An Overview of the Effects of Tenapanor on Visceral Hypersensitivity in the Treatment of Irritable Bowel Syndrome with Constipation.

Background: Patients with irritable bowel syndrome with constipation (IBS-C) experience persistent abdominal pain, a common symptom leading to greater healthcare utilization and reports of treatment non-response. Clinically significant improvements in abdominal pain were observed in clinical trials of tenapanor, a first-in-class inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), for the treatment of IBS-C in adults. Aim: This narrative review reports the current knowledge about visceral hypersensitivity as a mechanism for abdominal pain in patients with IBS-C and explores the published evidence for hypothesized mechanisms by which tenapanor may reduce visceral hypersensitivity leading to the observed clinical response of decreased abdominal pain. Findings: Abdominal pain is experienced through activation and signaling of nociceptive dorsal root ganglia that innervate the gut. These sensory afferent neurons may become hypersensitized through signaling of transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in reduced action potential thresholds. TRPV1 signaling is also a key component of the proinflammatory cascade involving mast cell responses to macromolecule exposure following permeation through the intestinal epithelium. Indirect evidence of this pathway is supported by observations of higher pain in association with increased intestinal permeability in patients with IBS. Tenapanor reduces intestinal sodium absorption, leading to increased water retention in the intestinal lumen, thereby improving gastrointestinal motility. In animal models of visceral hypersensitivity, tenapanor normalized visceromotor responses and normalized TRPV1-mediated nociceptive signaling. Conclusion: By improving gastrointestinal motility, decreasing intestinal permeability and inflammation, and normalizing nociception through decreased TRPV1 signaling, tenapanor may reduce visceral hypersensitivity, leading to less abdominal pain in patients with IBS-C. Therapies that have demonstrated effects on visceral hypersensitivity may be the future direction for meaningful abdominal pain relief for patients with IBS-C.

Development of eco-friendly biofilms by utilizing microcrystalline cellulose extract from banana pseudo-stem.

Banana pseudo-stem, often considered as an underutilized plant part was explored as a potential reinforced material to develop an eco-friendly biofilm for food packaging applications. In this study, Microcrystalline cellulose (MCC) was extracted from banana pseudo-stem by alkali and acid hydrolysis treatment. The extracted MCC was used as a reinforced material in different concentrated polyvinyl alcohol (PVA) matrix alone as well as both PVA and Carboxymethyl Cellulose (CMC) matrix to develop biofilm by solvent casting method. The synthesized MCC powder was characterized by scanning electron microscope to ensure its microcrystalline structure and to observe surface morphology. The biofilms composed of MCC, PVA, and CMC were assessed through Fourier-transform infrared spectroscopy (FTIR), mechanical properties, water content, solubility, swelling degree, moisture barrier property (Water Vapor Permeability - WVP), and light barrier property (Light Transmission and Transparency). The FTIR analysis showed the rich bonding between the materials of the biofilms. The film incorporating a combination of PVA, CMC, and MCC (S6) exhibited the highest tensile strength at 26.67 ± 0.152 MPa, making it particularly noteworthy for applications in food packaging. MCC incorporation increased the tensile strength. The WVP content of the films was observed low among the MCC-induced films which is parallel to other findings. The lowest WVP content was showed by 1% concentrated PVA with MCC (S4) (0.223 ± 0.020 10-9 g/Pahm). The WVP content of S6 film was also considerably low. MCC-incorporated films also acted as a good UV barrier. Transmittance of the MCC induced films at UV range were observed on average 38% (S2), 36% (S4) and 6% (S6) which were almost 6% lower than the control films. The S6 film demonstrated the lowest swelling capacity (1.42%) and water content, indicating a significantly low solubility of the film. The film formulated with mixing of PVA, CMC and MCC (S6) was ahead in terms of food packaging characteristics than other films. Also, the outcomes of this study point out that MCC can be a great natural resource for packaging applications and in that regard, banana pseudo-stem proves to be an excellent source for waste utilization.

Recent advancements in development and application of microbial cellulose in food and non-food systems.

Microbial cellulose is a fermented form of very pure cellulose with a fibrous structure. The media rich in glucose or other carbon sources are fermented by bacteria to produce microbial cellulose. The bacteria use the carbon to produce cellulose, which grows as a dense, gel-like mat on the surface of the medium. The product was then collected, cleaned, and reused in various ways. The properties of microbial cellulose, such as water holding capacity, gas permeability, and ability to form a flexible, transparent film make it intriguing for food applications. Non-digestible microbial cellulose has been shown to improve digestive health and may have further advantages. It is also very absorbent, making it a great option for use in wound dressings. The review discusses the generation of microbial cellulose and several potential applications of microbial cellulose in fields including pharmacy, biology, materials research, and the food industry.

Dietary vitamin A modifies the gut microbiota and intestinal tissue transcriptome, impacting intestinal permeability and the release of inflammatory factors, thereby influencing Aß pathology.

Background: Alzheimer's disease (AD) is an age-related neurodegenerative disorder with no effective interventions for curing or modifying its progression. However, emerging research suggests that vitamin A in the diet may play a role in both the prevention and treatment of AD, although the exact mechanisms are not fully understood. Objectives: This study aims to investigate the dietary vitamin A modifies the gut microbiota and intestinal tissue transcriptome, impacting intestinal permeability and the release of inflammatory factors, thereby influencing Aß pathology shedding light on its potential as a dietary intervention for AD prevention and treatment. Methods: The APP/PS1-AD mouse model was employed and divided into three dietary groups: vitamin A-deficient (VAD), normal vitamin A (VAN), and vitamin A-supplemented (VAS) for a 12-week study. Neurobehavioral functions were assessed using the Morris Water Maze Test (MWM). Enzyme-linked immunosorbent assay (ELISA) was used to quantify levels of Diamine Oxidase (DAO), D-lactate, IL-6, IL-1ß, and TNF-a cytokines. Serum vitamin A levels were analyzed via LC-MS/MS analysis. Immunohistochemical analysis and morphometry were performed to evaluate the deposition of Aß in brain tissue. The gut microbiota of APP/PS1 mice was analyzed using 16S rRNA sequencing analysis. Additionally, transcriptomic analysis was conducted on intestinal tissue from APP/PS1 mice. Results: No significant changes in food intake and body weight were observed among the groups. However, the VAD and VAS groups showed reduced food intake compared to the VAN group at various time points. In terms of cognitive function, the VAN group performed better in the Morris Water Maze Test, indicating superior learning and memory abilities. The VAD and VAS groups exhibited impaired performance, with the VAS group performing relatively better than the VAD group. Serum vitamin A concentrations differed significantly among the groups, with the VAS group having the highest concentration. Aß levels were significantly higher in the VAD group compared to both the VAN and VAS groups. Microbial analysis revealed that the VAS and VAN groups had higher microbial diversity than the VAD group, with specific taxa characterizing each group. The VAN group was characterized by taxa such as Actinohacteriota and Desulfovibrionaceae, while the VAD group was characterized by Parabacteroides and Tannerellaceae. The VAS group showed similarities with both VAN and VAD groups, with taxa like Desulfobacterota and Desulfovibrionaceae being present. The VAD vs. VAS, VAD vs. VAN, and VAS vs. VAN comparisons identified 571, 313, and 243 differentially expressed genes, respectively, which associated with cellular and metabolic processes, and pathway analysis revealed enrichment in pathways related to chemical carcinogenesis, drug metabolism, glutathione metabolism, and immune-related processes. The VAD group exhibited higher levels of D-lactate, diamine oxidase, and inflammatory cytokines (TNF-a, IL-1ß, IL-6) compared to the VAN and VAS groups. Conclusion: Dietary vitamin A supplementation modulates the gut microbiota, intestinal permeability, inflammatory factors, and Aß protein formation, offering insights into the pathogenesis of AD and potential therapeutic avenues for further exploration. This research highlights the intricate interplay between diet, gut microbiota, and neurodegenerative processes, emphasizing the importance of dietary interventions in managing AD-related pathologies.

Validation of a Caco-2 microfluidic Chip model for predicting intestinal absorption of BCS Class I-IV drugs.

Oral delivery is considered the most patient preferred route of drug administration, however, the drug must be sufficiently soluble and permeable to successfully formulate an oral formulation. There have been advancements in the development of more predictive solubility and dissolution tools, but the tools that has been developed for permeability assays have not been validated as extensively as the gold-standard Caco-2 Transwell assay. Here, we evaluated Caco-2 intestinal permeability assay in Transwells and a commercially available microfluidic Chip using 19 representative Biopharmaceutics Classification System (BCS) Class I-IV compounds. For each selected compound, we performed a comprehensive viability test, quantified its apparent permeability (Papp), and established an in vitro in vivo correlation (IVIVC) to the human fraction absorbed (fa) in both culture conditions. Permeability differences were observed across the models as demonstrated by antipyrine (Transwell Papp: 38.5 ± 6.1 × 10-8 cm/s vs Chip Papp: 32.9 ± 11.3 × 10-8 cm/s) and nadolol (Transwell Papp: 0.6 ± 0.1 × 10-7 cm/s vs Chip Papp: 3 ± 1.2 × 10-7 cm/s). The in vitro in vivo correlation (IVIVC; Papp vs. fa) of the Transwell model (r2 = 0.59-0.83) was similar to the Chip model (r2 = 0.41-0.79), highlighting similar levels of predictivity. Comparing to historical data, our Chip Papp data was more closely aligned to native tissues assessed in Ussing chambers. This is the first study to comprehensively validate a commercial Gut-on-a-Chip model as a predictive tool for assessing oral absorption to further reduce our reliance on animal models.

The microbiota drives diurnal rhythms in tryptophan metabolism in the stressed gut.

Chronic stress disrupts microbiota-gut-brain axis function and is associated with altered tryptophan metabolism, impaired gut barrier function, and disrupted diurnal rhythms. However, little is known about the effects of acute stress on the gut and how it is influenced by diurnal physiology. Here, we used germ-free and antibiotic-depleted mice to understand how microbiota-dependent oscillations in tryptophan metabolism would alter gut barrier function at baseline and in response to an acute stressor. Cecal metabolomics identified tryptophan metabolism as most responsive to a 15-min acute stressor, while shotgun metagenomics revealed that most bacterial species exhibiting rhythmicity metabolize tryptophan. Our findings highlight that the gastrointestinal response to acute stress is dependent on the time of day and the microbiome, with a signature of stress-induced functional alterations in the ileum and altered tryptophan metabolism in the colon.

Molecular Mechanisms of Neuroprotection after the Intermittent Exposures of Hypercapnic Hypoxia.

The review introduces the stages of formation and experimental confirmation of the hypothesis regarding the mutual potentiation of neuroprotective effects of hypoxia and hypercapnia during their combined influence (hypercapnic hypoxia). The main focus is on the mechanisms and signaling pathways involved in the formation of ischemic tolerance in the brain during intermittent hypercapnic hypoxia. Importantly, the combined effect of hypoxia and hypercapnia exerts a more pronounced neuroprotective effect compared to their separate application. Some signaling systems are associated with the predominance of the hypoxic stimulus (HIF-1α, A1 receptors), while others (NF-κB, antioxidant activity, inhibition of apoptosis, maintenance of selective blood-brain barrier permeability) are mainly modulated by hypercapnia. Most of the molecular and cellular mechanisms involved in the formation of brain tolerance to ischemia are due to the contribution of both excess carbon dioxide and oxygen deficiency (ATP-dependent potassium channels, chaperones, endoplasmic reticulum stress, mitochondrial metabolism reprogramming). Overall, experimental studies indicate the dominance of hypercapnia in the neuroprotective effect of its combined action with hypoxia. Recent clinical studies have demonstrated the effectiveness of hypercapnic-hypoxic training in the treatment of childhood cerebral palsy and diabetic polyneuropathy in children. Combining hypercapnic hypoxia with pharmacological modulators of neuro/cardio/cytoprotection signaling pathways is likely to be promising for translating experimental research into clinical medicine.

Feasibility of measuring blood-brain barrier permeability using ultra-short echo time radial magnetic resonance imaging.

BACKGROUND AND PURPOSE: The purpose of this study is to evaluate the feasibility of using 3-dimensional (3D) ultra-short echo time (UTE) radial imaging method for measurement of the permeability of the blood-brain barrier (BBB) to gadolinium-based contrast agent. In this study, we propose to use the golden-angle radial sparse parallel (GRASP) method with 3D center-out trajectories for UTE, hence named as 3D UTE-GRASP. We first examined the feasibility of using 3D UTE-GRASP dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) for differentiating subtle BBB disruptions induced by focused ultrasound (FUS). Then, we examined the BBB permeability changes in Alzheimer's disease (AD) pathology using Alzheimer's disease transgenic mice (5xFAD) at different ages. METHODS: For FUS experiments, we used four Sprague Dawley rats at similar ages where we compared BBB permeability of each rat receiving the FUS sonication with different acoustic power (0.4-1.0 MPa). For AD transgenic mice experiments, we included three 5xFAD mice (6, 12, and 16 months old) and three wild-type mice (4, 8, and 12 months old). RESULTS: The result from FUS experiments showed a progressive increase in BBB permeability with increase of acoustic power (p < .05), demonstrating the sensitivity of DCE-MRI method for detecting subtle changes in BBB disruption. Our AD transgenic mice experiments suggest an early BBB disruption in 5xFAD mice, which is further impaired with aging. CONCLUSION: The results in this study substantiate the feasibility of using the proposed 3D UTE-GRASP method for detecting subtle BBB permeability changes expected in neurodegenerative diseases, such as AD.

Altered lactate/pyruvate ratio may be responsible for aging-associated intestinal barrier dysfunction in male rats.

Some evidence points to a link between aging-related increased intestinal permeability and mitochondrial dysfunction in in-vivo models. Several studies have also demonstrated age-related accumulation of the of specific deletion 4834-bp of "common" mitochondrial DNA (mtDNA) in various rat tissues and suggest that this deletion may disrupt mitochondrial metabolism. The present study aimed to investigate possible associations among the mitochondrial DNA (mtDNA) common deletion, mitochondrial function, intestinal permeability, and aging in rats. The study was performed on the intestinal tissue from (24 months) and young (4 months) rats. mtDNA4834 deletion, mtDNA copy number, mitochondrial membrane potential, and ATP, lactate and pyruvate levels were analyzed in tissue samples. Zonulin and intestinal fatty acid-binding protein (I-FABP) levels were also evaluated in serum. Serum zonulin and I-FABP levels were significantly higher in 24-month-old rats than 4-month-old rats (p = 0.04, p = 0.026, respectively). There is not significant difference in mtDNA4834 copy levels was observed between the old and young intestinal tissues (p > 0.05). The intestinal mitochondrial DNA copy number was similar between the two age groups (p > 0.05). No significant difference was observed in ATP levels in the intestinal tissue lysates between old and young rats (p > 0.05). ATP levels in isolated mitochondria from both groups were also similar. Analysis of MMP using JC-10 in intestinal tissue mitochondria showed that mitochondrial membrane potentials (red/green ratios) were similar between the two age groups (p > 0.05). Pyruvate tended to be higher in the 24-month-old rat group and the L/P ratio was found to be approximately threefold lower in the intestinal tissue of the older rats compared to the younger rats (p < 0.002). The tissue lactate/pyruvate ratio (L/P) was three times lower in old rats than in young rats. Additionally, there were significant negative correlations between intestinal permeability parameters and L/P ratios. The intestinal tissues of aged rats are not prone to accumulate mtDNA common deletion, we suggest that this mutation does not explain the age-related increase in intestinal permeability. It seems to be more likely that altered glycolytic capacity could be a link to increased intestinal permeability with age. This observation strengthens assertions that the balance between glycolysis and mitochondrial metabolism may play a critical role in intestinal barrier functions.

Repurposing approved drugs as potential efflux pump inhibitors in multidrug-resistant Pseudomonas aeruginosa.

Aim: To evaluate the action of promethazine, fluoxetine and carbonyl cyanide 3-chlorophenylhydrazone as efflux pump inhibitors (EPIs) against multidrug-resistant Pseudomonas aeruginosa. Methods: The effect of the compounds was evaluated in planktonic cells and bacterial biofilms. Accumulation tests were performed with ethidium bromide to prove their action as EPIs. Then, they were associated with antimicrobials. Results: Effect on planktonic cells and biofilms was found. Assays with ethidium bromide indicate their action as EPIs. Significant reductions in the metabolic activity of biofilms were observed after the association with the antimicrobials, especially for meropenem. Conclusion: It is possible to prove the action of these compounds as EPIs for P. aeruginosa and demonstrate the relevance of efflux pumps in antimicrobial resistance.

Inorganic polyphosphate and ion transport across biological membranes.

Inorganic polyphosphate (polyP) is widely recognized for playing important roles and processes involved in energy and phosphate storage, regulation of gene expression, and calcium signaling. The less well-known role of polyP is as a direct mediator of ion transport across biological membranes. Here, we will briefly summarize current knowledge of the molecular mechanisms of how polyP can be involved in membrane ion transport. We discuss three types of mechanisms that might involve polyP: (1) formation of non-protein channel complex that includes calcium, polyP, and polyhydroxybutyrate (PHB); (2) modulation of the channel activity of PHBlated protein channels; and (3) direct effects of polyP on the function of the voltage-gated ion channels in the process that do not involve PHB.

The Effect of Inflammatory Bowel Disease and Irritable Bowel Syndrome on Pravastatin Oral Bioavailability: In vivo and in silico evaluation using bottom-up wbPBPK modeling.

The common disorders irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) can modify the drugs' pharmacokinetics via their induced pathophysiological changes. This work aimed to investigate the impact of these two diseases on pravastatin oral bioavailability. Rat models for IBS and IBD were used to experimentally test the effects of IBS and IBD on pravastatin pharmacokinetics. Then, the observations made in rats were extrapolated to humans using a mechanistic whole-body physiologically-based pharmacokinetic (wbPBPK) model. The rat in vivo studies done herein showed that IBS and IBD decreased serum albumin (> 11% for both), decreased PRV binding in plasma, and increased pravastatin absolute oral bioavailability (0.17 and 0.53 compared to 0.01) which increased plasma, muscle, and liver exposure. However, the wbPBPK model predicted muscle concentration was much lower than the pravastatin toxicity thresholds for myotoxicity and rhabdomyolysis. Overall, IBS and IBD can significantly increase pravastatin oral bioavailability which can be due to a combination of increased pravastatin intestinal permeability and decreased pravastatin gastric degradation resulting in higher exposure. This is the first study in the literature investigating the effects of IBS and IBD on pravastatin pharmacokinetics. The high interpatient variability in pravastatin concentrations as induced by IBD and IBS can be reduced by oral administration of pravastatin using enteric-coated tablets. Such disease (IBS and IBD)-drug interaction can have more drastic consequences for narrow therapeutic index drugs prone to gastric degradation, especially for drugs with low intestinal permeability.

Mitochondrial Permeability Transition, Cell Death and Neurodegeneration.

Neurodegenerative diseases are chronic conditions occurring when neurons die in specific brain regions that lead to loss of movement or cognitive functions. Despite the progress in understanding the mechanisms of this pathology, currently no cure exists to treat these types of diseases: for some of them the only help is alleviating the associated symptoms. Mitochondrial dysfunction has been shown to be involved in the pathogenesis of most the neurodegenerative disorders. The fast and transient permeability of mitochondria (the mitochondrial permeability transition, mPT) has been shown to be an initial step in the mechanism of apoptotic and necrotic cell death, which acts as a regulator of tissue regeneration for postmitotic neurons as it leads to the irreparable loss of cells and cell function. In this study, we review the role of the mitochondrial permeability transition in neuronal death in major neurodegenerative diseases, covering the inductors of mPTP opening in neurons, including the major ones-free radicals and calcium-and we discuss perspectives and difficulties in the development of a neuroprotective strategy based on the inhibition of mPTP in neurodegenerative disorders.

Molecular Simulation Study on the Hydrogen Permeation Behavior and Mechanism of Common Polymers.

This research aimed to provide an understanding of the selection and safe application of pipeline liner materials for hydrogen transport by examining the permeation properties and mechanisms of hydrogen within polymers commonly used for this purpose, such as high-density polyethylene (HDPE) and ethylene-vinyl alcohol copolymer (EVOH), through molecular simulation. The study was carried out within defined operational parameters of temperature (ranging from room temperature to 80 °C) and pressure (from 2.5 to 10 MPa) that are pertinent to hydrogen pipeline infrastructures. The results reveal that with an increase in temperature from 30 °C to 80 °C, the solubility, diffusion, and permeability coefficients of hydrogen in HDPE increase by 18.7%, 92.9%, and 129.0%, respectively. Similarly, in EVOH, these coefficients experience increments of 15.9%, 81.6%, and 112.7%. Conversely, pressure variations have a negligible effect on permeability in both polymers. HDPE exhibits significantly higher hydrogen permeability compared to EVOH. The unique chain segment configuration of EVOH leads to the formation of robust hydrogen bonds among the hydroxyl groups, thereby impeding the permeation of hydrogen. The process by which hydrogen is adsorbed in polymers involves aggregation at low potential energy levels. During diffusion, the hydrogen molecule primarily vibrates within a limited range, with intermittent occurrences of significant hole-to-hole transitions over larger distances. Hydrogen exhibits a stronger interaction with HDPE compared to EVOH, leading to a higher number of adsorption sites and increased hydrogen adsorption capacity in HDPE. Hydrogen molecules move more actively in HDPE than in EVOH, exhibiting greater hole amplitude and more holes in transition during the diffusion process.

Radio-Absorbing Magnetic Polymer Composites Based on Spinel Ferrites: A Review.

Ferrite-containing polymer composites are of great interest for the development of radar-absorbing and -shielding materials (RAMs and RSMs). The main objective of RAM and RSM development is to achieve a combination of efficient electromagnetic wave (EMW) absorption methods with advantageous technological and mechanical properties as well as acceptable weight and dimensions in the final product. This work deals with composite RAMs and RSMs containing spinel-structured ferrites. These materials are chosen since they can act as efficient RAMs in the form of ceramic plates and as fillers for radar-absorbing polymer composites (RAC) for electromagnetic radiation (EMR). Combining ferrites with conducting fillers can broaden the working frequency range of composite RAMs due to the activation of various absorption mechanisms. Ferrite-containing composites are the most efficient materials that can be used as the working media of RAMs and RSMs due to a combination of excellent dielectric and magnetic properties of ferrites. This work contains a brief review of the main theoretical standpoints on EMR interaction with materials, a comparison between the radar absorption properties of ferrites and ferrite-polymer composites and analysis of some phenomenological aspects of the radar absorption mechanisms in those composites.

Dampened Transient Actuation of Hydrogels Autonomously Controlled by pH-Responsive Bicontinuous Nanospheres.

The fabrication of a soft actuator with a dampened actuation response is presented. This was achieved via the incorporation into an actuating hydrogel of urease-loaded pH-responsive bicontinuous nanospheres (BCNs), whose membrane was able to regulate the permeability and thus conversion of fuel urea into ammonia. The dampened response of these nanoreactors to the enzymatically induced pH change was translated to a pH-responsive soft actuator. In hydrogels composed of a pH-responsive and nonresponsive layer, the transient pH gradient yielded an asymmetric swelling behavior, which induced a bending response. The transient actuation profile could be controlled by varying the external fuel concentrations. Furthermore, we showed that the spatial organization of the BCNs within the actuator had a great influence on the actuation response. Embedding the urease-loaded nanoreactors within the active, pH-responsive layer resulted in a reduced response due to local substrate conversion in comparison to embedding them within the passive layer of the bilayer hydrogel. Finally, we were able to induce transient actuation in a hydrogel comprising two identical active layers by the immobilization of the BCNs within one specific layer. Upon addition of urea, a local pH gradient was generated, which caused accelerated swelling in the BCN layer and transient bending of the device before the pH gradient was attenuated over time.

Alpha-synuclein interaction with mitochondria is the final mechanism of ferroptotic death induced by erastin in SH-SY5Y cells.

Ferroptosis has been characterized as a form of iron-dependent regulated cell death accompanied by an accumulation of reactive oxygen species and lipid oxidation products along with typical morphological alterations in mitochondria. Ferroptosis is activated by diverse triggers and inhibited by ferrostatin-1 and liproxstatin-1, apart from iron chelators and several antioxidants, and the process is implicated in multiple pathological conditions. There are, however, certain ambiguities about ferroptosis, especially regarding the final executioner of cell death subsequent to the accumulation of ROS. This study uses a typical inducer of ferroptosis such as erastin on SH-SY5Y cells, and shows clearly that ferroptotic death of cells is accompanied by the loss of mitochondrial membrane potential and intracellular ATP content along with an accumulation of oxidative stress markers. All these are prevented by ferrostatin-1 and liproxstatin-1. Additionally, cyclosporine A prevents mitochondrial alterations and cell death induced by erastin implying the crucial role of mitochondrial permeability transition pore (mPTP) activation in ferroptotic death. Furthermore, an accumulation of α-synuclein occurs during erastin induced ferroptosis which can be inhibited by ferrostatin-1 and liproxstatin-1. When the knock-down of α-synuclein expression is performed by specific siRNA treatment of SH-SY5Y cells, the mitochondrial impairment and ferroptotic death of the cells induced by erastin are markedly prevented. Thus, α-synuclein through the involvement of mPTP appears to be the key executioner protein of ferroptosis induced by erastin, but it needs to be verified if it is a generalized mechanism of ferroptosis by using other inducers and cell lines.

Structural Features of the Porous Network of poly(Urethane) Aerogels via Gas Permeability Measurements.

The permeability for gases through polyurethane (PUR) aerogels prepared from unsorted PUR scraps by means of a recycling technique is measured with a dynamic pressure method. The permeabilities are in the range of 10-15 to 10-13 m2 and thus reflect the pore morphology observed with scanning electron microscopy (SEM). The permeability depends on the envelope density and microstructural features of the aerogels and decreases with increasing inner surface area. The comparison of the permeability with the Porod constant, which is obtained independently via small angle X-ray scattering (SAXS), yields a high consistency with the expected theoretical relationship. However, a calculation of inner surface area based on permeability yields lower results than expected from data based on the established SAXS technique, revealing that the famous Carman-Kozeny law correlates only by trend, which is attributed to additional gas transport through the micro- and mesopores. A possible approach for the correlation of this behaviour to the tortuosity is given. Several models accounting for the combined action of viscous flow, Knudsen diffusion and molecular slip along pore walls are fitted to the experimental data, effectively qualifying the permeability measurement as time efficient and inexpensive technique for the characterization of structural features of aerogels. This article is protected by copyright. All rights reserved.

Evaluation of lipophilicity and drug-likeness of donepezil-like compounds using reversed-phase thin-layer chromatography.

Fourteen donepezil-like acetylcholinesterase (AChE) inhibitors from our library were analyzed using reversed-phase thin-layer chromatography to assess their lipophilicity and blood-brain barrier permeability. Compounds possessed N-benzylpiperidine and N,N-diarylpiperazine moieties connected via a short carboxamide or amine linker. Retention parameters RM 0, b, and C0 were considered as the measures of lipophilicity. Besides, logD of the investigated compounds was determined chromatographically using standard compounds with known logPow and logD values at pH 11. Experimentally obtained lipophilicity parameters correlated well with in silico generated results, and the effect of the nature of the linker between two pharmacophores and substituents on the arylpiperazine part of the molecule was observed. As a result of drug-likeness analysis, both Lipinski's rule of five and Veber's rule parameters were determined, suggesting that examined compounds could be potential candidates for further drug development. Principal component analysis was performed to obtain an insight into a grouping of compounds based on calculated structural descriptors, experimentally obtained values of lipophilicity, and AChE inhibitory activity.

Simulation test of short-term and long-term clogging of permeable pavement.

Permeable pavement is superior in functions such as reducing noise, improving traffic safety, and protecting urban water environment. However, contaminants on the pavement due to spillage of transported goods, deposits from vehicle wear and tear, and natural settlement can cause the risk of blockage when these contaminants enter the interior of the permeable pavement. Timely maintenance of permeable performance can effectively solve the degradation of environmental performance of permeable pavement caused by clogging. Consequently, exploring permeable pavement clogging patterns can support determining the timing of maintenance. In this paper, simulation clogging material gradations were formulated based on actual road clogging conditions. According to the self-developed permeable pavement clogging simulator, the clogging behavior of permeable pavement was comprehensively explored, taking external conditions, mix proportion, structural combination, and long-term clogging conditions into consideration. Moreover, the effect of external conditions on the clogging pattern was simulated by varying the rainfall intensity and clogging particle size. Furthermore, the effects of gradation, void rate, nominal maximum particle size, and the overwater section on the clogging resistance were investigated. The clogging-sensitive particle size under different structures was determined. It is demonstrated that the water head height is the crucial factor on the clogging behavior. Greater rainfall intensity and water head height lead to more severe clogging. The increase of nominal maximum aggregate size is beneficial to the anti-clogging ability of permeable pavement. Also, the clogging material with small particle sizes is more likely to cause structural clogging. Finally, the evaluation index of clogging level was put forward, which divides the clogging level of permeable pavement into mild, moderate, and severe. The research can support the rationalization, intelligence, and convenience of permeable pavement maintenance timing decisions. Meanwhile, there is key significance to the promotion application and performance maintenance.