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.

An angel or a devil? Current view on the role of CD8+ T cells in the pathogenesis of myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) and the experimental autoimmune MG (EAMG) animal model are characterized by T-cell-induced and B-cell-dominated autoimmune diseases that affect the neuromuscular junction. Several subtypes of CD4+ T cells, including T helper (Th) 17 cells, follicular Th cells, and regulatory T cells (Tregs), contribute to the pathogenesis of MG. However, increasing evidence suggests that CD8+ T cells also play a critical role in the pathogenesis and treatment of MG. MAIN BODY: Herein, we review the literature on CD8+ T cells in MG, focusing on their potential effector and regulatory roles, as well as on relevant evidence (peripheral, in situ, cerebrospinal fluid, and under different treatments), T-cell receptor usage, cytokine and chemokine expression, cell marker expression, and Treg, Tc17, CD3+CD8+CD20+ T, and CXCR5+ CD8+ T cells. CONCLUSIONS: Further studies on CD8+ T cells in MG are necessary to determine, among others, the real pattern of the Vß gene usage of autoantigen-specific CD8+ cells in patients with MG, real images of the physiology and function of autoantigen-specific CD8+ cells from MG/EAMG, and the subset of autoantigen-specific CD8+ cells (Tc1, Tc17, and IL-17+IFN-γ+CD8+ T cells). There are many reports of CD20-expressing T (or CD20 + T) and CXCR5+ CD8 T cells on autoimmune diseases, especially on multiple sclerosis and rheumatoid arthritis. Unfortunately, up to now, there has been no report on these T cells on MG, which might be a good direction for future studies.

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain.

Polyketides are a major class of natural products, including bioactive medicines such as erythromycin and rapamycin. They are often rich in stereocenters biosynthesized by the ketoreductase (KR) domain within the polyketide synthase (PKS) assembly line. Previous studies have identified conserved motifs in KR sequences that enable the bioinformatic prediction of product stereochemistry. However, the reliability and applicability of these prediction methods have not been thoroughly assessed. In this study, we conducted a comprehensive bioinformatic analysis of 1,762 KR sequences from cis-AT PKSs to reevaluate the residues involved in conferring stereoselectivity. Our findings indicate that the previously identified fingerprint motifs remain valid for KRs in ß-modules from actinobacteria, but their reliability diminishes for KRs from other module types or taxonomic origins. Additionally, we have identified several new motifs that exhibit a strong correlation with the stereochemical outcomes of KRs. These updated fingerprint motifs for stereochemical prediction not only enhance our understanding of the enzymatic mechanisms governing stereocontrol but also facilitate accurate stereochemical prediction and genome mining of polyketides derived from modular cis-AT PKSs.

HIF-1A as a prognostic biomarker related to invasion, migration and immunosuppression of cervical cancer.

Background: The incidence of cervical cancer ranks second among malignant tumors in women, exerting a significant impact on their quality of life and overall well-being. The hypoxic microenvironment plays a pivotal role in the initiation and progression of tumorigenesis. The present study aims to investigate the fundamental genes and pathways associated with the hypoxia-inducible factor (HIF-1A) in cervical cancer, aiming to identify potential downstream targets for diagnostic and therapeutic purposes. Methods: We obtained dataset GSE63514 from the Comprehensive Gene Expression Database (GEO). The dataset comprised of 24 patients in the normal group and 28 patients in the tumor group. Gene set difference analysis (GSVA) and gene set enrichment analysis (GSEA) were used to identify the genes related to HIF-1A expression and the specific signaling pathways involved.The association between HIF-1A and tumor immune infiltration was examined in the TCGA dataset. The WGCAN network was constructed to identify key genes within the blue module, and subsequent gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to determine the pathways and functional annotations associated with HIF-1A. The protein interaction network of the HIF-1A gene was obtained from the STRING database and visualized using Cytoscape in the meantime.The function of HIF-1A and its related gene expression were verified in vivo. Results: HIF-1A was a risk factor in both univariate and multivariate Cox regression analysis of cervical cancer patients. A total of 344 genes significantly correlated with the expression of HIF-1A were identified through correlation analysis, and the genes exhibiting the strongest correlation were obtained. The major signaling pathways involved in HIF-1A encompass TNF-α/NF-κB, PI3K/AKT/MTOR, TGF-ß, JAK-STAT, and various other signaling cascades. Reinforced by qRT-PCR, we identified Integrin beta-1 (ITGB1), C-C motif chemokine ligand 2 (CCL2), striatin 3 (STRN3), and endothelin-1 (EDN1) as pivotal downstream genes influenced by HIF-1A. HIF-1A is associated with immune infiltration of natural killer (NK) cells, mast cells, CD4+T cells, M0 macrophages, neutrophils, follicular helper T cells, CD8+T cells, and regulatory T cells (Treg). HIF-1A is associated with sensitivity to chemotherapy drugs. The identification of the HIF-1A pathway and its function primarily focuses on cytoplasmic translation, aerobic respiration, cellular respiration, oxidative phosphorylation, thermogenesis, among others. The results of in vivo experiments have confirmed that HIF-1A plays a crucial role in promoting the migration and invasion of cervical cancer cells. Moreover, the overexpression of HIF-1A led to an upregulation in the expressions of ITGB1, CCL2, STRN3, and EDN1. Conclusions: The role of HIF-1A in cervical cancer was determined through a combination of bioinformatics analysis and experimental validation. The genes potentially implicated in the tumorigenesis mechanism of HIF-1A were identified. These findings has the potential to enhance our comprehension of the progression of cervical cancer and offer promising therapeutic targets for its clinical management.

A longitudinal study on the effect of labor values on benign/malicious envy: the mindfulness reperceiving model.

This study investigates the relationship between labor values and two forms of envy-benign and malicious-as well as the potential mediating role of mindfulness using a mindfulness reperceiving model. Two thousand three hundred sixty three Chinese teenagers participated in a longitudinal study over an eight-month period, completing questionnaires measuring labor values, benign envy, malicious envy, and mindfulness. The cross-sectional data showed that labor values had an immediate negative effect on malicious envy, with mindfulness partially mediating this relationship. Additionally, labor values had an immediate positive effect on benign envy, but mindfulness did not mediate this relationship. Longitudinal data analysis revealed that the delayed effect of labor values on later benign/malicious envy was similar to its immediate effect. However, mindfulness only played a mediating role in the relationship between labor values and later malicious envy. Cross-gender stability was found in both the immediate effect model and the delayed effect model. Overall, this study sheds light on the influence of labor values on the development of social emotions and the potential mediating role of mindfulness in the Chinese cultural context.

Amplification of Oxygen-Independent Free Radicals Based on a Glutathione Depletion and Biosynthesis Inhibition Strategy for Photothermal and Thermodynamic Therapy of Hypoxic Tumors.

Thermodynamic therapy (TDT) based on oxygen-independent free radicals exhibits promising potential for the treatment of hypoxic tumors. However, its therapeutic efficacy is seriously limited by the premature release of the drug and the free radical scavenging effect of glutathione (GSH) in tumors. Herein, we report a GSH depletion and biosynthesis inhibition strategy using EGCG/Fe-camouflaged gold nanorod core/ZIF-8 shell nanoparticles embedded with azo initiator 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH) and L-buthionine-sulfoximine (BSO) for tumor-targeting photothermal (PTT) and thermodynamic therapy (TDT). This nanoplatform (GNR@ZIF-8-AIPH/BSO@EGCG/Fe, GZABEF) endows a pH-responsive release performance. With the 67 kDa lamin receptor (67LR)-targeting ability of EGCG, GZABEF could selectively release oxygen-independent free radicals in tumor cells under 1064 nm laser irradiation. More importantly, Fe3+-mediated GSH depletion and BSO-mediated GSH biosynthesis inhibition significantly boosted the accumulation of alkyl radicals. In 4T1 cells, GZABEF induced cancer cell death via intracellular GSH depletion and GSH peroxidase 4 (GPX4) inactivation. In a subcutaneous xenograft model of 4T1, GZABEF demonstrated remarkable tumor growth inhibition (78.2%). In addition, excellent biosafety and biocompatibility of GZABEF were observed both in vitro and in vivo. This study provides inspiration for amplified TDT/PTT-mediated antitumor efficacy.

Engineering of a double targeting nanoplatform to elevate ROS generation and DSF anticancer activity.

Intracellular oxidative protection mechanisms and adverse systemic toxicity are major obstacles for the success of chemodynamic therapy (CDT)/chemotherapy (CT) synergistic therapy. To tackle the fundamental challenges of current CDT and circumvent the side effects of conventional CT, we developed a copper peroxide (CP) and disulfiram (DSF)-loaded 3-aminotriazole (3-AT) doped ZIF-8 (MAF) with partial sequence-specificity using hyaluronic acid (HA) and triphenylphosphine (TPP) in this study. Upon intravenous administration, CP@MAF-DSF@PEG-TPP@HA (CPMDTH) nanoparticles (NPs) were enriched in tumor tissues through HA-mediated endocytosis, followed by enhanced accumulation in mitochondria by the TPP target. The acidic tumor environment (TME) triggered the decomposition of MAF to release CP, DSF and 3-AT. Cu2+ and H2O2 hydrated from CP NPs produced ˙OH via a Fenton-like reaction. CAT activity inhibition and GSH consumption induced by 3-AT dramatically amplified mitochondrial oxidative stress, thereby promoting the overproduction of ˙OH. In addition, the accumulation of DSF and Cu2+ led to the formation of a cytotoxic bis(N,N-diethyldithiocarbamate) copper(II) complex (Cu(DTC)2) in situ, achieving efficient CT. CPMDTH NPs demonstrated significantly improved antitumor efficiency and excellent biosafety both in vitro and in vivo. This study offers a promising therapeutic strategy for CDT/CT synergistic oncotherapy.

Degradation and potential metabolism pathway of polystyrene by bacteria from landfill site.

Microplastics pollution has garnered significant attention in recent years. The unique cross-linked structure of polystyrene microplastics makes them difficult to biodegrade. In this study, we investigated the microbial community in landfill soil that has the ability to degrade polystyrene, as well as two isolated strains, named Lysinibacillus sp. PS-L and Pseudomonas sp. PS-P. The maximum weight loss of polystyrene film and microplastic in 30 days is 2.25% and 6.99% respectively. The water contact angle of polystyrene film decreased by a maximum of 35.70% during biodegradation. The increase in hydrophilicity is attributed to the oxidation reaction and formation of hydroxyl groups during the degradation of polystyrene. The carbon and oxygen element contents of polystyrene decreased and increased by a maximum of 3.81% and 0.79% respectively. The peak intensity changes at wavelengths of 3285-3648 cm-1 and 1652 cm-1 in Fourier transform infrared spectroscopy confirmed the formation of hydroxyl and carbonyl groups. Furthermore, quantitative PCR revealed the gene expression levels of alkane monooxygenase and alcohol dehydrogenase were upregulated by 8.8-fold and 8.5-fold respectively in PS biodegradation. Additionally, genome annotation of Pseudomonas sp. PS-P identified nine genes associated with polystyrene metabolism. These findings highlight Pseudomonas sp. PS-P as a potential candidate strain for polystyrene degradation enzymes or genes. Thus, they lay the groundwork for understanding the potential metabolic mechanisms and pathways involved in polystyrene degradation.

True or false? Alzheimer's disease is type 3 diabetes: Evidences from bench to bedside.

Globally, Alzheimer's disease (AD) is the most widespread chronic neurodegenerative disorder, leading to cognitive impairment, such as aphasia and agnosia, as well as mental symptoms, like behavioral abnormalities, that place a heavy psychological and financial burden on the families of the afflicted. Unfortunately, no particular medications exist to treat AD, as the current treatments only impede its progression.The link between AD and type 2 diabetes (T2D) has been increasingly revealed by research; the danger of developing both AD and T2D rises exponentially with age, with T2D being especially prone to AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. A critical review of the relationship between insulin resistance, Aß, oxidative stress, mitochondrial hypothesis, abnormal phosphorylation of Tau protein, inflammatory response, high blood glucose levels, neurotransmitters and signaling pathways, vascular issues in AD and diabetes, and the similarities between the two diseases, is presented in this review. Grasping the essential mechanisms behind this detrimental interaction may offer chances to devise successful therapeutic strategies.

Ginkgo biloba and Its Chemical Components in the Management of Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD), a degenerative disease of the central nervous system, remains unclear. The main manifestations of AD include cognitive and behavioral disorders, neuropsychiatric symptoms, neuroinflammation, amyloid plaques, and neurofibrillary tangles. However, current drugs for AD once the dementia stage has been reached only treat symptoms and do not delay progression, and the research and development of targeted drugs for AD have reached a bottleneck. Thus, other treatment options are needed. Bioactive ingredients derived from plants are promising therapeutic agents. Specifically, Ginkgo biloba (Gb) extracts exert anti-oxidant, anticancer, neuroplastic, neurotransmitter-modulating, blood fluidity, and anti-inflammatory effects, offering alternative options in the treatment of cardiovascular, metabolic, and neurodegenerative diseases. The main chemical components of Gb include flavonoids, terpene lactones, proanthocyanidins, organic acids, polysaccharides, and amino acids. Gb and its extracts have shown remarkable therapeutic effects on various neurodegenerative diseases, including AD, with few adverse reactions. Thus, high-quality Gb extracts are a well-established treatment option for AD. In this review, we summarize the insights derived from traditional Chinese medicine, experimental models, and emerging clinical trials on the role of Gb and its chemical components in the treatment of the main clinical manifestations of AD.

Association between sugar-sweetened beverages and pure fruit juice with risk of six cardiovascular diseases: a Mendelian randomization study.

BACKGROUND: In observational and prospective cohort studies, intake of sugar-sweetened beverages (SSBs) and pure fruit juice (PFJ) has been associated with cardiovascular disease (CVD). Still, the causality of the connection has not yet been determined. Our objective was to uncover the relationship between SSBs/PFJ and CVD. METHODS: Genetically predicted causal associations between SSBs/PFJ (obtained in a published genome-wide association study) and six common CVDs (atrial fibrillation (AF), angina, heart failure (HF), acute myocardial infarction, hypertension, and coronary atherosclerosis) were assessed using MR analytic modeling. The primary analysis method utilized was the inverse variance weighted (IVW) method, complemented by additional methods such as the weighted median method, MR Egger regression, Cochran's Q test, MR pleiotropy residual, funnel plot, Bonferroni correction, and others for MR analysis. To ensure the robustness of the findings, F-values were calculated as a complementary test to set looser thresholds for exposing genetic instrumental variables (P < 1e-5). RESULTS: The results of MR analysis suggested genetically causal associations between SSBs and AF (odds ratio (OR): 1.023; 95% confidence interval (CI) 1.007-1.038; P = 0.0039) as well as between PFJ and angina (OR: 0.968; 95% CI, 0.943-0.993; P = 0.0138) there was genetic causality. However, MR analysis showed no causal association between SSBs/PFJ and other CVD risks. CONCLUSION: This study suggests that there may be a potential causal relationship between SSBs intake and AF and a causal negative association between PFJ intake and angina.

Research on carbon dioxide capture materials used for carbon dioxide capture, utilization, and storage technology: a review.

In recent years, climate change has increasingly become one of the major challenges facing mankind today, seriously threatening the survival and sustainable development of mankind. Dramatically increasing carbon dioxide concentrations are thought to cause a severe greenhouse effect, leading to severe and sustained global warming, associated climate instability and unwelcome natural disasters, melting glaciers and extreme weather patterns. The treatment of flue gas from thermal power plants uses carbon capture, utilization, and storage (CCUS) technology, one of the most promising current methods to accomplish significant CO2 emission reduction. In order to implement the technological and financial system of CO2 capture, which is the key technology of CCUS technology and accounts for 70-80% of the overall cost of CCUS technology, it is crucial to create more effective adsorbents. Nowadays, with the development and application of various carbon dioxide capture materials, it is necessary to review and summarize carbon dioxide capture materials in time. In this paper, the main technologies of CO2 capture are reviewed, with emphasis on the latest research status of CO2 capture materials, such as amines, zeolites, alkali metals, as well as emerging MOFs and carbon nanomaterials. More and more research on CO2 capture materials has used a variety of improved methods, which have achieved high CO2 capture performance. For example, doping of layered double hydroxides (LDH) with metal atoms significantly increases the active site on the surface of the material, which has a significant impact on improving the CO2 capture capacity and performance stability of LDH. Although many carbon capture materials have been developed, high cost and low technology scale remain major obstacles to CO2 capture. Future research should focus on designing low-cost, high-availability carbon capture materials.

Sulfonated Azocalix[4]arene-Modified Metal-Organic Framework Nanosheets for Doxorubicin Removal from Serum.

Chemotherapy is one of the most commonly used methods for treating cancer, but its side effects severely limit its application and impair treatment effectiveness. Removing off-target chemotherapy drugs from the serum promptly through adsorption is the most direct approach to minimize their side effects. In this study, we synthesized a series of adsorption materials to remove the chemotherapy drug doxorubicin by modifying MOF nanosheets with sulfonated azocalix[4]arenes. The strong affinity of sulfonated azocalix[4]arenes for doxorubicin results in high adsorption strength (Langmuir adsorption constant = 2.45-5.73 L mg-1) and more complete removal of the drug. The extensive external surface area of the 2D nanosheets facilitates the exposure of a large number of accessible adsorption sites, which capture DOX molecules without internal diffusion, leading to a high adsorption rate (pseudo-second-order rate constant = 0.0058-0.0065 g mg-1 min-1). These adsorbents perform effectively in physiological environments and exhibit low cytotoxicity and good hemocompatibility. These features make them suitable for removing doxorubicin from serum during "drug capture" procedures. The optimal adsorbent can remove 91% of the clinical concentration of doxorubicin within 5 min.

Antibody-Calixarene Drug Conjugate: A General Drug Delivery Platform for Tumor-Targeted Therapy.

Antibody-drug conjugates (ADCs), which combine the precise targeting capabilities of antibodies with the powerful cytotoxicity of small-molecule drugs, have evolved into a promising approach for tumor treatment. However, the traditional covalent coupling method requires the design of a specific linker tailored to the properties of the small-molecule drugs, which greatly limits the development of ADCs and the range of drugs that can be used. Herein, a novel type of antibody-calixarene drug conjugates (ACDCs) that function similarly to ADCs by delivering drugs to their targets using antibodies but without the requirement of covalent conjugation of the drugs with antibodies is presented. By replacement of conventional linkers with supramolecular linkers, the ACDCs can load various chemotherapeutic drugs through host-guest interactions. Furthermore, ACDCs are readily reduced upon reaching the hypoxic microenvironment, resulting in rapid release of the drugs. With this precise drug encapsulation and controlled release mechanism, ACDCs deliver drugs to tumor tissues effectively and achieve a significantly enhanced antitumor effect. Considering that the ACDCs can be easily prepared by combining antibody-calixarene conjugates derived from tumor-targeting antibodies with various small-molecule drugs, ACDCs may provide a promising platform technology to accelerate ADC development and thus improve the therapeutic efficacy of chemotherapy.