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Primary aldosteronism (PA) and diabetes mellitus (DM) may coexist. We previously found that DM and impaired glucose tolerance (IGT) may decrease the efficiency of the aldosterone-to-renin ratio (ARR) for screening PA. Thus, we wanted to determine appropriate ARR cut-off values for screening PA in patients with hypertension with DM and IGT. Data from 736 patients with hypertension were collected. They were divided into PA (77 cases), PA with DM (27 cases), PA with IGT (44 cases), hypertension without PA (353 cases), hypertension with DM (without PA, 127 cases), and hypertension with IGT (without PA, 108 cases). Receiver operating characteristic (ROC) curves were used to identify the appropriate ARR cut-off values in different conditions. Screening efficiencies of these cut-off values were evaluated across different groups. ARR cut-off values for screening PA in hypertensive patients without DM and IGT, with DM, and with IGT were 29.65, 23.15, and 26.9, respectively. All cut-off values demonstrated high sensitivity and specificity: 92.2% and 88.7%, 92.6% and 79.5%, and 88.6% and 85.2%, respectively, and areas under the ROC curves were 0.941, 0.904, and 0.909, respectively. Our results suggest that extra ARR cut-off values may be necessary for effective screening PA in hypertensive patients with DM and IGT, particularly in those with DM.
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Cholesterol is an essential membrane component, and the metabolites from cholesterol play important biological functions to intricately support cancer progression and dampen immune responses. Preclinical and clinical studies have demonstrated the role of cholesterol metabolism regulation on inhibiting tumor growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing anti-tumor immunity. In this minireview, we discuss complex cholesterol metabolism in tumors, its important role in cancer progression, and its influences on immune cells in the TME. We provide an overview of recent advances in cancer treatment through regulating cholesterol metabolism. We discuss the design of cholesterol-altering multifunctional nanomaterials to regulate oxidative stress, modulate immune checkpoints, manipulate mechanical stress responses, and alter cholesterol metabolic pathways. Additionally, we examine the interactions between cholesterol metabolism regulation and established cancer treatments with the aim of identifying efficient strategies to disrupt cholesterol metabolism and synergistic combination therapies for effective cancer treatment.
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The combination of cuproptosis and immune checkpoint inhibition has shown promise in treating malignant tumors. However, it remains a challenge to deliver copper ions and immune checkpoint inhibitors efficiently and simultaneously to tumors. Herein, a mitochondria-targeted nanoscale coordination polymer particle, Cu/TI, comprising Cu(II), and a triphenylphosphonium conjugate of 5-carboxy-8-hydroxyquinoline (TI), for effective cuproptosis induction and programmed cell death-1 (PD-L1) downregulation is reported. Upon systemic administration, Cu/TI efficiently accumulates in tumor tissues to induce immunogenic cancer cell death and reduce PD-L1 expression. Consequently, Cu/TI promotes the intratumoral infiltration and activation of cytotoxic T lymphocytes to greatly inhibit tumor progression of colorectal carcinoma and triple-negative breast cancer in mouse models without causing obvious side effects.
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The low success rate of cancer nanomedicines has raised debate on the role of the enhanced permeability and retention (EPR) effect on tumor deposition of nanotherapeutics. Here, we report a bifunctional nanoscale coordination polymer (NCP), oxaliplatin (OX)/2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), to overcome the EPR limitation through stimulator of interferon genes (STING) activation and enhance chemotherapeutic and STING agonist delivery for tumor eradication. OX/GA encapsulates GA and OX in the NCP to protect GA from enzymatic degradation and improve GA and OX pharmacokinetics. STING activation by OX/GA disrupts tumor vasculatures and increases intratumoral deposition of OX by 4.9-fold over monotherapy OX-NCP. OX/GA demonstrates exceptional antitumor effects with >95% tumor growth inhibition and high cure rates in subcutaneous, orthotopic, spontaneous, and metastatic tumor models. OX/GA induces immunogenic cell death of tumor cells and STING activation of innate immune cells to enhance antigen presentation. NCPs provide an excellent nanoplatform to overcome the EPR limitation for effective cancer therapy.
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Proteínas de Membrana , Animais , Proteínas de Membrana/metabolismo , Humanos , Camundongos , Linhagem Celular Tumoral , Oxaliplatina/farmacologia , Oxaliplatina/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Nucleotídeos Cíclicos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Nanopartículas/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Radiotherapy is widely used for cancer treatment, but its clinical utility is limited by radioresistance and its inability to target metastases. Nanoscale metal-organic frameworks (MOFs) have shown promise as high-Z nanoradiosensitizers to enhance radiotherapy and induce immunostimulatory regulation of the tumor microenvironment. We hypothesized that MOFs could deliver small-molecule therapeutics to synergize with radiotherapy for enhanced antitumor efficacy. Herein, we develop a robust nanoradiosensitizer, GA-MOF, by conjugating a STING agonist, 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), on MOFs for synergistic radiosensitization and STING activation. GA-MOF demonstrated strong anticancer efficacy by forming immune-cell-rich nodules (artificial leukocytoid structures) and transforming them into immunostimulatory hotspots with radiotherapy. Further combination with an immune checkpoint blockade suppressed distant tumors through systemic immune activation. Our work not only demonstrates the potent radiosensitization of GA-MOF, but also provides detailed mechanisms regarding MOF distribution, immune regulatory pathways and long-term immune effects.
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Covalent organic frameworks (COFs) have been explored for photodynamic therapy (PDT) of cancer, but their antitumor efficacy is limited by excited state quenching and low reactive oxygen species generation efficiency. Herein, we report a simultaneous protonation and metalation strategy to significantly enhance the PDT efficacy of a nanoscale two-dimensional imine-linked porphyrin-COF. The neutral and unmetalated porphyrin-COF (Ptp) and the protonated and metalated porphyrin-COF (Ptp-Fe) were synthesized via imine condensation between 5,10,15,20-tetrakis(4-aminophenyl)porphyrin and terephthalaldehyde in the absence and presence of ferric chloride, respectively. The presence of ferric chloride generated both doubly protonated and Fe3+-coordinated porphyrin units, which red-shifted and increased the Q-band absorption and disrupted exciton migration to prevent excited state quenching, respectively. Under light irradiation, rapid energy transfer from protonated porphyrins to Fe3+-coordinated porphyrins in Ptp-Fe enabled 1O2 and hydroxyl radical generation via type II and type I PDT processes. Ptp-Fe also catalyzed the conversion of hydrogen peroxide to hydroxy radical through a photoenhanced Fenton-like reaction under slightly acidic conditions and light illumination. As a result, Ptp-Fe-mediated PDT exhibited much higher cytotoxicity than Ptp-mediated PDT on CT26 and 4T1 cancer cells. Ptp-Fe-mediated PDT afforded potent antitumor efficacy in subcutaneous CT26 murine colon cancer and orthotopic 4T1 murine triple-negative breast tumors and prevented metastasis of 4T1 breast cancer to the lungs. This work underscores the role of fine-tuning the molecular structures of COFs in significantly enhancing their PDT efficacy.
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Abnormal cancer metabolism causes hypoxic and immunosuppressive tumor microenvironment (TME), which limits the antitumor efficacy of photodynamic therapy (PDT). Herein, we report a photosensitizing nanoscale metal-organic layer (MOL) with anchored 3-bromopyruvate (BrP), BrP@MOL, as a metabolic reprogramming agent to enhance PDT and antitumor immunity. BrP@MOL inhibited mitochondrial respiration and glycolysis to oxygenate tumors and reduce lactate production. This metabolic reprogramming enhanced reactive oxygen species generation during PDT and reshaped the immunosuppressive TME to enhance antitumor immunity. BrP@MOL-mediated PDT inhibited tumor growth by >90 % with 40 % of mice being tumor-free, rejected tumor re-challenge, and prevented lung metastasis. Further combination with immune checkpoint blockade potently regressed the tumors with >98 % tumor inhibition and 80 % of mice being tumor-free.
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Phosphine-ligated transition metal complexes play a pivotal role in modern catalysis, but our understanding of the impact of ligand counts on the catalysis performance of the metal center is limited. Here we report the synthesis of a low-coordinate mono(phosphine)-Rh catalyst on a metal-organic layer (MOL), P-MOL ⢠Rh, and its applications in the hydrogenation of mono-, di-, and tri-substituted alkenes as well as aryl nitriles with turnover numbers (TONs) of up to 390000. Mechanistic investigations and density functional theory calculations revealed the lowering of reaction energy barriers by the low steric hindrance of site-isolated mono(phosphine)-Rh sites on the MOL to provide superior catalytic activity over homogeneous Rh catalysts. The MOL also prevents catalyst deactivation to enable recycle and reuse of P-MOL ⢠Rh in catalytic hydrogenation reactions.
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Recent interest has surged in using heterogeneous carriers to boost synergistic photocatalysis for organic transformations. Heterogeneous catalysts not only facilitate synergistic enhancement of distinct catalytic centers compared to their homogeneous counterparts, but also allow for the easy recovery and reuse of catalysts. This mini-review summarizes recent advancements in developing heterogeneous carriers, including metal-organic frameworks, covalent-organic frameworks, porous organic polymers, and others, for synergistic catalytic reactions. The advantages of porous materials in heterogeneous catalysis originate from their ability to provide a high surface area, facilitate enhanced mass transport, offer a tunable chemical structure, ensure the stability of active species, and enable easy recovery and reuse of catalysts. Both photosensitizers and catalysts can be intricately incorporated into suitable porous carriers to create heterogeneous dual photocatalysts for organic transformations. Notably, experimental evidence from reported cases has shown that the catalytic efficacy of heterogeneous catalysts often surpasses that of their homogeneous analogues. This enhanced performance is attributed to the proximity and confinement effects provided by the porous nature of the carriers. It is expected that porous carriers will provide a versatile platform for integrating diverse catalysts, thus exhibiting superior performance across a range of organic transformations and appealing prospect for industrial applications.
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Photocatalytic direct hydrogen atom transfer (d-HAT) is a synthetically important strategy to convert C-H bonds to useful C-X bonds. Herein we report the synthesis of an anthraquinone-based two-dimensional covalent organic framework, DAAQ-COF, as a recyclable d-HAT photocatalyst for C-H functionalization. Powder X-ray diffraction, N2 sorption isotherms, solid-state NMR spectra, infrared spectra, and thermogravimetric analysis characterized DAAQ-COF as a crystalline, porous COF with a stable ketoenamine linkage and strong absorption in the visible region. Under visible light irradiation, DAAQ-COF is photo-excited to cleave C(sp3)-H or C(sp2)-H bonds via HAT to generate reactive carbon radicals, which add to different radical acceptors to achieve C-N or C-C coupling reactions. DAAQ-COF is easily recovered from the reaction mixture via centrifugation or filtration and used in six consecutive reaction runs without any decrease in catalytic efficiency. The ease of catalyst separation allows sequential conversion of the C-N coupling intermediate to synthetically useful amide, ester, or thioester products. Photophysical and isotope labelling experiments support the d-HAT mechanism of DAAQ-COF-catalyzed C-H bond functionalization.
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Photochemical generation of alkyl radicals from haloalkanes often requires strong energy input from ultraviolet light or a strong photoreductant. Haloalkanes can alternatively be activated with nitrogen-based nucleophiles through a sequential SN2 reaction and single-electron reduction to access alkyl radicals, but these two reaction steps have opposite steric requirements on the nucleophiles. Herein, we report the design of Hf12 metal-organic layers (MOLs) with iridium-based photosensitizer bridging ligands and secondary-building-unit-supported pyridines for photocatalytic alkyl radical generation from haloalkanes. By bringing the photosensitizer and pyridine pairs in proximity, the MOL catalysts allowed facile access to the pyridinium salts from SN2 reactions between haloalkanes and pyridines and at the same time enhanced electron transfer from excited photosensitizers to pyridinium salts to facilitate alkyl radical generation. Consequentially, the MOLs efficiently catalyzed Heck-type cross-coupling reactions between haloalkanes and olefinic substrates to generate functionalized alkenes. The MOLs showed 4.6 times higher catalytic efficiency than the homogeneous counterparts and were recycled and reused without a loss of catalytic activity.
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The recent discovery of copper-mediated and mitochondrion-dependent cuproptosis has aroused strong interest in harnessing this novel mechanism of cell death for cancer therapy. Here the design of a core-shell nanoparticle, CuP/Er, for the co-delivery of copper (Cu) and erastin (Er) to cancer cells for synergistic cuproptosis and ferroptosis is reported. The anti-Warburg effect of Er sensitizes tumor cells to Cu-mediated cuproptosis, leading to irreparable mitochondrial damage by depleting glutathione and enhancing lipid peroxidation. CuP/Er induces strong immunogenic cell death, enhances antigen presentation, and upregulates programmed death-ligand 1 expression. Consequently, CuP/Er promotes proliferation and infiltration of T cells, and when combined with immune checkpoint blockade, effectively reinvigorates T cells to mediate the regression of murine colon adenocarcinoma and triple-negative breast cancer and prevent tumor metastasis. This study suggests a unique opportunity to synergize cuproptosis and ferroptosis with combination therapy nanoparticles to elicit strong antitumor effects and potentiate current cancer immunotherapies.
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Cobre , Ferroptose , Imunoterapia , Nanopartículas , Ferroptose/efeitos dos fármacos , Animais , Camundongos , Imunoterapia/métodos , Modelos Animais de Doenças , Humanos , Linhagem Celular Tumoral , Feminino , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , PiperazinasRESUMO
Neural radiance fields (NeRF) achieve highly photo-realistic novel-view synthesis, but it's a challenging problem to edit the scenes modeled by NeRF-based methods, especially for dynamic scenes. We propose editable neural radiance fields that enable end-users to easily edit dynamic scenes and support topological changes. Input with an image sequence from a single camera, our network is trained automatically and models topologically varying dynamics using our picked-out surface key points. Then end-users can edit the scene by easily dragging the key points to desired new positions. To achieve this, we propose a scene analysis method to detect and initialize key points by considering the dynamics in the scene, and a weighted key points strategy to model topologically varying dynamics by joint key points and weights optimization. Our method supports intuitive multi-dimensional (up to 3D) editing and can generate novel scenes that are unseen in the input sequence. Experiments demonstrate that our method achieves high-quality editing on various dynamic scenes and outperforms the state-of-the-art.
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Chemoradiotherapy combines radiotherapy with concurrent chemotherapy to potentiate antitumor activity but exacerbates toxicities and causes debilitating side effects in cancer patients. Herein, we report the use of a nanoscale metal-organic layer (MOL) as a 2D nanoradiosensitizer and a reservoir for the slow release of chemotherapeutics to amplify the antitumor effects of radiotherapy. Coordination of phosphate-containing drugs to MOL secondary building units prolongs their intratumoral retention, allowing for continuous release of gemcitabine monophosphate (GMP) for effective localized chemotherapy. In the meantime, the MOL sensitizes cancer cells to X-ray irradiation and provides potent radiotherapeutic effects. GMP-loaded MOL (GMP/MOL) enhances cytotoxicity by 2-fold and improves radiotherapeutic effects over free GMP in vitro. In a colon cancer model, GMP/MOL retains GMP in tumors for more than four days and, when combined with low-dose radiotherapy, inhibits tumor growth by 98 %. The synergistic chemoradiotherapy enabled by GMP/MOL shows a cure rate of 50 %, improves survival, and ameliorates cancer-proliferation histological biomarkers.
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Neoplasias , Fosfatos , Humanos , Gencitabina , Quimiorradioterapia , Neoplasias/tratamento farmacológicoRESUMO
Blockade of programmed cell death-1/programmed cell death-ligand 1 (PD-L1) immune checkpoints with monoclonal antibodies has shown great promise for cancer treatment, but these antibodies can cause immune-related adverse events in normal organs. Here we report a dual-cell targeted chemo-immunotherapeutic nanoscale coordination polymer (NCP), OxPt/BP, comprising oxaliplatin (OxPt) and 2-bromopalmitic acid (BP), for effective downregulation of PD-L1 expression in both cancer cells and dendritic cells (DCs) by inhibiting palmitoyl acyltransferase DHHC3. OxPt/BP efficiently promotes DC maturation by increasing intracellular oxidative stress and enhancing OxPt-induced immunostimulatory immunogenic cancer cell death. Systemic administration of OxPt/BP reduces the growth of subcutaneous and orthotopic colorectal carcinoma by facilitating the infiltration and activation of cytotoxic T lymphocytes together with reducing the population of immunosuppressive regulatory T cells. As a result, OxPt/BP significantly extends mouse survival without causing side effects. This work highlights the potential of NCPs in simultaneously reprogramming cancer cells and DCs for potent cancer treatment.
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Antígeno B7-H1 , Neoplasias , Animais , Camundongos , Ligantes , Neoplasias/tratamento farmacológico , Imunoterapia , Imunidade Adaptativa , Apoptose , Células Dendríticas , Linhagem Celular TumoralRESUMO
Phthalocyanine photosensitizers (PSs) have shown promise in fluorescence imaging and photodynamic therapy (PDT) of malignant tumors, but their practical application is limited by the aggregation-induced quenching (AIQ) and inherent photobleaching of PSs. Herein, we report the synthesis of a two-dimensional nanoscale covalent organic framework (nCOF) with staggered (AB) stacking of zinc-phthalocyanines (ZnPc), ZnPc-PI, for fluorescence imaging and mitochondria-targeted PDT. ZnPc-PI isolates and confines ZnPc PSs in the rigid nCOF to reduce AIQ, improve photostability, enhance cellular uptake, and increase the level of reactive oxygen species (ROS) generation via mitochondrial targeting. ZnPc-PI shows efficient tumor accumulation, which allowed precise tumor imaging and nanoparticle tracking. With high cellular uptake and tumor accumulation, intrinsic mitochondrial targeting, and enhanced ROS generation, ZnPc-PI exhibits potent PDT efficacy with >95% tumor growth inhibition on two murine colon cancer models without causing side effects.
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Estruturas Metalorgânicas , Neoplasias , Compostos Organometálicos , Fotoquimioterapia , Compostos de Zinco , Camundongos , Humanos , Animais , Fotoquimioterapia/métodos , Estruturas Metalorgânicas/uso terapêutico , Espécies Reativas de Oxigênio , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Isoindóis , Neoplasias/tratamento farmacológico , Compostos Organometálicos/farmacologia , Compostos Organometálicos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Mitocôndrias , Linhagem Celular TumoralRESUMO
Covalent organic frameworks (COFs) have emerged as tunable, crystalline, and porous functional organic materials, but their application in photocatalysis has been limited by rapid excited-state quenching. Herein, we report the first example of dual photoredox/nickel catalysis by an sp2 carbon-conjugated spirobifluorene-based COF. Constructed from spirobifluorene and nickel-bipyridine linkers, the NiSCN COF adopted a two-dimensional structure with staggered stacking. Under light irradiation, NiSCN catalyzed amination and etherification/esterification reactions of aryl halides through the photoredox mechanism, with a catalytic efficiency more than 23-fold higher than that of its homogeneous control. NiSCN was used in five consecutive reactions without a significant loss of catalytic activity.
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The simultaneous use of two or more drugs due to multi-disease comorbidity continues to increase, which may cause adverse reactions between drugs that seriously threaten public health. Therefore, the prediction of drug-drug interaction (DDI) has become a hot topic not only in clinics but also in bioinformatics. In this study, we propose a novel pre-trained heterogeneous graph neural network (HGNN) model named HetDDI, which aggregates the structural information in drug molecule graphs and rich semantic information in biomedical knowledge graph to predict DDIs. In HetDDI, we first initialize the parameters of the model with different pre-training methods. Then we apply the pre-trained HGNN to learn the feature representation of drugs from multi-source heterogeneous information, which can more effectively utilize drugs' internal structure and abundant external biomedical knowledge, thus leading to better DDI prediction. We evaluate our model on three DDI prediction tasks (binary-class, multi-class and multi-label) with three datasets and further assess its performance on three scenarios (S1, S2 and S3). The results show that the accuracy of HetDDI can achieve 98.82% in the binary-class task, 98.13% in the multi-class task and 96.66% in the multi-label one on S1, which outperforms the state-of-the-art methods by at least 2%. On S2 and S3, our method also achieves exciting performance. Furthermore, the case studies confirm that our model performs well in predicting unknown DDIs. Source codes are available at https://github.com/LinsLab/HetDDI.
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Biologia Computacional , Aprendizagem , Interações Medicamentosas , Redes Neurais de Computação , SemânticaRESUMO
[This retracts the article PMC6681452.].
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While activating antitumor immunity with toll-like receptor (TLR) agonists provides a promising approach toward cancer immunotherapy, existing TLR agonists, including resiquimod (R848), have shown poor tumor selectivity and ineffective TLR activation in tumors for optimal antitumor effects. We hypothesized that improved delivery of TLR agonists to tumors and their effective combination with tumor antigens could significantly enhance their antitumor efficacy. Here, we report a novel nanoscale coordination polymer, Ce6/R848, for the co-delivery of Ce6 photosensitizer to elicit immunogenic cell death via photodynamic therapy (PDT) and cholesterol-conjugated R848 (Chol-R848) for tumor-selective TLR7/8 activation. Upon light irradiation, Ce6-mediated PDT released tumor antigens while selectively delivered R848 activated TLR7/8 in the tumors to synergistically activate antigen-presenting cells and prime T cells for enhanced innate and adaptive antitumor immune responses. Ce6/R848 achieved a 50% cure rate and 99.4% inhibition of tumor growth in subcutaneous MC38 colorectal tumors with minimal systemic toxicity.