Antimicrobial resistance (AMR) is considered one of the greatest threats to global health. Methicillin-resistant
(MRSA) remains at the core of this threat, accounting for about 90% of
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.
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.
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•Cholesterol and sphingomyelin increase membrane’s complexity, order and rigidity.•Vitamin B12’s affinity for the membrane decreases by increasing its complexity.•The location of ...Vitamin B12 in the membrane enables its binding to the receptor.•Vitamin B12 does not induce changes in the fluidity of the membrane.
Vitamin B12 (VB12) deficiency is one of the most common malnutrition problems worldwide and is related to its poor bioavailability. The lipid composition of cell membranes and molecule-cell membrane lipid interactions are major factors affecting the bioavailability of nutrients. So, the study of these interactions may allow predicting the behavior of VB12 at cellular membranes and the effects on its activity. Thus, lipid vesicles with lipid composition similar to the majority of eukaryotic cell membranes were used as biomembrane models, and their interactions with VB12 molecules were evaluated. For that, different parameters were assessed such as the lipophilicity of VB12, its preferential location in the membrane and its effect on the physical properties of the bilayer. VB12 showed high affinity for the biological membranes, not inducing any biophysical changes in their properties. The interactions of VB12 with the membrane was affected by the complexity of the bilayer, since its increase in order and rigidity hinders the diffusion of molecules. Thus, the low bioavailability of VB12 is not related with its interactions with the biological membranes.
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.
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.
Terbutaline sulphate (TS) is a selective short-acting β2 adrenoceptor agonist used for asthma treatment. The pharmacological activity of TS depends on its binding to the transmembrane protein, β2 ...adrenoceptor. Thus, the interactions of this drug with biological membranes are expected, affecting its pharmacological activity. Using in vitro models to study the interaction of TS with biological membranes can provide important information about the activity of the drug. Here, liposomes with different lipid compositions were used as biomimetic models of cell membranes to evaluate the effect of composition, complexity, and physical state of membranes on TS-membrane interactions. For that, liposomes containing dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and liposomes containing DMPC and cholesterol (CHOL) were prepared. For the study of TS-membrane interactions, the TS lipophilicity was evaluated in terms of i) partition coefficient; ii) the preferential location of the drug within the membrane; iii) and the effect of TS on the membrane fluidity. The obtained data suggest that TS has an affinity for the lipid membrane, partitioning from the aqueous to the lipid phase. The affinity was dependent on the liposomes' compositions, showing a greater affinity for DMPC membranes than for DMPC:CHOL model. Dynamic light scattering (DLS) results revealed that this is due to the rigidizing effect caused by CHOL molecules. These findings provide valuable insights in the understanding of the complex interaction of TS with biomembrane models as well as the relevance of lipid compositions and membrane structure in such interactions, which may be related to its pharmacological activity and side effects.
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•Terbutaline sulphate-membrane interactions are important to understand the drug's behavior.•Liposomes are a good model to simulate the interaction of terbutaline sulphate with the cell membranes.•Terbutaline sulphate presents a high affinity towards the biomembranes.•The complexity of the membrane affects the drug-membrane interactions.•Cholesterol decreases the interaction of terbutaline sulphate with membranes.
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•Drug-membrane interactions are crucial to understand the mechanisms of Alzheimer’s.•Liposomes are suitable for the study of drug–membrane interactions.•Cholesterol hampers the ...interaction of natural compounds with membranes.•Tannic acid has a significant higher affinity than caffeine and gallic acid.•Tannic acid may interact with extracellular Aβ fibrils and intracellular oligomers.
Natural compounds such as caffeine (CA), gallic acid (GA) and tannic acid (TA) have been reported to be useful for Alzheimer’s disease (AD) therapy. It was proved that some natural compounds inhibit the formation of senil plaques composed by beta-amyloid peptide (Aβ), a hallmark of AD. Evidences suggest that the therapeutic activity of compounds depends of their interaction with biological membranes. To understand why these compounds fail in vivo and in clinical trials, it is important to evaluate their pharmacokinetics properties. Thus, a biophysical approach to study drug-membrane interactions is essential to understand the mechanisms by which the drugs interact with the cellular membranes and affect the Aβ production, aggregation and clearance pathways. 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and cholesterol (chol) were used to mimic the biophysical properties of cell membranes and study their interactions with these compounds. The partition coefficient, influence on membrane fluidity and location within the bilayer of the drugs were studied by derivative spectrophotometry, dynamic light scattering and fluorescence quenching, respectively.
The results suggest that TA exhibited a significant higher partition than CA and GA and a preferential location near to the polar head of bilayer. The obtained results may explain the therapeutic mechanisms reported for these natural compounds.
Physical stress echocardiography is an established methodology for diagnosis and risk stratification of coronary artery disease in patients with physical capacity. In obese (body mass index ≥ 30 ...kg/m2) the usefulness of pharmacological stress echocardiography has been demonstrated; however, has not been reported the use of physical stress echocardiography in this growing population group.
To assess the frequency of myocardial ischemia in obese and non-obese patients undergoing physical stress echocardiography and compare their clinical and echocardiographic differences.
4,050 patients who underwent treadmill physical stress echocardiography were studied according to the Bruce protocol, divided into two groups: obese (n = 945; 23.3%) and non-obese (n = 3,105; 76.6%).
There was no difference regarding gender. Obese patients were younger (55.4 ± 10.9 vs. 57.56 ± 11.67) and had a higher frequency of hypertension (75.2% vs. 57, 2%; p < 0.0001), diabetis mellitus (15.2% vs. 10.9%; p < 0.0001), dyslipidemia (59.5% vs 51.9%; p < 0.0001), family history of coronary artery disease (59.3% vs. 55.1%; p = 0.023) and physical inactivity (71.4% vs. 52.9%, p < 0.0001). The obese had greater aortic dimensions (3.27 vs. 3.14 cm; p < 0.0001), left atrium (3.97 vs. 3.72 cm; p < 0.0001) and the relative thickness of the ventricule (33.7 vs. 32.8 cm; p < 0.0001). Regarding the presence of myocardial ischemia, there was no difference between groups (19% vs. 17.9%; p = 0.41). In adjusted logistic regression, the presence of myocardial ischemia remained independently associated with age, female gender, diabetes and hypertension.
Obesity did not behave as a predictor of the presence of ischemia and the physical stress echocardiography. The application of this assessment tool in large scale sample demonstrates the feasibility of the methodology, also in obese.
Alzheimer’s disease (AD) is a form of dementia with high impact worldwide, accounting with more than 46 million cases. It is estimated that the number of patients will be four times higher in 2050. ...The initial symptoms of AD are almost imperceptible and typically involve lapses of memory in recent events. However, the available medicines still focus on controlling the symptoms and do not cure the disease. Regarding the advances in the discovery of new treatments for this devastating disease, natural compounds are gaining increasing relevance in the treatment of AD. Nevertheless, they present some limiting characteristics such as the low bioavailability and the low ability to cross the blood-brain barrier (BBB) that hinder the development of effective therapies. To overcome these issues, the delivery of natural products by targeting nanocarriers has aroused a great interest, improving the therapeutic activity of these molecules. In this article, a review of the research progress on drug delivery systems (DDS) to improve the therapeutic activity of natural compounds with neuroprotective effects for AD is presented.
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Stress and anxiety are significant problems for individuals living with HIV. Mind-body therapies such as progressive muscle relaxation training and guided imagery (PMRT-GI) are effective in treating ...stress and anxiety in chronically ill persons. The purpose of this study was to identify key elements of an effective and culturally acceptable PMRT-GI intervention for economically disadvantaged persons with HIV. PMRT-GI was provided to 24 participants from African American, White, and Hispanic backgrounds. Using Colaizzi's phenomenological method, participants were interviewed about their experiences with PMRT-GI. Responses were tape-recorded, read, and reread; significant phrases and sentences were identified; meanings were formulated; and results were validated with participants. Five themes emerged: another world, feeling content, ease in muscle tension, one-on-one, and soft music. Background information and past experience with complementary and alternative methods were obtained.
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