Publications by authors named "C Salcedo"

78 Publications

Author Correction: Speciation by hybridization in Heliconius butterflies.

Nature 2021 Apr;592(7852):E4-E5

Instituto de Genética, Universidad de los Andes, Carrera 1E No 18ª-10, PO Box 4976, Santafé de Bogotá D.C., Colombia.

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http://dx.doi.org/10.1038/s41586-021-03330-8DOI Listing
April 2021

Downregulation of GABA Transporter 3 (GAT3) is Associated with Deficient Oxidative GABA Metabolism in Human Induced Pluripotent Stem Cell-Derived Astrocytes in Alzheimer's Disease.

Neurochem Res 2021 Mar 12. Epub 2021 Mar 12.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.

Alterations in neurotransmitter homeostasis, primarily of glutamate and GABA, is strongly implicated in the pathophysiology of Alzheimer's disease (AD). Homeostasis at the synapse is maintained by neurotransmitter recycling between neurons and astrocytes. Astrocytes support neuronal transmission through glutamine synthesis, which can be derived from oxidative metabolism of GABA. However, the precise implications of astrocytic GABA metabolism in AD remains elusive. The aim of this study was to investigate astrocytic GABA metabolism in AD pathology implementing human induced pluripotent stem cells derived astrocytes. Metabolic mapping of GABA was performed with [U-C]GABA stable isotopic labeling using gas chromatography coupled to mass spectrometry (GC-MS). Neurotransmitter and amino acid content was quantified via high performance liquid chromatography (HPLC) and protein expression was investigated by Western blot assay. Cell lines carrying mutations in either amyloid precursor protein (APP) or presenilin1 (PSEN-1) were used as AD models and were compared to a control cell line of the same genetic background. AD astrocytes displayed a reduced oxidative GABA metabolism mediated by a decreased uptake capacity of GABA, as GABA transporter 3 (GAT3) was downregulated in AD astrocytes compared to the controls. Interestingly, the carbon backbone of GABA in AD astrocytes was utilized to a larger extent to support glutamine synthesis compared to control astrocytes. The results strongly indicate alterations in GABA uptake and metabolism in AD astrocytes linked to reduced GABA transporter expression, hereby contributing further to neurotransmitter disturbances.
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http://dx.doi.org/10.1007/s11064-021-03276-3DOI Listing
March 2021

A Novel Model of Aortic Valve Calcification. A Preliminary Report.

Front Pharmacol 2020 17;11:568764. Epub 2020 Dec 17.

Division of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.

No pharmacological treatment exists to prevent or stop the calcification process of aortic valves causing aortic stenosis. The aim of this study was to develop a robust model of induced calcification in whole aortic valve leaflets which could be suitable for studies of the basic mechanisms and for testing potentially inhibitory drugs. Pig hearts were obtained from a commercial abattoir. The aortic valve leaflets were dissected free and randomized between experimental groups. Whole leaflets were cultured in individual wells. Two growth media were used for cultivation: standard growth medium and an antimyofibroblastic growth medium. The latter was employed to inhibit contraction of the leaflet into a ball-like structure. Calcification was induced in the growth medium by supplementation with an osteogenic medium. Leaflets were cultivated for four weeks and medium was changed every third day. To block calcification, the inhibitor SNF472 (a formulation of the hexasodium salt of myo-inositol hexaphosphate hexasodium salt) was used at concentrations between 1 and 100 µM. After cultivation for four weeks the leaflets were snap frozen in liquid nitrogen and kept at -80 °C until blind assessment of the calcium amount in leaflets by inductively coupled plasma optical emission spectroscopy. For statistical analysis, a Kruskal-Wallis test with Dunn's post-test was applied. Osteodifferentiation with calcium accumulation was in principle absent when standard medium was used. However, when the antimyofibroblastic medium was used, a strong calcium accumulation was induced ( = 0.006 compared to controls), and this was blocked in a dose-dependent manner by the calcification inhibitor SNF472 ( = 0.008), with an EC of 3.3 µM. A model of experimentally induced calcification in cultured whole leaflets from porcine aortic valves was developed. This model can be useful for studying the basic mechanisms of valve calcification and to test pharmacological approaches to inhibit calcification.
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http://dx.doi.org/10.3389/fphar.2020.568764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773652PMC
December 2020

A novel assay to measure calcification propensity: from laboratory to humans.

Sci Rep 2020 10 16;10(1):17578. Epub 2020 Oct 16.

Sanifit Therapeutics, Parc Bit - Europa Building, 2nd Floor, 07121, Palma de Mallorca, Spain.

Cardiovascular calcification (CVC) contributes to morbidity and mortality in patients undergoing dialysis. We examined the pharmacodynamic effects of SNF472, a calcification inhibitor, on plasma calcium phosphate crystallization using spectrometric measurements, and its correlations with effects on CVC in rats or humans. Rats (N = 38) injected with vitamin D (days 1-3) to induce CVC were infused with saline or SNF472 (days 1-12). Inhibition of CVC was 50-65% with SNF472 3 mg/kg and ~ 80% with SNF472 10 or 30 mg/kg. SNF472 dose-dependently inhibited calcium phosphate crystallization, which correlated with inhibition of CVC (r = 0.628, P = 0.005). In patients with calciphylaxis (N = 14), infusion of SNF472 (~ 7 mg/kg) during hemodialysis for 12 weeks inhibited calcium phosphate crystallization by nearly 70%. In patients with CVC (N = 274), infusion of SNF472 during hemodialysis for 52 weeks inhibited calcium phosphate crystallization (placebo: 15%; 300 mg: 61%; 600 mg: 75%), which correlated with inhibition of CVC (r = 0.401, P = 0.003). These findings show a direct correlation between inhibition of calcium phosphate crystallization in plasma and inhibition of CVC both in a rat model and in humans, supporting the use of the pharmacodynamic assay in clinical trials as a potentially predictive tool to evaluate the activity of calcification inhibitors.
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http://dx.doi.org/10.1038/s41598-020-74592-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568551PMC
October 2020

Brain endothelial cells metabolize glutamate via glutamate dehydrogenase to replenish TCA-intermediates and produce ATP under hypoglycemic conditions.

J Neurochem 2020 Oct 7. Epub 2020 Oct 7.

Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The endothelial cells of the blood-brain barrier participate in the regulation of glutamate concentrations in the brain interstitial fluid by taking up brain glutamate. However, endothelial glutamate metabolism has not been characterized, nor is its role in brain glutamate homeostasis and endothelial energy production known. The aim of this study was to investigate endothelial glutamate dehydrogenase (GDH) expression and glutamate metabolism and probe its functional significance. The primary brain endothelial cells were isolated from bovine and mouse brains, and human brain endothelial cells were derived from induced pluripotent stem cells. GDH expression on the protein level and GDH function were investigated in the model systems using western blotting, confocal microscopy, C-glutamate metabolism, and Seahorse assay. In this study, it was shown that GDH was expressed in murine and bovine brain capillaries and in cultured primary mouse and bovine brain endothelial cells as well as in human-induced pluripotent stem cell-derived endothelial cells. The endothelial GDH expression was confirmed in brain capillaries from mice carrying a central nervous system-specific GDH knockout. Endothelial cells from all tested species metabolized C-glutamate to α-ketoglutarate, which subsequently entered the tricarboxylic acid (TCA)-cycle. Brain endothelial cells maintained mitochondrial oxygen consumption rates, when supplied with glutamate alone, whereas glutamate supplied in addition to glucose did not lead to additional oxygen consumption. In conclusion, brain endothelial cells directly take up and metabolize glutamate and utilize the resulting α-ketoglutarate in the tricarboxylic acid cycle to ultimately yield ATP if glucose is unavailable.
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http://dx.doi.org/10.1111/jnc.15207DOI Listing
October 2020

Mechanism of action of SNF472, a novel calcification inhibitor to treat vascular calcification and calciphylaxis.

Br J Pharmacol 2020 10 23;177(19):4400-4415. Epub 2020 Aug 23.

Sanifit Therapeutics, Palma, Spain.

Background And Purpose: No therapy is approved for vascular calcification or calcific uraemic arteriolopathy (calciphylaxis), which increases mortality and morbidity in patients undergoing dialysis. Deposition of hydroxyapatite (HAP) crystals in arterial walls is the common pathophysiologic mechanism. The mechanism of action of SNF472 to reduce HAP deposition in arterial walls was investigated.

Experimental Approach: We examined SNF472 binding features (affinity, release kinetics and antagonism type) for HAP crystals in vitro, inhibition of calcification in excised vascular smooth muscle cells from rats and bone parameters in osteoblasts from dogs and rats.

Key Results: SNF472 bound to HAP with affinity (K ) of 1-10 μM and saturated HAP at 7.6 μM. SNF472 binding was fast (80% within 5 min) and insurmountable. SNF472 inhibited HAP crystal formation from 3.8 μM, with complete inhibition at 30.4 μM. SNF472 chelated free calcium with an EC of 539 μM. Chelation of free calcium was imperceptible for SNF472 1-10 μM in physiological calcium concentrations. The lowest concentration tested in vascular smooth muscle cells, 1 μM inhibited calcification by 67%. SNF472 showed no deleterious effects on bone mineralization in dogs or in rat osteoblasts.

Conclusion And Implications: These experiments show that SNF472 binds to HAP and inhibits further HAP crystallization. The EC for chelation of free calcium is 50-fold greater than a maximally effective SNF472 dose, supporting the selectivity of SNF472 for HAP. These findings indicate that SNF472 may have a future role in the treatment of vascular calcification and calcific uraemic arteriolopathy in patients undergoing dialysis.
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http://dx.doi.org/10.1111/bph.15163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484563PMC
October 2020

Locally-secreted interleukin-6 is related with radiological severity in smear-negative pulmonary tuberculosis.

Cytokine 2020 03 25;127:154950. Epub 2019 Dec 25.

Programa de Medicina, Facultad de Salud, Universidad Surcolombiana, Neiva, Huila, Colombia. Electronic address:

Pulmonary tuberculosis (PTB) has been identified as a substantial public health threat and diagnostic challenge. A large proportion of patients exhibit negative smear tests despite active infection. The role of cytokines in the pathophysiology and clinical severity of PTB remains a controversial question. We evaluated the pattern of cytokines presents locally in patients with smear-negative PTB. Levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-6, IL-10, and IL-17 in bronchoalveolar lavage fluid (BALf) from patients with smear-negative PTB, as well as in those with other pulmonary diseases and controls, were performed by flow cytometry. ROC curve and a radiological severity scale were used to establish the potential diagnosis use and the relationship of the cytokine levels with disease severity, respectively. The levels of IL-6 were higher in the PTB (P = 0.0249) and pneumonia (P = 0.0047) groups compared to controls. Low to undetectable levels of TNF-α, IFN-γ, IL-2, IL-4, IL-10, and IL-17 were found in BALf, even after sample concentration using filtration columns and centrifugation. IL-6 levels measured in BALf could distinguish PTB patients or pneumonia patients from controls (AUC: 0.91, P = 0.002 and AUC: 0.86, P = 0.001, respectively), but not patients with PTB from those with pneumonia (AUC: 0.51, P = 0.86). IL-6 levels were related with the severity of PTB, as levels were higher in patients with higher radiological severity. These results confirm the importance of IL-6 in the immunopathology of smear-negative PTB.
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http://dx.doi.org/10.1016/j.cyto.2019.154950DOI Listing
March 2020

Slowing Progression of Cardiovascular Calcification With SNF472 in Patients on Hemodialysis: Results of a Randomized Phase 2b Study.

Circulation 2020 03 11;141(9):728-739. Epub 2019 Nov 11.

Department of Medicine, Stanford University, Palo Alto, CA (A.G., G.M.C.).

Background: The high cardiovascular morbidity and mortality in patients with end-stage kidney disease could be partially caused by extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite.

Methods: This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium volume score and other measurements of cardiovascular calcification by computed tomography scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage kidney disease receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log coronary artery calcium volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least 1 dose of SNF472 or placebo and had an evaluable computed tomography scan after randomization.

Results: The mean change in coronary artery calcium volume score was 11% (95% CI, 7-15) for the combined SNF472 dose group and 20% (95% CI, 14-26) for the placebo group (=0.016). SNF472 compared with placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5-24] versus 98% [95% CI, 77-123]; <0.001) but not in the thoracic aorta (23% [95% CI, 16-30] versus 28% [95% CI, 19-38]; =0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least 1 treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg, and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively.

Conclusions: Compared with placebo, SNF472 significantly attenuated the progression of coronary artery calcium and aortic valve calcification in patients with end-stage kidney disease receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02966028.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044195DOI Listing
March 2020

Trial design and baseline characteristics of CaLIPSO: a randomized, double-blind placebo-controlled trial of SNF472 in patients receiving haemodialysis with cardiovascular calcification.

Clin Kidney J 2021 Jan 30;14(1):366-374. Epub 2019 Oct 30.

Research and Development, Sanifit Therapeutics, Palma, Spain.

Background: The objective of CaLIPSO, a Phase 2b, randomized, double-blind, placebo-controlled clinical trial, is to test the hypothesis that myo-inositol hexaphosphate (SNF472) attenuates the progression of cardiovascular calcification in patients receiving maintenance haemodialysis. Here we report the trial design and baseline characteristics of trial participants.

Methods: Adult patients on maintenance haemodialysis (≥6 months) with an Agatston coronary artery calcium score, as measured by a multidetector computed tomography scanner, of 100-3500 U were enrolled. Patients were stratified by Agatston score (100-<400, 400-1000 or >1000 U) and randomized in a 1:1:1 ratio to receive placebo, SNF472 300 mg or SNF472 600 mg administered intravenously three times weekly during each haemodialysis session.

Results: Overall, 274 patients were randomized. The mean age of trial participants was 63.6 (standard deviation 8.9) years and 39% were women. The coronary artery, aorta and aortic valve median (25th-75th percentile) Agatston scores at baseline were 730 U (315-1435), 1728 U (625-4978) and 103 U (31-262), respectively, and the median (25th-75th percentile) calcium volume scores at baseline were 666 (310-1234), 1418 (536-4052) and 107 (38-278), respectively. Older age and diabetes mellitus were associated with higher calcium scores at baseline.

Conclusions: The CaLIPSO trial enrolled patients on haemodialysis with pre-existent cardiovascular calcification to test the hypothesis that SNF472 attenuates its progression in the coronary arteries, aorta and aortic valve.
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http://dx.doi.org/10.1093/ckj/sfz144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857813PMC
January 2021

SNF472, a novel anti-crystallization agent, inhibits induced calcification in an in vitro model of human aortic valve calcification.

Vascul Pharmacol 2019 Nov - Dec;122-123:106583. Epub 2019 Aug 19.

Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

The purpose of the present study was to investigate whether SNF472, the hexasodium salt of myo-inositol hexaphosphate (IP6 or phytate): 1. Inhibits induced calcification in cultured aortic valve interstitial cells (VIC) as an in vitro model of aortic valve stenosis and 2. Whether inhibition is different in VIC obtained from healthy and calcified aortic valves. VIC from healthy (n = 5) and calcified (n = 7) human aortic valves were seeded in basic growth medium, osteogenic differentiation medium alone, or in osteogenic medium with SNF472 (3, 10, and 30 μM) and cultivated for 3 weeks. Calcification was quantified spectrophotometrically after Alizarin Red staining. In VIC from calcified valves, a complete inhibition of calcification was observed with SNF472 concentrations of 10 and 30 μM (p < .01), significantly stronger than in VIC from healthy valves. When SNF472 was added to VIC after 1 week in osteogenic medium, 30 and 100 μM SNF472 inhibited the progression of ongoing calcification by 81 and 100% (p < .01), respectively. The same concentrations of SNF472 given after 2 weeks reduced calcification by 35 and 40% respectively (not significant). SNF472 inhibited both the formation and the progression of calcification with the strongest effect in VIC from calcified valves.
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http://dx.doi.org/10.1016/j.vph.2019.106583DOI Listing
May 2020

Improvement in wound healing, pain, and quality of life after 12 weeks of SNF472 treatment: a phase 2 open-label study of patients with calciphylaxis.

J Nephrol 2019 Oct 10;32(5):811-821. Epub 2019 Aug 10.

Sanifit Therapeutics, Palma, Spain.

Background: Calciphylaxis in end-stage renal disease is characterized by painful necrotic skin ulcers and high mortality. There are no approved therapies. SNF472, an intravenous formulation of myo-inositol hexaphosphate, inhibits the formation and growth of hydroxyapatite crystals, the final common pathway in the pathogenesis of vascular calcification.

Methods: In this open-label, single-arm study, calciphylaxis patients on thrice-weekly hemodialysis and standard care, received intravenous SNF472 3 times per week for 12 weeks. The primary endpoint was wound healing assessed using the quantitative Bates-Jensen Wound Assessment Tool (BWAT). Pain visual analog scale (VAS), quality of life (wound-QoL), and qualitative wound image review were secondary endpoints. Quantitative changes from baseline were analyzed by paired t-tests using multiple imputation to account for missing observations.

Results: Fourteen patients received SNF472. Improvements from baseline to week 12 were observed for mean BWAT score (- 8.1; P < 0.001), pain VAS (- 23.6 mm; P = 0.015) and wound-QoL global score (- 0.90; P = 0.003). Of the 9 patients with ulcerated lesions at baseline who completed treatment, wound image review showed improvement for 7. SNF472 was well tolerated with no serious treatment-related adverse events. The most common adverse events were infections which occur frequently in patients on hemodialysis. None of these were considered as treatment-related.

Conclusions: SNF472 was well-tolerated and improvements from baseline to week 12 in wound healing, pain, and quality of life were observed. A randomized, double-blind, placebo-controlled trial is planned to evaluate SNF472 in patients with calciphylaxis.
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http://dx.doi.org/10.1007/s40620-019-00631-0DOI Listing
October 2019

Capacity to adhere to and invade human epithelial cells, as related to the presence of virulence genes in, motility of, and biofilm formation of Campylobacter jejuni strains isolated from chicken and cattle.

Can J Microbiol 2019 Feb 19;65(2):126-134. Epub 2018 Oct 19.

b Faculty of Veterinary and Animal Sciences, University of Chile, Santa Rosa 11735, La Pintana, Santiago, Chile.

Campylobacter jejuni is a zoonotic pathogen transmitted through the "farm to fork" route. Outbreaks are generally associated with the consumption of chicken meat; however, dairy cows, birds, wild and domestic food animals, and pets are other important sources. Currently, there are not enough data comparing the virulence of strains isolated from these reservoirs. In this study, we compared C. jejuni strains isolated from broiler chickens and dairy cattle by determining their ability to adhere to and invade in vitro human colonic epithelial cells in the T84 cell line with their motility, formation of biofilms, and presence of eight virulence genes. A Wilcoxon Rank Sum test was performed to establish the relationship between presence of the studied genes and cellular invasion and adhesion, as well as differences between the animal species of origin of the isolate. A Spearman correlation was performed to assess the relationship between invasion and motility, along with invasion and biofilm generation. The virB11 gene was positively associated with the adherence capacity of the strains (mean difference = 0.21, p = 0.006), and strains isolated from chickens showed a significant difference for adherence compared with strains isolated from cattle (p = 0.0001). Our results indicate that strains of C. jejuni have a difference in their adherence capacity depending on the animal reservoir from which they came, with chicken isolates displaying higher virulence than dairy cattle isolates.
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http://dx.doi.org/10.1139/cjm-2018-0503DOI Listing
February 2019

First-time-in-human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification.

Br J Clin Pharmacol 2018 12 3;84(12):2867-2876. Epub 2018 Oct 3.

Laboratoris Sanifit, Palma, Spain.

Aims: SNF472 is a calcification inhibitor being developed for the treatment of cardiovascular calcification in haemodialysis (HD) and in calciphylaxis patients. This study investigated the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) SNF472 in healthy volunteers (HV) and HD patients.

Methods: This is a first-time-in-human, double-blind, randomized, placebo-controlled Phase I study to assess the safety, tolerability and PK of SNF472 after ascending single IV doses in HV and a single IV dose in HD patients. A pharmacodynamic analysis was performed to assess the capability of IV SNF472 to inhibit hydroxyapatite formation.

Results: Twenty HV and eight HD patients were enrolled. The starting dose in HV was 0.5 mg kg and the dose ascended to 12.5 mg kg . The dose selected for HD patients was 9 mg kg . Safety analyses support the safety and tolerability of IV SNF472 in HD patients and HV. Most treatment-emergent adverse events were mild in intensity. No clinically significant effects were observed on vital signs or laboratory tests. PK results were similar in HD patients and HV and indicate a lack of significant dialysability. Pharmacodynamic analyses demonstrated that SNF472 administration reduced hydroxyapatite crystallization potential in HD patients who received IV SNF472 9 mg kg by 80.0 ± 2.4% (mean ± standard error of the mean, 95% CI, 75.3-84.8) compared to placebo (8.7 ± 21.0%, P < 0.001, 95% CI, -32.4 to 49.7).

Conclusion: The results from this study showed acceptable safety and tolerability, and lack of significant dialysability of IV SNF472. It is a potential novel treatment for cardiovascular calcification in end-stage renal disease and calciphylaxis warranting further human studies.
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http://dx.doi.org/10.1111/bcp.13752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255995PMC
December 2018

Characterization of SNF472 pharmacokinetics and efficacy in uremic and non-uremic rats models of cardiovascular calcification.

PLoS One 2018 9;13(5):e0197061. Epub 2018 May 9.

Laboratoris Sanifit SL, Research and Development Department, Palma, Spain.

End-stage renal disease is strongly associated with progressive cardiovascular calcification (CVC) and there is currently no therapy targeted to treat CVC. SNF472 is an experimental formulation under development for treatment of soft tissue calcification. We have investigated the pharmacokinetics of SNF472 administration in rats and its inhibitory effects on CVC. SNF472 was studied in three rat models: (1) prevention of vitamin D3-induced CVC with an intravenous SNF472 bolus of 1 mg/kg SNF472, (2) inhibition of progression of vitamin D3-induced CVC with a subcutaneous SNF472 bolus of 10 or 60 mg/kg SNF472, starting after calcification induction, (3) CVC in adenine-induced uremic rats treated with 50 mg/kg SNF472 via i.v. 4h -infusion. Uremic rats presented lower plasma levels of SNF472 than control animals after i.v. infusion. CVC in non-uremic rats was inhibited by 60-70% after treatment with SNF472 and progression of cardiac calcification completely blocked. Development of CVC in uremic rats was inhibited by up to 80% following i.v. infusion of SNF472. SNF472 inhibits the development and progression of CVC in uremic and non-uremic rats in the same range of SNF472 plasma levels but using in each case the required dose to obtain those levels. These results collectively support the development of SNF472 as a novel therapeutic option for treatment of CVC in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197061PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942814PMC
August 2018

SNF472, a novel inhibitor of vascular calcification, could be administered during hemodialysis to attain potentially therapeutic phytate levels.

J Nephrol 2018 04 19;31(2):287-296. Epub 2018 Jan 19.

Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.

Background: Cardiovascular calcification (CVC) is a major concern in hemodialysis (HD) and the loss of endogenous modulators of calcification seems involved in the process. Phytate is an endogenous crystallization inhibitor and its low molecular mass and high water solubility make it potentially dialyzable. SNF472 (the hexasodium salt of phytate) is being developed for the treatment of calciphylaxis and CVC in HD patients. We aimed to verify if phytate is lost during dialysis, and evaluate SNF472's behaviour during dialysis.

Methods: Dialyzability was assessed in vitro using online-hemodiafiltration and high-flux HD systems in blood and saline. SNF472 was infused for 20 min and quantified at different time points.

Results: Phytate completely dialyzed in 1 h at low concentrations (10 mg/l) but not when added at 30 or 66.67 mg/l SNF472. In bypass conditions, calcium was slightly chelated during SNF472 infusion but when the system was switched to dialysis mode the calcium in the bath compensated this chelation.

Conclusion: Phytate dialyses with a low clearance. The administration of SNF472 as an exogenous source of phytate allows to attain supra-physiological levels required for its potential therapeutic properties. As SNF472 is infused during the whole dialysis session, the low clearance would not affect the drug's systemic exposure.
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http://dx.doi.org/10.1007/s40620-018-0471-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829128PMC
April 2018

Effects of pre- and neonatal undernutrition on the kyphotic response and c-Fos activity in the caudal periaqueductal gray of primiparous lactating Wistar rats.

Physiol Behav 2018 03 18;185:87-94. Epub 2017 Dec 18.

Department of Developmental Neurobiology and Neurophysiology, Institute of Neurobiology, National Autonomous University of Mexico, Campus UNAM Juriquilla, Queretaro, Mexico. Electronic address:

In rodents, the most representative component of maternal behavior that meets the purpose of newborn nutrition is the kyphotic posture. During this posture, the mother maintains a unique environment for the protection, thermal regulation and breast-feeding of the progeny. The aim of this study was to investigate possible deficiencies in the kyphotic posture of adult lactating dams with pre- and neonatal undernutrition evoked by their own pups suckling in a home-cage situation. Wistar dams that had been previously exposed to perinatal undernutrition were mated at 90days of age, and pregnancy was confirmed by vaginal smears. Before testing if the perinatal underfed dam affected behavior, pups were removed (4h), and both the maternal response and the kyphotic posture were video-recorded (1h) and analyzed at 4 and 12days of lactation. Pre- and post-test litter weight gain was obtained. To immunostain the caudal periaqueductal gray, the litter was separated from their dams 24h before suckling stimulation. The results showed that underfed dams significantly reduced the duration of high kyphosis by choosing unconventional postures (prone and partial kyphosis). The body weight of the F1 offspring was significantly reduced, and the underfed F0 dams showed reduced c-Fos immunostaining at the caudal periaqueductal gray. The findings showed that early underfed dams have deficiencies in the mechanisms underlying the kyphosis, possibly because the pups' cues to evoke this posture were suboptimal and/or because the dam expressed deficient nursing. The results suggest that the abnormal kyphotic posture may affect the mother-litter bonds and have long-term effects on neonatal brain functions.
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http://dx.doi.org/10.1016/j.physbeh.2017.12.020DOI Listing
March 2018

A novel pharmacodynamic assay to evaluate the effects of crystallization inhibitors on calcium phosphate crystallization in human plasma.

Sci Rep 2017 07 31;7(1):6858. Epub 2017 Jul 31.

Laboratoris Sanifit SL, 07121, Palma, Spain.

Cardiovascular calcification (CVC) is a progressive complication of chronic kidney disease and a predictor of CV events and mortality. The use of biomarkers to predict CV risk and activities of potential or current treatment drugs in these patients could have a crucial impact on therapeutic approaches. Our aim was to develop a novel assay for measurement of the rate of calcium phosphate crystallization in human plasma and provide a tool to evaluate the effects of crystallization inhibitors. The efficacy of inhibitors was determined by adding inhibitory compounds (polyphosphates, fetuin-A, sodium thiosulfate or citrate) to control samples. The assay was additionally validated for SNF472, an experimental formulation of phytate being developed for the treatment of calciphylaxis and CVC in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). The method was repeatable and reproducible. The plasma crystallization rate was reduced up to 80% in a concentration-dependent manner following treatment with inhibitors in vitro, among which SNF472 was the most potent. This method appears beneficial in evaluating and discriminating between inhibitory activities of compounds such as polyphosphates on calcium phosphate crystallization, which present a novel therapeutic approach to treat CVC in ESRD patients.
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http://dx.doi.org/10.1038/s41598-017-07203-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537272PMC
July 2017

Developmental differences between a Chinese and a North American isolate of the pinewood nematode Bursaphelenchus xylophilus (Tylenchida: Aphelenchoididae) under laboratory conditions.

Sci China Life Sci 2017 08 27;60(8):921-923. Epub 2017 Jul 27.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.

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http://dx.doi.org/10.1007/s11427-017-9103-4DOI Listing
August 2017

Hypothesis: Phytate is an important unrecognised nutrient and potential intravenous drug for preventing vascular calcification.

Med Hypotheses 2016 Sep 12;94:89-92. Epub 2016 Jul 12.

Laboratoris Sanifit, Parc Bit, Palma de Mallorca, Spain; Institute of Health Sciences Research, University of Balearic Sciences, Palma de Mallorca, Spain.

Cardiovascular calcification (CVC) associated with conditions such as ageing, diabetes or renal impairment, results from the deposition of hydroxyapatite in the endothelium or media of blood vessels. Key medical management options are directed towards controlling plasma calcium and phosphate concentrations (e.g. parathormone inhibition, phosphate binders, dialysis), enhancing the effect of calcification inhibitors (e.g. fetuin-A, pyrophosphate, vitamin K, osteopontin, matrix Gla protein) and decreasing the effect of promoters of calcification (e.g. vitamin D, lipids, cytokines). Dietary phytate prevents the calcification of ageing in rats and epidemiological data suggest that phytate rich diets are associated with a lower incidence of CVC in the elderly. Intravenous phytate prevents aggressive CVC induced by vitamin D in rats. We propose that phytate should be added to the list of inhibitors of vascular calcification. We further suggest that adequate dietary phytate could prevent mild forms of calcification and that the low phytate content of diets for patients with renal disease can contribute to the increased risk of vascular calcification. It is also our contention that supra-physiological systemic phytate concentrations not achievable orally, might prevent aggressive vascular calcification. Appropriate epidemiological (to determine nutritional value) and clinical studies (evaluating safety and efficacy) are required to confirm, modify or reject our hypothesis.
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http://dx.doi.org/10.1016/j.mehy.2016.07.005DOI Listing
September 2016

[Pediatric tracheostomy: a ten-year analysis in the Intensive Care Unit of Sancti Spiritus “José Martí” Pediatric Teaching Hospital].

Medwave 2014 May 5;14(4):e5949. Epub 2014 May 5.

Unidad de Cuidados Intensivos, Hospital Pediátrico Docente de Sancti Spíritus “José Martí”, Cuba.

Introduction: There has been a significant change in the role of pediatric tracheostomy over the last twenty years. Obstruction of the upper airway caused by infectious agents is no longer the leading cause of tracheostomy in children. Structural anomalies of the upper airway as well as the need for prolonged ventilator assistance have become the most frequent indication for pediatric tracheostomy.

Objective: The purpose of this paper is to assess the incidence, indications, complications, and role in mortality of tracheostomy in our pediatric population.

Methods: A retrospective descriptive study of pediatric patients who underwent tracheostomy was conducted between 1999 and 2008 in the Pediatric Intensive Care Unit of the José Martí de Sancti Spiritus Pediatric Teaching Hospital in Cuba.

Results: Tracheostomy was performed in 14 patients during the period of the study (0.5% of admitted patients). Nine of them (64.2%) were younger than one year. The most frequent indication for the procedure was the need for prolonged mechanical ventilation in patients with neurologic disorders in 10 patients (71.42%). Upper airway malformations and acute infections were infrequent indications for tracheostomy. The most frequent complications were infectious in 10 patients (71.4%) and obstruction in four patients (28.5%). The following germs were found: Pseudomona aeruginosa in six patients (60%), Staphylococcus aureus in three patients (30%), and Enterobacter cloacae in three patients (30%). Furthermore, four patients were successfully decannulated (28.5%), five patients died (35.7%) but only in one (7.14%), death could be attributed to tracheostomy.

Conclusion: The need for prolonged mechanical ventilation in patients with neurologic disorders was the main indication for tracheostomy in our pediatric population; most of these children were younger than one year. The procedure had little impact in overall mortality in this group of patients.
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http://dx.doi.org/10.5867/medwave.2014.04.5949DOI Listing
May 2014

Antiradical activity of gallic acid included in lipid interphases.

Biochim Biophys Acta 2014 Oct 3;1838(10):2656-61. Epub 2014 Jul 3.

Laboratory of Biointerphases and Biomimetic Systems, Centro de Investigación y Transferencia de Santiago del Estero (CITSE) (University of Santiago del Estero-CONICET), 4200 Santiago del Estero, Argentina. Electronic address:

Polyphenols are well known as antioxidant agents and by their effects on the hydration layers of lipid interphases. Among them, gallic acid and its derivatives are able to decrease the dipole potential and to act in water as a strong antioxidant. In this work we have studied both effects on lipid interphases in monolayers and bilayers of dimyristoylphosphatidylcholine. The results show that gallic acid (GA) increases the negative surface charges of large unilamellar vesicles (LUVs) and decreases the dipole potential of the lipid interphase. As a result, positively charged radical species such as ABTS(+) are able to penetrate the membrane forming an association with GA. These results allow discussing the antiradical activity (ARA) of GA at the membrane phase which may be taking place in water spaces between the lipids.
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http://dx.doi.org/10.1016/j.bbamem.2014.06.019DOI Listing
October 2014

Surface and hysteresis properties of lipid interphases composed by head group substituted phosphatidylethanolamines.

Colloids Surf B Biointerfaces 2014 Jan 5;113:243-8. Epub 2013 Sep 5.

Laboratory of Biointerphases and Biomimetic Systems- CITSE (University of Santiago del Estero-CONICET), 4200 Santiago del Estero, Argentina.

This work analyzes the surface properties of PE-containing membranes modified at the head group region by the addition of methyl and ethyl residues at or near the amine group. These residues alter the lipid-lipid and lipid-water interactions by changes in the hydrogen bonding capability and the charge density of the amine group thus affecting the electrostatic interaction. The results obtained by measuring the dipole potential, the zeta potential, the area per lipid and the compressibility properties allow to conclude that the H-bonding capability prevails in the lipid-lipid interaction. The non polar groups attached to the C2-carbon of the ethanolamine chain introduces a steric hindrance against compression and increases the dipole potential. The analysis of areas suggests that lipids with methylated head groups have a much larger compressibility at expense of the elimination of hydration water, which is congruent with the broader extent of the hysteresis loop.
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http://dx.doi.org/10.1016/j.colsurfb.2013.08.044DOI Listing
January 2014

Is the H4 receptor a new drug target for allergies and asthma?

Front Biosci (Elite Ed) 2013 Jan 1;5:178-87. Epub 2013 Jan 1.

Palau Pharma SA, Avda Cami Reial 51-57, 08184 Palau-solita i Plegamans, Barcelona, Spain.

Histamine H4 receptor (H4R) has become a promising target for immuno-inflammatory diseases, such as allergic rhinitis, asthma or dermal allergies. Its distribution pattern in immune cells and the preclinical data obtained from different biological systems using diverse histamine H4 modulators (1) suggest a key role of H4R in immunity and in inflammatory cell trafficking. Recent results with UR-63325, the first H4R antagonist from which clinical data has been reported (2), confirm the feasibility of complete H4R blocking in humans without limiting safety concerns. Also, H4R blockade results in clear pharmacodynamic effects in relevant human cells, e.g. eosinophils. It is believed that allergic rhinitis and asthma are manifestations of one unique syndrome in two parts of the respiratory tract. Dermal allergies are also recognized as related manifestations in a different location. The coexistence of allergic-related diseases in the same patients could permit a single treatment approach e.g.. the systemic use of H4R antagonists. Further clinical studies are needed to establish the role of H4R antagonists in the treatment of allergic diseases.
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http://dx.doi.org/10.2741/e606DOI Listing
January 2013

Saccharide-mediated antagonistic effects of bark beetle fungal associates on larvae.

Biol Lett 2013 Feb;9(1):20120787

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China.

Bark beetles are among the most destructive of pine forest pests and they form close symbiotic relationships with ophiostomatoid fungi. Although some fungi are considered to be mutualistic symbionts of bark beetles with respect to the supply of nutrients, detrimental effects of fungal symbionts on larval growth have also been frequently reported. The mechanisms of such antagonistic effects are hypothesized to be a decrease in nutritional resources caused by competition for saccharides by the fungi. Here, we provide experimental evidence that three beetle-associated fungi modify the nutritional content of an artificial phloem diet, leading to a detrimental effect on the growth of Dendroctonus valens larvae. When larvae were fed a diet of pine phloem in agar medium colonized with any of these fungi, feeding activity was not affected but weight significantly decreased. Additional analysis showed that fungi depleted the fructose and glucose concentrations in the phloem media. Furthermore, these detrimental effects were neutralized by supplementing the media with fructose or glucose, suggesting that fungi may affect larval growth by modifying diet saccharide contents. These data indicate that fungus-induced nutritional changes in bark beetle diet can affect larval growth, and that the mechanism involves fungus-induced saccharide depletion from the larval diet.
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http://dx.doi.org/10.1098/rsbl.2012.0787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565487PMC
February 2013

Molecular epidemiology, antimicrobial susceptibilities and resistance mechanisms of Streptococcus pyogenes isolates resistant to erythromycin and tetracycline in Spain (1994-2006).

BMC Microbiol 2012 Sep 21;12:215. Epub 2012 Sep 21.

Servicio de Bacteriología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.

Background: Group A Streptococcus (GAS) causes human diseases ranging in severity from uncomplicated pharyngitis to life-threatening necrotizing fasciitis and shows high rates of macrolide resistance in several countries. Our goal is to identify antimicrobial resistance in Spanish GAS isolates collected between 1994 and 2006 and to determine the molecular epidemiology (emm/T typing and PFGE) and resistance mechanisms of those resistant to erythromycin and tetracycline.

Results: Two hundred ninety-five out of 898 isolates (32.8%) were erythromycin resistant, with the predominance of emm4T4, emm75T25, and emm28T28, accounting the 67.1% of the 21 emm/T types. Spread of emm4T4, emm75T25 and emm28T28 resistant clones caused high rates of macrolide resistance. The distribution of the phenotypes was M (76.9%), cMLSB (20.3%), iMLSB (2.7%) with the involvement of the erythromycin resistance genes mef(A) (89.5%), msr(D) (81.7%), erm(B) (37.3%) and erm(A) (35.9%).Sixty-one isolates were tetracycline resistant, with the main representation of the emm77T28 among 20 emm/T types. To note, the combination of tet(M) and tet(O) tetracycline resistance genes were similar to tet(M) alone reaching values close to 40%. Resistance to both antibiotics was detected in 19 isolates of 7 emm/T types, being emm11T11 and the cMLSB phenotype the most frequent ones. erm(B) and tet(M) were present in almost all the strains, while erm(A), mef(A), msr(D) and tet(O) appeared in less than half of them.

Conclusions: Spanish GAS were highly resistant to macrolides meanwhile showed minor resistance rate to tetracycline. A remarkable correlation between antimicrobial resistance and emm/T type was noticed. Clonal spread of emm4T4, emm75T25 and emm28T28 was the main responsable for macrolide resistance where as that emm77T28 clones were it to tetraclycline resistance. A wide variety of macrolide resistance genes were responsible for three macrolide resistance phenotypes.
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http://dx.doi.org/10.1186/1471-2180-12-215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490898PMC
September 2012

An overlooked component: (Z)-9-tetradecenal as a sex pheromone in Helicoverpa armigera.

J Insect Physiol 2012 Sep 23;58(9):1209-16. Epub 2012 Jun 23.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.

The sex pheromone blend of Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) is a multi-component system, as is that of many other moths, and (Z)-11-hexadecenal 90-99%+(Z)-9-hexadecenal 10-1% was recommended as a standard blend for attracting the species. However, this fails to account for the significance of other compounds that exist in the sex gland. The aim of the present study was to investigate the function of other compounds present in the female sex gland of H. armigera. Extract of female sex glands were analysed by GC-MS combined with GC-EAD. Total 10 compounds were identified, which two novel were reported in female sex gland: heptanal and nonanal, and some previously identified compounds were confirmed. We developed bioassays to evaluate the potential roles of these 10 compounds. In Y-tube bioassays, the gland constituents hexadecanal, (Z)-7-hexadecenal and (Z)-9-tetradecenal increased male attractiveness when added as a three-compound admixture to the standard blend. Field trapping tests showed that (Z)-9-tetradecenal doubled trap catch in comparison with the standard blend, but that the addition of (Z)-7-hexadecenal and hexadecanal did not significantly increase trap catch. These results indicated that while (Z)-7-hexadecenal and hexadecanal function well only at short range, (Z)-9-tetradecenal plays a very important role at both short and long ranges. We suggest that that (Z)-9-tetradecenal as a previously overlooked sex pheromone component of H. armigera, it should be added to sex pheromone lure formulations to improve pheromone trap sensitivity and the efficacy of commercial mating disruption.
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http://dx.doi.org/10.1016/j.jinsphys.2012.05.018DOI Listing
September 2012

Mutual interactions between an invasive bark beetle and its associated fungi.

Bull Entomol Res 2012 Feb 22;102(1):71-7. Epub 2011 Jul 22.

State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

Interactions between invasive insects and their fungal associates have important effects on the behavior, reproductive success, population dynamics and evolution of the organisms involved. The red turpentine beetle (RTB), Dendroctonus valens LeConte (Coleoptera: Scolytinae), an invasive forest pest in China, is closely associated with fungi. By carrying fungi on specialized structures in the exoskeleton, RTB inoculates fungi in the phloem of pines (when females dig galleries for egg laying and when males join them for mating). After eggs hatch, larvae gregariously feed on the phloem colonized by the fungi. We examined the effects of five isolates of RTB associated fungi (two from North America, Leptographium terebrantis and L. procerum, and three from China, Ophiostoma minus, L. sinoprocerum and L. procerum) on larval feeding activity, development and mortality. We also studied the effects of volatile chemicals produced in the beetle hindgut on fungal growth. Ophiostoma minus impaired feeding activity and reduced weight in RTB larvae. Leptographium sinoprocerum, L. terebrantis and L. procerum did not dramatically influence larval feeding and development compared to fungi-free controls. Larval mortality was not influenced by any of the tested fungi. Hindgut volatiles of RTB larvae, verbenol, myrtenol and myrtenal, inhibited growth rate of all the fungi. Our results not only show that D. valens associated fungus, O. minus, can be detrimental to its larvae; but, most importantly, they also show that these notorious beetles have an outstanding adaptive response evidenced by the ability to produce volatiles that inhibit growth of harmful fungus.
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http://dx.doi.org/10.1017/S000748531100037XDOI Listing
February 2012

Pollen preference for Psychotria sp. is not learned in the passion flower butterfly, Heliconius erato.

J Insect Sci 2011 ;11:25

Department of Entomology and Nematology, University of Florida, Gainesville, FL 32611, USA.

Heliconius butterflies are known to maximize fitness by feeding on pollen from Gurania sp. and Psiguria sp. (Cucurbitales: Curcurbitaceae), and Psychotria sp. (Gentianales: Rubiaceae). This specialization involves specific physical, physiological, and behavioral adaptations including efficient search strategies in the forest to locate pollen host plants, pollen removal, and pollen external digestion. Reducing pollen host plant search time is crucial to out-compete other flower visitors and to reduce exposure to predators. One way in which this can be achieved is by using chemical cues to learn from experienced foragers in roosting aggregations. Similar strategies have been documented in bumblebees, where inexperienced individuals learn floral odors from experienced foragers. Behavioral experiments using plants preferred by Heliconius erato suggest that pollen preference in H. erato is an innate trait and consequently learning of chemical cues at roosting aggregations is unlikely.
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http://dx.doi.org/10.1673/031.011.0125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281357PMC
August 2011