Fighting Methicillin-Resistant Staphylococcus aureus with Targeted Nanoparticles.

Antimicrobial resistance (AMR) is considered one of the greatest threats to global health. Methicillin-resistant Staphylococcus aureus (MRSA) remains at the core of this threat, accounting for about 90% of S. aureus infections widespread in the community and hospital settings. In recent years, the use of nanoparticles (NPs) has emerged as a promising strategy to treat MRSA infections. NPs can act directly as antibacterial agents via antibiotic-independent activity and/or serve as drug delivery systems (DDSs), releasing loaded antibiotics. Nonetheless, directing NPs to the infection site is fundamental for effective MRSA treatment so that highly concentrated therapeutic agents are delivered to the infection site while directly reducing the toxicity to healthy human cells. This leads to decreased AMR emergence and less disturbance of the individual's healthy microbiota. Hence, this review compiles and discusses the scientific evidence related to targeted NPs developed for MRSA treatment.

[What's new in endocrinology]. / Endocrinologie : ce qui a changé en 2022.

Thyroid problems are frequent in pregnant women; recent data allow observation only in women with positive antithyroperoxidase antibodies (anti-TPO) but normal thyroïd function. New minimally invasive techniques are being developed for the management of thyroid nodules; radiofrequency ablation is effective for benign nodules. The management of Cushing's syndrome is oriented towards a more personalized approach; new treatments are available, with increased efficacy and a very good safety profile.

Les problématiques thyroïdiennes sont fréquentes chez la femme enceinte, des données récentes permettent cependant une attitude de surveillance chez les femmes avec des anticorps antithyroperoxydase (anti-TPO) positifs mais en euthyroïdie. De nouvelles techniques minimalement invasives pour la prise en charge des nodules thyroïdiens sont développées et la thermoablation par radiofréquence est efficace pour les nodules bénins. La prise en charge du syndrome de Cushing s'oriente vers une approche personnalisée. Des nouveaux traitements sont proposés, avec une efficacité accrue et un très bon profil de sécurité.

Influence of in vitro neuronal membranes on the anti-amyloidogenic activity of gallic acid: Implication for the therapy of Alzheimer's disease.

Molecules inhibiting the amyloid beta (Aß) peptide aggregation and/or disaggregating mature fibrils are a promising approach for the Alzheimer's disease (AD) therapy, as the Aß fibrillation is one of the key triggers of the disease. Gallic acid (GA) is a phenolic acid with anti-amyloidogenic activity against Aß in buffered solutions. However, there is still no evidence of these properties in vivo. Given the rate of failures of AD drug development, there is a huge demand of replicating the in vivo environment in in vitro studies, thus allowing to stop earlier the study of molecules with no effect in vivo. Thus, this study aims to evaluate the effect of in vitro neuronal membranes on the GA's ability in preventing Aß1-42 aggregation and disrupting preformed fibrils. To this end, liposomes were employed to mimic the cell membrane environment. The results reveal that the lipid membranes did not affect the GA's ability in inhibiting Aß1-42 fibrillation. However, in vitro neuronal membranes modulate the GA-induced Aß fibrils disaggregation, which may be related with the moderate affinity of the compound for the lipid membrane. Even so, GA presented strong anti-amyloidogenic properties in the cell membrane-like environment. This work highlights the promising value of GA on preventing and treating AD, thus justifying its study in animal models.

The Role of Amyloid ß-Biomembrane Interactions in the Pathogenesis of Alzheimer's Disease: Insights from Liposomes as Membrane Models.

The aggregation and deposition of amyloid ß (Aß) peptide onto neuronal cells, with consequent cellular membrane perturbation, are central to the pathogenesis of Alzheimer's disease (AD). Substantial evidence reveals that biological membranes play a key role in this process. Thus, elucidating the mechanisms by which Aß interacts with biomembranes and becomes neurotoxic is fundamental to developing effective therapies for this devastating progressive disease. However, the structural basis behind such interactions is not fully understood, largely due to the complexity of natural membranes. In this context, lipid biomembrane models provide a simplified way to mimic the characteristics and composition of membranes. Aß-biomembrane interactions have been extensively investigated applying artificial membrane models to elucidate the molecular mechanisms underlying the AD pathogenesis. This review summarizes the latest findings on this field using liposomes as biomembrane model, as they are considered the most promising 3D model. The current challenges and future directions are discussed.

(De)stabilization of Alpha-Synuclein Fibrillary Aggregation by Charged and Uncharged Surfactants.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. An important hallmark of PD involves the pathological aggregation of proteins in structures known as Lewy bodies. The major component of these proteinaceous inclusions is alpha (α)-synuclein. In different conditions, α-synuclein can assume conformations rich in either α-helix or ß-sheets. The mechanisms of α-synuclein misfolding, aggregation, and fibrillation remain unknown, but it is thought that ß-sheet conformation of α-synuclein is responsible for its associated toxic mechanisms. To gain fundamental insights into the process of α-synuclein misfolding and aggregation, the secondary structure of this protein in the presence of charged and non-charged surfactant solutions was characterized. The selected surfactants were (anionic) sodium dodecyl sulphate (SDS), (cationic) cetyltrimethylammonium chloride (CTAC), and (uncharged) octyl ß-D-glucopyranoside (OG). The effect of surfactants in α-synuclein misfolding was assessed by ultra-structural analyses, in vitro aggregation assays, and secondary structure analyses. The α-synuclein aggregation in the presence of negatively charged SDS suggests that SDS-monomer complexes stimulate the aggregation process. A reduction in the electrostatic repulsion between N- and C-terminal and in the hydrophobic interactions between the NAC (non-amyloid beta component) region and the C-terminal seems to be important to undergo aggregation. Fourier transform infrared spectroscopy (FTIR) measurements show that ß-sheet structures comprise the assembly of the fibrils.

Natural Compounds for Alzheimer's Disease Therapy: A Systematic Review of Preclinical and Clinical Studies.

Alzheimer's Disease (AD) is a neurodegenerative disorder related with the increase of age and it is the main cause of dementia in the world. AD affects cognitive functions, such as memory, with an intensity that leads to several functional losses. The continuous increase of AD incidence demands for an urgent development of effective therapeutic strategies. Despite the extensive research on this disease, only a few drugs able to delay the progression of the disease are currently available. In the last years, several compounds with pharmacological activities isolated from plants, animals and microorganisms, revealed to have beneficial effects for the treatment of AD, targeting different pathological mechanisms. Thus, a wide range of natural compounds may play a relevant role in the prevention of AD and have proven to be efficient in different preclinical and clinical studies. This work aims to review the natural compounds that until this date were described as having significant benefits for this neurological disease, focusing on studies that present clinical trials.

Resveratrol and Grape Extract-loaded Solid Lipid Nanoparticles for the Treatment of Alzheimer's Disease.

The aggregation of amyloid-ß peptide (Aß) has been linked to the formation of neuritic plaques, which are pathological hallmarks of Alzheimer's disease (AD). Various natural compounds have been suggested as therapeutics for AD. Among these compounds, resveratrol has aroused great interest due to its neuroprotective characteristics. Here, we provide evidence that grape skin and grape seed extracts increase the inhibition effect on Aß aggregation. However, after intravenous injection, resveratrol is rapidly metabolized into both glucuronic acid and sulfate conjugations of the phenolic groups in the liver and intestinal epithelial cells (within less than 2 h), which are then eliminated. In the present study, we show that solid lipid nanoparticles (SLNs) functionalized with an antibody, the anti-transferrin receptor monoclonal antibody (OX26 mAb), can work as a possible carrier to transport the extract to target the brain. Experiments on human brain-like endothelial cells show that the cellular uptake of the OX26 SLNs is substantially more efficient than that of normal SLNs and SLNs functionalized with an unspecific antibody. As a consequence, the transcytosis ability of these different SLNs is higher when functionalized with OX-26.

Polymeric Nanoparticles for Biomedical Applications.

Polymeric nanoparticles (NPs), utilized extensively in biomedical applications, have received increasing interest in the preceding years and today represent an established part of the nanotechnology field [...].

Folic-Acid-Conjugated Poly (Lactic-Co-Glycolic Acid) Nanoparticles Loaded with Gallic Acid Induce Glioblastoma Cell Death by Reactive-Oxygen-Species-Induced Stress.

Glioblastoma (GBM) conventional treatment is not curative, and it is associated with severe toxicity. Thus, natural compounds with anti-cancer properties and lower systemic toxicity, such as gallic acid (GA), have been explored as alternatives. However, GA's therapeutic effects are limited due to its rapid metabolism, low bioavailability, and low permeability across the blood-brain barrier (BBB). This work aimed to develop poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) modified with folic acid (FA), as its receptor is overexpressed in BBB and GBM cells, for GA delivery to enhance its therapeutic efficacy. The preparation of NPs was optimized by a central composite design (CCD). The obtained NPs showed physicochemical features suitable for drug internalization in BBB and tumor cells (sizes below 200 nm, monodispersity, and negative surface charge) and the ability to maintain a slow and sustained release for 40 days. In vitro studies using a human GBM cell line (U215) revealed the NPs' ability to accumulate in the target cells, further promoting GA antiproliferative activity by inducing the production of intracellular reactive oxygen species (ROS). Furthermore, GA encapsulation in the developed nanosystems conferred higher protection to healthy cells.

Caffeic acid loaded into engineered lipid nanoparticles for Alzheimer's disease therapy.

Alzheimer's disease (AD) is an incurable neurological illness and the leading cause of dementia, characterized by amyloid ß (Aß) fibril deposits. Caffeic acid (CA) has demonstrated potential value for AD therapy due to its anti-amyloidogenic, anti-inflammatory, and antioxidant properties. However, its chemical instability and limited bioavailability limit its therapeutic potential in vivo. Herein, liposomes loading CA were produced by distinct techniques. Taking advantage of the overexpression of transferrin (Tf) receptors in brain endothelial cells, Tf was conjugated to the liposomes' surface to direct the CA-loaded nanoparticles (NPs) to the blood-brain barrier (BBB). The optimized Tf-modified NPs exhibited a mean size of around 140 nm, a polydispersity index lower than 0.2, and a neutral surface charge, being appropriate for drug delivery. The Tf-functionalized liposomes showed suitable encapsulation efficiency and physical stability for at least 2 months. Furthermore, in simulated physiological settings, the NPs ensured the sustained release of CA for 8 days. The anti-amyloidogenic efficacy of the optimized drug delivery system (DDS) was investigated. The data show that CA-loaded Tf-functionalized liposomes are capable of preventing Aß aggregation and fibril formation, and disaggregating mature fibrils. Hence, the proposed brain-targeted DDS may be a potential strategy for preventing and treating AD. Future studies in animal models of AD will be valuable to validate the therapeutic efficacy of the optimized nanosystem.

Therapeutic Potential of Natural Compounds in Neurodegenerative Diseases: Insights from Clinical Trials.

Neurodegenerative diseases are caused by the gradual loss of neurons' function. These neurological illnesses remain incurable, and current medicines only alleviate the symptoms. Given the social and economic burden caused by the rising frequency of neurodegenerative diseases, there is an urgent need for the development of appropriate therapeutics. Natural compounds are gaining popularity as alternatives to synthetic drugs due to their neuroprotective properties and higher biocompatibility. While natural compounds' therapeutic effects for neurodegenerative disease treatment have been investigated in numerous in vitro and in vivo studies, only few have moved to clinical trials. This article provides the first systematic review of the clinical trials evaluating natural compounds' safety and efficacy for the treatment of the five most prevalent neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease.

Exaggerated Systolic Blood Pressure Increase with Exercise and Myocardial Ischemia on Exercise Stress Echocardiography. / Resposta Exagerada da Pressão Arterial Sistólica ao Exercício e Isquemia Miocárdica à Ecocardiografia sob Estresse Físico.

BACKGROUND: Central Illustration : Exaggerated Systolic Blood Pressure Increase with Exercise and Myocardial Ischemia on Exercise Stress Echocardiography ESBPRE: exaggerated systolic blood pressure response to exercise; HR: heart rate; SBP: systolic blood pressure. BACKGROUND: The association between exaggerated systolic blood pressure response to exercise (ESBPRE) and myocardial ischemia is controversial and little studied in patients with established or suspected chronic coronary syndrome. OBJECTIVE: To verify the relationship between myocardial ischemia and ESBPRE in patients undergoing exercise stress echocardiography (ESE). METHODS: This is a cross-sectional study with 14,367 patients undergoing ESE, from January 2000 to January 2022, divided into the following 2 groups: G1, composed of patients whose peak systolic pressure increased ≥ 90 mmHg (value corresponding to the 95th percentile of the study population), and G2, patients who did not demonstrate an exaggerated hypertensive response. The groups were compared using Student's t and chi-square tests. P values < 0.05 were considered significant. Logistic regression was also performed to identify independent risk factors for myocardial ischemia, ESBPRE, complaints of typical chest pain prior to the exam, and angina during the test. RESULTS: Of the 14,367 patients, 1,500 (10.4%) developed ESBPRE, and 7,471 (52.0%) were female. The percentages of previous complaints of typical chest pain, angina during the test, and myocardial ischemia in patients with ESBPRE were 5.8%, 2.4% and 18.1%, compared to 7.4%, 3.9%, and 24.2%, in patients without ESBPRE, respectively (p = 0.021,p = 0.004, p < 0.001). In multivariate analysis, ESBPRE was independently associated with a lower probability of myocardial ischemia (odds ratio: 0.73; 95% confidence interval: 0.58 to 0.93; p = 0.009). CONCLUSION: Exaggerated increase in systolic blood pressure during ESE may be a marker for excluding myocardial ischemia.

Transferrin-Functionalized Liposomes for the Delivery of Gallic Acid: A Therapeutic Approach for Alzheimer's Disease.

Senile plaques composed of amyloid ß (Aß) fibrils are considered the leading cause of Alzheimer's disease (AD). Molecules with the ability to inhibit Aß aggregation and/or promote Aß clearance are thus a promising approach for AD therapy. Our group recently demonstrated that gallic acid (GA) has strong anti-amyloidogenic properties. In this study, stealth liposomes were prepared for the delivery of GA for AD therapy. The liposomes were functionalized with transferrin (Tf) to direct them to the brain, since Tf receptors are overexpressed in the endothelial cells of the blood-brain barrier. GA-loaded Tf-functionalized liposomes showed mean diameters of 130 nm, low polydispersity index values, and neutral zeta potential. Moreover, the produced nanocarriers promoted the sustained release of GA over 5 days and are physically stable for 1 month under storage conditions. Furthermore, GA-loaded Tf-functionalized liposomes showed a strong ability to interact with Aß1-42 monomers, slowing down the Aß monomer-to-oligomer and oligomer-to-fibril transitions and decreasing the number of fibrils formed by 56%. In addition, the NPs disaggregated approximately 30% of preformed Aß fibrils. The presented results suggest that Tf-functionalized liposomes could be a viable platform for the brain delivery of GA for AD therapy. Studies with animal models of AD will be valuable for validating the therapeutic efficacy of this novel liposomal formulation.

Transferrin-functionalized liposomes loaded with vitamin VB12 for Alzheimer's disease therapy.

Despite the efforts of the pharmaceutical and research sectors, Alzheimer's disease (AD) remains incurable, imposing the demand for new effective strategies. Vitamin B12 (VB12) has aroused interest due to its in vitro anti-amyloidogenic properties. However, the high molecular weight and hydrophilicity of VB12 are the main obstacles to its clinical application by hindering its passage through the blood-brain barrier (BBB). In recent years, drug delivery systems (DDSs) capable of transporting molecules across the BBB have gained attention for their effective brain delivery. In this work, VB12-loaded liposomes functionalized with transferrin (Tf) were produced, envisaging the dual-targeting of VB12 to the BBB and neuronal cells, due to the overexpression of Tf receptors in these cells. The produced liposomes presented sizes smaller than 200 nm, with low polydispersity and neutral zeta potential, being suitable for brain delivery. The nanoparticles exhibited an adequate encapsulation efficiency, a sustained release of VB12 for 9 days, and physical stability at storage conditions for up to 2 months. The developed nanosystem was capable of delaying the formation of Aß fibrils and disrupting mature fibrils, highlighting its great potential for the prevention and treatment of AD.

Interaction of Bortezomib with Cell Membranes Regulates Its Toxicity and Resistance to Therapy.

Bortezomib (BTZ) is a potent proteasome inhibitor currently being used to treat multiple myeloma. However, its high toxicity and resistance to therapy severely limit the treatment outcomes. Drug-membrane interactions have a crucial role in drugs' behavior in vivo, affecting their bioavailability and pharmacological activity. Additionally, drugs' toxicity often occurs due to their effects on the cell membranes. Therefore, studying BTZ's interactions with cell membranes may explain the limitations of its therapy. Due to the cell membranes' complexity, lipid vesicles were proposed here as biomembrane models, focusing on the membrane's main constituents. Two models with distinct composition and complexity were used, one composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and the other containing DMPC, cholesterol (Chol), and sphingomyelin (SM). BTZ's interactions with the models were evaluated regarding the drugs' lipophilicity, preferential location, and effects on the membrane's physical state. The studies were conducted at different pH values (7.4 and 6.5) to mimic the normal blood circulation and the intestinal environment, respectively. BTZ revealed a high affinity for the membranes, which proved to be dependent on the drug-ionization state and the membrane complexity. Furthermore, BTZ's interactions with the cell membranes was proven to induce changes in the membrane fluidity. This may be associated with its resistance to therapy, since the activity of efflux transmembrane proteins is dependent on the membrane's fluidity.

Polymeric Nanoparticles-Loaded Hydrogels for Biomedical Applications: A Systematic Review on In Vivo Findings.

Clinically available medications face several hurdles that limit their therapeutic activity, including restricted access to the target tissues due to biological barriers, low bioavailability, and poor pharmacokinetic properties. Drug delivery systems (DDS), such as nanoparticles (NPs) and hydrogels, have been widely employed to address these issues. Furthermore, the DDS improves drugs' therapeutic efficacy while reducing undesired side effects caused by the unspecific distribution over the different tissues. The integration of NPs into hydrogels has emerged to improve their performance when compared with each DDS individually. The combination of both DDS enhances the ability to deliver drugs in a localized and targeted manner, paired with a controlled and sustained drug release, resulting in increased drug therapeutic effectiveness. With the incorporation of the NPs into hydrogels, it is possible to apply the DDS locally and then provide a sustained release of the NPs in the site of action, allowing the drug uptake in the required location. Additionally, most of the materials used to produce the hydrogels and NPs present low toxicity. This article provides a systematic review of the polymeric NPs-loaded hydrogels developed for various biomedical applications, focusing on studies that present in vivo data.

Multi-Dose Intravenous Administration of Neutral and Cationic Liposomes in Mice: An Extensive Toxicity Study.

Liposomes are widely used as delivery systems for therapeutic purposes. However, the toxicity associated with the multi-dose administration of these nanoparticles is not fully elucidated. Here, we evaluated the toxicity of the prolonged administration of liposomes composed of neutral or cationic phospholipids often used in drug and gene delivery. For that purpose, adult wild-type mice (C57Bl6) were randomly distributed into three groups receiving either vehicle (PBS), neutral, or cationic liposomes and subjected to repeated intravenous injections for a total of 10 doses administered over 3 weeks. Several parameters, including mortality, body weight, and glucose levels, were monitored throughout the trial. While these variables did not change in the group treated with neutral liposomes, the group treated with the positively charged liposomes displayed a mortality rate of 45% after 10 doses of administration. Additional urinalysis, blood tests, and behavioral assays to evaluate impairments of motor functions or lesions in major organs were also performed. The cationic group showed less forelimb peak force than the control group, alterations at the hematological level, and inflammatory components, unlike the neutral group. Overall, the results demonstrate that cationic liposomes are toxic for multi-dose administration, while the neutral liposomes did not induce changes associated with toxicity. Therefore, our results support the use of the well-known neutral liposomes as safe drug shuttles, even when repetitive administrations are needed.

Green tea extract-biomembrane interaction study: The role of its two major components, (-)-epigallocatechin gallate and (-)-epigallocatechin.

The interaction of antioxidants with biological membranes is closely related with their efficacy to inhibit the lipid peroxidation, the cause of several pathologies including cancer, neurodegenerative and cardiovascular disorders. Despite being pointed as a promising antioxidant agent by some authors, the anti-lipid peroxidation of green tea extract (GTE) has not aroused consensus among the scientific community. Since the interaction of drugs with biological membranes plays a key role on their therapeutic activity, this study aims to evaluate the interaction of GTE with liposomes as in vitro biomembrane models composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine phospholipids in the absence and presence of cholesterol (CHOL) (15 mol%). The affinity of GTE and its main components (-)-epigallocatechin gallate (EGCG) and (-)-epigallocatechin (EGC) to the lipid bilayer, their membrane location as well as their effect on the membrane fluidity was investigated by diverse biophysical techniques. Derivative spectrophotometry results proved that GTE has high affinity to the membrane by establishing hydrophobic interactions with the non-polar region of phospholipids and electrostatic interactions with the polar phospholipid heads. Fluorescence and dynamic light scattering data confirm that GTE is located in both hydrophobic and hydrophilic regions of the lipid membrane, therefore affecting the structure of the biomembrane by increasing its fluidity. However, the increased stiffness and organization of the lipid bilayer caused by CHOL significantly affected the interaction of GTE with the membrane. Moreover, the obtained findings suggest a direct contribution of EGCG and EGC on the GTE-membrane interaction.

Vitamin B12 Inhibits Aß Fibrillation and Disaggregates Preformed Fibrils in the Presence of Synthetic Neuronal Membranes.

The aggregation of amyloid ß (Aß) peptide with subsequent formation of fibrils which deposit in senile plaques is considered one of the key triggers of Alzheimer's disease (AD). Molecules targeting the inhibition of Aß fibrillation and/or the disruption of Aß fibrils are thus promising approaches for the medical prevention and treatment of AD. However, amyloid formation is a complex process strongly influenced by the cellular environment, such as cell membranes, which may affect the effectiveness of therapeutic molecules. In this study, the effect of the vitamin B12 (VB12) on the formation and disaggregation of Aß1-42 fibrils was investigated in the presence of artificial neuronal membranes mimicked by liposomes. Evidence showed that VB12 slows down the Aß fibrillization and reduces the content of fibrils in aqueous solution. Moreover, the vitamin exhibited a strong ability to disrupt preformed fibrils. However, the presence of lipid vesicles compromised the VB12's antiamyloidogenic properties due to the competitive interaction of the vitamin with the lipid membrane and the Aß peptide. Even so, VB12 was effective in inhibiting the fibril formation and disaggregating fibrils in the lipid membrane environment. Thereby, these results indicate that VB12 could be a promising molecule both for the prevention and cure of AD, thus warranting its study in animal models.

Caffeic acid for the prevention and treatment of Alzheimer's disease: The effect of lipid membranes on the inhibition of aggregation and disruption of Aß fibrils.

The onset of Alzheimer's disease (AD) is triggered by the aggregation of amyloid ß (Aß) peptides which leads to the formation of fibrils. Molecules that are able to inhibit fibrillation and/or disrupt fibrils have aroused interest for AD therapy. Fibrillation is a complex process highly dependent on the surrounding environment. One of the most relevant factors affecting Aß aggregation is the presence of cellular membranes. Here, the ability of caffeic acid (CA) in preventing the Aß1-42 aggregation and disaggregating mature fibrils was evaluated in a membrane-like environment and in a bulk solution for comparison. To this end, liposomes were used as in vitro models of neuronal membranes. CA exhibited strong activity in inhibiting the fibrillation of Aß1-42 in the aqueous medium, which remained in the presence of liposomes. Furthermore, CA disrupted instantly preformed fibrils in the aqueous medium. However, the CA's disaggregating activity was disturbed by the presence of lipid membranes. Instead of being immediate, the CA's disaggregating activity increased over time. The moderate affinity of CA for the lipid bilayer may explain the distinct fibrils disaggregation profiles. These findings emphasize the therapeutic potential of CA in preventing and treating AD, thus justifying further investigations in animal models.