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We propose a theoretical approach to estimate the permeability coefficients of substrates (permeants) for crossing membranes from donor (D) phase to acceptor (A) phase by means of molecular dynamics (MD) simulation. A fundamental aspect of our approach involves reformulating the returning probability (RP) theory, a rigorous bimolecular reaction theory, to describe permeation phenomena. This reformulation relies on the parallelism between permeation and bimolecular reaction processes. In the present method, the permeability coefficient is represented in terms of the thermodynamic and kinetic quantities for the reactive (R) phase that exists within the inner region of a membrane. One can evaluate these quantities using multiple MD trajectories starting from phase R. We apply the RP theory to the permeation of ethanol and methylamine at different concentrations (infinitely dilute and 1 mol % conditions of permeants). Under the 1 mol% condition, the present method yields a larger permeability coefficient for ethanol (0.12 ± 0.01 cm s−1) than for methylamine (0.069 ± 0.006 cm s−1), while the values of the permeability coefficient are satisfactorily close to those obtained from the brute-force MD simulations (0.18 ± 0.03 and 0.052 ± 0.005 cm s−1 for ethanol and methylamine, respectively). Moreover, upon analyzing the thermodynamic and kinetic contributions to the permeability, we clarify that a higher concentration dependency of permeability for ethanol, as compared to methylamine, arises from the sensitive nature of ethanol's free-energy barrier within the inner region of the membrane against ethanol concentration. [ABSTRACT FROM AUTHOR]

The current research aims to improve oral bioavailability, reduce the variability in absorption, and decrease GI intolerance of Nitrofurantoin (NFT) by presenting in a lipid-based liquid self-nanoemulsifying drug delivery system (L-SNEDDS). L-SNEDDS formulations were developed using a thermosolvency technique. Physicochemical properties including in-vitro drug diffusion were exercised to optimize the formula, further, comparative ex-vivo permeability, in-vitro cell line, in-vitro anti-microbial, and in-vivo pharmacokinetic evaluation of optimized formulation was carried out. Based on the highest saturation solubility, soybean oil, oleoyl polyoxyl-6-glycerides, and diethylene glycol monoethyl ether were selected as oil, surfactant, and co-surfactant, respectively. A Smix ratio of 1:2 was selected based on pseudoternary phase diagrams. The formulation prepared with an equal ratio of oil and Smix exhibited the lowest globule size (59.4 ± 0.8 nm), optimum zeta potential (−21.3 ± 1.1 mV), and faster drug release (95.4 ± 4.2 % in 30 min), and hence was selected for further evaluation. Optimized formulation (SF5) was found stable and showed improved membrane permeability against pure drug suspension (1.84 times) and marketed suspension formulation (1.15 times). SF5 exhibited similar % cell viability and % cell toxicity in Caco-2 cell lines compared to the marketed suspension. However, it showed the highest zone of inhibition against both the gram-negative and gram-positive organisms. The relative bioavailability of NFT-loaded L-SNEDDS was enhanced by 1.46 and 1.55 times compared to the marketed and pure drug, respectively. Thus, it can be concluded that the variability of oral absorption is minimized, and oral bioavailability is improved by the novel lipid-based nanocarrier system of NFT. [ABSTRACT FROM AUTHOR]

In this study, a series of sphingosine-derived molecules with different structures were synthesized and their mechanism on increasing membrane permeability was elucidated in model lipid bilayers. [Display omitted] Sphingosine, an amphiphilic molecule, plays a pivotal role as the core structure of sphingolipids, essential constituents of cell membranes. Its unique capability to enhance the permeability of lipid membranes profoundly influences crucial life processes. The molecular structure of sphingosine dictates its mode of entry into lipid bilayers and governs its interactions with lipids, thereby determining membrane permeability. However, the incomplete elucidation of the relationship between the molecular structure of sphingosine and the permeability of lipid membranes persists due to challenges associated with synthesizing sphingosine molecules. A series of sphingosine-derived molecules, featuring diverse hydrophobic chain lengths and distinct headgroup structure, were meticulously designed and successfully synthesized. These molecules were employed to investigate the permeability of large unilamellar vesicles, functioning as model lipid bilayers. With a decrease in the hydrophobic chain length of sphingosine from C15 to C11, the transient leakage ratio of vesicle contents escalated from ∼ 13 % to ∼ 28 %. Although the presence of double bond did not exert a pronounced influence on transient leakage, it significantly affected the continuous leakage ratio. Conversely, modifying the chirality of the C-3 hydroxyl group gives the opposite result. Notably, methylation at the C-3 hydroxyl significantly elevates transient leakage while suppressing the continuous leakage ratio. Additionally, sphingosines that significantly affect vesicle permeability tend to have a more pronounced impact on cell viability. Throughout this leakage process, the charge state of sphingosine-derived molecule aggregates in the solution emerged as a pivotal factor influencing vesicle permeability. Fluorescence lifetime experiments further revealed discernible variations in the effect of sphingosine molecular structure on the mobility of hydrophobic regions within lipid bilayers. These observed distinctions emphasize the impact of molecular structure on intermolecular interactions, extending to the microscopic architecture of membranes, and underscore the significance of subtle alterations in molecular structure and their associated aggregation behaviors in governing membrane permeability. [ABSTRACT FROM AUTHOR]

Practical Application Medicago sativa L. is gaining attention as a sustainable plant‐based food protein. Alfalfa saponins (ASs) typically exist in a glycosylated form in nature, which has poor cell membrane permeability, while the deglycosylated saponins may show better bioactivity. The AS was deglycosylated by β‐glucosidase from Aspergillus niger, and the chemical structures and biological activities, including in vivo assays, of AS and deglycosylated AS (DAS) were determined. The results showed that the half maximal inhibitory concentration for 2,2‐diphenyl‐1‐picrylhydrazyl inhibition of DAS was 29.5 µg/mL, demonstrating a significantly higher reducing capacity compared to AS (p < 0.05). The DAS induced 33.8% antibacterial activity against Escherichia coli and enhanced the proliferation of human airway epithelial cells (BEAS‐2B) at a concentration of 125 µg/mL. In vivo experiments on C57BL/6 mice fed a high‐fat diet demonstrated that high‐level DAS treatment produced significantly greater hypolipidemic effects compared to AS (p < 0.05). Thus, the AS can be deglycosylated, which leads to an improvement in biological activity, particularly since the DAS exhibits significantly enhanced hypolipidemic activity.Alfalfa saponins were deglycosylated by β‐glucosidase from Aspergillus niger, which contributed to increased bioactivity, particularly its hypolipidemic activity. [ABSTRACT FROM AUTHOR]

Mitochondria are crucial sites for biological oxidation and substance metabolism and plays a vital role in maintaining intracellular homeostasis. When mitochondria undergo oxidative damage or dysfunction, they can harm the organism, leading to various reactive oxygen species (ROS)-related diseases. Therefore, therapies targeting mitochondria are a strategy for treating multiple diseases. Many nanozymes can mimic antioxidant enzymes, which enables them to eliminate ROS to mitigate mitochondrial dysfunction. The therapeutic approaches and drugs targeting the mitochondrial electron transport chain (ETC) have emerged as effective treatments for oxidative stress-related diseases resulting from mitochondrial respiratory chain disorders. Therefore, nanozymes that can regulate homeostasis in the mitochondrial ETC have emerged as effective therapeutic agents for treating oxidative stress-related diseases. In addition, benefit from the controllability and modifiability of nanozymes, their modification with TPP, SS-31 peptide, and mitochondrial permeability membrane peptide to eliminate ROS and repair mitochondrial function. The nanozymes that specifically target mitochondria are powerful tools for the treatment of ROS-associated disorders. We discussed the design strategies pertaining to mitochondrion-targeted nanozymes to treat various diseases to develop more efficacious nanozyme tools for the treatment of ROS-related diseases in the future. • The therapies targeting mitochondria are a strategy for treating multiple ROS-related diseases. • Nanozymes has antioxidant enzyme activity, which can eliminate ROS to alleviate mitochondrial dysfunction. • Nanozymes are controllable and modifiable, which enables them to target mitochondria. • We present recent advancements in the design strategies of mitochondria-repairing nanozymes for the treatment of diseases. [ABSTRACT FROM AUTHOR]

In an effort to identify novel antibacterial agents, we presented two series of aminoguanidine derivatives that were designed by incorporating 1,2,4-triazol moieties. All compounds exhibited strong in vitro antibacterial activity against a variety of testing strains. Compound 5f was identified as a potent antibacterial agent with a minimum inhibitory concentration (MIC) of 2–8 µg/mL against S. aureus, E. coli, S. epidermidis, B. subtilis, C. albicans, multi-drug resistant Staphylococcus aureus and multi-drug resistant Escherichia coli and low toxicity (Hela > 100 µM). Membrane permeability and transmission electron microscopy (TEM) image studies demonstrated that compound 5f permeabilized bacterial membranes, resulting in irregular cell morphology and the rapid death of bacteria. The results of the present study suggested that aminoguanidine derivatives with 1,2,4-triazol moieties were the intriguing scaffolds for the development of bactericidal agents. [ABSTRACT FROM AUTHOR]

Abstract\nNOVELTY STATEMENTA hydroponic experiment was conducted to investigate the variations in membrane permeabilities, chlorophyll contents, antioxidase activities, the ascorbic acid (AsA)-glutathione (GSH) cycle, and the glyoxalase system in the leaves of Pontederia cordata with 0 ∼ 15.0 mg L−1 lead ion (Pb2+) exposure. The concentrations of Pb2+ accumulated in the plant roots, stems, and leaves were also evaluated. After 7 days of exposure, the plants maintained normal growth, and there was a significant increase in ascorbate peroxidase and dehydroascorbate reductase activities. With 5.0 mg L−1 Pb2+ exposure for 28 days, nearly 66.36% of Pb2+ accumulated in the roots, while excess Pb2+ immobilized in the leaves was not observed. Exposure to 10.0 and 15.0 mg L−1 Pb2+ for 28 days significantly increased Pb2+ contents in the leaves. This led to decrease in chlorophyll a, b, and carotenoid contents, and to increase in the methylglyoxal content in the leaves. With 10 and 15 mg L−1 Pb2+ exposure, NPT and PCs contents in leaves increased. however, the glyoxalase system did not function well in the plant tolerant to Pb2+ at higher concentrations. The AsA-GSH cycle did not cooperate with the glyoxalase system in the plant defense against Pb2+ exposure in the present investigation.The role of the ascorbic acid (AsA)-glutathione (GSH) cycle and the glyoxalase system separately has been reported in numerous studies. however, the synergistic role of both in plants’ defense against heavy metal exposure was discussed in our present study. [ABSTRACT FROM AUTHOR]

The effects of foliar application of sodium nitroprusside (SNP), magnesium sulfate (MgSO4) and magnesium oxide nanoparticles (MgO-NPs) on the growth, physiology, and gas exchange parameters of two varieties of spinach (Spinacia oleracea L.) under cadmium (Cd) stress were examined. The experiment was arranged in a completely randomized design with 72 pots. Two varieties of S. oleracea (Desi Palak & Lahori Palak) were used. Two concentrations of Cd (0 µM and 150 µM) in the form of cadmium chloride (CdCl2) were used. Two levels of SNP (0 ppm and 100 ppm) and two levels for each form of Mg i.e. MgSO4 and MgO-NPs (0 and 200 ppm) were foliar sprayed on plants in control and Cd stress. Both varieties behaved similarly under Cd stress and caused reductions in growth, physiology, gas exchange, water content parameters and inorganic ion uptake. However, the biochemical parameters like relative membrane permeability (RMP), malondialdehyde (MDA), and hydrogen peroxide (H2O2) contents were increased. However, all foliar spray treatments increased growth, physiological and gas exchange parameters, water content and inorganic ion uptake. However, this reduced the MDA, RMP, and H2O2 contents. Desi Palak showed the more positive results under foliar application of MgO-NPs. However, Lahori palak showed more positive results under the SNP + MgO-NP treatment. It is concluded that foliar application of SNP, MgSO4 and MgO-NPs could be an innovative approach to alleviated the heavy metals (Cd) toxicity in crop plants. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii's extensive antibiotic resistance makes its infections difficult to treat, so effective strategies to fight this bacterium are urgently needed. This study aims to evaluate the effectiveness of antimicrobial photodynamic therapy (aPDT) mediated by Rutin-Gal(III) complex and Quercetin against A. baumannii. Absorbance spectra, fluorescence spectra, and minimum inhibitory concentration (MIC) of Rutin-Gal(III) complex and Quercetin were determined. The intracellular reactive oxygen species (ROS), extracellular polymeric substances (EPS), cell membrane permeability, expression of ompA and blaOXA−23, anti-biofilm activity, and anti-metabolic activity of Rutin-Gal(III) complex- and Quercetin-mediated aPDT were measured. Rutin-Gal(III) complex and Quercetin revealed absorption peaks in the visible spectra. Quercetin and Rutin-Gal(III) complex displayed fluorescence peaks at 524 nm and 540 nm, respectively. MIC values for the Rutin-Gal(III) complex and Quercetin were 64 µg/mL and 256 µg/mL, respectively. Quercetin- and Rutin-Gal(III) complex-mediated aPDT significantly reduced the colony forming units/mL (58.4% and 67.5%), EPS synthesis (47.4% and 56.5%), metabolic activity (30.5% and 36.3%), ompA (5.5- and 10.5-fold), and blaOXA−23 (4.1-fold and 7.8-fold) genes expression (respectively; all P < 0.05). Quercetin- and Rutin-Gal(III) complex-mediated aPDT enhanced notable biofilm degradation (36.2% and 40.6%), ROS production (2.55- and 2.90-folds), and membrane permeability (10.8– and 9.6-folds) (respectively; all P < 0.05). The findings indicate that Rutin-Gal(III) complex- and Quercetin-mediated aPDT exhibits antibacterial properties and could serve as a valuable adjunctive strategy to conventional antibiotic treatments for A. baumannii infections. One limitation of this study is that it was conducted solely on the standard strain; testing on clinical isolates would allow for more reliable interpretation of the results. [ABSTRACT FROM AUTHOR]

While met with initial and ground-breaking success targeting blood borne cancers, cellular immunotherapy remains significantly hindered in the context of solid tumors by the tumor microenvironment. Focused ultrasound, in conjunction with microbubbles, has found tremendous potential as a targeted and local drug/gene delivery technique for cancer therapy. The specific immunomodulating effects of this technique on immune cells, including T-cells, remain unexplored. Here, with freshly isolated human immune cells, we examine how focused ultrasound can viably modulate immune cell membrane permeability and influence the secretion of over 90 cytokines, chemokines and other analytes relevant to a potent immune response against cancer. We determine that microbubble-mediated focused ultrasound modulates the immune cell secretome in a time-dependent manner – ranging in ~0.1-3.6-fold changes in the concentration of a given cytokine compared to sham controls over 48 hours post-treatment (e.g. IL-1β, TNF-α, CX3CL1, CCL21). Further, we determine the general trend of a negative correlation between secreted cytokine concentration and viable ultrasound-assisted membrane permeability with negligible loss of cell viability. Taken together, the data presented here highlights the potential of microbubble-mediated focused ultrasound to viably enhance T-cell permeability and modulate key pro-immune pathways, offering a novel approach to augment targeted cellular therapies for solid tumors. [ABSTRACT FROM AUTHOR]

This study aims to clarify the process of oral drug absorption from jelly formulations. Agar and pectin-based jellies containing drugs with different membrane permeability (high: antipyrine [ANT], medium: metoprolol [MET], low: atenolol [ATE]) were prepared and tested for in vitro drug release and in vivo drug absorption in rats. All drugs showed similar release profiles in vitro from both jelly formulations, except for the faster release from pectin jelly at neutral pH. In contrast, in vivo absorption of ATE but not of ANT from jelly formulations was significantly lower than from solution. Absorption of ATE and MET was low from agar jelly after oral administration, whereas additional water intake significantly increased the absorption. The process of drug absorption was described by the compartmental model consisting of jelly, intestinal fluid, and blood compartments. Drugs in the jelly diffuse into the intestinal fluid and then permeate the intestinal membrane. By considering the rate-limiting process, membrane permeability-dependent drug absorption from agar jelly and the effects of water intake were identified. In conclusion, jelly formulations may potentially decrease and delay drug oral absorption, especially of poorly permeable drugs. Intestinal fluid volume is one of the important factors to control the drug absorption. [Display omitted] • Although oral jelly formulations are often used for pediatric or elderly patients because of their high swallowability, the precise process and mechanism of gastrointestinal (GI) drug absorption from oral jelly formulations are not fully understood. This study examined the process of drug absorption from oral jelly formulations. • In this study, the compartmental model was used to describe the unique process of drug absorption from oral jelly formulations, in which drugs dissolved in the jelly reach the intestinal fluid via diffusion through the jelly matrix. By defining the rate-limiting process of drug absorption from oral jelly formulations, the effects of the membrane permeability of the drug and GI fluid volume were identified. • The correlation between in vitro drug release and in vivo oral absorption from oral jelly formulations observed in this study will help to consider the bioequivalence of oral jelly formulations with other formulations (e.g., solution, tablet). • To clearly demonstrate the effect of membrane permeability, three model drugs with different permeabilities were incorporated in the jelly and administered to rats as a cassette. • Two different methods, intra-intestinal and oral administration, were used for in vivo drug administration to rats. The results of the intra-intestinal administration study revealed the basic mechanism of drug absorption from oral jelly formulations, whereas the oral administration study highlighted the clinical importance of water intake for drug absorption. [ABSTRACT FROM AUTHOR]

Significant progress has recently been made in the biosynthesis of germacrene A using microbial cell factories. Germacrene A is a crucial precursor for the synthesis of anti‐cancer active compounds. However, its hydrophobic characteristics lead to its aggregation in cell membranes and cause severe cytotoxicity. In the present study, we found that rhamnolipids (RLs), as toxicity antidotes, could promote the production of germacrene A. An optimal RLs concentration of 1.25 g L−1 resulted in an increase of over 30% in the germacrene A titer at both shake flask and bioreactor scales. Mechanistic analysis showed that the addition of RLs could dramatically reduce aqueous‐phase surface tension and cell surface hydrophobicity (CSH), and increase the cell membrane permeability. This, in turn, promoted an efficient transfer of germacrene A from cell membrane to extraction phases. The addition of RLs also increased the adenosine triphosphate (ATP) concentration and the nicotinamide adenine dinucleotide (NAD+/NADH) ratio, while reducing reactive oxygen species (ROS) levels. Correspondingly, gene transcripts for key enzymes associated with germacrene A biosynthesis, the respiratory chain, and ROS scavenging were upregulated significantly. This study provides an effective RLs‐regulated fermentation method for the biosynthesis of hydrophobic natural products. [ABSTRACT FROM AUTHOR]

Essential oils are promising antimicrobial agents against various bacteria. The aim of the study was to examine anti- Acinetobacter baumannii activity of nine essential oils and to elucidate essential oil mechanisms of action against this. In total, 8 out of 9 examined different essential oils exhibited activity against multidrug-resistant (MDR) A. baumannii isolates. The best anti- A. baumannii activity expressed Thymus serpyllum, Satureja hortensis and Oreganum majorana essential oil (MBC 1.29 to 2.58 µg mL−1), while essential oils of Menta x piperita, Hyssopus officinalis, Foeniculum vulgare and Artemisia dracunculus expressed the same effect in higher concentrations (1.80 to 3.80 µg mL−1). The effect of Juniperus sabina, Juniperus sibirica and S. hortensis essential oils against A. baumannii is for the first time reported here. The mechanisms of Myrtus communis, Eucalyptus camaldulensis, S. hortensis and T. serpyllum essential oils were further examined. The essential oil treatments led to concentration dependent leakage of biomolecules form the cells, causing an increase in the concentrations of lipids, carbohydrates, and proteins in the suspensions. Microstructural observations confirmed the essential oil effect on cell membranes and disruption the membrane integrity, with obvious leakage of intercellular substance, collapsed cells with perforations, debris presence and autoaggregated cells. The subinhibitory concentrations of oils did not obviously changed protein patterns determined by SDS-PAGE. These results indicate that the essential oils, particularly T. serpyllum, S. hortensis, M. communis and E. camaldulensis express its anti- A. baumannii activity via membrane disruption and increased membrane permeability, representing very promising alternative antibacterial agents against MDR wound isolates. [Display omitted] • Essential oils (EO) exhibit promising antimicrobial activity against MDR A.baumannii. • M. communis, E. camaldulensis, S. hortensis, T. serpyllum EOs disrupt membranes. • EOs increase cell autoaggregation, membrane permeability and biomolecules leakage. • Microstructural observations confirmed cell collapse, perforations, debris presence. • Subinhibitory concentrations of oils did not significantly alter protein patterns. [ABSTRACT FROM AUTHOR]

Blue mold caused by Penicilliumexpansum (P. expansum) causes severe fruit losses, and there is an urgent need to explore safe natural products to control post-harvest diseases and investigate potential antifungal mechanisms. In this study, flavonoids (GBLF) were extracted and purified from mature Ginkgo biloba leaves (GBL). According to an analysis of UV-visible spectroscopy, FTIR, and LC-MS, GBLF contained 10 flavonoids, including 8 quercetin and kaempferol derivatives. The inhibition halo diameter by GBLF ethanol solution reached a maximum of 11.2 ± 0.3 mm, which significantly inhibited the growth of P. expansum. In the GBLF ethanol solution treatment trial, the mycelial cells of P. expansum reached their maximum cell conductivity, protein leakage rate, and malondialdehyde (MDA) content at 48 h, with values of 3.89 ± 0.17 ms/cm, 5.22 ± 0.08 mg/L, and 5.76 ± 0.09 mmol/kg, respectively, which were 2.7, 13.74, and 4.76 times higher than those of the control. Compared with 12 h, the activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) in the enzyme antioxidant system were 3.38 ± 0.11 U/mg, 5.23 ± 0.09 U/mg, and 2.66 ± 0.10 U/mg, respectively, which decreased by 30.2%, 20.09%, and 51.47%. In conclusion, quercetin and kaempferol derivatives in GBLF may act on P. expansum by increasing the permeability of cell membranes, reducing enzymatic antioxidant activity, and accelerating lipid peroxidation. [ABSTRACT FROM AUTHOR]

To preserve the quality traits of late-harvested 'Galaxy' apples during extended storage, the effects of 1-methylcyclopropene (1-MCP) treatment and storage conditions on postharvest quality were analysed. Alongside quality measures, indicators like ethylene production, respiration rate, aminocyclopropane-1-carboxylic acid oxidase (ACO) activity, and membrane permeability were assessed. Apples were harvested at an optimal harvest date or later and stored for 7 months at 1°C under regular atmosphere or controlled atmosphere. Treatments with 1–MCP at 300, 600 or 900 nL L−1 were applied pre- or post-storage. After 7 days shelf-life, apples subjected to 1-MCP and controlled atmosphere exhibited reduced ethylene production, respiration rate, and ACO activity compared to untreated or regular atmosphere counterparts. While the time of 1-MCP application and its concentration did not impact the respiration rate during shelf-life, controlled atmosphere effectively decreased it. The combination of controlled atmosphere and 1–MCP pre-storage was most effective in lowering ACO activity. Irrespective of conditions, 1-MCP curtailed ethylene production, respiration rate, and ACO activity during shelf-life, alleviating firmness and acidity loss. Only controlled atmosphere preserved quality and minimised disorders for optimally harvested apples, not late-harvested ones. None of the treatments maintained late-harvested apples' quality after long-term storage plus shelf-life. [ABSTRACT FROM AUTHOR]

Proteolysis targeting chimeras (PROTACs) have recently emerged as promising therapeutic agents for cancer therapy. However, their clinical application is considerably hindered by the poor membrane permeability and insufficient tumor distribution of PROTACs. Here we proposed a nanoengineered targeting strategy to construct a self-assembled affibody-PROTAC conjugate nanomedicine (APCN) for tumor-specific delivery of PROTACs. As proof of concept, a hydrophobic PROTAC MZ1 (a bromodomain-containing protein 4 degrader) was selected to couple with a hydrophilic affibody ZHER2:342 (an affinity protein of human epidermal growth factor receptor 2, HER2) via a smart linker containing disulfide bond to form an amphiphilic ZHER2:342-MZ1 conjugate. It spontaneously self-assembled into nanoparticles (ZHER2:342-MZ1 APCN) in water. Upon the excellent targeting property of ZHER2:342 and HER2 receptor-mediated endocytosis, ZHER2:342-MZ1 APCN was accumulated in tumor sites and internalized by cancer cells effectively in vitro. Under the intracellular high level of glutathione (GSH), ZHER2:342-MZ1 APCN released MZ1 to specifically degrade bromodomain-containing protein 4 (BRD4) and subsequently induced BRD4 deficiency-mediated apoptosis of cancer cells. By the tail-vein injection, ZHER2:342-MZ1 APCN showed the outstanding tumor-specific targeting ability, drug accumulation capacity, enhanced BRD4 degradation and antitumor efficacy in vivo for an HER2-positive SKOV-3 tumor model. Such an affibody mediated nanoengineered strategy would facilitate the application of PROTACs for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

In sepsis, bacterial components, particularly lipopolysaccharide (LPS), trigger organ injuries such as liver dysfunction. Although sepsis induces hepatocyte damage, the mechanisms underlying sepsis‐related hepatic failure remain unclear. In this study, we demonstrated that the LPS‐treated rat hepatocyte cell line Clone 9 not only induced reactive oxygen species (ROS) generation and apoptosis but also increased the expression of the autophagy marker proteins LC3‐II and p62, and decreased the expression of intact Lamp2A, a lysosomal membrane protein. Additionally, LPS increased lysosomal membrane permeability and galectin‐3 puncta formation, and promoted lysosomal alkalization in Clone 9 cells. Pharmacological inhibition of caspase‐8 and cathepsin D (CTSD) suppressed the activation of caspase‐3 and rescued the viability of LPS‐treated Clone 9 cells. Furthermore, LPS induced CTSD release associated with lysosomal leakage and contributed to caspase‐8 activation. Pretreatment with the antioxidant N‐acetylcysteine (NAC) not only diminished ROS generation and increased the cell survival rate, but also decreased the expression of activated caspase‐8 and caspase‐3 and increased the protein level of Lamp2A in LPS‐treated Clone 9 cells. These results demonstrate that LPS‐induced ROS causes lysosomal membrane permeabilization and lysosomal cell death, which may play a crucial role in hepatic failure in sepsis. Our results may facilitate the development of new strategies for sepsis management. [ABSTRACT FROM AUTHOR]

The microenvironmental factors of kiwifruit are constantly changing over long-distance transportation, but there are no reliable methods for monitoring and predicting quality changes. An artificial neural network (ANN) kiwifruit integrated quality dynamic prediction model based on microenvironmental parameters (i.e., temperature, relative humidity, carbon dioxide, oxygen, and ethylene levels) was developed using the correlation between microenvironmental parameters and changes in quality indicators during storage. The results showed that storage at 4 °C effectively delayed weight loss, increase in cell membrane permeability and soluble solids, as well as decrease in firmness, titratable acid content, ascorbic acid content and color (C* and L* values), delayed the onset of respiratory peaks, lowered ethylene release, and preserved kiwifruit freshness compared to 10 °C and 20 °C. The optimized back-propagation (BP) neural network model had a hidden layer neuron count of 10, and the coefficient of determination (R2) between the predicted and measured values was 0.998, with an average error within ± 5%, which was highly accurate in predicting the overall quality changes of kiwifruit during storage and transportation. [ABSTRACT FROM AUTHOR]

Background: Microecological equilibrium is essential for human health. Previous research has demonstrated that Streptococcus strain A, the main bacterial group in the respiratory tract, can suppress harmful microbes and protect the body. In this study, Streptococcus strain D19T was isolated from the oral and pharyngeal cavities of healthy children. Its antibacterial mechanism against Acinetobacter baumannii was examined, as well as its potential to prevent inflammatory damage to cells. We evaluated the effect of the fermentation conditions of D19T on inhibition of Acinetobacter baumannii growth; Isolation and purification of antibacterial active components of strain D19T and molecular mechanism of inhibition of Acinetobacter baumannii; Molecular mechanism of D19T antibacterial protein reversing cellular inflammatory injury induced by Acinetobacter baumannii. Results: The supernatant of fermentation broth of Streptococcus D19T was the active component against Acinetobacter baumannii, but the bacteria had no antibacterial activity. The supernatant of D19T fermentation broth was precipitated by (NH4)2SO4 solution, and the protein was the active antibacterial component. After gel filtration chromatography and anion gel filtration chromatography, the molecular weight of antibacterial protein was 53kD. D19T antibacterial protein can improve cell membrane permeability, limit extracellular soluble protein release, inhibit Acinetobacter baumannii biofilm formation, and prevent Acinetobacter baumannii adhesion. Acinetobacter baumannii induces inflammatory damage to respiratory cells via ferroptosis, and the D19T antibacterial protein can counteract this damage, protecting the respiratory tract. Conclusion: Streptococcus strain D19T, as a potential probiotic, inhibits the growth of Acinetobacter baumannii and the inflammatory damage of respiratory cells, playing a protective role in human respiratory health. [ABSTRACT FROM AUTHOR]

Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo‐ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity‐limiting nitrilimine intermediate (8‐Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo‐electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity‐limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X‐ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism‐inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)‐bis‐hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)‐stereoisomers especially in medicinal chemistry and protein modification. [ABSTRACT FROM AUTHOR]

In this study, the separation of neroli from water by PDMS‐ZSM5 mixed matrix membrane and separation performance of the pervaporative process of the prepared membranes with the parameters of permeability flux and separation factor was investigated. The effect of adding nanoparticles in the polymer matrix, the effect of the operating parameter of temperature and concentration on the efficiency of the membrane in the pervaporative process to be placed. Comparison of the results for pure membrane and mixed matrix membrane shows a 3‐fold increase in flux along with a 5‐fold increase in the separation factor in the mixed matrix membrane with a ratio of 12% nano in the membrane matrix so that the permeability and separation factor are 1.256 kg/m2h and 550, respectively. Membrane function was also evaluated in the temperature range of 298–353 K and feed concentration of 122–209 ppm. With increasing temperature to 353 K, permeability of membrane containing 8% ZSM‐5 nanoparticles increased from 0.63 to 0.89 kg/m2h. Also, with increasing feed concentration, permeability increased from to 0.96 kg/m2h. The optimization of these conditions was investigated by response surface method (RSM) based on the design of central points (CCD). The effect of all three parameters on the permeability, flux, and separation factor was investigated simultaneously and the optimal conditions were obtained at 12 wt% of ZSM‐5, a concentration of 209 mg/L of neroli, and a temperature of 304 K. Under these optimal conditions, the values of permeability, flux, and separation factor were 1.414 kg/m2h and 1039.57, respectively. [ABSTRACT FROM AUTHOR]

The objective was to investigate the effect of co-administration of hydrochlorothiazide and lisinopril as fixed dose combination on their intestinal absorption. The scope was extended to enhance intestinal absorption of both drugs. In situ rabbit intestinal absorption through the duodenum and jejuno-ileum was used to monitor membrane permeability of both drugs when perfused alone or in combination. Niosomes containing glycerols (glyceroniosomes) were loaded with both drugs. Glyceroniosomes comprised Span 60 or Tween 40 in combination with cholesterol and glycerol were prepared by bath sonication. Glyceroniosomes were characterized with respect to vesicle size, drug entrapment efficiency and were examined using transmission electron microscope (TEM). The prepared vesicles were nanosized spherical vesicles with average size of 202.4 nm and 108.8 nm for span free and span containing glyceroniosomes, respectively. The recorded Zeta potential values suggested good stability of the prepared formulations. Intestinal absorption studies reflected incomplete absorption of hydrocholothiazide and lisinopril correlating with their categorization as class IV and III drugs, respectively. Co-perfusion of both drugs reduced the intestinal absorption of lisinopril. Simultaneous encapsulation in glyceroniosomes enhanced the intestinal absorption of both drugs. Tween based systems were more efficient. The study introduced glyceroniosomes as carriers of simultaneous delivery of hydrochlorothiazide and lisinopril. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs), or tumor-initiating cells (TICs), are small subpopulations (0.0001–0.1%) of cancer cells that are crucial for cancer relapse and therapy resistance. The elimination of each CSC is essential for achieving long-term remission. Metabolic reprogramming, particularly lipids, has a significant impact on drug efficacy by influencing drug diffusion, altering membrane permeability, modifying mitochondrial function, and adjusting the lipid composition within CSCs. These changes contribute to the development of chemoresistance in various cancers. The intricate relationship between lipid metabolism and drug resistance in CSCs is an emerging area of research, as different lipid species play essential roles in multiple stages of autophagy. However, the link between autophagy and lipid metabolism in the context of CSC regulation remains unclear. Understanding the interplay between autophagy and lipid reprogramming in CSCs could lead to the development of new approaches for enhancing therapies and reducing tumorigenicity in these cells. In this review, we explore the latest findings on lipid metabolism in CSCs, including the role of key regulatory enzymes, inhibitors, and the contribution of autophagy in maintaining lipid homeostasis. These recent findings may provide critical insights for identifying novel pharmacological targets for effective anticancer treatment. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is the sudden decrease in renal function that can be attributed to dysregulated reactive oxygen species (ROS) production and impaired mitochondrial function. Irisin, a type I membrane protein secreted by skeletal muscles in response to physical activity, has been reported to alleviate kidney damage through regulation of mitochondrial biogenesis and oxidative metabolism. In this study, a macrophage membrane‐coated metal‐organic framework (MCM@MOF) is developed as a nanocarrier for encapsulating irisin to overcome the inherent characteristics of irisin, including a short circulation time, limited kidney‐targeting ability, and low membrane permeability. The engineered irisin‐mediated biomimetic nanotherapeutics have extended circulation time and enhanced targeting capability toward injured kidneys due to the preservation of macrophage membrane proteins. The irisin‐encapsulated biomimetic nanotherapeutics effectively mitigate acute ischemia‐reperfusion injury by protecting mitochondrial function and modulating SOD2 levels in renal tubular epithelial cells. The present study provides novel insights to advance the development of irisin as a potential therapeutic approach for AKI. [ABSTRACT FROM AUTHOR]

The mTOR inhibitor everolimus has been approved as a sequential or second‐line therapy for renal cell carcinoma (RCC). However, the development of drug resistance limits its clinical applications. This study aims to address the challenge of everolimus resistance and provide new insights into the treatment of advanced RCC. Here, the cytotoxicity of the DNA methyltransferase 1 (DNMT1) inhibitor SGI‐1027 in inducing cell vacuolation and methuosis is discovered and demonstrated for the first time. Additionally, SGI‐1027 exerts synergistic effects with everolimus, as their combination suppresses the growth, migration, and invasion of renal cancer cells. Mechanistically, apoptosis and GSDME‐dependent pyroptosis triggered by lysosomal membrane permeability (LMP) are observed. The upregulation of GSDME expression and increased lysosomal activity in renal cancer cells provide a therapeutic window for the combination of these two drugs to treat renal cancer. The combination treatment exhibits effective anti‐tumor activity and is well tolerated in a subcutaneous tumor model. Overall, this study validates and reveals the specific cytotoxicity property of SGI‐1027 and its potent synergistic effect with everolimus, offering new insights into advanced RCC therapy and everolimus‐resistance overcoming. [ABSTRACT FROM AUTHOR]

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Imidacloprid (IMI), a neonicotinoid pesticide, has been widely used due to its high efficiency against insect pests. However, its prolonged exposure may pose significant risks to non-target organisms, including mammals. Recent studies have raised concerns about its potential neurotoxicity, yet the underlying mechanisms remain poorly understood. This study aimed to assess the neurotoxic effects of chronic Imidacloprid exposure in Wistar rats, focusing on oxidative stress, mitochondrial dysfunction, and lysosomal disruption. Wistar rats were orally administered two doses of Imidacloprid (5 mg/kg and 50 mg/kg body weight) for three months. Neurotoxic effects were assessed by measuring key biochemical markers such as the enzymatic activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione S-transferase (GST). Non-enzymatic markers, including glutathione (GSH) levels and malondialdehyde (MDA) index, were also evaluated. Mitochondrial function was assessed by analyzing oxygen consumption, swelling, and membrane permeability and histopathological changes. Lysosomal stability was examined using the Neutral Red Retention Time (NRRT) assay. Neutral red is a dye that accumulates in the acidic environment of lysosomes. Healthy lysosomes retain the dye, while compromised lysosomes lose it, indicating destabilization. By measuring the amount of neutral red retained in lysosomes, the NRRT assay assesses lysosomal integrity. Lysosomal pH variations were also monitored to evaluate functional changes. Microscopic analysis provided insight into structural changes in lysosomes and other cell components. Lysosomal destabilization was further confirmed by morphological alterations observed through light microscopy, revealing a progressive, time-dependent degeneration of lysosomal structures, including lysosomal expansion, neutral red dye leakage, and cell rounding. These changes reflected a temporal evolution of lysosomal damage, progressing from minor structural disruptions to more severe alterations as exposure continued, observable at the microscopic level. During the study, clinical observations of intoxicated rats included symptoms such as lethargy, reduced activity levels, and impaired motor coordination. High-dose Imidacloprid exposure led to noticeable behavioral changes, including decreased exploratory behavior and altered grooming patterns. Additionally, signs of neurotoxic effects, such as tremors or ataxia, were observed in the rats exposed to the higher dose, reflecting the systemic impact of chronic pesticide exposure. The results revealed a significant decrease in the enzymatic activities of CAT, GPx, and SOD, accompanied by an increase in GST activity. A notable reduction in glutathione levels and a rise in MDA index were observed, indicating enhanced oxidative stress in the brain. Mitochondrial impairment was evidenced by disturbances in oxygen consumption, increased swelling, and altered membrane permeability. Lysosomal destabilization was confirmed by reduced retention of neutral red dye, structural changes in lysosomes, and a significant rise in lysosomal pH in the IMI-exposed groups. In addition, the histopathological features indicate that imidacloprid at the given dose and exposure duration may have caused notable neurotoxic effects in Wistar rat brain tissue. Chronic exposure to Imidacloprid induces oxidative stress, mitochondrial dysfunction, lysosomal disruption and histopathological alterations in the central nervous system of Wistar rats. These findings provide valuable insights into the neurotoxic mechanisms of neonicotinoid pesticides, highlighting the need for further research to understand the long-term effects of Imidacloprid exposure on mammalian health. [ABSTRACT FROM AUTHOR]

Neuronal cytotoxic edema is implicated in neuronal injury and death, yet mitigating brain edema with osmotic and surgical interventions yields poor clinical outcomes. Importantly, neuronal swelling and its downstream consequences during early brain development remain poorly investigated, and new treatment approaches are needed. We explored Ca2+-dependent downstream effects after neuronal cytotoxic edema caused by diverse injuries in mice of both sexes using multiphoton Ca2+ imaging in vivo [Postnatal Day (P)12-17] and in acute brain slices (P8-12). After different excitotoxic insults, cytosolic GCaMP6s translocated into the nucleus after a few minutes in a subpopulation of neurons, persisting for hours. We used an automated morphology-detection algorithm to detect neuronal soma and quantified the nuclear translocation of GCaMP6s as the nuclear to cytosolic intensity (N/C ratio). Elevated neuronal N/C ratios occurred concurrently with persistent elevation in Ca2+ loads and could also occur independently from neuronal swelling. Electron microscopy revealed that the nuclear translocation was associated with the increased nuclear pore size. The nuclear accumulation of GCaMP6s in neurons led to neocortical circuit dysfunction, mitochondrial pathology, and increased cell death. Inhibiting calpains, a family of Ca2+-activated proteases, prevented elevated N/C ratios and neuronal swelling. In summary, in the developing brain, we identified a calpain-dependent alteration of nuclear transport in a subpopulation of neurons after disease-relevant insults leading to long-term circuit dysfunction and cell death. The nuclear translocation of GCaMP6 and other cytosolic proteins after acute excitotoxicity can be an early biomarker of brain injury in the developing brain. [ABSTRACT FROM AUTHOR]

Membrane reactors for the production of hydrogen are interesting devices that allow for the decentralized production of pure hydrogen while reducing the energy cost of the traditional steam reforming process. The performance of these systems is strongly dependent on the permeability and selectivity of the membrane employed for the separation of the produced hydrogen. Several studies have shown that the actual rate of hydrogen permeation is lower than the one that would be expected based on studies of membrane permeability carried out with pure hydrogen. This difference has been attributed to the competitive adsorption of other species, specifically CO, on the membrane surface. Here we show that this phenomenon could also lead to steady state multiplicity and analyze the dynamics of membrane reactors in the presence of competitive adsorption by CO. Emphasis has been placed on the effect of temperature and gas composition on possible multistable behavior. The results have been interpreted in terms of a transition between kinetics- and permeation-controlled regimes, in which the behavior of the reactor is limited, respectively, by the rate of the chemical reactions or the rate of hydrogen permeation. [Display omitted] • Dynamics of membrane reactors in the presence of permeance inhibition were analyzed. • Effect of gas composition and temperature on multistable behavior was investigated. • Relationship between observed multistability and membrane inhibition was assessed. • Multistability due to competition between rate of H 2 production and permeation is observed. [ABSTRACT FROM AUTHOR]

A comparative evaluation of the brand-name drug Mycospor and six generic drugs (IWAKI, Bifonol, F, YD, Sawai, and TEVA), all comprising a cream formulation containing the antifungal drug bifonazole, was performed based on physicochemical measurements. The pH of the various formulations was significantly higher for the generics Bifonol (pH 7.1), Sawai (pH 6.7), and TEVA (pH 7.3) and significantly lower for YD (pH 4.3) than for the brand-name drug Mycospor (pH 5.5). The viscosity of the various formulations was significantly higher for TEVA (25,011 mPa·s) versus Mycospor (22,376 mPa·s) and significantly lower for IWAKI, Bifonol, F, YD, and Sawai, with Bifonol (8,572 mPa·s) being particularly low. Considering the hysteresis loop area obtained for the shear rate vs. shear stress, which represents the thixotropic properties, and using the value of Mycospor as the reference for 100%, YD (179%), Sawai (557%), and TEVA (201%) showed significantly higher values. Furthermore, the membrane permeability of bifonazole at 24 hours was significantly higher for Bifonol (309 µg/mL) and F (182 µg/mL) and significantly lower for Sawai (124 µg/mL) and TEVA (92 µg/mL) than for Mycospor (153 µg/mL). Finally, optical micrographs showed that the dispersion of particles was similar in the various formulations, but the particles of F and TEVA were uniformly dispersed with a smaller particle size than the other formulations. Overall, significant differences were observed in the formulation characteristics between the brandname drug and generic drugs, which were attributed to differences in the manufacturing process and the types of additives. [ABSTRACT FROM AUTHOR]

Categorised as a nonsteroidal anti-inflammatory drug targeting the COX-2 enzyme over COX-1, celecoxib (CXB) demonstrates high membrane permeability and low aqueous solubility, placing it in class II of the biopharmaceutical classification system. Therefore, comprehension of its solubility behaviour under different configurations is desirable. The current study explores CXB solubility in propylene glycol and ethanol binary mixtures by varying temperature and cosolvent concentration, using the shake-flask method followed by spectroscopy analysis. The results show increased solubility of CXB in this mixture as ethanol mass fraction and temperature increase. Several cosolvency models were used to correlate data, including van't Hoff, Jouyban-Acree, Jouyban-Acree-van't Hoff, and mixture response surface/modified Wilson models. The mathematical models' accuracy was investigated through mean relative deviation. The Gibbs and van't Hoff equations were employed to establish the thermodynamic features of CXB dissolution. [ABSTRACT FROM AUTHOR]

This study explores the in vitro antifungal effects of nerol, a linear acyclic monoterpene alcohol of plant origin, on Fusarium oxysporum, Pestalotiopsis neglecta, and Valsa mali. To further investigate the antifungal mechanism of nerol against F. oxysporum, we examined changes in mycelial morphology and cell membrane integrity-related indices, as well as the activities of antioxidant and pathogenicity-related enzymes. The results demonstrated that nerol exhibited significant concentration-dependent inhibition of mycelial growth in all three fungi, with EC50 values of 0.46 μL/mL for F. oxysporum, 1.81 μL/mL for P. neglecta, and 1.26 μL/mL for V. mali, with the strongest antifungal activity observed against F. oxysporum. Scanning electron microscopy revealed that nerol severely disrupted the mycelial structure of F. oxysporum, causing deformation, swelling, and even rupture. Treatment with 0.04 μL/mL nerol led to significant leakage of soluble proteins and intracellular ions in F. oxysporum, and the Na+/K+-ATPase activity was reduced to 28.02% of the control, indicating enhanced membrane permeability. The elevated levels of hydrogen peroxide and malondialdehyde, along with propidium iodide staining of treated microconidia, further confirmed cell membrane disruption caused by nerol. Additionally, after 12 h of exposure to 0.04 μL/mL nerol, the activity of superoxide dismutase in F. oxysporum decreased to 55.81% of the control, and the activities of catalase and peroxidase were also significantly inhibited. Nerol markedly reduced the activities of pathogenicity-related enzymes, such as endo-1,4-β-D-glucanase, polygalacturonase, and pectin lyase, affecting fungal growth and virulence. In conclusion, nerol disrupts the cell membrane integrity and permeability of F. oxysporum, reduces its virulence, and ultimately inhibits fungal growth, highlighting its potential as an alternative to chemical fungicides for controlling F. oxysporum. [ABSTRACT FROM AUTHOR]

Background/Objectives: Physiologically based pharmacokinetic (PBPK) absorption models are instrumental for assessing drug absorption prior to clinical food effect studies, though discrepancies in predictive and actual outcomes are observed. This study focused on immediate release formulations of weakly basic water-insoluble compounds, namely rivaroxaban, ticagrelor, and PB-201, to investigate factors that could improve the predictive accuracy of PBPK models regarding food effects. Methods: Comprehensive in vitro experimental results provided the basis for the development of mechanistic absorption models, which were then combined with mechanistic disposition models to predict the systemic exposure of the model drugs in both fasted and fed states. Results: The developed PBPK models showed moderate to high predictive accuracy for food effects in Caucasian populations. For the Chinese population, the ticagrelor model's initial overestimation of fed-state absorption was addressed by updating the permeability parameters from Caco-2 cell assays to those derived from parallel artificial membrane permeability assays in FaSSIF and FeSSIF media. This refinement was also applied to the rivaroxaban and ticagrelor models, leading to a more accurate representation of absorption in Caucasians. Conclusions: This study highlights the importance of apparent permeability in enhancing the predictive accuracy of PBPK absorption models for weakly basic water-insoluble compounds. Furthermore, the precipitation of PB-201 in the two-stage transfer experiments suggests that precipitation may not be a universal phenomenon for such compounds in vivo. Consequently, the precipitation rate constant, a theoretically essential parameter, should be determined based on experimental evidence to avoid overparameterization and ensure robust predictive accuracy of PBPK models. [ABSTRACT FROM AUTHOR]

Background/Objectives: The beneficial effects of the flavonoid chrysin can be reduced by its poor oral bioavailability. It has been shown that chrysin-8-C-glucoside (1) has a better absorption capability. The aim of this study was to evaluate the antioxidant and anti-inflammatory activity of this glucoside, as well as the respective hexa-acetate derivative 1a and the hexa-ethyl carbonate derivative 1b since the inclusion of moieties in bioactive molecules may increase or modify their biological effects. Methods: THP-1 macrophages were used to determine the viability in the presence of chrysin derivatives, and non-cytotoxic concentrations were selected. Subsequently, lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) production and inflammatory mediators were examined. The involvement of chrysin derivatives with the Keap1 and Nrf2 antioxidant system was determined by docking and Western blotting studies. Results: Our data demonstrated, for the first time, that pretreatment with the three compounds caused a significant reduction in LPS-induced reactive oxygen species (ROS) production and pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) levels, as well as in cyclooxygenase 2 (COX-2) expression. The mechanisms underlying these protective effects were related, at least in part, to the competitive molecular interactions of these phenolic compounds with Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2), which would allow the dissociation of Nrf2 and its translocation into the nucleus and the subsequent up-regulation of hemo-oxygenase 1 (HO-1) expression. Conclusions: Compared to the 8-C-glucoside parent chrysin, compound 1a exhibited the strongest antioxidant and anti-inflammatory activity. We hypothesized that the incorporation of an acetate group (1a) may reduce its polarity and, thus, increase membrane permeability, leading to better pharmacological activity. These findings support the potential use of these phenolic compounds as Nrf2 activators against oxidative-stress-related inflammatory diseases. [ABSTRACT FROM AUTHOR]

Introduction: Over the last few years, there has been an increase in the prevalence of Blastocystis spp. in colorectal cancer (CRC) patients. Moreover, various in vitro and in vivo studies have highlighted that intestinal colonisation of Blastocystis spp. has an influence on host immune responses leading to cellular apoptosis and membrane permeability. It has been suggested that Blastocystis spp. is an important risk factor for the worsening of CRC. Aim: To present evidence concerning the association between CRC and Blastocystis spp. Material and methods: A review of the literature was performed by searching Science Direct, PubMed, Scopus and Google Scholar databases up to December, 2023. Results and discussion: Out of all in vitro and in vivo studies selected for this review, the majority of them have confirmed a significantly higher prevalence of Blastocystis spp. in colorectal cancer patients in comparison to the control groups. Several in vitro human colorectal carcinoma cell line studies have shown significant cytopathic and immunological effects of Blastocystis spp. Additionally, in vivo experimental animal model studies have shown that Blastocystis spp. infection significantly contributed to large intestinal polyp (colorectal adenoma) formation and the progression of colorectal carcinogenesis. Conclusions: These studies strongly support suggestions that Blastocystis spp. could be an important factor to existing CRC development by influencing the host immune response and increasing oxidative damage. [ABSTRACT FROM AUTHOR]

Taxillμs chinensis (DC.) Danser is a traditional Chinese herbal medicine. It has not been reported regarding antibacterial active ingredients and mechanisms of action. However, the Chinese patent medicine Yinhua Miyanling Tablets containing Taxillμs chinensis has an obvious anti-infective effect in our patent. Therefore, we speculate that Taxillμs chinensis may have antibacterial activity. The purpose of this paper is to study the antibacterial effect and mechanism of Taxillμs chinensis and find active compounds with antibacterial activity and a mechanism. We studied the antibacterial effect and mechanism of Taxillμs chinensis extract. The compounds in the ethyl acetate extract of Taxillμs chinensis were preliminarily identified by UPLC-Q-Orbitrap and analyzed by mass spectrometry. Above all, the antibacterial effect and antibacterial mechanism of the active components of Taxillμs chinensis were determined. Finally, we found, for the first time, that Taxillμs chinensis has a good antibacterial effect and ethyl acetate extract has the best effect. In addition, we found, for the first time, that it has an active component, 4-indolecarbaldehyde, and the component has a good broad-spectrum antibacterial effect. Above all, the active chemical 4-indolecarbaldehyde of Taxillμs chinensis can destroy the bacterial structure, make it unable to maintain normal morphology, and significantly increase the number of deaths. In short, Taxillμs chinensis has an antibacterial effect, and one of its main antibacterial components is 4-indolecarbaldehyde. The antibacterial mechanism of Taxillμs chinensis and 4-indolecarbaldehyde is related to the change in bacterial membrane permeability. [ABSTRACT FROM AUTHOR]

Calcium alginate spheres with a volume of about 5 mL can be used for important purposes. Those that incorporate oolong tea give, in addition to the recreational aspect, the possibility of drinking small quantities of this tea, because oolong tea can be used as a compound with antioxidant properties. This incorporation can be achieved by reverse spherification (5 mL). Six types of spheres have been made, all of them with calcium alginate and the presence or absence of agar-agar and xanthan gum—XG—in two concentrations. The weight loss of the spheres, the release of bioactive compounds over time (a total of 48 h), the surface (internal and external) of the membranes, and the physical characteristics of these membranes have been analyzed. The data obtained indicate that the presence of XG prevents the formation of precipitates inside the spheres and slows down weight loss. It also provides opacity to the spheres. However, the incorporation of agar-agar does not have a significant influence on the different parameters analyzed. The release of catechins reaches a maximum of 80% of what could be achieved under ideal conditions, and it reaches 90% in the first 3 h. The incorporation of XG increases the shelf life of the spheres, slows down the release of chelate, and decreases weight loss over time, allowing for a new perspective on the spherification process. [ABSTRACT FROM AUTHOR]

Cryopreservation of bovine oocytes and embryos is essential for long‐term preservation and widespread distribution of genetic material, particularly in bovine in vitro embryo production, which has witnessed substantial growth in the past decade due to advancements in reproductive biotechnologies. Among current cryopreservation methods, vitrification has emerged as the preferred cryopreservation technique over slow freezing for preserving oocytes and in vitro‐produced (IVP) embryos, as it effectively addresses membrane chilling injury and ice crystal formation. Nonetheless, challenges remain and a simple and robust vitrification protocol that guarantees the efficiency and viability after warming has not yet been developed. Furthermore, although slow cooling can easily be adapted for direct transfer, an easier and more practical vitrification protocol for IVP embryos is required to allow the transfer of IVP embryos on farms using in‐straw dilution. In addition, the susceptibility of bovine oocytes and embryos to cryoinjuries highlights the need for novel strategies to improve their cryotolerance. This manuscript examines various methodological approaches for increasing the viability of bovine oocytes and IVP embryos during vitrification. Strategies such as modifying lipid content or mitigating oxidative damage have shown promise in improving cryotolerance. Additionally, mathematical modelling of oocyte and embryo membrane permeability has facilitated the rational design of cryopreservation protocols, optimizing the exposure time and concentration of cryoprotectants to reduce cytotoxicity. [ABSTRACT FROM AUTHOR]

Summary: This study explores enhancing lipid recovery from the lipid‐rich marine microalgae Aurantiochytrium sp. SW1, known for its robust cell wall posing challenges, which necessitates energy‐intensive cell‐disruption for efficient intracellular lipid extraction. Despite advancements in other microalgae, there is lack of reports on efficient cell disruption for Aurantiochytrium sp. SW1 which is vital to reduce the energy costs and minimising the downstream process while maximising lipid yields. Three process intensification technologies (PIT) – microwave treatment, autoclave treatment and ultrasonication were employed on wet Aurantiochytrium sp. SW1 cells to improve the lipid extraction efficiency. Assessing the disruption effectiveness via lipid content, suspension turbidity and particle size distribution, alongside scanning electron microscopy (SEM) for cellular morphology changes post‐PIT treatments, this study indicates all three methods reduced particle size with prolonged treatment time, implying successful cell wall disruption and intracellular component release. Ultrasonication, especially at 50 W power for 10 min, exhibited the highest efficacy, yielding lipid content of 67.76 ± 0.03%. Microscopic analysis unveiled ultrasonication‐induced cell shrinkage and increased membrane permeability, supporting its effectiveness in enhancing solvent penetration for improved lipid recovery. This research underscores PIT techniques' potential as sustainable, energy‐efficient strategies for lipid extraction from Aurantiochytrium sp. SW1 microalgae. [ABSTRACT FROM AUTHOR]

Bacterial antibiotic resistance has been recognized as a global threat to public health. It challenges the antibiotics currently used in clinical practice and causes severe and often fatal infectious diseases. Fighting against antibiotic-resistant bacteria (ARB) is growing more urgent. While understanding the molecular mechanisms that underlie resistance is a prerequisite, several major mechanisms have been previously proposed including bacterial efflux systems, reduced cell membrane permeability, antibiotic inactivation by enzymes, target modification, and target protection. In this context, this review presents a panel of promising and potential strategies to combat antibiotic resistance/resistant bacteria. Different types of direct-acting and indirect resistance breakers, such as efflux pump inhibitors, antibiotic adjuvants, and oxidative treatments are discussed. In addition, the emerging multi-omics approaches for rapid resistance identification and promising alternatives to existing antibiotics are highlighted. Overall, this review suggests that continued effort and investment in research are required to develop new antibiotics and alternatives to existing antibiotics and translate them into environmental and clinical applications. [ABSTRACT FROM AUTHOR]

The objective of this work is to evaluate the effects of ozone combined with ultrasound (ozone+US), pasteurization (PT), and high-temperature short-time sterilization (HTST) on antimicrobial capacity, antioxidant activity, carotenoid distribution and in vitro bioaccessibility of carotenoids in high-sugar concentrated orange juice. The enhancement of cellular membrane permeability and the leakage of cytoplasmic contents in Penicillium citrinum and Saccharomyces cerevisiae induced by ozone+US treatment were confirmed by fluorescence and FTIR spectrum. Ozone+US treatment exhibited higher antimicrobial activity than PT, and ozone+US treatment could decrease 4.22 ± 0.08 log CFU/mL of P. citrinum and 4.49 ± 0.10 log CFU/mL of S. cerevisiae. Additionally, ozone+US treated samples showed significantly lower peroxidase and polyphenoloxidase residual activity, higher bioactive compounds, and antioxidant capacity of orange juice as compared to thermal treatment. Among these treatments, ozone+US-treated orange juice showed the highest retention rates of carotenoid content and carotenoid bioavailability of 3.76 ± 0.05 mg/L and 24.53 ± 1.37%, respectively. Interestingly, particle size reduction and uniform distribution of carotenoids in ozone+US-treated samples enhanced the bioaccessibility of carotenoids. Compared with those thermal treatments, ozone+US treatment would be an alternative to improve microbial safety and decrease the degradation of antioxidant components in high-sugar concentrated orange juice. [ABSTRACT FROM AUTHOR]

Nosodes are solutions prepared from pests, capable of controlling those same pests in crops. The use of these solutions in agriculture is an emerging technology for producing eco-friendly and inexpensive plant-based foods free from toxic compounds. The effects of applying nosodes to bean (Phaseolus vulgaris L.) crops before and after harvest were evaluated. The experiment was conducted in the field, with nosode 200CH applied once, three times, biweekly, and weekly from the flowering stage of the "Delgado" bean plant. The application of nosodes resulted in a 108% higher yield, 26% greater biomass, a 32% increase in root length, 34% more pods, and up to a 227% decrease in damaged pods compared to untreated plants. Furthermore, compared to the untreated plants, treated plants exhibited a 37% higher membrane stability and a phenolic content that was up to 27% higher in seeds and 22% higher in leaves. Plants under conventional management showed 61% less Diabrotica balteata (LeConte) incidence than nosode-treated ones. Seeds treated with nosodes exhibited a mortality in Zabrotes subfasciatus (Boh.) of up to 80%. This study highlights the use of nosodes in bean cultivation as an agronomic strategy to enhance seed production and quality, aiding producers in informed decision making about their application. [ABSTRACT FROM AUTHOR]

Background: Microplastic aging affects the dynamics of antibiotic resistance genes (ARGs) on microplastics, yet no review presents the effects of microplastic aging on the associated ARGs. Objectives: This review, therefore, aims to discuss the effects of different types of microplastic aging, as well as the other pollutants on or around microplastics and the chemicals leached from microplastics, on the associated ARGs. Results: It highlights that microplastic photoaging generally results in higher sorption of antibiotics and ARGs due to increased microplastic surface area and functional group changes. Photoaging produces reactive oxygen species, facilitating ARG transfer by increasing bacterial cell membrane permeability. Reactive oxygen species can interact with biofilms, suggesting combined effects of microplastic aging on ARGs. The effects of mechanical aging were deduced from studies showing larger microplastics anchoring more ARGs due to rough surfaces. Smaller microplastics from aging penetrate deeper and smaller places and transport ARGs to these places. High temperatures are likely to reduce biofilm mass and ARGs, but the variation of ARGs on microplastics subjected to thermal aging remains unknown due to limited studies. Biotic aging results in biofilm formation on microplastics, and biofilms, often with unique microbial structures, invariably enrich ARGs. Higher oxidative stress promotes ARG transfer in the biofilms due to higher cell membrane permeability. Other environmental pollutants, particularly heavy metals, antibacterial, chlorination by-products, and other functional genes, could increase microplastic-associated ARGs, as do microplastic additives like phthalates and bisphenols. Conclusions: This review provides insights into the environmental fate of co-existing microplastics and ARGs under the influences of aging. Further studies could examine the effects of mechanical and thermal MP aging on their interactions with ARGs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cold storage is one of the most effective methods to maintain postharvest fruit quality. However, loquat fruits are prone to chilling injury (CI) during cold storage, appearing as symptoms such as browning and pitting, which leads to quality deterioration and economic losses. In this study, the effects of melatonin on CI alleviation and the potential role of reactive oxygen species (ROS) metabolism in loquat fruit were investigated. The results showed that 50 μM melatonin was the optimal concentration to inhibit the increase in CI index and cell membrane permeability. Moreover, compared to control fruits, 50 μM melatonin inhibited the malonaldehyde (MDA) content, O2−. production rate and H2O2 content (ROS accumulation) by 17.8%, 7.2% and 11.8%, respectively, during cold storage. Compared to non-treated loquats, 50 μM melatonin maintained higher levels of 1-diphenyl-2-picrylhydrazyl radical-scavenging ability and reducing power, as well as the contents of ascorbic acid (AsA) and glutathione (GSH). Additionally, 50 μM melatonin enhanced the activities of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) by increasing relevant gene expressions. The activities of SOD, CAT and APX were increased by up to 1.1-, 1.1- and 1.1-times (16 d) by melatonin, as compared with the control fruits. These findings indicate that melatonin mitigation of CI is involved in maintaining cellular redox apphomeostasis in loquat fruit during cold storage. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is a biofilm-forming bacterium responsible for various human infections, one particularly challenging to treat due to its antibiotic resistance. Biofilms can form on both soft tissues and medical devices, leading to persistent and hard-to-treat infections. Combining multiple antimicrobials is a potential approach to overcoming this resistance. This study explored the effects of ursodeoxycholic acid (UDCA) combined with the antibiotic ciprofloxacin against S. aureus biofilms, aiming to evaluate any synergistic effects. Results showed that UDCA and ciprofloxacin co-treatment significantly reduced biofilm formation and disrupted pre-formed biofilms more effectively than either agent alone (p < 0.01). The combination also displayed a slight synergistic effect, with a fractional inhibitory concentration of 0.65. Additionally, the treatment reduced the production of extracellular polymeric substances, increased reactive oxygen species production, decreased metabolic activity, altered cell membrane permeability, and lowered cell surface hydrophobicity in S. aureus. Furthermore, it diminished biofilm-associated pathogenic factors, including proteolytic activity and staphyloxanthin production. Overall, the UDCA–ciprofloxacin combination shows considerable promise as a strategy to combat infections related to staphylococcal biofilms, offering a potential solution to the healthcare challenges posed by antibiotic-resistant S. aureus. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cationic antimicrobial peptides (AMPs) possess broad‐spectrum biological activities with less inclination to inducing antibiotic resistance. Herein a battery of amphiphilic amidines were designed by mimicking the characteristics of AMPs. The antifungal activities and the effects to the hyphal morphology and membrane permeability were investigated. RESULTS: The results indicated the inhibitory rates of ten compounds were over 80% to Botrytis cinerea and ten compounds over 90% to Valsa mali Miyabe et Yamada at 50 mg L−1. The half maximal effective concentration (EC50) values of compound 5g and 6g to V. mali were 1.21 and 1.90 mg L−1 respectively. The protective rate against apple canker of compound 5g reached 93.4% at 100 mg L−1 on twigs, superior to carbendazim (53.3%). When treated with 5g, the cell membrane permeability and leakage of content of V. mali increased, accompanied with the decrease of superoxide dismutase (SOD) and catalase (CAT) level. Concurrently, the mycelial hyphae contracted, wrinkled, and collapsed, providing evidence of membrane perturbation. A three‐dimensional quantitative structure–activity relationship (3D‐QSAR) between the topic compounds and the EC50 to V. mali was established showing good predictability (r2 = 0.971). CONCLUSION: Amphiphilic amidines can acquire antifungal activities by acting on the plasmic membrane. Compound 5g could be a promising lead in discovering novel fungicidal candidates. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Cyclometalated iridium(III) compounds have been widely explored due to their outstanding photo-physical properties and multiple anticancer activities. In this paper, three cyclometalated iridium(III) compounds [Ir(ppy)2(DBDIP)]PF6 (5a), [Ir(bzq)2(DBDIP)]PF6 (5b), and [Ir(piq)2(DBDIP)]PF6 (5c) (ppy: 2-phenylpyridine; bzq: benzo[h]quinoline; piq: 1-phenylisoquinoline, and DBDIP: 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) were synthesized and the mechanism of antitumor activity was investigated. Compounds photoactivated by visible light show strong cytotoxicity against tumor cells, especially toward A549 cells. Biological experiments such as migration, cellular localization, mitochondrial membrane potential and permeability, reactive oxygen species (ROS) and calcium ion level detection were performed, and they demonstrated that the compounds induced the apoptosis of A549 cells through a mitochondrial pathway. At the same time, oxidative stress caused by ROS production increases the release of damage-related molecules and the expression of porogen gasdermin D (GSDMD), and the content of LDH released from damaged cell membranes also increased. Besides, the content of the lipid peroxidation product, malondialdehyde (MDA), increased and the expression of GPX4 decreased. These indicate that the compounds promote cell death by combining ferroptosis and pyroptosis. The results reveal that cyclometalated iridium(III) compounds 5a–5c may be a potential chemotherapeutic agent for photodynamic therapy of cancers. [ABSTRACT FROM AUTHOR]

Photocatalytic membranes (PM) have been investigated as an antifouling strategy for membrane separation processes. Coating ceramic membranes with photocatalytic layers can provide a highly active surface capable of degrading foulants and smaller molecules improving the membrane's performance when the surface is irradiated by a suitable light. Nevertheless, the coating process often leads to pore blockage due to the formation or deposition of thick layers of photocatalyst on membrane surfaces, which modifies the original membranes' average pore size and reduces membrane permeability. A facile sol-gel dip coating process was used to produce PM without modifying the original surface morphology of alumina microfiltration membranes. A 3.7-fold increase in permeate volume after 90 min of permeation of an acetaminophen solution in continuous filtration mode under UV light (λ = 365 nm LED, 10W) using titania as photocatalyst compared to the bare alumina membrane without irradiation. Furthermore, fouling modelling proved a reduction in the fouling constant, while fouling mechanisms were not modified. Raman analysis showed 100% anatase formed on the membrane surface. Although membranes could remove up to 87% TOC for oily wastewater filtration, antifouling capabilities for this type of effluent were not observed for the photocatalytic membranes mainly due to fouling inside the pores and light attenuation due to the thick fouling layer on the membrane surface. [ABSTRACT FROM AUTHOR]

High-entropy perovskite materials (HEPMs), characterized by their multi-element composition and highly disordered structure, can incorporate multiple rare earth elements at the A-site, producing perovskites with enhanced CO2 resistance, making them stay high performance and structurally stable in the CO2 atmosphere. However, this modification may result in reduced oxygen permeability. In this study, we investigated La0.2Pr0.2Nd0.2Ba0.2Sr0.2Co0.8Fe0.2O3-δ (L0.2M1.8) high-entropy perovskite materials, focusing on enhancing their oxygen permeability in both air and CO2 atmospheres through strategic design modifications at the B-sites and A/B-sites. We prepared Ni-substituted La0.2Pr0.2Nd0.2Ba0.2Sr0.2Co0.7Fe0.2Ni0.1O3-δ (L0.2M1.7N0.1) HEPMs by introducing Ni elements at the B-site, and further innovatively introduced A-site defects to prepare La0.2Pr0.2Nd0.2Ba0.2Sr0.2Co0.7Fe0.2Ni0.1O3-δ (L0.1M1.7N0.1) materials. In a pure CO2 atmosphere, the oxygen permeation flux of the L0.1M1.7N0.1 membrane can reach 0.29 mL·cm−2·min−1. Notably, the L0.1M1.7N0.1 membrane maintained a good perovskite structure after stability tests extending up to 120 h under 20% CO2/80% He atmosphere. These findings suggest that A-site-defect high-entropy perovskites hold great promise for applications in CO2 capture, storage, and utilization. [ABSTRACT FROM AUTHOR]