Anti-inflammatory bicyclic polyprenylated acylphloroglucinols with diverse architectures including an unprecedented 6/6/6 tricyclic core from Garcinia yunnanensis.

Garciyunnanol A (1), an unprecedented 1,2-seco-bicyclic polyprenylated acylphloroglucinol (BPAP) possessing a unique 6/6/6 tricyclic core, was characterized from Garcinia yunnanensis together with 16 BPAPs, including eight new compounds (garciyunnanols B-I, 2-9). Biogenetically, the bicyclo[3.3.1]nonane-2,4,9-trione moiety of 12 reconstructed the bicyclic δ-lactone core of 2 through Norrish type Ⅰ cleavage and cyclization, followed by a cyclization of two side chains to form an intriguing 6/6/6 tricyclic core of 1. Their structures were elucidated through analysis of spectroscopic data, calculation and comparison of ECD spectra. Bioactivity evaluation manifested that compounds 1, 2, 5, 6 and 14 demonstrated superior inhibition of NO production compared to the positive control dexamethasone. Notably, compound 5 exhibited a dose-dependent inhibitory effect on NO production, with an IC50 value of 0.25 ± 0.87 µM. Furthermore, experiments involving ELISA, Western blotting, and immunofluorescence staining revealed that 5 effectively reduced the secretion of interleukin-1ß in LPS plus nigericin-stimulated THP-1 macrophages by inhibiting the activation of the NLRP3 inflammasome.

Single Molecular Nanomedicines Based on Macrocyclic Carrier-Drug Conjugates for Concentration-Independent Encapsulation and Precise Activation of Drugs.

Nanomedicines often rely on noncovalent self-assembly and encapsulation for drug loading and delivery. However, challenges such as reproducibility issues due to the multicomponent nature, off-target activation caused by premature drug release, and complex pharmacokinetics arising from assembly dissociation have hindered their clinical translation. In this study, we introduce an innovative design concept termed single molecular nanomedicine (SMNM) based on macrocyclic carrier-drug conjugates. Through the covalent linkage of two chemotherapy drugs to a hypoxia-cleavable macrocyclic carrier, azocalix[4]arene, we obtained two self-included complexes to serve as SMNMs. The intramolecular inclusion feature of the SMNMs has not only demonstrated comprehensive shielding and protection for the drugs but also effectively prevented off-target drug leakage, thereby significantly reducing their side effects and enhancing their antitumor therapeutic efficacy. Additionally, the attributes of being a single component and molecularly dispersed confer advantages such as ease of preparation and good reproducibility for SMNMs, which is desirable for clinical applications.

Risk Factors Asscociated with Hypokalemia during Postanesthesia Recovery and Its Impact on Outcomes in Gynecological Patients: A Propensity Score Matching Study.

OBJECTIVE: This study aimed to explore the risk factors and outcomes of hypokalemia during the recovery period from anesthesia in the gynecological population. METHODS: This retrospective cohort study included 208 patients who underwent gynecological surgery at our institution between January 2021 and March 2022. Data were collected for each patient, including demographics, disease status, surgical data, and clinical information. Preoperative bowel preparation, postoperative gastrointestinal function, and electrolyte levels were compared between the two groups using propensity score matching (PSM). RESULTS: The incidence of hypokalemia (serum potassium level <3.5 mmol/L) during the recovery period from anesthesia was approximately 43.75%. After PSM, oral laxative use (96.4% vs. 82.4%, P=0.005), the number of general enemas (P=0.014), and the rate of ≥2 general enemas (92.9% vs. 77.8%, P=0.004) were identified as risk factors for hypokalemia, which was accompanied by decreased PaCO2 and hypocalcemia. There were no significant differences in postoperative gastrointestinal outcomes, such as the time to first flatus or feces, the I-FEED score (a scoring system was created to evaluate impaired postoperative gastrointestinal function), or postoperative recovery outcomes, between the hypokalemia group and the normal serum potassium group. CONCLUSION: Hypokalemia during postanesthesia recovery period occurred in 43.75% of gynecological patients, which resulted from preoperative mechanical bowel preparation; however, it did not directly affect clinical outcomes, including postoperative gastrointestinal function, postoperative complications, and length of hospital stay.

Active targeting tumor therapy using host-guest drug delivery system based on biotin functionalized azocalix[4]arene.

Host-guest drug delivery systems (HGDDSs) provided a facile method for incorporating biomedical functions, including efficient drug-loading, passive targeting, and controlled drug release. However, developing HGDDSs with active targeting is hindered by the difficult functionalization of popular macrocycles. Herein, we report an active targeting HGDDS based on biotin-modified sulfonated azocalix[4]arene (Biotin-SAC4A) to efficiently deliver drug into cancer cells for improving anti-tumor effect. Biotin-SAC4A was synthesized by amide condensation and azo coupling. Biotin-SAC4A demonstrated hypoxia responsive targeting and active targeting through azo and biotin groups, respectively. DOX@Biotin-SAC4A, which was prepared by loading doxorubicin (DOX) in Biotin-SAC4A, was evaluated for tumor targeting and therapy in vitro and in vivo. DOX@Biotin-SAC4A formulation effectively killed cancer cells in vitro and more efficiently delivered DOX to the lesion than the similar formulation without active targeting. Therefore, DOX@Biotin-SAC4A significantly improved the in vivo anti-tumor effect of free DOX. The facilely prepared Biotin-SAC4A offers strong DOX complexation, active targeting, and hypoxia-triggered release, providing a favorable host for effective breast cancer chemotherapy in HGDDSs. Moreover, Biotin-SAC4A also has potential to deliver agents for other therapeutic modalities and diseases.

Aptamer-functionalized hydrogels promote bone healing by selectively recruiting endogenous bone marrow mesenchymal stem cells.

Bone regeneration heavily relies on bone marrow mesenchymal stem cells (BMSCs). However, recruiting endogenous BMSCs for in situ bone regeneration remains challenging. In this study, we developed a novel BMSC-aptamer (BMSC-apt) functionalized hydrogel (BMSC-aptgel) and evaluated its functions in recruiting BMSCs and promoting bone regeneration. The functional hydrogels were synthesized between maleimide-terminated 4-arm polyethylene glycols (PEG) and thiol-flanked PEG crosslinker, allowing rapid in situ gel formation. The aldehyde group-modified BMSC-apt was covalently bonded to a thiol-flanked PEG crosslinker to produce high-density aptamer coverage on the hydrogel surface. In vitro and in vivo studies demonstrated that the BMSC-aptgel significantly increased BMSC recruitment, migration, osteogenic differentiation, and biocompatibility. In vivo fluorescence tomography imaging demonstrated that functionalized hydrogels effectively recruited DiR-labeled BMSCs at the fracture site. Consequently, a mouse femur fracture model significantly enhanced new bone formation and mineralization. The aggregated BMSCs stimulated bone regeneration by balancing osteogenic and osteoclastic activities and reduced the local inflammatory response via paracrine effects. This study's findings suggest that the BMSC-aptgel can be a promising and effective strategy for promoting in situ bone regeneration.

Triple targeting host-guest drug delivery system based on lactose-modified azocalix[4]arene for tumor ablation.

Host-guest drug delivery systems (HGDDSs) have been studied in an effort to modify the characteristics of therapeutic agents through noncovalent interactions, reduce toxic side effects and improve therapeutic effects. However, it is still an important task to continuously improve the targeting ability of HGDDSs, which is conducive to the development of precision medicine. Herein, we utilize the lactose-modified azocalix[4]arene (LacAC4A) as a triple targeting drug carrier customized for antitumor purposes. LacAC4A integrates three targeting features, passive targeting through the enhancing permeability and retention effect, active targeting by the interactions of lactose and the asialoglycoprotein receptors on the surface of tumor cells, and stimuli-responsive targeting via the reduction of the azo group under a hypoxia microenvironment. After loading doxorubicin (DOX) in LacAC4A, the supramolecular nanoformulation DOX@LacAC4A clearly showed the effective suppression of tumor growth through in vivo experiments. LacAC4A can achieve effective targeting, rapid release, and improve drug bioavailability. This design principle will provide a new material for drug delivery systems.

An Antitumor Dual-Responsive Host-Guest Supramolecular Polymer Based on Hypoxia-Cleavable Azocalix[4]arene.

The exploitation of specific guests which can respond to external stimuli is the main approach for the construction of stimuli-responsive supramolecular polymers (SPs) based on host-guest interactions. Most functional guests, however, fail to manifest stimuli-responses. Herein, a hypoxia-responsive dimeric azocalixarene (D-SAC4A) with outstanding hosting properties was used as the macrocyclic building block for the preparation of host stimuli-responsive SPs. Since azocalixarenes can also be compatible with stimuli-responsive guests, an antitumor drug, camptothecin (CPT), was chosen and linked via a disulfide-containing linker to afford a glutathione (GSH)-responsive ditropic guest (D-CPT). A unique dual-responsive SP was obtained by 1 : 1 mixing of D-SAC4A and D-CPT in water, which further assembled into SP nanoparticles (DSPNs). DSPNs displayed outstanding stability against dilution and biological interferants, as well as precise CPT-release under GSH and hypoxia conditions. In vitro and in vivo experiments demonstrated the good biosafety and tumor-suppressive effects of DSPNs.

A heteromultivalent host-guest sensor array for cell recognition and discrimination.

We present a supramolecular sensor array based on a series of heteromultivalent macrocyclic coassemblies using amphiphilic calixarenes and cyclodextrin as the building blocks for cell recognition. The corresponding cross-reactivity between the coassemblies and cells served as the unique fingerprint for cell classification, and successfully identified the normal cell lines, cancerous cell lines, and cross-contaminated cells.

Structural Elucidation and Total Synthesis for the Pair of Unprecedented Polypyridines with Anti-AChE and HIV-1 Protease Activities from Alangium chinense.

Unlike reported pyridine hybrids, 2S (1a) and 2R-alanginenmine A (1b) from Alangium chinense featuring an unprecedented piperidine-bridged polypyridine skeleton represented a pair of alkaloid subtypes with a unique multiple pyridine scaffold. Enlightened by the rare structural characteristics and possible biosynthetic pathway, (±)-alanginenmine A (1) have been achieved in ideal yield by gram-class total synthesis with four steps. In addition, both compounds 1a and 1b exhibited anti-acetylcholinesterase (AChE) and HIV-1 protease activities in the biological activity evaluation. Further, molecular docking was investigated for the mechanism of action between the isolated compounds and HIV-1 protease. The stronger Coulomb interactions and van der Waals interaction, as well as the hydrogen bond interactions of 1a, might be the main cause for its better anti-HIV-1 protease activity than 1b. This work provided a comprehensive research including natural product discovery, bioactivity evaluation, and total synthesis for the new type of leading anti-HIV-1 protease.

Coassembly of hypoxia-sensitive macrocyclic amphiphiles and extracellular vesicles for targeted kidney injury imaging and therapy.

BACKGROUND: Hypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising therapeutic option against both acute kidney injury and chronic kidney disease; however, an effective strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly (Pc/C5A@EVs) via molecular recognition and self-assembly, which is composed of the macrocyclic amphiphile C5A, the commercial dye sulfonated aluminum phthalocyanine (Pc) and mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs). RESULTS: In murine models of unilateral or bilateral ischemia/reperfusion injury, MSC-EVs protected the Pc/C5A complex from immune metabolism, prolonged the circulation time of the complex, and specifically led Pc/C5A to hypoxic kidneys via surface integrin receptor α4ß1 and αLß2, where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation. Mechanistically, the Pc/C5A coassembly induced M1-to-M2 macrophage transition by inhibiting the HIF-1α expression in hypoxic renal tubular epithelial cells (TECs) and downstream NF-κB signaling pathway to exert their regenerative effects. CONCLUSION: This synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs.

Supramolecular imaging of spermine in cancer cells.

As an important biomarker, the overexpressed spermine has been widely investigated for cancer diagnosis and treatment. However, bioimaging of spermine in living cells is still a formidable challenge. Herein, we design a supramolecular imaging ensemble for spermine by the host-guest complexation of amphiphilic sulfonatocalix[5]arene (SC5A12C) assembly with lucigenin (LCG). Strong binding ability and complexation-induced fluorescence quenching properties enable SC5A12C to quench the fluorescence of LCG dramatically and to recover it completely due to the competition of overexpressed spermine in cancer cells. SC5A12C also exhibits excellent biocompatibility and promotes cellular uptake due to its ability to form ultra-stable assembly. Co-assembling folate further promotes the cellular uptake of folate receptor overexpressed cancer cells, contributing to enhanced bioimaging.

Genus Alangium - A review on its traditional uses, phytochemistry and pharmacological activities.

The species from Alangium have been used as folk medicine to treat rheumatism, skin diseases, diabetes by the people of Southeast Asia. Previous phytochemical studies have shown this genus are rich sources of alkaloids, glycosides, and terpenoids, which have attracted considerable attention of many researchers due to their markedly diverse and complex architecture. The crude extracts as well as the monomeric compounds from the title genus possess anti-tumor, anti-inflammatory, antibacterial, anti-oxidant pharmacological activities. Besides, some isolates from Alangium exhibited the effects on skeletal, smooth muscle and the nervous system. As a large genus of medicinal plants, the medicinal value of Alangium has been widely reported, but there is no review that provide a systematic summary towards its chemical constituents and pharmacological activities, to our knowledge. This work aims to present a comprehensive overview on the traditional uses, phytochemistry, and pharmacological activities of medicinal plants in the genus Alangium, and to explore the evidence supporting its ethnopharmacological effectiveness.

HIF-1α is a Potential Molecular Target for Herbal Medicine to Treat Diseases.

HIF-1α is an important factor regulating oxygen balance in mammals, and its expression is closely related to various physiological and pathological conditions of the body. Because HIF-1α plays an important role in the occurrence and development of cancer and other diseases, it has become an enduring research hotspot. At the same time, natural medicines and traditional Chinese medicine compounds have amazing curative effects in various diseases related to HIF-1 subtype due to their unique pharmacological effects and more effective ingredients. Therefore, in this article, we first outline the structure of HIF-1α and the regulation related to its expression, then introduce various diseases closely related to HIF-1α, and finally focus on the regulation of natural medicines and compound Chinese medicines through various pathways. This will help us understand HIF-1α systematically, and use HIF-1α as a target to discover more natural medicines and traditional Chinese medicines that can treat related diseases.

A host-guest drug delivery nanosystem for supramolecular chemotherapy.

Supramolecular chemotherapy is currently a new strategy to improve the therapeutic efficacy as well as overcome the side effects of traditional chemotherapy. Herein, a supramolecular chemotherapy platform based on the pegylated guanidinium-modified calix[5]arene pentadodecyl ether (GC5A-12C) nanoassembly was prepared. Three commercially available antitumor drugs: oxaliplatin, methotrexate and chlorambucil, all showed strong binding to this GC5A-12C nanocarrier. The supramolecular nanodrugs achieved higher anticancer performances compared with free drugs in cell experiments. Furthermore, the cellular uptake mechanisms and efficacy are confirmed by fluorescence imaging.

A General Hypoxia-Responsive Molecular Container for Tumor-Targeted Therapy.

Enhanced drug delivery can improve the therapeutic efficacy of drugs and help overcome side effects. However, many reported drug-delivery systems are too complex and irreproducible for practical use. In this work, the design of a hypoxia-responsive molecular container based on calixarene, called CAC4A, which presents a significant advance in practical, hypoxia-targeted drug-delivery, is reported. CAC4A enables a wide variety of clinical drugs to be quantitatively loaded to improve their solubility and stability, as well as enable the administration of reduced doses. Furthermore, as a result of its azo functional groups, which are sensitive to reduction within a hypoxic environment, it is possible to achieve tumor-targeted drug-release with reduced side effects. CAC4A fulfils all essential requirements for a drug-delivery system in addition to multiple advantages, including facile preparation, well-defined molecular weight, and structure, and universal applicability. Such features collectively enable supramolecular prodrugs to be formulated simply and reproducibly, with potential for bench-to-bedside translation. Moreover, CAC4A is amenable to other therapy modalities and can be facilely decorated with functional groups and hybridized with nanomaterials, providing ample possibilities for its role in future drug-delivery systems.

A hyaluronidase/ATP tandem stimuli-responsive supramolecular assembly.

We designed a tandem stimuli-responsive assembly based on a guanidinium-modified calix[5]arene (GC5A-6C) and eosin Y modified hyaluronic acid (EY-HA), which showed hyaluronidase-triggered disassembly and ATP-activated release of EY. Both hyaluronidase and ATP are tumor biomarkers, and therefore, the present system shows potential in precision delivery with respect to tumor phototheranostics.

An EGFR-targeting antibody-drug conjugate LR004-VC-MMAE: potential in esophageal squamous cell carcinoma and other malignancies.

Epidermal growth factor receptor (EGFR) is a rational target for cancer therapy, because its overexpression plays an important oncogenic role in a variety of solid tumors; however, EGFR-targeted antibody-drug conjugate (ADC) therapy for esophageal squamous cell carcinoma (ESCC) is exceedingly rare. LR004 is a novel anti-EGFR antibody with the advantages of improved safety and fewer hypersensitivity reactions. It may be of great value as a carrier in ADCs with high binding affinity and internalization ability. Here, we prepared an EGFR-targeting ADC, LR004-VC-MMAE, and evaluated its antitumor activities against ESCC and EGFR-positive cells. LR004 was covalently conjugated with monomethyl auristatin E (MMAE) via a VC linker by antibody interchain disulfide bond reduction. VC-MMAE was conjugated with LR004 with approximately 4.0 MMAE molecules per ADC. LR004-VC-MMAE showed a potent antitumor effect against ESCC and other EGFR-positive cells with IC50 values of nM concentrations in vitro. The in vivo antitumor effects of LR004-VC-MMAE were investigated in ESCC KYSE520 and A431 xenograft nude mice models. Significant activity was seen at 5 mg·kg-1 , and complete tumor regression was observed at 15 mg·kg-1 in the KYSE520 xenograft nude mice after four injections, while the naked antibody LR004 had little effect on inhibiting tumor growth. Similar promising results were obtained in the A431 models. In addition, the tumors also remained responsive to LR004-VC-MMAE for large tumor experiments (tumor volume 400-500 mm3 ). The study results demonstrated that LR004-VC-MMAE could be a potential therapeutic agent for ESCC and other EGFR-expressing malignancies. We also evaluated PK profile of LR004-VC-MMAE ADC in the mice model, which would provide qualitative guiding significance for the further research.

A supramolecular brush polymer via the self-assembly of bridged tris(ß-cyclodextrin) with a porphyrin derivative and its magnetic resonance imaging.

Accurate imaging of soft tissues is one of the ultimate goals in biomedical imaging. Different imaging modalities can improve their disadvantages, and promote the imaging ability. However, once an imaging agent has been prepared, it is usually hard to adjust it according to the actual needs. Herein, we developed a supramolecular brush polymer (SBP) as a versatile imaging agent platform. The SBP platform (SBPP) is constructed by the intermolecular inclusion complexation of bridged tris(ß-cyclodextrin) (1) with Mn(iii)-porphyrin-bearing poly(ethylene glycol) (PEG) side chains (Mn(iii)-TPP), and can further bind other functional groups by host-guest interactions of cyclodextrin and adamantine. The SBPP is characterized by UV/vis absorption spectroscopy, NMR, dynamic light scattering (DLS), atomic force microscopy (AFM) and transmission electron microscopy (TEM). We demonstrated that this SBPP not only has no cellular toxicity against NIH 3T3 cells in in vitro cell experiments, but it also shows an efficient enhanced T1 relaxivity in in vitro MR imaging experiments. When used as multifunctional imaging agents, different imaging probes and/or targeting agents can be introduced to this SBPP as needed through simple host-guest interactions. In in vitro imaging experiments, it shows accurate imaging of different kinds of cancer cells by choosing on-demand targeting agents. These results suggest a promising strategy for engineering multifunctional imaging agents with SBPs.