Construction of a dual "off-on" near-infrared fluorescent probe for bioimaging of HClO in rheumatoid arthritis.

Hypochlorous acid (HClO) serves as a critical biomarker in inflammatory diseases such as rheumatoid arthritis (RA), and its real-time imaging is essential for understanding its biological functions. In this study, we designed and synthesized a novel probe, RHMB, which ingeniously integrates rhodamine B and methylene blue fluorophores with HClO-specific responsive moieties into a single molecular framework. Upon exposure to HClO, RHMB exhibited significant dual-channel fluorescence enhancement characterized by high sensitivity (LODs of 2.55 nM and 14.08 nM), excellent selectivity, and rapid response time (within 5 s). Notably, RHMB enabled reliable imaging of both exogenous and endogenous HClO in living cells and in zebrafish, employing a unique duplex-imaging turn-on approach that highlighted its adaptability across various biological contexts. Furthermore, RHMB effectively monitored HClO fluctuations in an RA mouse model and assessed the therapeutic efficacy of diclofenac (Dic) in alleviating RA symptoms. These findings underscore the potential of RHMB as an invaluable tool for elucidating the biological roles of HClO in various diseases.

Radiotherapy-triggered reduction of platinum-based chemotherapeutic prodrugs in tumours.

Pt(II) drugs are a widely used chemotherapeutic, yet their side effects can be severe. Here we show that the radiation-induced reduction of Pt(IV) complexes to cytotoxic Pt(II) drugs is rapid, efficient and applicable in water, that it is mediated by hydrated electrons from water radiolysis and that the X-ray-induced release of Pt(II) drugs from an oxaliplatin prodrug in tumours inhibits their growth, as we show with nearly complete tumour regression in mice with subcutaneous human tumour xenografts. The combination of low-dose radiotherapy with a Pt(IV)-based antibody-trastuzumab conjugate led to the tumour-selective release of the chemotherapeutic in mice and to substantial therapeutic benefits. The radiation-induced local reduction of platinum prodrugs in the reductive tumour microenvironment may expand the utility of radiotherapy.

A Λ-Ir(iii)-phenylquinazolinone complex enhances ferroptosis by selectively inhibiting metallothionein-1.

Chirality plays an indispensable role in various biological processes, and interactions between chiral enantiomers and biomolecular targets provide new perspectives in precision drug development. While ferroptosis has received increasing attention as a novel pathway to reverse drug resistance, work on the design of precise ferroptosis-targeting molecules through chiral programming was limited. In this work, we designed and synthesized a pair of chirality-dependent ferroptosis-inducing Ir(iii)-phenylquinazolinone complexes (Δ-IrPPQ and Λ-IrPPQ) by inhibiting ferroptosis suppressor protein-1 (FSP1), while the pair of IrPPQ complexes induced extremely different ferroptosis effects as well as distinct photodynamic therapy (PDT) responses toward pancreatic cancer cells. Interestingly, this chirality-dependent biological mechanism through proteomic analysis and molecular simulation revealed that the specific binding and inhibition of metallothionein-1 (MT1) by Λ-IrPPQ sensitized cancer cells to ferroptosis, inducing a burst of reactive oxygen species, lipid peroxidation, glutathione depletion, and inactivation of FSP1. While in comparison, Δ-IrPPQ induced mild ferroptotic cell death. Through simple chiral resolution, the obtained Λ-IrPPQ achieved precise regulation of ferroptosis in pancreatic cancer cells. This work provides new insights into the design of chiral ferroptosis-inducing metallodrugs for future pancreatic cancer therapy.

Correlation between environmental nickel exposure and the development of arthritis: A large-sample cross-sectional investigation.

BACKGROUND: Nickel is a common metallic element in orthopedic implanted devices and living environment exposures. It is associated with varieties of diseases. The purpose of this investigation was to explore the correlation between nickel exposure and the prevalence of arthritis. METHODS: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) database from 2017 to 2018. Multivariate logistic regression was utilized to analyze the relationship between urinary nickel levels and arthritis. In addition, hierarchical modeling further explored the interactions and trends between urinary nickel levels and arthritis. Propensity score matching (PSM) method was used to reduce the effect of confounders. Additionally, restricted cubic spline curve (RCS) was used to assess the possible nonlinear association between urinary nickel and arthritis. RESULTS: The investigation was comprised of 139 arthritis patients and 547 healthy participants. After correction by PSM, there was a positive correlation between arthritis and Nickel exposure levels. The risk of developing arthritis was significantly increased when nickel exposure levels were in the Q4 interval (OR=2.25, 95 % CI=1.03-5.02). When stratified by age and sex, nickel exposure was significantly and positively associated with arthritis in the subgroup aged over 65 years. (OR=2.78,95 %CI=1.20-6.46). Also, the difference between nickel exposure and arthritis was significant in the different gender subgroups (interaction P<0.05). Restricted cubic spline (RCS) results showed a significant linear association between nickel exposure levels and arthritis. In addition, there was a non-linear association between nickel exposure and arthritis across gender and age subgroups. CONCLUSION: A significant positive association between nickel exposure levels and arthritis was showed by the experimental data. Controlling the use of nickel-containing medical prostheses and reducing exposure to nickel-containing daily necessity could help to slow the onset of arthritis.

Click Chemistry-Based Force Spectroscopy Revealed Enhanced Binding Dynamics of Phosphorylated HMGB1 to Cisplatin-DNA.

Cisplatin, a cornerstone in cancer chemotherapy, is known for its DNA-binding capacity and forms lesions that lead to cancer cell death. However, the repair of these lesions compromises cisplatin's effectiveness. This study investigates how phosphorylation of HMGB1, a nuclear protein, modifies its binding to cisplatin-modified DNA (CP-DNA) and thus protects it from repair. Despite numerous methods for detecting protein-DNA interactions, quantitative approaches for understanding their molecular mechanism remain limited. Here, we applied click chemistry-based single-molecule force spectroscopy, achieving high-precision quantification of the interaction between phosphorylated HMGB1 and CP-DNA. This method utilizes a synergy of click chemistry and enzymatic ligation for precise DNA-protein immobilization and interaction in the system. Our results revealed that HMGB1 binds to CP-DNA with a significantly high rupture force of ∼130 pN, stronger than most natural DNA-protein interactions and varying across different DNA sequences. Moreover, Ser14 is identified as the key phosphorylation site, enhancing the interaction's kinetic stability by 35-fold. This increase in stability is attributed to additional hydrogen bonding suggested by molecular dynamics (MD) simulations. Our findings not only reveal the important role of phosphorylated HMGB1 in potentially improving cisplatin's therapeutic efficacy but also provide a precise method for quantifying protein-DNA interactions.

Rational design of CT-coupled J-aggregation platform based on Aza-BODIPY for highly efficient phototherapy.

Supramolecular engineering is exceptionally appealing in the design of functional materials, and J-aggregates resulting from noncovalent interactions offer intriguing features. However, building J-aggregation platforms remains a significant challenge. Herein, we report 3,5-dithienyl Aza-BODIPYs with a donor-acceptor-donor (D-A-D) architecture as the first charge transfer (CT)-coupled J-aggregation BODIPY-type platform. The core acceptor moieties in one molecule interact with donor units in neighboring molecules to generate slip-stacked packing motifs, resulting in CT-coupled J-aggregation with a redshifted wavelength up to 886 nm and an absorption tail over 1100 nm. The J-aggregates show significant photoacoustic signals and high photothermal conversion efficiency of 66%. The results obtained in vivo show that the J-aggregates have the potential to be used for tumor photothermal ablation and photoacoustic imaging. This study not only demonstrates Aza-BODIPY with D-A-D as a novel CT-coupled J-aggregation platform for NIR phototherapy materials but also motivates further study on the design of J-aggregation.

Fluorescence and Lifetime Imaging of Endoplasmic Reticulum Polarity Change During Ferroptosis.

As a new form of regulated cell death, ferroptosis is closely related to various diseases. Tracing ferroptosis related biological behavior is helpful to better understand this process and its related biology. Considering that ferroptosis is featured with remarkable lipid peroxidation which can easily change the membranes' compositions and structures, it is potential to detect intracellular environmental changes for direct assessment of ferroptosis. In view of the close relationship between endoplasmic reticulum (ER) and ferroptosis, we designed an ER-targeted and polarity-sensitive fluorescent probe SBD-CH, which has superior photostability and can respond to polarity with high selectivity without the affection of viscosity. SBD-CH can monitor the trend of ER polarity during ferroptosis by confocal laser scanning microscopy (CLSM), and analyze the distribution of polarity in ferroptosis by fluorescence lifetime imaging microscopy (FLIM). During Erastin induced ferroptosis, the polarity of ER in HT-1080 cells increased and the polarity distribution in ER was more dispersed. Our work provides an effective strategy for evaluating the process of ferroptosis by monitoring the changes of ER polarity.

Nucleic Acid Materials-Mediated Innate Immune Activation for Cancer Immunotherapy.

Abnormally localized nucleic acids (NAs) are considered as pathogen associated molecular patterns (PAMPs) in innate immunity. They are recognized by NAs-specific pattern recognition receptors (PRRs), leading to the activation of associated signaling pathways and subsequent production of type I interferons (IFNs) and pro-inflammatory cytokines, which further trigger the adaptive immunity. Notably, NAs-mediated innate immune activation is highly dependent on the conformation changes, especially the aggregation of PRRs. Evidence indicates that the characteristics of NAs including their length, concentration and even spatial structure play essential roles in inducing the aggregation of PRRs. Therefore, nucleic acid materials (NAMs) with high valency of NAs and high-order structures hold great potential for activating innate and adaptive immunity, making them promising candidates for cancer immunotherapy. In recent years, a variety of NAMs have been developed and have demonstrated significant efficacy in achieving satisfactory anti-tumor immunity in multiple mouse models, exhibiting huge potential for clinical application in cancer treatment. This review aims to discuss the mechanisms of NAMs-mediated innate immune response, and summarize their applications in cancer immunotherapy.

Mitochondria-targeted BODIPY dyes for small molecule recognition, bio-imaging and photodynamic therapy.

Mitochondria are essential for a diverse array of biological functions. There is increasing research focus on developing efficient tools for mitochondria-targeted detection and treatment. BODIPY dyes, known for their structural versatility and excellent spectroscopic properties, are being actively explored in this context. Numerous studies have focused on developing innovative BODIPYs that utilize optical signals for imaging mitochondria. This review presents a comprehensive overview of the progress made in this field, aiming to investigate mitochondria-related biological events. It covers key factors such as design strategies, spectroscopic properties, and cytotoxicity, as well as mechanism to facilitate their future application in organelle imaging and targeted therapy. This work is anticipated to provide valuable insights for guiding future development and facilitating further investigation into mitochondria-related biological sensing and phototherapy.

A NIR-II Photoacoustic Probe for High Spatial Quantitative Imaging of Tumor Nitric Oxide in Vivo.

Nitric oxide (NO) exhibits both pro- and anti-tumor effects. Therefore, real-time in vivo imaging and quantification of tumor NO dynamics are essential for understanding the conflicting roles of NO played in pathophysiology. The current molecular probes, however, cannot provide high-resolution imaging in deep tissues, making them unsuitable for these purposes. Herein, we designed a photoacoustic probe with an absorption maximum beyond 1000 nm for high spatial quantitative imaging of in vivo tumor NO dynamics. The probe exhibits remarkable sensitivity, selective ratiometric response behavior, and good tumor-targeting abilities, facilitating ratiometric imaging of tumor NO throughout tumor progression in a micron-resolution level. Using the probe as the imaging agent, we successfully quantified NO dynamics in tumor, liver and kidney. We have pinpointed an essential concentration threshold of around 80 nmol/cm3 for NO, which plays a crucial role in the "double-edged-sword" function of NO in tumors. Furthermore, we revealed a reciprocal relationship between the NO concentration in tumors and that in the liver, providing initial insights into the possible NO-mediated communication between tumor and the liver. We believe that the probe will help resolve conflicting aspects of NO biology and guide the design of imaging agents for tumor diagnosis and anti-cancer drug screening.

Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer.

Mounting evidence suggests that strategies combining DNA-damaging agents and stimulator of interferon genes (STING) agonists are promising cancer therapeutic regimens because they can amplify STING activation and remodel the immunosuppressive tumor microenvironment. However, a single molecular entity comprising both agents has not yet been developed. Herein, we designed two PtIV-MSA-2 conjugates (I and II) containing the DNA-damaging chemotherapeutic drug cisplatin and the innate immune-activating STING agonist MSA-2; these conjugates showed great potential as multispecific small-molecule drugs against pancreatic cancer. Mechanistic studies revealed that conjugate I upregulated the expression of transcripts associated with innate immunity and metabolism in cancer cells, significantly differing from cisplatin and MSA-2. An analysis of the tumor microenvironment demonstrated that conjugate I could enhance the infiltration of natural killer (NK) cells into tumors and promote the activation of T cells, NK cells and dendritic cells in tumor tissues. These findings indicated that conjugate I, which was created by incorporating a Pt chemotherapeutic drug and STING agonist into one molecule, is a promising and potent anticancer drug candidate, opening new avenues for small-molecule-based cancer metalloimmunotherapy.

An AIE-based monofunctional Pt(ii) complex for photodynamic therapy through synergism of necroptosis-ferroptosis.

Side effects and drug resistance are among the major problems of platinum-based anticancer chemotherapies. Photodynamic therapy could show improved tumor targeting ability and better anticancer effect by region-selective light irradiation. Here, we report an aggregation-induced emission (AIE)-based monofunctional Pt(ii) complex (TTC-Pt), which shows enhanced singlet oxygen production by introduction of a Pt atom to elevate the intersystem crossing (ISC) rate. Moreover, TTC-Pt exhibits decent capacity of inhibition on tumor cell growth upon light irradiation, with negligible dark toxicity compared to the commonly used chemodrug cisplatin. Mechanistic study suggests that TTC-Pt enters HeLa cells via the endocytosis pathway and locates mainly in lysosomes, causing FSP1 down-regulation and intracellular lipid peroxidation accumulation under irradiation, finally leading to ferroptosis and necroptosis. The synergistic dual cell death pathways could help to kill apoptosis-resistant tumor cells. Therefore, TTC-Pt could serve as a potent antitumor photosensitizer, which overcomes the drug resistance with minimum side effects.

Simultaneous single-cell analysis of 5mC and 5hmC with SIMPLE-seq.

Dynamic 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications to DNA regulate gene expression in a cell-type-specific manner and are associated with various biological processes, but the two modalities have not yet been measured simultaneously from the same genome at the single-cell level. Here we present SIMPLE-seq, a scalable, base resolution method for joint analysis of 5mC and 5hmC from thousands of single cells. Based on orthogonal labeling and recording of 'C-to-T' mutational signals from 5mC and 5hmC sites, SIMPLE-seq detects these two modifications from the same molecules in single cells and enables unbiased DNA methylation dynamics analysis of heterogeneous biological samples. We applied this method to mouse embryonic stem cells, human peripheral blood mononuclear cells and mouse brain to give joint epigenome maps at single-cell and single-molecule resolution. Integrated analysis of these two cytosine modifications reveals distinct epigenetic patterns associated with divergent regulatory programs in different cell types as well as cell states.

A Ferroptosis-Inducing Arsenene-Iridium Nanoplatform for Synergistic Immunotherapy in Pancreatic Cancer.

Due to multidrug resistance and the high risk of recurrence, effective and less toxic alternative pancreatic cancer treatments are urgently needed. Pancreatic cancer cells are highly resistant to apoptosis but sensitive to ferroptosis. In this study, an innovative nanoplatform (AsIr@PDA) was developed by electrostatic adsorption of a cationic iridium complex (IrFN) onto two-dimensional (2D) arsenene nanosheets. This nanoplatform exhibits superior ferroptosis-inducing effects with high drug loading capacity and, importantly, excellent anti-cancer immune activation function, leading to efficient elimination of pancreatic tumors with no observable side effects. Interestingly, AsIr@PDA significantly prevents the recurrence of pancreatic cancer in vivo when compared with a cisplatin-loaded nanoplatform. This designed nanoplatform demonstrated superior therapeutic efficacy by synergistic ferroptosis-induced chemotherapy with immunotherapy via an all-in-one strategy, providing new insights for future pancreatic cancer therapy.

Glycerol-3-phosphate acyltransferase 3-mediated lipid droplets accumulation confers chemoresistance of colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy worldwide. It is well known that lipid metabolism reprogramming contributes to the tumor progression. However, the lipid metabolic alterations and potential remodeling mechanism underlying the chemoresistance of CRC remain largely unclear. In this study, we compared the gene expression profiles of chemoresistant versus control CRC cells from the GEO database and identified a key factor, Glycerol-3-phosphate acyltransferase 3 (GPAT3), that promotes lipid droplet (LD) production and confers chemoresistance of CRC. With applying of HPLC-MS and molecular dynamics simulation, we also demonstrated that the activity of lysophosphatidic acid synthesis by GPAT3 was dependent on its acetylation at K316 site. In particular, GPAT3-mediated LD accumulation inhibited immunogenic cell death of tumor, and thus facilitated CD8+ T-cell exhaustion and malignant progression in mouse xenografts and hepatic-metastasis tumors in CRC patients. High GPAT3 expression turned CRC cells into nonimmunogenic cells after (Oxaliplatin) Oxa treatment, which was supported by a decrease in cytotoxic IFN-γ release and CD8+ T-cell exhaustion. In conclusion, these findings revealed the role of GPAT3-associated LD accumulation, which conferred a malignant phenotype (chemoresistance) and regulated the tumor microenvironment of CRC. These results suggest that GPAT3 is a potential target to enhance CRC chemosensitivity and develop novel therapeutic interventions.

Establishment and validation of a nomogram predicting the risk of deep vein thrombosis before total knee arthroplasty.

PURPOSE: This study aimed to analyze the independent risk factors contributing to preoperative DVT in TKA and constructed a predictive nomogram to accurately evaluate its occurrence based on these factors. METHODS: The study encompassed 496 patients who underwent total knee arthroplasty at our hospital between June 2022 and June 2023. The dataset was randomly divided into a training set (n = 348) and a validation set (n = 148) in a 7:3 ratio. The least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analysis were used to screen the predictors of preoperative DVT occurrence in TKA and construct a nomogram. The performance of the predictive models was evaluated using the concordance index (C-index), calibration curves, and the receiver operating characteristic (ROC) curves. Decision curve analysis was used to analyze the clinical applicability of nomogram. RESULTS: A total of 496 patients who underwent TKA were included in this study, of which 28 patients were examined for lower extremity DVT preoperatively. Platelet crit, Platelet distribution width, Procalcitonin, prothrombin time, and D-dimer were predictors of preoperative occurrence of lower extremity DVT in the nomograms of the TKA patients. In addition, the areas under the curve of the ROC of the training and validation sets were 0.935 (95%CI: 0.880-0.990) and 0.854 (95%CI: 0.697-1.000), and the C-indices of the two sets were 0.919 (95%CI: 0.860-0.978) and 0.900 (95%CI: 0.791-1.009). The nomogram demonstrated precise risk prediction of preoperative DVT occurrence in TKA as confirmed by the calibration curve and decision curve analysis. CONCLUSIONS: This Nomogram demonstrates great differentiation, calibration and clinical validity. By assessing individual risk, clinicians can promptly detect the onset of DVT, facilitating additional life monitoring and necessary medical interventions to prevent the progression of DVT effectively.

Rubus Occidentalis and its bioactive compounds against cancer: From molecular mechanisms to translational advances.

BACKGROUND: Cancer ranks as the second leading cause of death globally, imposing a significant public health burden. The rise in cancer resistance to current therapeutic agents underscores the potential role of phytotherapy. Black raspberry (BRB, Rubus Occidentalis) is a fruit rich in anthocyanins, ellagic acid, and ellagitannins. Accumulating evidence suggests that BRB exhibits promising anticancer effects, positioning it as a viable candidate for phytotherapy. PURPOSE: This article aims to review the existing research on BRB regarding its role in cancer prevention and treatment. It further analyzes the effective components of BRB, their metabolic pathways, and the potential mechanisms underlying the fruit's anticancer effects. METHODS: Ovid MEDLINE, EMBASE, Web of Science, and CENTRAL were searched through the terms of Black Raspberry, Raspberry, and Rubus Occidentali up to January 2023. Two reviewers performed the study selection by screening the title and abstract. Full texts of potentially eligible studies were retrieved to access the details. RESULTS: Out of the 767 articles assessed, 73 papers met the inclusion criteria. Among them, 63 papers investigated the anticancer mechanisms, while 10 conducted clinical trials focusing on cancer treatment or prevention. BRB was found to influence multiple cancer hallmarks by targeting various pathways. Decomposition of free radicals and regulation of estrogen metabolism, BRB can reduce DNA damage caused by reactive oxygen species. BRB can also enhance the function of nucleotide excision repair to repair DNA lesions. Through regulation of epigenetics, BRB can enhance the expression of tumor suppressor genes, inducing cell cycle arrest, and promoting apoptosis and pyroptosis. BRB can reduce the energy and nutrients supply to the cancer nest by inhibiting glycolysis and reducing angiogenesis. The immune and inflammatory microenvironment surrounding cancer cells can also be ameliorated by BRB, inhibiting cancer initiation and progression. However, the limited bioavailability of BRB diminishes its anticancer efficacy. Notably, topical applications of BRB, such as gels and suppositories, have demonstrated significant clinical benefits. CONCLUSION: BRB inhibits cancer initiation, progression, and metastasis through diverse anticancer mechanisms while exhibiting minimal side effects. Given its potential, BRB emerges as a promising phototherapeutic agent for cancer treatment.

Modulation of Metal Homeostasis for Cancer Therapy.

Metal ions such as iron, zinc, copper, manganese, and calcium are essential for normal cellular processes, including DNA synthesis, enzyme activity, cellular signaling, and oxidative stress regulation. When the balance of metal homeostasis is disrupted, it can lead to various pathological conditions, including cancer. Thus, understanding the role of metal homeostasis in cancer has led to the development of anti-tumor strategies that specifically target the metal imbalance. Up to now, diverse small molecule-based chelators, ionophores, metal complexes, and metal-based nanomaterials have been developed to restore the normal balance of metals or exploit the dysregulation for therapeutic purposes. They hold great promise in inhibiting tumor growth, preventing metastasis, and enhancing the effectiveness of existing cancer therapies. In this review, we aim to provide a comprehensive summary of the strategies employed to modulate the homeostasis of iron, zinc, copper, manganese, and calcium for cancer therapy. Their modulation mechanisms for metal homeostasis are succinctly described, and their recent applications in the field of cancer therapy are discussed. At the end, the limitations of these approaches are addressed, and potential avenues for future developments are explored.

A Small-Molecule Ratiometric Photoacoustic Probe for the High-Spatiotemporal-Resolution Imaging of Copper(II) Dynamics in the Mouse Brain.

Copper dysmetabolism is associated with various neurodegenerative disorders, making high-spatiotemporal-resolution imaging of Cu2+ in the brain essential for understanding the underlying pathophysiological processes. Nevertheless, the current probes encounter obstacles in crossing the blood-brain barrier (BBB) and providing high-spatial-resolution in deep tissues. Herein, we present a photoacoustic probe capable of imaging Cu2+ dynamics in the mouse brain with high-spatiotemporal-resolution. The probe demonstrates selective ratiometric and reversible responses to Cu2+ , while also efficiently crossing the BBB. Using the probe as the imaging agent, we successfully visualized Cu2+ in the brain of Parkinson's disease (PD) model mouse with a remarkable micron-level resolution. The imaging results revealed a significant increase in Cu2+ levels in the cerebral cortex as PD progresses, highlighting the close association between Cu2+ alternations in the region and the disease. We also demonstrated that the probe can be used to monitor changes in Cu2+ distribution in the PD model mouse brain during L-dopa intervention. Mechanism studies suggest that the copper dyshomeostasis in the PD mouse brain was dominated by the expression levels of divalent metal transporter 1. The application of our probe in imaging Cu2+ dynamics in the mouse brain offers valuable insights into the copper-related molecular mechanisms underlying neurodegenerative diseases.