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Article: Editorial: Pathophysiology of bone and mineral metabolism.

Ambrogini, Elena / Sato, Amy Y / Naves-Diaz, Manuel / Díaz-Tocados, Juan M

2024 Volume 15, Page(s) 1383660

Language	English
Publishing date	2024-02-23
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2024.1383660
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Novel Biomarkers of Bone Metabolism.

Fernández-Villabrille, Sara / Martín-Carro, Beatriz / Martín-Vírgala, Julia / Rodríguez-Santamaria, Mª Del Mar / Baena-Huerta, Francisco / Muñoz-Castañeda, Juan Rafael / Fernández-Martín, José Luis / Alonso-Montes, Cristina / Naves-Díaz, Manuel / Carrillo-López, Natalia / Panizo, Sara

Nutrients

2024 Volume 16, Issue 5

Abstract: Bone represents a metabolically active tissue subject to continuous remodeling orchestrated by the dynamic interplay between osteoblasts and osteoclasts. These cellular processes are modulated by a complex interplay of biochemical and mechanical factors, ...

Abstract	Bone represents a metabolically active tissue subject to continuous remodeling orchestrated by the dynamic interplay between osteoblasts and osteoclasts. These cellular processes are modulated by a complex interplay of biochemical and mechanical factors, which are instrumental in assessing bone remodeling. This comprehensive evaluation aids in detecting disorders arising from imbalances between bone formation and reabsorption. Osteoporosis, characterized by a reduction in bone mass and strength leading to heightened bone fragility and susceptibility to fractures, is one of the more prevalent chronic diseases. Some epidemiological studies, especially in patients with chronic kidney disease (CKD), have identified an association between osteoporosis and vascular calcification. Notably, low bone mineral density has been linked to an increased incidence of aortic calcification, with shared molecules, mechanisms, and pathways between the two processes. Certain molecules emerging from these shared pathways can serve as biomarkers for bone and mineral metabolism. Detecting and evaluating these alterations early is crucial, requiring the identification of biomarkers that are reliable for early intervention. While traditional biomarkers for bone remodeling and vascular calcification exist, they suffer from limitations such as low specificity, low sensitivity, and conflicting results across studies. In response, efforts are underway to explore new, more specific biomarkers that can detect alterations at earlier stages. The aim of this review is to comprehensively examine some of the emerging biomarkers in mineral metabolism and their correlation with bone mineral density, fracture risk, and vascular calcification as well as their potential use in clinical practice.
MeSH term(s)	Humans ; Chronic Kidney Disease-Mineral and Bone Disorder/complications ; Osteoporosis/etiology ; Bone Density/physiology ; Renal Insufficiency, Chronic/complications ; Fractures, Bone/etiology ; Vascular Calcification/complications ; Biomarkers ; Minerals
Chemical Substances	Biomarkers ; Minerals
Language	English
Publishing date	2024-02-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu16050605
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Article ; Online: Soluble Klotho, a Potential Biomarker of Chronic Kidney Disease-Mineral Bone Disorders Involved in Healthy Ageing: Lights and Shadows.

Martín-Vírgala, Julia / Martín-Carro, Beatriz / Fernández-Villabrille, Sara / Ruiz-Torres, María Piedad / Gómez-Alonso, Carlos / Rodríguez-García, Minerva / Fernández-Martín, José Luis / Alonso-Montes, Cristina / Panizo, Sara / Cannata-Andía, Jorge B / Naves-Díaz, Manuel / Carrillo-López, Natalia

International journal of molecular sciences

2024 Volume 25, Issue 3

Abstract: Shortly after the discovery of Klotho, interest grew in its potential role in chronic kidney disease (CKD). There are three isoforms of the Klotho protein: αKlotho, βKlotho and γKlotho. This review will focus on αKlotho due to its relevance as a ... ...

Abstract	Shortly after the discovery of Klotho, interest grew in its potential role in chronic kidney disease (CKD). There are three isoforms of the Klotho protein: αKlotho, βKlotho and γKlotho. This review will focus on αKlotho due to its relevance as a biomarker in CKD. αKlotho is synthesized mainly in the kidneys, but it can be released into the bloodstream and urine as soluble Klotho (sKlotho), which undertakes systemic actions, independently or in combination with FGF23. It is usually accepted that sKlotho levels are reduced early in CKD and that lower levels of sKlotho might be associated with the main chronic kidney disease-mineral bone disorders (CKD-MBDs): cardiovascular and bone disease. However, as results are inconsistent, the applicability of sKlotho as a CKD-MBD biomarker is still a matter of controversy. Much of the inconsistency can be explained due to low sample numbers, the low quality of clinical studies, the lack of standardized assays to assess sKlotho and a lack of consensus on sample processing, especially in urine. In recent decades, because of our longer life expectancies, the prevalence of accelerated-ageing diseases, such as CKD, has increased. Exercise, social interaction and caloric restriction are considered key factors for healthy ageing. While exercise and social interaction seem to be related to higher serum sKlotho levels, it is not clear whether serum sKlotho might be influenced by caloric restriction. This review focuses on the possible role of sKlotho as a biomarker in CKD-MBD, highlighting the difference between solid knowledge and areas requiring further research, including the role of sKlotho in healthy ageing.
MeSH term(s)	Humans ; Biomarkers ; Chronic Kidney Disease-Mineral and Bone Disorder/diagnosis ; Fibroblast Growth Factors ; Glucuronidase ; Healthy Aging/metabolism ; Minerals ; Renal Insufficiency, Chronic/complications ; Klotho Proteins/blood ; Klotho Proteins/metabolism
Chemical Substances	Biomarkers ; Fibroblast Growth Factors (62031-54-3) ; Glucuronidase (EC 3.2.1.31) ; Minerals ; Klotho Proteins (EC 3.2.1.31)
Language	English
Publishing date	2024-02-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25031843
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Article ; Online: Dietary phosphate restriction prevents the appearance of sarcopenia signs in old mice.

Alcalde-Estévez, Elena / Sosa, Patricia / Asenjo-Bueno, Ana / Plaza, Patricia / Valenzuela, Pedro L / Naves-Díaz, Manuel / Olmos, Gemma / López-Ongil, Susana / Ruiz-Torres, María P

Journal of cachexia, sarcopenia and muscle

2023 Volume 14, Issue 2, Page(s) 1060–1074

Abstract: Background: Sarcopenia is defined by the progressive and generalized loss of muscle mass and function associated with aging. We have previously proposed that aging-related hyperphosphataemia is linked with the appearance of sarcopenia signs. Because ... ...

Abstract	Background: Sarcopenia is defined by the progressive and generalized loss of muscle mass and function associated with aging. We have previously proposed that aging-related hyperphosphataemia is linked with the appearance of sarcopenia signs. Because there are not effective treatments to prevent sarcopenia, except for resistance exercise, we propose here to analyse whether the dietary restriction of phosphate could be a useful strategy to improve muscle function and structure in an animal model of aging. Methods: Five-month-old (young), 24-month-old (old) and 28-month-old (geriatric) male C57BL6 mice were used. Old and geriatric mice were divided into two groups, one fed with a standard diet (0.6% phosphate) and the other fed with a low-phosphate (low-P) diet (0.2% phosphate) for 3 or 7 months, respectively. A phosphate binder, Velphoro®, was also supplemented in a group of old mice, mixed with a standard milled diet for 3 months. Muscle mass was measured by the weight of gastrocnemius and tibial muscles, and quality by nuclear magnetic resonance imaging (NMRI) and histological staining assays. Muscle strength was measured by grip test and contractile properties of the tibialis muscle by electrical stimulation of the common peroneal nerve. Gait parameters were analysed during the spontaneous locomotion of the mice with footprinting. Orientation and motor coordination were evaluated using a static rod test. Results: Old mice fed with low-P diet showed reduced serum phosphate concentration (16.46 ± 0.77 mg/dL young; 21.24 ± 0.95 mg/dL old; 17.46 ± 0.82 mg/dL low-P diet). Old mice fed with low-P diet displayed 44% more mass in gastrocnemius muscles with respect to old mice (P = 0.004). NMRI revealed a significant reduction in T2 relaxation time (P = 0.014) and increased magnetization transfer (P = 0.045) and mean diffusivity (P = 0.045) in low-P diet-treated mice compared with their coetaneous. The hypophosphataemic diet increased the fibre size and reduced the fibrotic area by 52% in gastrocnemius muscle with respect to old mice (P = 0.002). Twitch force and tetanic force were significantly increased in old mice fed with the hypophosphataemic diet (P = 0.004 and P = 0.014, respectively). Physical performance was also improved, increasing gait speed by 30% (P = 0.032) and reducing transition time in the static rod by 55% (P = 0.012). Similar results were found when diet was supplemented with Velphoro®. Conclusions: The dietary restriction of phosphate in old mice improves muscle quantity and quality, muscle strength and physical performance. Similar results were found using the phosphate binder Velphoro®, supporting the role of phosphate in the impairment of muscle structure and function that occurs during aging.
MeSH term(s)	Male ; Animals ; Mice ; Sarcopenia/etiology ; Phosphates ; Mice, Inbred C57BL ; Muscle, Skeletal/pathology ; Aging/physiology
Chemical Substances	Phosphates
Language	English
Publishing date	2023-02-28
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2586864-0
ISSN	2190-6009 ; 2190-5991
ISSN (online)	2190-6009
ISSN	2190-5991
DOI	10.1002/jcsm.13194
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Article: Vitamin D Treatment Prevents Uremia-Induced Reductions in Aortic microRNA-145 Attenuating Osteogenic Differentiation despite Hyperphosphatemia

Carrillo-López, Natalia / Panizo, Sara / Arcidiacono, Maria Vittoria / de la Fuente, Sandra / Martínez-Arias, Laura / Ottaviano, Emerenziana / Ulloa, Catalina / Ruiz-Torres, María Piedad / Rodríguez, Isabel / Cannata-Andía, Jorge B. / Naves-Díaz, Manuel / Dusso, Adriana S.

Nutrients. 2022 June 22, v. 14, no. 13

2022

Abstract: In chronic kidney disease, systemic inflammation and high serum phosphate (P) promote the de-differentiation of vascular smooth muscle cells (VSMC) to osteoblast-like cells, increasing the propensity for medial calcification and cardiovascular mortality. ...

Abstract	In chronic kidney disease, systemic inflammation and high serum phosphate (P) promote the de-differentiation of vascular smooth muscle cells (VSMC) to osteoblast-like cells, increasing the propensity for medial calcification and cardiovascular mortality. Vascular microRNA-145 (miR-145) content is essential to maintain VSMC contractile phenotype. Because vitamin D induces aortic miR-145, uremia and high serum P reduce it and miR-145 directly targets osteogenic osterix in osteoblasts, this study evaluated a potential causal link between vascular miR-145 reductions and osterix-driven osteogenic differentiation and its counter-regulation by vitamin D. Studies in aortic rings from normal rats and in the rat aortic VSMC line A7r5 exposed to calcifying conditions corroborated that miR-145 reductions were associated with decreases in contractile markers and increases in osteogenic differentiation and calcium (Ca) deposition. Furthermore, miR-145 silencing enhanced Ca deposition in A7r5 cells exposed to calcifying conditions, while miR-145 overexpression attenuated it, partly through increasing α-actin levels and reducing osterix-driven osteogenic differentiation. In mice, 14 weeks after the induction of renal mass reduction, both aortic miR-145 and α-actin mRNA decreased by 80% without significant elevations in osterix or Ca deposition. Vitamin D treatment from week 8 to 14 fully prevented the reductions in aortic miR-145 and attenuated by 50% the decreases in α-actin, despite uremia-induced hyperphosphatemia. In conclusion, vitamin D was able to prevent the reductions in aortic miR-145 and α-actin content induced by uremia, reducing the alterations in vascular contractility and osteogenic differentiation despite hyperphosphatemia.
Keywords	blood serum ; bone formation ; calcification ; calcium ; inflammation ; mortality ; osteoblasts ; phenotype ; phosphates ; rats ; smooth muscle ; uremia ; vitamin D
Language	English
Dates of publication	2022-0622
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu14132589
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Effects of a Losartan-Antioxidant Hybrid (GGN1231) on Vascular and Cardiac Health in an Experimental Model of Chronic Renal Failure.

Martínez-Arias, Laura / Fernández-Villabrille, Sara / Alonso-Montes, Cristina / García-Navazo, Gonzalo / Ruíz-Torres, María P / Alajarín, Ramón / Alvarez-Builla, Julio / Gutiérrez-Calabres, Elena / Vaquero-López, Juan José / Carrillo-López, Natalia / Rodríguez-Puyol, Diego / Cannata-Andía, Jorge B / Panizo, Sara / Naves-Díaz, Manuel

Nutrients

2023 Volume 15, Issue 8

Abstract: Drugs providing antihypertensive and protective cardiovascular actions are of clinical interest in controlling cardiovascular events and slowing the progression of kidney disease. We studied the effect of a hybrid compound, GGN1231 (derived from losartan ...

Abstract	Drugs providing antihypertensive and protective cardiovascular actions are of clinical interest in controlling cardiovascular events and slowing the progression of kidney disease. We studied the effect of a hybrid compound, GGN1231 (derived from losartan in which a powerful antioxidant was attached), on the prevention of cardiovascular damage, cardiac hypertrophy, and fibrosis in a rat model of severe chronic renal failure (CRF). CRF by a 7/8 nephrectomy was carried out in male Wistar rats fed with a diet rich in phosphorous (0.9%) and normal calcium (0.6%) for a period of 12 weeks until sacrifice. In week 8, rats were randomized in five groups receiving different drugs including dihydrocaffeic acid as antioxidant (Aox), losartan (Los), dihydrocaffeic acid+losartan (Aox+Los) and GGN1231 as follows: Group 1 (CRF+vehicle group), Group 2 (CRF+Aox group), Group 3 (CRF+Los group), Group 4 (CRF+Aox+Los group), and Group 5 (CRF+GGN1231 group). Group 5, the CRF+GGN1231 group, displayed reduced proteinuria, aortic TNF-α, blood pressure, LV wall thickness, diameter of the cardiomyocytes, ATR1, cardiac TNF-α and fibrosis, cardiac collagen I, and TGF-β1 expression. A non-significant 20% reduction in the mortality was also observed. This study showed the possible advantages of GGN1231, which could help in the management of cardiovascular and inflammatory processes. Further research is needed to confirm and even expand the positive aspects of this compound.
MeSH term(s)	Rats ; Male ; Animals ; Losartan/pharmacology ; Losartan/therapeutic use ; Antioxidants/pharmacology ; Antioxidants/therapeutic use ; Tumor Necrosis Factor-alpha/pharmacology ; Rats, Wistar ; Kidney Failure, Chronic ; Models, Theoretical ; Fibrosis ; Kidney/metabolism
Chemical Substances	Losartan (JMS50MPO89) ; 3,4-dihydroxyphenylpropionic acid (1078-61-1) ; Antioxidants ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2023-04-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu15081820
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Article ; Online: Experimental Models to Study Diabetes Mellitus and Its Complications: Limitations and New Opportunities.

Martín-Carro, Beatriz / Donate-Correa, Javier / Fernández-Villabrille, Sara / Martín-Vírgala, Julia / Panizo, Sara / Carrillo-López, Natalia / Martínez-Arias, Laura / Navarro-González, Juan F / Naves-Díaz, Manuel / Fernández-Martín, José L / Alonso-Montes, Cristina / Cannata-Andía, Jorge B

International journal of molecular sciences

2023 Volume 24, Issue 12

Abstract: Preclinical biomedical models are a fundamental tool to improve the knowledge and management of diseases, particularly in diabetes mellitus (DM) since, currently, the pathophysiological and molecular mechanisms involved in its development are not fully ... ...

Abstract	Preclinical biomedical models are a fundamental tool to improve the knowledge and management of diseases, particularly in diabetes mellitus (DM) since, currently, the pathophysiological and molecular mechanisms involved in its development are not fully clarified, and there is no treatment to cure DM. This review will focus on the features, advantages and limitations of some of the most used DM models in rats, such as the spontaneous models: Bio-Breeding Diabetes-Prone (BB-DP) and LEW.1AR1-
MeSH term(s)	Humans ; Rats ; Animals ; Disease Models, Animal ; Streptozocin ; Rats, Zucker ; Diabetes Mellitus, Type 1/complications ; Diabetes Mellitus, Type 2/complications
Chemical Substances	Streptozocin (5W494URQ81)
Language	English
Publishing date	2023-06-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241210309
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Article ; Online: MicroRNA-145 and microRNA-486 are potential serum biomarkers for vascular calcification.

Fernández-Villabrille, Sara / Martín-Carro, Beatriz / Martín-Vírgala, Julia / Alonso-Montes, Cristina / Palomo-Antequera, Carmen / García-Castro, Raúl / López-Ongil, Susana / Dusso, Adriana S / Fernández-Martín, José Luis / Naves-Díaz, Manuel / Cannata-Andía, Jorge B / Carrillo-López, Natalia / Panizo, Sara

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

2023 Volume 38, Issue 7, Page(s) 1729–1740

Abstract: Introduction: MicroRNAs (miRs) regulate vascular calcification (VC), and their quantification may contribute to suspicion of the presence of VC.: Methods: The study was performed in four phases. Phase 1: miRs sequencing of rat calcified and non- ... ...

Abstract	Introduction: MicroRNAs (miRs) regulate vascular calcification (VC), and their quantification may contribute to suspicion of the presence of VC. Methods: The study was performed in four phases. Phase 1: miRs sequencing of rat calcified and non-calcified aortas. Phase 2: miRs with the highest rate of change, plus miR-145 [the most abundant miR in vascular smooth muscle cells (VSMCs)], were validated in aortas and serum from rats with and without VC. Phase 3: the selected miRs were analyzed in epigastric arteries from kidney donors and recipients, and serum samples from general population. Phase 4: VSMCs were exposed to different phosphorus concentrations, and miR-145 and miR-486 were overexpressed to investigate their role in VC. Results: miR-145, miR-122-5p, miR-486 and miR-598-3p decreased in the rat calcified aortas, but only miR-145 and miR-486 were detected in serum. In human epigastric arteries, miR-145 and miR-486 were lower in kidney transplant recipients compared with donors. Both miRs inversely correlated with arterial calcium content and with VC (Kauppila index). In the general population, the severe VC was associated with the lowest serum levels of both miRs. The receiver operating characteristic curve showed that serum miR-145 was a good biomarker of VC. In VSMCs exposed to high phosphorus, calcium content, osteogenic markers (Runx2 and Osterix) increased, and the contractile marker (α-actin), miR-145 and miR-486 decreased. Overexpression of miR-145, and to a lesser extent miR-486, prevented the increase in calcium content induced by high phosphorus, the osteogenic differentiation and the loss of the contractile phenotype. Conclusion: miR-145 and miR-486 regulate the osteogenic differentiation of VSMCs, and their quantification in serum could serve as a marker of VC.
MeSH term(s)	Animals ; Humans ; Rats ; Biomarkers ; Calcium ; MicroRNAs/genetics ; Muscle, Smooth, Vascular ; Myocytes, Smooth Muscle ; Osteogenesis/genetics ; Phosphorus ; Vascular Calcification/genetics
Chemical Substances	Biomarkers ; Calcium (SY7Q814VUP) ; MicroRNAs ; MIRN-598 microRNA, human ; MIRN145 microRNA, human ; MIRN145 microRNA, rat ; MIRN486 microRNA, human ; Phosphorus (27YLU75U4W)
Language	English
Publishing date	2023-01-30
Publishing country	England
Document type	Journal Article
ZDB-ID	90594-x
ISSN	1460-2385 ; 0931-0509
ISSN (online)	1460-2385
ISSN	0931-0509
DOI	10.1093/ndt/gfad027
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Article ; Online: Phosphorus May Induce Phenotypic Transdifferentiation of Vascular Smooth Muscle Cells through the Reduction of microRNA-145.

Fernández-Villabrille, Sara / Martín-Carro, Beatriz / Martín-Vírgala, Julia / Alonso-Montes, Cristina / Fernández-Fernández, Alejandra / Martínez-Salgado, Carlos / Fernández-Martín, José L / Naves-Díaz, Manuel / Cannata-Andía, Jorge B / Carrillo-López, Natalia / Panizo, Sara

Nutrients

2023 Volume 15, Issue 13

Abstract: Phosphorus is a vital element for life found in most foods as a natural component, but it is also one of the most used preservatives added during food processing. High serum phosphorus contributes to develop vascular calcification in chronic kidney ... ...

Abstract	Phosphorus is a vital element for life found in most foods as a natural component, but it is also one of the most used preservatives added during food processing. High serum phosphorus contributes to develop vascular calcification in chronic kidney disease; however, it is not clear its effect in a population without kidney damage. The objective of this in vivo and in vitro study was to investigate the effect of high phosphorus exposure on the aortic and serum levels of miR-145 and its effect on vascular smooth muscle cell (VSMCs) changes towards less contractile phenotypes. The study was performed in aortas and serum from rats fed standard and high-phosphorus diets, and in VSMCs exposed to different concentrations of phosphorus. In addition, miR-145 silencing and overexpression experiments were carried out. In vivo results showed that in rats with normal renal function fed a high P diet, a significant increase in serum phosphorus was observed which was associated to a significant decrease in the aortic α-actin expression which paralleled the decrease in aortic and serum miR-145 levels, with no changes in the osteogenic markers. In vitro results using VSMCs corroborated the in vivo findings. High phosphorus first reduced miR-145, and afterwards α-actin expression. The miR-145 overexpression significantly increased α-actin expression and partially prevented the increase in calcium content. These results suggest that miR-145 could be an early biomarker of vascular calcification, which could give information about the initiation of the transdifferentiation process in VSMCs.
MeSH term(s)	Rats ; Animals ; Phosphorus/metabolism ; Muscle, Smooth, Vascular ; Actins/metabolism ; Cell Transdifferentiation ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Phenotype ; Vascular Calcification/genetics ; Vascular Calcification/metabolism ; Myocytes, Smooth Muscle ; Cells, Cultured
Chemical Substances	Phosphorus (27YLU75U4W) ; Actins ; MicroRNAs ; MIRN145 microRNA, rat
Language	English
Publishing date	2023-06-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu15132918
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Article: Fracturas por osteoporosis en la mujer española.

Naves Díaz, Manuel

Medicina clinica

2006 Volume 127, Issue 11, Page(s) 413–414

Title translation	Osteoporotic fractures in Spanish women.
MeSH term(s)	Female ; Fractures, Bone/epidemiology ; Fractures, Bone/etiology ; Humans ; Incidence ; Osteoporosis, Postmenopausal/complications ; Osteoporosis, Postmenopausal/epidemiology ; Risk Factors ; Spain/epidemiology
Language	Spanish
Publishing date	2006-07-07
Publishing country	Spain
Document type	Comment ; Editorial
ZDB-ID	411607-0
ISSN	1578-8989 ; 0025-7753
ISSN (online)	1578-8989
ISSN	0025-7753
DOI	10.1157/13092775
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