Advances in local drug delivery technologies for improved rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by an inflammatory microenvironment and cartilage erosion within the joint cavity. Currently, antirheumatic agents yield significant outcomes in RA treatment. However, their systemic administration is limited by inadequate drug retention in lesion areas and non-specific tissue distribution, reducing efficacy and increasing risks such as infection due to systemic immunosuppression. Development in local drug delivery technologies, such as nanostructure-based and scaffold-assisted delivery platforms, facilitate enhanced drug accumulation at the target site, controlled drug release, extended duration of the drug action, reduced both dosage and administration frequency, and ultimately improve therapeutic outcomes with minimized damage to healthy tissues. In this review, we introduced pathogenesis and clinically used therapeutic agents for RA, comprehensively summarized locally administered nanostructure-based and scaffold-assisted drug delivery systems, aiming at improving the therapeutic efficiency of RA by alleviating the inflammatory response, preventing bone erosion and promoting cartilage regeneration. In addition, the challenges and future prospects of local delivery for clinical translation in RA are discussed.

Nanozyme-based Clusterphene for Enhanced Electrically Catalytic Cancer Therapy.

Nanozyme mediated catalytic therapy is an attractive strategy for cancer therapy. However, the nanozymes are tended to assemble into 3D architectures, resulting in poor catalytic efficiency for therapy. This study designs the assembly of nanozymes and natural enzymes into the layered structures featuring hexagonal pores as nanozyme clusterphene and investigates their catalytic therapy with the assistance of electric field. The nanozyme-based clusterphene consists of polyoxometalate (POM) and natural glucose oxidase (GOx), named POMG-based clusterphene, which facilitate multi-enzyme activities including peroxidase (POD), catalase (CAT), and glutathione oxidase (GPx). The highly ordered layers with hexagonal pores of POMG units significantly improve the peroxidase-like (POD-like) activity of the nanozyme and thus the sustained production of reactive oxygen species (ROS). At the same time, GOx can increase endogenous H2O2 and produce gluconic acid while consuming glucose, the nutrient of tumor cell growth. The results indicate that the POD-like activity of POMG-based clusterphene increase approximately sevenfold under electrical stimulation compared with Nd-substituted keggin type POM cluster (NdPW11). The experiments both in vitro and in vivo show that the proposed POMG-based clusterphene mediated cascade catalytic therapy is capable of efficient tumor inhibiting and preventing tumor proliferation in tumor-bearing mice model, promising as an excellent candidate for catalytic therapy.

Strategies to Reverse Hypoxic Tumor Microenvironment for Enhanced Sonodynamic Therapy.

Sonodynamic therapy (SDT) has emerged as a highly effective modality for the treatment of malignant tumors owing to its powerful penetration ability, noninvasiveness, site-confined irradiation, and excellent therapeutic efficacy. However, the traditional SDT, which relies on oxygen availability, often fails to generate a satisfactory level of reactive oxygen species because of the widespread issue of hypoxia in the tumor microenvironment of solid tumors. To address this challenge, various approaches are developed to alleviate hypoxia and improve the efficiency of SDT. These strategies aim to either increase oxygen supply or prevent hypoxia exacerbation, thereby enhancing the effectiveness of SDT. In view of this, the current review provides an overview of these strategies and their underlying principles, focusing on the circulation of oxygen from consumption to external supply. The detailed research examples conducted using these strategies in combination with SDT are also discussed. Additionally, this review highlights the future prospects and challenges of the hypoxia-alleviated SDT, along with the key considerations for future clinical applications. These considerations include the development of efficient oxygen delivery systems, the accurate methods for hypoxia detection, and the exploration of combination therapies to optimize SDT outcomes.

Polyoxometalate-Nanozyme-Integrated Nanomotors (POMotors) for Self-Propulsion-Promoted Synergistic Photothermal-Catalytic Tumor Therapy.

Enzyme-powered nanomotors have demonstrated promising potential in biomedical applications, especially for catalytic tumor therapy, owing to their ability of self-propulsion and bio-catalysis. However, the fragility of natural enzymes limits their environmental adaptability and also therapeutic efficacy in catalysis-enabled tumor therapy. Herein, polyoxometalate-nanozyme-based light-driven nanomotors were designed and synthesized for targeted synergistic photothermal-catalytic tumor therapy. In this construct, the peroxidase-like activity of the P2 W18 Fe4 polyoxometalates-based nanomotors can provide self-propulsion and facilitate their production of reactive oxygen species thus killing tumor cells, even in the weakly acidic tumor microenvironment. Conjugated polydopamine endows the nanomotors with the capability of light-driven self-propulsion behavior. After 10 min of NIR (808 nm) irradiation, along with the help of epidermal growth factor receptor antibody, the targeted accumulation and penetration of nanomotors in the tumor enabled highly efficient synergistic photothermal-catalytic therapy. This approach overcomes the disadvantages of the intrinsically fragile nature of enzyme-powered nanomotors in physiological environments and, more importantly, provides a motility-behavior promoted synergistic anti-tumor strategy.

Recent Advances in Polyoxometalate Based Nanoplatforms Mediated Reactive Oxygen Species Cancer Therapy.

The potential of reactive oxygen species (ROS) cancer therapy in tumor treatment has been greatly enhanced by the introduction of catalytically superior polyoxometalate (POM)-based nanoplatforms, mainly composed of atomic clusters consisting of pre-transition metals and oxygen. These nanoplatforms have unique advantages, such as Fenton activity at neutral pH, induction of cellular ferroptosis instead of just apoptosis, and sensitivity to external field stimulation. However, there are also inevitable challenges such as neutralization of ROS by the antioxidant system of the tumor microenvironment (TME), hypoxia, and limited hydrogen peroxide concentrations. This review article aims to provide an overview of recent research advancements in POM-based nanoplatforms for ROS therapy from the perspective of chemical reactions and biological processes, addressing endogenous and exogenous factors that affect the antitumor efficacy. Endogenous factors include the mechanism of ROS generation by POM, the impact of pH and antioxidant systems on POM, and the various manners of tumor cell death. Exogenous stimuli mainly include light, heat, X-rays, and electricity. The article analyzes the specific mechanisms of action of each influencing factor in the first two sections, concluding with the limitations of the present study and some possible directions for future research.

Identification of TAC1 Associated with Alzheimer's Disease Using a Robust Rank Aggregation Approach.

BACKGROUND: Alzheimer's disease (AD) brings heavy burden to society and family. There is an urgent need to find effective methods for disease diagnosis and treatment. The robust rank aggregation (RRA) approach that could aggregate the resulting gene lists has been widely utilized in genomic data analysis. OBJECTIVE: To identify hub genes using RRA approach in AD. METHODS: Seven microarray datasets in frontal cortex from GEO database were used to identify differential expressed genes (DEGs) in AD patients using RRA approach. STRING was performed to explore the protein-to-protein interaction (PPI). Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were utilized for enrichment analysis. Human Gene Connectome and Gene Set Enrichment Analysis were used for functional annotation. Finally, the expression levels of hub genes were validated in the cortex of 5xFAD mice by quantitative real-time polymerase chain reaction. RESULTS: After RRA analysis, 473 DEGs (216 upregulated and 257 downregulated) were identified in AD samples. PPI showed that DEGs had a total of 416 nodes and 2750 edges. These genes were divided into 17 clusters, each of which contains at least three genes. After functional annotation and enrichment analysis, TAC1 is identified as the hub gene and may be related to synaptic function and inflammation. In addition, Tac1 was found downregulated in cortices of 5xFAD mice. CONCLUSION: In the current study, TAC1 is identified as a key gene in the frontal cortex of AD, providing insight into the possible pathogenesis and potential therapeutic targets for this disease.

Manganese-Based Nanozymes: Preparation, Catalytic Mechanisms, and Biomedical Applications.

Manganese (Mn) has attracted widespread attention due to its low-cost, nontoxicity, and valence-rich transition. Various Mn-based nanomaterials have sprung up and are employed in diverse fields, particularly Mn-based nanozymes, which combine the physicochemical properties of Mn-based nanomaterials with the catalytic activity of natural enzymes, and are attracting a surge of research, especially in the field of biomedical research. In this review, the typical preparation strategies, catalytic mechanisms, advances and perspectives of Mn-based nanozymes for biomedical applications are systematically summarized. The application of Mn-based nanozymes in tumor therapy and sensing detection, together with an overview of their mechanism of action is highlighted. Finally, the prospective directions of Mn-based nanozymes from five perspectives: innovation, activity enhancement, selectivity, biocompatibility, and application broadening are discussed.

Two birds with one stone: innovative ceria-loaded gold@platinum nanospheres for photothermal-catalytic therapy of tumors.

Photothermal therapy (PTT) has been widely employed in tumor treatment due to the non-invasive, highly selective, and low toxic side effects. However, the limited penetration of laser couples with the metastasis and recurrence of tumors, thus failing to eliminate them. Here, we report that ceria-loaded gold@platinum (CeO2/Au@Pt) nanospheres modified with polyethylene glycol (PEG). exhibit dual enzymatic activities for photothermal-catalytic synergistic therapy of tumors. CeO2/Au@Pt nanospheres are constructed through the loading of ultra-small CeO2 into core-shell Au@Pt nanospheres. In such a construct, Au@Pt enables targeted PTT, thanks to exceptional photothermal properties, while CeO2 nanozymes alleviate tumor hypoxia and kill tumor cells by producing highly toxic hydroxyl radicals (·OH) based on catalase- and peroxidase-like activities. Synergistic photothermal-catalytic therapy is achieved by delivering nanozymes to the tumor microenvironment (TME) coupled with PTT. This photothermal-catalytic approach that combines simultaneous exogenous and endogenous activation is a potential option for tumor co-therapy.

MXenes Quantum Dots for Biomedical Applications: Recent Advances and Challenges.

MXenes have aroused widespread interest in the biomedical field owing to their remarkable photo-thermal conversion capabilities combined with large specific surface areas. MXenes quantum dots (MQDs) have been synthesized either by the physical or chemical methods based on MXenes as precursors, which possess smaller size, higher photoluminescence, coupled with low cytotoxicity and many beneficial properties of MXenes, thereby having potential biomedical applications. Given this, this review summarized the synthesis methods, optical, surface and biological properties of MQDs along with their practical applications in the field of biomedicine. Finally, the authors make an outlook towards the synthesis, properties and applications of MQDs in the future biomedicine field.

Single-Atom Nanozymes for Biomedical Applications: Recent Advances and Challenges.

Nanozymes have received extensive attention in the fields of sensing and detection, medical therapy, industry, and agriculture thanks to the combination of the catalytic properties of natural enzymes and the physicochemical properties of nanomaterials, coupled with superior stability and ease of preparation. Despite the promise of nanozymes, conventional nanozymes are constrained by their oversized size and low catalytic capacity in sophisticated practical application environments. single-atom nanozymes (SAzymes) were characterized as nanozymes with high catalytic efficiency by uniformly distributed single atoms as catalysis sites, thus effectively addressing the defects of conventional nanozymes. This paper reviews the activity improvement scheme and catalytic mechanism of SAzymes and highlights the latest research progress of SAzymes in the fields of biomedical sensing and therapy. Eventually, the challenges and future directions of SAzymes are discussed in this paper.

Polyoxometalate-covalent organic framework hybrid materials for pH-responsive photothermal tumor therapy.

Photothermal therapy (PTT) has become one of the most effective methods for tumor treatment. With the development of medicine, studies focusing primarily on therapeutic and diagnostic agents with desirable biocompatibility, targeting and stability are still of great significance. Heteropoly blue (HPB) is an ideal photothermal therapy agent (PTA) with decent photothermal conversion efficiency. Covalent organic frameworks (COFs) are considered to be good carriers with excellent biocompatibility. Due to their superior characteristics, such as being adjustable, and having high thermal stability and porous structures, COFs have been broadly applied in various fields. In this study, HPB was successfully in situ loaded into a COF via a one-pot method. The resultant HPB@COF platform exhibited desirable biocompatibility, pH-responsive release properties and high tumor inhibition efficiency, which can be used for PTT to effectively inhibit tumor growth. Our work provides a valuable paradigm for the fabrication of safer and effective HPB@COF NPs for future pH-responsive photothermal therapy.

Polyoxometalate Modified by Zeolite Imidazole Framework for the pH-Responsive Electrodynamic/Chemodynamic Therapy.

Electrodynamic therapy (EDT) and chemodynamic therapy (CDT) have the potential for future tumor treatment; however, their underlying applications are greatly hindered owing to their inherent drawbacks. The combination of EDT and CDT has been considered to be an effective way to maximize the superiorities of these two ROS-based methodologies. However, the development of novel nanomaterials with "one-for-all" functions still remains a big challenge. In this work, the polyoxometalate nanoparticles (NPs) were decorated using the zeolite imidazole framework (POM@ZIF-8) in order to integrate the EDT with CDT. The resulting POM@ZIF-8 NPs can effectively induce the generation of reactive oxygen species (ROS) via a catalytic reaction on the surface of POM NPs induced by an electric field (E). At the same time, POM@ZIF-8 NPs can catalyze the intracellular H2O2 into ROS via a Fenton-like reaction, thereby achieving the combination of EDT and CDT. Besides, since ZIF-8 is acid-responsive, it can protect normal tissues and avoid side effects. Of great note is that the cytotoxicity and the apoptosis rate of the POM@ZIF-8+E group (80%) were found to be significantly higher than that of the E group (55%). As a result, a high tumor inhibition phenomenon can be observed both in vitro and in vivo. The present study thus provides an alternative concept for combinational therapeutic modality with exceptional efficacy.

Sensitive visual detection of intracellular zinc ions based on signal-on polydopamine carbon dots.

The concentration of intracellular zinc ions is a significant clinical parameter for diagnosis. However, it is still a challenge for direct visual detection of zinc ions in cells at single-cell level. To address this issue, herein, water-soluble amino-rich polydopamine carbon quantum dots (PDA-CQDs) were successfully synthesized, with strong blue-green fluorescence as the probes for zinc ions detection in cells. The structure and properties of PDA-CQDs were confirmed by transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transformed infrared (FT-IR), UV-visible spectrophotometry (UV-vis), and fluorescence spectroscopy. Importantly, by successfully linking salicylaldehyde (SA) to PDA-CQDs via nucleophilic reaction, the FL quenching and Zn ions induced FL-recovering system was built up, thus offering a signal-on platform for the detection of zinc ions. This PDA-CQDs-SA nanoprobe can be applied for the detection of Zn2+with a detection limit of 0.09µM, with good biocompatibility confirmed using cytotoxicity assay. Of significance, the results of fluorescence bioimaging showed that PDA-CQDs-SA is able to detect Zn2+in single-cell visually, with the detection limit of Zn ions in cells as low as 0.11µM per cell, which was confirmed using flow cytometry. Therefore, this work offers a potential probe for Zn2+detection in cells at single-cell level, towards the precise diagnosis of zinc ions related diseases.

Continuous positive airway pressure effectively ameliorates arrhythmias in patients with obstructive sleep apnea-hypopnea via counteracting the inflammation.

INTRODUCTION: This work is aimed at evaluating the therapeutic effect of continuous positive airway pressure (CPAP) in treatment of patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) combined with arrhythmias as well as clarifying the possible mechanism underpinning such an intervention. METHODS: Through exclusions, a total of 108 OSAHS patients combined with arrhythmias were enrolled from June 2017 to June 2019 with full clinical information in this work. A computerized permuted block design with varying block stratification and size according to age, sex, AHI and type of arrhythmia was used to randomize 108 patients to CPAP versus sham CPAP for a period of 12-week. All were subjected to unchanged pharmacological anti-arrhythmia therapy combined with CPAP. Before and after CPAP treatment, the improvement of various arrhythmias was compared between the CPAP group and the sham-CPAP group. The levels of CRP, IL-6 and TNF-ɑ were measured simultaneously. RESULTS: During follow-up, the mean (±SD) CPAP pressure used in the CPAP group was 12.3 (±3.1) cm H2O. The use of CPAP and sham CPAP was on average of 5.2 ± 0.56 and 5.1 ± 0.63 h/night, respectively. After 12 weeks of CPAP therapy, the AHI was significantly decreased and the lowest blood oxygen saturation was notably elevated in the CPAP group compared to the sham-CPAP group, P < 0.05. The CPAP therapy, compared with the sham-CPAP group, significantly reduced the incidence of all types of arrhythmia in patients with OSAHS. The level of the c-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) was significantly lower in the CPAP group than in the sham-CPAP group (P < 0.05). Pearson correlation analysis showed that the reduction in the incidence of total arrhythmias was positively correlated with the decrease of CRP, IL-6 and TNF-ɑ levels, respectively. CONCLUSION: Findings from this work suggest that proper use of CPAP significantly benefits to OSAHS patients combined with arrhythmias, possibly via counteracting the inflammation.

Amyloid ß and tau are involved in sleep disorder in Alzheimer's disease by orexin A and adenosine A(1) receptor.

Sleep disorder is confirmed as a core component of Alzheimer's disease (AD), while the accumulation of amyloid ß (Aß) in brain tissue is an important pathological feature of AD. However, how Aß affects AD­associated sleep disorder is not yet well understood. In the present study, experiments on animal and cell models were performed to detect the association between sleep disorder and Aß. It was observed that Aß25­35 administration significantly decreased non­rapid eye movement sleep, while it increased wakefulness in mice. In addition, reverse transcription­quantitative polymerase chain reaction and western blot analysis revealed that the expression levels of tau, p­tau, orexin A and orexin neurons express adenosine A1 receptor (A1R) were markedly upregulated in the brain tissue of AD mice compared with that in samples obtained from control mice. Furthermore, the in vitro study revealed that the expression levels of tau, p­tau, orexin A and adenosine A1R were also significantly increased in human neuroblastoma SH­SY5Y cells treated with Aß25­35 as compared with the control cells. In addition, the tau inhibitor TRx 0237 significantly reversed the promoting effects of Aß25­35 on tau, p­tau, orexin A and adenosine A1R expression levels, and adenosine A1R or orexin A knockdown also inhibited tau and p­tau expression levels mediated by Aß25­35 in AD. These results indicate that Aß and tau may be considered as novel biomarkers of sleep disorder in AD pathology, and that they function by regulating the expression levels of orexin A and adenosine A1R.

Systematic tracking of dysregulated modules identifies disrupted pathways in narcolepsy.

OBJECTIVE: The objective of this work is to identify disrupted pathways in narcolepsy according to systematically tracking the dysregulated modules of reweighted Protein-Protein Interaction (PPI) networks. Here, we performed systematic identification and comparison of modules across normal and narcolepsy conditions by integrating PPI and gene-expression data. METHODS: Firstly, normal and narcolepsy PPI network were inferred and reweighted based on Pearson correlation coefficient (PCC). Then, modules in PPI network were explored by clique-merging algorithm and we identified altered modules using a maximum weight bipartite matching and in non-increasing order. Finally, pathways enrichment analyses of genes in altered modules were carried out based on Expression Analysis Systematic Explored (EASE) test to illuminate the biological pathways in narcolepsy. RESULTS: Our analyses revealed that 235 altered modules were identified by comparing modules in normal and narcolepsy PPI network. Pathway functional enrichment analysis of disrupted module genes showed 59 disrupted pathways within threshold P < 0.001. The most significant five disrupted pathways were: oxidative phosphorylation, T cell receptor signaling pathway, cell cycle, Alzheimer's disease and focal adhesion. CONCLUSIONS: We successfully identified disrupted pathways and these pathways might be potential biological processes for treatment and etiology mechanism in narcolepsy.

Reproducibility of quantitative real-time PCR assay in microRNA expression profiling and comparison with microarray analysis in narcolepsy.

MicroRNAs (miRNAs) have been shown in the pathogenesis of human neurological disorders. The study aims to identify the involvement of miRNAs in the pathophysiology of narcolepsy. Here, we conducted three independent high-throughput analysis of miRNA (miRNA microarray) in peripheral blood from 20 narcolepsy patients who fulfilled the criteria compared to 20 healthy controls with validation experiment using quantitative real-time polymerase chain reaction (real-time PCR) panels. By analyzing 2805 miRNAs in peripheral blood with microarray we identified 128 miRNAs (105 high expression and 23 low expression) that were different in patients with narcolepsy in comparison with healthy control. Then we chose six high expression candidates and six low expression candidates of at least twofold difference and p value < 0.05 to validate the changes in three independent experiments in vitro using real-time PCR. The validation test showed that levels of hsa-mir-1267, hsa-miR-4309, hsa-miR-554, hsa-miR-1272, hsa-miR-4501, hsa-miR-182-3p were higher, whereas the level of hsa-miR-625-5p, hsa-miR-100-5p, hsa-miR-125b-5p, hsa-miR-197-3p, hsa-miR-4522, hsa-miR-493-5p was lower in narcolepsy patients than healthy controls. The levels of 12 miRNAs differed significantly in peripheral blood from narcolepsy patients which suggested that alterations of miRNAs expression may be involved in the pathophysiology of narcolepsy.