A smart hypochlorous acid fluorescent probe enabling Ibuprofen-release for osteoarthritis theranostics.

Background: Osteoarthritis (OA) standing as the most prevalent form of arthritis, closely associates with heightened levels of reactive oxygen species, particularly hypochlorous acid (HOCl). Although there are numerous probes available for detecting HOCl in the OA region, probes with dual functions of diagnostic and therapeutic capabilities are still significantly lacking. While this type of probe can reduce the time gap between diagnosis and treatment, which is clinically needed. Methods: We developed a fluorescent probe (DHU-CBA1) toward HOCl with theranostics functions through the release of methylene blue (MB) and ibuprofen (IBP) in this work. DHU-CBA1 can detect HOCl with high specificity and sensitivity, releasing MB and IBP with an impressive efficiency of ≥ 95% in vitro. Results: DHU-CBA1 exhibits good biosafety, enabling in vivo imaging of endogenous HOCl, along with reducing arthritis scores, improving synovitis and cartilage damage, and maintaining catabolic balance while alleviating senescence in cartilage. Conclusions: This study proposes a novel approach to enhance osteoarthritis therapy by releasing IBP via a smart HOCl-enabled fluorescent probe.

Collective chiroptical activity through the interplay of excitonic and charge-transfer effects in localized plasmonic fields.

The collective light-matter interaction of chiral supramolecular aggregates or molecular ensembles with confined light fields remains a mystery beyond the current theoretical description. Here, we programmably and accurately build models of chiral plasmonic complexes, aiming to uncover the entangled effects of excitonic correlations, intra- and intermolecular charge transfer, and localized surface plasmon resonances. The intricate interplay of multiple chirality origins has proven to be strongly dependent on the site-specificity of chiral molecules on plasmonic nanoparticle surfaces spanning the nanometer to sub-nanometer scale. This dependence is manifested as a distinct circular dichroism response that varies in spectral asymmetry/splitting, signal intensity, and internal ratio of intensity. The inhomogeneity of the surface-localized plasmonic field is revealed to affect excitonic and charge-transfer mixed intermolecular couplings, which are inherent to chirality generation and amplification. Our findings contribute to the development of hybrid classical-quantum theoretical frameworks and the harnessing of spin-charge transport for emergent applications.

Identification and Characterization of a ceRNA Regulatory Network Involving LINC00482 and PRRC2B in Peripheral Blood Mononuclear Cells: Implications for COPD Pathogenesis and Diagnosis.

Purpose: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, characterized by intense lung infiltrations of immune cells (macrophages and monocytes). While existing studies have highlighted the crucial role of the competitive endogenous RNA (ceRNA) regulatory network in COPD development, the complexity and characteristics of the ceRNA network in monocytes remain unexplored. Methods: We downloaded messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA) microarray data from GSE146560, GSE102915, and GSE71220 in the Gene Expression Omnibus (GEO) database. This data was used to identify differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs). Predicted miRNAs that bind to DElncRNAs were intersected with DEmiRNAs, forming a set of intersecting miRNAs. This set was then used to predict potential binding mRNAs, intersected with DEmRNAs, and underwent functional enrichment analysis using R software and the STRING database. The resulting triple regulatory network and hub genes were constructed using Cytoscape. Comparative Toxicomics Database (CTD) was utilized for disease correlation predictions, and ROC curve analysis assessed diagnostic accuracy. Results: Our study identified 5 lncRNAs, 4 miRNAs, and 149 mRNAs as differentially expressed. A lncRNA-miRNA-mRNA regulatory network was constructed, and hub genes were selected through hub analysis. Enrichment analysis highlighted terms related to cell movement and gene expression regulation. We established a LINC00482-has-miR-6088-PRRC2B ceRNA network with diagnostic relevance for COPD. ROC analysis demonstrated the diagnostic value of these genes. Moreover, a positive correlation between LINC00482 and PRRC2B expression was observed in COPD PBMCs. The CTD database indicated their involvement in inflammatory responses. Conclusion: In summary, our study not only identified pivotal hub genes in peripheral blood mononuclear cells (PBMCs) of COPD but also constructed a ceRNA regulatory network. This contributes to understanding the pathophysiological processes of COPD through bioinformatics analysis, expanding our knowledge of COPD, and providing a foundation for potential diagnostic and therapeutic targets for COPD.

Single-Component Dual-Functional Autoboost Strategy by Dual Photodynamic and Cyclooxygenase-2 Inhibition for Lung Cancer and Spinal Metastasis.

Coloading adjuvant drugs or biomacromolecules with photosensitizers into nanoparticles to enhance the efficiency of photodynamic therapy (PDT) is a common strategy. However, it is difficult to load positively charged photosensitizers and negatively charged adjuvants into the same nanomaterial and further regulate drug release simultaneously. Herein, a single-component dual-functional prodrug strategy is reported for tumor treatment specifically activated by tumor microenvironment (TME)-generated HOCl. A representative prodrug (DHU-CBA2) is constructed using indomethacin grafted with methylene blue (MB). DHU-CBA2 exhibited high sensitivity toward HOCl and achieved simultaneous release of dual drugs in vitro and in vivo. DHU-CBA2 shows effective antitumor activity against lung cancer and spinal metastases via PDT and cyclooxygenase-2 (COX-2) inhibition. Mechanistically, PDT induces immunogenic cell death but stimulates the gene encoding COX-2. Downstream prostaglandins E2 and Indoleamine 2,3 dioxygenase 1 (IDO1) mediate immune escape in the TME, which is rescued by the simultaneous release of indomethacin. DHU-CBA2 promotes infiltration and function of CD8+ T cells, thus inducing a robust antitumor immune response. This work provides an autoboost strategy for a single-component dual-functional prodrug activated by TME-specific HOCl, thereby achieving favorable tumor treatment via the synergistic therapy of PDT and a COX-2 inhibitor.

Voltage-Mode Ferroelectric Synapse for Neuromorphic Computing.

Ferroelectric materials with a modulable polarization extent hold promise for exploring voltage-driven neuromorphic hardware, in which direct current flow can be minimized. Utilizing a single active layer of an insulating ferroelectric polymer, we developed a voltage-mode ferroelectric synapse that can continuously and reversibly update its states. The device states are straightforwardly manifested in the form of variable output voltage, enabling large-scale direct cascading of multiple ferroelectric synapses to build a deep physical neural network. Such a neural network based on potential superposition rather than current flow is analogous to the biological counterpart driven by action potentials in the brain. A high accuracy of over 97% for the simulation of handwritten digit recognition is achieved using the voltage-mode neural network. The controlled ferroelectric polarization, revealed by piezoresponse force microscopy, turns out to be responsible for the synaptic weight updates in the ferroelectric synapses. The present work demonstrates an alternative strategy for the design and construction of emerging artificial neural networks.

Near-Infrared Emissive Cascaded Artificial Light-Harvesting System with Enhanced Antibacterial Efficiency.

Combination of platinum(II) metallacycles and photodynamic inactivation presents a promising antibacterial strategy. Herein, a cascaded artificial light-capturing system is developed in which an aggregation-induced emission-active platinum(II) metallacycle (PtTPEM) is utilized as the antenna, sulforhodamine 101 (SR101) as a key conveyor, and the near-infrared emissive photosensitizer Chlorin-e6 (Ce6) as the final energy acceptor. The well-dispersed Ce6 in the proximity of energy donors not only avoids self-quenching in the physiological environment but also contributes to energy transfer from donor to acceptor, thereby significantly improving the 1 O2 generation ability of the light-harvesting system under white light irradiation. By integrating the platinum(II) metallacycle and 1 O2 , a more efficient synergistic antibacterial effect is achieved at low concentrations, along with a significant decrease in dark toxicity caused by PtTPEM.

Activated aggregation strategies to construct size-increasing nanoparticles for cancer therapy.

The development of novel therapeutic strategies and modalities for tumors is still one of the important areas of current scientific research. Low permeability and short residence time of drugs in solid tumor areas are important reasons for the low efficiency of existing therapeutic strategies. Typically, nanoparticles with large size displayed enhanced residence time but low permeability. Therefore, to prolong the retention time of materials in solid tumors, size-increasing strategies have been developed to directly generate large-scale nanoparticles using small molecular compounds or increase the size of small nanoparticles in solid tumor areas. In this review, we summarize recently reported activatable aggregation systems that could be activated by cancer-related substances for cancer therapy and classify them by the mechanisms that lead to aggregation. In the end, we propose some potential challenges briefly from the view of our opinion. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

HOCl-Activated Reactive Organic Selenium Delivery Platform for Alleviation of Inflammation.

Selenium plays an important role in the biological system and can be used to treat various types of diseases. However, the current selenium delivery systems face the problems of low activity of released Se-containing compounds or nonspecific toxicity of reactive organic selenium donors in living systems. In response to these problems, we constructed a reactive organic selenium delivery platform by the activation of HOCl. Compared with prodrugs without activation capability, the hypochloroselenoite derivatives released from the present platform after activation displayed higher reactivity and could react with various nucleophiles to participate in specific life processes. Taking the selected compound (DHU-Se1) as an example, we found that it could alleviate the process of inflammation by blocking the polarization of macrophages from M0 to M1. Therefore, the development of this system is of great significance for expanding the application of selenium-containing compounds and treating related diseases.

DNASE1L3 as a Novel Diagnostic and Prognostic Biomarker for Lung Adenocarcinoma Based on Data Mining.

Previous researches have highlighted that low-expressing deoxyribonuclease1-like 3 (DNASE1L3) may play a role as a potential prognostic biomarker in several cancers. However, the diagnosis and prognosis roles of DNASE1L3 gene in lung adenocarcinoma (LUAD) remain largely unknown. This research aimed to explore the diagnosis value, prognostic value, and potential oncogenic roles of DNASE1L3 in LUAD. We performed bioinformatics analysis on LUAD datasets downloaded from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus), and jointly analyzed with various online databases. We found that both the mRNA and protein levels of DNASE1L3 in patients with LUAD were noticeably lower than that in normal tissues. Low DNASE1L3 expression was significantly associated with higher pathological stages, T stages, and poor prognosis in LUAD cohorts. Multivariate analysis revealed that DNASE1L3 was an independent factor affecting overall survival (HR = 0.680, p = 0.027). Moreover, decreased DNASE1L3 showed strong diagnostic efficiency for LUAD. Results indicated that the mRNA level of DNASE1L3 was positively correlated with the infiltration of various immune cells, immune checkpoints in LUAD, especially with some m6A methylation regulators. In addition, enrichment function analysis revealed that the co-expressed genes may participate in the process of intercellular signal transduction and transmission. GSEA indicated that DNASE1L3 was positively related to G protein-coupled receptor ligand biding (NES = 1.738; P adjust = 0.044; FDR = 0.033) and G alpha (i) signaling events (NES = 1.635; P adjust = 0.044; FDR = 0.033). Our results demonstrated that decreased DNASE1L3 may serve as a novel diagnostic and prognostic biomarker associating with immune infiltrates in lung adenocarcinoma.

Mindray BC-6900 Scattergram Analysis Combined with Peripheral Blood Smear in the Diagnosis of T. Marneffei Infection in an HIV-Positive Patient: a Case Report.

BACKGROUND: Rapid and accurate diagnosis of HIV-positive patients with Talaromyces marneffei (T. marneffei) infections remains challenging. A 60-year-old woman came to our inpatient department presenting with hematuria, abdominal pain, and diarrhea for one week. The patient had a past medical history of Acquired Immune Deficiency Syndrome (AIDS). The patient's stool was watery and the color of soy sauce. The patient was without fever, cough, and skin lesions. METHODS: The blood routine was performed with a Mindray BC-6900 hematology analyzer. RESULTS: Blood routine showed leukocytosis with neutrophilia and basophils and the WBC/DIFF scattergram showed a cluster of neutrophils connected with a monocyte and lymphocyte cluster and an additional cluster of immature granulocytes and heterotypic lymphocytes or primitive cells. Surprisingly, the peripheral blood film evaluation revealed small round-to-ovoid yeast cells within the cytoplasm of neutrophils. A T. marneffei infection was suspected and anti-fungal therapy was initiated. The patient's diarrhea improved after treatment with amphotericin B for two days. A second blood routine showed a normal number of leukocytes and basophils and a diminished cluster of immature granulocytes and heterotypic lymphocytes or primitive cells. After one week, blood cultures had grown T. marneffei. CONCLUSIONS: The WBC/DIFF scattergram obtained from a Mindray BC-6900 analyzer provided significant hints to enhance diagnosis of T. marneffei when combined with results of a peripheral blood smear.

A Near-Infrared Ratiometric Fluorescent Probe for Highly Selective Recognition and Bioimaging of Cysteine.

A benzothiazole-based near-infrared (NIR) ratiometric fluorescent probe (HBT-Cys) was developed for discriminating cysteine (Cys) from homocysteine (Hcy) and glutathione (GSH). The probe was designed by masking phenol group in the conjugated benzothiazole derivative with methacrylate group that could be selectively removed by Cys, and therefore an intramolecular charge transfer (ICT) fluorescence was switched on in the NIR region. In the absence of Cys, the probe exhibited a strong blue fluorescence emission at 431 nm, whereas a NIR fluorescence emission at 710 nm was significantly enhanced accompanied by a decrease of emission at 431 nm in the presence of Cys, allowing a ratiometric fluorescence detection of Cys. The fluorescence intensity ratio (I710nm/I431nm) showed a good linear relationship with Cys concentration of 1-40 µM with the detection limit of 0.5 µM. The sensing mechanism was explored based on MS experimental analysis and DFT theoretical calculation. Moreover, the fluorescent probe was successfully used for fluorescence bioimaging of Cys in living cells.

A selective fluorescent chemosensor for Cd2+ based on 8-hydroxylquinoline-benzothiazole conjugate and imaging application.

A 8-hydroxylquinoline-benzothiazole conjugate (HQ-BT) was facilely synthesized by two steps with >60% total reaction yield. The HQ-BT showed a weak fluorescence that could be strongly enhanced by coordination with various metal ions such as Al3+, Cd2+, Zn2+ in methanol containing 1% water. Interestingly, the selectivity toward Cd2+ was achieved by increasing water fraction to 30% aqueous methanol solution. Thus, the HQ-BT was developed as a new and selective fluorescent chemosensor for Cd2+ in aqueous solution with a broad pH region 4-12. A good linear relationship between the fluorescence intensity and the Cd2+ concentration was found in the range of 0-5 µM with a detection limit of 0.1 µM (S/N = 3). It was also succesfully used for fluorescence imaging of Cd2+ in living cells.