Search Results (409)

Familial hypercholesterolemia (FH) is a genetic disorder marked by significantly elevated levels of low-density lipoprotein cholesterol (LDL-C) since childhood, substantially increasing the risk of premature atherosclerosis and cardiovascular disease. While dysfunction of hepatic LDL-C receptors is the main underlying cause, the gastrointestinal tract plays a key role in cholesterol homeostasis and represents an important therapeutic target. Inhibition of intestinal cholesterol absorption has emerged as an effective strategy in the management of pediatric FH, particularly in patients for whom statins may not be the ideal first-line treatment. Ezetimibe, an inhibitor of the Niemann-Pick C1-like 1 (NPC1L1) protein, has been shown to reduce LDL-C levels in children with FH, with a greater efficacy observed when used in combination with statins. Bile acid sequestrants also enhance cholesterol excretion but are often limited by gastrointestinal side effects, while dietary interventions, such as phytosterol supplementation and fiber-enriched diets, provide additional benefits in lowering LDL-C and are generally well tolerated. Emerging therapies, including microbiota-targeted strategies and novel cholesterol absorption inhibitors, show promise for expanding future treatment options. This review explores the mechanisms of intestinal cholesterol absorption and their relevance to pediatric FH. We examine key pathways, including dietary cholesterol uptake through NPC1L1, bile acid reabsorption, and cholesterol efflux mediated by ATP-binding cassette transporters, while also discussing clinical and experimental evidence on pharmacological and dietary interventions that modulate these pathways. A deeper understanding of cholesterol metabolism, the emerging role of the gut microbiota, and innovative therapeutic agents can support the development of more effective and personalized approaches to the treatment of children with FH. Full article

Breast cancer is the most frequently diagnosed cancer among women. In recent years, immunotherapy, a key targeted treatment strategy, has gained prominence in the management of this disease. Immune cells within the tumor microenvironment can significantly affect treatment outcomes. Among immunotherapeutic approaches, or programmed death protein 1(PD-1) and programmed death-ligand 1(PD-L1)-targeted therapies are increasingly recognized for their role in modulating cancer–immune system interactions. This study investigated the impact of PD-1/PD-L1 pathway inhibition on the expression of drug resistance-related proteins in an in vitro breast cancer model incorporating immune cells. MDA-MB-231 and MCF-7 cell lines were used as breast cancer cells, while THP-1 and Jurkat cells represented monocytes and lymphocytes, respectively. The effects of paclitaxel (PTX), doxorubicin (Dox), and PD-1/PD-L1 inhibitors (BMS-1166 and Human PD-L1 Inhibitor IV (PI4)) on cell viability were evaluated using an MTT assay, and the IC₅₀ values were determined. Flow cytometry was used to analyze PD-1/PD-L1 expression and the drug resistance proteins ABCG2 (ATP-binding cassette sub-family G member 2, breast cancer resistance protein), MDR-1 (multidrug resistance protein 1), and MRP-1 (multidrug resistance-associated protein 1) across co-culture models. Based on the results, Dox reduced PD-L1 expression in all groups except for MDA-MB-231:THP-1, while generally lowering drug resistance protein levels, except in MDA-MB-231:Jurkat. BMS-1166 significantly decreased cell viability and enhanced chemotherapy-induced cytotoxicity. Interestingly, in the MDA-MB-231:Jurkat co-culture, both inhibitors reduced PD-L1 but increased drug resistance protein expression. Paclitaxel’s effect on PD-L1 varied depending on the immune context. These findings highlight that PD-1/PD-L1 inhibitors and chemotherapeutic agents differentially affect PD-L1 and drug resistance-related protein expression depending on the immune cell composition within the tumor microenvironment. Full article

The development of resistance to standard cytostatics, such as 5-fluorouracil (5-FU), significantly limits the efficacy of colon cancer therapy, prompting the search for novel anticancer agents, particularly among natural compounds. This study evaluated the anticancer effects of isorhamnetin, a plant-derived flavonol, and its ability to modulate the expression of drug-resistance-related biomarkers in SW-480 and HT-29 colon cancer cells, with a focus on ATP-binding cassette (ABC) transporters. Isorhamnetin demonstrated strong cytotoxic and proapoptotic activity on both cell lines, while showing lower toxicity toward normal HaCaT cells. In addition to suppressing the mRNA expression of drug-metabolizing enzymes (CYP1A1 and CYP1B1), isorhamnetin significantly reduced the mRNA levels of multidrug resistance-associated proteins 1 and 5 (MRP1 and MRP5), as well as the P-glycoprotein (P-gp) level in SW-480 and HT-29 cells. Molecular docking analysis revealed a high binding affinity of isorhamnetin to CYP1A1, CYP1B1, P-gp, MRP1, MRP5, and glutathione S-transferase (GST) proteins, with stronger interactions than those observed for 5-FU, suggesting potential interference with their function. These results provide a solid basis for future investigations to confirm the therapeutic potential of isorhamnetin as a modulator of drug resistance in colon cancer cells. Full article

Background: Tariquidar (Tq) is an inhibitor of the multidrug resistance (MDR) proteins relevant to ATP-binding cassette transporters (ABC transporters), which suppresses the ATP-dependent efflux of a variety of hydrophilic and amphipathic compounds, including anticancer drugs. Tq is a representative of a new generation of MDR inhibitors with high affinity to ABC proteins. However, there are still no data on the possible effect of Tq on mitochondria as an important target in the regulation of cell death or survival. Methods: We investigated the influence of Tq on the Ca²⁺-dependent mitochondrial permeability transition pore (mPTP). The effect of Tq was assessed using several parameters, including the calcium load, membrane potential, and mitochondrial swelling. To evaluate the specific targets of Tq, selective inhibitors of components of the mitochondrial pore were used, including adenine nucleotides, carboxyatractylozide (Catr) and bongkrekic acid (BA), oligomycin, and cyclosporine A. Results: Tq decreased the calcium retention capacity, activated mitochondrial swelling, and lowered the influence of ADP and ATP, the inhibitors of the Ca²⁺-induced pore opening, at their low concentrations. These effects of Tq were observed in both calcium-load and swelling assays, thus mimicking the effect of Catr, a selective inhibitor of adenine nucleotide translocase (ANT). Tq also decreased the protective effect of BA, an inhibitor of ANT and mPTP, on the calcium retention capacity of mitochondria. Further, Tq dose-dependently decreased the inhibitory effect of a low ATP concentration but not of high concentrations, at which the effect of Tq was activated by oligomycin, an inhibitor of F-ATP synthase. Conclusions: The influence of Tq extends to mitochondria, specifically to the regulation of membrane permeability, promoting the activation of pore opening, probably through an interaction with ANT, a component of the pore-forming complex. The effect of Tq on the opening of mPTP is strongly dependent on the concentrations of adenine nucleotides and, consequently, on the functional state of mitochondria. The direct influence of Tq on mitochondria can be considered as a new activity that promotes the sensitization of cells to various treatments and stimuli. Full article

Chemotherapy resistance is a major obstacle in the treatment of ovarian cancer, often resulting in disease recurrence and poor prognosis for patients. A key contributor to this resistance is the overexpression of ATP-binding cassette (ABC) transporters, including breast cancer resistance protein (BCRP/ABCG2), which actively effluxes chemotherapeutic agents such as topotecan (TOP) or mitoxantrone (MIT), limiting their intracellular accumulation and efficacy. This study investigated the potential of elacridar (GG918), a potent dual P-gp and BCRP inhibitor, to overcome drug resistance in ovarian cancer cell lines. Both TOP-sensitive and TOP-resistant ovarian cancer cells were grown in two-dimensional (2D) monolayers and three-dimensional (3D) spheroid models to better mimic the tumor microenvironment. The expression of the ABCG2 gene was quantified via qPCR and BCRP protein levels were assessed by western blotting and immunofluorescence. Drug response was evaluated using MTT viability assays, while BCRP transporter activity was examined using flow cytometry and microscopic assessment of the intracellular retention of BCRP fluorescent substrates (Hoechst 33342 and MIT). In both 2D and 3D cultures, elacridar effectively inhibited BCRP function and significantly enhanced sensitivity to TOP. These findings suggest that elacridar can inhibit BCRP-mediated drug resistance in ovarian cancer cell models. Full article

Paraquat is one of the most widely used nonselective herbicides globally. Although the emergence of weed resistance to paraquat has progressed relatively slowly since the first reported case in Japan in 1980, it has been steadily increasing. Resistance in weedy plants is predominantly associated with non-target-site resistance (NTSR), particularly via reduced uptake and translocation to target sites (i.e., chloroplasts) and/or enhanced sequestration; increased antioxidant capacity is also a common mechanism by which plants cope with various stresses, including reactive oxygen species (ROS). However, direct evidence for paraquat transport mediated by membrane transporters in weeds has not been established. Over the past decade, research, especially in model plants such as Arabidopsis thaliana, has advanced our understanding of the mechanisms underlying plant resistance to paraquat. This brief review summarized recent studies on paraquat resistance, with a particular focus on uptake, translocation, and sequestration mechanisms. For instance, three L-amino acid transporter (LAT) proteins (LAT1/3/4) and one (PDR11) belonging to the PDR (pleiotropic drug resistance) subfamily within the ABC (ATP-binding cassette) transporter family were confirmed to exhibit paraquat transporter activity; furthermore, transporters such as DTX6 (detoxification efflux carrier) can export/sequestrate paraquat inside the cell to the vacuole and apoplast, which confers stronger paraquat resistance to nearly commercial doses. In addition, the evolving perspectives in paraquat resistance research integrating big data and artificial intelligence, development of paraquat-tolerant crops, and a proposal of ryegrass (Lolium. spp.) and/or goosegrass (Eleusine indica) as a model weed species for paraquat resistance studies were also briefly discussed. Further advances in elucidating the molecular mechanisms of paraquat resistance in plants, including weeds, are anticipated. Full article

Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic variations in the ABCB11 (ATP-binding cassette B11) gene encoding the canalicular bile salt export pump (BSEP). Some missense variants identified in patients with PFIC2 do not traffic properly to the canalicular membrane. However, 4-phenybutyrate (4-PB) has been shown in vitro to partially correct the mis-trafficking of selected variants, resulting in an improvement of the medical conditions of corresponding PFIC2 patients. Herein, we report the ability of 4-PB analogous or homologous drugs and of non-4-PB related chemical correctors to rescue the canalicular expression and the activity of the folding-defective Abcb11^R1128C variant. New compounds, either identified by screening a chemical library or designed by structural homology with 4-PB (or its metabolites) and synthesized, were evaluated in vitro for their ability to (i) correct the canalicular localization of Abcb11^R1128C after transfection in hepatocellular polarized cell lines; (ii) restore the ³H-taurocholate transport of the Abcb11^R1128C protein in Madin–Darby canine kidney (MDCK) cells stably co-expressing Abcb11 and the sodium taurocholate co-transporting polypeptide (Ntcp/Slc10A1). Glycerol phenylbutyrate (GPB), phenylacetate (PA, the active metabolite of 4-PB), 3-hydroxy-2-methyl-4-phenylbutyrate (HMPB, a 4-PB metabolite analog chemically synthesized in our laboratory) and 4-oxo-1,2,3,4-tetrahydro-naphthalene-carboxylate (OTNC, from the chemical library screening) significantly increased the proportion of canalicular Abcb11^R1128C protein. GPB, PA, ursodeoxycholic acid (UDCA), alone or in combination with 4-PB, suberoylanilide hydroxamic acid (SAHA), C18, VX-445, and/or VX-661, significantly corrected both the traffic and the activity of Abcb11^R1128C. Such correctors could represent new pharmacological insights for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the transporter’s traffic. Full article

Hyperuricemia (HUA) is a metabolic disease caused by disrupted purine metabolism, characterized by abnormally elevated uric acid (UA) levels. Stachydrine, an alkaloid in natural foods, exhibits multiple biological activities. This study aimed to evaluate the effects of stachydrine on alleviating HUA. An HUA mouse model was established through high-nucleoside diet induction, and stachydrine’s effects on UA levels and renal injury were investigated. Our findings revealed that stachydrine enhanced uric acid excretion by upregulating ATP-binding cassette subfamily G member 2 (ABCG2). Furthermore, stachydrine mitigated HUA-induced renal inflammation, mitochondrial oxidative stress and apoptosis. Mechanistically, stachydrine facilitated the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) by downregulating Kelch-like ECH-associated protein 1 (Keap1), subsequently activating the Keap1/Nrf2 signaling pathway and alleviating local oxidative stress. This study demonstrated the UA-lowering and renoprotective effects of stachydrine, suggesting its potential as a functional food ingredient for mitigating HUA. Full article

Searching for new anticancer drugs is a significant challenge for the medical community due to the current limitations of existing treatments. The primary objective of this study was to design and optimize multi-targeted drug candidates based on a quinoline scaffold. In this paper, we adopt various in silico techniques, including molecular docking, molecular dynamics simulations, and ADMET property modeling, to predict the binding affinity and interactions of 7-ethyl-10-hydroxycamptothecin derivatives with multiple biological targets. The interactions of these compounds with three potential molecular targets, topoisomerase I, bromodomain-containing protein 4, and ATP-binding cassette sub-family G member 2 proteins, were analyzed. It has been previously proved that the inhibition of these molecular targets may have beneficial effects on cancer treatment. The designed chemical compounds can effectively interact with selected proteins, thereby establishing their potential as drug candidates. Molecular docking revealed promising binding affinities, with topoisomerase I docking scores ranging from −9.0 to −10.3 kcal/mol, BRD4 scores from −6.6 to −8.0 kcal/mol, and ABCG2 scores from −8.0 to −10.0 kcal/mol. Furthermore, the ADMET property analysis indicates promising pharmacological profiles, protein binding affinity, selectivity, and bioavailability while minimizing toxicity. For example, satisfactory logP values have been demonstrated in the favorable range for bioavailability after oral administration. Additionally, several compounds exhibited predicted aqueous solubility values greater than −3, suggesting moderate-to-good solubility, which is crucial for oral drug delivery. Full article

Background: Hyperuricemia is a prevalent metabolic disorder characterized by elevated serum uric acid (UA) levels. Methods: In this study, hydrolysate (SPP) derived from silkworm pupae protein was isolated and identified, demonstrating anti-hyperuricemic activity. The research aimed to investigate its anti-hyperuricemic and nephroprotective effects, along with potential mechanisms, through in vitro assays and in vivo experiments using potassium oxonate/hypoxanthine-induced hyperuricemic mice. Results: The SPP exhibited significant xanthine oxidase (XOD) inhibitory activity, with an IC₅₀ value of 7.41 mg/mL. Furthermore, SPP administration effectively reduced serum UA, blood urea nitrogen (BUN), creatinine levels, and renal pro-inflammatory cytokines in hyperuricemic mice. Mechanistic studies revealed that the anti-hyperuricemic effects of SPP may involve XOD inhibition and the modulation of renal UA transporters, specifically upregulating organic anion transporter 1 (OAT1) and ATP-binding cassette subfamily G member 2 (ABCG2) expression. Histopathological analysis and inflammatory cytokine profiling further demonstrated that SPP alleviated renal inflammation and pathological damage. Conclusions: These findings suggest that SPP possesses a notable urate-lowering efficacy and renal protective properties, highlighting its potential as a therapeutic agent for the management and prevention of hyperuricemia (HUA). Full article

Chalcones, potential anticancer agents, have shown promise in the suppression of multidrug resistance due to the inhibition of drug efflux driven by certain adenosine triphosphate (ATP)-binding cassette (ABC) transporters. The gene and protein expression of chosen ABC transporters (multidrug resistance protein 1, ABCB1; multidrug resistance-associated protein 1, ABCC1; and breast cancer resistance protein, ABCG2) in human colorectal cancer cells (COLO 205 and COLO 320, which overexpress active ABCB1) was mainly studied in this work under the influence of a novel synthetic acridine-based chalcone, 1C. While gene expression dropped just at 24 h, compound 1C selectively suppressed colorectal cancer cell growth and greatly lowered ABCB1 protein levels in COLO 320 cells at 24, 48, and 72 h. It also reduced ABCC1 protein levels after 48 h. Molecular docking and ATPase tests show that 1C probably acts as an allosteric modulator of ABCB1. It also lowered galectin-1 (GAL1) expression in COLO 205 cells at 24 h. Functional tests on COLO cells revealed ABCB1 and ABCC1/2 to be major contributors to multidrug resistance in both. Overall, 1C transiently lowered GAL1 in COLO 205 while affecting important functional ABC transporters, mostly ABCB1 and to a lesser extent ABCC1 in COLO 320 cells. COLO 320’s absence of GAL1 expression points to a possible yet unknown interaction between GAL1 and ABCB1. Full article

Background: Multidrug resistance (MDR) in triple-negative breast cancer (TNBC) leads to treatment failure and tumor recurrence. Dysregulation of the MYC oncogene is associated with the pathogenesis of TNBC and the development of chemoresistance via overexpression of ATP-binding cassette (ABC) transporters. Therefore, in the present study, we aimed to identify molecules from a natural product origin that prevent the development of MDR in TNBC by targeting the MYC signaling. Methods: The cell viability of TNBC was evaluated using sulforhodamine assay. Protein levels were detected by western blots or enzyme-linked immunosorbent assays. Intracellular calcein and hoechst33342 accumulation assay aimed to evaluate the inhibitory ability of phytocompounds on drug-efflux functions of ABCB1 and ABCG2 transporters. The Cancer Genome Atlas (TCGA) database was used to explore clinical genomic data. Furthermore, the zebrafish xenotransplantation model bearing Dil-labeled TNBC cells was applied to testify the in vivo effects of phyto-sesquiterpene lactones. Results: The results of the present study demonstrated that the phyto-sesquiterpene lactones exhibited an MDR prevention effect by repressing efflux activities of ABCB1 and ABCG2 transporters. Mechanistic studies showed that phyto-sesquiterpene lactones inducted TNBC cell apoptosis and cell cycle G2/M arrested by blocking the STAT3/MYC pathway. Clinical genomic data demonstrated that the percentages of MYC amplification and mRNA were upregulated approximately two-fold higher in the TNBC patients than the non-TNBC breast cancer patients. The survival of patients with an alteration in MYC was significantly lower in TNBC as compared to other subtypes. Moreover, the results of the zebrafish xenograft model confirmed that phyto-sesquiterpene lactones exerted stronger inhibitory effects on TNBC tumor growth in vivo. Conclusions: In conclusion, these three phyto-sesquiterpene lactones were promising candidates for TNBC treatment and shed light on the prevention of developing MDR TNBC. Full article

The pathogen Alternaria alternata infects a variety of plants and crops, notably poplars, and results in large financial losses. Using twelve chemical fungicides for fungicide sensitivity tests (FSTs) on A. alternata, the result showed that prochloraz (PCZ), mancozeb (MZ), and fludioxonil (FLU) have potent inhibitory effects against the pathogen through different mechanisms. To investigate how the pathogen responded to fungicide-induced stress, transcriptome and physiological investigations were carried out after treatments with three fungicides at their corresponding 50% effective concentration (EC₅₀) doses. The MZ treatment produced a distinct genetic response; FLU treatment produced the greatest number of differentially expressed genes (DEGs), followed by PCZ. DEGs from FLU treatment were mostly engaged in ribosome biosynthesis, those from MZ treatment in lipid and carbohydrate metabolism, and those from PCZ treatment in carbohydrate metabolism, according to Gene Ontology (GO) analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that FLU and PCZ treatments were associated with ribosome biogenesis, whereas MZ treatment was linked to the pyruvate metabolic pathway. Collinear trend analysis indicates that MZ exhibits a unique pattern, with FLU treatment causing the most significant overexpression of genes, followed by PCZ. The six categories of 88 elevated DEGs associated with fungal resistance include tyrosinase, ATP-binding cassette (ABC) transporters, major facilitator superfamily (MFS) transporters, antioxidant and cellular resilience genes, as well as genes involved in cell wall and membrane biosynthesis. Notably, the pathways involved in the synthesis of melanin and ergosterol exhibited the strongest response to FLU. The results of a correlation analysis between physiological indices and resistance-related genes indicated that melanin content, malondialdehyde (MDA) content, and tyrosinase activity were positively correlated with the majority of resistance-related DEGs, whereas soluble protein content, superoxide dismutase (SOD) activity, and catalase (CAT) activity were negatively correlated, which is consistent with the observed trends in the measured physiological indicators. Taken together, this study provides a theoretical basis for developing more effective fungicides and chemical control strategies against A. alternata. Full article

Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder characterized by recurrent fevers and inflammation of the serous membranes in the abdomen, lungs, and joints. Currently, the standard treatment of FMF includes colchicine, which is an alkaloid, derived from Colchicum autumnale. Colchicine’s efficacy in FMF is well-established as it is used both to prevent acute attacks and reduce the risk of long-term complications. However, despite these available treatments, 5–10% of patients exhibit resistance to the drug. It has been demonstrated that polymorphisms in several genes involved in inflammation can influence treatment outcomes and the risk of FMF complications like amyloidosis. Among them, some research focused on polymorphism affecting adenosine triphosphate (ATP)-binding cassette sub-family B member 1 (ABCB1) gene encoding for P-glycoprotein. P-glycoprotein is considered a key transporter protein as it regulates the absorption, distribution, and excretion of several drugs, including colchicine. In diseases like FMF, ABCB1 polymorphisms have been shown to affect the response to colchicine, potentially leading to treatment resistance or altered toxicity. Based on this evidence, this systematic review aims to analyze available evidence on ABCB1-mediated colchicine transport and its clinical implications in FMF, showing how relevant ABCB1 variants are in response to therapy. Full article

The escalating global health crisis of antibiotic resistance, driven by the rapid emergence of multidrug-resistant (MDR) bacterial pathogens, necessitates urgent and innovative countermeasures. This review comprehensively examines the diverse mechanisms employed by bacteria to evade antibiotic action, including alterations in cell membrane permeability, efflux pump overexpression, biofilm formation, target site modifications, and the enzymatic degradation of antibiotics. Specific focus is given to membrane transport systems such as ATP-binding cassette (ABC) transporters, resistance–nodulation–division (RND) efflux pumps, major facilitator superfamily (MFS) transporters, multidrug and toxic compound extrusion (MATE) systems, small multidrug resistance (SMR) families, and proteobacterial antimicrobial compound efflux (PACE) families. Additionally, the review explores the global burden of MDR pathogens and evaluates emerging therapeutic strategies, including quorum quenching (QQ), probiotics, postbiotics, synbiotics, antimicrobial peptides (AMPs), stem cell applications, immunotherapy, antibacterial photodynamic therapy (aPDT), and bacteriophage. Furthermore, this review discusses novel antimicrobial agents, such as animal-venom-derived compounds and nanobiotics, as promising alternatives to conventional antibiotics. The interplay between clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) in bacterial adaptive immunity is analyzed, revealing opportunities for targeted genetic interventions. By synthesizing current advancements and emerging strategies, this review underscores the necessity of interdisciplinary collaboration among biomedical scientists, researchers, and the pharmaceutical industry to drive the development of novel antibacterial agents. Ultimately, this comprehensive analysis provides a roadmap for future research, emphasizing the urgent need for sustainable and cooperative approaches to combat antibiotic resistance and safeguard global health. Full article