subsequent contraction induced by the addition of calcium was inhibited by hypothermia. Conversely, the transition from profound hypothermia back to normothermia reversed the hypothermia-induced inhibition of subsequent calcium-induced contractions. Hypothermia inhibited any contraction induced by KCl, PDBu, and NaF, as well as PKC and MLC20 phosphorylation and Rho-kinase membrane translocation induced by dexmedetomidine. These results suggest that hypothermia inhibits dexmedetomidine-induced contraction, which is mediated mainly by the impediment of calcium influx and partially by the attenuation of pathways involving PKC and Rho-kinase activation.


Assuntos
Dexmedetomidina , Hipotermia , Ratos , Animais , Dexmedetomidina/farmacologia , Quinases Associadas a rho/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Cálcio/metabolismo , Hipotermia/metabolismo , Proteína Quinase C/metabolismo , Endotélio Vascular/metabolismo , Contração Muscular
18.
Molecules ; 29(5)2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38474548

RESUMO

Transient receptor potential vanilloid 4 (TRPV4) is a widely expressed cation channel that plays an important role in many physiological and pathological processes. However, most TRPV4 drugs carry a risk of side effects. Moreover, existing screening methods are not suitable for the high-throughput screening (HTS) of drugs. In this study, a cell model and HTS method for targeting TRPV4 channel drugs were established based on a calcium-activated chloride channel protein 1 Anoctamin 1 (ANO1) and a double mutant (YFP-H148Q/I152L) of the yellow fluorescent protein (YFP). Patch-clamp experiments and fluorescence quenching kinetic experiments were used to verify that the model could sensitively detect changes in intracellular Ca2+ concentration. The functionality of the TRPV4 cell model was examined through temperature variations and different concentrations of TRPV4 modulators, and the performance of the model in HTS was also evaluated. The model was able to sensitively detect changes in the intracellular Ca2+ concentration and also excelled at screening TRPV4 drugs, and the model was more suitable for HTS. We successfully constructed a drug cell screening model targeting the TRPV4 channel, which provides a tool to study the pathophysiological functions of TRPV4 in vitro.


Assuntos
Ensaios de Triagem em Larga Escala , Canais de Cátion TRPV , Canais de Cátion TRPV/metabolismo , Anoctamina-1 , Cálcio/metabolismo
19.
Nutrients ; 16(5)2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38474779

RESUMO

Menopause marks a critical life stage characterized by hormonal changes that significantly impact bone health, leading to a heightened susceptibility to bone fractures. This research seeks to elucidate the impact of daidzein and tempeh on calcium status, calcium transporters, and bone metabolism in an ovariectomized rat model. Forty female Wistar rats, aged 3 months, participated in a two-phase experiment. The initial phase involved inducing a calcium deficit, while the second phase comprised dietary interventions across five groups: Sham (S) and Ovariectomy (O) with a standard diet, O with bisphosphonate (OB), O with pure daidzein (OD), and O with tempeh (OT). Multiple parameters, encompassing calcium levels, calcium transporters, bone histopathology, and serum bone metabolism markers, were evaluated. The findings revealed that the OT group showcased heightened levels of bone turnover markers, such as pyridinoline, C-telopeptide of type I collagen, bone alkaline phosphatase, and procollagen type I N-terminal propeptide, in contrast to S and O groups, with statistical significance (p < 0.05). Histopathologically, both the OD and OT groups exhibited effects akin to the OB group, indicating a decrease in the surface area occupied by adipocytes in the femoral bone structure, although statistically non-equivalent, supporting the directionally similar trends. Although TRPV5 and TRPV6 mRNA expression levels in the jejunum and duodenum did not display statistically significant differences (p > 0.05), the OD and OT groups exhibited increased expression compared to the O group. We hypothesized that obtained results may be related to the effect of isoflavones on estrogen pathways because of their structurally similar to endogenous estrogen and weak estrogenic properties. In conclusion, the daily consumption of pure daidzein and tempeh could potentially improve and reinstate calcium status, calcium transport, and bone metabolism in ovariectomized rats. Additionally, isoflavone products demonstrate effects similar to bisphosphonate drugs on these parameters in ovariectomized rats.


Assuntos
Isoflavonas , Osteoporose , Alimentos de Soja , Ratos , Feminino , Animais , Humanos , Cálcio , Osteoporose/etiologia , Ratos Wistar , Cálcio da Dieta/farmacologia , Isoflavonas/farmacologia , Estrogênios/farmacologia , Biomarcadores , Difosfonatos , Ovariectomia/efeitos adversos , Densidade Óssea
20.
Nutrients ; 16(5)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38474792

RESUMO

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.


Assuntos
Cálcio , Colostro , Gravidez , Feminino , Animais , Camundongos , Bovinos , Cálcio/metabolismo , Colostro/metabolismo , Cálcio da Dieta/metabolismo , Osso e Ossos/metabolismo , Desenvolvimento Ósseo , Densidade Óssea , Proteínas na Dieta/farmacologia
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