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Aim This study investigated the effectiveness of a drug-modified tissue conditioner in an animal model of denture stomatitis. Methods and Results Wistar rats wore a Candida albicans -contaminated palatal device for 4 days. Next, nystatin (Nys) or chlorhexidine (Chx) were added to a tissue conditioner in their raw or β-cyclodextrin-complexed (βCD) forms at their minimum inhibitory concentrations. As controls, one group was not subjected to any procedure (NC), one group used sterile devices, one group had denture stomatitis but was not treated (DS), and another had the devices relined with the tissue conditioner without the addition of any drug (Soft). After 4 days of treatment, treatment effectiveness was assessed visually, histologically, and through CFU count, and myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) assays. Rats from the Soft, Nys, Nys:βCD, and Chx groups presented a significant decrease in the microbial load compared with the untreated group. Treatment groups showed lower MPO and NAG activity compared to the non-treated group. Conclusions The addition of antifungals to a soft tissue conditioner can be a promising approach for denture stomatitis treatment. [ABSTRACT FROM AUTHOR]

In today's context, prolonged exposure to sunlight is widely recognized as a threat to human health, leading to a range of adverse consequences, including skin cancers, premature skin aging, and erythema. To mitigate these risks, preventive actions mainly focus on advocating the application of sunscreen lotions and minimizing direct exposure to sunlight. This research study specifically centered on ensulizole (ENS), a prominent ingredient in sunscreens. The objective was to create inclusion complexes (ICs) with Beta-cyclodextrin (B–CD) and its hydroxypropyl derivatives (H–CD). Using phase solubility measurements, we determined that both B–CD and H–CD form 1:1 stoichiometric ICs with ENS. Proton nuclear magnetic resonance spectral (1H NMR) analysis confirmed that the phenyl portion of ENS is encapsulated within the B–CD cavity. Significant changes in surface morphology were observed during the formation of these ICs compared to ENS and CDs alone. Quantum mechanical calculations were employed to further support the formation of ICs by providing energy data. Particularly, the photostability of the ENS:B–CD ICs remained intact for up to four hours of UV exposure, with no significant alterations in the structure of ENS. Furthermore, comprehensive biocompatibility assessments yielded encouraging results, suggesting the potential application of these inclusion complexes in cosmetics as a UVB sunscreen. In summary, our research underscores the successful creation of inclusion complexes characterized by enhanced photostability and safe biocompatibility. [Display omitted] [ABSTRACT FROM AUTHOR]

The emergence of resistant fungal species and the toxicity of currently available antifungal drugs are relevant issues that require special consideration. Cyclodextrins inclusion complexes could optimize the antimicrobial activity of such drugs and create a controlled release system with few side effects. This study aimed to assess the in vitro toxicity and antifungal effectiveness of nystatin (Nys) and chlorhexidine (Chx) complexed or not with β‐cyclodextrin (βCD). First, a drug toxicity screening was performed through the Artemia salina bioassay. Then, the minimum inhibitory concentrations (MICs) against Candida albicans were determined with the broth microdilution test. After MICs determination, the cytotoxicity of the drugs was evaluated through the methyl‐thiazolyl‐tetrazolium (MTT) and neutral red (NR) assays and through cell morphology analysis. The PROBIT analysis was used to determine the median lethal concentration (LC50), and the cell viability values were submitted to one‐way analysis of variance(ANOVA)/Tukey (α = 0.05). Overall, the βCD‐complexed antifungals were less toxic against A. salina than their raw forms, suggesting that inclusion complexes can reduce the toxicity of drugs. The MICs obtained were as follows: Nys 0.5 mg/L; Nys:βCD 4 mg/L; Chx 4 mg/L; and Chx:βCD 8 mg/L. Chx showed significant cytotoxicity (MTT: 12.9 ± 9.6%; NR: 10.6 ± 12.5%) and promoted important morphological changes. Cells exposed to the other drugs showed viability above 70% with no cellular damage. These results suggest that antifungals complexed with βCD might be a biocompatible option for the treatment of Candida‐related infections. Our study aimed to evaluate the in vitro toxicity of nystatin and chlorhexidine complexed with β‐cyclodextrin (βCD) against Artemia salina, to determine their minimum inhibitory concentrations against Candida albicans, and to assess their cytotoxicity on murine fibroblasts at these concentrations. The complexed antifungals were less toxic to A. salina than their raw forms. βCD‐complexed drugs also showed excellent antifungal activity against C. albicans and did not promote cellular damage. [ABSTRACT FROM AUTHOR]

Zinc diethyldithiocarbamate (Zn (DDC)2), a disulfiram metabolite (anti-alcoholism drug), has shown a strong anti-cancer activity in vitro. However, its application was limited by its low aqueous solubility and rapid metabolism. In this study, the solubility enhancement of Zn (DDC)2 is investigated by forming inclusion complexes with cyclodextrins. The inclusion complexes were prepared using two different types of beta-cyclodextrins, SBE-CD and HP-CD. Phase solubility diagrams for the resulting solutions were assessed; subsequently, the solutions were freeze-dried for further characterisation studies using DSC, TGA, XRD, and FTIR. The cytotoxic activity of the produced inclusion complexes was evaluated on human lung carcinoma cells using the MTT assay. The solubility of Zn (DDC)2 increased significantly upon adding beta-cyclodextrins, reaching approximately 4 mg/mL for 20% w/w CD solutions. The phase solubility diagram of Zn (DDC)2 was of the Ap-type according to the Higuchi and Connors model. Characterisation studies confirmed the inclusion of the amorphous drug in the CD-Zn (DDC)2 complexes. The cytotoxicity of Zn (DDC)2 was enhanced 10-fold by the inclusion complexes compared to the free drug. Overall, the resulting CD-Zn (DDC)2 inclusion complexes have a potential for treatment against lung cancer. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp) plays a critical role in drug oral bioavailability, and modulation of this transporter can alter the safety and/or efficacy profile of substrate drugs. Individual oral molecular excipients that inhibit P-gp function have been considered a mechanism for improving drug absorption, but a systematic evaluation of the interaction of excipients with P-gp is critical for informed selection of optimal formulations of proprietary and generic drug products. A library of 123 oral molecular excipients was screened for their ability to inhibit P-gp in two orthogonal cell-based assays. β-Cyclodextrin and light green SF yellowish were identified as modest inhibitors of P-gp with IC50 values of 168 μM (95% CI, 118-251 μM) and 204 μM (95% CI, 5.9-1745 μM), respectively. The lack of effect of most of the tested excipients on P-gp transport provides a wide selection of excipients for inclusion in oral formulations with minimal risk of influencing the oral bioavailability of P-gp substrates.

Using host-guest chemistries in a biphasic system, a novel supramolecular nanoparticle surfactant (s-NPS) with redox-responsiveness is presented to structure liquids. The in situ assembly/jamming and disassembly/unjamming of s-NPSs at the oil-water interface are reversibly controlled by a switchable redox process, imparting a nanoscale redox-responsiveness, affecting the assemblies on all length scales. "Smart" all-liquid constructs including structured emulsions and programmable liquid devices are easily prepared, showing promising applications in responsive delivery, release, and reaction systems.

We investigate the binding of native β-cyclodextrin (β-CD) and eight novel β-CD derivatives with two different guest compounds, using isothermal calorimetry and 2D NOESY NMR. In all cases, the stoichiometry is 1:1 and binding is exothermic. Overall, modifications at the 3' position of β-CD, which is at the secondary face, weaken binding by several kJ/mol relative to native β-CD, while modifications at the 6' position (primary face) maintain or somewhat reduce the binding affinity. The variations in binding enthalpy are larger than the variations in binding free energy, so entropy-enthalpy compensation is observed. Characterization of the bound conformations with NOESY NMR shows that the polar groups of the guests may be situated at either face, depending on the host molecule, and, in some cases, both orientations are populated. The present results were used in the SAMPL7 blinded prediction challenge whose results are detailed in the same special issue of JCAMD.

Cholesterol-laden macrophage foam cells are a hallmark of atherosclerosis. For that reason, cholesterol metabolism in macrophages has attracted considerable scrutiny, particularly the mechanisms by which macrophages unload surplus cholesterol (a process referred to as "cholesterol efflux"). Many studies of cholesterol efflux in macrophages have focused on the role of ABC transporters in moving cholesterol onto high-density lipoproteins (HDLs), but other mechanisms for cholesterol efflux likely exist. We hypothesized that macrophages have the capacity to unload cholesterol directly onto adjacent cells. To test this hypothesis, we used methyl-β-cyclodextrin (MβCD) to load mouse peritoneal macrophages with [13C]cholesterol. We then plated the macrophages (in the absence of serum or HDL) onto smooth muscle cells (SMCs) that had been metabolically labeled with [15N]choline. After incubating the cells overnight in the absence of HDL or serum, we visualized 13C and 15N distribution by nanoscale secondary ion mass spectrometry (NanoSIMS). We observed substantial 13C enrichment in SMCs that were adjacent to [13C]cholesterol-loaded macrophages-including in cytosolic lipid droplets of SMCs. In follow-up studies, we depleted "accessible cholesterol" from the plasma membrane of [13C]cholesterol-loaded macrophages with MβCD before plating the macrophages onto the SMCs. After an overnight incubation, we again observed substantial 13C enrichment in the SMCs adjacent to macrophages. Thus, macrophages transfer cholesterol to adjacent cells in the absence of serum or HDL. We suspect that macrophages within tissues transfer cholesterol to adjacent cells, thereby contributing to the ability to unload surplus cholesterol.

Designing ligands that bind their target biomolecules with high affinity and specificity is a key step in small-molecule drug discovery, but accurately predicting protein-ligand binding free energies remains challenging. Key sources of errors in the calculations include inadequate sampling of conformational space, ambiguous protonation states, and errors in force fields. Noncovalent complexes between a host molecule with a binding cavity and a druglike guest molecule have emerged as powerful model systems. As model systems, host-guest complexes reduce many of the errors in more complex protein-ligand binding systems, as their small size greatly facilitates conformational sampling, and one can choose systems that avoid ambiguities in protonation states. These features, combined with their ease of experimental characterization, make host-guest systems ideal model systems to test and ultimately optimize force fields in the context of binding thermodynamics calculations. The Open Force Field Initiative aims to create a modern, open software infrastructure for automatically generating and assessing force fields using data sets. The first force field to arise out of this effort, named SMIRNOFF99Frosst, has approximately one tenth the number of parameters, in version 1.0.5, compared to typical general small molecule force fields, such as GAFF. Here, we evaluate the accuracy of this initial force field, using free energy calculations of 43 α and β-cyclodextrin host-guest pairs for which experimental thermodynamic data are available, and compare with matched calculations using two versions of GAFF. For all three force fields, we used TIP3P water and AM1-BCC charges. The calculations are performed using the attach-pull-release (APR) method as implemented in the open source package, pAPRika. For binding free energies, the root-mean-square error of the SMIRNOFF99Frosst calculations relative to experiment is 0.9 [0.7, 1.1] kcal/mol, while the corresponding results for GAFF 1.7 and GAFF 2.1 are 0.9 [0.7, 1.1] kcal/mol and 1.7 [1.5, 1.9] kcal/mol, respectively, with 95% confidence ranges in brackets. These results suggest that SMIRNOFF99Frosst performs competitively with existing small molecule force fields and is a parsimonious starting point for optimization.

Zinc diethyldithiocarbamate (Zn (DDC)2), a disulfiram metabolite (anti-alcoholism drug), has shown a strong anti-cancer activity in vitro. However, its application was limited by its low aqueous solubility and rapid metabolism. In this study, the solubility enhancement of Zn (DDC)2 is investigated by forming inclusion complexes with cyclodextrins. The inclusion complexes were prepared using two different types of beta-cyclodextrins, SBE-CD and HP-CD. Phase solubility diagrams for the resulting solutions were assessed; subsequently, the solutions were freeze-dried for further characterisation studies using DSC, TGA, XRD, and FTIR. The cytotoxic activity of the produced inclusion complexes was evaluated on human lung carcinoma cells using the MTT assay. The solubility of Zn (DDC)2 increased significantly upon adding beta-cyclodextrins, reaching approximately 4 mg/mL for 20% w/w CD solutions. The phase solubility diagram of Zn (DDC)2 was of the Ap-type according to the Higuchi and Connors model. Characterisation studies confirmed the inclusion of the amorphous drug in the CD-Zn (DDC)2 complexes. The cytotoxicity of Zn (DDC)2 was enhanced 10-fold by the inclusion complexes compared to the free drug. Overall, the resulting CD-Zn (DDC)2 inclusion complexes have a potential for treatment against lung cancer.

BackgroundIn theory, binding enthalpies directly obtained from calorimetry (such as ITC) and the temperature dependence of the binding free energy (van't Hoff method) should agree. However, previous studies have often found them to be discrepant.MethodsExperimental binding enthalpies (both calorimetric and van't Hoff) are obtained for two host-guest pairs using ITC, and the discrepancy between the two enthalpies is examined. Modeling of artificial ITC data is also used to examine how different sources of error propagate to both types of binding enthalpies.ResultsFor the host-guest pairs examined here, good agreement, to within about 0.4kcal/mol, is obtained between the two enthalpies. Additionally, using artificial data, we find that different sources of error propagate to either enthalpy uniquely, with concentration error and heat error propagating primarily to calorimetric and van't Hoff enthalpies, respectively.ConclusionsWith modern calorimeters, good agreement between van't Hoff and calorimetric enthalpies should be achievable, barring issues due to non-ideality or unanticipated measurement pathologies. Indeed, disagreement between the two can serve as a flag for error-prone datasets. A review of the underlying theory supports the expectation that these two quantities should be in agreement.General significanceWe address and arguably resolve long-standing questions regarding the relationship between calorimetric and van't Hoff enthalpies. In addition, we show that comparison of these two quantities can be used as an internal consistency check of a calorimetry study.

Cyclodextrins (CDs) are cyclic oligosaccharides; the most common CDs contain six, seven, or eight glucose units called α-CDs, β-CDs, and γ-CDs, respectively. The use of CDs in biomedical research is increasing due to their ability to interact with membrane lipids as well as a wide variety of poorly water-soluble molecules. We assessed the impact of CD cavity size, occupancy, and substitutions on cytotoxicity and cholesterol homeostasis. The potency of CD-mediated cytotoxicity was in the order of β-CDs, α-CDs, and γ-CDs. Substitutions with hydroxypropyl or carboxymethyl group attenuated cytotoxicity compared with the native CDs, whereas CDs substituted with methyl groups exhibited cytotoxicity that was similar to that of the native CDs. The lipid components in blood exerted remarkable hemolysis-alleviating effects in methyl-β-CD-induced hemolysis. Occupancy of the CD cavity with cholesterol or a structurally related lipid molecule abrogated the cytotoxic capacity of the CDs. Interestingly, hydroxypropyl-γ-CD (HPγCD) was able to reduce intracellular cholesterol accumulation in Niemann⁻Pick disease type C (NPC) patient-derived fibroblasts as efficiently as HPβCD. Proteomic study indicated that HPβCD and HPγCD treatments altered the expression pattern of cellular proteins, suggesting that some of the CD-induced cellular proteins may play an important function in modulating intracellular cholesterol homeostasis.

Aurisin A (AA), an aristolane dimer sesquiterpene isolated from the luminescent mushroom Neonothopanus nambi, exhibits various biological and pharmacological effects. However, its poor solubility limits its use for further medicinal applications. This study aimed to improve the water solubility of AA via complexation with β-cyclodextrin (βCD) and its derivatives (2,6-di-O-methyl-βCD (DMβCD) and 2-hydroxypropyl-βCD (HPβCD). A phase solubility analysis demonstrated that the solubility of AA linearly enhanced with increasing concentrations of βCDs (ranked in the order of AA/DMβCD > AA/HPβCD > AA/βCD). Notably, βCDs, especially DMβCD, increased the thermal stability of the inclusion complexes. The thermodynamic study indicated that the complexation between AA and βCD(s) was a spontaneous endothermic reaction, and AA/DMβCD possesses the highest binding strength. The complex formation between AA and DMβCD was confirmed by means of FT-IR, DSC, and SEM. Molecular dynamics simulations revealed that the stability and compactness of the AA/DMβCD complex were higher than those of the DMβCD alone. The encapsulation of AA led to increased intramolecular H-bond formations on the wider rim of DMβCD, enhancing the complex stability. The antiproliferative activity of AA against A549 and H1975 lung cancer cells was significantly improved by complexation with DMβCD. Altogether, the satisfactory water solubility, high thermal stability, and enhanced antitumor potential of the AA/DMβCD inclusion complex would be useful for its application as healthcare products or herbal medicines. [ABSTRACT FROM AUTHOR]

Depression, anxiety and psychotic disorders are common perinatal mental health disorders in the postpartum period. Depressive symptoms that occur postpartum are also present in the prenatal period in 50% of patients. Risk factors for the development of postpartum depression include poor relationship with the partner, lack of social support, mother’s low socioeconomic status and multiparity. It has been determined that reproductive hormones change significantly during peripartum. Progesterone is one of these hormones and acts on the central nervous system starting from the fetal period; neurogenesis, neuromodulation, sedation are some of these effects. It has also been observed that progesterone has positive effects on learning, memory and mood. Progesterone exerts its effects on the central nervous system by converting into its metabolite allopregnanolone. Allopregnanolone is one of the neuroactive steroids, and found in similar amounts in the circulation of pregnant women and fetuses. It acts on synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA) receptors and is a positive allosteric modulator of the GABAA receptor. Allopregnanolone increases both the receptor’s opening frequency and its open duration and improves GABAergic current. Low serum allopregnanolone levels in the second trimester are predictive of postpartum depression. Each 1 ng/mL increase in serum allopregnanolone level reduces the risk of development of postpartum depression by 63%. Brexanolone and zuranolone are synthetic allopregnanolone preparations approved by the FDA for use in female patients with postpartum depression. They act via positive allosteric modulation on the GABAA receptor. Brexanolone is administered via intravenous infusion at varying infusion rates in a healthcare facility over 60 hours. Its effect starts immediately after treatment and continues until the 30th day of follow-up, and depressive mood does not recur. Zuranolone was developed for oral use, and administered as a single dose of 50 mg after a fatty meal. Their effectiveness has been demonstrated in patients with treatment-resistant depression. The development of other novel agents that act on the GABAA receptor and other pathways for the treatment of postpartum depression is in progress.

Cholesterol is a crucial lipid within the plasma membrane of mammalian cells. Recent biochemical studies showed that one pool of cholesterol in the plasma membrane is "accessible" to binding by a modified version of the cytolysin perfringolysin O (PFO*), whereas another pool is sequestered by sphingomyelin and cannot be bound by PFO* unless the sphingomyelin is destroyed with sphingomyelinase (SMase). Thus far, it has been unclear whether PFO* and related cholesterol-binding proteins bind uniformly to the plasma membrane or bind preferentially to specific domains or morphologic features on the plasma membrane. Here, we used nanoscale secondary ion mass spectrometry (NanoSIMS) imaging, in combination with 15N-labeled cholesterol-binding proteins (PFO* and ALO-D4, a modified anthrolysin O), to generate high-resolution images of cholesterol distribution in the plasma membrane of Chinese hamster ovary (CHO) cells. The NanoSIMS images revealed preferential binding of PFO* and ALO-D4 to microvilli on the plasma membrane; lower amounts of binding were detectable in regions of the plasma membrane lacking microvilli. The binding of ALO-D4 to the plasma membrane was virtually eliminated when cholesterol stores were depleted with methyl-β-cyclodextrin. When cells were treated with SMase, the binding of ALO-D4 to cells increased, largely due to increased binding to microvilli. Remarkably, lysenin (a sphingomyelin-binding protein) also bound preferentially to microvilli. Thus, high-resolution images of lipid-binding proteins on CHO cells can be acquired with NanoSIMS imaging. These images demonstrate that accessible cholesterol, as judged by PFO* or ALO-D4 binding, is not evenly distributed over the entire plasma membrane but instead is highly enriched on microvilli.

Kinetic properties may serve as critical differentiators and predictors of drug efficacy and safety, in addition to the traditionally focused binding affinity. However the quantitative structure-kinetics relationship (QSKR) for modeling and ligand design is still poorly understood. This review provides an introduction to the kinetics of drug binding from a fundamental chemistry perspective. We focus on recent developments of computational tools and their applications to non-covalent binding kinetics.

The absolute binding free energies and binding enthalpies of twelve host-guest systems in the SAMPL5 blind challenge were computed using our attach-pull-release (APR) approach. This method has previously shown good correlations between experimental and calculated binding data in retrospective studies of cucurbit[7]uril (CB7) and β-cyclodextrin (βCD) systems. In the present work, the computed binding free energies for host octa acid (OA or OAH) and tetra-endo-methyl octa-acid (TEMOA or OAMe) with guests are in good agreement with prospective experimental data, with a coefficient of determination (R2) of 0.8 and root-mean-squared error of 1.7 kcal/mol using the TIP3P water model. The binding enthalpy calculations achieve moderate correlations, with R2 of 0.5 and RMSE of 2.5 kcal/mol, for TIP3P water. Calculations using the newly developed OPC water model also show good performance. Furthermore, the present calculations semi-quantitatively capture the experimental trend of enthalpy-entropy compensation observed, and successfully predict guests with the strongest and weakest binding affinity. The most populated binding poses of all twelve systems, based on clustering analysis of 750 ns molecular dynamics (MD) trajectories, were extracted and analyzed. Computational methods using MD simulations and explicit solvent models in a rigorous statistical thermodynamic framework, like APR, can generate reasonable predictions of binding thermodynamics. Especially with continuing improvement in simulation force fields, such methods hold the promise of making substantial contributions to hit identification and lead optimization in the drug discovery process.

High cholesterol levels in the blood increase the risk of atherosclerosis. A common explanation is that the cholesterol increase in the plasma membrane perturbs the shape and functions of cells by disrupting the cell signaling pathways and the formation of membrane rafts. In this work, we show that after enhanced transient uptake of cholesterol, mono-component lipid bilayers change their shape similarly to cell membranes in vivo. The bilayers either expel lipid protrusions or spread laterally as a result of the ensuing changes in their lipid density, the mechanical constraints imposed on them, and the properties of cyclodextrin used as a cholesterol donor. In light of the increasingly recognized link between membrane tension and cell behavior, we propose that the physical adaptation of the plasma membrane to cholesterol uptake may play a substantial role in the biological response.

LDL Receptor-related Protein-1 (LRP1) is an endocytic receptor for diverse ligands. In neurons and neuron-like cells, ligand-binding to LRP1 initiates cell-signaling. Herein, we show that in PC12 and N2a neuron-like cells, LRP1 distributes into lipid rafts and non-raft plasma membrane fractions. When lipid rafts were disrupted, using methyl-β-cyclodextrin or fumonisin B1, activation of Src family kinases and ERK1/2 by the LRP1 ligands, tissue-type plasminogen activator and activated α2-macroglobulin, was blocked. Biological consequences of activated LRP1 signaling, including neurite outgrowth and cell growth, also were blocked. The effects of lipid raft disruption on ERK1/2 activation and neurite outgrowth, in response to LRP1 ligands, were reproduced in experiments with cerebellar granule neurons in primary culture. Because the reagents used to disrupt lipid rafts may have effects on the composition of the plasma membrane outside lipid rafts, we studied the effects of these reagents on LRP1 activities unrelated to cell-signaling. Lipid raft disruption did not affect the total ligand binding capacity of LRP1, the affinity of LRP1 for its ligands, or its endocytic activity. These results demonstrate that well described activities of LRP1 require localization of this receptor to distinct plasma membrane microdomains.

Context: The therapeutic potential of andrographolide is hindered by its poor oral bioavailability and unpredictable pharmacokinetics, primarily due to its limited water solubility., Objective: This work aimed to enhance the solubility and pharmacokinetics of andrographolide, a bioactive compound in Andrographis paniculata (Burm. f.) Nees (Acanthaceae), using solubilizing agents and a bioenhancer., Materials and Methods: Four groups of beagles were compared: (1) A. paniculata powder alone (control), (2) A. paniculata powder with 50% weight/weight (w/w) β-cyclodextrin solubilizer, (3) A. paniculata powder with 1% w/w sodium dodecyl sulfate (SDS) solubilizer, and (4) A. paniculata powder co-administered with 1% w/w SDS solubilizer and 10% piperine bioenhancer. All groups received a consistent oral dose of 3 mg/kg of andrographolide, administered both as a single dose and multiple doses over seven consecutive days., Results: Thirteen chemical compounds were identified in A. paniculata powder, including 7 diterpenoids, 5 flavonoids, and 1 phenolic compound. A. paniculata co-administration with either 50% w/w β-cyclodextrin or 1% w/w SDS, alone or in combination with 10% w/w piperine, significantly increased systemic andrographolide exposure by enhancing bioavailability (131.01% to 196.05%) following single and multiple oral co-administration. Glucuronidation is one possible biotransformation pathway for andrographolide, as evidenced by the excretion of glucuronide conjugates in urine and feces., Conclusion: The combination of solubilizing agents and a bioenhancer improved the oral bioavailability and pharmacokinetics of andrographolide, indicating potential implications for A. paniculata formulations and clinical therapeutic benefits. Further investigation in clinical studies is warranted.

The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-β-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core, and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery.

Atherosclerotic plaques exhibit high cholesterol deposition and oxidative stress resulting from high reactive oxygen species (ROS). These are the major components in plaques and the main pro-inflammatory factor. Therefore, it is crucial to develop an effective therapeutic strategy that can simultaneously address the multiple pro-inflammatory factors via removing cholesterol and inhibiting the overaccumulated ROS. In this study, we constructed macrophage membrane-encapsulated biomimetic nanoparticles (MM@DA-pCD@MTX), which not only alleviate cholesterol deposition at the plaque lesion via reverse cholesterol transport but also scavenge the overaccumulated ROS. β-Cyclodextrin (β-CD) and the loaded methotrexate (MTX) act synergistically to induce cholesterol efflux for inhibiting the formation of foam cells. Among them, MTX up-regulated the expression of ABCA1, CYP27A1, and SR-B1. β-CD increased the solubility of cholesterol crystals. In addition, the ROS scavenging property of dopamine (DA) was perfectly preserved in MM@DA-pCD@MTX, which could scavenge the overaccumulated ROS to alleviate the oxidative stress at the plaque lesion. Last but not least, MM-functionalized "homing" targeting of atherosclerotic plaques not only enables the targeted drug delivery but also prolongs in vivo circulation time and drug half-life. In summary, MM@DA-pCD@MTX emerges as a potent, multifunctional therapeutic platform for AS treatment, offering a high degree of biosafety and efficacy in addressing the complex pathophysiology of atherosclerosis.

We developed a method for the determination of chloropropanol esters and glycidyl esters (GE) in instant noodles using solid-phase microextraction with chitosan-β-cyclodextrin (CS-β-CD) coated fiber coupled with gas chromatography-tandem mass spectrometry. The developed low-cost fiber coating can improve the sensitivity of the method. Immobilized enzymes can improve operational stability and reusability compared to free enzymes, thereby reducing costs. The adsorption isotherm was modeled using the Langmuir model, while the adsorption kinetics followed the pseudo second-order model. The limit of detection was 0.3 ng/L. The method exhibited satisfactory recoveries for the analytes, ranging from 80.2 % to 105.3 %, with relative standard deviations < 9.9 %. Furthermore, the results of the exposure assessment showed that chloropropanol esters do not pose unacceptable risks to different age groups. However, the margin of exposure for GE suggested a potential health risk for populations between the ages of 3 and 12 years old., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Electroporation is pivotal in bioelectrochemistry for cellular manipulation, with prominent applications in drug delivery and cell membrane studies. A comprehensive understanding of pore generation requires an in-depth analysis of the critical pore size and the corresponding energy barrier at the onset of cell rupture. However, many studies have been limited to basic models such as artificial membranes or theoretical simulations. Challenging this paradigm, our study pioneers using a microfluidic electroporation chip array. This tool subjects live breast cancer cell species to a diverse spectrum of alternating current electric field conditions, driving electroporation-induced cell rupture. We conclusively determined the rupture voltages across varying applied voltage loading rates, enabling an unprecedented characterization of electric cell rupture dynamics encompassing critical pore radius and energy barrier. Further bolstering our investigation, we probed cells subjected to cholesterol depletion via methyl-β-cyclodextrin and revealed a strong correlation with electroporation. This work not only elucidates the dynamics of electric rupture in live cell membranes but also sets a robust foundation for future explorations into the mechanisms and energetics of live cell electroporation.

The limited application of garlic essential oil (GEO) is attributed to its pungent taste, poor water solubility and low bioavailability. Liposomes are nontoxic, biodegradable and biocompatible, and β-cyclodextrin can inhibit undesirable odors and improve the stability and bioavailability. Thus a promising dual-layer GEO β-cyclodextrin inclusion compound liposome (GEO-DCL) delivery system with both advantages was designed and prepared in this study. Experimental results indicated that the encapsulation efficiency of GEO-DCLs was 5% higher than that of GEO liposomes (GEO-CLs), reaching more than 88%. In vitro release experiment showed that the release rate of GEO in GEO-DCLs was 40% lower than that of GEO-CLs after incubation in gastric juice for 6-h, indicating that the stability of GEO-DCLs was better than GEO-CLs. Evaluation of the effects of GEO-DCLs on lowering blood lipid levels in hypercholesterolemia mice. GEO-DCLs could reduce the weight and fat deposition in hypercholesterolemia mice. Inhibiting the increase of TC, LDL-C, and decrease of HDL-C in mice. The degree of liver injury was decreased, the number of round lipid droplets in liver cytoplasm was reduced, and the growth of fat cells was inhibited. The lipid-lowering effects of GEO-DCLs were dose-dependent. GEO-DCL can improve the bioavailability of GEO and improve dyslipidemia. Based on GEO's efficacy in lowering blood lipids, this study developed a kind of GEO-DCL compound pomegranate juice beverage with good taste, miscibility and double effect of reducing blood lipids. This study lays a foundation for the application of GEO in the field of functional food., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The aim of this study was to exploit the versatility of inkjet printing to develop flexible doses of drug-loaded orodispersible films that encoded information in a data matrix pattern, and to introduce a specialised data matrix-generator software specifically focused on the healthcare sector. Pharma-inks (drug-loaded inks) containing hydrocortisone (HC) were developed and characterised based on their rheological properties and drug content. Different strategies were investigated to improve HC solubility: formation of β-cyclodextrin complexes, Soluplus® based micelles, and the use of co-solvent systems. The software automatically adapted the data matrix size and identified the number of layers for printing. HC content deposited in each film layer was measured, and it was found that the proportion of co-solvent used directly affected the drug solubility and simultaneously played a role in the modification of the viscosity and surface tension of the inks. The formation of β-cyclodextrin complexes improved the drug quantity deposited in each layer. On the contrary, micelle-based inks were not suitable for printing. Orodispersible films containing flexible and low doses of personalised HC were successfully prepared, and the development of a code generator software oriented to medical use provided an additional, innovative, and revolutionary advantage to personalised medicine safety and accessibility., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alvaro Goyanes reports a relationship with FABRX Ltd. that includes: employment and equity or stocks. Abdul Basit reports a relationship with FABRX Ltd. that includes: Carlos Rial reports a relationship with FABRX AI Ltd. that includes: employment. Corresponding author part of the editorial board in International Journal of Pharmaceutics - A.B. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Sildenafil citrate (SIL) as a first-line treatment for erectile dysfunction is currently reported to have poor solubility and bioavailability. Moreover, SIL undergoes first-pass metabolism when taken orally and its injection can lead to discomfort. In this study, we introduce a novel transdermal delivery system that integrates hydrogel-forming microneedles with the inclusion complex tablet reservoir. The hydrogel-forming microneedle was prepared from a mixture of polymers and crosslinkers through a crosslinking process. Importantly, the formulations showed high swelling capacity (>400 %) and exhibited adequate mechanical and penetration properties (needle height reduction < 10 %), penetrating up to five layers of Parafilm® M (assessed to reach the dermis layer). Furthermore, to improve the solubility of SIL in the reservoir, the SIL was pre-complexed with β-cyclodextrin. Molecular docking analysis showed that SIL was successfully encapsulated into the β-cyclodextrin cavity and was the most suitable conformation compared to other CD derivatives. Moreover, to maximize SIL delivery, sodium starch glycolate was also added to the reservoir formulation. As a proof of concept, in vivo studies demonstrated the effectiveness of this concept, resulting in a significant increase in AUC (area under the curve) compared to that obtained after administration of pure SIL oral suspension, inclusion complex, and Viagra® with relative bioavailability > 100 %. Therefore, the approach developed in this study could potentially increase the efficacy of SIL in treating erectile dysfunction by being non-invasive, safe, avoiding first-pass metabolism, and increasing drug bioavailability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Trypsin, a pancreatic enzyme associated with diseases like pancreatic cancer and cystic fibrosis, requires effective diagnostic tools. Current detection systems seldom utilize macrocyclic molecules and tetraphenyl ethylene (TPE) derivative-based supramolecular assemblies, known for their biocompatibility and aggregation-induced emission (AIE) properties, for trypsin detection. This study presents an enzyme-responsive, AIE-based fluorescence 'Turn-On' sensing platform for trypsin detection, employing sulfated-β-cyclodextrin (S-βCD), an imidazolium derivative of TPE (TPE-IM), and protamine sulfate (PrS). The anionic S-βCD and cationic TPE-IM formed a strongly fluorescent supramolecular aggregation complex in an aqueous buffer. However, PrS suppresses fluorescence because of its strong binding affinity with S-βCD. The non-fluorescent TPE-IM/S-βCD/PrS supramolecular assembly system exhibits trypsin-responsive properties, as PrS is a known trypsin substrate. Trypsin restores fluorescence in the TPE-IM/S-βCD system through the enzymatic cleavage of PrS, correlating linearly with trypsin catalytic activity in the 0-10 nM concentration range. The limit of detection is 10 pM. This work contributes to the development of self-assembled supramolecular biosensors using charged TPE derivatives and β-cyclodextrin-based host-guest chemistry, offering an innovative fluorescence 'Turn-On' trypsin sensing platform. The sensing system is highly stable under various conditions, selective for trypsin, and demonstrates potential for biological analysis and disease diagnosis in human serum. Additionally, it shows promise for the screening of trypsin inhibitors.

The ability of β-CD to form inclusion complexes with ibuprofen (IBU) and at the same time to make a two-phase system with citric acid was explored in the present study for achieving improved solubility and dissolution rate of IBU. Mechanical milling as well as mechanical milling combined with thermal annealing of the powder mixtures were applied as synthetic methods. Solubility and dissolution kinetics of the complexes were studied in compliance with European Pharmacopoeia (ICH Q4B). β-CD and citric acid (CA) molecules were shown to interact by both ball milling (BM), thermal annealing, as well as BM with subsequent annealing. Complexes were also formed by milling the three compounds (β-CD, CA and IBU) simultaneously, as well as by a consecutive first including IBU into β-CD and then binding the formed β-CD/IBU inclusion complex with CA. As a result, ternary β-CD/IBU/CA complex formed by initial incorporation of ibuprofen into β-CD, followed by successive formation of a two-phase mixture with CA, exhibited notably improved dissolution kinetics compared to the pure ibuprofen and slightly better compared to the binary β-CD/IBU system. Although the addition of CA to β-CD/IBU does not significantly increase the solubility rate of IBU, it must be considered that the amount of β-CD is significantly less in the ternary complex compared to the binary β-CD/IBU.

By combining two different materials, metal-organic frameworks (MOF) and β-cyclodextrins (β-CD), a signal amplification electrochemical luminescence (ECL) immunosensor was constructed to realize the sensitive detection of AFP. The indium-based metal-organic framework (In-MOF) was used as the carrier of Ru(bpy) 3 2+ , and Ru(bpy) 3 2+ was immobilized by In-MOF through suitable pore size and electrostatic interaction. At the same time, using host-guest recognition, β-CD enriched TPA into the hydrophobic cavity for accelerating the electronic excitation of TPA, then, achieving the purpose of signal amplification. The signal amplification immunosensor structure is constructed among the primary antibody Ab 1 connected to the Ru(bpy) 3 2+ @In-MOF modified electrode, AFP, BSA and the secondary antibody (Ab 2 ) loaded with TPA-β-CD. The immunosensor has a good linearity in the range of 10 -5 ng/mL-50 ng/mL, and the low limit of detection (LOD) is 1.1 × 10 -6 ng/mL. In addition, the electrochemiluminescence immunosensor that we designed has strong stability, good selectivity and repeatability, which provides a choice for the analysis of AFP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Hesperidin (Hsd), a bioactive phytomedicine, experienced an antidiabetic activity versus both Type 1 and Type 2 Diabetes mellitus. However, its intrinsic poor solubility and bioavailability is a key challenging obstacle reflecting its oral delivery. From such perspective, the purpose of the current study was to prepare and evaluate Hsd-loaded sulfobutylether-β-cyclodextrin/chitosan nanoparticles (Hsd/CD/CS NPs) for improving the hypoglycemic activity of the orally administered Hsd. Hsd was first complexed with sulfobutylether-β-cyclodextrin (SBE-β-CD) and the complex (CX) was found to be formed with percent complexation efficiency and percent process efficiency of 50.53 ± 1.46 and 84.52 ± 3.16%, respectively. Also, solid state characterization of the complex ensured the inclusion of Hsd inside the cavity of SBE-β-CD. Then, Hsd/CD/CS NPs were prepared using the ionic gelation technique. The prepared NPs were fully characterized to select the most promising one (F1) with a homogenous particle size of 455.7 ± 9.04 nm, a positive zeta potential of + 32.28 ± 1.12 mV, and an entrapment efficiency of 77.46 ± 0.39%. The optimal formula (F1) was subjected to further investigation of in vitro release, ex vivo intestinal permeation, stability, cytotoxicity, and in vivo hypoglycemic activity. The results of the release and permeation studies of F1 manifested a modulated pattern between Hsd and CX. The preferential stability of F1 was observed at 4 ± 1 °C. Also, the biocompatibility of F1 with oral epithelial cell line (OEC) was retained up to a concentration of 100 µg/mL. After oral administration of F1, a noteworthy synergistic hypoglycemic effect was recorded with decreased blood glucose level until the end of the experiment. In conclusion, Hsd/CD/CS NPs could be regarded as a hopeful oral delivery system of Hsd with enhanced antidiabetic activity., (© 2023. The Author(s).)

UnlabelledWe have recently shown that the prolongation of prostaglandin E2 hyperalgesia in a preclinical model of chronic pain-hyperalgesic priming-is mediated by release of cyclic adenosine monophosphate from isolectin B4-positive nociceptors and its metabolism by ectonucleotidases to produce adenosine. The adenosine, in turn, acts in an autocrine mechanism at an A1 adenosine receptor whose downstream signaling mechanisms in the nociceptor are altered to produce nociceptor sensitization. We previously showed that antisense against an extracellular matrix molecule, versican, which defines the population of nociceptors involved in hyperalgesic priming, eliminated the prolongation of prostaglandin E2 hyperalgesia. To further evaluate the mechanisms at the interface between the extracellular matrix and the nociceptor's plasma membrane involved in hyperalgesia prolongation, we interrupted a plasma membrane molecule involved in versican signaling, integrin β1, with an antisense oligodeoxynucleotide. Integrin β1 antisense eliminated mechanical hyperalgesia induced by an adenosine A1 receptor agonist, cyclopentyladenosine, in the primed rat. We also disrupted a molecular complex of signaling molecules that contains integrin β1, lipid rafts, with methyl-β-cyclodextrin, which attenuated the prolongation without affecting the acute phase of prostaglandin E2 hyperalgesia, while having no effect on cyclopentyladenosine hyperalgesia. Our findings help to define the plasma membrane mechanisms involved in a preclinical model of chronic pain.PerspectiveThe present study contributes to a further understanding of mechanisms involved in the organization of messengers at the plasma membrane that participate in the transition from acute to chronic pain.

Constructing safe and effective gene delivery carriers is becoming highly desirable for gene therapy. Herein, a series of supramolecular crosslinking system were prepared through host-guest binding of adamantyl-modified low molecular weight of polyethyleneimine with L-cystine-bridged bis(β-cyclodextrin)s and characterized by (1)H NMR titration, electron microscopy, zeta potential, dynamic light-scattering, gel electrophoresis, flow cytometry and confocal fluorescence microscopy. The results showed that these nanometersized supramolecular crosslinking systems exhibited higher DNA transfection efficiencies and lower cytotoxicity than the commercial DNA carrier gold standard (25 kDa bPEI) for both normal cells and cancer cells, giving a very high DNA transfection efficiency up to 54% for 293T cells. Significantly, this type of supramolecular crosslinking system possesses a number of enzyme-responsive disulfide bonds, which can be cleaved by reductive enzyme to promote the DNA release but recovered by oxidative enzyme to make the carrier renewable. These results demonstrate that these supramolecular crosslinking systems can be used as promising gene carriers.

Aurisin A (AA), an aristolane dimer sesquiterpene isolated from the luminescent mushroom Neonothopanus nambi, exhibits various biological and pharmacological effects. However, its poor solubility limits its use for further medicinal applications. This study aimed to improve the water solubility of AA via complexation with β-cyclodextrin (βCD) and its derivatives (2,6-di-O-methyl-βCD (DMβCD) and 2-hydroxypropyl-βCD (HPβCD). A phase solubility analysis demonstrated that the solubility of AA linearly enhanced with increasing concentrations of βCDs (ranked in the order of AA/DMβCD > AA/HPβCD > AA/βCD). Notably, βCDs, especially DMβCD, increased the thermal stability of the inclusion complexes. The thermodynamic study indicated that the complexation between AA and βCD(s) was a spontaneous endothermic reaction, and AA/DMβCD possesses the highest binding strength. The complex formation between AA and DMβCD was confirmed by means of FT-IR, DSC, and SEM. Molecular dynamics simulations revealed that the stability and compactness of the AA/DMβCD complex were higher than those of the DMβCD alone. The encapsulation of AA led to increased intramolecular H-bond formations on the wider rim of DMβCD, enhancing the complex stability. The antiproliferative activity of AA against A549 and H1975 lung cancer cells was significantly improved by complexation with DMβCD. Altogether, the satisfactory water solubility, high thermal stability, and enhanced antitumor potential of the AA/DMβCD inclusion complex would be useful for its application as healthcare products or herbal medicines.

This study investigated the steady-state and time-resolved fluorescence properties of 17α-ethinylestradiol (EE2) and 17β-estradiol (E2) in the presence of ordered media (β-cyclodextrins (β-CD) and cetyltrimethylammonium bromide (CTAB)). In addition, we analyzed the effects of four room temperature ionic liquids (RTILs) on the fluorescence intensities (FIs) of EE2/β-CD and E2/β-CD inclusion complexes in methanol. Both β-CD and CTAB enhanced the fluorescence of EE2 and E2. The FIs of EE2 and E2 with β-CD or CTAB in methanol were greater than those in water, possibly resulting from decreased oxygen-quenching in H2O molecules. β-CD and CTAB may form inclusion complexes with estrogen in both water and methanol. The inclusion ratio of the complex was 1:1 and the inclusion constant (K) values in water were greater than those in methanol. The fluorescence lifetimes were 2.50 and 4.13 ns for EE2 and 2.58 and 4.03 ns for E2 in aqueous solution and methanol, respectively. The changing trend of fluorescence lifetimes for EE2 and E2 in β-CD or CTAB was similar to the steady-state FIs. The four RTILs had a significant quenching effect on the FIs of EE2/β-CD and E2/β-CD, and the quenching process for EE2/β-CD and E2/β-CD by RTILs was demonstrated to be a dynamic quenching mechanism. Fluorescent data obtained from these complex systems provide a theoretical foundation for understanding the interaction mechanisms between ordered media and RTILs in the analysis of estrogens.

Substrate-mediated gene delivery is a promising method due to its unique ability to preconcentrate exogenous genes onto designated substrates. However, many challenges remain to enable continuous and multiround delivery of the gene using the same substrates without depositing payloads and immobilizing cells in each round of delivery. Herein we introduce a gene delivery system, nanosubstrate-mediated delivery (NSMD) platform, based on two functional components with nanoscale features, including (1) DNA⊂SNPs, supramolecular nanoparticle (SNP) vectors for gene encapsulation, and (2) Ad-SiNWS, adamantane (Ad)-grafted silicon nanowire substrates. The multivalent molecular recognition between the Ad motifs on Ad-SiNWS and the β-cyclodextrin (CD) motifs on DNA⊂SNPs leads to dynamic assembly and local enrichment of DNA⊂SNPs from the surrounding medium onto Ad-SiNWS. Subsequently, once cells settled on the substrate, DNA⊂SNPs enriched on Ad-SiNWS were introduced through the cell membranes by intimate contact with individual nanowires on Ad-SiNWS, resulting in a highly efficient delivery of exogenous genes. Most importantly, sequential delivery of multiple batches of exogenous genes on the same batch cells settled on Ad-SiNWS was realized by sequential additions of the corresponding DNA⊂SNPs with equivalent efficiency. Moreover, using the NSMD platform in vivo, cells recruited on subcutaneously transplanted Ad-SiNWS were also efficiently transfected with exogenous genes loaded into SNPs, validating the in vivo feasibility of this system. We believe that this nanosubstrate-mediated delivery platform will provide a superior system for in vitro and in vivo gene delivery and can be further used for the encapsulation and delivery of other biomolecules.

Accumulation of lipofuscin bisretinoids (LBs) in the retinal pigment epithelium (RPE) is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there are no approved treatments for these diseases; hence, agents that efficiently remove LBs from RPE would be valuable therapeutic candidates. Here, we show that beta cyclodextrins (β-CDs) bind LBs and protect them against oxidation. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of LBs within the hydrophobic cavity of β-CD. Importantly, β-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from Abca4-Rdh8 double knock-out (DKO) mice, respectively. Furthermore, intravitreal administration of β-CDs reduced significantly the content of bisretinoids in the RPE of DKO animals. Thus, our results demonstrate the effectiveness of β-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs.

Through the high affinity of the β-cyclodextrin (β-CD) cavity for adamantane moieties, novel polysaccharide-gold nanocluster supramolecular conjugates (HACD-AuNPs) were successfully constructed from gold nanoparticles (AuNPs) bearing adamantane moieties and cyclodextrin-grafted hyaluronic acid (HACD). Due to their porous structure, the supramolecular conjugates could serve as a versatile and biocompatible platform for the loading and delivery of various anticancer drugs, such as doxorubicin hydrochloride (DOX), paclitaxel (PTX), camptothecin (CPT), irinotecan hydrochloride (CPT-11), and topotecan hydrochloride (TPT), by taking advantage of the controlled association/dissociation of drug molecules from the cavities formed by the HACD skeletons and AuNPs cores as well as by harnessing the efficient targeting of cancer cells by hyaluronic acid. Significantly, the release of anticancer drugs from the drug@HACD-AuNPs system was pH-responsive, with more efficient release occurring under a mildly acidic environment, such as that in a cancer cell. Taking the anticancer drug DOX as an example, cell viability experiments revealed that the DOX@HACD-AuNPs system exhibited similar tumor cell inhibition abilities but lower toxicity than free DOX due to the hyaluronic acid reporter-mediated endocytosis. Therefore, the HACD-AuNPs supramolecular conjugates may possess great potential for the targeted delivery of anticancer drugs.

Photoactivation of "snap-top" stoppers over the pore openings of mesoporous silica nanoparticles releases intact cargo molecules from the pores. The on-command release can be stimulated by either one UV photon or two coherent near-IR photons. Two-photon activation is particularly desirable for use in biological systems because it enables good tissue penetration and precise spatial control. Stoppers were assembled by first binding photolabile coumarin-based molecules to the nanoparticle surface. Then, after the particles were loaded with cargo, bulky β-cyclodextrin (CD) molecules were noncovalently associated with the substituted coumarin molecule, blocking the pores and preventing the cargo from escaping. One-photon excitation at 376 nm or two-photon excitation at 800 nm cleaves the bond holding the coumarin to the nanopore, releasing both the CD cap and the cargo. The dynamics of both the cleavage of the cap and the cargo release was monitored using fluorescence spectroscopy. This system traps intact cargo molecules without the necessity of chemical modification, releases them with tissue-penetrating near-IR light, and has possible applications in photostimulated drug delivery.

TGR5 is a G protein-coupled receptor that mediates bile acid (BA) effects on energy balance, inflammation, digestion, and sensation. The mechanisms and spatiotemporal control of TGR5 signaling are poorly understood. We investigated TGR5 signaling and trafficking in transfected HEK293 cells and colonocytes (NCM460) that endogenously express TGR5. BAs (deoxycholic acid (DCA), taurolithocholic acid) and the selective agonists oleanolic acid and 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated cAMP formation but did not induce TGR5 endocytosis or recruitment of β-arrestins, as assessed by confocal microscopy. DCA, taurolithocholic acid, and oleanolic acid did not stimulate TGR5 association with β-arrestin 1/2 or G protein-coupled receptor kinase (GRK) 2/5/6, as determined by bioluminescence resonance energy transfer. 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated a low level of TGR5 interaction with β-arrestin 2 and GRK2. DCA induced cAMP formation at the plasma membrane and cytosol, as determined using exchange factor directly regulated by cAMP (Epac2)-based reporters, but cAMP signals did not desensitize. AG1478, an inhibitor of epidermal growth factor receptor tyrosine kinase, the metalloprotease inhibitor batimastat, and methyl-β-cyclodextrin and filipin, which block lipid raft formation, prevented DCA stimulation of ERK1/2. Bioluminescence resonance energy transfer analysis revealed TGR5 and EGFR interactions that were blocked by disruption of lipid rafts. DCA stimulated TGR5 redistribution to plasma membrane microdomains, as localized by immunogold electron microscopy. Thus, TGR5 does not interact with β-arrestins, desensitize, or traffic to endosomes. TGR5 signals from plasma membrane rafts that facilitate EGFR interaction and transactivation. An understanding of the spatiotemporal control of TGR5 signaling provides insights into the actions of BAs and therapeutic TGR5 agonists/antagonists.

Efficient production of cyclodextrins (CDs) has always been challenging. CDs are primarily produced from starch via cyclodextrin glycosyltransferase (CGTase), which acts on α-1,4 glucosidic bonds; however, α-1,6 glucosidic bonds in starch suppress the enzymatic production of CDs. In this study, a glycogen debranching enzyme from Saccharolobus solfataricus STB09 (SsGDE) was utilized to promote the production of β-CD by hydrolyzing α-1,6 glucosidic bonds. The addition of SsGDE (750 U/g of starch) at the liquefaction stage remarkably improved the β-CD yield, with a 43.9% increase. Further mechanism exploration revealed that SsGDE addition could hydrolyze specific branches with less generation of byproducts, thereby promoting CD production. The chain segments of a degree of polymerization ≥13 produced by SsGDE debranching could also be utilized by β-CGTase to convert into CDs. Overall, these findings proposed a new approach of combining SsGDE with β-CGTase to enhance the CD yield.

In this study, binary amorphous solid dispersions (ASDs, fisetin-Eudragit ® ) and ternary amorphous solid inclusions (ASIs, fisetin-Eudragit ® -HP-β-cyclodextrin) of fisetin (FIS) were prepared by the mechanochemical method without solvent. The amorphous nature of FIS in ASDs and ASIs was confirmed using XRPD (X-ray powder diffraction). DSC (Differential scanning calorimetry) confirmed full miscibility of multicomponent delivery systems. FT-IR (Fourier-transform infrared analysis) confirmed interactions that stabilize FIS's amorphous state and identified the functional groups involved. The study culminated in evaluating the impact of amorphization on water solubility and conducting in vitro antioxidant assays: 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)-ABTS, 2,2-diphenyl-1-picrylhydrazyl-DPPH, Cupric Reducing Antioxidant Capacity-CUPRAC, and Ferric Reducing Antioxidant Power-FRAP and in vitro neuroprotective assays: inhibition of acetylcholinesterase-AChE and butyrylcholinesterase-BChE. In addition, molecular docking allowed for the determination of possible bonds and interactions between FIS and the mentioned above enzymes. The best preparation turned out to be ASI&#95;30&#95;EPO (ASD fisetin-Eudragit ® containing 30% FIS in combination with HP-β-cyclodextrin), which showed an improvement in apparent solubility (126.5 ± 0.1 µg∙mL -1 ) and antioxidant properties (ABTS: IC 50 = 10.25 µg∙mL -1 , DPPH: IC 50 = 27.69 µg∙mL -1 , CUPRAC: IC 0.5 = 9.52 µg∙mL -1 , FRAP: IC 0.5 = 8.56 µg∙mL -1 ) and neuroprotective properties (inhibition AChE: 39.91%, and BChE: 42.62%).

The pathogenic mechanisms of bacterial infections and resultant sepsis are partly attributed to dysregulated inflammatory responses sustained by some late-acting mediators including the procathepsin-L (pCTS-L). It was entirely unknown whether any compounds of the U.S. Drug Collection could suppress pCTS-L-induced inflammation, and pharmacologically be exploited into possible therapies. Here, we demonstrated that a macrophage cell-based screening of a U.S. Drug Collection of 1360 compounds resulted in the identification of progesterone (PRO) as an inhibitor of pCTS-L-mediated production of several chemokines [e.g., Epithelial Neutrophil-Activating Peptide (ENA-78), Monocyte Chemoattractant Protein-1 (MCP-1) or MCP-3] and cytokines [e.g., Interleukin-10 (IL-10) or Tumor Necrosis Factor (TNF)] in primary human peripheral blood mononuclear cells (PBMCs). In vivo , these PRO-entrapping 2,6-dimethal-β-cyclodextrin (DM-β-CD) nanoparticles (containing 1.35 mg/kg PRO and 14.65 mg/kg DM-β-CD) significantly increased animal survival in both male (from 30% to 70%, n = 20, P = 0.041) and female (from 50% to 80%, n = 30, P = 0.026) mice even when they were initially administered at 24 h post the onset of sepsis. This protective effect was associated with a reduction of sepsis-triggered accumulation of three surrogate biomarkers [e.g., Granulocyte Colony Stimulating Factor (G-CSF) by 40%; Macrophage Inflammatory Protein-2 (MIP-2) by 45%; and Soluble Tumor Necrosis Factor Receptor I (sTNFRI) by 80%]. Surface Plasmon Resonance (SPR) analysis revealed a strong interaction between PRO and pCTS-L (K D = 78.2 ± 33.7 nM), which was paralleled with a positive correlation between serum PRO concentration and serum pCTS-L level (ρ = 0.56, P = 0.0009) or disease severity (Sequential Organ Failure Assessment, SOFA; ρ = 0.64, P = 0.0001) score in septic patients. Our observations support a promising opportunity to explore DM-β-CD nanoparticles entrapping lipophilic drugs as possible therapies for clinical sepsis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qiang, Chen, Zhu, Li, Qi, Lou, Wang, Tracey and Wang.)

Macrophages are critical regulators of the tumor microenvironment and often present an immuno-suppressive phenotype, supporting tumor growth and immune evasion. Promoting a robust pro-inflammatory macrophage phenotype has emerged as a therapeutic modality that supports tumor clearance, including through synergy with immune checkpoint therapies. Polyglucose nanoparticles (macrins), which possess high macrophage affinity, are useful vehicles for delivering drugs to macrophages, potentially altering their phenotype. Here, we examine the potential of functionalized macrins, synthesized by crosslinking carboxymethyl dextran with L- lysine, as effective carriers of immuno-stimulatory drugs to tumor-associated macrophages (TAMs). Azide groups incorporated during particle synthesis provided a handle for click-coupling of propargyl-modified β-cyclodextrin to macrins under mild conditions. Fluorescence-based competitive binding assays revealed the ability of β-cyclodextrin to non-covalently bind to hydrophobic immuno-stimulatory drug candidates (K eq ~ 10 3 M -1 ), enabling drug loading within nanoparticles. Furthermore, transcriptional profiles of macrophages indicated robust pro-inflammatory reprogramming (elevated Nos2 and Il12 ; suppressed Arg1 and Mrc1 expression levels) for a subset of these immuno-stimulatory agents (UNC2025 and R848). Loading of R848 into the modified macrins improved the drug's effect on primary murine macrophages by three-fold in vitro . Intravital microscopy in IL-12-eYFP reporter mice (24 h post-injection) revealed a two-fold enhancement in mean YFP fluorescence intensity in macrophages targeted with R848-loaded macrins, relative to vehicle controls, validating the desired pro-inflammatory reprogramming of TAMs in vivo by cell-targeted drug delivery. Finally, in an intradermal MC38 tumor model, cyclodextrin-modified macrin NPs loaded with immunostimulatory drugs significantly reduced tumor growth. Therefore, efficient and effective repolarization of tumor-associated macrophages to an M1-like phenotype-via drug-loaded macrins-inhibits tumor growth and may be useful as an adjuvant to existing immune checkpoint therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sarkar, Arlauckas, Cuccarese, Garris, Weissleder and Rodell.)

Cholesterol is one of the major markers for cardiovascular diseases. Herein, a portable cholesterol measurement system based on fluorescence color detection was constructed by combining the high sensitivity of fluorescence analysis with the ease of color sensing to determine low levels of serum cholesterol. Cyclodextrin capping gold nanoclusters with blue-green emission were used as fluorescent probes because cholesterol exposure induced fluorescence enhancement of the probe due to the host-guest inclusion interaction between cholesterol and the cavity of cyclodextrin. The integrated sensing system consisted of modules including a microprocessor, a power supply, an LED light with a constant current source, an RGB color sensor, a display, and a darkroom. All the modules except the display screen were placed in a 3D printing darkroom to avoid interference from ambient light. An RGB color sensor TCS230 was applied to capture the RGB signals of the fluorescent color of the probe solution before and after cholesterol addition. Then the obtained RGB signals were converted into the signals in Hue, Saturation, and Value (HSV) color space with a central control chip STM32F407. The Hue value of the fluorescent color of the solution can discriminate the concentration change of cholesterol. Experimental results demonstrate that the system responds linearly to cholesterol in the concentration range of 20.00 ∼ 150.00 μmol·L -1 with a detection limit of 16.07 μmol·L -1 (3σ, n = 3). The detection of the system has good consistency and accuracy compared with the standard instrument, showing potential for the detection of low levels of serum cholesterol., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Dimethyl phthalate (DMP) is widely used as plasticizer, and this kind of plastic industry wastewater is refractory due to the complex chemical structure and endocrine disrupting property. In order to effectively degrade and mineralize DMP contaminated wastewater, a heterogeneous UVC/VUV-Fenton catalyst system was designed with the amendment of targeted design catalyst Fe 3 O 4 @CM-β-CD/rGO with core-shell like structure covered with loose convex folded lamellar. The optimum removal and mineralization efficiency of DMP were 98.6 % and 62.8 % in 30 min with 150 mg L -1 Fe 3 O 4 @CM-β-CD/rGO and 8 mmol L -1 H 2 O 2 . This efficient and fast removal were attributed to a variety of photocatalytic oxidative active species •OH, •O 2 - and h + with 59.6%, 29.1% and 9.9% contribution ratio, which mainly took effect on benzene ring open and side-chain fracture by oxidative, hydrolysis and hydrogen substitution determined by the rupture energy requirement from chemical bond in DMP. The target function of CM-β-CD in catalyst controlled the photo-electron generation rate and shorten mass transfer distance by the cladding lamellar, moreover, rGO accelerated the redox between Fe (II) and Fe (III) and electron transfer. The catalytic recovery and removal to DMP kept above 90 % after five recycles. This study provided an excellent performance catalyst and an effective photo-Fenton approach and for the treatment of endocrine disrupting wastewater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Multifunctional hydrogel adhesives inhibiting infections and enabling the electrical stimulation (ES) of tissue reparation are highly desirable for the healing of surgical wounds and other skin injuries. Herein, a therapeutic nanocomposite hydrogel is designed by integrating β-cyclodextrin-embedded Ag nanoparticles ( CD AgNPs) in a polyvinyl alcohol (PVA) matrix enhanced with free β-cyclodextrin (CD) and an atypical macromolecule made of β-glucan grafted with hyaluronic acid (HAG). The main objective is to develop a biocompatible dressing combining the electroconductivity and antibacterial activity of CD AgNPs with the cohesiveness and porosity of PVA and the anti-inflammatory, moisturizing, and cell proliferation-promoting properties of HAG. The last component, CD, is added to strengthen the network structure of the hydrogel. PVA/CD/HAG/ CD AgNP exhibited excellent adhesion strength, biocompatibility, electroconductivity, and antimicrobial activity against a wide range of bacteria. In addition, the nanocomposite hydrogel has a swelling ratio and water retention capacity suitable to serve as a wound dressing. PVA/CD/HAG/ CD AgNP promoted the proliferation of fibroblast in vitro, accelerated the healing of skin wounds in an animal model, and is hemostatic. Upon ES, the PVA/CD/HAG/ CD AgNP nanocomposite hydrogel became more efficient both in vitro and in vivo further speeding up the skin healing process thus demonstrating its potential as a next-generation electroconductive wound dressing., (© 2023 Wiley‐VCH GmbH.)

Taste, especially unpleasant taste, can be key for patient compliance. In the formulation development process, drug-cyclodextrin (CD) inclusion complexes are often used to improve the solubility of a drug and/or mask its bitterness. This study aimed to evaluate the bitter masking effect of CDs on different drugs using NMR-ROESY analysis, human sensory tests, and e-tongue measurements. The strength of inclusion complex formation between drugs and CDs was investigated by NMR-ROSEY, and these results were compared to human sensory test results. In the sensory test, participants identified which drug-CD inclusion complexes were not bitter. NMR-ROSEY results aligned with the sensory tests; short magnetization transfer times corresponded to masked bitterness. The electrical tongue was not able to detect the taste of any of the drug-CD inclusion complexes. Additionally, we used NMR-ROSEY to determine which drug-CD inclusion complex formed in a system with multiple drug substances present. This research offers valuable insights into the bitter masking effect of CDs on different drugs and presents a comprehensive evaluation approach using various methods. This knowledge has significant implications for the pharmaceutical industry, clinical practice, and patient care, contributing to improved patient compliance and satisfaction with bitter medications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)