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Salvia miltiorrhiza Bunge (SM) has been extensively used in Alzheimer’s disease treatment, the permeability through the blood-brain barrier (BBB) determining its efficacy. However, the transport mechanism of SM components across the BBB remains to be clarified. A simple, precise, and sensitive method using LC-MS/MS was developed for simultaneous quantification of tanshinone I (TS I), dihydrotanshinone I (DTS I), tanshinone IIA (TS IIA), cryptotanshinone (CTS), protocatechuic aldehyde (PAL), protocatechuic acid (PCTA), and caffeic acid (CFA) in transport samples. The analytes were separated on a C18 column by gradient elution. Multiple reaction monitoring mode via electrospray ionization source was used to quantify the analytes in positive mode for TS I, DTS I, TS IIA, CTS, and negative mode for PAL, PCTA, and CFA. The linearity ranges were 0.1–8 ng/mL for TS I and DTS I, 0.2–8 ng/mL for TS IIA, 1–80 ng/mL for CTS, 20–800 ng/mL for PAL and CFA, and 10–4000 ng/mL for PCTA. The developed method was accurate and precise for the compounds. The relative matrix effect was less than 15%, and the analytes were stable for analysis. The established method was successfully applied for transport experiments on a BBB cell model to evaluate the apparent permeability of the seven components.

Botrytis cinerea is a widespread plant pathogenic ascomycete that causes grey mould in over 1400 species and impacts global crop yields. Double-stranded RNA (dsRNA)-induced gene silencing is a promising technology for pest control, but efficient delivery remains a major challenge. This work presents a star polycation (SPc)-based nano-delivery platform that enhances dsRNA internalization and enables effective control of B. cinerea. SPc assembles with dsRNA via electrostatic interactions, hydrogen bonding and Van der Waals forces, forming stable nanoscale complexes. SPc facilitates dsRNA uptake into fungal mycelia by 2.19-fold, primarily via two activated routes: endocytosis and transmembrane transport, which increase vesicle and particle numbers by 3.74- and 1.87-fold, respectively. Six genes (pkc, ypt10, pil1, mfs1, mfs2 and mfs3) in these two routes play crucial roles in the delivery process. RNA interference, chemical inhibition and mutation experiments demonstrate that the two routes interact to optimize the cellular uptake of SPc-loaded dsRNA. Finally, a high-efficiency RNA fungicide is developed, comparable to commercial fungicide in protecting cucumber leaves and tomato fruits. This study reveals the synergistic mechanism of nanocarrier-mediated gene delivery and identifies key genes, supporting the design and application of RNA pesticides.

Comprehensively covers protein subcellular localization from single-label prediction to multi-label prediction, and includes prediction strategies for virus, plant, and eukaryote species. Three machine learning tools are introduced to improve classification refinement, feature extraction, and dimensionality reduction.

In this paper we demonstrate the transmembrane chloride transport properties of a series of calix[4]pyrroles appended with squaramide moieties for the first time. The flexibility imparted by the methylene group between the squaramide and macrocycle allowed for changes between 1 : 1 and 1 : 2 (host : guest) binding modes at high chloride concentrations. Electroneutral transport was observed in the substituted compounds compared to the parent calix[4]pyrrole, with an improvement in transport activity when distal electron withdrawing groups were appended. These results highlight the important role of the squaramide in facilitating transmembrane transport for the substituted macrocycles. Keywords: calix[4]pyrrole, squaramide, chloride, transmembrane transport.

Understanding carboxylate transport through lipid membranes under physiological conditions is critical in biomedicine and biotechnology, as it allows for the emulation of biological membrane functions and can enhance the absorption of hydrophobic carboxylate-based drugs. However, the structural diversity of carboxylates has made it challenging to study their transport, and the limited available examples do not provide a comprehensive understanding of the role of the organic moiety in this process. Here, we present an in-depth analysis of the diffusion and transport of various aliphatic and aromatic carboxylates into liposomes. We assessed the influence of their size, number of carboxylate groups, and presence of hydroxyl groups. Our findings from fluorescence assays, using lucigenin and HPTS as probes, revealed that most carboxylates can spontaneously diffuse into liposomes in their protonated state, facilitated by the efflux of HNO3 when using NaNO3 solutions at pH 7. The Cl-ISE assay showed chloride/carboxylate exchange by a synthetic anion transporter. Clear trends were observed when the organic moiety was systematically varied, with a particular enhancement of anion transport by the presence of hydroxyl groups in the aromatic carboxylates. Our findings provide insights into the processes by which carboxylates can enter liposomes, which can contribute to understanding the transport of other biologically relevant organic anions.

Vitamin A has diverse biological functions and is essential for human survival at every point from embryogenesis to adulthood. Vitamin A and its derivatives have been used to treat human diseases including vision diseases, skin diseases, and cancer. Both insufficient and excessive vitamin A uptake are detrimental, but how its transport is regulated is poorly understood. STRA6 is a multitransmembrane domain cell-surface receptor and mediates vitamin A uptake from plasma retinol binding protein (RBP). STRA6 can mediate both cellular vitamin A influx and efflux, but what regulates these opposing activities is unknown. To answer this question, we purified and identified STRA6-associated proteins in a native mammalian cell type that takes up vitamin A through STRA6 using mass spectrometry. We found that the major protein repeatedly identified as STRA6-associated protein is calmodulin, consistent with the cryogenic electron microscopy (cryo-EM) study of zebrafish STRA6 associated with calmodulin. Using radioactivity-based, high-performance liquid chromatography (HPLC)-based and real-time fluorescence techniques, we found that calmodulin profoundly affects STRA6’s vitamin A transport activity. Increased calcium/calmodulin promotes cellular vitamin A efflux and suppresses vitamin A influx through STRA6. Further mechanistic studies revealed that calmodulin enhances the binding of apo-RBP to STRA6, and this enhancement is much more pronounced for apo-RBP than holo-RBP. This study revealed that calmodulin regulates STRA6’s vitamin A influx or efflux activity by modulating its preferential interaction with apo-RBP or holo-RBP. This molecular mechanism of regulating vitamin A transport may point to new directions to treat human diseases associated with insufficient or excessive vitamin A uptake.

Non-invasive micro-test technology (NMT) reveals dynamic ionic/molecular concentration gradients by measuring fluxes of ions and small molecules in liquid media in 1D, 2D or 3D fashions with sensitivity up to pico- (10 ) or femto- (10 ) moles per cm per second. NMT has been applied to study metabolism, signal transduction, genes and/or proteins physiological functions related to transmembrane ionic/molecular activities with live samples under normal conditions or stress. Data on ion and/or molecule homeostasis (IMH) by NMT in biomedical sciences, plant and crop sciences, environmental sciences, marine and space biology as well as traditional Chinese medicine are reviewed.

Copper is an important micronutrient required as a redox co-factor in the catalytic centers of enzymes. However, free copper is a potential hazard because of its high chemical reactivity. Consequently, organisms exert a tight control on Cu(+) transport (entry-exit) and traffic through different compartments, ensuring the homeostasis required for cuproprotein synthesis and prevention of toxic effects. Recent studies based on biochemical, bioinformatics, and metalloproteomics approaches, reveal a highly regulated system of transcriptional regulators, soluble chaperones, membrane transporters, and target cuproproteins distributed in the various bacterial compartments. As a result, new questions have emerged regarding the diversity and apparent redundancies of these components, their irregular presence in different organisms, functional interactions, and resulting system architectures.

Na+/H+ exchangers are essential for Na+ and pH homeostasis in all organisms. Human Na+/H+ exchangers are of high medical interest, and insights into their structure and function are aided by the investigation of prokaryotic homologues. Most prokaryotic Na+/H+ exchangers belong to either the Cation/Proton Antiporter (CPA) superfamily, the Ion Transport (IT) superfamily, or the Na+-translocating Mrp transporter superfamily. Several structures have been solved so far for CPA and Mrp members, but none for the IT members. NhaA from E. coli has served as the prototype of Na+/H+ exchangers due to the high amount of structural and functional data available. Recent structures from other CPA exchangers, together with diverse functional information, have allowed elucidation of some common working principles shared by Na+/H+ exchangers from different families, such as the type of residues involved in the substrate binding and even a simple mechanism sufficient to explain the pH regulation in the CPA and IT superfamilies. Here, we review several aspects of prokaryotic Na+/H+ exchanger structure and function, discussing the similarities and differences between different transporters, with a focus on the CPA and IT exchangers. We also discuss the proposed transport mechanisms for Na+/H+ exchangers that explain their highly pH-regulated activity profile.

The purpose of this study was to develop mixed polymeric micelles with high drug loading capacity to improve the oral bioavailability of icaritin with Soluplus® and Poloxamer 407 using a creative acid-base shift (ABS) method, which exhibits the advantages of exclusion of organic solvents, high drug loading and ease of scaling-up. The feasibility of the ABS method was successfully demonstrated by studies of icaritin-loaded polymeric micelles (IPMs). The prepared IPMs were characterized to have a spherical shape with a size of 72.74 ± 0.51 nm, and 13.18% drug loading content. In vitro release tests confirmed the faster release of icaritin from IPMs compared to an oil suspension. Furthermore, bioavailability of icaritin in IPMs in beagle dogs displayed a 14.9-fold increase when compared with the oil suspension. Transcellular transport studies of IPMs across Caco-2 cell monolayers confirmed that the IPMs were endocytosed in their intact forms through macropinocytosis, clathrin-, and caveolae-mediated pathways. In conclusion, the results suggested that the mixed micelles of Soluplus® and Poloxamer 407 could be a feasible drug delivery system to enhance oral bioavailability of icaritin, and the ABS method might be a promising technology for the preparation of polymeric micelles to encapsulate poorly water-soluble weakly acidic and alkaline drugs.