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Abstract The diagnostic spectrum for AML patients is increasingly based on genetic abnormalities due to their prognostic and predictive value. However, information on the AML blast phenotype regarding their maturational arrest has started to regain importance due to its predictive power for drug responses. Here, we deconvolute 1350 bulk RNA-seq samples from five independent AML cohorts on a single-cell healthy BM reference and demonstrate that the morphological differentiation stages (FAB) could be faithfully reconstituted using estimated cell compositions (ECCs). Moreover, we show that the ECCs reliably predict ex-vivo drug resistances as demonstrated for Venetoclax, a BCL-2 inhibitor, resistance specifically in AML with CD14+ monocyte phenotype. We validate these predictions using LUMC proteomics data by showing that BCL-2 protein abundance is split into two distinct clusters for NPM1-mutated AML at the extremes of CD14+ monocyte percentages, which could be crucial for the Venetoclax dosing patients. Our results suggest that Venetoclax resistance predictions can also be extended to AML without recurrent genetic abnormalities and possibly to MDS-related and secondary AML. Lastly, we show that CD14+ monocytic dominated Ven/Aza treated patients have significantly lower overall survival. Collectively, we propose a framework for allowing a joint mutation and maturation stage modeling that could be used as a blueprint for testing sensitivity for new agents across the various subtypes of AML.

Abstract The growing disparity between the demand for transplants and the available donor supply, coupled with an aging donor population and increasing prevalence of chronic diseases, highlights the urgent need for the development of platforms enabling reconditioning, repair, and regeneration of deceased donor organs. This necessitates the ability to preserve metabolically active kidneys ex vivo for days. However, current kidney normothermic machine perfusion (NMP) approaches allow metabolic preservation only for hours. Here we show that human kidneys discarded for transplantation can be preserved in a metabolically active state up to 4 days when perfused with a cell-free perfusate supplemented with TCA cycle intermediates at subnormothermia (25 °C). Using spatially resolved isotope tracing we demonstrate preserved metabolic fluxes in the kidney microenvironment up to Day 4 of perfusion. Beyond Day 4, significant changes were observed in renal cell populations through spatial lipidomics, and increases in injury markers such as LDH, NGAL and oxidized lipids. Finally, we demonstrate that perfused kidneys maintain functional parameters up to Day 4. Collectively, these findings provide evidence that this approach enables metabolic and functional preservation of human kidneys over multiple days, establishing a solid foundation for future clinical investigations.

ABSTRACT Infections with multidrug-resistant bacteria pose a major healthcare problem which urges the need for novel treatment options. Besides its potent antiplatelet properties, ticagrelor has antibacterial activity against Gram-positive bacteria, including methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). Several retrospective studies in cardiovascular patients support an antibacterial effect of this drug which is not related to its antiplatelet activity. We investigated the mechanism of action of ticagrelor in Staphylococcus aureus and model Bacillus subtilis, and assessed cross-resistance with two conventional anti-MRSA antibiotics, vancomycin and daptomycin. Bacillus subtilis bioreporter strains revealed ticagrelor-induced cell envelope-related stress responses. Sub-inhibitory drug concentrations caused membrane depolarization, impaired positioning of both the peripheral membrane protein MinD and the peptidoglycan precursor lipid II, and it affected cell shape. At the MIC, ticagrelor destroyed membrane integrity, indicated by the influx of membrane impermeable dyes, and lipid aggregate formation. Whole-genome sequencing of in vitro-generated ticagrelor-resistant MRSA clones revealed mutations in genes encoding ClpP, ClpX, and YjbH. Lipidomic analysis of resistant clones displayed changes in levels of the most abundant lipids of the Staphylococcus aureus membrane, for example, cardiolipins, phosphatidylglycerols, and diacylglycerols. Exogeneous cardiolipin, phosphatidylglycerol, or diacylglycerol antagonized the antibacterial properties of ticagrelor. Ticagrelor enhanced MRSA growth inhibition and killing by vancomycin and daptomycin in both exponential and stationary phases. Finally, no cross-resistance was observed between ticagrelor and daptomycin, or vancomycin. Our study demonstrates that ticagrelor targets multiple lipids in the cytoplasmic membrane of Gram-positive bacteria, thereby retaining activity against multidrug-resistant staphylococci including daptomycin- and vancomycin-resistant strains.IMPORTANCEInfections with multidrug-resistant bacteria pose a major healthcare problem with an urgent need for novel treatment options. The antiplatelet drug ticagrelor possesses antibacterial activity against Gram-positive bacteria including methicillin-resistant and vancomycin-resistant Staphylococcus aureus strains. We report a unique, dose-dependent, antibacterial mechanism of action of ticagrelor, which alters the properties and integrity of the bacterial cytoplasmic membrane. Ticagrelor retains activity against multidrug-resistant staphylococci, including isolates carrying the most common in vivo selected daptomycin resistance mutations and vancomycin-intermediate Staphylococcus aureus. Our data support the use of ticagrelor as adjunct therapy against multidrug-resistant strains. Because of the presence of multiple non-protein targets of this drug within the bacterial membrane, resistance development is expected to be slow. All these findings corroborate the accumulating observational clinical evidence for a beneficial anti-bacterial effect of ticagrelor in cardiovascular patients in need of such treatment.

Abstract Background People living with HIV (PLWH), even when viral replication is controlled through antiretroviral therapy (ART), experience persistent inflammation. This inflammation is partly attributed to intestinal microbial dysbiosis and translocation, which may lead to non-AIDS-related aging-associated comorbidities. The extent to which living with HIV — influenced by the infection itself, ART usage, sexual orientation, or other associated factors — affects the biological age of the intestines is unclear. Furthermore, the role of microbial dysbiosis and translocation in the biological aging of PLWH remains to be elucidated. To investigate these uncertainties, we used a systems biology approach, analyzing colon and ileal biopsies, blood samples, and stool specimens from PLWH on ART and people living without HIV (PLWoH) as controls. Results PLWH exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to PLWoH. Investigating the relationship between microbial translocation and biological aging, PLWH had decreased levels of tight junction proteins in the intestines, along with increased microbial translocation. This intestinal permeability correlated with faster biological aging and increased inflammation. When investigating the relationship between microbial dysbiosis and biological aging, the intestines of PLWH had higher abundance of specific pro-inflammatory bacteria, such as Catenibacterium and Prevotella. These bacteria correlated with accelerated biological aging. Conversely, the intestines of PLWH had lower abundance of bacteria known for producing the anti-inflammatory short-chain fatty acids, such as Subdoligranulum and Erysipelotrichaceae, and these bacteria were associated with slower biological aging. Correlation networks revealed significant links between specific microbial genera in the colon and ileum (but not in feces), increased aging, a rise in pro-inflammatory microbe-related metabolites (e.g., those in the tryptophan metabolism pathway), and a decrease in anti-inflammatory metabolites like hippuric acid. Conclusions We identified specific microbial compositions and microbiota-related metabolic pathways that are intertwined with intestinal and systemic biological aging. This microbial signature of biological aging is likely reflecting various factors including the HIV infection itself, ART usage, sexual orientation, and other aspects associated with living with HIV. A deeper understanding of the mechanisms underlying these connections could offer potential strategies to mitigate accelerated aging and its associated health complications. Video Abstract

Abstract Aim The aim of the study was to describe nursing teams' theoretical knowledge of delirium and their perceptions of the way in which it is handled in acute inpatient units. Design This is a descriptive cross‐sectional study using a questionnaire comprising ten questions on knowledge and seven on perception. Methods The sample consisted of 216 professionals working at a hospital complex in Madrid, Spain. Descriptive and non‐parametric bivariate analyses were performed for a p

Abstract Background Alzheimer’s disease (AD) is characterized by a polyetiological origin. Despite the global burden of AD and the advances made in AD drug research and development, the cure of the disease remains elusive, since any developed drug has demonstrated effectiveness to cure AD. Strikingly, an increasing number of studies indicate a linkage between AD and type 2 diabetes mellitus (T2DM), as both diseases share some common pathophysiological features. In fact, β-secretase (BACE1) and acetylcholinesterase (AChE), two enzymes involved in both conditions, have been considered promising targets for both pathologies. In this regard, due to the multifactorial origin of these diseases, current research efforts are focusing on the development of multi-target drugs as a very promising option to derive effective treatments for both conditions. In the present study, we evaluated the effect of rhein-huprine hybrid (RHE-HUP), a synthesized BACE1 and AChE inhibitor, both considered key factors not only in AD but also in metabolic pathologies. Thus, the aim of this study is to evaluate the effects of this compound in APP/PS1 female mice, a well-established familial AD mouse model, challenged by high-fat diet (HFD) consumption to concomitantly simulate a T2DM-like condition. Results Intraperitoneal treatment with RHE-HUP in APP/PS1 mice for 4 weeks reduced the main hallmarks of AD, including Tau hyperphosphorylation, Aβ42 peptide levels and plaque formation. Moreover, we found a decreased inflammatory response together with an increase in different synaptic proteins, such as drebrin 1 (DBN1) or synaptophysin, and in neurotrophic factors, especially in BDNF levels, correlated with a recovery in the number of dendritic spines, which resulted in memory improvement. Notably, the improvement observed in this model can be attributed directly to a protein regulation at central level, since no peripheral modification of those alterations induced by HFD consumption was observed. Conclusions Our results suggest that RHE-HUP could be a new candidate for the treatment of AD, even for individuals with high risk due to peripheral metabolic disturbances, given its multi-target profile which allows for the improvement of some of the most important hallmarks of the disease.

Thyme oil (THO) possesses excellent antibacterial and antioxidant properties which are suitable for skin inflammatory disorders such as acne vulgaris. However, THO is insoluble in water and its components are highly volatile. Therefore, these drawbacks may be overcome by its encapsulation in biodegradable PLGA nanoparticles (THO-NPs) that had been functionalized using several strategies. Moreover, cell viability was studied in HaCat cells, confirming their safety. In order to assess therapeutic efficacy against acne, bacterial reduction capacity and antioxidant properties were assessed. Moreover, the anti-inflammatory and wound-healing abilities of THO-NPs were also confirmed. Additionally, ex vivo antioxidant assessment was carried out using pig skin, demonstrating the suitable antioxidant properties of THO-NPs. Moreover, THO and THO-NPs were dispersed in a gelling system, and stability, rheological properties, and extensibility were assessed. Finally, the biomechanical properties of THO-hydrogel and THO-NP-hydrogel were studied in human volunteers, confirming the suitable activity for the treatment of acne. As a conclusion, THO has been encapsulated into PLGA NPs, and in vitro, ex vivo, and in vivo assessments had been carried out, demonstrating excellent properties for the treatment of inflammatory skin disorders.

Summary: 2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8+ T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.

Introduction: Pharmacogenetics-informed drug prescribing is increasingly applied in clinical practice. Typically, drug metabolizing phenotypes are determined based on genetic test results, whereupon dosage or drugs are adjusted. Drug-drug-interactions (DDIs) caused by concomitant medication can however cause mismatches between predicted and observed phenotypes (phenoconversion). Here we investigated the impact of CYP2C19 genotype on the outcome of CYP2C19-dependent DDIs in human liver microsomes.Methods: Liver samples from 40 patients were included, and genotyped for CYP2C19*2, *3 and *17 variants. S-mephenytoin metabolism in microsomal fractions was used as proxy for CYP2C19 activity, and concordance between genotype-predicted and observed CYP2C19 phenotype was examined. Individual microsomes were subsequently co-exposed to fluvoxamine, voriconazole, omeprazole or pantoprazole to simulate DDIs.Results: Maximal CYP2C19 activity (Vmax) in genotype-predicted intermediate metabolizers (IMs; *1/*2 or *2/*17), rapid metabolizers (RMs; *1/*17) and ultrarapid metabolizers (UMs; *17/*17) was not different from Vmax of predicted normal metabolizers (NMs; *1/*1). Conversely, CYP2C19*2/*2 genotyped-donors exhibited Vmax rates ∼9% of NMs, confirming the genotype-predicted poor metabolizer (PM) phenotype. Categorizing CYP2C19 activity, we found a 40% concordance between genetically-predicted CYP2C19 phenotypes and measured phenotypes, indicating substantial phenoconversion. Eight patients (20%) exhibited CYP2C19 IM/PM phenotypes that were not predicted by their CYP2C19 genotype, of which six could be linked to the presence of diabetes or liver disease. In subsequent DDI experiments, CYP2C19 activity was inhibited by omeprazole (−37% ± 8%), voriconazole (−59% ± 4%) and fluvoxamine (−85% ± 2%), but not by pantoprazole (−2 ± 4%). The strength of CYP2C19 inhibitors remained unaffected by CYP2C19 genotype, as similar percental declines in CYP2C19 activity and comparable metabolism-dependent inhibitory constants (Kinact/KI) of omeprazole were observed between CYP2C19 genotypes. However, the consequences of CYP2C19 inhibitor-mediated phenoconversion were different between CYP2C19 genotypes. In example, voriconazole converted 50% of *1/*1 donors to a IM/PM phenotype, but only 14% of *1/*17 donors. Fluvoxamine converted all donors to phenotypic IMs/PMs, but *1/*17 (14%) were less likely to become PMs than *1/*1 (50%) or *1/*2 and *2/*17 (57%).Conclusion: This study suggests that the differential outcome of CYP2C19-mediated DDIs between genotypes are primarily dictated by basal CYP2C19 activity, that may in part be predicted by CYP2C19 genotype but likely also depends on disease-related factors.

Abstract Background Acne is a common skin disorder that involves an infection inside the hair follicle, which is usually treated with antibiotics, resulting in unbalanced skin microbiota and microbial resistance. For this reason, we developed polymeric nanoparticles encapsulating thymol, a natural active compound with antimicrobial and antioxidant properties. In this work, optimization physicochemical characterization, biopharmaceutical behavior and therapeutic efficacy of this novel nanostructured system were assessed. Results Thymol NPs (TH-NP) resulted on suitable average particle size below 200 nm with a surface charge around − 28 mV and high encapsulation efficiency (80%). TH-NP released TH in a sustained manner and provide a slow-rate penetration into the hair follicle, being highly retained inside the skin. TH-NP possess a potent antimicrobial activity against Cutibacterium acnes and minor effect towards Staphylococcus epidermis, the major resident of the healthy skin microbiota. Additionally, the stability and sterility of developed NPs were maintained along storage. Conclusion TH-NP showed a promising and efficient alternative for the treatment of skin acne infection, avoiding antibiotic administration, reducing side effects, and preventing microbial drug resistance, without altering the healthy skin microbiota. Additionally, TH-NP enhanced TH antioxidant activity, constituting a natural, preservative-free, approach for acne treatment. Graphical Abstract

Somatic idioms – those including a part of the body – have been traditionally studied from a synchronic perspective, yielding different explanations for their semantic value. The main objective of this paper is to highlight the diachronic origin of idiomatic meaning, by illustrating the process of phraseologization from a historical, usage-based perspective. As the first step, we will reflect on the general nature of phraseological meaning, and then on the semantic particularities of somatic idioms. Secondly, we will carry out a corpus-based diachronic analysis of the Catalan idiom tapar-se elnas (to hold one’s nose) within the framework of the Invited Inference Theory of Semantic Change. The different stages of the process will be exemplified and discussed. As a result, a new notion of somatic idioms as frozen human actions will be presented

Abstract Epilepsy is the second most prevalent neurological disease worldwide. It is mainly characterized by an electrical abnormal activity in different brain regions. The massive entrance of Ca2+ into neurons is the main neurotoxic process that lead to cell death and finally to neurodegeneration. Although there are a huge number of antiseizure medications, there are many patients who do not respond to the treatments and present refractory epilepsy. In this context, nanomedicine constitutes a promising alternative to enhance the central nervous system bioavailability of antiseizure medications. The encapsulation of different chemical compounds at once in a variety of controlled drug delivery systems gives rise to an enhanced drug effectiveness mainly due to their targeting and penetration into the deepest brain region and the protection of the drug chemical structure. Thus, in this review we will explore the recent advances in the development of drugs associated with polymeric and lipid‐based nanocarriers as novel tools for the management of epilepsy disorders.

Synthetic glucocorticoids are clinically used to treat auto-immune and inflammatory disease. Despite the high efficacy, glucocorticoid treatments causes side effects such as obesity and insulin resistance in many patients. Via their pharmacological target, the glucocorticoid receptor (GR), glucocorticoids suppress endogenous glucocorticoid secretion. Endogenous, but not synthetic, glucocorticoids activate the mineralocorticoid receptor (MR) and side effects of synthetic glucocorticoids may thus not only result from GR hyperactivation but also from MR hypoactivation. Here, we tested the hypothesis that reactivation of MR with corticosterone add-on treatment can attenuate the metabolic effects of the synthetic glucocorticoid dexamethasone. Male 8-week-old C57Bl/6J mice received a high-fat diet supplemented with dexamethasone or vehicle, and were subcutaneously implanted with low-dose corticosterone- or vehicle-containing pellets. Dexamethasone strongly reduced body weight and fat mass gain, while corticosterone add-on partially normalized this. Dexamethasone-induced hyperglycemia and hyperinsulinemia were exacerbated by corticosterone add-on, which was prevented by MR antagonism. In subcutaneous white adipose tissue, corticosterone add-on prevented the dexamethasone-induced expression of intracellular lipolysis genes. In brown adipose tissue, dexamethasone also upregulated gene expression of brown adipose tissue identity markers, lipid transporters and lipolysis enzymes, which was prevented by corticosterone add-on. In conclusion, corticosterone add-on treatment prevents several, while exacerbating other metabolic effects of dexamethasone. While the exact role of MR remains elusive, this study suggests that corticosterone suppression by dexamethasone contributes to its effects in mice.

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ), the most PPAR abundant isotype in the central nervous system, is involved in microglial homeostasis and metabolism, whose disturbances have been demonstrated to play a key role in memory impairment. Although PPARβ/δ function is well-established in metabolism, its contribution to neuronal and specifically memory process is underexplored. Therefore, the aim of the study is to determine the role of PPARβ/δ in the neuropathological pathways involved in memory impairment and as to whether a risk factor implicated in memory loss such as obesity modulates neuropathological markers. To carry out this study, 6-month-old total knock-out for the Ppard gene male mice with C57BL/6X129/SV background (PPARβ/δ-/-) and wild-type (WT) littermates with the same genetic background were used. Animals were fed, after the weaning (at 21 days old), and throughout their growth, either conventional chow (CT) or a palmitic acid-enriched diet (HFD). Thus, four groups were defined: WT CT, WT HFD, PPARβ/δ-/- CT, and PPARβ/δ-/- HFD. Before sacrifice, novel object recognition test (NORT) and glucose and insulin tolerance tests were performed. After that, animals were sacrificed by intracardiac perfusion or cervical dislocation. Different techniques, such as GolgiStain kit or immunofluorescence, were used to evaluate the role of PPARβ/δ in memory dysfunction. Our results showed a decrease in dendritic spine density and synaptic markers in PPARβ/δ-/- mice, which were corroborated in the NORT. Likewise, our study demonstrated that the lack of PPARβ/δ receptor enhances gliosis in the hippocampus, contributing to astrocyte and microglial activation and to the increase in neuroinflammatory biomarkers. Additionally, alterations in the hippocampal insulin receptor pathway were found. Interestingly, while some of the disturbances caused by the lack of PPARβ/δ were not affected by feeding the HFD, others were exacerbated or required the combination of both factors. Taken together, the loss of PPARβ/δ-/- affects neuronal and synaptic structure, contributing to memory dysfunction, and they also present this receptor as a possible new target for the treatment of memory impairment.

Abstract Increasing life expectancy has led to an aging population, which has consequently increased the prevalence of dementia. Alzheimer's disease (AD), the most common form of dementia worldwide, is estimated to make up 50–80% of all cases. AD cases are expected to reach 131 million by 2050, and this increasing prevalence will critically burden economies and health systems in the next decades. There is currently no treatment that can stop or reverse disease progression. In addition, the late diagnosis of AD constitutes a major obstacle to effective disease management. Therefore, improved diagnostic tools and new treatments for AD are urgently needed. In this review, we investigate and describe both well-established and recently discovered AD biomarkers that could potentially be used to detect AD at early stages and allow the monitoring of disease progression. Proteins such as NfL, MMPs, p-tau217, YKL-40, SNAP-25, VCAM-1, and Ng / BACE are some of the most promising biomarkers because of their successful use as diagnostic tools. In addition, we explore the most recent molecular strategies for an AD therapeutic approach and nanomedicine-based technologies, used to both target drugs to the brain and serve as devices for tracking disease progression diagnostic biomarkers. State-of-the-art nanoparticles, such as polymeric, lipid, and metal-based, are being widely investigated for their potential to improve the effectiveness of both conventional drugs and novel compounds for treating AD. The most recent studies on these nanodevices are deeply explained and discussed in this review. Graphic Abstract

Nanocarriers, and especially nanostructured lipid carriers (NLC), represent one of the most effective systems for topical drug administration. NLCs are biodegradable, biocompatible and provide a prolonged drug release. The glutamate release inhibitor Riluzole (RLZ) is a drug currently used for amyotrophic lateral sclerosis (ALS), with anti-proliferative effects potentially beneficial for diseases with excessive cell turnover. However, RLZ possesses low water solubility and high light-sensibility. We present here optimized NLCs loaded with RLZ (RLZ-NLCs) as a potential topical treatment. RLZ-NLCs were prepared by the hot-pressure homogenization method using active essential oils as liquid lipids, and optimized using the design of experiments approach. RLZ-NLCs were developed obtaining optimal properties for dermal application (mean size below 200 nm, negative surface charge and high RLZ entrapment efficacy). In vitro release study demonstrates that RLZ-NLCs allow the successful delivery of RLZ in a sustained manner. Moreover, RLZ-NLCs are not angiogenic and are able to inhibit keratinocyte cell proliferation. Hence, a NLCs delivery system loading RLZ in combination with natural essential oils constitutes a promising strategy against keratinocyte hyperproliferative conditions.

Among the extracellular vesicles, apoptotic bodies (ABs) are only formed during the apoptosis and perform a relevant role in the pathogenesis of different diseases. Recently, it has been demonstrated that ABs from human renal proximal tubular HK-2 cells, either induced by cisplatin or by UV light, can lead to further apoptotic death in naïve HK-2 cells. Thus, the aim of this work was to carry out a non-targeted metabolomic approach to study if the apoptotic stimulus (cisplatin or UV light) affects in a different way the metabolites involved in the propagation of apoptosis. Both ABs and their extracellular fluid were analyzed using a reverse-phase liquid chromatography-mass spectrometry setup. Principal components analysis showed a tight clustering of each experimental group and partial least square discriminant analysis was used to assess the metabolic differences existing between these groups. Considering the variable importance in the projection values, molecular features were selected and some of them could be identified either unequivocally or tentatively. The resulting pathways indicated that there are significant, stimulus-specific differences in metabolites abundancies that may propagate apoptosis to healthy proximal tubular cells; thus, we hypothesize that the share in apoptosis of these metabolites might vary depending on the apoptotic stimulus.

Abstract Infectious diseases kill over 17 million people a year, among which bacterial infections stand out. From all the bacterial infections, tuberculosis, diarrhoea, meningitis, pneumonia, sexual transmission diseases and nosocomial infections are the most severe bacterial infections, which affect millions of people worldwide. Moreover, the indiscriminate use of antibiotic drugs in the last decades has triggered an increasing multiple resistance towards these drugs, which represent a serious global socioeconomic and public health risk. It is estimated that 33,000 and 35,000 people die yearly in Europe and the United States, respectively, as a direct result of antimicrobial resistance. For all these reasons, there is an emerging need to find novel alternatives to overcome these issues and reduced the morbidity and mortality associated to bacterial infectious diseases. In that sense, nanotechnological approaches, especially smart polymeric nanoparticles, has wrought a revolution in this field, providing an innovative therapeutic alternative able to improve the limitations encountered in available treatments and capable to be effective by theirselves. In this review, we examine the current status of most dangerous human infections, together with an in-depth discussion of the role of nanomedicine to overcome the current disadvantages, and specifically the most recent and innovative studies involving polymeric nanoparticles against most common bacterial infections of the human body.

An analytical methodology based on an O-[2-(methacryloyloxy)-ethylcarbamoyl]-10,11-dihydroquinidine (MQD)-silica hybrid monolithic column was developed for the enantioseparation of 9-fluorenylmethoxycarbonyl (FMOC) derivatized amino acids by nano-liquid chromatography. The mobile phase was optimized including the apparent pH, content of ACN, and concentration of the buffer to obtain a satisfactory enantioresolution performance. 27 FMOC derivatized amino acids including 19 protein and 8 non-protein amino acids were tested, and 19 out of them were enantiomerically discriminated obtaining baseline separation for 11 of them. Analytical characteristics of the method were evaluated for norvaline and tryptophan in terms of linearity, precision, accuracy, limits of detection (LOD) and quantitation (LOQ) showing good performance to be applied to the enantiomeric determination of these amino acids in dietary supplements. LOD and LOQ values were 9.3 and 31 μM for norvaline enantiomers and 7.5 and 25 μM for tryptophan enantiomers, respectively. The contents of d-norvaline and d-tryptophan were below their respective LODs in all the analyzed samples. Quantitation of l-tryptophan and l-norvaline showed good agreement with the labeled contents except for one sample which did not show presence of l-norvaline, contrary to the label indication. Keywords: 9-Fluorenylmethoxycarbonyl, Amino acids, Chiral separation, Nano-LC, Quinidine-silica hybrid monolithic column

Neurodegenerative diseases constitute a group of pathologies whose etiology remains unknown in many cases, and there are no treatments that stop the progression of such diseases. Moreover, the existence of the blood–brain barrier is an impediment to the penetration of exogenous molecules, including those found in many drugs. Exosomes are extracellular vesicles secreted by a wide variety of cells, and their primary functions include intercellular communication, immune responses, human reproduction, and synaptic plasticity. Due to their natural origin and molecular similarities with most cell types, exosomes have emerged as promising therapeutic tools for numerous diseases. Specifically, neurodegenerative diseases have shown to be a potential target for this nanomedicine strategy due to the difficult access to the brain and the strategy’s pathophysiological complexity. In this regard, this review explores the most important biological-origin drug delivery systems, innovative isolation methods of exosomes, their physicochemical characterization, drug loading, cutting-edge functionalization strategies to target them within the brain, the latest research studies in neurodegenerative diseases, and the future challenges of exosomes as nanomedicine-based therapeutic tools.

A novel teicoplanin functionalized organic-silica hybrid chiral monolithic column was prepared by a facile single-step approach. The conditions for the preparation of the organic-silica hybrid chiral monolithic column were systematically optimized, including the amount of poly (ethylene glycol) (PEG) and urea, the tetramethyl orthosilicate (TMOS)/3-(trimethoxysilyl)-propylmethacrylate (γ-MAPS) ratio (v/v), the content of teicoplanin-2-isocyanatoethyl methacrylate (Tei-ICNEML) monomer, and the reaction temperature and time. The optimum column exhibited satisfactory efficiency, permeability and stability. In order to obtain satisfactory enantioseparation performance, reversed phase (RPM) and polar organic phase (POM) modes were employed, and different experimental conditions were optimized, such as buffer concentration and pH, amount of the organic solvent, concentration and ratio of TEA/HAc, and MeOH/ACN ratio. The stability of the Tei-ICNEML organic-silica hybrid monolithic column was also investigated in both POM and RPM separation modes. Then, this novel monolithic column was successfully applied to achieve the enantioseparation of amino alcohols, N-derivatized amino acids and mandelic acids. 15 out of 20 amino alcohols were baseline separated with good column efficiency in the POM mode, and 3 out of 5 mandelic acids and 5 out of 6 N-derivatized amino acids were baseline separated in the RPM mode.

Cancer is identified as one of the main causes of death worldwide, and an effective treatment that can reduce/eliminate serious adverse effects is still an unmet medical need. Diclofenac, a non-steroidal anti-inflammatory drug (NSAID), has demonstrated promising antitumoral properties. However, the prolonged use of this NSAID poses several adverse effects. These can be overcome by the use of suitable delivery systems that are able to provide a controlled delivery of the payload. In this study, Diclofenac was incorporated into biodegradable polymeric nanoparticles based on PLGA and the formulation was optimized using a factorial design approach. A monodisperse nanoparticle population was obtained with a mean size of ca. 150 nm and negative surface charge. The release profile of diclofenac from the optimal formulation followed a prolonged release kinetics. Diclofenac nanoparticles demonstrated antitumoral and antiangiogenic properties without causing cytotoxicity to non-tumoral cells, and can be pointed out as a safe, promising and innovative nanoparticle-based formulation with potential antitumoral effects.

The physical properties of table olive fruit are an important factor in the design of harvesting, transport, classification, and commercialization. The visual quality of the fruits harvested is the most important factor limiting the commercialization of table olives. The mechanical damage during harvesting consists of local tissue degradation, resulting in bruising of the fruits. In recent years, several studies have been carried out to identify physical properties and to calculate indices that characterize the damage to olives. However, all of them are based on 2D techniques. The aim of this work is the determination of new geometric parameters based on a 3D analysis of the scanned olives. The 3D shape parameters have been collated with those obtained by standard 2D shape analysis methods. From the results, it is observed that the use of high-resolution, medium-cost 3D technologies allows a more precise characterization of the shape of damages observed in table olives. To carry out three-dimensional analysis, Boolean operations of the solid and parametric surfaces of the meshes obtained by a 3D scanner have been used.

The aim of this work was to design innovative nanostructured lipid carriers (NLCs) for the delivery of dexibuprofen (DXI) as an antiproliferative therapy against tumoral processes, and overcome its side effects. DXI-NLC samples were prepared with beeswax, Miglyol 812 and Tween 80 using high-pressure homogenization. A two-level factorial design 24 was applied to optimize the formulation, and physicochemical properties such as particle size, zeta potential, polydispersity index and entrapment efficiency were measured. Optimized parameters of DXI-NLCs exhibited a mean particle size of 152.3 nm, a polydispersity index below 0.2, and high DXI entrapment efficiency (higher than 99%). Moreover, DXI-NLCs provided a prolonged drug release, slower than the free DXI. DXI-NLCs were stable for 2 months and their morphology revealed that they possess a spherical shape. In vitro cytotoxicity and anticancer potential studies were performed towards prostate (PC-3) and breast (MDA-MB-468) cancer cell lines. The highest activity of DXI-NLCs was observed towards breast cancer cells, which were effectively inhibited at 3.4 μM. Therefore, DXI-NLCs constitute a promising antiproliferative therapy that has proven to be especially effective against breast cancer.

Endodontic-related diseases constitute the fourth most expensive pathologies in industrialized countries. Specifically, endodontics is the part of dentistry focused on treating disorders of the dental pulp and its consequences. In order to treat these problems, especially endodontic infections, dental barriers and complex root canal anatomy should be overcome. This constitutes an unmet medical need since the rate of successful disinfection with the currently marketed drugs is around 85%. Therefore, nanoparticles constitute a suitable alternative in order to deliver active compounds effectively to the target site, increasing their therapeutic efficacy. Therefore, in the present review, an overview of dental anatomy and the barriers that should be overcome for effective disinfection will be summarized. In addition, the versatility of nanoparticles for drug delivery and their specific uses in dentistry are comprehensively discussed. Finally, the latest findings, potential applications and state of the art nanoparticles with special emphasis on biodegradable nanoparticles used for endodontic disinfection are also reviewed.

Benzodiazepines (BZDs) and Z-drugs are compounds widely prescribed in medical practice due to their anxiolytic, hypnotic, and muscle relaxant properties. Yet, their chronic use is associated with cases of abuse, dependence, and relapse in many patients. Furthermore, elderly people are susceptible to alterations in pharmacodynamics, pharmacokinetics as well as to drug interaction due to polypharmacy. These situations increase the risk for the appearance of cognitive affectations and the development of pathologies like Alzheimer's disease (AD). In the present work, there is a summary of some clinical studies that have evaluated the effect of BZDs and Z-drugs in the adult population with and without AD, focusing on the relationship between their use and the loss of cognitive function. Additionally, there is an assessment of preclinical studies focused on finding molecular proof on the pathways by which these drugs could be involved in AD pathogenesis. Moreover, available data (1990–2019) on BZD and Z-drug use among elderly patients, with and without AD, was compiled in this work. Finally, the relationship between the use of BZD and Z-drugs for the treatment of insomnia and the appearance of AD biomarkers was analyzed. Results pointed to a vicious circle that would worsen the condition of patients over time. Likewise, it put into relevance the need for close monitoring of those patients using BZDs that also suffer from AD. Consequently, future studies should focus on optimizing strategies for insomnia treatment in the elderly by using other substances like melatonin agonists, which is described to have a much more significant safety profile.

Licochalcone-A is a natural compound with anti-inflammatory properties. However, it possesses low water solubility, making its application for the treatment of ocular inflammation difficult. To overcome this drawback, biodegradable nanoparticles incorporating Licochalcone-A have been developed. Additionally, to avoid fast clearance and increase cellular internalization into the ocular tissues, PLGA nanoparticles have been functionalized using PEG and cell penetrating peptides (Tet-1 and B6). To optimize the formulations, a factorial design was carried out and short-term stability of the nanoparticles was studied. Moreover, morphology was also observed by transmission electron microcopy and in vitro drug release was carried out. Ocular tolerance of the formulations was ensured in vitro and in vivo and anti-inflammatory therapeutic efficacy was also assessed. Surface functionalized nanoparticles loading Licochalcone-A were developed with an average size below 200 nm, a positive surface charge, and a monodisperse population. The formulations were non-irritant and showed a prolonged Licochalcone-A release. Despite the fact that both Licochalcone-A Tet-1 and B6 functionalized nanoparticles demonstrated to be suitable for the treatment of ocular inflammation, B6 targeted nanoparticles provided greater therapeutic efficacy in in vivo assays.

Abstract Background Memantine, drug approved for moderate to severe Alzheimer’s disease, has not shown to be fully effective. In order to solve this issue, polylactic-co-glycolic (PLGA) nanoparticles could be a suitable solution to increase drug’s action on the target site as well as decrease adverse effects. For these reason, Memantine was loaded in biodegradable PLGA nanoparticles, produced by double emulsion method and surface-coated with polyethylene glycol. MEM–PEG–PLGA nanoparticles (NPs) were aimed to target the blood–brain barrier (BBB) upon oral administration for the treatment of Alzheimer’s disease. Results The production parameters were optimized by design of experiments. MEM–PEG–PLGA NPs showed a mean particle size below 200 nm (152.6 ± 0.5 nm), monomodal size distribution (polydispersity index, PI

This review highlights the application of lipid nanoparticles (Solid Lipid Nanoparticles, Nanostructured Lipid Carriers, or Lipid Drug Conjugates) as effective drug carriers for pathologies affecting the posterior ocular segment. Eye anatomy and the most relevant diseases affecting the posterior segment will be summarized. Moreover, preparation methods and different types and subtypes of lipid nanoparticles will also be reviewed. Lipid nanoparticles used as carriers to deliver drugs to the posterior eye segment as well as their administration routes, pharmaceutical forms and ocular distribution will be discussed emphasizing the different targeting strategies most recently employed for ocular drug delivery.

Epilepsy is a chronic disease of the central nervous system characterized by an electrical imbalance in neurons. It is the second most prevalent neurological disease, with 50 million people affected around the world, and 30% of all epilepsies do not respond to available treatments. Currently, the main hypothesis about the molecular processes that trigger epileptic seizures and promote the neurotoxic effects that lead to cell death focuses on the exacerbation of the glutamate pathway and the massive influx of Ca2+ into neurons by different factors. However, other mechanisms have been proposed, and most of them have also been described in other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, or multiple sclerosis. Interestingly, and mainly because of these common molecular links and the lack of effective treatments for these diseases, some antiseizure drugs have been investigated to evaluate their therapeutic potential in these pathologies. Therefore, in this review, we thoroughly investigate the common molecular pathways between epilepsy and the major neurodegenerative diseases, examine the incidence of epilepsy in these populations, and explore the use of current and innovative antiseizure drugs in the treatment of refractory epilepsy and other neurodegenerative diseases.

Dry eye disease (DED) is a high prevalent multifactorial disease characterized by a lack of homeostasis of the tear film which causes ocular surface inflammation, soreness, and visual disturbance. Conventional ophthalmic treatments present limitations such as low bioavailability and side effects. Lactoferrin (LF) constitutes a promising therapeutic tool, but its poor aqueous stability and high nasolacrimal duct drainage hinder its potential efficacy. In this study, we incorporate lactoferrin into hyaluronic acid coated liposomes by the lipid film method, followed by high pressure homogenization. Pharmacokinetic and pharmacodynamic profiles were evaluated in vitro and ex vivo. Cytotoxicity and ocular tolerance were assayed both in vitro and in vivo using New Zealand rabbits, as well as dry eye and anti-inflammatory treatments. LF loaded liposomes showed an average size of 90 nm, monomodal population, positive surface charge and a high molecular weight protein encapsulation of 53%. Biopharmaceutical behaviour was enhanced by the nanocarrier, and any cytotoxic effect was studied in human corneal epithelial cells. Developed liposomes revealed the ability to reverse dry eye symptoms and possess anti-inflammatory efficacy, without inducing ocular irritation. Hence, lactoferrin loaded liposomes could offer an innovative nanotechnological tool as suitable approach in the treatment of DED.

The present work is focused on the development of novel surface-functionalized poly(lactic-co-glycolic acid) nanoparticles loaded with thymol (TH-NPs) for topical administration enhancing thymol anti-inflammatory, antioxidant and wound healing activities against acne. TH-NPs were prepared by solvent evaporation method using different surface functionalization strategies and obtaining suitable physicochemical parameters and a good short-term stability at 4 °C. Moreover, TH-NPs skin penetration and antioxidant activity were assessed in ex vivo pig skin models. Skin penetration of TH-NPs followed the follicular route, independently of the surface charge and they were able to enhance antioxidant capacity. Furthermore, antimicrobial activity against Cutibacterium acnes was evaluated in vitro by the suspension test showing improved antibacterial performance. Using human keratinocyte cells (HaCat), cytotoxicity, cellular uptake, antioxidant, anti-inflammatory and wound healing activities were studied. TH-NPs were non-toxic and efficiently internalized inside the cells. In addition, TH-NPs displayed significant anti-inflammatory, antioxidant and wound healing activities, which were highly influenced by TH-NPs surface modifications. Moreover, a synergic activity between TH-NPs and their surface functionalization was demonstrated. To conclude, surface-modified TH-NPs had proven to be suitable to be used as anti-inflammatory, antioxidant and wound healing agents, constituting a promising therapy for treating acne infection and associated inflammation.

Metal nanoparticles have been extensively investigated for different types of pharmaceutical applications. However, their use has raised some concerns about their toxicity involving the increase of reactive oxygen species causing cellular apoptosis. Therefore, in this review we summarize the most relevant toxicity mechanisms of gold, silver, copper and copper oxide nanoparticles as well as production methods of metal nanoparticles. Parameters involved in their toxicity such as size, surface charge and concentration are also highlighted. Moreover, a critical revision of the literature about the strategies used to reduce the toxicity of this type of nanoparticles is carried out throughout the review. Additionally, surface modifications using different coating strategies, nanoparticles targeting and morphology modifications are deeply explained.

Oxygen deficiency in cells, tissues, and organs can not only prevent the proper development of biological functions but it can also lead to several diseases and disorders. In this sense, the kidney deserves special attention since hypoxia can be considered an important factor in the pathophysiology of both acute kidney injury and chronic kidney disease. To provide better knowledge to unveil the molecular mechanisms involved, new studies are necessary. In this sense, this work aims to study, for the first time, an in vitro model of hypoxia-induced metabolic alterations in human proximal tubular HK-2 cells because renal proximal tubules are particularly susceptible to hypoxia. Different groups of cells, cultivated under control and hypoxia conditions at 0.5, 5, 24, and 48 h, were investigated using untargeted metabolomic approaches based on reversed-phase liquid chromatography–mass spectrometry. Both intracellular and extracellular fluids were studied to obtain a large metabolite coverage. On the other hand, multivariate and univariate analyses were carried out to find the differences among the cell groups and to select the most relevant variables. The molecular features identified as affected metabolites were mainly amino acids and Amadori compounds. Insights about their biological relevance are also provided.

Research in the pathogenesis of inflammatory skin diseases, such as skin dermatitis and psoriasis, has experienced some relevant breakthroughs in recent years. The understanding of age-related factors, gender, and genetic predisposition of these multifactorial diseases has been instrumental for the development of new pharmacological and technological treatment approaches. In this review, we discuss the molecular mechanisms behind the pathological features of psoriasis, also addressing the currently available treatments and novel therapies that are under clinical trials. Innovative therapies developed over the last 10 years have been researched. In this area, advantages of nanotechnological approaches to provide an effective drug concentration in the disease site are highlighted, together with microneedles as innovative candidates for drug delivery systems in psoriasis and other inflammatory chronic skin diseases.

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that accounts for about 60% of all diagnosed cases of dementia worldwide. Although there are currently several drugs marketed for its treatment, none are capable of slowing down or stopping the progression of AD. The role of the blood-brain barrier (BBB) plays a key role in the design of a successful treatment for this neurodegenerative disease. Nanosized particles have been proposed as suitable drug delivery systems to overcome BBB with the purpose of increasing bioavailability of drugs in the brain. Biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA-NPs) have been particularly regarded as promising drug delivery systems as they can be surface-tailored with functionalized molecules for site-specific targeting. In this review, a thorough discussion about the most recent functionalization strategies based on PLGA-NPs for AD and their mechanisms of action is provided, together with a description of AD pathogenesis and the role of the BBB in brain targeting.

The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα. Moreover, DXI reduced soluble β-amyloid (Aβ1-42) plaque deposition by decreasing APP, BACE1 and facilitating Aβ degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks.

Nowadays, Alzheimer’s disease (AD) is a severe sociological and clinical problem. Since it was first described, there has been a constant increase in its incidence and, for now, there are no effective treatments since current approved medications have only shown short-term symptomatic benefits. Therefore, it is imperative to increase efforts in the search for molecules and non-pharmacological strategies that are capable of slowing or stopping the progress of the disease and, ideally, to reverse it. The amyloid cascade hypothesis based on the fundamental role of amyloid has been the central hypothesis in the last 30 years. However, since amyloid-directed treatments have shown no relevant beneficial results other theories have been postulated to explain the origin of the pathology. The brain is a highly metabolically active energy-consuming tissue in the human body. It has an almost complete dependence on the metabolism of glucose and uses most of its energy for synaptic transmission. Thus, alterations on the utilization or availability of glucose may be cause for the appearance of neurodegenerative pathologies like AD. In this review article, the hypothesis known as Type 3 Diabetes (T3D) will be evaluated by summarizing some of the data that has been reported in recent years. According to published research, the adherence over time to low saturated fatty acids diets in the context of the Mediterranean diet would reduce the inflammatory levels in brain, with a decrease in the pro-inflammatory glial activation and mitochondrial oxidative stress. In this situation, the insulin receptor pathway would be able to fine tune the mitochondrial biogenesis in neuronal cells, regulation the adenosine triphosphate/adenosine diphosphate intracellular balance, and becoming a key factor involved in the preservation of the synaptic connexions and neuronal plasticity. In addition, new targets and strategies for the treatment of AD will be considered in this review for their potential as new pharmacological or non-pharmacological approaches.

This work is aimed at describing the design of a mechanical and programmable 3D capturing system to be used by either 3D scanner or DSLR camera through photogrammetry. Both methods are widely used in diverse areas, from engineering, architecture or archaeology, up to the field of medicine; but they also entail certain disadvantages, such as the high costs of certain equipment, such as scanners with some precision, and the need to resort to specialized operatives, among others. The purpose of this design is to create a robust, precise and cost-effective system that improves the limitations of the present equipment on the market, such as robotic arms or rotary tables. For this reason, a preliminary study has been conducted to analyse the needs of improvement, later, we have focused on the 3D design and prototyping. For its construction, there have been used the FDM additive technology and structural components that are easy to find in the market. With regards to electronic components, basic electronics and Arduino-based 3D printers firmware have been selected. For system testing, the capture equipment consists of a Spider Artec 3D Scanner and a Nikon 5100 SLR Camera. Finally, 3D models have been developed by comparing the 3D meshes obtained by the two methods, obtaining satisfactory results.

S-(+) enantiomer of ibuprofen (IBU) dexibuprofen (DXI) is known to be more potent than its R-(−) form and exhibits many advantages over the racemic mixture of IBU such as lower toxicity, greater clinical efficacy, and lesser variability in therapeutic effects. Moreover, DXI potential has been recently advocated to reduce cancer development and prevent the development of neurodegenerative diseases in addition to its anti-inflammatory properties. During the last decade, many attempts have been made to design novel formulations of DXI aimed at increasing its therapeutic benefits and minimizing the adverse effects. Therefore, this article summarizes pharmacological information about DXI, its pharmacokinetics, safety, and therapeutic outcomes. Moreover, modified DXI drug delivery approaches are extensively discussed. Recent studies of DXI prodrugs and novel DXI nanoformulations are analyzed as well as reviewing their efficacy for ocular, skin, and oral applications.

The last decades have been successively warmer at the Earth’s surface. An increasing interest in climate variability is appearing, and many research works have investigated the main effects on different climate variables. Some of them apply complex networks approaches to explore the spatial relation between distinct grid points or stations. In this work, the authors investigate whether topological properties change over several years. To this aim, we explore the application of the horizontal visibility graph (HVG) approach which maps a time series into a complex network. Data used in this study include a 60-year period of daily mean temperature anomalies in several stations over the Iberian Peninsula (Spain). Average degree, degree distribution exponent, and global clustering coefficient were analyzed. Interestingly, results show that they agree on a lack of significant trends, unlike annual mean values of anomalies, which present a characteristic upward trend. The main conclusions obtained are that complex networks structures and nonlinear features, such as weak correlations, appear not to be affected by rising temperatures derived from global climate conditions. Furthermore, different locations present a similar behavior and the intrinsic nature of these signals seems to be well described by network parameters.

The effective use of fusion inhibitor peptides against cervical and colorectal infections requires the development of sustained release formulations. In this work we comparatively study two different formulations based on polymeric nanoparticles and lipid vesicles to propose a suitable delivery nanosystem for releasing an HIV-1 fusion inhibitor peptide in vaginal mucosa. Polymeric nanoparticles of poly-d,l-lactic-co-glycolic acid (PLGA) and lipid large unilamellar vesicles loaded with the inhibitor peptide were prepared. Both formulations showed average sizes and polydispersity index values corresponding to monodisperse systems appropriate for vaginal permeation. High entrapment efficiency of the inhibitor peptide was achieved in lipid vesicles, which was probably due to the peptide’s hydrophobic nature. In addition, both nanocarriers remained stable after two weeks stored at 4 °C. While PLGA nanoparticles (NPs) did not show any delay in peptide release, lipid vesicles demonstrated favorably prolonged release of the peptide. Lipid vesicles were shown to improve the retention of the peptide on ex vivo vaginal tissue in a concentration sufficient to exert its pharmacological effect. Thus, the small size of lipid vesicles, their lipid-based composition as well as their ability to enhance peptide penetration on vaginal tissue led us to consider this formulation as a better nanosystem than polymeric nanoparticles for the sustained delivery of the HIV-1 fusion inhibitor peptide in vaginal tissues.

Ocular inflammation is one of the most prevalent diseases in ophthalmology, which can affect various parts of the eye or the surrounding tissues. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, are commonly used to treat ocular inflammation in the form of eye-drops. However, their bioavailability in ocular tissues is very low (less than 5%). Therefore, drug delivery systems such as biodegradable polymeric PLGA nanoparticles constitute a suitable alternative to topical eye administration, as they can improve ocular bioavailability and simultaneously reduce drug induced side effects. Moreover, their prolonged drug release can enhance patient treatment adherence as they require fewer administrations. Therefore, several formulations of PLGA based nanoparticles encapsulating dexibuprofen (active enantiomer of Ibuprofen) were prepared using the solvent displacement method employing different surfactants. The formulations have been characterized and their interactions with a customized lipid corneal membrane model were studied. Ex vivo permeation through ocular tissues and in vivo anti-inflammatory efficacy have also been studied.

Metal-based nanoparticles have been extensively investigated for a set of biomedical applications. According to the World Health Organization, in addition to their reduced size and selectivity for bacteria, metal-based nanoparticles have also proved to be effective against pathogens listed as a priority. Metal-based nanoparticles are known to have non-specific bacterial toxicity mechanisms (they do not bind to a specific receptor in the bacterial cell) which not only makes the development of resistance by bacteria difficult, but also broadens the spectrum of antibacterial activity. As a result, a large majority of metal-based nanoparticles efficacy studies performed so far have shown promising results in both Gram-positive and Gram-negative bacteria. The aim of this review has been a comprehensive discussion of the state of the art on the use of the most relevant types of metal nanoparticles employed as antimicrobial agents. A special emphasis to silver nanoparticles is given, while others (e.g., gold, zinc oxide, copper, and copper oxide nanoparticles) commonly used in antibiotherapy are also reviewed. The novelty of this review relies on the comparative discussion of the different types of metal nanoparticles, their production methods, physicochemical characterization, and pharmacokinetics together with the toxicological risk encountered with the use of different types of nanoparticles as antimicrobial agents. Their added-value in the development of alternative, more effective antibiotics against multi-resistant Gram-negative bacteria has been highlighted.

An untargeted metabolomics strategy using hydrophilic interaction chromatography-mass spectrometry (HILIC-MS) was developed in this work enabling the study of the coffee roasting process. Green coffee beans and coffee beans submitted to three different roasting degrees (light, medium, and strong) were analyzed. Chromatographic separation was carried out using water containing 10 mM ammonium formate with 0.2 % formic acid (mobile phase A) and acetonitrile containing 10 mM ammonium formate with 0.2 % formic acid (mobile phase B). A total of 93 molecular features were considered from which 31 were chosen as the most statistically significant using variable in the projection values. 13 metabolites were tentatively identified as potential biomarkers of the coffee roasting process using this metabolomic platform. Results obtained in this work were complementary to those achieved using orthogonal techniques such as reversed-phase liquid chromatography-mass spectrometry (RPLC-MS) and capillary electrophoresis-mass spectrometry (CE-MS) since only one metabolite was found to be common between HILIC-MS and RPLC-MS platforms (caffeoylshikimic acid isomer) and other between HILIC-MS and CE-MS platforms (choline). On the basis of these results, an untargeted metabolomics multiplatform is proposed in this work based on the integration of the three orthogonal techniques as a powerful tool to expand the coverage of the roasted coffee metabolome.

Diabetic nephropathy is characterized by the chronic loss of kidney function due to high glucose renal levels. HK-2 proximal tubular cells are good candidates to study this disease. The aim of this work was to study an in vitro model of high glucose-induced metabolic alterations in HK-2 cells to contribute to the pathogenesis of this diabetic complication. An untargeted metabolomics strategy based on CE-MS was developed to find metabolites affected under high glucose conditions. Intracellular and extracellular fluids from HK-2 cells treated with 25 mM glucose (high glucose group), with 5.5 mM glucose (normal glucose group), and with 5.5 mM glucose and 19.5 mM mannitol (osmotic control group) were analyzed. The main changes induced by high glucose were found in the extracellular medium where increased levels of four amino acids were detected. Three of them (alanine, proline, and glutamic acid) were exported from HK-2 cells to the extracellular medium. Other affected metabolites include Amadori products and cysteine, which are more likely cause and consequence, respectively, of the oxidative stress induced by high glucose in HK-2 cells. The developed CE-MS platform provides valuable insight into high glucose-induced metabolic alterations in proximal tubular cells and allows identifying discriminative molecules of diabetic nephropathy.

Digital images of food for later analysis tend to be heterogeneous in terms of color and luminosity. Improving these images by using filters is necessary and crucial before further processing. This paper compares the non-use of filters and the use of high-pass filters in the images of hand-cut Iberian ham that will be used in a multifractal analysis for the study of fat and its infiltration. The yielded results show that with the use of a high-pass filter, more accurate fractal dimensions were obtained, which can be featured in predictive techniques of Iberian ham quality.

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia together with disturbances in the metabolism of carbohydrates, proteins and fat, which in general results from an insulin availability and need imbalance. In a great number of patients, marketed anti-glycemic agents have shown poor effectiveness in maintaining a long-term glycemic control, thus being associated with severe adverse effects and leading to an emerging interest in natural compounds (e.g., essential oils and other secondary plant metabolites, namely, flavonoid-rich compounds) as a novel approach for prevention, management and/or treatment of either non-insulin-dependent diabetes mellitus (T2DM, type 2 DM) and/or Metabolic Syndrome (MS). In this review, some of these promising glucose-lowering agents will be comprehensively discussed.