Sex-Specific Effect of Ethanol on Colon Content Lipidome in a Mice Model Using Nontargeted LC/MS.

Consumption of alcohol has widespread effects on the human body. The organs that are most significantly impacted are the liver and digestive system. When alcohol is consumed, it is absorbed in the intestines and processed by the liver. However, excessive alcohol use may affect gut epithelial integrity, microbiome composition, and lipid metabolism. Despite past studies investigating the effect of ethanol on hepatic lipid metabolism, the focus on colonic lipid metabolism has not been well explored. In this study, we investigated the sex-specific effect of ethanol on the colonic content lipidome in a mouse model using nontargeted liquid chromatography-mass spectrometry. Comprehensive lipidome analysis of colonic flush samples was performed using ethanol-fed (EF) and pair-fed (PF) mice of each sex. Partial least-squares discriminant analysis revealed that ethanol altered colonic lipid composition largely in male mice compared with female mice. A significant increase in free fatty acids, ceramides, and hexosylceramides and decreased phosphatidylglycerols (PG) was observed in the EF group compared to the PF group in male mice. Phosphatidylethanolamine (PE) levels were increased significantly in the EF group of both sexes compared to the PF group. The volcanic plot shows that PG (O-15:1/15:0) and PE (O-18:2/15:0) are common markers that are increased in both sexes of the EF group. In addition, decreased fatty acid esters of hydroxy fatty acids (FAHFA) were observed specifically in the EF group of female mice. Overall, a significant variation in the mice colonic content lipidome between the EF and PF groups was observed. Target pathways, such as sphingolipid metabolism in males, FAHFA in females, and PE metabolism in both sexes, were suggested. This study provides new insight into the sex-dependent lipid change associated with alcohol-induced gut-microbiota dysfunction and its potential health impacts.

Unlocking therapeutic potential: integration of drug repurposing and immunotherapy for various disease targeting.

Drug repurposing, also known as drug repositioning, entails the application of pre-approved or formerly assessed drugs having potentially functional therapeutic amalgams for curing various disorders or disease conditions distinctive from their original remedial indication. It has surfaced as a substitute for the development of drugs for treating cancer, cardiovascular diseases, neurodegenerative disorders, and various infectious diseases like Covid-19. Although the earlier lines of findings in this area were serendipitous, recent advancements are based on patient centered approaches following systematic, translational, drug targeting practices that explore pathophysiological ailment mechanisms. The presence of definite information and numerous records with respect to beneficial properties, harmfulness, and pharmacologic characteristics of repurposed drugs increase the chances of approval in the clinical trial stages. The last few years have showcased the successful emergence of repurposed drug immunotherapy in treating various diseases. In this light, the present review emphasises on incorporation of drug repositioning with Immunotherapy targeted for several disorders.

Paneth cell dysfunction in radiation injury and radio-mitigation by human α-defensin 5.

Introduction: The mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin expression and its impact on microbiota composition and mucosal tissue injury and evaluated the radio-mitigative effect of human α-defensin 5 (HD5). Methods: Adult mice were subjected to total body irradiation, and Paneth cell α-defensin expression was evaluated by measuring α-defensin mRNA by RT-PCR and α-defensin peptide levels by mass spectrometry. Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. HD5 was administered in a liquid diet 24 hours before or after irradiation. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by cytokine expression. Systemic inflammation was evaluated by measuring plasma cytokine levels. Results: Ionizing radiation reduced the Paneth cell α-defensin expression and depleted α-defensin peptides in the intestinal lumen. α-Defensin down-regulation was associated with the time-dependent alteration of gut microbiota composition, increased gut permeability, and endotoxemia. Administration of human α-defensin 5 (HD5) in the diet 24 hours before irradiation (prophylactic) significantly blocked radiation-induced gut microbiota dysbiosis, disruption of intestinal epithelial tight junction and adherens junction, mucosal barrier dysfunction, and mucosal inflammatory response. HD5, administered 24 hours after irradiation (treatment), reversed radiation-induced microbiota dysbiosis, tight junction and adherens junction disruption, and barrier dysfunction. Furthermore, HD5 treatment also prevents and reverses radiation-induced endotoxemia and systemic inflammation. Conclusion: These data demonstrate that radiation induces Paneth cell dysfunction in the intestine, and HD5 feeding prevents and mitigates radiation-induced intestinal mucosal injury, endotoxemia, and systemic inflammation.

Role of graphene in scavenging methyl cations: a DFT study.

CONTEXT: It is known that methylating agents methylate DNA by transferring a methyl cation (CH3+) to the nucleophilic sites in DNA bases and DNA methylation is implicated in cancer and other pathological conditions. Therefore, it is important to scavenge CH3+ ion in order to protect DNA from methylation. Graphene is considered to be a versatile material for use in a wide variety of fields including sensors, antioxidants, drug delivery and DNA sequencing. In this work, we have theoretically investigated the interaction of CH3+ ions with graphene surface with an aim to understand if pristine graphene can be used as a substrate to adsorb CH3+ cations generated from harmful methylating agents. The computed adsorption energies show that adsorption of one, two and three CH3+ ions on graphene is favourable as the adducts thus formed are found to be substantially stable in both gas phase and aqueous media. The Bader charge transfer analysis and density of states (DOS) calculation also indicate a strong interaction between graphene and CH3+ ions. Thus, our results show that pristine graphene can be used as a substrate to scavenge CH3+ ions. METHODS: The spin polarised density functional theory (DFT) calculations employing PBE functional, ultrasoft pseudopotentials and plane wave basis set having kinetic energy cut-offs of 40 Ry and 400 Ry, respectively, for wave functions and charge densities were carried out to study the adsorption of CH3+ ion(s) on the pristine graphene surface. The Grimme's DFT-D2 method was used for the estimation of van der Waals interactions. The 'dipole correction' along z-direction was also applied for adsorption study. The Marzari-Vanderbilt smearing and Monkhorst-Pack k-point grid were employed for the Brillouin zone sampling. A 6 × 6 graphene supercell with a vertical cell dimension of 18 Å was considered for the adsorption study. The charge transfer between the CH3+ ion(s) and graphene was estimated using Bader charge analysis. The implicit solvation model (SCCS) was used to estimate the solvent effect of aqueous media. All the calculations were performed using QUANTUM ESPRESSO package.

Using foam fractionation to estimate PFAS air-water interface adsorption behaviour at ng/L and µg/L concentrations.

PFAS are biologically recalcitrant compounds that are persistent in the environment and have subsequently contaminated groundwater, landfill leachate and surface water. Due to their persistence and toxicity, there are environmental concentration limits imposed on some PFAS compounds that extend down to a few nanograms per litre and even proposals for reducing these to picogram per litre levels. Since PFAS concentrates at water-air interfaces as a result of their amphiphilic nature, this characteristic is important for the successful modelling and prediction of transport behaviour of PFAS through various systems. Here we present a procedure for using a foam fractionation method to experimentally determine the PFAS adsorption behaviour at ng/L and µg/L concentrations in the presence of salts. The equilibrium air-water adsorption coefficients for PFHxS and PFOA at different salinities and concentrations are experimentally shown to be constant across the range of PFAS concentrations investigated (approx. 0.1-100 µg/L). The adsorption isotherms may consequently be modelled by Henry or Langmuir style equations at these low concentrations.

TRPV6 deficiency attenuates stress and corticosterone-mediated exacerbation of alcohol-induced gut barrier dysfunction and systemic inflammation.

Introduction: Chronic stress is co-morbid with alcohol use disorder that feedback on one another, thus impeding recovery from both disorders. Stress and the stress hormone corticosterone aggravate alcohol-induced intestinal permeability and liver damage. However, the mechanisms involved in compounding tissue injury by stress/corticosterone and alcohol are poorly defined. Here we explored the involvement of the TRPV6 channel in stress (or corticosterone) 3and alcohol-induced intestinal epithelial permeability, microbiota dysbiosis, and systemic inflammation. Methods: Chronic alcohol feeding was performed on adult wild-type and Trpv6-/- mice with or without corticosterone treatment or chronic restraint stress (CRS). The barrier function was determined by evaluating inulin permeability in vivo and assessing tight junction (TJ) and adherens junction (AJ) integrity by immunofluorescence microscopy. The gut microbiota composition was evaluated by 16S rRNA sequencing and metagenomic analyses. Systemic responses were assessed by evaluating endotoxemia, systemic inflammation, and liver damage. Results: Corticosterone and CRS disrupted TJ and AJ, increased intestinal mucosal permeability, and caused endotoxemia, systemic inflammation, and liver damage in wild-type but not Trpv6-/- mice. Corticosterone and CRS synergistically potentiated the alcohol-induced breakdown of intestinal epithelial junctions, mucosal barrier impairment, endotoxemia, systemic inflammation, and liver damage in wild-type but not Trpv6-/- mice. TRPV6 deficiency also blocked the effects of CRS and CRS-mediated potentiation of alcohol-induced dysbiosis of gut microbiota. Conclusions: These findings indicate an essential role of TRPV6 in stress, corticosterone, and alcohol-induced intestinal permeability, microbiota dysbiosis, endotoxemia, systemic inflammation, and liver injury. This study identifies TRPV6 as a potential therapeutic target for developing treatment strategies for stress and alcohol-associated comorbidity.

Sex-Specific Whole-Transcriptome Analysis in the Cerebral Cortex of FAE Offspring.

Fetal alcohol spectrum disorders (FASDs) are associated with systemic inflammation and neurodevelopmental abnormalities. Several candidate genes were found to be associated with fetal alcohol exposure (FAE)-associated behaviors, but a sex-specific complete transcriptomic analysis was not performed at the adult stage. Recent studies have shown that they are regulated at the developmental stage. However, the sex-specific role of RNA in FAE offspring brain development and function has not been studied yet. Here, we carried out the first systematic RNA profiling by utilizing a high-throughput transcriptomic (RNA-seq) approach in response to FAE in the brain cortex of male and female offspring at adulthood (P60). Our RNA-seq data analysis suggests that the changes in RNA expression in response to FAE are marked sex-specific. We show that the genes Muc3a, Pttg1, Rec8, Clcnka, Capn11, and pnp2 exhibit significantly higher expression in the male offspring than in the female offspring at P60. FAE female mouse brain sequencing data also show an increased expression of Eno1, Tpm3, and Pcdhb2 compared to male offspring. We performed a pathway analysis using a commercial software package (Ingenuity Pathway Analysis). We found that the sex-specific top regulator genes (Rictor, Gaba, Fmri, Mlxipl) are highly associated with eIF2 (translation initiation), synaptogenesis (the formation of synapses between neurons in the nervous system), sirtuin (metabolic regulation), and estrogen receptor (involved in obesity, aging, and cancer) signaling. Taken together, our transcriptomic results demonstrate that FAE differentially alters RNA expression in the adult brain in a sex-specific manner.

Effect of different co-foaming agents on PFAS removal from the environment by foam fractionation.

Per- and poly-fluoroalkyl substances (PFAS) are recalcitrant, synthetic chemicals that are ubiquitous in the environment because of their widespread use in a variety of consumer and industrial products. PFAS contamination has become an increasing issue in recent years, which needs to be urgently addressed. Foam fractionation is emerging as a potential remediation option that removes PFAS by adsorption to the surface of rising air bubbles which are removed from the system as a foam. PFAS concentrations in the environment are often not sufficient to allow for formation of a foam by itself and often a co-foaming agent is required to be added to enhance the foamability of the solution. In this study, the effect of different classes of co-foaming agents, anionic, non-ionic, zwitterionic and cationic surfactants on the removal of PFAS with varying fluorocarbon chain length from 3 to 8 in a foam fractionation process have been investigated. Evaluation of the air-water interface partitioning coefficient (k') in addition with surface tension and PFAS removal results support the contention that using a co-foaming agent with the opposite charge to the PFAS in question significantly facilitates the adsorption of PFAS to the air-water interface, enhancing the efficiency of the process. Using the non-ionic surfactant (no headgroup electrostatic interaction with PFAS), as a reference, it was observed, in terms of PFAS separation and rate of PFAS removal, that anionic co-surfactant performed worst, zwitterionic was better, and cationic co-surfactant performed best. All of the PFAS species were able to be removed below the limit of detection (0.05 µg/L) after 45 minutes of foaming time with the cationic surfactant.

Foam fractionation of per- and polyfluoroalkyl substances (PFASs) in landfill leachate using different cosurfactants.

Foam fractionation is one solution to recover per- and polyfluoroalkyl substances (PFASs) from aqueous sources. The separation process is based on the sorption of PFASs to the air-water interface of bubbles. In many practical cases, the PFAS concentration in the polluted liquid is too low to sustain foam formation and requires the support of a cosurfactant not only to act as a collector of PFAS but also to produce and sustain foam for effective separation. However, there is a lack of information regarding the appropriate choice of cosurfactant and its quantitative effect on the interfacial partitioning of PFASs on the air bubbles. This study is directed to (i) evaluate the effectiveness of four cosurfactants with different-charged headgroups (i.e., anionic, cationic, zwitterionic and nonionic) for foam fractionation of PFASs, and (ii) estimate the air-water interfacial partitioning (Ki) of PFASs in the presence of four different types of cosurfactants. The Ki values span over 4 orders of magnitude with good correlation with PFASs molar volume. All of the cosurfactants were effective for the removal of the long chain PFASs (1.2-4 logs). The cationic and zwitterionic surfactants have oppositely charged head groups with respect to the anionic PFASs and therefore facilitate increased separation due to charge interactions. Some short chain PFASs (e.g., Perfluorobutanesulfonic acid (PFBS), Perfluoropentanesulfonic acid (PFPeS)) can be effectively removed using cationic and zwitterionic cosurfactants.

Reactions of Ru(III)-drugs KP1019 and KP418 with guanine, 2'-deoxyguanosine and guanosine: a DFT study.

Ruthenium (Ru)-based anticancer drugs are considered to be novel alternatives of platinum-based drugs. They exhibit potent cytotoxicity against the cancer cells and hence are useful for the treatment of cancer. Herein, the density functional theory calculations in the gas phase and aqueous media are carried out to study the reactions of two Ru(III)-based drugs such as KP1019 and KP418 with the N7 site of guanine (G), 2'-deoxyguanosine (dGua), and guanosine (Gua) to understand their reactivity against the DNA and RNA. All the reactions are found to be exothermic. The activation free energies and rate constants of these reactions indicate that KP1019 and KP418 would react with the dGua more readily than Gua. Hence, the binding of these drugs with the DNA would be more preferred as compared to RNA. It is further found that among these drugs, KP1019 would be more reactive than KP418 in agreement with the experimental observation. Thus, this study is expected to aid in the future development of potent anticancer drugs.

Mechanism and kinetics of chlorpyrifos co-metabolism by using environment restoring microbes isolated from rhizosphere of horticultural crops under subtropics.

The indiscriminate use of organophosphate insecticide chlorpyrifos in agricultural crops causes significant soil and water pollution and poses a serious threat to the global community. In this study, a microbial consortium ERM C-1 containing bacterial strains Pseudomonas putida T7, Pseudomonas aeruginosa M2, Klebsiella pneumoniae M6, and a fungal strain Aspergillus terreus TF1 was developed for the effective degradation of chlorpyrifos. Results revealed that microbial strains were not only utilizing chlorpyrifos (500 mg L-1) but also coupled with plant growth-promoting characteristics and laccase production. PGP traits, that is, IAA (35.53, 45.53, 25.19, and 25.53 µg mL-1), HCN (19.85, 17.85, 12.18, and 9.85 µg mL-1), and ammonium (14.73, 16.73, 8.05, and 10.87 µg mL-1) production, and potassium (49.53, 66.72, 46.14, and 52.72 µg mL-1), phosphate (52.37, 63.89, 33.33, and 71.89 µg mL-1), and zinc (29.75, 49.75, 49.12, and 57.75 µg mL-1) solubilization tests were positive for microbial strains T7, M2, M6, and TF1, respectively. The laccase activity by ERM C-1 was estimated as 37.53, 57.16, and 87.57 enzyme U mL-1 after 5, 10, and 15 days of incubation, respectively. Chlorpyrifos degradation was associated with ERM C-1 and laccase activity, and the degree of enzyme activity was higher in the consortium than in individual strains. The biodegradation study with developed consortium ERM C-1 showed a decreased chlorpyrifos concentration from the 7th day of incubation (65.77% degradation) followed by complete disappearance (100% degradation) after the 30th day of incubation in the MS medium. First-order degradation kinetics with a linear model revealed a high k -day value and low t 1/2 value in ERM C-1. The results of HPLC and GC-MS analysis proved that consortium ERM C-1 was capable of completely removing chlorpyrifos by co-metabolism mechanism.

Synthesis of a Pyridone-Based Phthalimide Fleximer and Its Characterization and Supramolecular Property Evaluation.

In this study, a novel pyridone-based phthalimide fleximer, that is, ethyl 5-cyano-6-(3-(1,3-dioxoisoindolin-2-yl)propoxy)-4-(3-methoxyphenyl)-2-methylnicotinate, was synthesized, and its structure was established by the single-crystal X-ray diffraction method. The supramolecular self-assembly of the titled compound through noncovalent interactions was then investigated thoroughly. The titled compound crystallized with two symmetry-independent molecules (A and B, Z' = 2). In agreement with experimental observations, our density functional theory calculations also showed that the titled compound has a flexible motif and can occur in various conformations, including molecules A and B. The investigation of the supramolecular framework revealed that the molecules are notably bound by the nonclassical C-H···O and C-H···N hydrogen bonds and C-H···π interactions. Hirshfeld surface analysis was carried out to quantify the various intermolecular interactions. The dual anti-inflammatory activity of the tilted compound was also explored by molecular docking in the active sites of 5-LOX and COX-2 receptors, which revealed good binding affinities of -9.0 and -8.6 kcal/mol, respectively.

Photonics probing of pup brain tissue and molecular-specific nuclear nanostructure alterations due to fetal alcoholism via light scattering/localization approaches.

SIGNIFICANCE: Light is a good probe for studying the nanoscale-level structural or molecular-specific structural properties of brain cells/tissue due to stress, alcohol, or any other abnormalities. Chronic alcoholism during pregnancy, i.e., fetal alcoholism, being teratogenic, results in fetal alcohol syndrome, and other neurological disorders. Understanding the nano-to-submicron scale spatial structural properties of pup brain cells/tissues using light/photonic probes could provide a plethora of information in understanding the effects of fetal alcoholism. AIM: Using both light scattering and light localization techniques to probe alterations in nano- to-submicron scale mass density or refractive index fluctuations in brain cells/tissues of mice pups, exposed to fetal alcoholism. APPROACH: We use the mesoscopic physics-based dual spectroscopic imaging techniques, partial wave spectroscopy (PWS) and molecular-specific inverse participation ratio (IPR) using confocal imaging, to quantify structural alterations in brain tissues and chromatin/histone in brain cells, respectively, in 60 days postnatal mice pup brain, exposed to fetal alcoholism. RESULTS: The finer focusing PWS analysis on tissues shows an increase in the degree of structural disorder strength in the pup brain tissues. Furthermore, results of the molecular-specific light localization IPR technique show an increase in the degree of spatial molecular mass density structural disorder in DNA and a decrease in the degree in histone. CONCLUSIONS: In particular, we characterize the spatial pup brain structures from the molecular to tissue levels and address the plausible reasons for such as mass density fluctuations in fetal alcoholism.

TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response.

Intestinal epithelial tight junction disruption is a primary contributing factor in alcohol-associated endotoxemia, systemic inflammation, and multiple organ damage. Ethanol and acetaldehyde disrupt tight junctions by elevating intracellular Ca2+. Here we identify TRPV6, a Ca2+-permeable channel, as responsible for alcohol-induced elevation of intracellular Ca2+, intestinal barrier dysfunction, and systemic inflammation. Ethanol and acetaldehyde elicit TRPV6 ionic currents in Caco-2 cells. Studies in Caco-2 cell monolayers and mouse intestinal organoids show that TRPV6 deficiency or inhibition attenuates ethanol- and acetaldehyde-induced Ca2+ influx, tight junction disruption, and barrier dysfunction. Moreover, Trpv6-/- mice are resistant to alcohol-induced intestinal barrier dysfunction. Photoaffinity labeling of 3-azibutanol identifies a histidine as a potential alcohol-binding site in TRPV6. The substitution of this histidine, and a nearby arginine, reduces ethanol-activated currents. Our findings reveal that TRPV6 is required for alcohol-induced gut barrier dysfunction and inflammation. Molecules that decrease TRPV6 function have the potential to attenuate alcohol-associated tissue injury.

Emerging technologies for PFOS/PFOA degradation and removal: A review.

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are highly recalcitrant anthropogenic chemicals that are ubiquitously present in the environment and are harmful to humans. Typical water and wastewater treatment processes (coagulation, flocculation, sedimentation, and filtration) are proven to be largely ineffective, while adsorption with granular activated carbon (GAC) has been the chief option to capture them from aqueous sources followed by incineration. However, this process is time-consuming, and produces additional solid waste and air pollution. Treatment methods for PFOS and PFOA generally follow two routes: (1) removal from source and reduce the risk; (2) degradation. Emerging technologies focusing on degradation are critically reviewed in this contribution. Various processes such as bioremediation, electrocoagulation, foam fractionation, sonolysis, photocatalysis, mechanochemical, electrochemical degradation, beams of electron and plasma have been developed and studied in the past decade to address PFAS crisis. The underlying mechanisms of these PFAS degradation methods have been categorized. Two main challenges have been identified, namely complexity in large scale operation and the release of toxic byproducts. Based on the literature survey, we have provided a strength-weakness-opportunity-threat (SWOT) analysis and quantitative rating on their efficiency, environmental impact and technology readiness.

Biochar sorption of perfluoroalkyl substances (PFASs) in aqueous film-forming foams-impacted groundwater: Effects of PFASs properties and groundwater chemistry.

The widespread use of per- and polyfluoroalkyl substances (PFASs)-related products such as aqueous film-forming foams (AFFF) has led to increasing contamination of groundwater systems. The concentration of PFASs in AFFF-impacted groundwater can be several orders of magnitude higher than the drinking water standard. There is a need for a sustainable and effective sorbent to remove PFASs from groundwater. This work aims to investigate the sorption of PFASs in groundwater by biochar column. The specific objectives are to understand the influences of PFASs properties and groundwater chemistry to PFASs sorption by biochar. The PFASs-spiked Milli-Q water (including 19 PFASs) and four aqueous film-forming foams (AFFF)-impacted groundwater were used. The partitioning coefficients (log Kd) of long chain PFASs ranged from 0.77 to 4.63 while for short chain PFASs they remained below 0.68. For long chain PFASs (C ≥ 7), log Kd increased by 0.5 and 0.8 for each CF2 moiety of PFCAs and PFSAs, respectively. Dissolved organic matter (DOM) was the most influential factor in PFASs sorption over pH, salinity, and specific ultraviolet absorbance (SUVA). DOM contained hydrophobic compounds and metal ions which can form DOM-PFASs complexes to provide more sorption sites for PFASs. The finding is useful for executing PFASs remediation by biochar filtration column, especially legacy long chain PFASs, for groundwater remediation.