Search Results (438)

The ATP-binding cassette (ABC) transporter family is one of the oldest conserved protein families and is widely present in animal and plant cells. However, few studies have investigated the role of ABC in the forest musk deer (FMD; Moschus berezovskii). In this study, we employed bioinformatics methods to identify and analyze the ABC transporter genes in M. berezovskii to elucidate the potential function of ABC genes in musk secretion. A total of 51 members of the MbABC gene family were identified. The analysis encompassed various aspects including physical and chemical properties, phylogenetic tree, structure prediction, conserved motifs, gene structures, chromosome localization, collinearity analysis, and KEGG and GO enrichment. Collinearity analysis revealed that the ABC transporter gene family is conserved in FMD, Cervidae, and five Bovinae species. MbABCB6, MbABCD4, MbABCF3, and MbABCG5 are key genes in protein–protein interaction networks, which are primarily involved in the transport of vitamins, lipids, and proteins. Tissue expression analysis showed that MbABCs were expressed at different stages. The RT-qPCR analysis revealed that 12 MbABC genes were up-regulated in musk gland cells during the non-secretion phase and stimulation phase, particularly MbABCC4d and MbABCC3. This study provides comprehensive information on the ABC gene family in FMD which can be further used for their functional validation. Full article

Multidrug resistance (MDR) remains a major obstacle in the treatment of ovarian cancer. MDR is often mediated by the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). In this study, we evaluated the ability of elacridar, a dual P-gp and BCRP inhibitor, to overcome MDR in W1, an ovarian cancer cell line sensitive to Paclitaxel (PAC) and its PAC-resistant variants. Cells were cultured under both two-dimensional (2D) and three-dimensional (3D) conditions to account for differences in tumor-like microenvironments. The MDR1 gene and P-gp protein expression were determined for the analyzed model; P-gp activity was measured by flow-cytometry and fluorescent observation, with and without elacridar. The MTT tests were carried out to evaluate how elacridar, combined with chemotherapeutics, affects cell viability. Our results demonstrate that elacridar effectively inhibited transporter activity and increased cellular sensitivity to PAC and DOX. The inhibitory effect was observed in both 2D and 3D cultures, although the re-sensitization effect in 3D conditions was less pronounced, reflecting the complexity of tumor-specific resistance mechanisms. These findings highlight elacridar as a promising compound for reversing MDR in ovarian cancer and emphasize the importance of 3D models in preclinical drug evaluation. Further studies in advanced in vitro and in vivo models are required to assess the potential of elacridar better. Full article

The active efflux of drugs by adenosine triphosphate (ATP)-binding cassette (ABC) trans-porters, such as multidrug resistance protein 1 (MDR1/ABCB1), multidrug resistance-associated protein 1 and 2 (MRP1/ABCC1; MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2), is a well-established mechanism contributing to multidrug resistance (MDR). Interestingly, various vitamin A-based molecules have been found to influence the expression or function of these transporters. This work investigated the current evidence on the effects of retinoids, rexinoids, and carotenoids on ABC transporters and their potential to reverse MDR. Several studies indicated that these compounds could inhibit ABC transporter activity at non-toxic concentrations, either by downregulating gene/protein expression or by directly blocking efflux function. These effects were often associated with increased chemosensitivity to several conventional anticancer agents. Overall, the degree of inhibition varied depending on several factors, including compound type and their chemical modification, dose, incubation time, treatment timing, the type of target cells, method of transporter overexpression, and coadministration with other compounds. Although particular attention was paid to elucidating the underlying mechanisms, current knowledge in this area remains limited. Moreover, extensive in vivo and clinical studies validating these findings are still lacking, emphasizing the need for further research to evaluate their translational potential. Full article

Fructophilic lactic acid bacteria (FLAB), Apilactobacillus kunkeei strains AG8 and AG9 were selected in the current study for in-depth analysis. Cultivation on fructose yeast peptone (FYP) medium with varying fructose concentrations (1%, 10%, and 30%) revealed that higher fructose levels promoted acetate production over lactate, confirming a heterofermentative metabolic profile. Ethanol production was negligible, consistent with the absence of alcohol dehydrogenase (ADH) activity. Enzyme assays showed fructokinase activity doubled at 30% fructose, while acetate kinase activity increased and L-lactate dehydrogenase activity decreased. This shift in enzyme ratios from 1:1 at 1% fructose to 10:1 or 15:1 at higher concentrations explains the metabolic preference for acetate. Apb. kunkeei is an obligate FLAB, growing poorly on glucose unless supplemented with external electron acceptors like pyruvate or oxygen. It lacks ADH, but retains acetaldehyde dehydrogenase (ALDH), enabling acetate production and additional ATP generation, enhancing biomass yield. The absence of the adhE gene contributes to NAD+/NADH imbalance and favors acetate production. Gene expression studies targeting fructose transport enzymes showed elevated expression of ABC transporters and carbohydrate metabolism genes in response to fructose. ADH expression remained low across sugar concentrations. Fructokinase gene expression was shown to be strain specific. Neither strain expressed the ABC transporter ATP-binding protein gene on glucose, nor the bacteriocin ABC transporter gene, correlating with the absence of antibacterial activity. These findings underscore the metabolic specialization of Apb. kunkeei, its reliance on fructose, and the role of ABC transporters in optimizing fermentation. The strain-specific gene expression and metabolic flexibility highlight its potential as a probiotic and feed additive in apiculture and biotechnology. Full article

Simulating carbohydrate digestion in physiologically relevant ways remains a challenge for in vitro models. In this study, the Dynamic In vitro Human Stomach (DIVHS) system was applied to investigate cereal digestion and subsequent intestinal cellular responses. Rice, millet, and corn were digested under dynamic and static conditions. Compared with the static model, the dynamic system generated smaller grain fragments, a larger chyme–enzyme contact area (451.2 ± 4.4 cm² vs. 160.4 ± 6.0 cm²), and higher average intragastric pressure (25.0 ± 1.2 kPa vs. 7.2 ± 0.7 kPa). Salivary amylase activity also declined more gradually in the dynamic system. An empirical approach for predicting the glycemic index (eGI) was proposed, which showed improved agreement with reported human GI values compared with earlier in vitro methods. Exposure of Caco-2 cells to digested products significantly altered transcriptional profiles, including protein binding, ATP binding, and glucose transporter activity. Notably, products from the dynamic model induced stronger transcriptional responses than those from the static model, including 421 genes up-regulated and 138 down-regulated. Functional enrichment highlighted pathways related to glucose transport, energy metabolism, and cellular regulation. Overall, this study demonstrates the advantages of dynamic digestion models in replicating gastrointestinal conditions, improving GI prediction, and providing mechanistic insights into intestinal cellular responses to digested carbohydrates. Full article

A hypercaloric diet is associated with oxidative stress and the dysfunction of ATP-Binding Cassette transporter A1 (ABCA1), a key element in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. Nicotinamide (NAM) presents antioxidant properties, which may contribute to maintaining lipid metabolism. Therefore, we aimed to evaluate the effect of NAM on HDL-cholesterol (HDL-C) level, oxidative stress markers, and the gene expression and protein levels of ABCA1 in Sprague-Dawley rats fed a hypercaloric diet. Forty male rats were divided into five groups: one group received a standard diet, and the remaining groups received a single high-fat, high-fructose diet (HFDF). Three of the HFDF groups received NAM treatment (5, 10, and 15 mM) in drinking water for 16 weeks (5 h/day). While HDL-C and oxidative stress were measured in serum samples, oxidative stress markers, and the gene expression and protein levels of ABCA1 were quantified in liver samples. The HDL-C level altered by the HFDF was improved by treatment with NAM. Furthermore, NAM reduces systemic lipid peroxidation levels and enhances the hepatic antioxidant response affected by the HFDF. In addition, NAM modulates the hepatic ABCA1 gene expression and protein level, altered by the HFDF. Our results suggest that NAM may modify the serum HDL-C level by an improvement of antioxidant response, and a possible modulation of the hepatic ABCA1 gene and protein expression. Further metabolic and molecular studies are needed to support the potential therapeutic role of NAM to prevent or treat lipid alterations promoted by a hypercaloric diet. Full article

The ABCB subfamily, a subset transporter of the ATP-binding cassette (ABC) superfamily, is vital for various plant life processes, especially in the transport of polar auxin and brassinosteroids. Although ABCB transporters have been characterized in diverse plant species, their specific functions in wheat remain largely unexplored. In this study, we identified 99 TaABCB members in wheat and categorized them into four groups based on their conserved domains and phylogenetic relationships. These members were found to be unevenly distributed across all 21 wheat chromosomes. We conducted a comprehensive genome-wide analysis encompassing gene structure, protein motifs, gene duplication events, collinearity, and cis-acting elements. Transcriptome analysis revealed that different TaABCB members displayed distinct expression patterns under phosphate starvation stress. Notably, we discovered that TaABCB7 might play a role in regulating wheat’s phosphate starvation. Crucially, we pinpointed an elite haplotype, H001, of the candidate gene TaABCB7, which has been progressively selected and employed in wheat breeding improvement programs. Overall, this study enhances our comprehensive understanding of TaABCB members and offers a potential gene resource for molecular marker-assisted selection breeding in wheat. Full article

Background/Objectives: Polygoni Cuspidati Rhizoma et Radix (PCRR) is an herb and a source of a resveratrol-containing dietary supplement. Breast cancer resistance protein (BCRP) is an ATP-binding cassette transporter involved in numerous drug-related pharmacokinetic interactions. This study used both in vivo and in vitro models to investigate the modulation effect of PCRR ingestion on BCRP. Methods: Three groups of rats were orally administered methotrexate (MTX), a probe substrate of BCRP, without and with PCRR at 1.0 g/kg and 2.0 g/kg in a parallel design, and the MTX pharmacokinetics were compared among three treatments. The modulation effects of PCRR and its serum metabolites (PCRRM) on BCRP were assayed by in vitro models. Results: PCRR at 1.0 g/kg and 2.0 g/kg significantly decreased the area under the serum level–time curve from 0 to 240 min (AUC_0-240) of MTX by 31% and 58%, respectively; 2.0 g/kg of PCRR markedly increased the area under the serum level–time curve from 240 to 2880 min (AUC_240-2880) and the mean residence time (MRT) of MTX by 39% and 74%, respectively. The results of in vitro assays indicated that PCRR enhanced the function of BCRP by 33~48%; on the contrary, PCRRM reduced the function of BCRP by 200~209%. Conclusions: PCRR activated BCRP, whereas PCRRM inhibited BCRP, thereby the coadministration of PCRR reduced both the absorption and excretion of MTX in rats. In clinical practice, the concurrent use of PCRR with critical BCRP substrate drugs should be avoided. Full article

The inner mitochondrial membrane proteins ATP/ADP carrier protein 1 (AAC1) and Uncoupling protein 1 (UCP1) belong to the SLC25 mitochondrial carrier family. AAC1 is responsible for ATP/ADP exchange, while UCP1-dependent proton transport, which also requires small molecules known as activators, is the basis of brown fat thermogenesis. Arachidonic acid (AA) is an endogenous activator capable of inducing proton transport in both proteins. As such, both AAC1- and UCP1-dependent proton transport are potential targets of weight loss drugs. While AAC1 structures have long been available, only recently have structures of UCP1 been determined. Unfortunately, no AA-bound structure of either protein is available. To explore their interactions with AA, we performed molecular dynamics (MD) simulations of both proteins. Six parallel simulations of each protein were run with an average length of just over 6 μs, for a total of 75 μs of aggregate simulation across both proteins. AA bound deeply between transmembrane helix (TM) helices or in the central cavity of AAC1 in 14 events and between TM helices of UCP1 in 6 events. All AA involved in these deep binding events came from the intermembrane space-facing (C) leaflet. In AAC1, AA most often bound between TM1/TM2 and TM5/TM6. In four cases the fatty acid bound at the bottom of the central cavity rather than in an interhelical groove. In UCP1, all but one deeply bound AA sat between TM5 and TM6. No AA fully entered the cavity as observed in AAC1. In addition to entering the proteins, AAs were enriched around them in the surrounding membrane adjacent to the TM helices. While both protein structures exhibit hydrophobic stretches separating the intermembrane space (IMS) from the matrix, water wires formed through both AAC1 and UCP1, connecting the bulk water in both regions. Grotthuss shuttling along water wires has been proposed as a possible mechanism of AAC1/UCP1-dependent proton transport, but water wires are not present in experimental structures and have not previously been reported in MD simulations. Calculations of electric potentials along these water wires find a large 0.75–1 V electrostatic barrier along water wires through AAC1 and a substantially smaller such barrier of ~0.5 V through UCP1. Full article

To elucidate the molecular mechanisms underlying salt tolerance in rice (Oryza sativa L.), this study investigated differential transcriptional responses during the tillering stage. Salt-tolerant (N14) and salt-sensitive (N6) varieties were subjected to 0.3% and 0.6% NaCl treatments for 72 h, and their transcriptomes were analyzed via RNA-Seq. The results revealed distinct response strategies: 372 differentially expressed genes (DEGs) were identified in N14 and 393 in N6, with only 17 genes responding similarly. Gene Ontology (GO) analysis showed the tolerant N14 activated protein phosphorylation and lipid transport, primarily in the membrane and extracellular regions (e.g., ATP binding), whereas the sensitive N6 activated photosynthesis and protein folding, localized to chloroplasts and peroxisomes. KEGG analysis highlighted the activation of “Plant-pathogen interaction” in N14 versus “Metabolic pathways” in N6. Differential transcription factor activation was also observed, with N14 mobilizing 52 TFs (mainly WRKY and MYB) and N6 mobilizing 36 TFs (mainly MYB and b-ZIP). This study demonstrates that N14 and N6 utilize significantly different molecular pathways to cope with salinity, providing a crucial theoretical foundation for identifying novel salt tolerance genes and developing molecular breeding strategies. Full article

Prosopis cineraria (L.) Druce is a keystone tree species in the arid and semi-arid regions of West and South Asia, with critical ecological, cultural, and conservation significance. In the United Arab Emirates (UAE) and other regions of the Arabian Peninsula, this beneficial tree is called Ghaf. Despite its importance, genomic resources and population-level diversity data for the tree remain limited. Here, we present the first comprehensive population genomics study of Ghaf based on whole-genome resequencing of 204 individual trees collected across the UAE. Following Single-Nucleotide Polymorphism (SNP) discovery and stringent filtering, we analyzed 57,183 high-quality LD-pruned SNPs to assess population structure, diversity, and gene flow. Principal component analysis (PCA), sparse non-negative matrix factorization (sNMF), and discriminant analysis of principal components (DAPC) revealed four well-defined genetic clusters, broadly corresponding to geographic origins. The genetic diversity varied significantly among the groups, with observed heterozygosity (Ho), inbreeding coefficients (F), and nucleotide diversity ($\pi$) showing strong population-specific trends. Genome-wide fixation index F_ST scans identified multiple highly differentiated genomic regions, enriched for genes involved in stress response, transport, and signaling. Functional enrichment using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Pfam annotations indicated overrepresentation of protein kinase activity, ATP binding, and hormone signaling pathways. TreeMix analysis revealed gene flow into one of the genetic clusters from both others, suggesting historical admixture and geographic connectivity. This work provides foundational insights into the population genomic profile of P. cineraria, supporting conservation planning, restoration strategies, and long-term genetic monitoring in arid ecosystems. Full article

Since the first paper published by Susan Cole in 1990 detailing multidrug resistance mediated by ABCC1/MRP1, research into the C-subfamily of ATP-binding cassette transporters has continued to uncover a wide range of functionally divergent proteins. However, several orphan transporters remain in the C-subfamily, and the physiological function and substrates of ABCC5, ABCC11, and ABCC12 remain elusive. This review explores the emerging understanding of human ABCC5. Unlike other ABC transporters with well-defined drug export functions, ABCC5’s physiological roles remain only partially understood. While it is known for its involvement in multidrug resistance in cancers, recent studies suggest broader implications in development, metabolism, neurobiology, and male fertility. ABCC5 exports various endogenous substrates, including cyclic nucleotides (cAMP and cGMP), glutamate conjugates like NAAG, and possibly haem. Knockout models in mice, zebrafish, and sea urchins reveal ABCC5’s role in gut formation, brain function, eye development, and iron metabolism. In mice, its deletion results in lower adipose tissue mass, enhanced insulin sensitivity, and neurobehavioral changes resembling schizophrenia, highlighting its role in glutamatergic signalling and circadian regulation. Functionally, ABCC5 appears to impact adipocyte differentiation and GLP-1 release, implicating it in type 2 diabetes susceptibility in humans. Structural studies using human ABCC5 revealed a novel autoinhibitory mechanism involving a peptide segment (C46–S64) that blocks substrate binding, offering new potential for selective inhibitor development. However, this review emphasises caution in targeting ABCC5 for cancer therapy due to its underappreciated physiological function(s), particularly in the brain and male reproductive system. Understanding ABCC5’s substrate specificity, regulatory mechanisms, and functional redundancy with its paralog ABCC12 remains critical for successful therapeutic strategies in humans. Full article

Epigenetic modifications are long-lasting changes to the genome that influence a cell’s transcriptional potential, thereby altering its function. These modifications can trigger adaptive responses that impact protein expression and various cellular processes, including differentiation and growth. The primary epigenetic mechanisms identified to date include DNA and RNA methylation, histone modifications, and microRNA-mediated regulation of gene expression. The intricate crosstalk among these mechanisms makes epigenetics a compelling field for the development of novel control strategies, particularly through the use of epigenetic drugs targeting arthropod vectors such as ticks. In this study, we identified the Rhipicephalus microplus orthologs of canonical histone-modifying enzymes, along with components of the machinery responsible for m⁵C and ⁶mA-DNA, and m⁶A-RNA methylations. We further characterized their transcriptional profiles and enzymatic activities during embryonic development. To explore the functional consequences of epigenetic regulation in R. microplus, we evaluated the effects of various epigenetic inhibitors on the BME26 tick embryonic cell line. Molecular docking simulations were performed to predict the binding modes of these inhibitors to tick enzymes, followed by in vitro assessment of their effects on cell viability and morphology. Tick cells exposed to these inhibitors presented phenotypic and molecular alterations. Notably, we observed high levels of DNA methylation in the nuclear genome. Importantly, inhibition of DNA methylation using 5′-azacytidine (5′-AZA) was associated with increased activity of the mitochondrial electron transport chain and ATP synthesis but reduced cellular proliferation. Our findings highlight the importance of epigenetic regulation during tick embryogenesis and suggest that targeting these pathways may constitute a novel and promising strategy for tick control. Full article

In this study, we aimed to characterize intramuscular fat (IMF) tissue in fattening steers through a comparison with subcutaneous fat (SCF) tissue. The IMF of the longissimus thoracis et lumborum and the SCF of the back fat from three fattening steers (mean body weight of 703.50 ± 11.45 kg) were collected, and the muscle tissue, connective tissue, and fascia were carefully removed. Gene and protein expressions and the lipid contents were assessed via transcriptomic, proteomic, and lipidomic analyses, respectively. Subsequently, tissue-specific factors were identified using integrated analysis. The results revealed that the expressions of sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 2 (ATP2A2), enolase 3 (ENO3), fructose-bisphosphatase 2 (FBP2), myosin heavy chain 7 (MYH7), myosin light chain 3 (MYL3), myosin light chain kinase (MYLK), glycogen phosphorylase (PYGM), troponin C1 (TNNC1), and tropomyosin 2 (TPM2) significantly increased in IMF at both the mRNA and protein levels, whereas those of fatty acid-binding protein 4 (FABP4), stearoyl-CoA desaturase (SCD), and apolipoprotein E (APOE) were reduced. The abundances of both phosphatidylinositol (PI) (18:1/20:4) and phosphatidylcholine (PC) (15:0/18:2) were positively correlated with APOE. Conversely, that of PI (18:1/20:4) was negatively correlated with ENO3 and PYGM, whereas PC (15:0/18:2) was negatively correlated with TNNC1 and MYLK. In conclusion, we identified calcium signaling and glycolysis as key IMF-regulating pathways. ATP2A2, ENO3, FBP2, MYH7, MYL3, MYLK, PYGM, TNNC1, TPM2, and LPE 18:0 were negatively associated with IMF deposition, whereas FABP4, SCD, APOE, PI (18:1/20:4), and PC (15:0/18:2) were positively associated with it. These findings offer underlying IMF-related targets to promote IMF deposition in cattle. Full article

Histone deacetylase inhibitors (HDACis) induce the expression of multidrug resistance (MDR) pumps and can even display the MDR phenotype in cell lines. This is the first report to include the profiles of ATP-binding cassette (ABC) transporters in intrinsically expressed HeLa cells as well as those acquired due to a 5 mM valproic acid (VPA) treatment. Expression of ABC transporters related to the MDR phenotype was analyzed by RT-PCR in untreated HeLa cells and HeLa cells treated with 5 mM VPA. The ABCB5 protein was identified in HeLa cells by immunocytochemistry. HeLa cell treatment with 5 mM VPA increased ABCB1 expression and triggered the de novo expression of ABCB5 in mRNA and protein. Despite the expression of ABCB5 and the overexpression of ABCB1, VPA reduced the growth rate by 20%, delayed doubling time by 25%, and decreased the number of living cells per well to 50% after 72 h. Pretreatment with VPA for 24 h followed by cotreatment with doxorubicin (DOX) sensitized HeLa cells to DOX. However, for the de novo expression of ABCB5, HeLa cells did not acquire the MDR phenotype from the 5 mM VPA treatment. The ABCB5 isoform induced by VPA treatment probably lacks MDR activity. Full article