Comparative pharmacokinetic study of Anisodamine Hydrobromide tablets and injection in septic acute lung injury rats.

Aim: We aimed to establish a sensitive LC-MS/MS method to analyze the pharmacokinetics of Ani HBr tablets and injection. Methods: Around 10 mmNH4Ac containing 0.1% formic acid and acetonitrile were used as the mobile phase. Acute lung injury in septic and normal rats, respectively, were administered Ani HBr tablets at doses of 12.5, 25 and 50 mg/kg and injection at doses of 4, 8 and 16 mg/kg, followed by extraction of the drugs from plasma using ethyl acetate for subsequent analysis. Results & conclusion: The method met the requirements for biological analysis. Ani HBr tablets absorbed slowly in rats with disease, tail vein administration was a more promising approach for treating septic acute lung injury.

[Box: see text].

Photon-gated foldaxane assembly/disassembly.

Integrating multiple anthracene motifs into aromatic oligoamide sequences gives rise to photoactive foldamers that can sequester a molecular thread forming helix-on-axle assemblies. Photoirradiation is shown to distort the helical host and drive dissociation of the supramolecular assembly and thread liberation as signalled by a photonic output, while thermal reversion regenerates the assembly.

Population structure of Taenioides sp. (Gobiiformes, Gobiidae) reveals their invasion history to inland waters of China based on mitochondrial DNA control region.

Taenioides sp. is a small temperate fish originally known to inhabit muddy bottoms of brackish waters in coastal areas of China. However, it began to invade multiple inland freshwaters and caused severe damage to Chinese aquatic ecosystems in recent years. To investigate the sources and invasive history of this species, we examined the population structure of 141 individuals collected from seven locations based on partial mitochondrial D-loop regions. The results revealed that the genetic diversity gradually decreased from south to north, with the Yangtze River Estuary and Taihu Lake populations possessing the highest haplotype diversity (Hd), average number of differences (k), and nucleotide diversity (π) values, suggesting that they may be the sources of Taenioides sp. invasions. Isolation-by-distance analysis revealed a non-significant correlation (p = 0.166) between genetic and geographic distances among seven populations, indicating that dispersal mediated through the regional hydraulic projects may have played an essential role in Taenioides sp. invasions. The population genetic structure analysis revealed two diverged clades among seven populations, with clade 2 only detected in source populations, suggesting a possible difference in the invasion ability of the two clades. Our results provide insights into how native estuary fish become invasive through hydraulic projects and may provide critical information for the future control of this invasive species.

Kaempferol efficacy in metabolic diseases: Molecular mechanisms of action in diabetes mellitus, obesity, non-alcoholic fatty liver disease, steatohepatitis, and atherosclerosis.

The incidence of metabolic diseases has progressively increased, which has a negative impact on human health and life safety globally. Due to the good efficacy and limited side effects, there is growing interest in developing effective drugs to treat metabolic diseases from natural compounds. Kaempferol (KMP), an important flavonoid, exists in many vegetables, fruits, and traditional medicinal plants. Recently, KMP has received widespread attention worldwide due to its good potential in the treatment of metabolic diseases. To promote the basic research and clinical application of KMP, this review provides a timely and comprehensive summary of the pharmacological advances of KMP in the treatment of four metabolic diseases and its potential molecular mechanisms of action, including diabetes mellitus, obesity, non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and atherosclerosis. According to the research, KMP shows remarkable therapeutic effects on metabolic diseases by regulating multiple signaling transduction pathways such as NF-κB, Nrf2, AMPK, PI3K/AKT, TLR4, and ER stress. In addition, the most recent literature on KMP's natural source, pharmacokinetics studies, as well as toxicity and safety are also discussed in this review, thus providing a foundation and evidence for further studies to develop novel and effective drugs from natural compounds. Collectively, our manuscript strongly suggested that KMP could be a promising candidate for the treatment of metabolic diseases.

Phillygenin Inhibits TGF-ß1-induced Hepatic Stellate Cell Activation and Inflammation: Regulation of the Bax/Bcl-2 and Wnt/ß-catenin Pathways.

Hepatic fibrosis (HF), a precursor to cirrhosis and hepatocellular carcinoma, is caused by abnormal proliferation of connective tissue and excessive accumulation of extracellular matrix in the liver. Notably, activation of hepatic stellate cells (HSCs) is a key link in the development of HF. Phillygenin (PHI, C21H24O6) is a lignan component extracted from the traditional Chinese medicine Forsythiae Fructus, which has various pharmacological activities such as anti-inflammatory, antioxidant and anti-tumour effects. However, whether PHI can directly inhibit HSC activation and ameliorate the mechanism of action of HF has not been fully elucidated. Therefore, the aim of the present study was to investigate the in vitro anti-HF effects of PHI and the underlying molecular mechanisms. Transforming growth factor-ß1 (TGF-ß1)-activated mouse HSCs (mHSCs) and human HSCs (LX-2 cells) were used as an in vitro model of HF and treated with different concentrations of PHI for 24 h. Subsequently, cell morphological changes were observed under the microscope, cell viability was analyzed by MTT assay, cell cycle and apoptosis were detected by flow cytometry, and the mechanism of anti-fibrotic effect of PHI was explored by immunofluorescence, ELISA, RT-qPCR and western blot. The results showed that PHI suppressed the proliferation of TGF-ß1-activated mHSCs and LX-2 cells, arrested the cell cycle at the G0/G1 phase, decreased the levels of α-SMA, Collagen I, TIMP1 and MMP2 genes and proteins, and promoted apoptosis in activated mHSCs and LX-2 cells. Besides, PHI reduced the expression of inflammatory factors in activated mHSCs and LX-2 cells, suggesting a potential anti-inflammatory effect. Mechanically, PHI inhibited TGF-ß1-induced HSC activation and inflammation, at least in part through modulation of the Bax/Bcl-2 and Wnt/ß-catenin pathways. Overall, PHI has significant anti-HF effects and may be a promising agent for the treatment of HF.

A comprehensive review on pharmacological, toxicity, and pharmacokinetic properties of phillygenin: Current landscape and future perspectives.

Forsythiae Fructus is a traditional Chinese medicine frequently in clinics. It is extensive in the treatment of various inflammation-related diseases and is renowned as 'the holy medicine of sores'. Phillygenin (C21H24O6, PHI) is a component of lignan that has been extracted from Forsythiae Fructus and exhibits notable biological activity. Modern pharmacological studies have confirmed that PHI demonstrates significant activities in the treatment of various diseases, including inflammatory diseases, liver diseases, cancer, bacterial infection and virus infection. Therefore, this review comprehensively summarizes the pharmacological effects of PHI up to June 2023 by searching PubMed, Web of Science, Science Direct, CNKI, and SciFinder databases. According to the data, PHI shows remarkable anti-inflammatory, antioxidant, hepatoprotective, antitumour, antibacterial, antiviral, immunoregulatory, analgesic, antihypertensive and vasodilatory activities. More importantly, NF-κB, MAPK, PI3K/AKT, P2X7R/NLRP3, Nrf2-ARE, JAK/STAT, Ca2+-calcineurin-TFEB, TGF-ß/Smads, Notch1 and AMPK/ERK/NF-κB signaling pathways are considered as important molecular targets for PHI to exert these pharmacological activities. Studies of its toxicity and pharmacokinetic properties have shown that PHI has very low toxicity, incomplete absorption in vivo and low oral bioavailability. In addition, the physico-chemical properties, new formulations, derivatives and existing challenges and prospects of PHI are also reviewed and discussed in this paper, aiming to provide direction and rationale for the further development and clinical application of PHI.

Luteolin as a potential hepatoprotective drug: Molecular mechanisms and treatment strategies.

Luteolin is a flavonoid widely present in various traditional Chinese medicines. In recent years, luteolin has received more attention due to its impressive liver protective effect, such as metabolic associated fatty liver disease, hepatic fibrosis and hepatoma. This article summarizes the pharmacological effects, pharmacokinetic characteristics, and toxicity of luteolin against liver diseases, and provides prospect. The results indicate that luteolin improves liver lesions through various mechanisms, including inhibiting inflammatory factors, reducing oxidative stress, regulating lipid balance, slowing down excessive aggregation of extracellular matrix, inducing apoptosis and autophagy of liver cancer cells. Pharmacokinetics research manifested that due to metabolic effects, the bioavailability of luteolin is relatively low. It is worth noting that appropriate modification, new delivery systems, and derivatives can enhance its bioavailability. Although many studies have shown that the toxicity of luteolin is minimal, strict toxicity experiments are still needed to evaluate its safety and promote its reasonable development. In addition, this study also discussed the clinical applications related to luteolin, indicating that it is a key component of commonly used liver protective drugs in clinical practice. In view of its excellent pharmacological effects, luteolin is expected to become a potential drug for the treatment of various liver diseases.

[3]Foldarotaxane-mediated synthesis of an improbable [2]rotaxane.

The wrapping of an aromatic oligoamide helix around an active ester-containing [2]rotaxane enforced the sliding and the sequestration of the surrounding macrocycle around a part of the axle for which it has no formal affinity. The foldamer-mediated compartmentalization of the [2]rotaxane shuttle was subsequently used to prepare an improbable rotaxane.

Self-assembling figure-of-eight and pseudoplectoneme aromatic oligoamide ribbons.

Two oligoamide macrocycles composed of eight and twelve 7-amino-8-fluoro-2-quinolinecarboxylic acid monomers were synthesised despite the propensity of their acyclic precursors to fold and self-assemble into double helices. Macrocyclisations were made possible through the transient use of helicity disruptors. The resulting macrocyclic ribbons were found to adopt figure-of-eight and pseudoplectoneme shapes that maintain an ability to self-assemble.

Biomimetic Separation of Transport and Matrix Functions in Lamellar Block Copolymer Channel-Based Membranes.

Cell membranes control mass, energy, and information flow to and from the cell. In the cell membrane a lipid bilayer serves as the barrier layer, with highly efficient molecular machines, membrane proteins, serving as the transport elements. In this way, highly specialized transport properties are achieved by these composite materials by segregating the matrix function from the transport function using different components. For example, cell membranes containing aquaporin proteins can transport ∼4 billion water molecules per second per aquaporin while rejecting all other molecules including salts, a feat unmatched by any synthetic system, while the impermeable lipid bilayer provides the barrier and matrix properties. True separation of functions between the matrix and the transport elements has been difficult to achieve in conventional solute separation synthetic membranes. In this study, we created membranes with distinct matrix and transport elements through designed coassembly of solvent-stable artificial (peptide-appended pillar[5]arene, PAP5) or natural (gramicidin A) model channels with block copolymers into lamellar multilayered membranes. Self-assembly of a lamellar structure from cross-linkable triblock copolymers was used as a scalable replacement for lipid bilayers, offering better stability and mechanical properties. By coassembly of channel molecules with block copolymers, we were able to synthesize nanofiltration membranes with sharp selectivity profiles as well as uncharged ion exchange membranes exhibiting ion selectivity. The developed method can be used for incorporation of different artificial and biological ion and water channels into synthetic polymer membranes. The strategy reported here could promote the construction of a range of channel-based membranes and sensors with desired properties, such as ion separations, stimuli responsiveness, and high sensitivity.

A Four-Armed Unsymmetrical Cryptand: From Two Different Host-Guest Interactions to Responsive Supramolecular Polymer.

By linking BMP32C10 and DB24C8 motifs together, a four-armed cryptand 1 is synthesized successfully, in which BMP32C10 motif can bind paraquat 2 while DB24C8 motif can complex dibenzylammonium salt 3 in spite of the electrostatic repulsion between guests 2 and 3. The base/acid-responsive supramolecular polymer is constructed further via two kinds of host-guest interactions between cryptand 1 and two homoditopic paraquat 4 and dibenzylammonium salt 5 similar to guests 2 and 3.

GSH-Responsive supramolecular nanoparticles constructed by ß-d-galactose-modified pillar[5]arene and camptothecin prodrug for targeted anticancer drug delivery.

Supramolecular construction of a targeted and stimuli-responsive drug delivery system is still a challenging task. Herein, GSH-responsive supramolecular prodrug nanoparticles were constructed by the host-guest complexation between a ß-d-galactose-functionalized water-soluble pillar[5]arene (GalP5) and a disulfide bond containing camptothecin prodrug (G). The obtained prodrug nanoparticles were stable under physiological conditions, whereas efficient drug release was triggered in a simulated tumor environment with high GSH concentration. In vitro studies revealed that these prodrug nanoparticles preferentially entered asialoglycoprotein receptor-overexpressing HepG2 cells due to the active targeting effect of galactose units. This active targeting effect resulted in the maximization of anticancer efficacy and reduction of the undesirable side effects to normal cells.

Glucose-Responsive Supramolecular Vesicles Based on Water-Soluble Pillar[5]arene and Pyridylboronic Acid Derivatives for Controlled Insulin Delivery.

The stimuli-responsive behavior of supramolecular nanocarriers is crucial for their potential applications as smart drug delivery systems. We hereby constructed a glucose-responsive supramolecular drug delivery system based on the host-guest interaction between a water-soluble pillar[5]arene (WP5) and a pyridylboronic acid derivative (G) for insulin delivery and controlled release under physiological conditions. The approach represents the ideal treatment of diabetes mellitus. The drug loading and in vitro drug release experiments demonstrated that large molecular weight insulin could be encapsulated into the vesicles with high loading efficiency, which, to our knowledge, is the first example of small-size supramolecular vesicles with excellent encapsulation capacity of a large protein molecule. Moreover, FITC-labeled insulin was used to evaluate the release behavior of insulin, and it was demonstrated that high glucose concentration could facilitate the quick release of insulin, suggesting a smart drug delivery system for potential application in controlled insulin release only under hyperglycemic conditions. Finally, we demonstrated that these supramolecular nanocarriers have good cytocompatibility, which is essential for their further biomedical applications. The present study provides a novel strategy for the construction of glucose-responsive smart supramolecular drug delivery systems, which has potential applications for the treatment of diabetes mellitus.

Dual-Responsive Bola-Type Supra-Amphiphile Constructed from Water-Soluble Pillar[5]arene and Naphthalimide-Containing Amphiphile for Intracellular Drug Delivery.

Supramolecular construction of multistimuli platform for drug delivery is a challenging task. In this work, a pH and GSH (glutathione) dual-responsive bola-type supramolecular amphiphile was successfully fabricated by the complexation between a water-soluble pillar[5]arene (WP5) and a bolaform naphthalimide guest (G) in water. The resulting bola-type amphiphile further self-assembled into supramolecular binary vesicles, which could be disassembled by low pH, a high-GSH-concentration environment, or both. Furthermore, the results of drug loading and releasing tests showed that doxorubicin (DOX), the hydrophobic anticancer drug, could be successfully encapsulated into the Stern region of the obtained supramolecular vesicles and generated the DOX-loaded vesicles with good drug-loading efficiency. Moreover, the obtained DOX-loaded vesicles displayed efficient and rapid DOX release at a simulated tumor microenvironment with low-pH or excess-GSH conditions or both. Significantly, cytotoxicity experiments revealed that the DOX-loaded supramolecular vesicles could obviously improve the anticancer efficiency of free DOX for tumor cells while remarkably reducing its side effects for normal cells. In vitro cellular uptake and subcellular localization assays further proved that these smart drug nanovehicles, entering cancer cells mainly via endocytosis, could cause excellent drug accumulation in cancer cells. The present study provides a successful example with which to rational design an effective bola-type stimuli-responsive supramolecular nanocarrier, which might have wide potential applications in the construction of various controlled drug-delivery systems.

Photolysis of a bola-type supra-amphiphile promoted by water-soluble pillar[5]arene-induced assembly.

A bola-type supra-amphiphile assembled from a water-soluble pillar[5]arene host (WP5) and a rod-coil guest molecule (G) containing a photoactive 9,10-dialkoxyanthracene group was successfully constructed, which could further assemble into a monolayer supramolecular vesicle. Interestingly, the photodecomposition rate of G was remarkably promoted after its aggregation with WP5, accompanied by the disassembly of the formed supramolecular vesicle, especially with the coassembly of a photosensitizer eosin Y, which has potential applications in phototherapy.

4-Methylcoumarin-bridged fluorescent responsive cryptand: from [2+2] photodimerization to supramolecular polymer.

A fluorescent responsive BMP32C10-based cryptand host was successfully synthesized by introducing a 4-methylcoumarin group to the third arm of the cryptand. The cryptand was able to undergo [2+2] photodimerization on UV irradiation (λ = 365 nm) and, based on the photodimerization and host-guest interaction, a new supramolecular polymer was constructed in a convenient manner.

Dramatically Promoted Swelling of a Hydrogel by Pillar[6]arene-Ferrocene Complexation with Multistimuli Responsiveness.

The swelling-shrinking transition of hydrogels is crucial for their wide applications such as actuators and drug delivery. We hereby fabricated a smart hydrogel with ferrocene groups on pendant of polymer networks. While it was immersed in the water-soluble pillar[6]arene (WP6) aqueous solution, the hydrogel was dramatically swollen, which was an approximately 11-fold promotion in weight compared with that in pure water, due to the formation of the inclusion complexes between WP6 and ferrocene groups in the hydrogel. In particular, the well-swollen hydrogel exhibited good responsiveness to multistimuli including temperature, pH, redox, and competitive guests by tuning the dissociation/formation of WP6-ferrocene inclusion complexes or the strength of their charges. Meanwhile, potential application of such a smart hydrogel in pH-responsive drug release was demonstrated as well.