Search Results (194)

The blood–brain barrier (BBB) is a highly selective interface between the bloodstream and the brain that prevents systemically administered therapeutics from effectively reaching tumor cells. As tumors progress, this barrier undergoes structural and functional alterations, giving rise to the blood–tumor barrier (BTB)—a pathologically modified structure that, despite increased permeability, often exhibits heterogeneous and clinically insufficient drug transport. Although a new generation of therapies is promising, their therapeutic potential cannot be realized unless the challenges posed by these barriers are effectively addressed. Various pharmacological strategies were explored to enhance brain tumor drug delivery. These include receptor-mediated disruption, inhibition of efflux transporters, and the engineering of delivery platforms that leverage endogenous transport pathways—such as carrier-mediated, adsorptive-mediated, and receptor-mediated mechanisms—as well as cell-mediated drug delivery. This review synthesizes (1) the BBB and BTB’s structural characteristics; (2) the influence of the tumor microenvironment (TME) on drug delivery; (3) pharmacological strategies to enhance drug accumulation within brain tumors; (4) the integration of pharmacological methods with neurosurgical techniques to enhance drug delivery. As efforts to improve drug delivery across the BBB and BTB accelerate, this review aims to map the current landscape of pharmacological approaches for enhancing drug penetration into brain tumors. Full article

Highly efficient photocatalysts for solar energy conversion require effective charge carrier separation and rapid interfacial transport kinetics to maximize electron availability. Two-dimensional Ti₃CNT_x, a novel conductive material in the MXene family with exceptional electrical conductivity, has emerged as an ideal electron transfer mediator due to its large specific surface area and abundant active terminal groups. In this work, we strategically integrated the 2D multi-metal sulfide Cu-Zn-In-S (CZIS) with 2D Ti₃CNT_x nanosheets through physical mixture, constructing a heterostructured 2D/2D CZIS/Ti₃CNT_x composite photocatalyst for the hydrogen evolution reaction. The unique architecture significantly accelerates electron migration from CZIS to Ti₃CNT_x, while synergistically promoting the spatial separation and directional transfer of photogenerated electron–hole pairs (e⁻/h⁺). When the hydrogen evolution reaction is carried out under identical conditions, the hydrogen yield rate is 4.3 mmol g⁻¹ h⁻¹ with pristine CZIS but is improved dramatically to 14.3 mmol g⁻¹ h⁻¹ when the composite containing an adequate amount of 2D Ti₃CNT_x is used. This study offers new insight into the rational design and controllable synthesis of Ti₃CNT_x-based composite photocatalytic systems for efficient photocatalytic hydrogen production. 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

Longer inflorescence stalks in oil palm enhance harvesting efficiency and reduce labor costs. However, the research on this topic is limited. This study aimed to investigate the differences in stalk lengths between male and female inflorescences in Tenera oil palm and to elucidate the underlying hormonal and transcriptomic mechanisms. The stalk lengths from inflorescences associated with the fourth to eighteenth leaf positions of Tenera oil palm trees were measured, and hormone profiling and RNA sequencing (RNA-seq) were conducted in immature (F4 and M5) and mature (F14 and M13) stalks from an individual tree. The male stalks were significantly longer than the female stalks since the thirteenth inflorescences and the differences increased with maturation. The elevated levels of indole-3-acetic acid (IAA) in both immature and mature male stalks suggested auxin’s critical role in promoting stalk elongation. In M13, we identified the upregulated auxin influx carrier LAX2, Gibberellic Acid-Stimulated Arabidopsis 6 (GASA6), and SMALL AUXIN UP RNA (SAUR) genes, indicating enhanced auxin accumulation, signaling, and response. Moreover, the auxin response factor (ARF11) was upregulated, linking auxin transport to gene activation for cell elongation. Conversely, in F14, higher levels of abscisic acid (ABA) and the expression of ABA receptor PYL3 and gibberellin 2-beta-dioxygenase 8 GA2ox8, which may inhibit stalk elongation, were identified. The results suggested that LAX2-mediated IAA accumulation activates ARF11 and SAURs, promoting stalk elongation, with GASA6 possibly acting as a downstream modulator. This study provides insights into the hormonal and genetic regulators of stalk elongation in oil palm and may guide breeding strategies for oil palm varieties with longer stalks of female inflorescences, thereby enhancing harvesting efficiency. Full article

Tumor cell heterogeneity, e.g., in stroma-rich pancreatic ductal adenocarcinoma (PDAC), includes a differential metabolism of lactate. While being secreted as waste product by most cancer cells characterized by the glycolytic Warburg metabolism, it is utilized by a subset of highly malignant cancer cells running the reverse Warburg metabolism. Key drivers of lactate transport are the carrier proteins SLC16A1 (import/export) and SLC16A3 (export). Expression and function of both carriers are controlled by the chaperone Basigin (BSG), which itself is functionally controlled by the transmembrane protease serine 11B (TMPRSS11B). In this study we explored the impact of TMPRSS11B on the phenotype of PDAC cells under reverse Warburg conditions. Amongst a panel of PDAC cell lines, Panc1 and BxPc3 cells were identified to express TMPRSS11B at a high level, whilst other cell lines such as T3M4 did not. ShRNA-mediated TMPRSS11B knock-down in Panc1 and BxPc3 cells enhanced lactate import through SLC16A1, as shown by GFP/iLACCO1 lactate uptake assay, whereas TMPRSS1B overexpression in T3M4 dampened SLC16A1-driven lactate uptake. Moreover, knock-down and overexpression of TMPRSS11B differentially impacted proliferation and chemoresistance under reverse Warburg conditions in Panc1 or BxPc3 and T3M4 cells, respectively, as well as their stemness properties indicated by altered colony formation rates and expression of the stem cell markers Nanog, Sox2, KLF4 and Oct4. These effects of TMPRSS11B depended on both SLC16A1 and BSG as shown by gene silencing. Immunohistochemical analysis revealed a reciprocal expression of TMPRSS11B and BSG together with SLC16A1 in some areas of tumor tissues from PDAC patients. Those regions exhibiting low or no TMPRSS11B expression but concomitant high expression of SLC16A1 and BSG revealed greater amounts of KLF4. In contrast, other tumor areas exhibiting high expression of TMPRSS11B together with BSG and SLC16A1 were largely negative for KLF4 expression. Thus, the differential expression of TMPRSS11B adds to metabolic heterogeneity in PDAC and its absence supports the reverse Warburg metabolism in PDAC cells by the enhancement of BSG-supported lactate uptake through SLC16A1 and subsequent phenotype alterations towards greater stemness. Full article

The blood–brain barrier (BBB) is a highly selective and natural protective membrane that restricts the entry of therapeutic agents into the central nervous system (CNS). This restrictive nature poses a major challenge for pharmacological treatment of a wide range of CNS disorders, including neurodegenerative disorders, brain tumors, and psychiatric conditions. Many chemical drugs and biopharmaceuticals are unable to cross the BBB, and conventional drug delivery methods often fail to achieve sufficient brain concentrations, leading to reduced therapeutic efficacy and increased risk of systemic toxicity. In recent years, targeted drug delivery strategies have emerged as promising approaches to overcome the BBB and enhance the delivery of therapeutic agents to the brain. Among these, receptor-mediated transcytosis (RMT) and transporter-mediated transcytosis (TMT) are two of the most extensively studied mechanisms for transporting drugs across brain endothelial cells into the brain parenchyma. Advances in materials science and nanotechnology have facilitated the development of multifunctional carriers with optimized properties, improving drug targeting, stability, and release profiles within the brain. This review summarizes the physiological structure of the BBB and highlights recent innovations in RMT- and TMT-mediated brain drug delivery systems, emphasizing their potential not only to overcome current challenges in CNS drug development, but also to pave the way for next-generation therapies that enable more precise, effective, and personalized treatment of brain-related diseases. Full article

Hemoglobin-based oxygen carriers (HBOCs) represent a promising alternative to traditional blood transfusions, offering the advantages of extended shelf life and avoiding blood compatibility limitations and infection risks. Positive effects of hemoglobin-based oxygen carriers (HBOCs) on hemorrhagic shock have been researched across various animal species, including swine, rats, rabbits, guinea pigs, and dogs. As previously described, HBOCs based on ovine hemoglobin display better efficiency in the context of hemorrhagic shock compared to those based on the more commonly used bovine hemoglobin. This was evidenced through higher survival rates and more favorable histopathological and immunological outcomes. The vascular effects of ovine hemoglobin polymerized with glutaraldehyde exposure included the absence of hypertension, minimal endothelial damage with slight alterations in inducible nitric oxide synthase (iNOS), and reduced vascular inflammation mediated by interleukin-10 (IL-10). Ovine hemoglobin has emerged as a particularly promising raw material for the development of HBOCs, surpassing bovine and human hemoglobin due to its advantages in availability and efficacy. Furthermore, reducing oxidative stress by polymerizing hemoglobin with glutaraldehyde is most effective with ovine hemoglobin compared to bovine hemoglobin. This study evaluates the effectiveness of ovine hemoglobin polymerized with glutaraldehyde in managing hemorrhagic shock in rabbits, with a focus on its ability to maintain blood pressure, support oxygen transport, and assess potential systemic and oxidative responses. Fifteen adult New Zealand white rabbits, divided into three equal groups, were included in this study: a negative control group transfused with colloid solutions, a positive control group treated with autotransfusion, and a group receiving HBOCs. All groups underwent a hemorrhagic shock protocol, with 40% of their total blood volume withdrawn under deep anesthesia, followed by transfusions 30 min later. Vital parameters, including invasive arterial blood pressure, heart rate, and end-tidal CO₂, were measured throughout the experimental procedures. Arterial blood gas samples were collected before the procedures, after hemorrhagic shock induction, and at the conclusion of the transfusion. In summary, HBOCs offer a promising solution for oxygen delivery, but their effects on blood chemistry, particularly CO₂ and lactate levels, must be considered. Although no direct oxygenation issues were observed in experimental models, elevated CO₂ levels and the interference of HBOCs with lactate measurements emphasize the importance of vigilant clinical monitoring. Polymerized hemoglobin provides a non-nephrotoxic alternative, but challenges persist in preventing nitric oxide scavenging and ensuring effective oxygen delivery. Full article

Engineered exosomes have emerged as transformative drug carriers, uniquely equipped to overcome biological barriers in central nervous system (CNS) disorders and cancer therapy. These natural extracellular vesicles, derived from cell membranes, offer inherent biocompatibility, low immunogenicity, and the ability to traverse physiological obstacles such as the blood–brain barrier (BBB) and dense tumor stroma. Recent advances in exosome engineering—including surface modification (e.g., ligand conjugation for receptor-mediated targeting) and cargo loading (siRNA, CRISPR-Cas systems, and chemotherapeutics)—have enhanced their precision and therapeutic utility. For CNS delivery, exosomes functionalized with brain-homing peptides (e.g., RVG or TfR ligands) have enabled the efficient transport of neuroprotective agents or gene-editing tools to treat Alzheimer’s disease or glioblastoma. In oncology, engineered exosomes loaded with tumor-suppressive miRNAs or immune checkpoint inhibitors exploit tumor microenvironment (TME) features, such as acidity or enzyme overexpression, for spatially controlled drug release. Furthermore, hybrid exosome–liposome systems and exosome–biomaterial composites are being explored to improve payload capacity and stability. Despite progress, challenges persist in scalable production, batch consistency, and regulatory standardization. This review critically evaluates engineering strategies, preclinical success, and translational hurdles while proposing innovations such as AI-driven exosome design and patient-derived exosome platforms for personalized therapy. By bridging nanotechnology and biomedicine, engineered exosomes can represent a paradigm shift in targeted drug delivery, offering safer and more effective solutions for historically intractable diseases. Full article

Solute carrier family 25 member A22 (SLC25A22) is a glutamate transporter in the inner mitochondrial membrane that is known to suppress ferroptosis in pancreatic ductal adenocarcinoma (PDAC). Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase, and we previously demonstrated that targeting SIRT3 sensitized glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11. The purpose of this study was to analyze the effect of SIRT3-mediated deacetylation of mitochondrial SLC25A22 on RAS-selective lethal 3 (RSL3)-induced ferroptosis in lung adenocarcinoma (LUAD). We found that the expression of SLC25A22 and SIRT3 had a high positive correlation and that their expression was greater in LUAD tissues than in adjacent tissues. The RSL3-induced ferroptosis of LUAD led to upregulation of SLC25A22 and SIRT3, and SIRT3 protected RSL3-induced LUAD from ferroptosis in vitro and in vivo. At the molecular level, SIRT3 bound with SLC25A22 and deacetylated this protein. Targeting SIRT3 enhanced the acetylation of SLC25A22, decreased its ubiquitination, and promoted 26S proteasome degradation in LUAD cells. Therefore, our results demonstrated that SIRT3 protected LUAD cells from RSL3-induced ferroptosis, and this effect is at least partially due to its deacetylation of SLC25A22, revealing that the SIRT3-SLC25A22 axis has an important role in regulating the ferroptosis of LUAD cells. Full article

Karyopherins, carrier proteins that recognize particular cargo protein patterns known as nuclear localization signals (NLSs), mediate the nuclear translocation of big proteins. In order to better understand the process of nuclear transport of proteins and create the groundwork for the development of innovative treatments that specifically target importins, it is imperative to clarify the intricate interactions between nuclear transporters and their cargo proteins. Until recently, very few NLSs have been documented. In the current work, an in silico method was used to identify NLSs for importin 8. It was determined that the sequence RRKLPVGRS serves as a recognition motif for importin 8 binding a karyopherin that is involved in the nuclear transportation of several important proteins like AGOs, SMADs, RPL23A, and TFE3. The sequence was validated in vitro in the breast cancer cell line T47D. This work subscribes to the effort to clarify the intricate relationships between nuclear transporters and their cargo proteins, in order to better understand the mechanism of nuclear transport of proteins and lay the groundwork for the development of novel therapeutics that target particular importins and have an immediate translational impact. Full article

Aluminum (Al) toxicity is a serious environmental constraint facing crop production in acidic soils, primarily due to the oxidative damage it causes to plant tissues. Alfalfa (Medicago sativa), a globally important forage crop, is highly susceptible to Al-induced stress, necessitating the development of Al-tolerant cultivars for sustainable forage production. In this study, we investigated the regulatory role of miR156 in Al stress response in alfalfa. Transcript analysis revealed significant downregulation of miR156 in alfalfa roots after 8 h of Al exposure, suggesting a negative role for miR156 in response to Al. To further investigate the role of miR156 in regulating agronomic traits and alfalfa’s Al tolerance, we utilized the short tandem target mimic (STTM) method to silence miR156 in alfalfa (MsSTTM156), which led to an upregulation of SQUAMOSA PROMOTER BINDING-LIKE (SPL) target genes, albeit with variable miR156 dose-dependent effects across different transgenic genotypes. Morphological characterization of MsSTTM156 plants revealed significant negative changes in root architecture, root and shoot biomass, as well as flowering time. Under Al stress, overexpression of miR156 in alfalfa (MsmiR156OE) resulted in stunted growth and reduced biomass, whereas moderate MsmiR156 silencing enhanced root dry weight and increased stem basal diameter. In contrast, MsmiR156OE reduced plant height, stem basal diameter, shoot branching, and overall biomass under Al stress conditions. At the molecular level, silencing miR156 modulated the transcription of cell wall-related genes linked to Al tolerance, such as polygalacturonase 1(MsPG1) and polygalacturonase 4 (MsPG4). Furthermore, miR156 influenced the expression of indole-3-acetic acid (IAA) transport-related genes auxin transporter-like protein (MsAUX1) and auxin efflux carrier components 2 (MsPIN2), with MsSTTM156 and MsmiR156OE plants showing lower and higher transcript levels, respectively, upon Al exposure. These findings reveal the multi-layered role of miR156 in mediating Al tolerance, providing valuable insights into the genetic strategies that regulate response to Al stress in alfalfa. Full article

Photodegradation of antibiotics based on photocatalytic semiconductors is a promising option to alleviate water pollution. Despite its limitations, TiO₂-based photocatalysts are still the most widely studied materials for pollutant degradation. In this work, a pomegranate-like g-C₃N₄/C/TiO₂ nano-heterojunction was constructed using the hydrothermal–calcination method, consisting of interconnected small crystals with a dense structure and closely contacted interface. Low-crystallized carbon filled the gap between TiO₂ and g-C₃N₄, forming a large interface. The local in-plane heterostructures generated by C/g-C₃N₄ are further improved for carrier transport. As expected, the optimal sample calcined at 300 °C (GTC-300) efficiently eliminated tetracycline hydrochloride (TC-HCl, 20 mg L⁻¹), achieving a removal rate of up to 92.9% within 40 min under full-spectrum irradiation and 87.8% within 60 min under the visible spectrum (λ > 400 nm). The electron mediator, low-crystallized carbon, successfully promoted the formation of new internal electric fields via the widespread heterojunction interface, which accelerated the separation and migration of photogenerated carriers between g-C₃N₄ and TiO₂. These results confirm that the g-C₃N₄/C/TiO₂ nano-heterojunction exhibited outstanding photodegradation performance of TC-HCl. The electron mediator shows great potential in promoting carrier transfer and enhancing photocatalytic performance of heterogeneous photocatalysts in water treatment. Full article

This review discusses the literature data on the synthesis, physicochemical properties, and cytotoxicity of composite nanoparticles bearing the mitochondrial protein cytochrome c (cytC), which can act as a proapoptotic mediator in addition to its main function as an electron carrier in the electron transport chain. The introduction of exogenous cytC via absorption of carrier particles, the phagocytosis of colloid particles of submicrometric size, or the receptor-mediated endocytosis of nanoparticles in cancer cells, initiates the process of apoptosis—a multistage cascade of biochemical reactions leading to complete destruction of the cells. CytC–carrier composite particles have the potential for use in the treatment of neoplasms with superficial localization: skin, mouth, stomach, colon, etc. This approach can solve the two main problems of anticancer therapy: selectivity and non-toxicity. Selectivity is based on the incapability of the normal cell to absorb (nano)particles, except for the cells of the immune system. The use of cytC as a protein that normally functions in mitochondria is harmless for the macroorganism. In this review, the factors limiting cytotoxicity and the ways to increase it are discussed from the point of view of the physicochemical properties of the cytC–carrier particles. The different techniques used for the preparation of cytC-bearing colloids and nanoparticles are discussed. Articles reporting the achievement of high cytotoxicity with each of the techniques are critically analyzed. Full article

The dysfunction of the blood–brain barrier (BBB) is well described in several diseases, and is considered a pathological factor in many neurological disorders. This review summarizes the most important groups of natural compounds, including alkaloids, flavonoids, anthocyanidines, carotenoids, lipids, and vitamins that were investigated for their potential protective effects on brain endothelium. The brain penetration of these compounds and their interaction with BBB efflux transporters and solute carriers are discussed. The cerebrovascular endothelium is considered a therapeutic target for natural compounds in diseases. In preclinical studies modeling systemic and central nervous system diseases, nutraceuticals exerted beneficial effects on the BBB. In vivo, they decreased BBB permeability, brain edema, astrocyte swelling, and morphological changes in the vessel structure and basal lamina. At the level of brain endothelial cells, nutraceuticals increased cell survival and decreased apoptosis. From the general endothelial functions, decreased angiogenesis and increased levels of vasodilating agents were demonstrated. From the BBB functions, elevated barrier integrity by tightened intercellular junctions, and increased expression and activity of BBB transporters, such as efflux pumps, solute carriers, and metabolic enzymes, were shown. Nutraceuticals enhanced the antioxidative defense and exerted anti-inflammatory effects at the BBB. The most important signaling changes mediating the increased cell survival and BBB stability were the activation of the WNT, PI3K-AKT, and NRF2 pathways, and inhibition of the MAPK, JNK, ERK, and NF-κB pathways. Nutraceuticals represent a valuable source of new potentially therapeutic molecules to treat brain diseases by protecting the BBB. Full article

Background/Objectives: The proton-coupled amino acid transporter (PAT1) is an intestinal absorptive solute carrier responsible for the oral bioavailability of some GABA-mimetic drug substances such as vigabatrin and gaboxadol. In the present work, we investigate if non-steroidal anti-inflammatory drug substances (NSAIDs) interact with substrate transport via human (h)PAT1. Methods: The transport of substrates via hPAT1 was investigated in Caco-2 cells using radiolabeled substrate uptake and in X. laevis oocytes injected with hPAT1 cRNA, measuring induced currents using the two-electrode voltage clamp technique. The molecular interaction between NSAIDs and hPAT1 was investigated using an AlphaFold2 model and molecular docking. Results: NSAIDs such as ibuprofen, diclofenac, and flurbiprofen inhibited proline uptake via hPAT1, with IC₅₀ values of 954 (logIC₅₀ 2.98 ± 0.1) µM, 272 (logIC₅₀ 2.43 ± 0.1) µM, and 280 (logIC₅₀ 2.45 ± 0.1) µM, respectively. Ibuprofen acted as a non-competitive inhibitor of hPAT1-mediated proline transport. In hPAT1-expressing oocytes, ibuprofen and diclofenac did not induce inward currents, and inhibited inward currents caused by proline. Molecular modeling pointed to a binding mode involving an allosteric site. Conclusions: NSAIDs interact with hPAT1 as non-translocated non-competitive inhibitors, and molecular modeling points to a binding mode involving an allosteric site distinct from the substrate binding site. The present findings could be used as a starting point for developing specific hPAT1 inhibitors. Full article