ATP-binding Cassette Transporter Research Articles

Molecular Imaging in Cancer Chemoresistance: What's Brewing?

Cancer therapy has advanced with molecularly targeted approaches and immunotherapy, yet chemotherapy remains essential for many aggressive cancers, including breast, lung, ovarian, pancreatic, bladder, sarcoma, and lymphomas. A major challenge is chemoresistance, in which cancer cells evade chemotherapy's cytotoxic effects. Overexpression of adenosine triphosphate-binding cassette transporters, especially P-glycoprotein, significantly contributes to this resistance. Thus, imaging biomarkers are urgently needed to detect P-glycoprotein overexpression invivo, identify resistant cancer cell clones, and map their distribution and heterogeneity within tumors. This article reviews the applications of SPECT, PET, and optical imaging in addressing chemoresistance. It emphasizes the potential of these modalities to enhance cancer treatment by enabling early identification of resistant clones and improving therapeutic strategies. The article outlines key steps required for the integration of molecular imaging into clinical practice, aiming to overcome chemoresistance and optimize patient outcomes.

Metabolism of hemicelluloses by root-associated Bacteroidota species.

Bacteroidota species are enriched in the plant microbiome and provide several beneficial functions for their host, including disease suppression. Determining the mechanisms that enable bacteroidota to colonise plant roots may therefore provide opportunities for enhancing crop production through microbiome engineering. By focusing on nutrient acquisition mechanisms, we discovered Bacteroidota species lack high affinity ATP-binding cassette transporters common in other plant bacteria for capturing simple carbon exudates. Instead, bacteroidota possess TonB-dependent transporters predicted to import glycans produced by plant polysaccharide breakdown. Metatranscriptomics (oat rhizosphere) identified several TonB-dependent transporters genes that were highly expressed in Flavobacterium (phylum Bacteroidota). Using Flavobacterium johnsoniae as the model, we experimentally validated the function of one highly expressed TonB-dependent transporters, identifying a conserved Xyloglucan Utilisation Loci conferring an ability to import xyloglucan, the major hemicellulose secreted from plant roots. Xyloglucan utilisation loci harbour an endoxyloglucanase related to family 5 subfamily 4 subclade 2D glycoside hydrolases carrying a mutation that we demonstrate is required for full activity towards xyloglucan. Based on analysing 700 soil metagenomes, subclade 2D glycoside hydrolases have radiated in soil and are prevalent among plant-associated bacteroidota and certain taxa affiliated with Gammaproteobacteria. In bacteroidota, particularly Flavobacterium species, xyloglucan utilisation loci organisation was highly conserved, which may increase their competitive ability to utilise xyloglucan. Given bacteroidota lack high-affinity nutrient transporters for simple carbon, instead possessing xyloglucan utilisation loci and similar gene clusters, our data suggests hemicellulose exudates provide them with an important carbon source in the rhizosphere.

Fatty Acid ABCG Transporter GhSTR1 Mediates Resistance to Verticillium dahliae and Fusarium oxysporum in Cotton

Verticillium wilt and Fusarium wilt cause significant losses in cotton (Gossypium hirsutum) production and have a significant economic impact. This study determined the functional role of GhSTR1, a member of the ABCG subfamily of ATP-binding cassette (ABC) transporters, that mediates cotton defense responses against various plant pathogens. We identified GhSTR1 as a homolog of STR1 from Medicago truncatula and highlighted its evolutionary conservation and potential role in plant defense mechanisms. Expression profiling revealed that GhSTR1 displays tissue-specific and spatiotemporal dynamics under stress conditions caused by Verticillium dahliae and Fusarium oxysporum. Functional validation using virus-induced gene silencing (VIGS) showed that silencing GhSTR1 improved disease resistance, resulting in milder symptoms, less vascular browning, and reduced fungal growth. Furthermore, the AtSTR1 loss-of-function mutant in Arabidopsis thaliana exhibited similar resistance phenotypes, highlighting the conserved regulatory role of STR1 in pathogen defense. In addition to its role in disease resistance, the mutation of AtSTR1 in Arabidopsis also enhanced the vegetative and reproductive growth of the plant, including increased root length, rosette leaf number, and plant height without compromising drought tolerance. These findings suggest that GhSTR1 mediates a trade-off between defense and growth, offering a potential target for optimizing both traits for crop improvement. This study identifies GhSTR1 as a key regulator of plant–pathogen interactions and growth dynamics, providing a foundation for developing durable strategies to enhance cotton’s resistance and yield under biotic and abiotic stress conditions.

Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD

BackgroundCellular senescence, a hallmark of aging, has been implicated in Alzheimer’s disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis, and its expression and trafficking are altered in APOE4 and AD models. However, the role of ABCA1 trafficking in cellular senescence associated with APOE4 and AD remains unclear.MethodsWe examined the association between cellular senescence and ABCA1 expression in human postmortem brain samples using transcriptomic, histological, and biochemical analyses. Unbiased proteomic screening was performed to identify the proteins that mediate cellular ABCA1 trafficking. We created ABCA1 knock out cell lines and mouse models to validate the role of ABCA1 in cholesterol-induced mTORC1 activation and senescence. Additionally, we used APOE4-TR mice and induced pluripotent stem cell (iPSC) models to explore cholesterol-ABCA1-senescence pathways.ResultsTranscriptomic profiling of the human dorsolateral prefrontal cortex from the Religious Order Study/Memory Aging Project (ROSMAP) cohort revealed the upregulation of cellular senescence transcriptome signatures in AD, which correlated with ABCA1 expression and oxysterol levels. Immunofluorescence and immunoblotting analyses confirmed increased lipofuscin-stained lipids and ABCA1 expression in AD brains and an association with mTOR phosphorylation. Discovery proteomics identified caveolin-1, a sensor of cellular cholesterol accumulation, as a key promoter of ABCA1 endolysosomal trafficking. Greater caveolin-1 expression was observed in APOE4-TR mouse models and AD human brains. Oxysterol induced mTORC1 activation and senescence were regulated by ABCA1 lysosomal trapping. Treatment of APOE4-TR mice with cyclodextrin reduced brain oxysterol levels, ABCA1 lysosome trapping, mTORC1 activation, and attenuated senescence and neuroinflammation markers. In human iPSC-derived astrocytes, the reduction of cholesterol by cyclodextrin attenuated inflammatory responses.ConclusionsOxysterol accumulation in APOE4 and AD induced ABCA1 and caveolin-1 expression, contributing to lysosomal dysfunction and increased cellular senescence markers. This study provides novel insights into how cholesterol metabolism accelerates features of brain cellular senescence pathway and identifies therapeutic targets to mitigate these processes.

Integration of transcriptomics and metabolomics reveals the mechanism of enrofloxacin resistance in Aeromonas schubertii.

Aeromonas schubertii infections has caused severe economic losses in aquaculture in China. In this study, we first induced enrofloxacin (ENR) resistance in A. schubertii strains and then analyzed the mechanisms of drug resistance using transcriptomics and metabolomics. We found that the minimal inhibitory concentration (MIC) was 0.03125 μg/mL for the sensitive strain (WL23S) and 32 μg/mL for the resistant strain (WL23R), which is a 1,024-fold increase. After 40 serial passages, the WL23R strain maintained a MIC of 32 μg/mL, even in the absence of ENR-induced stress. Notably, it had also developed resistance to several other antibiotics, such as neomycin sulfate and flumequine. There was no significant difference in the growth rates of the two strains, highlighting the strong adaptability and growth characteristics of the WL23R strain. Comparison of the transcriptome data between the WL23R and WL23S strains identified 579 differentially expressed genes. Expression of the efflux pump-related genes (e.g., acrA, acrB, pstB, pstC, pstS) was significantly upregulated in the WL23R strain (P < 0.05). The highest enrichment of differential genes in the Gene Ontology analysis was in the catabolism of various amino acids, and that in the Kyoto Encyclopedia of Genes and Genomes pathway was in ATP-binding cassette (ABC) transport. Comparison of the metabolomics data between the WL23R and WL23S strains revealed 1, 059 differentially expressed metabolites. Metabolomics analysis revealed the impact of drug resistance on the levels of amino acids, the activity of amino acid biosynthesis/metabolism pathways, and the ABC transport protein pathway, which confirmed the transcriptomics results. The joint analysis results showed that ABC transporters were most prominent in the shared pathways between enriched differentially expressed genes and metabolites. To further validate the resistance mechanism of A. schubertii, we exposed the WL23R strain to the efflux pump inhibitor carbonyl cyanide 3-chlorophenylhydrazone. The minimal inhibitory concentration of the induced resistant strain decreased by 4-fold after the addition of the inhibitor, indicating the overexpression of active efflux pumps in WL23R. Our results indicate that the efflux system and ABC transporters play crucial roles during the development of multidrug resistance in A. schubertii. This study will serve as an important reference for understanding bacterial resistance to quinolones and multidrug resistance in aquatic environments.

Genome-wide identification, phylogeny, evolutionary expansion, and expression analyses of ABC gene family in Castanea mollissima under temperature stress.

The ATP-binding cassette (ABC) gene family comprises some of the most critical transporter proteins in plants, playing vital roles in maintaining cellular homeostasis and adapting to environmental changes. While ABC transporters have been extensively characterized in various plant species, their profile in C. mollissima remains less understood. In this study, 164 ABC genes were identified and characterized within the C. mollissima genome, and subsequently classified into eight subfamilies. Collinear analysis suggested that dispersed duplication was the primary mechanism driving the expansion of the CmABC gene family. The study also examined morphological and physiological changes in C. mollissima under temperature stress, highlighting significant decreases in photosynthetic indicators and SOD enzyme activity, while other indicators varied. Transcriptome analysis revealed distinct expression patterns of various CmABC genes under temperature stress, identifying CmABCG29c and CmABCB11e as key candidates for responding to temperature stress. This was based on their expression patterns, correlation with physiological indicators, and WGCNA analysis. The expression levels of CmABC genes measured in RT-qPCR experiments were consistent with those observed in RNA-seq analysis. This research provides a theoretical foundation for understanding the physiological and gene expression responses of C. mollissima to temperature stress.

Vodobatinib overcomes cancer multidrug resistance by attenuating the drug efflux function of ABCB1 and ABCG2.

Multidrug resistance (MDR) remains a significant obstacle in cancer treatment, primarily attributable to the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2 within cancer cells. These transporters actively diminish the effectiveness of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux, thereby reducing intracellular drug accumulation. Given the absence of approved treatments for multidrug-resistant cancers and the established benefits of combining tyrosine kinase inhibitors (TKIs) with conventional anticancer drugs, we investigate the potential of vodobatinib, a potent c-Abl TKI presently in clinical trials, to restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells overexpressing ABCB1 and ABCG2. Results indicate that vodobatinib, administered at sub-toxic concentrations, effectively restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. Moreover, vodobatinib enhances drug-induced apoptosis in these cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, while maintaining their expression levels. Moreover, we found that while vodobatinib enhances the ATPase activity of ABCB1 and ABCG2, the overexpression of these transporters does not induce resistance to vodobatinib. These results strongly suggest that increased levels of ABCB1 or ABCG2 are unlikely to play a significant role in the development of resistance to vodobatinib in cancer patients. Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach.

Characterization of a Topramezone-Resistant Rice Mutant TZR1: Insights into GST-Mediated Detoxification and Antioxidant Responses

Mutagenesis breeding, combined with the application of corresponding herbicides to develop herbicide-resistant rice germplasm, provides great promise for the management of weeds and weedy rice. In this study, a topramezone-resistant rice mutant, TZR1, was developed from the indica rice line Chuangyu 9H (CY9H) through radiation mutagenesis and topramezone selection. Dose–response curves revealed that the resistance index of TZR1 to topramezone was 1.94-fold compared to that of CY9H. The resistance mechanism of TZR1 was not due to target-site resistance. This resistance could be reversed by a specific inhibitor of glutathione S-transferase (GST). The activity of antioxidant enzymes was analyzed. SNPs and Indels were detected using whole-genome resequencing; differentially expressed genes were identified through RNA sequencing. Then, they underwent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Key candidate genes associated with topramezone resistance were validated via a real-time quantitative PCR assay. Five GST genes, two UDP-glycosyltransferase genes, and three ATP-binding cassette transporter genes were identified as potential contributors to topramezone detoxification in TZR1. Overall, these findings suggest that GST enzymes possibly play an important role in TZR1 resistance to topramezone. This study will provide valuable information for the scientific application of 4-hydroxyphenylpyruvate dioxygenase inhibitors in paddy fields in future.

Aging Reduces ATP-Binding Cassette Transporter Expression in Brain Microvessels of Mice

Background: ATP-binding cassette (ABC) transporters are expressed in the vascular walls of brain capillaries and remove toxic chemicals from the brain. The expression of ABC transporters in peripheral organs is transcriptionally regulated by clock genes and exhibits 24 h periodic fluctuations. In addition, clock gene outputs diminish with aging. In this study, we evaluated whether the expression of ABC transporters in the blood–brain barrier (BBB) of young mice had a 24 h cycle, and whether the expression of ABC transporters in the BBB decreased with age. Methods: Brain microvascular (BMV) fractions from the cerebral cortex of male C57BL/6J mice were prepared using dextran. BMV fractions from young mice (12 weeks old) were prepared every four hours to evaluate 24 h rhythmicity. BMV fractions from both young and aged mice (85 weeks old) were prepared when protein expression peaked (Zeitgeber Time 5). Protein and mRNA expression of ABC transporters in BMV fractions were measured. Results: In young mice, protein expression of P-glycoprotein, breast cancer resistance protein, and multidrug resistance protein 4 showed time-dependent variations with a peak in the light phase (Zeitgeber Time 5); mRNA expression showed no time-dependent variation. The protein expression of these transporters was lower in the BBB of aged mice than in that of young mice, although mRNA expression did not differ between young and aged mice. Conclusions: ABC transporter protein expression levels in BMV endothelial cells decreased with aging; however, mRNA levels did not change, which suggests changes in protein expression did not result from diminished clock gene output. Further studies are needed to elucidate the mechanisms by which ABC transporter expression in the BBB decreases with aging.

Blocking constitutive autophagy rescues the loss of acquired heat resistance in Arabidopsis fes1a.

High temperature is one of several major abiotic stresses that can cause substantial loss of crop yields. Heat shock proteins (HSPs) are key components of heat stress resistance. Mutation of FES1A, an auxiliary molecular chaperone of HSP70, leads to defective acquired thermotolerance. Autophagy is a positive regulator of basal thermotolerance and a negative regulator of heat stress memory, but its function in acquired thermotolerance is unclear. We found that blocking constitutive autophagy rescued the heat sensitivity of fes1a in Arabidopsis thaliana. Immunoblot and proteomic analyses showed that the rescue was not due to increased HSP levels. Instead, proteomic analysis and confocal microscopy studies revealed that knocking out the core autophagy-related (ATG) genes leads to accumulation of peroxisomes, thus upregulating the metabolic pathways within the peroxisomes. Accumulation of peroxisomes promotes both reactive oxygen species scavenging and indole-3-acetic acid (IAA) production in atg7 fes1a. Overexpression of ABCD1/PXA1/CTS, a peroxisomal ATP-binding cassette transporter, in atg7 fes1a leads to abnormal peroxisomal function and subsequently thermosensitivity. Moreover, we found that exogenous application of indole-3-butyric acid, IAA or naphthalene-1-acetic acid rescued fes1a heat sensitivity. We propose that autophagy is detrimental to the survival of the fes1a mutant, which has acquired thermosensitivity.

ABC-type salt tolerance transporter genes are abundant and mutually shared among the microorganisms of the hypersaline Sambhar Lake.

To fish-out novel salt-tolerance genes, metagenomic DNA of moderately saline sediments of India's largest hypersaline Sambhar Lake was cloned in fosmid. Two functionally-picked clones helped the Escherichia coli host to tolerate 0.6M NaCl. Deep sequencing of their fosmid DNA insert revealed 32-37% of genes to encode transporters, mostly belonging to ABC (ATP-Binding Cassette)-type, but none specific to channelNa+. The complete metagenome sequence of Sambhar Lake brines, and reanalysed data of twelve other hypersaline metagenomesequences, however, have only around 5% transporter genes, suggesting metagenomic DNAfragments being biasedly-cloned during functional screening. Almost half of the ~ 40Kb inserts in the two clones was shared, and encode several transporters, and some transposase. This advocates that these transporter-loaded DNA lengths are shuttled among microorganisms of hypersaline environments. Interestingly, one clone showed retarded growth with prominent cell disruptions in scanning electron microscopic images, when fosmid copy number was increased or transporters were NaCl-induced. Its cloned insert exclusively has three genes, encoding a structurally functional ATP-binding protein and its efflux component, whose possible overexpression led to membrane crowding and cell rupture. Thus, microorganisms thriving in hypersaline lakes have plentiful ABC transporters that are mutually shared among themselves. These novel salt tolerance genes have future agricultural biotechnological potential.

The ABC transporter A7 modulates neuroinflammation via NLRP3 inflammasome in Alzheimer’s disease mice

BackgroundSpecific genetic variants in the ATP-binding cassette transporter A7 locus (ABCA7) are associated with an increased risk of Alzheimer’s disease (AD). ABCA7 transports lipids from/across cell membranes, regulates Aβ peptide processing and clearance, and modulates microglial and T-cell functions to maintain immune homeostasis in the brain. During AD pathogenesis, neuroinflammation is one of the key mechanisms involved. Therefore, we wanted to investigate the specific role of ABCA7 in microglial activation via the NLRP3 inflammasome.MethodsWe developed the first humanized, Cre-inducible ABCA7flx knock-in mouse model, crossbred it with the APPPS1-21 β-amyloidosis model, and generated constitutive ABCA7ko and microglia Cx3cr1-specific conditional ABCA7ko AD mice. The role of ABCA7 was analyzed using histological, biochemical, molecular and mass spectrometry methods.ResultsConstitutive knockout of the Abca7 gene in APPPS1 mice increased the levels of Aβ42 and the number of IBA1+ (microglia) and GFAP+ (astrocytes) cells. Changes in the levels of astrocytes and microglia are associated with the activation of the NLRP3 inflammasome and increased levels of proinflammatory cytokines, such as IL1β and TNFα. Interestingly, microglia-specific ABCA7ko restored Aβ42 peptide levels and IBA1+ and GFAP+ and NLRP3-related gene expression to the original APPPS1 mouse levels. In primary glial cell cultures of APPPS1-hA7ko microglia and APPPS1 astrocytes from newborn pups, we observed that conditioned media from LPS-stimulated microglia was able to induce NLRP3 inflammasome expression and proinflammatory cytokine release in astrocytes.ConclusionsOur data suggest that ABCA7 transporters regulate the communication between microglia and astrocytes through the NLRP3 inflammasome and the release of proinflammatory cytokines. This regulation implicates ABCA7 as a key driver ultimately involved in the persistence of the inflammatory response observed in AD.

Genomic analyses reveal high diversity and rapid evolution of Pichia kudriavzevii within a neonatal intensive care unit in Delhi, India.

Pichia kudriavzevii causes life-threatening infections in immunocompromised hosts, including hospitalized neonates. This pathogen is intrinsically resistant to fluconazole, while uncommon P. kudriavzevii strains resistant to multiple antifungal drugs, including voriconazole, amphotericin B, and echinocandins, have also been reported from healthcare environments. Thus, understanding how P. kudriavzevii spread, persist, and adapt to healthcare settings could help us develop better infection management strategies. In this study, whole genome sequencing identifies multiple outbreaks of bloodstream infections in a single neonatal intensive care unit (NICU) over 5 years caused by genetically diverse strains of P. kudriavzevii. Interestingly, two genetically distinct clusters of P. kudriavzevii strains showed frequent loss of heterozygosity (LOH) events between two temporal samples. The first outbreak cluster (2015-2016) showed LOH at chromosomes 1, 4, and 5, and the other outbreak cluster (2020) exhibited LOH at chromosome 2. The circulation of two separate strain clusters of P. kudriavzevii suggests nosocomial transmission in the NICU in different time periods. Furthermore, we compared the transcriptomic profiles of three isolates of clusters I and II that exhibited distinct fluconazole and itraconazole MICs. While no significant difference in gene expression was found at the azole-target gene ERG11 or the ATP-binding cassette (ABC) transporter genes, such differences were found in genes involved in cell division and filamentation, such as SIR2 (sirtuin deacetylase) and RFA1 (replication factor A). Interestingly, increased filamentation was observed in clade I isolate exhibiting high fluconazole MICs. Together, our study indicates significant diversity, persistence, and rapid evolution of P. kudriavzevii within a single NICU.

3D Bioprinted Multidrug Resistance (MDR)-Dependent Tumor Spheroids.

Multidrug resistance (MDR) refers to the ability of cancer cells to resist various anticancer drugs and release them from the cells. This phenomenon is widely recognized as a significant barrier that must be overcome in chemotherapy. MDR varies depending on the number and expression level of the ATP-binding cassette transporter (ABC transporter), which is expressed differently in various cancer cells. Therefore, the dose of anticancer drugs should be adjusted according to the extent of MDR. The demand for drug screening that considers the differences in MDR is increasing in the process of drug discovery. In this study, three types of tumor spheroids were fabricated from HeLa (MRP1-/BCRP-), HepG2 (MRP1+/BCRP-), and A549 cells (MRP1+/BCRP+) using three-dimensional (3D) bioprinting. The fabricated tumor spheroids maintained their own MDR phenotypes. The EC50 values of doxorubicin (DOX) against the three tumor spheroids were more than 2-fold higher than those against the 2D cells. In addition, the EC50 value of DOX against tumor spheroids was proportional to the number of ABC transporters. The EC50 value of DOX against A549 tumor spheroids had the largest value of 9.5 μM among the three spheroids. In addition, the EC50 values of DOX against HepG2 and A549 tumor spheroids were remarkably reduced when they were treated with ABC transporter inhibitors, such as MK-571 against MRP1 and/or NOV against BCRP. These results demonstrate the successful construction of a 3D bioprinting-based screening platform to quantitatively evaluate the anticancer efficacy of chemodrugs, considering the MDR of cancer cells.

C1GALT1 expression predicts poor survival in osteosarcoma and is crucial for ABCC1 transporter-mediated doxorubicin resistance.

Osteosarcoma is an aggressive bone malignancy with a high propensity for drug resistance and metastasis, leading to poor clinical outcomes. This study investigates the role of core 1 β1,3-galactosyltransferase 1 (C1GALT1) in osteosarcoma, focusing on its implications in chemoresistance. Our findings reveal that high expression of C1GALT1 is associated with advanced stages, adverse overall survival, and increased recurrence rates. Elevated levels of C1GALT1 were observed in doxorubicin-selected osteosarcoma cells, where its suppression significantly promoted doxorubicin-induced apoptosis and reduced drug efflux. Pharmacological inhibition of C1GALT1 using itraconazole replicated these effects, suggesting a potential therapeutic strategy to overcome chemoresistance. Additionally, we identified the involvement of the ATP-binding cassette (ABC) transporter ABCC1 in the drug-resistance phenotype mediated by C1GALT1. C1GALT1-mediated O-glycan changes were found to influence the cell-surface targeting and lysosomal degradation of ABCC1, thereby modulating its efflux capacity. In vitro and in vivo studies confirmed that C1GALT1 impacts ABCC1 expression and function, further supporting its role in osteosarcoma chemoresistance. These results highlight the clinical relevance of C1GALT1 as a biomarker for prognosis and a potential therapeutic target for osteosarcoma. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Pine (Pinus koraiensis) Nut Oil Ameliorates Cholesterol Homeostasis and Inflammation via Modulating the miR-34a/122 Pathways in the Liver of Rats Fed a High-Cholesterol Diet.

Pine (Pinus koraiensis) nut oil (PNO) has been reported to have various beneficial effects on hepatic triglyceride accumulation and atherosclerosis in animal models. MicroRNAs (miRs) are involved in various diseases by modulating physiological processes. However, the mechanism underlying PNO's effects on the regulation of miRs involved in hepatic cholesterol homeostasis and inflammation remains unclear. This study investigated the effects of PNO on the regulation of the miR-34a/122 pathways involved in cholesterol homeostasis and inflammation in the liver using a high-cholesterol diet (HCD) rat model. Six-week-old male Sprague-Dawley rats were randomly divided into three groups (n = 8/group) and provided with (1) a cholesterol-free diet, (2) an HCD containing 1% cholesterol and 0.5% cholic acid, or (3) an HCD containing 5% PNO for 4 weeks. Lipid analysis of serum and liver, histological evaluation, and analysis of gene and protein expression were performed. PNO supplementation in HCD improved hepatic lipid profiles and elevated serum high-density lipoprotein cholesterol compared to the HCD group. PNO significantly upregulated hepatic gene expression levels of liver X receptor α and ATP-binding cassette transporter A1/G1, which are involved in cholesterol efflux (P < 0.05). Gene expressions of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β, monocyte chemoattractant protein-1, and inducible nitric oxide synthase were downregulated by PNO (P < 0.05). PNO also suppressed TNF-α and IL-6 protein levels by 22.3% and 17.3%, respectively (P < 0.05). PNO reduced hepatic nuclear factor-kappa B activity by 16.4% and decreased nitric oxide production in the liver and serum (P < 0.05). Furthermore, hepatic miR-34a and miR-122 expressions decreased by 16.4% and 15.7% by PNO, respectively (P < 0.05). These results suggest that PNO may affect cholesterol homeostasis and inflammation, which are partially associated with the miR-34a/122 pathways in the liver under an HCD.

Two stages of substrate discrimination dictate selectivity in the E. coli MetNI-Q ABC transporter system.

The Escherichia coli MetNI-Q importer, an ATP-binding cassette (ABC) transporter, mediates the uptake of both L- and D-enantiomers of methionine. Original in vivo uptake studies show a strong preference for L-Met over D-Met, but the molecular basis of this selectivity is unclear. In this work, we systematically examine substrate discrimination by the MetNI transporter and MetQ substrate binding protein using an array of biophysical and biochemical techniques. Based on the kinetic and thermodynamic parameters of individual intermediates in the transport cycle, we uncover multiple steps in the transport cycle that confer substrate specificity. As in many other ABC importer systems, selectivity is applied at the level of binding to the substrate binding protein: MetQ dictates a 1,000-fold preference for L-Met over D-Met. However, beyond this initial level of selectivity, MetQ displays distinct binding preferences for the MetNI transporter depending on the substrate. We propose that the differences in binding affinities reflect the more favored release of L-Met into the permeation pathway when compared to D-Met. In support of this model, under saturating conditions, MetNI transports L-Met across the lipid bilayer at a faster rate than D-Met. Interestingly, the ATPase activity of the MetNI-Q complex is not modulated by the presence of substrate. Our studies reveal that the MetNI-Q system incorporates two separate steps in tuning methionine uptake to substrate chirality and availability. This method of discrimination ensures the import of the most biologically preferred substrate while also allowing for adaptability to more limiting nutrient conditions.

A novel micromagnetic carrier-modified integrated fixed-film activated sludge system for simultaneous efficient removal of tetracycline and mitigation of antibiotic resistance genes proliferation and dissemination.

To address the challenge of antibiotic-containing wastewater, a novel micromagnetic carrier-modified integrated fixed-film activated sludge system (MC-IFAS) was developed for treating tetracycline (TC)-containing swine wastewater in this study. The magnetic effects of the MC significantly enhanced TC removal by improving TC biosorption and biodegradation in both the suspended activated sludge and the carrier-attached biofilm in the MC-IFAS. The increased electrostatic attraction and number of binding sites in both the activated sludge and the biofilm enhanced their TC biosorption capacities, particularly in the activated sludge. Additionally, the MC shifted microbial community assembly from stochastic to deterministic factors, amplifying the selection pressure induced by TC on the microbial community, thus enriching organic compound-degrading genera Dokdonella and TM7a; it also stimulated ammonia monooxygenase-mediated and cytochrome P450-mediated TC metabolisms and upregulated functional genes encoding lyases, transferases, hydrolases, and oxidoreductases- all of which enhanced TC biodegradation capacity in the MC-IFAS, particularly in the biofilm. While enhancing TC removal efficiency, the MC mitigated the proliferation and dissemination of antibiotic resistance genes (ARGs) by suppressing the abundances of ARGs hosts, the mobile genetic element intI1, and genes encoding ATP-binding cassette transporters and putative transposases. This study provides novel insights into the large-scale applications of magnetic field-enhanced TC removal strategies.

High levels of sinigrin trigger synthesis of fatty acids in Plutella xylostella (L.).

Diamondback moth (Lepidoptera: Plutellidae; Plutella xylostella L.) is a specialist insect of the Brassicaceae family, damaging economically important crops, such as cabbage and cauliflower. Glucosinolates, also known as 'mustard oil bombs' are present in all Brassicaceae members, of which sinigrin (allyl-glucosinolate or 2-propenyl-glucosinolate) is a major aliphatic compound. During herbivory, glucosinolates are converted to toxic isothiocyanates that deter insect pests. P. xylostella possesses glucosinolate sulfatases that desulfate them. Such a conversion renders them unfit for degradation to toxic products. Changes in the larval performance prompted us for RNA sequencing to understand probable adaptation mechanism under sinigrin stress. Differentially expressed genes were found to be related to larval cuticle proteins. Further, gene ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses depict genes belonging to the categories, integral component of membrane, cellular processes and those involved in biosynthesis of fatty acids. Upregulation of cuticular genes viz. larval cuticle protein-17 (LCP-17), cuticular protein-19 (2CP-19) and ATP binding cassette transporter C7 (ABCC7), ABCC16 was validated by qRT-PCR. Liquid chromatography quadrupole time of flight mass spectrometry analysis of whole larvae feeding on sinigrin and their separated cuticle, depicted abundance of fatty acids. Changes in the topography of the larval cuticle were evident by scanning electron microscopy. Expression of PxABCH1 was corroborated to its role in the transport of cuticular lipids. Notably, molecular docking of PxABCH1 with cuticular fatty acids showed favorable binding interactions. To summarize, integrated transcriptomic and metabolomic analyses suggest that in response to a diet containing a high dose of sinigrin, P. xylostella re-programs metabolic pathways related to fatty acid biosynthesis that directly influence insect development.

Genetic Structure of Hereditary Forms of Diabetes Mellitus in Russia.

Analyzing the genetic architecture of hereditary forms of diabetes in different populations is a critical step toward optimizing diagnostic and preventive algorithms. This requires consideration of regional and population-specific characteristics, including the spectrum and frequency of pathogenic variants in targeted genes. As part of this study, we used a custom-designed NGS panel to screen for mutations in 28 genes associated with the pathogenesis of hereditary diabetes mellitus in 506 unrelated patients from Russia. The study identified 180 pathogenic or likely pathogenic variants across 13 genes (GCK, HNF1A, HNF1B, HNF4A, ABCC8, INS, INSR, KCNJ11, PAX4, PDX1, ZFP57, BLK, WFS1), representing 46.44% of the analyzed cohort (235 individuals). The glucokinase gene (GCK) had the highest number of identified variants, with 111 variants detected in 161 patients, 20 of which were identified for the first time. In the tissue-specific transcription factor genes HNF1A, HNF4A, and HNF1B, 34 variants were found in 38 patients, including 13 that were previously unreported. Seventeen variants were identified in the ABCC8 gene, which encodes the ATP-binding cassette transporter 8 of subfamily C, each found in a different patient; four of these were novel discoveries. Nine pathogenic or likely pathogenic variants were identified in the insulin gene (INS) and its receptor gene (INSR), including four previously unreported variants. Additionally, we identified 10 previously unreported variants in six other genes among 11 patients. Variants in the genes GCK, HNF1A, HNF1B, HNF4A, ABCC8, INS, and INSR were the main contributors to the genetic pathogenesis of hereditary diabetes mellitus in the Russian cohort. These findings enhance our understanding of the molecular mechanisms underlying the disease and provide a solid basis for future studies aimed at improving diagnostic accuracy and advancing personalized therapeutic strategies. This knowledge provides a foundation for developing region-specific genetic testing algorithms and personalized therapeutic strategies, which are critical for future initiatives in precision medicine.