Phenazine Cations as Anticancer Theranostics†.

The biological properties of two water-soluble organic cations based on polypyridyl structures commonly used as ligands for photoactive transition metal complexes designed to interact with biomolecules are investigated. A cytotoxicity screen employing a small panel of cell lines reveals that both cations show cytotoxicity toward cancer cells but show reduced cytotoxicity to noncancerous HEK293 cells with the more extended system being notably more active. Although it is not a singlet oxygen sensitizer, the more active cation also displayed enhanced potency on irradiation with visible light, making it active at nanomolar concentrations. Using the intrinsic luminescence of the cations, their cellular uptake was investigated in more detail, revealing that the active compound is more readily internalized than its less lipophilic analogue. Colocalization studies with established cell probes reveal that the active cation predominantly localizes within lysosomes and that irradiation leads to the disruption of mitochondrial structure and function. Stimulated emission depletion (STED) nanoscopy and transmission electron microscopy (TEM) imaging reveal that treatment results in distinct lysosomal swelling and extensive cellular vacuolization. Further imaging-based studies confirm that treatment with the active cation induces lysosomal membrane permeabilization, which triggers lysosome-dependent cell-death due to both necrosis and caspase-dependent apoptosis. A preliminary toxicity screen in the Galleria melonella animal model was carried out on both cations and revealed no detectable toxicity up to concentrations of 80 mg/kg. Taken together, these studies indicate that this class of synthetically easy-to-access photoactive compounds offers potential as novel therapeutic leads.

Pillar[n]arenes in the Fight against Biofilms: Current Developments and Future Perspectives.

The global surge in bacterial infections, compounded by the alarming escalation of drug-resistant strains, has evolved into a critical public health crisis. Among the challenges posed, biofilms stand out due to their formidable resistance to conventional antibiotics. This review delves into the burgeoning potential of pillar[n]arenes, distinctive macrocyclic host molecules, as promising anti-biofilm agents. The review is structured into two main sections, each dedicated to exploring distinct facets of pillar[n]arene applications. The first section scrutinizes functionalized pillar[n]arenes with a particular emphasis on cationic derivatives. This analysis reveals their significant efficacy in inhibiting biofilm formation, underscoring the pivotal role of specific chemical attributes in combating microbial communities. The second section of the review shifts its focus to inclusion complexes, elucidating how pillar[n]arenes serve as encapsulation platforms for antibiotics. This encapsulation enhances the stability of antibiotics and enables a controlled release, thereby amplifying their antibacterial activity. The examination of inclusion complexes provides valuable insights into the potential synergy between pillar[n]arenes and traditional antibiotics, offering a novel avenue for overcoming biofilm resistance. This comprehensive review highlights the escalating global threat of bacterial infections and the urgent need for innovative strategies to counteract drug-resistant biofilms. The unique properties of pillar[n]arenes, both as functionalized molecules and as inclusion complex hosts, position them as promising candidates in the quest for effective anti-biofilm agents. The exploration of their distinct mechanisms opens new avenues for research and development in the ongoing battle against bacterial infections and biofilm-related health challenges.

Establishment and inactivation of mono-species biofilm in a semipilot-scale water distribution system using nanocomposite of silver nanoparticles/montmorillonite loaded cationic chitosan.

This study presents a novel approach in the synthesis and characterization of nanocomposites comprising cationic chitosan (CCS) blended with varying concentrations of silver nanoparticles/montmorillonite (AgNPs/MMT). AgNPs/MMT was synthesized using soluble starch as a reducing and stabilizing agent. Subsequently, nanocomposites, namely CCS/AgMMT-0, CCS/AgMMT-0.5, CCS/AgMMT-1.5, and CCS/AgMMT-2.5, were developed by blending 2.5 g of CCS with 0, 0.5, 1.5, and 2.5 g of AgNPs/MMT, respectively, and the corresponding nanocomposites were prepared using ball milling technique. Transmission electron microscopy (TEM) analysis revealed the formation of nanocomposites that exhibiting nearly spherical morphologies. Dynamic light scattering (DLS) measurements displayed average particle sizes of 1183 nm, 131 nm, 140 nm, and 188 nm for CCS/AgMMT-0, CCS/AgMMT-0.5, CCS/AgMMT-1.5, and CCS/AgMMT-2.5, respectively. The narrow polydispersity index (~0.5) indicated uniform particle size distributions across the nanocomposites, affirming monodispersity. Moreover, the zeta potential values exceeding 30 mV across all nanocomposites that confirmed their stability against agglomeration. Notably, CCS/AgMMT-2.5 nanocomposite exhibited potent antibacterial and antibiofilm properties against diverse pipeline materials. Findings showed that after 15 days of incubation, the highest populations of biofilm cells, Pseudomonas aeruginosa biofilm, developed over UPVC, MDPE, DCI, and SS, with corresponding HPCs of 4.79, 6.38, 8.81, and 7.24 CFU/cm2. The highest cell densities of Enterococcus faecalis biofilm in the identical situation were 4.19, 5.89, 8.12, and 6.9 CFU/cm2. The nanocomposite CCS/AgMMT-2.5 exhibited the largest measured zone of inhibition (ZOI) against both P. aeruginosa and E. faecalis, with measured ZOI values of 19 ± 0.65 and 17 ± 0.21 mm, respectively. Remarkably, the research indicates that the youngest biofilm exhibited the most notable rate of inactivation when exposed to a dose of 150 mg/L, in comparison to the mature biofilm. These such informative findings could offer valuable insights into the development of effective antibiofilm agents and materials applicable in diverse sectors such as water treatment facilities, medical devices, and industrial pipelines.

Constructing a Photothermal and Quaternary Ammonium Cation Bactericidal Platform onto SEBS for Synergistic Therapy.

Poly(styrene-b-(ethylene-co-butylene)-b-styrene) (SEBS) with eminent elasticity, thermoplastic ability, and biological stability has aroused great interest in the medical area. However, bacteria can easily adhere to the hydrophobic SEBS surface to cause medical device-related infections. In this work, SEBS is modified to prepare the SEBS-polydopamine (PDA)-poly(lysine) quaternary ammonium derivative (PLQ) antibacterial surface by PDA deposition and surface grafting techniques to solve bacterial infections. PDA is used as an intermediate layer and presents an excellent photothermal effect. The grafted polymer PLQ has antimicrobial quaternary ammonium cation groups, which plays synergistic bactericidal therapy with PDA. The SEBS-PDA-PLQ surface almost totally suppresses the growth of bacteria with a surface bacterial survival rate of 0.05% under laser irradiation. The outstanding antibacterial activity of the SEBS-PDA-PLQ surface is attributed to the synergistic effects of the photothermal performance of PDA and quaternary ammonium cationic functional groups of PLQ. In addition, the membrane SEBS-PDA-PLQ shows good hydrophilicity, antiprotein adsorption ability, chemical stability, and biocompatibility. This antibiotic-free antimicrobial approach has great potential for practical application in solving infections associated with medical devices.

Identification of RNA reads encoding different channels in isolated rat ventricular myocytes and the effect of cell stretching on L-type Ca2+current.

BACKGROUND: The study aimed to identify transcripts of specific ion channels in rat ventricular cardiomyocytes and determine their potential role in the regulation of ionic currents in response to mechanical stimulation. The gene expression levels of various ion channels in freshly isolated rat ventricular cardiomyocytes were investigated using the RNA-seq technique. We also measured changes in current through CaV1.2 channels under cell stretching using the whole-cell patch-clamp method. RESULTS: Among channels that showed mechanosensitivity, significant amounts of TRPM7, TRPC1, and TRPM4 transcripts were found. We suppose that the recorded L-type Ca2+ current is probably expressed through CaV1.2. Furthermore, stretching cells by 6, 8, and 10 µm, which increases ISAC through the TRPM7, TRPC1, and TRPM4 channels, also decreased ICa,L through the CaV1.2 channels in K+ in/K+ out, Cs+ in/K+ out, K+ in/Cs+ out, and Cs+ in/Cs+ out solutions. The application of a nonspecific ISAC blocker, Gd3+, during cell stretching eliminated ISAC through nonselective cation channels and ICa,L through CaV1.2 channels. Since the response to Gd3+ was maintained in Cs+ in/Cs+ out solutions, we suggest that voltage-gated CaV1.2 channels in the ventricular myocytes of adult rats also exhibit mechanosensitive properties. CONCLUSIONS: Our findings suggest that TRPM7, TRPC1, and TRPM4 channels represent stretch-activated nonselective cation channels in rat ventricular myocytes. Probably the CaV1.2 channels in these cells exhibit mechanosensitive properties. Our results provide insight into the molecular mechanisms underlying stretch-induced responses in rat ventricular myocytes, which may have implications for understanding cardiac physiology and pathophysiology.

Design and Synthesis of Poly(2,2'-Bipyridyl) Ligands for Induction of Cell Death in Cancer Cells: Control of Anticancer Activity by Complexation/Decomplexation with Biorelevant Metal Cations.

Chelation therapy is a medical procedure for removing toxic metals from human organs and tissues and for the treatment of diseases by using metal-chelating agents. For example, iron chelation therapy is designed not only for the treatment of metal poisoning but also for some diseases that are induced by iron overload, cancer chemotherapy, and related diseases. However, the use of such metal chelators needs to be generally carried out very carefully, because of the side effects possibly due to the non-specific complexation with intracellular metal cations. Herein, we report on the preparation and characterization of some new poly(bpy) ligands (bpy: 2,2'-bipyridyl) that contain one-three bpy ligand moieties and their anticancer activity against Jurkat, MOLT-4, U937, HeLa S3, and A549 cell lines. The results of MTT assays revealed that the tris(bpy) and bis(bpy) ligands exhibit potent activity for inducing the cell death in cancer cells. Mechanistic studies suggest that the main pathway responsible for the cell death by these poly(bpy) ligands is apoptotic cell death. It was also found that the anticancer activity of the poly(bpy) ligands could be controlled by the complexation (anticancer activity is turned OFF) and decomplexation (anticancer activity is turned ON) with biorelevant metal cations. In this paper, these results will be described.

Modeling the Interaction and Uptake of Cd-As(V) Mixture to Wheat Roots Affected by Humic Acids, in Terms of root cell Membrane Surface Potential (ψ0).

The joint toxicological effects of Cd2+ and As(V) mixture on wheat root as affected by environmental factors, such as pH, coexisting cations, and humic acids etc., were investigated using hydroponic experiments. The interaction and toxicological mechanisms of co-existing Cd2+ and As(V) at the interface of solution and roots in presence of humic acid were further explored by incorporating root cell membrane surface potential ψ0 into a mechanistic model of combined biotic ligand model (BLM)-based Gouy-Chapman-Stern (GCS) model and NICA-DONNAN model. Besides, molecular dynamics (MD) simulations of lipid bilayer equilibrated with solution containing Cd2+ and H2AsO4- further revealed the molecular distribution of heavy metal(loid) ions under different membrane surface potentials. H2AsO4- and Cd2+ can be adsorbed on the surface of the membrane alone or as complexes, which consolidate the limitation of the macroscopic physical models.

Mechanisms of Phototoxic Effects of Cationic Porphyrins on Human Cells In Vitro.

The toxic effects of four cationic porphyrins on various human cells were studied in vitro. It was found that, under dark conditions, porphyrins are almost nontoxic, while, under the action of light, the toxic effect was observed starting from nanomolar concentrations. At a concentration of 100 nM, porphyrins caused inhibition of metabolism in the MTT test in normal and cancer cells. Furthermore, low concentrations of porphyrins inhibited colony formation. The toxic effect was nonlinear; with increasing concentrations of various porphyrins, up to about 1 µM, the effect reached a plateau. In addition to the MTT test, this was repeated in experiments examining cell permeability to trypan blue, as well as survival after 24 h. The first visible manifestation of the toxic action of porphyrins is blebbing and swelling of cells. Against the background of this process, permeability to porphyrins and trypan blue appears. Subsequently, most cells (even mitotic cells) freeze in this swollen state for a long time (24 and even 48 h), remaining attached. Cellular morphology is mostly preserved. Thus, it is clear that the cells undergo mainly necrotic death. The hypothesis proposed is that the concentration dependence of membrane damage indicates a limited number of porphyrin targets on the membrane. These targets may be any ion channels, which should be considered in photodynamic therapy.

Loss of TRPV4 Cation Channel Inhibition of Macrophage Infiltration and Neovascularization in a Mouse Cornea.

Corneal injury-associated inflammation could induce inward-growing neovascularization from the periphery of the tissue. Such neovascularization could cause stromal opacification and curvature disturbance, and both potentially impair visual function. In this study, we determined the effects of the loss of transient receptor potential vanilloid 4 (TRPV4) expression on the development of neovascularization in the corneal stroma in mice by producing a cauterization injury in the central area of the cornea. New vessels were immunohistochemically labeled with anti-TRPV4 antibodies. TRPV4 gene knockout suppressed the growth of such CD31-labeled neovascularization in association with the suppression of infiltration of macrophages and tissue messenger RNA expression of the vascular endothelial cell growth factor A level. Treatment of cultured vascular endothelial cells with supplementation of HC-067047 (0.1 µM, 1 µM, or 10 µM), a TRPV4 antagonist, attenuated the formation of a tube-like structure with sulforaphane (15 µM, for positive control) that modeled the new vessel formation. Therefore, the TRPV4 signal is involved in injury-induced macrophagic inflammation and neovascularization activity by vascular endothelial cells in a mouse corneal stroma. TRPV4 could be a therapeutic target to prevent unfavorable postinjury neovascularization in the cornea.

Mitochondria-targeting NIR AIEgens with cationic amphiphilic character for imaging and efficient photodynamic therapy.

A new dual-cationic amphiphilic AIEgen TPhBT-PyP with NIR emission and efficient 1O2 generation was designed. The amphiphilicity of TPhBT-PyP was tuned with dual-positive charges of pyridinium and TPP groups, efficiently targeting mitochondria and distinguishing Gram-positive bacteria. TPhBT-PyP performed well in photodynamic therapy, inducing cancer cell apoptosis and killing S. aureus bacteria.

Modulating Cytotoxicity with Lego-like Chemistry: Upgrading Mitochondriotropic Antioxidants with Prototypical Cationic Carrier Bricks.

Although the lipophilic triphenylphosphonium (TPP+) cation is widely used to target antioxidants to mitochondria, TPP+-based derivatives have shown cytotoxicity in several biological in vitro models. We confirmed that Mito.TPP is cytotoxic to both human neuronal (SH-SY5Y) and hepatic (HepG2) cells, decreasing intracellular adenosine triphosphate (ATP) levels, leading to mitochondrial membrane depolarization and reduced mitochondrial mass after 24 h. We surpassed this concern using nitrogen-derived cationic carriers (Mito.PICO, Mito.ISOQ, and Mito.IMIDZ). As opposed to Mito.TPP, these novel compounds were not cytotoxic to SH-SY5Y and HepG2 cells up to 50 µM and after 24 h of incubation. All of the cationic derivatives accumulated inside the mitochondrial matrix and acted as neuroprotective agents against iron(III), hydrogen peroxide, and tert-butyl hydroperoxide insults. The overall data showed that nitrogen-based cationic carriers can modulate the biological performance of mitochondria-directed antioxidants and are an alternative to the TPP cation.

Antimalarials Targeting the Malaria Parasite Cation ATPase P. falciparum ATP4 (PfATP4).

Malaria, caused by parasites of the Plasmodium species and transmitted through the bites of infected female Anopheles mosquitoes, is still a fatal and dangerous disease in mainly tropical and subtropical regions. The widespread resistance of P. falciparum to antimalarial drugs forces the search for new molecules with activity against this parasite. While a large number of compounds can inhibit P. falciparum growth in vitro, unfortunately, only a limited number of targets have been identified so far. One of the most promising approaches has been the identification of effective inhibitors of P-type cation-transporter ATPase 4 (PfATP4) in P. falciparum. PfATP4 is a Na+ efflux pump that maintains a low cytosolic Na+ in the parasite. Thus, upon treatment with PfATP4 inhibitors, the parasites rapidly accumulate Na+, which triggers processes leading to parasite death. PfATP4 is present in the parasite plasma membrane but is absent in mammals; its exclusivity thus makes it a good antimalarial drug target. The current review presents PfATP4 function in the context of the pharmacological influence of its inhibitors. In addition, compounds with inhibitory activities belonging to spiroindolones, dihydroisoquinolones, aminopyrazoles, pyrazoleamides, and 4-cyano-3-methylisoquinolines, are also reviewed. Particular emphasis is placed on the results of preclinical and clinical studies in which their effectiveness was tested. PfATP4-associated antimalarials rapidly cleared parasites in mouse models and preliminary human trials. These findings highlight a fundamental biochemical mechanism sensitive to pharmacological intervention that can form a medicinal chemistry approach for antimalarial drug design to create new molecules with potent PfATP4 inhibitory activity.

Selective and reversible disruption of mitochondrial inner membrane protein complexes by lipophilic cations.

Triphenylphosphonium (TPP) derivatives are commonly used to target chemical into mitochondria. We show that alkyl-TPP cause reversible, dose- and hydrophobicity-dependent alterations of mitochondrial morphology and function and a selective decrease of mitochondrial inner membrane proteins including subunits of the respiratory chain complexes, as well as components of the mitochondrial calcium uniporter complex. The treatment with alkyl-TPP resulted in the cleavage of the pro-fusion and cristae organisation regulator Optic atrophy-1. The structural and functional effects of alkyl-TPP were found to be reversible and not merely due to loss of membrane potential. A similar effect was observed with the mitochondria-targeted antioxidant MitoQ.

Development of biaromatic core-linked antimicrobial peptide mimics: Substituent position significantly affects antibacterial activity and hemolytic toxicity.

The development of bacterial resistance to the majority of clinically significant antimicrobials has made it more difficult to treat bacterial infections with conventional antibiotics. As part of ongoing research on antimicrobial peptide mimetics, a series of quaternary ammonium cationic compounds with various linkers were designed and synthesized, with some demonstrating high antibacterial activity against Gram-negative and Gram-positive bacteria. The structure-activity relationship study revealed that the spatial position of substituents had a significant impact on antibacterial activity and hemolytic toxicity. The best compound, 3e, has good antibacterial activity against Staphylococcus aureus [minimum inhibitory concentration (MIC = 1 µg/mL)] and the least hemolytic toxicity [hemolytic concentration (HC50 = 905 µg/mL)], is stable in mammalian body fluids, and rarely induces bacterial resistance. The mechanism study revealed that the membrane action mode may be its potential bactericidal mechanism, and it can effectively cause the accumulation of intracellular reactive oxygen species (ROS) for killing bacteria. Importantly, 3e can effectively reduce the load of methicillin-resistant Staphylococcus aureus (MRSA) in mouse skin and has a higher in vivo bactericidal efficiency than vancomycin. These findings highlight the significance of divergent linkers in quaternary ammonium cations as antimicrobial peptide mimics and the potential of these cations to treat bacterial infections.

Efficacy of Novel Quaternary Ammonium and Phosphonium Salts Differing in Cation Type and Alkyl Chain Length against Antibiotic-Resistant Staphylococcus aureus.

Antibacterial resistance poses a critical public health threat, challenging the prevention and treatment of bacterial infections. The search for innovative antibacterial agents has spurred significant interest in quaternary heteronium salts (QHSs), such as quaternary ammonium and phosphonium compounds as potential candidates. In this study, a library of 49 structurally related QHSs was synthesized, varying the cation type and alkyl chain length. Their antibacterial activities against Staphylococcus aureus, including antibiotic-resistant strains, were evaluated by determining minimum inhibitory/bactericidal concentrations (MIC/MBC) ≤ 64 µg/mL. Structure-activity relationship analyses highlighted alkyl-triphenylphosphonium and alkyl-methylimidazolium salts as the most effective against S. aureus CECT 976. The length of the alkyl side chain significantly influenced the antibacterial activity, with optimal chain lengths observed between C10 and C14. Dose-response relationships were assessed for selected QHSs, showing dose-dependent antibacterial activity following a non-linear pattern. Survival curves indicated effective eradication of S. aureus CECT 976 by QHSs at low concentrations, particularly compounds 1e, 3e, and 5e. Moreover, in vitro human cellular data indicated that compounds 2e, 4e, and 5e showed favourable safety profiles at concentrations ≤ 2 µg/mL. These findings highlight the potential of these QHSs as effective agents against susceptible and resistant bacterial strains, providing valuable insights for the rational design of bioactive QHSs.

Visible light-regulated cationic polymer coupled with photodynamic inactivation as an effective tool for pathogen and biofilm elimination.

BACKGROUND: Pathogenic microorganism pollution has been a challenging public safety issue, attracting considerable scientific interest. A more problematic aspect of this phenomenon is that planktonic bacteria exacerbate biofilm formation. There is an overwhelming demand for developing ultra-efficient, anti-drug resistance, and biocompatibility alternatives to eliminate stubborn pathogenic strains and biofilms. RESULTS: The present work aims to construct a visible light-induced anti-pathogen agents to ablate biofilms using the complementary merits of ROS and cationic polymers. The photosensitizer chlorin e6-loaded polyethyleneimine-based micelle (Ce6-TPP-PEI) was constructed by an amphiphilic dendritic polymer (TPP-PEI) and physically loaded with photosensitizer chlorin e6. Cationic polymers can promote the interaction between photosensitizer and Gram-negative bacteria, resulting in enhanced targeting of PS and lethality of photodynamic therapy, and remain active for a longer duration to prevent bacterial re-growth when the light is turned off. As expected, an eminent antibacterial effect was observed on the Gram-negative Escherichia coli, which is usually insensitive to photosensitizers. Surprisingly, the cationic polymer and photodynamic combination also exert significant inhibitory and ablative effects on fungi and biofilms. Subsequently, cell hemolysis assessments suggested its good biocompatibility. CONCLUSIONS: Given the above results, the platform developed in this work is an efficient and safe tool for public healthcare and environmental remediation.

Structural Studies Reveal that Endosomal Cations Promote Formation of Infectious Coxsackievirus A9 A-Particles, Facilitating RNA and VP4 Release.

Coxsackievirus A9 (CVA9), an enterovirus, is a common cause of pediatric aseptic meningitis and neonatal sepsis. During cell entry, enterovirus capsids undergo conformational changes leading to expansion, formation of large pores, externalization of VP1 N termini, and loss of the lipid factor from VP1. Factors such as receptor binding, heat, and acidic pH can trigger capsid expansion in some enteroviruses. Here, we show that fatty acid-free bovine serum albumin or neutral endosomal ionic conditions can independently prime CVA9 for expansion and genome release. Our results showed that CVA9 treatment with albumin or endosomal ions generated a heterogeneous population of virions, which could be physically separated by asymmetric flow field flow fractionation and computationally by cryo-electron microscopy (cryo-EM) and image processing. We report cryo-EM structures of CVA9 A-particles obtained by albumin or endosomal ion treatment and a control nonexpanded virion to 3.5, 3.3, and 2.9 Å resolution, respectively. Whereas albumin promoted stable expanded virions, the endosomal ionic concentrations induced unstable CVA9 virions which easily disintegrated, losing their genome. Loss of most of the VP4 molecules and exposure of negatively charged amino acid residues in the capsid's interior after expansion created a repulsive viral RNA-capsid interface, aiding genome release. IMPORTANCE Coxsackievirus A9 (CVA9) is a common cause of meningitis and neonatal sepsis. The triggers and mode of action of RNA release into the cell unusually do not require receptor interaction. Rather, a slow process in the endosome, independent of low pH, is required. Here, we show by biophysical separation, cryogenic electron microscopy, and image reconstruction that albumin and buffers mimicking the endosomal ion composition can separately and together expand and prime CVA9 for uncoating. Furthermore, we show in these expanded particles that VP4 is present at only ~10% of the occupancy found in the virion, VP1 is externalized, and the genome is repelled by the negatively charged, repulsive inner surface of the capsid that occurs due to the expansion. Thus, we can now link observations from cell biology of infection with the physical processes that occur in the capsid to promote genome uncoating.

Review: Dietary cation-anion difference to prevent hypocalcemia with emphasis on over-acidification in prepartum dairy cows.

Hypocalcemia remains a common metabolic disorder of dairy cattle; therefore, an efficient prevention is still challenging. Among the various prevention strategies for hypocalcemia is the use of anionic compounds to induce a mild metabolic acidosis during the prepartum period. Acid-base status can be readily assessed through urine pH. Accordingly, a target urine pH during the prepartum period between 6.0 and 6.8 has been recommended for Holstein cows; however, in several countries, including the US, certain nutritional strategies are still focused on benchmarking the urine pH to below 6.0. Unfortunately, over-acidification can have no advantages and/or detrimental effects on both the dam and her offspring. In this review, updated information regarding the use of anionic diets on prepartum dairy cows and the potential negative impact of such diets on both cow and calf performance are discussed. There is an urgent need for studies that will elucidate the pathophysiological mechanisms by which very acidotic diets may impact the well-being and productive efficiency of dairy cows, and the transgenerational effects of such diets on offspring performance and survival.

Ionic Liquids as Biocompatible Antibacterial Agents: A Case Study on Structure-Related Bioactivity on Escherichia coli.

The potential of ionic liquids (ILs) to be used as antimicrobial agents for biomedical applications has been hindered by the fact that most of them are cytotoxic toward mammalian cells. Understanding the mechanism of bacterial and mammalian cellular damage of ILs is key to their safety design. In this work, we evaluate the antimicrobial activity and mode of action of several ILs with varying anions and cations toward the clinically relevant Gram-negative Escherichia coli. Langmuir monolayer technique was used to evaluate if the IL's mode of action was related to the bacterial cell membrane interaction for an effective E. coli killing. 1-Decyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide [DMIM][TFSI] and trihexyltetradecyl phosphonium bis(trifluoromethylsulfonyl) imide [P6,6,6,14][TFSI] were surface-active and induced bacterial cell lysis, through a membrane-disruption phenomenon on bacteria, in a mechanism that was clearly related to the long alkyl chains of the cation. 1-Ethyl-3-methylimidazolium hydrogen sulfate [EMIM][HSO4] was highly antimicrobial toward E. coli and found suitable for biological applications since it was harmless to mammalian cells at most of the tested concentrations. The results suggest that the imidazolium cation of the ILs is mostly responsible not only for their antimicrobial activity but also for their cytotoxicity, and the inclusion of different anions may tailor the ILs' biocompatibility without losing the capacity to kill bacteria, as is the case of [EMIM][HSO4]. Importantly, this IL was found to be highly antimicrobial even when incorporated in a polymeric matrix.

Amoebicidal activity of cationic carbosilane dendrons derived with 4-phenylbutyric acid against Acanthamoeba griffini and Acanthamoeba polyphaga trophozoites and cysts.

Amoebae from the genus Acanthamoeba are important pathogens responsible for severe illnesses in humans such as Acanthamoeba keratitis and granulomatous amoebic encephalitis. In the last few decades, AK diagnoses have steadily increased. Most patients suffering from AK were contact lens users and the infection was related to poor hygiene. However, therapy is not yet well established, and treatments may last for several months due to resistance. Moreover, these treatments have been described to generate cytotoxicity. Therefore, there is an urgent need to develop new therapeutic strategies against AK. In this study, the amoebicidal activity of different generation cationic carbosilane dendrons derived with 4-phenylbutyric acid was demonstrated against Acanthamoeba polyphaga and Acanthamoeba griffini trophozoites and cysts. In addition, the combination of chlorhexidine digluconate and the most effective dendron (ArCO2G2(SNMe3I)4) showed an in vitro effect against Acanthamoeba trophozoites and cysts, reducing the minimal trophozoite amoebicidal concentration as well as concentrations with cysticidal activity.