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Molecules (Basel, Switzerland) Feb 2022Cochlear implants, like other active implants, rely on precise and effective electrical stimulation of the target tissue but become encapsulated by different amounts of...
Cochlear implants, like other active implants, rely on precise and effective electrical stimulation of the target tissue but become encapsulated by different amounts of fibrous tissue. The current study aimed at the development of a dual drug release from a PLLA coating and from the bulk material to address short-term and long-lasting release of anti-inflammatory drugs. Inner-ear cytocompatibility of drugs was studied in vitro. A PLLA coating (containing diclofenac) of medical-grade silicone (containing 5% dexamethasone) was developed and release profiles were determined. The influence of different coating thicknesses (2.5, 5 and 10 µm) and loadings (10% and 20% diclofenac) on impedances of electrical contacts were measured with and without pulsatile electrical stimulation. Diclofenac can be applied to the inner ear at concentrations of or below 4 × 10 mol/L. Release of dexamethasone from the silicone is diminished by surface coating but not blocked. Addition of 20% diclofenac enhances the dexamethasone release again. All PLLA coatings serve as insulator. This can be overcome by using removable masking on the contacts during the coating process. Dual drug release with different kinetics can be realized by adding drug-loaded coatings to drug-loaded silicone arrays without compromising electrical stimulation.
Topics: Animals; Anti-Inflammatory Agents; Coated Materials, Biocompatible; Cochlear Implants; Dexamethasone; Diclofenac; Drug Delivery Systems; Drug Liberation; Rats; Rats, Sprague-Dawley
PubMed: 35209205
DOI: 10.3390/molecules27041417 -
The American Journal of Clinical... Apr 2024Predicting response to exclusive enteral nutrition (EEN) in active Crohn's disease (CD) could lead to therapy personalization and pretreatment optimization.
BACKGROUND
Predicting response to exclusive enteral nutrition (EEN) in active Crohn's disease (CD) could lead to therapy personalization and pretreatment optimization.
OBJECTIVES
This study aimed to explore the ability of pretreatment parameters to predict fecal calprotectin (FCal) levels at EEN completion in a prospective study in children with CD.
METHODS
In children with active CD, clinical parameters, dietary intake, cytokines, inflammation-related blood proteomics, and diet-related metabolites, metabolomics and microbiota in feces, were measured before initiation of 8 wk of EEN. Prediction of FCal levels at EEN completion was performed using machine learning. Data are presented with medians (IQR).
RESULTS
Of 37 patients recruited, 15 responded (FCal < 250 μg/g) to EEN (responders) and 22 did not (nonresponders). Clinical and immunological parameters were not associated with response to EEN. Responders had lesser (μmol/g) butyrate [responders: 13.2 (8.63-18.4) compared with nonresponders: 22.3 (12.0-32.0); P = 0.03], acetate [responders: 49.9 (46.4-68.4) compared with nonresponders: 70.4 (57.0-95.5); P = 0.027], phenylacetate [responders: 0.175 (0.013-0.611) compared with nonresponders: 0.943 (0.438-1.35); P = 0.021], and a higher microbiota richness [315 (269-347) compared with nonresponders: 243 (205-297); P = 0.015] in feces than nonresponders. Responders consumed (portions/1000 kcal/d) more confectionery products [responders: 0.55 (0.38-0.72) compared with nonresponders: 0.19 (0.01-0.38); P = 0.045]. A multicomponent model using fecal parameters, dietary data, and clinical and immunological parameters predicted response to EEN with 78% accuracy (sensitivity: 80%; specificity: 77%; positive predictive value: 71%; negative predictive value: 85%). Higher taxon abundance from Ruminococcaceae, Lachnospiraceae, and Bacteroides and phenylacetate, butyrate, and acetate were the most influential variables in predicting lack of response to EEN.
CONCLUSIONS
We identify microbial signals and diet-related metabolites in feces, which could comprise targets for pretreatment optimization and personalized nutritional therapy in pediatric CD.
Topics: Child; Humans; Crohn Disease; Enteral Nutrition; Prospective Studies; Remission Induction; Microbiota; Metabolome; Butyrates; Acetates; Phenylacetates
PubMed: 38569785
DOI: 10.1016/j.ajcnut.2023.12.027 -
Scientific Reports Sep 2023The formation of protein aggregates is a hallmark of many neurodegenerative diseases and systemic amyloidoses. These disorders are associated with the fibrillation of a...
The formation of protein aggregates is a hallmark of many neurodegenerative diseases and systemic amyloidoses. These disorders are associated with the fibrillation of a variety of proteins/peptides, which ultimately leads to cell toxicity and tissue damage. Understanding how amyloid aggregation occurs and developing compounds that impair this process is a major challenge in the health science community. Here, we demonstrate that pathogenic proteins associated with Alzheimer's disease, diabetes, AL/AA amyloidosis, and amyotrophic lateral sclerosis can aggregate within stress-inducible physiological amyloid-based structures, termed amyloid bodies (A-bodies). Using a limited collection of small molecule inhibitors, we found that diclofenac could repress amyloid aggregation of the β-amyloid (1-42) in a cellular setting, despite having no effect in the classic Thioflavin T (ThT) in vitro fibrillation assay. Mapping the mechanism of the diclofenac-mediated repression indicated that dysregulation of cyclooxygenases and the prostaglandin synthesis pathway was potentially responsible for this effect. Together, this work suggests that the A-body machinery may be linked to a subset of pathological amyloidosis, and highlights the utility of this model system in the identification of new small molecules that could treat these debilitating diseases.
Topics: Humans; Diclofenac; Amyloidogenic Proteins; Amyloidosis; Prostaglandin-Endoperoxide Synthases; Immunoglobulin Light-chain Amyloidosis
PubMed: 37660155
DOI: 10.1038/s41598-023-41712-2 -
Pharmacology, Biochemistry, and Behavior Jul 2022Prescription psychostimulants, such as methylphenidate (MPH), have served as a first line treatment for ADHD and associated developmental disorders since 1961....
Prescription psychostimulants, such as methylphenidate (MPH), have served as a first line treatment for ADHD and associated developmental disorders since 1961. Psychostimulants has been shown to improve attention, response inhibition, and reduce hyperactivity in patients with ADHD, as well as in non-clinical human populations and animals. While there is a considerable amount of preclinical research investigating the effects of stimulant medications on reward sensitivity and basic learning in male rats, less is understood about their effects in females. Further, there are competing theories on the long-term cognitive impact of MPH, specifically in children who do not have ADHD. To this end, Long-Evans female and male rats were exposed to methylphenidate (0, 2.5, 5 mg/kg, BID, IP) for 20 days during early development (PD10-29). After discontinuation of MPH into adulthood, rats (beginning PD 60) were trained and tested for risk-preference using a 2-choice probabilistic discounting task. For this task, rats were given an option between a 'large-risky' choice (3 sugar pellets delivered on a probabilistic VR schedule) and 'small-certain' choice (1 sugar pellet delivered on a FR schedule). Rats were subsequently tested on an open field conflict test. The results demonstrate that prepubertal exposure to MPH can have lasting effects on decision-making. Specifically, female rats treated with 2.5 mg/kg MPH displayed a decrease in preference for the risky option, whereas male rats treated with the same dose showed an overall increase in preference compared to sex-matched controls. Irrespective of sex, rats treated with 2.5 mg/kg MPH also demonstrated a decrease in anxiety/inhibitory behavior on the modified open field test compared to controls. These results were not due to differences in locomotor behavior. Overall, the study contributes to the growing body of evidence to suggest that MPH exposure early in development can have a sex-dependent impact on decision-making in adulthood.
Topics: Adult; Animals; Central Nervous System Stimulants; Child; Female; Humans; Male; Methylphenidate; Rats; Rats, Long-Evans; Sex Characteristics; Sugars
PubMed: 35780911
DOI: 10.1016/j.pbb.2022.173424 -
Basic & Clinical Pharmacology &... Apr 2022Several studies investigated diclofenac tissue concentrations using microdialysis (MD). However, thorough evaluations of the optimal MD set-up for diclofenac are...
Several studies investigated diclofenac tissue concentrations using microdialysis (MD). However, thorough evaluations of the optimal MD set-up for diclofenac are unavailable. Thus, this in vitro MD study aimed to compare different set-ups to improve quantitative recovery of diclofenac. In forward and reverse in vitro MD experiments with diclofenac at two concentrations (1 and 100 ng/ml), the perfusion solutions physiological saline 0.9% (PS) and human albumin 1% (HSA) were compared using tissue probes (10-mm membrane) and customized intravenous (iv) probes (30-mm membrane). Using PS, the mean relative recovery of diclofenac at 1 ng/ml was 1.6% ± 0.04% and 3.12% ± 0.00% with the tissue probe and the iv probe, respectively. The respective mean relative recovery for diclofenac at 100 ng/ml was 0.02% ± 0.01% and 0.21% ± 0.11%. Using HSA, the mean relative recovery was 314% ± 25% (tissue probe) and 1064% ± 97% (iv probe) for diclofenac at 1 ng/ml and 444% ± 91% and 1415% ± 217% for diclofenac at 100 ng/ml. In reverse dialysis using PS, the mean relative loss of diclofenac was 99.2% ± 0.5% (tissue probe) and 95.8% ± 1.7% (iv probe). Using HSA, the mean relative loss was -4.4% ± 7.2% and 0.2% ± 7.5%, respectively. PS and HSA were not suitable perfusion solutions for quantification of absolute diclofenac concentrations. Despite methodological challenges, HSA may be used for comparative experiments or bioequivalence studies.
Topics: Administration, Cutaneous; Diclofenac; Humans; Microdialysis; Perfusion
PubMed: 35048557
DOI: 10.1111/bcpt.13709 -
Journal of Oleo Science 2022Disorganization and breakdown of extracellular matrix proteins like fibronectin, collagen, and elastin are key characteristics of skin aging due to the increased...
Disorganization and breakdown of extracellular matrix proteins like fibronectin, collagen, and elastin are key characteristics of skin aging due to the increased activation of important proteolytic enzymes like elastases and collagenase enzymes. Also, inhibition of their enzymatic activities by natural molecules might be a promising factor to prevent extrinsic skin aging. All chemicals were obtained from Sigma-Aldrich unless otherwise stated. The assay employed was based on spectrophotometric methods reported in the literature. The collagenase and elastase inhibition assays of some phenolic compounds were performed according to the previous studies. These compounds showed excellent to good inhibitory activities of vulpinic acid against studied these enzymes with IC50 values of 195.36 µM for collagenase and 25.24 µM for elastase. The molecular docking calculations were conducted to investigate the chemical and biological activity of vulpinic acid and usnic acid against collagenase and elastase. The results indicated that these two compounds can interact with the essential residues of the enzymes and affect their activities. The calculations of binding free energies were also performed to obtain more details about the characteristics and free energies of the ligand-enzyme complexes. Additionally, both compounds exhibited the most potent inhibition in the three lung cancer cells, with an IC50 value of 21-68 µM, indicating that vulpinic acid is more potent than Doxorubicin, which exhibited an IC50 value of 21-29 µM.
Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Collagenases; Dose-Response Relationship, Drug; Extracellular Matrix Proteins; Furans; Geroscience; Humans; Lung Neoplasms; Models, Molecular; Pancreatic Elastase; Phenylacetates; Skin Aging
PubMed: 35110467
DOI: 10.5650/jos.ess21276 -
Molecules (Basel, Switzerland) May 2022Self-assembly of organic ions in aqueous solutions is a hot topic at the present time, and substances that are well-soluble in water are usually studied. In this work,...
Self-assembly of organic ions in aqueous solutions is a hot topic at the present time, and substances that are well-soluble in water are usually studied. In this work, aqueous solutions of sodium diclofenac are investigated, which, like most medicinal compounds, is poorly soluble in water. Classical MD modeling of an aqueous solution of diclofenac sodium showed equilibrium between the hydrated anion and the hydrated dimer of the diclofenac anion. The assignment and interpretation of the bands in the UV, NIR, and IR spectra are based on DFT calculations in the discrete-continuum approximation. It has been shown that the combined use of spectroscopic methods in various frequency ranges with classical MD simulations and DFT calculations provides valuable information on the association processes of medical compounds in aqueous solutions. Additionally, such a combined application of experimental and calculation methods allowed us to put forward a hypothesis about the mechanism of the effect of diclofenac sodium in high dilutions on a solution of diclofenac sodium.
Topics: Anions; Diclofenac; Ions; Solutions; Water
PubMed: 35630826
DOI: 10.3390/molecules27103350 -
International Journal of Molecular... Dec 2022Alkaptonuria (AKU) is an ultra-rare metabolic disease caused by the accumulation of homogentisic acid (HGA), an intermediate product of phenylalanine and tyrosine...
Alkaptonuria (AKU) is an ultra-rare metabolic disease caused by the accumulation of homogentisic acid (HGA), an intermediate product of phenylalanine and tyrosine degradation. AKU patients carry variants within the gene coding for homogentisate-1,2-dioxygenase (HGD), which are responsible for reducing the enzyme catalytic activity and the consequent accumulation of HGA and formation of a dark pigment called the ochronotic pigment. In individuals with alkaptonuria, ochronotic pigmentation of connective tissues occurs, leading to inflammation, degeneration, and eventually osteoarthritis. The molecular mechanisms underlying the multisystemic development of the disease severity are still not fully understood and are mostly limited to the metabolic pathway segment involving HGA. In this view, untargeted metabolomics of biofluids in metabolic diseases allows the direct investigation of molecular species involved in pathways alterations and their interplay. Here, we present the untargeted metabolomics study of AKU through the nuclear magnetic resonance of urine from a cohort of Italian patients; the study aims to unravel molecular species and mechanisms underlying the AKU metabolic disorder. Dysregulation of metabolic pathways other than the HGD route and new potential biomarkers beyond homogentisate are suggested, contributing to a more comprehensive molecular signature definition for AKU and the development of future adjuvant treatment.
Topics: Humans; Alkaptonuria; Metabolomics; Homogentisic Acid; Biomarkers; Dioxygenases; Magnetic Resonance Spectroscopy
PubMed: 36555443
DOI: 10.3390/ijms232415805 -
ACS Applied Materials & Interfaces Jan 2022The path to greater sustainability and the development of polymeric drug delivery systems requires innovative approaches. The adaptation and use of biobased materials...
The path to greater sustainability and the development of polymeric drug delivery systems requires innovative approaches. The adaptation and use of biobased materials for applications such as targeted therapeutic delivery is, therefore, in high demand. A crucial part of this relates to the development of porous and hollow structures that are biocompatible, pH-responsive, deliver active substances, and contribute to pain relief, wound healing, tissue regeneration, and so forth. In this study, we developed a facile single-step and water-based method for the fabrication of hollow spherical cellulose beads for targeted drug release in response to external pH stimuli. Through base-catalyzed deprotection, hydrophobic solid and spherical cellulose acetate beads are transformed into hydrophilic cellulose structures with a hollow interior (wall thickness: 150 μm and inner diameter: 650 μm) by a stepwise increment of temperature and treatment time. Besides the pH-responsive fluid uptake properties, the hollow cellulose structures exhibit a maximum encapsulation efficiency of 20-85% diclofenac (DCF), a nonsteroidal anti-inflammatory drug, used commonly to treat pain and inflammatory diseases. The maximum amount of DCF released increased from 20 to 100% when the pH of the release medium increased from pH 1.2 to 7.4. As for the DCF release patterns and kinetic models at specific pH values, the release showed a diffusion- and swelling-controlled profile, effortlessly fine-tuned by external environmental pH stimuli. Overall, we show that the modified beads exhibit excellent characteristics for transport across the gastrointestinal tract and enhance the bioavailability of the drug. Their therapeutic efficacy and biocompatibility are also evident from the studies on human fibroblast cells. We anticipate that this platform could support and inspire the development of novel sustainable and effective polysaccharide-based delivery systems.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Biocompatible Materials; Cellulose; Diclofenac; Drug Carriers; Drug Delivery Systems; Humans; Hydrogen-Ion Concentration; Inflammation; Materials Testing; Molecular Structure; Pain; Particle Size; Porosity; Surface Properties
PubMed: 35014252
DOI: 10.1021/acsami.1c19577 -
Nutrients Jan 2022Regular intake of polyphenol-rich food has been associated with a wide variety of beneficial health effects, including the prevention of cardiovascular diseases....
Regular intake of polyphenol-rich food has been associated with a wide variety of beneficial health effects, including the prevention of cardiovascular diseases. However, the parent flavonoids have mostly low bioavailability and, hence, their metabolites have been hypothesized to be bioactive. One of these metabolites, 3-hydroxyphenylacetic acid (3-HPAA), formed by the gut microbiota, was previously reported to exert vasorelaxant effects ex vivo. The aim of this study was to shed more light on this effect in vivo, and to elucidate the mechanism of action. 3-HPAA gave rise to a dose-dependent decrease in arterial blood pressure when administered i.v. both as a bolus and infusion to spontaneously hypertensive rats. In contrast, no significant changes in heart rate were observed. In ex vivo experiments, where porcine hearts from a slaughterhouse were used to decrease the need for laboratory animals, 3-HPAA relaxed precontracted porcine coronary artery segments via a mechanism partially dependent on endothelium integrity. This relaxation was significantly impaired after endothelial nitric oxide synthase inhibition. In contrast, the blockade of SKCa or IKCa channels, or muscarinic receptors, did not affect 3-HPAA relaxation. Similarly, no effects of 3-HPAA on cyclooxygenase nor L-type calcium channels were observed. Thus, 3-HPAA decreases blood pressure in vivo via vessel relaxation, and this mechanism might be based on the release of nitric oxide by the endothelial layer.
Topics: Animals; Blood Pressure; Disease Models, Animal; Flavonoids; Phenylacetates; Rats; Rats, Inbred SHR
PubMed: 35057508
DOI: 10.3390/nu14020328