Mode Of Action Research Articles

Synthesis of Cd (II), Fe (III), Cu (II), and Cr (VI) complexes of Schiff bases and their antibacterial activities

Schiff base and the metal derivatives have been utilized in numerous areas of the economy. Synthesis and antibacterial activities of Cd (II), Cr (VI), Cu (II), and Fe (III) complexes of Schiff bases were evaluated in this work. Complexes synthesized were Bis(1-phenyl-3-methyl-4-Phenyl acetyl 5-pyrazolone)Cadmium (II) (Cd(HPMPP)2), Tris(1-phenyl-3-methyl-4-benzoyl-5-pyrazolone)Iron(III)(Fe(HPMBP)3), Bis(1-phenyl-3-methyl-4-phenylacetyl-5-pyrazolone)Copper (II) (Cu(HPMPP)2), Hexakis(1-phenyl-3-methyl-4-palmitoyl-5-pyrazolone)Chromium (VI) (Cr(HPMPP)6), and Tris(1-phenyl-3-methyl-4- palmitoyl-5-pyrazolone)Iron (III) (Fe(HPMPP)3). The physical state, colour, and melting point of these complexes were determined using appropriate analytical techniques. Results showed that all the complexes were crystalline in nature; their colours were variable, while their melting points were sharp. The solubility of these complexes in deionized water, acetone, methanol, and ethanol was also carried out. The outcome revealed that all the metal complexes were insoluble in deionized water, Cr(HPMPP)6 was soluble in acetone, methanol, and ethanol. However, the solubility of other metal complexes in the organic solvents used was variable. The antibacterial activities of these metal complexes at different concentrations were also tested against distilled water, E. coli, S. aureus, B. subtillus, and S. typhi. The results showed that, antimicrobial activity of these complexes against distilled water was negative whereas, the bacterial growth of all the bacteria was inhibited by the complexes though at different rates. The inhibition rate of microorganisms was inversely proportional to the concentration of the complexes. The antibacterial activities of Cd(HPMPP)2 and Cr(HPMPP)6 were outstanding against the growth of all the bacteria. Thus, a proper processing of these complexes might result in excellent antibacterial drugs. However, more studies on the mode of action of these complexes against microorganisms and their toxicity should be done in order to establish their potentials for pharmaceutical applications.

Entomopathogenic fungi in crops protection with an emphasis on bioactive metabolites and biological activities.

Plant pathogens with their abundance are harmful and cause huge damage to different agricultural crops and economy of a country as well as lead towards the shortage of food for humans. For their management, the utilization of entomopathogenic fungi is an eco-friendly technique, sustainable to the environment, safe for humans and has promising effect over chemical-based pesticides. This process requires a biochemical mechanism, including the production of enzymes, toxins, and other metabolites that facilitate host infection and invasion. Essential enzymes such as chitinase, proteinase, and lipase play a direct role in breaking down the host cuticle, the primary barrier to EPF (Entomopathogenic Fungi) infection. Additionally, secondary metabolites such as destruxins in Metarhizium, beauvericin in Beauveria, hirsutellides in Hirsutella, isarolides in Isaria, cordyols in Cordyceps, and vertihemipterins in Verticillium, among others, act both directly and indirectly to disable the defense mechanisms of insect hosts, thereby accelerating the EPF infection process. The chemical composition of these secondary metabolites varies, ranging from simple non-peptide pigments such as oosporine to highly complex piperazine derivatives such as vertihemiptellides. The biocontrol efficacy of EPF is extensively studied, with numerous fungal strains commercially available on a large scale for managing arthropod pests. This review emphasizes the role of proteins and enzymes against crop pathogens, detailing their mode of action, and describing the metabolites from entomopathogenic fungi and their biological activities. In doing so, these findings contribute to establishing a symbiotic equilibrium between agricultural productivity and environmental conservation.

Investigating Anti-Bacterial and Anti-COVID-19 Virus Properties and Mode of Action of Pure Mg(OH)2 and Copper-infused Mg(OH)2 Nanoparticles and Coated Polypropylene Surfaces

Robust anti-microbial surfaces that are non-toxic to users have widespread application in medical, industrial, and domestic arenas. Magnesium hydroxide has recently gained attention as an anti-microbial compound that is non-toxic, biocompatible, and environmentally friendly. Here we demonstrate melt compound and thermally embossed methods for coating polypropylene with Mg(OH)2 nanoplatelets and copper-infused Mg(OH)2 nanoplatelets. Polypropylene articles coated with Mg(OH)2 nanoplatelets and copper-infused Mg(OH)2 nanoplatelets exhibit a log 8 kill of E.coli within 24 hours. In addition, Mg(OH)2 NPs suspension, at 0.25% reduced SARSCoV-2 virus titers in the solution by 2.5 x 103 PFU/mL or 29.4%, while the Cu-infused Mg(OH)2 NPs suspension, at 0.25% reduced titers by 8.1 x 103 PFU/mL or 95.3%. Fluorescence microscopy revealed that reactive oxygen species (ROS) are produced in bacteria in response to Mg(OH)2 and Cu-infused Mg(OH)2 nanoplatelets which appears to be an important but not the sole mode of anti-microbial action of the nanoplatelets. Plastics with anti-microbial surfaces from where biocides are non-leachable are highly desirable. This work provides a general fabrication strategy for developing anti-microbial plastic surfaces.

Butein derivatives prevent obesity and improve insulin resistance through the induction of energy expenditure in high-fat diet-fed obese mice

Obesity is a global public health problem and is related with fatal diseases such as cancer and cardiovascular and metabolic diseases. Medical and lifestyle-related strategies to combat obesity have their limitations. White adipose tissue (WAT) browning is a promising strategy for increasing energy expenditure in individuals with obesity. Uncoupling protein 1 (UCP1) drives WAT browning. We previously screened natural products that enable induction of Ucp1 and demonstrated that these natural products induced WAT browning and increased energy expenditure in mice with diet-induced obesity. In this study, we aimed to extensively optimise the structure of compound 1, previously shown to promote WAT browning. Compound 3 s exhibited a significantly higher ability to induce Ucp1 in white and brown adipocytes than did compound 1. A daily injection of compound 3 s at 5 mg/kg prevented weight gain by 13.6 % in high-fat diet–fed mice without any toxicological observation. In addition, compound 3 s significantly improved glucose homeostasis, decreased serum triacylglycerol levels, and reduced total cholesterol and LDL cholesterol levels, without altering dietary intake or physical activity. Pharmaceutical properties such as solubility, lipophilicity, and membrane permeability as well as metabolic stability, half-life (T1/2), and blood exposure ratio of i.p to i.v were significantly improved in compound 3 s when compared with those in compound 1. Regarding the mode of action of WAT browning, the induction of Ucp1 and Prdm4 by compounds 1 and 3 s was dependent on Akt1 in mouse embryonic fibroblasts. Therefore, this study suggests the potential of compound 3 s as a therapeutic agent for individuals with obesity and related metabolic diseases, which acts through the induction of WAT browning as well as brown adipose tissue activation.

Cyclopenta[b]indoles as novel antimicrotubule agents with antileukemia activity

Acute leukemias present therapeutic challenges despite advances in treatments. Microtubule inhibitors have played a pivotal role in cancer therapy, inspiring exploration into novel compounds like C2E1 from the cyclopenta[b]indole class. In the present study, we investigated C2E1's potential as a therapeutic agent for acute leukemia at molecular, cellular, and genetic levels. C2E1 demonstrated tubulin depolarization activity, significantly reducing leukemia cell viability. Its impact involved multifaceted mechanisms: inducing apoptosis, arrest of cell cycle progression, and inhibition of clonogenicity and migration in leukemia cells. At a molecular level, C2E1 triggered DNA damage, antiproliferative, and apoptosis markers and altered gene expression related to cytoskeletal regulation, disrupting essential cellular processes crucial for leukemia cell survival and proliferation. These findings highlight C2E1's promise as a potential candidate for novel anti-cancer therapies. Notably, its distinct mode of action from conventional microtubule-targeting drugs suggests the potential to bypass common resistance mechanisms encountered with existing treatments. In summary, C2E1 emerges as a compelling compound with diverse effects on leukemia cells, showcasing promising antineoplastic properties. Its ability to disrupt critical cellular functions selective to leukemia cells positions it as a candidate for future therapeutic development.

Plant Growth Regulator from the Essential Oil of Syzygium aromaticum L. for Inhibition of Secondary Growth of Garlic Cultivated under Tropical Conditions

Garlic cultivation in tropical regions, such as the Brazilian Cerrado, faces the problem of secondary growth in the field induced by climatic conditions, which affects bulb quality and value. Clove essential oil (CEO) contains high levels of eugenol, which has the potential as an eco-friendly plant growth retardant (PGR) capable of reducing or inhibiting the secondary growth of bulbs in garlic cultivation. In this study, field experiments were carried out in two consecutive years (winter 2021 and 2022), spraying garlic plants with different concentrations of emulsion of CEO (0.0, 0.2, and 0.4%) in the differentiation phase; for comparison, the effects of water deficit, a prevalent agricultural technique in the region, were also evaluated. At a dose of 0.4%, the CEO reduced the prevalence of secondary growth and split bulbs without affecting yield. The mode of action of PGR was investigated by analyzing photosynthetic, enzymatic, and metabolomic parameters. The plants reduced amylolytic activity, and the photosynthetic parameters, after 7 days, were restored in both treatments. The analysis of the metabolomic profile of garlic leaves revealed changes in the pathways associated with the biosynthesis of fatty acids, wax, cutin, and suberin in plants treated with CEO, indicating possible damage to the surface coating of the leaf.

Biocontrol of strawberry Botrytis gray mold and prolong the fruit shelf-life by fumigant Trichoderma spp.

Objectives To screen high active volatile organic compounds (VOCs)-producing Trichoderma isolates against strawberry gray mold caused by Botrytis cinerea, and to explore their antagonistic mode of action against the pathogen. VOCs produced by nine Trichoderma isolates (Trichoderma atroviride T1 and T3; Trichoderma harzianum T2, T4 and T5; T6, T7, T8 and T9 identified as Trichoderma asperellum in this work) significantly inhibited the mycelial growth (13.9-63.0% reduction) and conidial germination (17.6-96.3% reduction) of B. cinerea, the highest inhibition percentage belonged to VOCs of T7; in a closed space, VOCs of T7 shared 76.9% and 100% biocontrol efficacy against gray mold on strawberry fruits and detached leaves, respectively, prolonged the fruit shelf-life by 3 days in presence of B. cinerea, completely protected the leaves from B. cinerea infecting; volatile metabolites of T7 damaged the cell membrane permeability and integrity of B. cinerea, thereby inhibiting the mycelial growth and conidial germination. Gas chromatography-mass spectrometry (GC-MS) analysis revealed the VOCs contain 23 potential compounds, and the majority of these compounds were categorised as alkenes, alcohols, and esters, including PEA and 6PP, which have been reported as substances produced by Trichoderma spp. T. asperellum T7 showed high biofumigant activity against mycelial growth especially conidial germination of B. cinerea and thus protected strawberry fruits and leaves from gray mold, which acted by damaging the pathogen's plasma membrane and resulting in cytoplasm leakage, was a potential biofumigant for controlling pre- and post-harvest strawberry gray mold.

Modeling HepaRG metabolome responses to pyrrolizidine alkaloid exposure for insight into points of departure and modes of action

The new challenges in toxicology demand novel and innovative in vitro approaches for deriving points of departure (PODs) and determining the mode of action (MOA) of chemicals. Therefore, the aim of this original study was to couple in vitro studies with untargeted metabolomics to model the concentration-response of extra- and intracellular metabolome data on human HepaRG cells treated for 48 h with three pyrrolizidine alkaloids (PAs): heliotrine, retrorsine and lasiocarpine. Modeling revealed that the three PAs induced various monotonic and, importantly, biphasic curves of metabolite content. Based on unannotated metabolites, the endometabolome was more sensitive than the exometabolome in terms of metabolomic effects, and benchmark concentrations (BMCs) confirmed that lasiocarpine was the most hepatotoxic PA. Regarding its MOA, impairment of lipid metabolism was highlighted at a very low BMC (first quartile, 0.003 µM). Moreover, results confirmed that lasiocarpine targets bile acids, as well as amino acid and steroid metabolisms. Analysis of the endometabolome, based on coupling concentration-response and PODs, gave encouraging results for ranking toxins according to their hepatotoxic effects. Therefore, this novel approach is a promising tool for next-generation risk assessment, readily applicable to a broad range of compounds and toxic endpoints.

ESAT-6 undergoes self-association at phagosomal pH and an ESAT-6-specific nanobody restricts M. tuberculosis growth in macrophages

Mycobacterium tuberculosis (Mtb) is known to survive within macrophages by compromising the integrity of the phagosomal compartment in which it resides. This activity primarily relies on the ESX-1 secretion system, predominantly involving the protein duo ESAT-6 and CFP-10. CFP-10 likely acts as a chaperone, while ESAT-6 likely disrupts phagosomal membrane stability via a largely unknown mechanism. we employ a series of biochemical analyses, protein modeling techniques, and a novel ESAT-6-specific nanobody to gain insight into the ESAT-6’s mode of action. First, we measure the binding kinetics of the tight 1:1 complex formed by ESAT-6 and CFP-10 at neutral pH. Subsequently, we demonstrate a rapid self-association of ESAT-6 into large complexes under acidic conditions, leading to the identification of a stable tetrameric ESAT-6 species. Using molecular dynamics simulations, we pinpoint the most probable interaction interface. Furthermore, we show that cytoplasmic expression of an anti-ESAT-6 nanobody blocks Mtb replication, thereby underlining the pivotal role of ESAT-6 in intracellular survival. Together, these data suggest that ESAT-6 acts by a pH-dependent mechanism to establish two-way communication between the cytoplasm and the Mtb-containing phagosome.

ESAT-6 undergoes self-association at phagosomal pH and an ESAT-6-specific nanobody restricts M. tuberculosis growth in macrophages.

Mycobacterium tuberculosis (Mtb) is known to survive within macrophages by compromising the integrity of the phagosomal compartment in which it resides. This activity primarily relies on the ESX-1 secretion system, predominantly involving the protein duo ESAT-6 and CFP-10. CFP-10 likely acts as a chaperone, while ESAT-6 likely disrupts phagosomal membrane stability via a largely unknown mechanism. we employ a series of biochemical analyses, protein modeling techniques, and a novel ESAT-6-specific nanobody to gain insight into the ESAT-6's mode of action. First, we measure the binding kinetics of the tight 1:1 complex formed by ESAT-6 and CFP-10 at neutral pH. Subsequently, we demonstrate a rapid self-association of ESAT-6 into large complexes under acidic conditions, leading to the identification of a stable tetrameric ESAT-6 species. Using molecular dynamics simulations, we pinpoint the most probable interaction interface. Furthermore, we show that cytoplasmic expression of an anti-ESAT-6 nanobody blocks Mtb replication, thereby underlining the pivotal role of ESAT-6 in intracellular survival. Together, these data suggest that ESAT-6 acts by a pH-dependent mechanism to establish two-way communication between the cytoplasm and the Mtb-containing phagosome.

Cell proliferation and carcinogenesis: an approach to screening for potential human carcinogens.

Cancer arises from multiple genetic errors occurring in a single stem cell (clonality). Every time DNA replicates, mistakes occur. Thus, agents can increase the risk of cancer either by directly damaging DNA (DNA-reactive carcinogens) or increasing the number of DNA replications (increased cell proliferation). Increased cell proliferation can be achieved either by direct mitogenesis or cytotoxicity with regenerative proliferation. Human carcinogens have a mode of action of DNA reactivity, immunomodulation (mostly immunosuppression), increased estrogenic activity (mitogenesis), or cytotoxicity and regeneration. By focusing on screening for these four effects utilizing in silico, in vitro, and short-term in vivo assays, a biologically based screening for human chemical carcinogens can be accomplished with greater predictivity than the traditional 2-year bioassay with considerably less cost, less time, and the use of fewer animals.

Development of a Zebrafish Embryo-Based Test System for Thyroid Hormone System Disruption: 3Rs in Ecotoxicological Research.

There is increasing concern regarding pollutants disrupting the vertebrate thyroid hormone (TH) system, which is crucial for development. Thus, identification of TH system-disrupting chemicals (THSDCs) is an important requirement in the Organisation for Economic Co-operation and Development (OECD) testing framework. The current OECD approach uses different model organisms for different endocrine modalities, leading to a high number of animal tests. Alternative models compatible with the 3Rs (replacement, reduction, refinement) principle are required. Zebrafish embryos, not protected by current European Union animal welfare legislation, represent a promising model. Studies show that zebrafish swim bladder inflation and eye development are affected by THSDCs, and the respective adverse outcome pathways (AOPs) have been established. The present study compared effects of four THSDCs with distinct molecular modes of action: Propylthiouracil (PTU), potassium perchlorate, iopanoic acid, and the TH triiodothyronine (T3) were tested with a protocol based on the OECD fish embryo toxicity test (FET). Effects were analyzed according to the AOP concept from molecular over morphological to behavioral levels: Analysis of thyroid- and eye-related gene expression revealed significant effects after PTU and T3 exposure. All substances caused changes in thyroid follicle morphology of a transgenic zebrafish line expressing fluorescence in thyrocytes. Impaired eye development and swimming activity were observed in all treatments, supporting the hypothesis that THSDCs cause adverse population-relevant changes. Findings thus confirm that the FET can be amended by TH system-related endpoints into an integrated protocol comprising molecular, morphological, and behavioral endpoints for environmental risk assessment of potential endocrine disruptors, which is compatible with the 3Rs principle. Environ Toxicol Chem 2024;00:1-18. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Expression and potential molecular mechanism of TOP2A in metastasis of non-small cell lung cancer

DNA topoisomerase II alpha (TOP2A) expression, gene alterations, and enzyme activity have been studied in various malignant tumors. Abnormal elevation of TOP2A expression is considered to be related to the development of non-small cell lung cancer (NSCLC). However, its association with tumor metastasis and its mode of action remains unclear. Bioinformatics, real-time quantitative PCR, immunohistochemistry and immunoblotting were used to detect TOP2A expression in NSCLC tissues and cells. Cell migration and invasion assays as well as cytoskeletal staining were performed to analyze the effects of TOP2A on the motility, migration and invasion ability of NSCLC cells. Cell cycle and apoptosis assays were used to verify the effects of TOP2A on apoptosis as well as cycle distribution in NSCLC. TOP2A expression was considerably upregulated in NSCLC and significantly correlated with tumor metastasis and the occurrence of epithelial–mesenchymal transition (EMT) in NSCLC. Additionally, by interacting with the classical ligand Wnt3a, TOP2A may trigger the canonical Wnt signaling pathway in NSCLC. These observations suggest that TOP2A promotes EMT in NSCLC by activating the Wnt/β-catenin signaling pathway and positively regulates malignant events in NSCLC, in addition to its significant association with tumor metastasis. TOP2A promotes the metastasis of NSCLC by stimulating the canonical Wnt signaling pathway and inducing EMT. This study further elucidates the mechanism of action of TOP2A, suggesting that it might be a potential therapeutic target for anti-metastatic therapy.

Mechanistic investigations of polyaza[7]helicene in photoredox and energy transfer catalysis.

Organic photocatalysts frequently possess dual singlet and triplet photoreactivity and a thorough photochemical characterization is essential for efficient light-driven applications. In this article, the mode of action of a polyazahelicene catalyst (Aza-H) was investigated using laser flash photolysis (LFP). The study revealed that the chromophore can function as a singlet-state photoredox catalyst in the sulfonylation/arylation of styrenes and as a triplet sensitizer in energy transfer catalysis. The singlet lifetime is sufficiently long to exploit the exceptional excited state reduction potential for the activation of 4-cyanopyridine. Photoinduced electron transfer generating the radical cation was directly observed confirming the previously proposed mechanism of a three-component reaction. Several steps of the photoredox cycle were investigated separately, providing deep insights into the complex mechanism. The triplet-excited Aza-H, which was studied with quantitative LFP, is formed with a quantum yield of 0.34. The pronounced triplet formation was exploited for the isomerization reaction of (E)-stilbene to the Z-isomer and the cyclization of cinnamyl chloride. Catalyst degradation mainly occurs through the long-lived Aza-H triplet (28 µs), but the photostability is greatly increased when the triplet efficiently reacts in a catalytic cycle such that turnover numbers exceeding 4400 are achievable with this organocatalyst.

Study on triaxial compression performance and damage characteristics of fiber-reinforced ecological matrix cementing gangue gypsum fill material.

Polypropylene fiber was equally mixed into alkali-activated slag fly ash geopolymer in order to ensure the filling effect of mine goaf and improve the stability of cemented gangue paste filling material with ecological matrix. Triaxial compression tests were then conducted under various conditions. The mechanical properties and damage characteristics of composite paste filling materials are studied, and the damage evolution model of paste filling materials under triaxial compression is established, based on the deviatoric stress-strain curve generated by the progressive failure behavior of samples. Internal physical and chemical mechanisms of the evolution of structure and characteristics are elucidated and comprehended via the use of SEM-EDS and XRD micro-techniques. The results show that the fiber can effectively improve the ultimate strength and the corresponding effective stress strength index of the sample within the scope of the experimental study. The best strengthening effect is achieved when the amount of NaOH is 3% of the mass of the solid material, the amount of fiber is 5‰ of the mass of the solid material, and the length of the fiber is about 12 mm. The action mode of the fiber in the sample is mainly divided into single-grip anchoring and three-dimensional mesh traction. As the crack initiates and develops, connection occurs in the matrix, where the fiber has an obvious interference and retardation effect on the crack propagation, thereby transforming the brittle failure into a ductile failure and consequently improving the fracture properties of the ecological cementitious coal gangue matrix. The theoretical damage evolution model of a segmented filling body is constructed by taking the initial compaction stage end point as the critical point, and the curve of the damage evolution model of the specimen under different conditions is obtained. The theoretical model is verified by the results from the triaxial compression test. We concluded that the experimental curve is in good agreement with the theoretical curve. Therefore, the established theoretical model has a certain reference value for the analysis and evaluation of the mechanical properties of paste filling materials. The research results can improve the utilization rate of solid waste resources.

Oxydifficidin, a potent Neisseria gonorrhoeae antibiotic due to DedA assisted uptake and ribosomal protein RplL sensitivity.

Gonorrhea, which is caused by Neisseria gonorrhoeae, is the second most prevalent sexually transmitted infection worldwide. The increasing appearance of isolates that are resistant to approved therapeutics raises the concern that gonorrhea may become untreatable. Here, we serendipitously identified oxydifficidin as a potent N. gonorrhoeae antibiotic through the observation of a Bacillus amyloliquefaciens contaminant in a lawn of N. gonorrhoeae. Oxydifficidin is active against both wild-type and multidrug-resistant N. gonorrhoeae. It's potent activity results from a combination of DedA-assisted uptake into the cytoplasm and the presence of an oxydifficidin-sensitive ribosomal protein L7/L12 (RplL). Our data indicates that oxydifficidin binds to the ribosome at a site that is distinct from other antibiotics and that L7/L12 is uniquely associated with its mode of action. This study opens a potential new avenue for addressing antibiotic resistant gonorrhea and underscores the possibility of identifying overlooked natural products from cultured bacteria, particularly those with activity against previously understudied pathogens.

Ergosterol promotes aggregation of natamycin in the yeast plasma membrane

Polyene macrolides are antifungal substances, which interact with cells in a sterol-dependent manner. While being widely used, their mode of action is poorly understood. Here, we employ ultraviolet-sensitive (UV) microscopy to show that the antifungal polyene natamycin binds to the yeast plasma membrane (PM) and causes permeation of propidium iodide into cells. Right before membrane permeability became compromised, we observed clustering of natamycin in the PM that was independent of PM protein domains. Aggregation of natamycin was paralleled by cell deformation and membrane blebbing as revealed by soft X-ray microscopy. Substituting ergosterol for cholesterol decreased natamycin binding and caused a reduced clustering of natamycin in the PM. Blocking of ergosterol synthesis necessitates sterol import via the ABC transporters Aus1/Pdr11 to ensure natamycin binding. Quantitative imaging of dehydroergosterol (DHE) and cholestatrienol (CTL), two analogues of ergosterol and cholesterol, respectively, revealed a largely homogeneous lateral sterol distribution in the PM, ruling out that natamycin binds to pre-assembled sterol domains. Depletion of sphingolipids using myriocin increased natamycin binding to yeast cells, likely by increasing the ergosterol fraction in the outer PM leaflet. Importantly, binding and membrane aggregation of natamycin was paralleled by a decrease of the dipole potential in the PM, and this effect was enhanced in the presence of myriocin. We conclude that ergosterol promotes binding and aggregation of natamycin in the yeast PM, which can be synergistically enhanced by inhibitors of sphingolipid synthesis.

1.8-cineole prevents platelet activation and aggregation by activating the cAMP pathway via the adenosine A2A receptor

AimsDysregulated platelet aggregation is a fatal condition in many bacterial- and virus-induced diseases. However, classical antithrombotics cannot completely prevent immunothrombosis, due to the unaddressed mechanisms towards inflammation. Thus, targeting platelet hyperactivation together with inflammation might provide new treatment options in diseases, characterized by immunothrombosis, such as COVID-19 and sepsis. The aim of this study was to investigate the antiaggregatory effect and mode of action of 1.8-cineole, a monoterpene derived from the essential oil of eucalyptus leaves, known for its anti-inflammatory proprieties. Main methodsPlatelet activity was monitored by measuring the expression and release of platelet activation markers, i.e., P-selectin, CD63 and CCL5, as well as platelet aggregation, upon treatment with 1.8-cineole and stimulation with several classical stimuli and bacteria. A kinase activity assay was used to elucidate the mode of action, followed by a detailed analysis of the involvement of the adenylyl-cyclase (AC)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway by Western blot and ELISA. Key findings1.8-cineole prevented the expression and release of platelet activation markers, as well as platelet aggregation, upon induction of aggregation with classical stimuli and immunological agonists. Mechanistically, 1.8- cineole influences the activation of the AC-cAMP-PKA pathway, leading to higher cAMP levels and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Finally, blocking the adenosine A2A receptor reversed the antithrombotic effect of 1.8-cineole. SignificanceGiven the recognized anti-inflammatory attributes of 1.8-cineole, coupled with our findings, 1.8-cineole might emerge as a promising candidate for treating conditions marked by platelet activation and abnormal inflammation.

Black-Pigmented Marine Pseudomonas aeruginosa Exhibiting Anti-Bacterial Activity against Multidrug-Resistant (MDR) Wound Infection Bacteria

The urgency of multidrug-resistant (MDR) bacterial infections in wounds is a significant concern due to the high prevalence of MDR in healthcare settings. Black pigmented marine bacteria, strain PS1C, were isolated from marine sediment on Awur Beach Jepara, Central Java, Indonesia, and cultured in the laboratory. The aim of this research includes molecular identification of strain PS1C, extracting black pigment from strain PS1C, isolation of MDR bacteria from wounds, and evaluating the antibacterial activity of black pigment from strain PS1C against MDR bacteria isolates of wound infections. We examined the 16S rRNA gene sequences strain PS1C to identify the species. Then, the black pigment from PS1C was extracted using methanol: acetone (7:3) solvent. Antibacterial activity was evaluated against MDR bacteria from wounds with the microdilution method. A black-pigmented bacterium was isolated and identified as Pseudomonas aeruginosa PS1C. We found that the black pigment from P. aeruginosa PS1C can be developed as an antibacterial agent against the MDR bacterial isolate of wounds with MIC and MBC values of 6.25-12.5 mg/ml and 6.25-25 mg/ml, respectively. In conclusion, the study's findings highlight the potential of the extract of black pigment from P. aeruginosa PS1C as an antibacterial agent against wound-causing MDR bacteria and reinforce previous research into P. aeruginosa can be isolated from marine sources. Additional in vivo investigations and the identification of the antibacterial activity's mode of action are required.

Addressing Toxicity Concerns: State-of-the-Art Synthesis Methods and Emerging Multifaceted Applications of Silver Nanoparticles

Abstract: Silver nanoparticles (AgNPs), typically ranging in size from 10 to 1000 nm, are synthesize through physical, chemical, or biological methods. The biological approach, which often uses plant extracts, microbes, or fungi, is recommended for its eco-friendliness and lower dangers, while physical and chemical procedures can be costly and potentially dangerous. AgNPs are widely used in treatments and diagnostics in the medical field. Their exceptional antibacterial, antifungal, antiviral, anticancer, antiangiogenic, leishmanicidal, anti-inflammatory, antidiabetic, antioxidant, and anthelmintic action are just a few of their special qualities. However, AgNPs do have certain disadvantages due to worries about their nanotoxicity. This thorough study covers a wide range of AgNP topics, including their synthesis, properties, factors affecting particle size, and modes of action. Additionally, it covers their uses in the medical field, any potential toxicity issues, and the difficulties associated with their application.