A novel near-infrared polymethine dye biosensor for rapid and selective detection of lithocholic acid.

Lithocholic acid (LCA), a secondary bile acid, has emerged as a potential early diagnostic biomarker for various liver diseases. In this study, we introduce a novel near-infrared (NIR) polymethine dye-based biosensor, capable of sensitive and selective detection of LCA in phosphate buffer and artificial urine (AU) solutions. The detection mechanism relies on the formation of J-aggregates resulting from the interplay of 3,3-Diethylthiatricarbocyanine iodide (DiSC2(7)) dye molecules and LCA, which induces a distinctive red shift in both absorption and fluorescence spectra. The biosensor demonstrates a detection limit for LCA of 70 µM in PBS solution (pH 7.4), while in AU solution, it responds to an LCA concentration as low as ∼60 µM. Notably, the proposed biosensor exhibits outstanding selectivity for LCA, effectively distinguishing it from common interferents such as uric acid, ascorbic acid, and glucose. This rapid, straightforward, and cost-effective spectrometer-based method underscores its potential for early diagnosis of liver diseases by monitoring LCA concentrations.

Injectable Bioadhesive Hydrogels Scavenging ROS and Restoring Mucosal Barrier for Enhanced Ulcerative Colitis Therapy.

Despite the progress in the therapy of ulcerative colitis (UC), long-lasting UC remission can hardly be achieved in the majority of UC patients. The key pathological characteristics of UC include an impaired mucosal barrier and local inflammatory infiltration. Thus, a two-pronged approach aiming at repairing damaged mucosal barrier and scavenging inflammatory mediators simultaneously might hold great potential for long-term remission of UC. A rectal formulation can directly offer preferential and effective drug delivery to inflamed colon. However, regular intestinal peristalsis and frequent diarrhea in UC might cause transient drug retention. Therefore, a bioadhesive hydrogel with strong interaction with intestinal mucosa might be preferable for rectal administration to prolong drug retention. Here, we designed a bioadhesive hydrogel formed by the cross-linking of sulfhydryl chondroitin sulfate and polydopamine (CS-PDA). The presence of PDA would ensure the mucosa-adhesive behavior, and the addition of CS in the hydrogel network was expected to achieve the restoration of the intestinal epithelial barrier. To scavenge the key player (excessive reactive oxygen species, ROS) in inflamed colon, sodium ferulic (SF), a potent ROS inhibitor, was incorporated into the CS-PDA hydrogel. After rectal administration, the SF-loaded CS-PDA hydrogel could adhere to the colonic mucosa to allow prolonged drug retention. Subsequently, sustained SF release could be achieved to persistently scavenge ROS in inflammatory areas. Meanwhile, the presence of CS would promote the restoration of the mucosal barrier. Ultimately, scavenging ROS and restoring the mucosal barrier could be simultaneously achieved via this SF-loaded bioadhesive hydrogel scaffold. Our two-pronged approach might provide new insight for effective UC treatment.

Transcriptome analysis of the muscle of fast- and slow-growing phoenix barb (Spinibarbus denticulatus denticulatus).

Growth rate is a commercial trait in aquaculture that is influenced by multiple factors, among which genetic composition plays a fundamental role in the growth rate of species. The phoenix barb (Spinibarbus denticulatus denticulatus) is a widely distributed freshwater fish species in South China. Although S. d. denticulatus is reared in South China, the molecular mechanisms underlying the growth rate of the species remain unclear. Here, the authors performed transcriptome analysis of muscle tissues from fast-growing (FG) and slow-growing (SG) S. d. denticulatus at 90, 150, and 300 days after hatch (DAH) to elucidate its growth mechanism. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that differentially expressed genes (DEGs) between the two groups were enriched in pathways related to muscle growth, glycolysis, and energy and lipid metabolism. Nonetheless, a higher number of DEGs were identified in the FG vs. SG groups at 90 and 300 DAH compared with 150 DAH. DEGs identified at 90 DAH were mainly enriched in the GH/IGF axis, PI3K-Akt signalling pathway, AMPK signalling pathway and lipid metabolism highly expressed in FG individuals. DEGs identified at 300 DAH were mainly enriched in PI3K-Akt signalling pathway, glycolysis/gluconeogenesis, gene translation and lipid metabolism. In addition, some genes were expressed during the early growth stage in FG individuals but expressed during the late stage in SG individuals, indicating considerable variations in the expression profiles of growth-related genes at different developmental stages. Overall, these findings contribute to the understanding of the growth mechanism of S. d. denticulatus, which would be useful for the propagation of fast-growing breeds.

Antibacterial, Adhesive, and Conductive Hydrogel for Diabetic Wound Healing.

Diabetic mellitus is one of the leading causes of chronic wounds and remains a challenging issue to be resolved. Herein, a hydrogel with conformal tissue adhesivity, skin-like conductivity, robust mechanical characteristics, as well as active antibacterial function is developed. In this hydrogel, silver nanoparticles decorated polypyrrole nanotubes (AgPPy) and cobalt ions (Co2+ ) are introduced into an in situ polymerized poly(acrylic acid) (PAA) and branched poly(ethylenimine) (PEI) network (PPCA hydrogel). The PPCA hydrogel provides active antibacterial function through synergic effects from protonated PEI and AgPPy nanotubes, with a tissue-like mechanical property (≈16.8 ± 4.5 kPa) and skin-like electrical conductivity (≈0.048 S m-1 ). The tensile and shear adhesive strength (≈15.88 and ≈12.76 kPa, respectively) of the PPCA hydrogel is about two- to threefold better than that of fibrin glue. In vitro studies show the PPCA hydrogel is highly effective against both gram-positive and gram-negative bacteria. In vivo results demonstrate that the PPCA hydrogel promotes diabetic wounds with accelerated healing, with notable inflammatory reduction and prominent angiogenesis regeneration. These results suggest the PPCA hydrogel provide a promising approach to promote diabetic wound healing.

Inflammation-responsive nanoparticles suppress lymphatic clearance for prolonged arthritis therapy.

The clearance of nanomedicine in inflamed joints has been accelerated due to the increased lymph angiogenesis and lymph flow in arthritic sites. To maximize the therapeutic efficacy for rheumatoid arthritis (RA), it is necessary to facilitate targeted delivery and extended drug retention in inflamed synovium simultaneously. In general, nanosized particles are more likely to achieve prolonged circulation and targeted delivery. While drug carriers with larger dimension might be more beneficial for extending drug retention. To balance the conflicting requirements, an inflammation-responsive shape transformable nanoparticle, comprised of amyloid ß-derived KLVFF peptide and polysialic acid (PSA), coupled with therapeutic agent dexamethasone (Dex) via an acid-sensitive linker, was fabricated and termed as Dex-KLVFF-PSA (DKPNPs). Under physiological condition, DKPNPs can keep stable nanosized morphology, and PSA shell could endow DKPNPs with long circulation and active targeting to arthritic sites. While in inflamed joints, acidic pH-triggered Dex dissociation or macrophages-induced specific binding with PSA would induce the re-assembly of DKPNPs from nanoparticles to nanofibers. Our results reveal that intravenously injected DKPNPs display prolonged in vivo circulation and preferential distribution in inflamed joints, where DKPNPs undergo shape transition to fibrous structures, leading to declined lymphatic clearance and prolonged efficacy. Overall, our dual-stimulus responsive transformable nanoparticle offers an intelligent solution to achieve enhanced therapeutic efficacy in RA.

Targeting the resolution pathway of inflammation using Ac2-26 peptide-loaded PEGylated lipid nanoparticles for the remission of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint inflammation and immune dysfunction. Although various therapeutic approaches have been utilized for the treatment of RA in clinical applications, the low responsiveness of RA patients and undesired systemic toxicity are still unresolved problems. Targeting the resolution pathway of inflammation with pro-resolving mediators would evoke the protective actions of patient for combating the inflammation. Ac2-26, a 25-amino acid peptide derived from Annexin A (a pro-resolving mediator), has shown good efficacy in the treatment of inflammatory disorders. However, the low bioavailability of Ac2-26 peptides hinders their efficacy in vivo. In this paper, we formed PEGylated lipid nanoparticles (LDNPs) by the co-assembly of l-ascorbyl palmitate (L-AP) and N-(carbonyl methoxypolyethylene glycol-2000)-1,2-distearoyl-sn­glycero-3-phosphoethanolamine (DSPE-PEG2k) to encapsulate and deliver Ac2-26 peptides to the arthritic rats. They showed good stability and biocompatibility. After being intravenously administrated, Ac2-26 peptide-loaded PEGylated lipid nanoparticles (ADNPs) showed the prolonged in vivo circulation time and enhanced accumulation in inflamed sites. In vivo therapeutic evaluations revealed that ADNPs could attenuate synovial inflammation and improve joint pathology. Therefore, the pro-resolving therapeutic strategy using ADNPs is effective in RA treatment.

Injectable Micelle-Incorporated Hydrogels for the Localized Chemo-Immunotherapy of Breast Tumors.

Although immune checkpoint blockade (ICB) holds potential for the treatment of various tumors, a considerable proportion of patients show a limited response to ICB therapy due to the low immunogenicity of a variety of tumors. It has been shown that some chemotherapeutics can turn low-immunogenic tumors into immunogenic phenotypes by inducing a cascade of immune responses. In this paper, we synthesized an injectable micelle-incorporated hydrogel, which was able to sequentially release the chemotherapeutic gemcitabine (GEM) and the hydrophobic indoleamine 2, 3-dioxygenase inhibitor, d-1-methyltryptophan (d-1MT) at tumor sites. The hydrogel was formed via the thiol-ene click reaction between the thiolated chondroitin sulfate and the micelle formed by amphiphilic methacrylated Pluronic F127, in which hydrophobic d-1MT was encapsulated in the core of the F127 micelles and the hydrophilic GEM was dispersed in the hydrogel network. The successive release of chemotherapeutics and immune checkpoint inhibitors at tumor tissues will first promote the infiltration of cytotoxic T lymphocytes and subsequently induce a robust antitumor immune response, ultimately exerting a synergetic therapeutic efficacy. In a 4T1 tumor-bearing mice model, our results showed that the combination of chemotherapy and immunotherapy through the micelle-incorporated hydrogel triggered an effective antitumor immune response and inhibited tumor metastasis to the lung. Our results highlight the potential of the injectable micelle-incorporated hydrogel for the localized chemo-immunotherapy in the treatment of breast tumors.

Improving the anti-inflammatory efficacy of dexamethasone in the treatment of rheumatoid arthritis with polymerized stealth liposomes as a delivery vehicle.

Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints of the body. Although liposomes are a promising drug delivery vehicle, there is still a challenge of using conventional liposomes for the treatment of RA due to their short circulation time and physicochemical instability in blood vessels. Here, we report the formation of polymerized stealth liposomes composed of 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC8,9PC) and 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-poly(ethyleneglycol) (DSPE-PEG2000) with a thin-film hydration method, in which DC8,9PC molecules are cross-linked in the bilayer of the liposomes by UV irradiation and the PEG chains present at the surface of the liposomes provide a stealth layer. We demonstrate that the polymerized stealth liposomes are stable and show long circulation time in blood vessels. They can be internalized by cells without significant toxicity. After being injected into arthritic rats, the polymerized stealth liposomes with loaded dexamethasone (Dex) show long blood circulation time and accumulate preferentially in inflamed joints, consequently suppressing the level of proinflammatory cytokines (TNF-α and IL-1ß) in joint tissues, reducing the swelling of inflamed joints and alleviating the progression of RA. We believe that polymerized stealth liposomes can be used as a promising drug delivery vehicle for various therapeutic applications.

PLA2-Triggered Release of Drugs from Self-Assembled Lipid Tubules for Arthritis Treatments.

Environment-responsive drug delivery is a promising approach for tailoring the drug release in drug therapy. In this study, we develop lipid tubules by the self-assembly of 1,2-bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8,9PC). These lipid tubules are capable of encapsulating hydrophobic dexamethasone (Dex) and hydrophilic dexamethasone sodium phosphate (DSP) simultaneously. In vitro studies show that the lipid tubules can be internalized by cells with no significant toxicity. We find that phospholipase (PLA2) is able to slowly digest the lipid tubules and trigger the sustained release of Dex and DSP. After being subcutaneously administrated to the inflammatory sites of arthritic rats, we show that a single dose of drug-loaded lipid tubules can remarkably inhibit the degree of joint swelling at the inflammatory sites and suppress the content of proinflammatory cytokines in inflamed tissues for a long time by this sustained release of both Dex and DSP triggered by the highly expressed PLA2 at the inflamed sites. Our results highlight the potential of using PLA2-responsive lipid tubules as on-demand carriers for treating inflammatory diseases.

Matrix Metalloproteinase-Responsive PEGylated Lipid Nanoparticles for Controlled Drug Delivery in the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder. It causes inflammation, swelling, and pain in the joints of the human body. Overexpressed matrix metalloproteinases (MMPs) at the inflammatory sites of RA are a target in the construction of inflammation-responsive drug delivery vehicles for enhancing the therapeutic effect of anti-inflammatory drugs in the treatment of RA. In this paper, we report MMP-responsive PEGylated lipid nanoparticles through the co-assembly of triglycerol monostearate (TGMS) and 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-poly(ethyleneglycol) (DSPE-PEG2000) in which the ester bond of TGMS is cleavable by MMPs and the PEG chain provides a stealth layer. The lipid nanoparticles show high biocompatibility, extended blood circulation, and preferential distribution in the inflammatory joints of RA. The loaded dexamethasone (Dex) can be rapidly released from the lipid nanoparticles in response to MMPs. After being intravenously administered to arthritic rats, Dex-loaded MMP-responsive PEGylated lipid nanoparticles significantly reduce the degree of joint swelling and inhibit the production of TNF-α and IL-1ß in joint tissues. These results demonstrate that MMP-responsive PEGylated lipid nanoparticles are a smart drug vehicle for the treatment of RA with improved therapeutic efficacy.

Morphology Transformation of Supramolecular Structures in Aqueous Mixtures of Two Oppositely Charged Amphiphiles.

The co-assembly of oppositely charged amphiphiles provides a fascinating approach for forming complex supramolecular structures, which are interesting from both fundamental and technological viewpoints. Here, we report a stepwise morphology transformation of co-assembled supramolecular structures in the aqueous mixture of lithocholic acid (LCA) and cetyltrimethylammonium bromide (CTAB) at mixed molar ratios of 1:1 and 2:1. The co-assembly of LCA and CTAB initially forms multilamellar vesicles followed by the spontaneous growth of membrane tubes from the vesicles. The vesicle-to-tube transition is accompanied by a fluidic-to-crystalline phase transition. After being aged, the membrane tubes twist into left-handed helices, which then intertwine into left-handed double helices and multihelix bundles. The single handedness of these supramolecular structures is a reflection of the amplification of the chirality of LCA. An understanding of the co-assembly mechanism and pathway is a key step toward producing supramolecular structures with distinguished morphologies.

A new quinoline-derived highly-sensitive fluorescent probe for the detection of hydrazine with excellent large-emission-shift ratiometric response.

Hydrazine is an important industrial material yet highly toxic and extremely harmful to people's health when over-exposed in the environment, thus monitoring hydrazine is of great significance. In this work, a novel highly fluorescent fluorophore BQ-OH, based on hydroxyl- and benzo[d]oxazole-substituted quinoline structure, was synthesized and esterified with 4-biomobutyric acid to afford a fluorescent probe BQABr for the selective detection of hydrazine. The probe follows SN2(nucleophilic substitution)-cyclization sensing mechanism with remarkable response, excellent sensitivity and selectivity. Spectra experiments in aqueous solutions demonstrated that BQABr exhibited an excellent ratiometric fluorescence response toward hydrazine with two well separated emission bands before/after sensing reaction. Emission peak shifted over 130 nm from 387 nm to 521 nm, and unexpectedly outstanding ratio signal enhancement over 3000-fold was achieved. Due to the large spectra response, a very low detection limit of 5.8 nM (0.19 ppb) was obtained. Selectivity experiment was performed, showing BQABr had nearly no spectra response to other possible disturbing analytes. The probe-coated test papers were fabricated and successfully applied to detect gaseous hydrazine. Furthermore, potential application for the detection of hydrazine in both environmental samples and biological samples (living cells) has been demonstrated.

Soft-Templated Synthesis of Lightweight, Elastic, and Conductive Nanotube Aerogels.

Conductive polymer (CP) nanotubes are fascinating nanostructures with high electrical conductivity, fast charge/discharge capability, and high mechanical strength. Despite these attractive physical properties, progress in the synthesis of CP nanotube hydrogels is still limited. Here, we report a facile and effective approach for the synthesis of polypyrrole (PPy) nanotube hydrogels by using the weakly interconnected network of self-assembled nanotubes of lithocholic acid as a soft template. The PPy nanotube hydrogels are then converted to aerogels by freeze drying, in which PPy nanotubes form elastic and conductive networks with a density of 38 mg/cm3 and an electrical conductivity of 1.13 S/m. The PPy nanotube aerogels are able to sustain a compressive strain as high as 70% and show an excellent cyclic compressibility due to their robust nanotube networks and hierarchically porous structures, which allow the compressive stress to be easily dissipated. Furthermore, PPy nanotube aerogels show negative strain-dependent electrical resistance changes under compressive strains. The lightweight, elastic, and conductive PPy nanotube aerogels may find potential applications in strain sensors, supercapacitors, and tissue scaffolds.

Quinoline-derived fluorescent probes for the discrimination of Cys from Hcys/GSH and bioimaging in living cells.

Development of thiol-specific fluorescent probes with selectivity in different thiol compounds is more practical and significant than those without that capacity. In this work, a new quinoline-derived fluorophore, hydroxyl-substituted quinoline-benzo[d]oxazole 6 with high fluorescence quantum yield is synthesized and esterified with acrylic acid to afford two fluorescent probes, BQA-1 and BQA-2 for selectively discriminating Cys from Hcys/GSH based on conjugate addition-cyclization mechanism. BQA-1 exhibits a large ratiometric fluorescence response toward Cys in aqueous pH 7.4 solution with big emission peak-shifting from 383 nm to 518 nm, over 130 nm. The detection limit is determined to be as low as 0.59 µM. In contrast to BQA-1, BQA-2 whose acrylic ester moiety is further modified with pyridine group, displays a turn-on fluorescence response to Cys with detection limit of 0.98 µM. Both BQA-1 and BQA-2 have relatively weak response to another two biothiols, Hcys and GSH and nearly no response to other nucleophiles. Furthermore, the potential application for the detection of biothiols in living cells has been demonstrated by cell imaging experiment.

Formation of Spherulitic J-Aggregates from the Coassembly of Lithocholic Acid and Cyanine Dye.

Supramolecular aggregates of organic dyes through noncovalent interactions have attracted great interest because they exhibit collective optical and excitonic properties. We report the formation of spherulitic J-aggregates from the coassembly of lithocholic acid (LCA) and 3,3'-diethylthiacarbocyanine iodide (DiSC2(3)) in ammonia solution. Each spherulite contains a core, which serves as a nucleus for the growth of radially oriented J-aggregate fibrils. We find that the growth of spherulitic J-aggregates exhibits a sigmoidal kinetic curve with an initial lag time, followed by a period of rapid growth and a finally slow approach to equilibrium.

Crosslinking hydroxylated reduced graphene oxide with RAFT-CTA: A nano-initiator for preparation of well-defined amino acid-based polymer nanohybrids.

Here, we demonstrate a novel reversible addition-fragmentation chain transfer agent (RAFT-CTA)-modified reduced graphene oxide nanosheets (CTA-rGONSs) by crosslinking rGONSs with a RAFT-CTA via esterification reaction. These nano CTA-rGONSs were used to polymerize a hydrophobic amino acid-based methacrylamide (N-acryloyl-l-phenylalanine methyl ester) monomer with different monomer/initiator ratios. Thermogravimetric analysis showed that the polymer-graphene composites were thermally more stable than GO itself. Mn of the polymers increased with increasing monomer/initiator ratio, while the polydispersity index decreased, indicating controlled polymerization. The composites were stable in DMF even after two months.

Liquid Crystal Droplet-Embedded Biopolymer Hydrogel Sheets for Biosensor Applications.

The development of simple, portable, and low-cost biosensing platforms is of great interest in the clinical diagnosis of disease. Here, we report liquid crystal (LC) droplet-embedded chitosan (CHI) hydrogel films formed by the Ag(+) ion-triggered fast gelation of the CHI/surfactant complex-stabilized LC emulsion which is cast on substrates. The small sheets cut from the LC droplet-embedded hydrogel films combine the advantages of both hydrogels and LC droplets, offering a portable and label-free sensing platform for the real-time detection of bile acids in a small amount of solution. We find that the response time and detection limit of LC droplet-embedded hydrogel sheets for bile acids depend on their chemical structures.

Bile acid-surfactant interactions at the liquid crystal/aqueous interface.

The interaction between bile acids and surfactants at interfaces plays an important role in fat digestion. In this paper, we study the competitive adsorption of cholic acid (CA) at the sodium dodecyl sulfate (SDS)-laden liquid crystal (LC)/aqueous interface formed with cyanobiphenyl (nCB, n = 5-8) and the mixture of 5CB with 4-(4-pentylcyclohexyl)benzonitrile (5PCH). We find that the critical concentration of CA required to displace SDS from the interface linearly decreases from 160 µM to 16 µM by reducing the alkyl chain length of nCB from n = 8 to n = 5 and from 16 µM to 1.5 µM by increasing the 5PCH concentration from 0 wt% to 19 wt% in the 5PCH-5CB binary mixture. Our results clearly demonstrate that the sensitivity of 5PCH-5CB mixtures for monitoring the interaction between CA and SDS at the LC/aqueous interface can be increased by one order of magnitude, compared to 5CB.

Morphology and shape control of porous silica nanostructures with dual-templating approaches.

There has been great interest in the synthesis of porous silica nanostructures because of their potential applications in catalysis, adsorption, molecular separation, and biomedical engineering. In this paper, we report the synthesis of porous silica nanostructures with varied morphologies and shapes from two-phase systems by using lithocholic acid (LCA) and cetyltrimethylammmonium bromide (CATB) or LCA and Pluronic F127 in the lower ammonia aqueous phase as dual directing agents and tetraethylsiloxane (TEOS) in the upper oil phase as a silica precursor. Porous silica spheres are formed by using LCA/CTAB as a dual directing agent, while silica fibers with pits are synthesized by using LCA/F127 as a dual directing agent. The straight-to-helical shape transition of silica fibers with pits can be achieved by increasing the ammonia concentration in the low aqueous phase.

Longitudinal zipping/unzipping of self-assembled organic tubes.

Stimuli-responsive organic tubes are an attractive supramolecular assembly which has potential applications as a controlled release vehicle. We synthesize a smart organic tube by the coassembly of lithocholic acid (LCA) and taurolithocholic acid (TLCA) in aqueous solution. The coassembled LCA/TLCA tubes can be longitudinally unzipped into flat sheets by capillary force after being dehydrated on substrates. Consequently, the encapsulated guest molecules are released from the unzipping tubes. After the release of guest molecules, the flat sheets can be zipped back into hollow tubes upon hydration with aqueous solution. The zipping/unzipping LCA/TLCA tubes provide a new type of delivery vehicles, which may have potential for surface decontaminations.