Comparison of the Antibacterial Activity of Selected Deep Eutectic Solvents (DESs) and Deep Eutectic Solvents Comprising Organic Acids (OA-DESs) Toward Gram-Positive and Gram-Negative Species.

Deep eutectic solvents (DESs) have been intensively investigated in recent years for their antibacterial properties, with DESs that comprise organic acids (OA-DESs) showing promising antibacterial action. However a majority of the reports focused only on a limited number strains and techniques, which is not enough to determine the antibacterial potential of a substance. To bridge this gap, the antibacterial activity of classical DESs and OA-DESs is assessed on twelve Gram-negative and Gram-positive bacteria strains, with some of them exhibiting specific resistance toward antibiotics. The investigated formulations of OA-DESs comprise glycolic, malic, malonic, and oxalic acids as representatives of this group. Using a range of microbiological assays as well as physicochemical characterization methods, a major difference of the effectiveness between the two groups is demonstrated, with OA-DESs exhibiting, as expected, greater antibacterial effectiveness than classical DESs. Most interestingly, slight differences in the minimum inhibitory and bactericidal concentration values as well as time-kill kinetics profiles are observed between Gram-positive and Gram-negative strains. Transmission electron microscopy analysis reveals the effect of the treatment of the bacteria with the representatives of both groups of DESs, which allows us to better understand the possible mechanism-of-action of these novel materials.

Solar-Driven Ammonia Production through Engineering of the Electronic Structure of a Zr-Based MOF.

As a hydrogen carrier and a vital component in fertilizer production, ammonia (NH3) is set to play a crucial role in the planet's future. While its industrial production feeds half of the global population, it uses fossil fuels and emits greenhouse gases. To tackle this issue, photocatalytic nitrogen fixation using visible light is emerging as an effective alternative method. This strategy avoids carbon dioxide (CO2) emissions and harnesses the largest share of sunlight. In this work, we successfully incorporated a 5-nitro isophthalic acid linker into MOF-808 to introduce structural defects and open metal sites. This has allowed modulation of the electronic structure of the MOF and effectively reduced the band gap energy from 3.8 to 2.6 eV. Combination with g-C3N4 enhanced further NH3 production, as these two materials possess similar band gap energies, and g-C3N4 has shown excellent performance for this reaction. The nitro groups serve as acceptors, and their integration into the MOF structure allowed effective interaction with the free electron pairs on N-(C)3 in the g-C3N4 network nodes. Based on DFT calculations, it was concluded that the adsorption of N2 molecules on open metal sites caused a decrease in their triple bond energy. The modified MOF-808 showed superior performance compared with the other MOFs studied in terms of N2 photoreduction under visible light. This design concept offers valuable information about how to engineer band gap energy in MOF structures and their combination with appropriate semiconductors for solar-powered photocatalytic reactions, such as N2 or CO2 photoreduction.

Correction: Bilyy et al. Rapid Generation of Coronaviral Immunity Using Recombinant Peptide Modified Nanodiamonds. Pathogens 2021, 10, 861.

In the original publication [...].

Enhancing paracellular and transcellular permeability using nanotechnological approaches for the treatment of brain and retinal diseases.

Paracellular permeability across epithelial and endothelial cells is, in large part, regulated by apical intercellular junctions also referred to as tight junctions (TJs). These junctions contribute to the spatial definition of different tissue compartments within organisms, separating them from the outside world as well as from inner compartments, with their primary physiological role of maintaining tissue homeostasis. TJs restrict the free, passive diffusion of ions and hydrophilic small molecules through paracellular clefts and are important for appropriate cell polarization and transporter protein localisation, supporting the controlled transcellular diffusion of smaller and larger hydrophilic as well as hydrophobic substances. This traditional diffusion barrier concept of TJs has been challenged lately, owing to a better understanding of the components that are associated with TJs. It is now well-established that mutations in TJ proteins are associated with a range of human diseases and that a change in the membrane fluidity of neighbouring cells can open possibilities for therapeutics to cross intercellular junctions. Nanotechnological approaches, exploiting ultrasound or hyperosmotic agents and permeation enhancers, are the paradigm for achieving enhanced paracellular diffusion. The other widely used transport route of drugs is via transcellular transport, allowing the passage of a variety of pro-drugs and nanoparticle-encapsulated drugs via different mechanisms based on receptors and others. For a long time, there was an expectation that lipidic nanocarriers and polymeric nanostructures could revolutionize the field for the delivery of RNA and protein-based therapeutics across different biological barriers equipped with TJs (e.g., blood-brain barrier (BBB), retina-blood barrier (RBB), corneal TJs, etc.). However, only a limited increase in therapeutic efficiency has been reported for most systems until now. The purpose of this review is to explore the reasons behind the current failures and to examine the emergence of synthetic and cell-derived nanomaterials and nanotechnological approaches as potential game-changers in enhancing drug delivery to target locations both at and across TJs using innovative concepts. Specifically, we will focus on recent advancements in various nanotechnological strategies enabling the bypassing or temporally opening of TJs to the brain and to the retina, and discuss their advantages and limitations.

Petroleum Coke Embedded in Cigarette Butts: All Waste-Derived Solar Evaporator for Effective Water Evaporation.

Solar-driven interfacial evaporation is an eco-friendly solution for tackling the impending water scarcity the world is facing in our century. In this work, a solar-driven interfacial evaporator was prepared from cigarette butts loaded with petroleum coke powder (Filter-PetCoke), a by-product of the oil refinery processes, for the improvement of the absorption of the incident solar light. A comparison between a flat 2D and a 3D evaporator with a surface composed of orderly patterned protrusions of 2.1 cm was carried out to assess the influence of the evaporator configuration on the evaporation performance. The 3D evaporator (3D Filter-PetCoke) achieved by far the best performance (evaporation rate: 1.97 ± 0.08 kg m-2 h-1 and solar conversion efficiency: 93.2 ± 5.4%) among the prepared samples (3D Filter-PetCoke, 3D Filter, 2D Filter-PetCoke, and 2D Filter). In addition, this configuration seems to be adaptable for real and more massive operation because of the geometry of the evaporator. The high efficiency was ascribed to the good heat generation of the petroleum coke and the excellent heat management of the 3D structure of the evaporator. Moreover, this evaporator was resistant to multiple repeated usages without significant efficiency loss and capable of producing drinking water from seawater and Escherichia coli (E. coli)-contaminated water. The findings in this work indicate that this evaporator is pertinent to real situations to supply safe freshwater very efficiently from chemically/biologically contaminated water.

Deep Eutectic Solvents Comprising Organic Acids and Their Application in (Bio)Medicine.

Over the last years, we observed a significant increase in the number of published studies that focus on the synthesis and characterization of deep eutectic solvents (DESs). These materials are of particular interest mainly due to their physical and chemical stability, low vapor pressure, ease of synthesis, and the possibility of tailoring their properties through dilution or change of the ratio of parent substances (PS). DESs, considered as one of the greenest families of solvents, are used in many fields, such as organic synthesis, (bio)catalysis, electrochemistry, and (bio)medicine. DESs applications have already been reported in various review articles. However, these reports mainly described these components' basics and general properties without focusing on the particular, PS-wise, group of DESs. Many DESs investigated for potential (bio)medical applications comprise organic acids. However, due to the different aims of the reported studies, many of these substances have not yet been investigated thoroughly, which makes it challenging for the field to move forward. Herein, we propose distinguishing DESs comprising organic acids (OA-DESs) as a specific group derived from natural deep eutectic solvents (NADESs). This review aims to highlight and compare the applications of OA-DESs as antimicrobial agents and drug delivery enhancers-two essential fields in (bio)medical studies where DESs have already been implemented and proven their potential. From the survey of the literature data, it is evident that OA-DESs represent an excellent type of DESs for specific biomedical applications, owing to their negligible cytotoxicity, fulfilling the rules of green chemistry and being generally effective as drug delivery enhancers and antimicrobial agents. The main focus is on the most intriguing examples and (where possible) application-based comparison of particular groups of OA-DESs. This should highlight the importance of OA-DESs and give valuable clues on the direction the field can take.

Polymer-Based Nanostructures for Pancreatic Beta-Cell Imaging and Non-Invasive Treatment of Diabetes.

Diabetes poses major economic, social, and public health challenges in all countries worldwide. Besides cardiovascular disease and microangiopathy, diabetes is a leading cause of foot ulcers and lower limb amputations. With the continued rise of diabetes prevalence, it is expected that the future burden of diabetes complications, early mortality, and disabilities will increase. The diabetes epidemic is partly caused by the current lack of clinical imaging diagnostic tools, the timely monitoring of insulin secretion and insulin-expressing cell mass (beta (ß)-cells), and the lack of patients' adherence to treatment, because some drugs are not tolerated or invasively administrated. In addition to this, there is a lack of efficient topical treatment capable of stopping the progression of disabilities, in particular for treating foot ulcers. In this context, polymer-based nanostructures garnered significant interest due to their tunable physicochemical characteristics, rich diversity, and biocompatibility. This review article emphasizes the last advances and discusses the prospects in the use of polymeric materials as nanocarriers for ß-cell imaging and non-invasive drug delivery of insulin and antidiabetic drugs in the management of blood glucose and foot ulcers.

Venom Peptides, Polyphenols and Alkaloids: Are They the Next Antidiabetics That Will Preserve ß-Cell Mass and Function in Type 2 Diabetes?

Improvement of insulin secretion by pancreatic ß-cells and preservation of their mass are the current challenges that future antidiabetic drugs should meet for achieving efficient and long-term glycemic control in patients with type 2 diabetes (T2D). The successful development of glucagon-like peptide 1 (GLP-1) analogues, derived from the saliva of a lizard from the Helodermatidae family, has provided the proof of concept that antidiabetic drugs directly targeting pancreatic ß-cells can emerge from venomous animals. The literature reporting on the antidiabetic effects of medicinal plants suggests that they contain some promising active substances such as polyphenols and alkaloids, which could be active as insulin secretagogues and ß-cell protectors. In this review, we discuss the potential of several polyphenols, alkaloids and venom peptides from snake, frogs, scorpions and cone snails. These molecules could contribute to the development of new efficient antidiabetic medicines targeting ß-cells, which would tackle the progression of the disease.

Influence of the Size and Charge of Carbon Quantum Dots on Their Corneal Penetration and Permeation Enhancing Properties.

Reaching the corneal endothelium through the topical administration of therapeutic drugs remains a challenge in ophthalmology. Besides, endothelial cells are not able to regenerate, and diseases at this site can lead to corneal blindness. Targeting the corneal endothelium implies efficient penetration through the three corneal layers, which still remains difficult for small molecules. Carbon quantum dots (CQDs) have demonstrated great potential for ocular nanomedicine. This study focuses on the corneal penetration abilities of differently charged CQDs and their use as permeation enhancers for drugs. Excised whole bovine eyes were used as an ex vivo model to investigate corneal penetration of CQDs derived from glucosamine using ß-alanine, ethylenediamine, or spermidine as a passivation agent. It was found that negatively charged CQDs have limited corneal penetration ability, while positively charged CQDs derived from glucosamine hydrochloride and spermidine (CQD-S) penetrate the entire corneal epithelium all the way down to the endothelium. CQD-S were shown to enhance the penetration of FITC-dextran 150 kDa, suggesting that they could be used as efficient penetration enhancers for therapeutic delivery to the corneal endothelium.

A colorimetric assay and MCR-ALS analysis of the peroxidase-like activity of poly (N-phenylglycine) functionalized with polyethylene glycol (PNPG-PEG) nanozyme for the determination of dopamine.

This report describes, for the first time, the coupling of UV-visible spectroscopy with multivariate curve resolution-alternative least-squares (MCR-ALS) algorithm to study peroxidase-like catalytic reaction of polyethylene glycol-functionalized poly (N-phenyl glycine) (PNPG-PEG) as an efficient and intrinsic peroxidase mimic activity (PMA) class of conducting organic polymer for selective detection of dopamine (DA) in the PNPG-PEG + TMB + H2O2 reaction system. PNPG-PEG was produced by means of a chemical route using ammonium persulphate (APS) as an oxidant agent of N-phenyl glycine monomer. The chemical composition, morphology, and thermal behavior of PNPG-PEG were examined by various instrumental techniques. PNPG-PEG exhibited significant peroxidase-mimic activity to catalyze the oxidation 3,3',5,5'- tetramethylbenzidine (TMB) substrate to oxidized TMB (oxTMB). The qualitative and quantitative determination of the oxidized TMB can easily be detected by the naked-eye and the recorded UV-vis absorbance spectra at 652 nm, respectively. Owing to the superior peroxidase-mimic activity of PNPG-PEG, the colorimetric detection of dopamine was successfully achieved at pH 4.0. Under optimal conditions, acceptable linear dependency was recorded in the concentration range of 5.1-125.0 µM, with a limit of detection (LOD) and limit of quantification (LOQ) equal to 4.6 µM and 13.8 µM (S/N = 3), respectively. Furthermore, this colorimetric assay was successfully used for quantitative analysis of dopamine in fetal bovine serum (FBS) and horse serum (HS) samples with recoveries in the range of 97-105% and 100-122%, respectively. After resolving the bilinear data matrix using MCR-ALS, three chemical components were found for different concentrations and pure spectral profiles. Based on the resolved profiles, the presence of free, slightly penetrated, and majorly penetrated TMB molecules entering the polymeric structure can be easily detected using MCR-ALS as an available statical method without any complex separation instruments. This peroxidase mimetic nanozyme as a visual, simple, low-cost, sensitive, and reproducible colorimetric platform can provide great potential applications in the monitoring and diagnosis of dopamine-related diseases.

Anti-aggregation effect of carbon quantum dots on diabetogenic and beta-cell cytotoxic amylin and beta amyloid heterocomplexes.

Pancreatic islet amyloid deposition is a pathological hallmark of Type 2 diabetes (T2D), contributing to reduced functional ß-cell mass. Islet amyloids result not only from the aggregation and fibrillation of human islet amyloid polypeptide (hIAPP), but also from beta-amyloid 42 (Aß42), the key amyloidogenic peptide linked to Alzheimer's disease. Importantly, Aß42 and hIAPP aggregates (IAPP:Aß42) can interact with each other and form some harmful heterocomplex fibrils. While it is well-documented that hIAPP aggregation occurs only when islets are exposed to a diabetic environment, including hyperglycemia and/or elevated concentrations of saturated fatty acids (SFAs), it remains unclear if hIAPP and IAPP:Aß42 heteromer fibrillations are directly or indirectly triggered by this environment. In this study, we show the interplay between high glucose concentrations and palmitate as the SFA in the aggregation of hIAPP. In addition, we outline that the interaction of hIAPP and Aß42 leads to the formation of complex protein aggregates, which are toxic to ß-cells. Carbon nanocolloids in the form of positively charged carbon quantum dots (CQD-pos) efficiently prevent single amyloid aggregation and the formation of IAPP:Aß42 heterocomplexes. We provide clear evidence with this study that the diabetogenic environment of islets could directly contribute to the formation of homomeric and heteromeric amyloid aggregates and fibrils in T2D. We also propose carbon nanocolloids as biocompatible nanomaterials for developing innovative therapeutic strategies that prevent the decline of functional ß-cell mass.

Heat-based transdermal delivery of a ramipril loaded cream for treating hypertension.

Angiotensin-converting enzyme (ACE) inhibitors play an important role in the development of anti-hypertension approaches, with ramipril being one of the most widely used ACE inhibitor prodrugs orally administered once or twice a day. Due to its low bioavailability, large amounts have to be administered to obtain a therapeutic effect. In this work, we propose a ramipril loaded pharmaceutical formulation in contact with an electrothermal actuator based on a gold nanohole array as an efficient approach to increase the transdermal ramipril flux. Using rats as an in vivo model, the effect on the systolic and diastolic blood pressure is evaluated, showing that under optimized conditions the blood pressure could be regulated. Heat activation resulted in total drug delivery out of a bandage loaded with 1 mg ramipril, revealing a flux of 50.9 ± 2.8 µg cm-2 h-1. Importantly, heat-based transdermal dispensing allowed efficient and rapid delivery of ramipril in spontaneously hypertensive rats, with its active form (ramiprilat) detected in blood as early as 5 minutes after delivery onset, accompanied by significant decrease in blood pressure.

TRPM8 as an Anti-Tumoral Target in Prostate Cancer Growth and Metastasis Dissemination.

In the fight against prostate cancer (PCa), TRPM8 is one of the most promising clinical targets. Indeed, several studies have highlighted that TRPM8 involvement is key in PCa progression because of its impact on cell proliferation, viability, and migration. However, data from the literature are somewhat contradictory regarding the precise role of TRPM8 in prostatic carcinogenesis and are mostly based on in vitro studies. The purpose of this study was to clarify the role played by TRPM8 in PCa progression. We used a prostate orthotopic xenograft mouse model to show that TRPM8 overexpression dramatically limited tumor growth and metastasis dissemination in vivo. Mechanistically, our in vitro data revealed that TRPM8 inhibited tumor growth by affecting the cell proliferation and clonogenic properties of PCa cells. Moreover, TRPM8 impacted metastatic dissemination mainly by impairing cytoskeleton dynamics and focal adhesion formation through the inhibition of the Cdc42, Rac1, ERK, and FAK pathways. Lastly, we proved the in vivo efficiency of a new tool based on lipid nanocapsules containing WS12 in limiting the TRPM8-positive cells' dissemination at metastatic sites. Our work strongly supports the protective role of TRPM8 on PCa progression, providing new insights into the potential application of TRPM8 as a therapeutic target in PCa treatment.

Enhancing Colistin Activity against Colistin-Resistant Escherichia coli through Combination with Alginate Nanoparticles and Small Molecules.

Bacterial resistance to antibiotics has become a major public health problem worldwide, with the yearly number of deaths exceeding 700,000. To face this well-acknowledged threat, new molecules and therapeutic methods are considered. In this context, the application of nanotechnology to fight bacterial infection represents a viable approach and has experienced tremendous developments in the last decades. Escherichia coli (E. coli) is responsible for severe diarrhea, notably in the breeding sector, and especially in pig farming. The resulting infection (named colibacillosis) occurs in young piglets and could lead to important economic losses. Here, we report the design of several new formulations based on colistin loaded on alginate nanoparticles (Alg NPs) in the absence, but also in the presence, of small molecules, such as components of essential oils, polyamines, and lactic acid. These new formulations, which are made by concomitantly binding colistin and small molecules to Alg NPs, were successfully tested against E. coli 184, a strain resistant to colistin. When colistin was associated with Alg NPs, the minimal inhibition concentration (MIC) decreased from 8 to 1 µg/mL. It is notable that when menthol or lactic acid was co-loaded with colistin on Alg NPs, the MIC of colistin drastically decreased, reaching 0.31 or 0.62 µg/mL, respectively. These novel bactericidal formulations, whose innocuity towards eukaryotic HT-29 cells was established in vitro, are presumed to permeabilize the bacterial membrane and provoke the leakage of intracellular proteins. Our findings revealed the potentiating effect of the Alg NPs on colistin, but also of the small molecules mentioned above. Such ecological and economical formulations are easy to produce and could be proposed, after confirmation by in vivo and toxicology tests, as therapeutic strategies to replace fading antibiotics.

Enhanced Antibacterial Activity of Dermaseptin through Its Immobilization on Alginate Nanoparticles-Effects of Menthol and Lactic Acid on Its Potentialization.

Dermaseptin B2 (DRS-B2) is an antimicrobial peptide secreted by Phyllomedusa bicolor, which is an Amazonian tree frog. Here, we show that the adsorption of DRS-B2 on alginate nanoparticles (Alg NPs) results in a formulation (Alg NPs + DRS-B2) with a remarkable antibacterial activity against Escherichia coli ATCC 8739 and E. coli 184 strains, which are sensitive and resistant, respectively, to colistin. The antibacterial activity, obtained with this new formulation, is higher than that obtained with DRS-B2 alone. Of note, the addition of lactic acid or menthol to this new formulation augments its antibacterial activity against the aforementioned Gram-negative bacilli. The safety of DRS-B2, and also that of the new formulation supplemented or not with a small molecule such as lactic acid or menthol has been proven on the human erythrocytes and the eukaryotic cell line types HT29 (human) and IPEC-1 (animal). Similarly, their stability was determined under the conditions mimicking the gastrointestinal tract with different conditions: pH, temperature, and the presence of digestive enzymes. Based on all the obtained data, we assume that these new formulations are promising and could be suggested, after in vivo approval and completing regulation aspects, as alternatives to antibiotics to fight infections caused by Gram-negative bacilli such as E. coli.

Influence of graphene oxide on the toxicity of polystyrene nanoplastics to the marine microalgae Picochlorum sp.

Graphene oxide (GO) features distinctive physical and chemical characteristics; therefore, it has been intensively investigated in environmental remediation as a promising material for clean-up of soil contamination and water purification and used as immobilization material. Plastic is a widespread pollutant, and its breakdown products such as nanoplastics (NPs) should be evaluated for potential harmful effects. This study is aimed to evaluate the influence of GO on the toxicity of polystyrene (PS) NPs to the marine microalgae Picochlorum sp. over a period of 4 weeks. The capability of GO to reduce the toxic effects of PS NPs was assessed through investigating exposure sequence of GO in the presence of 20 nm diameter-sized polystyrene NPs. This was accomplished through five test groups: microalgae pre-exposed to GO prior to incubation with PS NPs, microalgae post-exposed to GO after incubation with PS NPs, microalgae simultaneously exposed to GO and PS NPs, and individual exposure of microalgae to either GO or PS NPs. Cytotoxicity assay results demonstrated that microalgae pre-exposed to GO prior to incubation with PS NPs showed an increased viability and chlorophyll a content. The pre-exposure to GO has reduced the growth inhibition rate (IR) from 50%, for microalgae simultaneously exposed to GO and PS NPs, to 26%, for microalgae pre-exposed to GO. Moreover, the lowest level of reactive oxygen species (ROS) was recorded for microalgae exposed to GO only and microalgae pre-exposed to GO. Fourier-transform infrared (FTIR) analysis, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) observations revealed some morphological changes of both algae and their extracellular polymeric substances (EPS) upon GO and PS NPs exposure combinations. The sequence of GO exposure to aquatic microorganisms might affect the level of harm caused by the PS NPs. Therefore, application of GO as part of an immobilization material and in the removal of pollutants from water should be carefully investigated using different pollutants and aquatic organisms.

Surface modification of carbon dots with tetraalkylammonium moieties for fine tuning their antibacterial activity.

The widespread of bacterial infections including biofilms drives the never-ending quest for new antimicrobial agents. Among the great variety of nanomaterials, carbon dots (CDs) are the most promising antibacterial material, but still require the adjustment of their surface properties for enhanced activity. In this contribution, we report a facile functionalization method of carbon dots (CDs) by tetraalkylammonium moieties using diazonium chemistry to improve their antibacterial activity against Gram-positive and Gram-negative bacteria. CDs were modified by novel diazonium salts bearing tetraalkylammonium moieties (TAA) with different alkyl chains (C2, C4, C9, C12) for the optimization of antibacterial activity. Variation of the alkyl chain allows to reach the significant antibacterial effect for CDs-C9 towards Gram-positive Staphylococcus aureus (S. aureus) (MIC = 3.09 ± 1.10 µg mL-1) and Gram-negative Escherichia coli (E. coli) (MIC = 7.93 ± 0.17 µg mL-1) bacteria. The antibacterial mechanism of CDs-C9 is ascribed to the balance between the positive charge and hydrophobicity of the alkyl chains. TAA moieties are responsible for enhanced adherence on the bacterial cell membrane, its penetration and disturbance of physiological metabolism. CDs-C9 were not effective in the generation of reactive oxygen species excluding the oxidative damage mechanism. In addition, CDs-C9 effectively promoted the antibiofilm treatment of S. aureus and E. coli biofilms outperforming previously-reported CDs in terms of treatment duration and minimal inhibitory concentration. The good biocompatibility of CDs-C9 was demonstrated on mouse fibroblast (NIH/3T3), HeLa and U-87 MG cell lines for concentrations up to 256 µg mL-1. Collectively, our work highlights the correlation between the surface chemistry of CDs and their antimicrobial performance.