Self-assembled Pt(II) metallacycles enable precise cancer combination chemotherapy.

Combination chemotherapy, which involves the simultaneous use of multiple anticancer drugs in adequate combinations to disrupt multiple mechanisms associated with tumor growth, has shown advantages in enhanced therapeutic efficacy and lower systemic toxicity relative to monotherapy. Herein, we employed coordination-driven self-assembly to construct discrete Pt(II) metallacycles as monodisperse, modular platforms for combining camptothecin and combretastatin A4, two chemotherapy agents with a disparate mechanism of action, in precise arrangements for combination chemotherapy. Formulation of the drug-loaded metallacycles with folic acid­functionalized amphiphilic diblock copolymers furnished nanoparticles with good solubility and stability in physiological conditions. Folic acids on the surface of the nanoparticles promote their internalization into cancer cells. The intracellular reductive environment of cancer cells induces the release of the drug molecules at an exact 1:1 ratio, leading to a synergistic anticancer efficacy. In vivo studies on tumor-bearing mice demonstrated the favorable therapeutic outcome and minimal side effects of the combination chemotherapy approach based on a self-assembled metallacycle.

Engineering a Dual-Receptor Targeted Multivalent Probe for Enhanced Magnetic Resonance Imaging of Metastatic Cancer.

Noninvasive monitoring of cancer metastasis is essential to improving clinical outcomes. Molecular MRI (mMRI) is a special implementation of noninvasive molecular imaging that promises to offer a powerful means for early detection and analysis of pathological states of cancer by tracking molecular markers. However, this is often hindered by the challenging issue of obtaining transformable mMRI contrast agents with high sensitivity, specificity, and broad applicability, given the high tumor heterogeneity and complex metastatic features. Herein, we present a dual-receptor targeted, multivalent recognition strategy and report a new class of mMRI probes for enhanced imaging of metastatic cancer. This probe is designed by covalently conjugating Gd-chelate with phenylboronic acid and an aptamer via an affordable polymerization chemistry to concurrently target two different cell-membrane receptors that are commonly overexpressed and highly implicated in both tumorigenesis and metastasis. Moreover, the polymerization chemistry allows the probe to contain a bunch of targeting ligands and signal reporters in a single chain, which not only leads to more than 2-fold enhancement in T1 relaxivity at 1.5 T compared to the commercial contrast agent but also enables it to actively target tumor cells in a multivalent recognition manner, contributing to a much higher imaging contrast than single-receptor targeted probes and the commercial agent in mouse models with lung metastases, yet without inducing systemic side effects. We expect this study to offer a useful molecular tool to promote transformable applications of mMRI and a better understanding of molecular mechanisms involved in cancer development.

Aptamer Conjugate-Based Ratiometric Fluorescent Probe for Precise Imaging of Therapy-Induced Cancer Senescence.

Therapy-induced cellular senescence has been increasingly recognized as a key mechanism to promote various aspects of carcinogenesis in a nonautonomous manner. Thus, real-time imaging monitoring of cellular senescence during cancer therapy is imperative not only to further elucidate its roles in cancer progression but also to provide guidance for medical management of cancer. However, it has long been a challenging task due to the lack of effective imaging molecule tools with high specificity and accuracy toward cancer senescence. Herein, we report the rational design, synthesis, and evaluation of an aptamer conjugate-based ratiometric fluorescent probe for precise imaging of therapy-induced cancer senescence. Unlike traditional senescence imaging systems, our probe targets two senescence-associated markers at both cellular and subcellular dimensions, namely, aptamer-mediated membrane marker recognition for active cell targeting and lysosomal marker-triggered ratiometric fluorescence changes of two cyanine dyes for site-specific, high-contrast imaging. Moreover, such a two-channel fluorescence response is activated after a one-step reaction and at the same location, avoiding the diffusion-caused signal decay previously encountered in dual-marker activated probes, contributing to spatiotemporally specific imaging of therapy-induced cancer senescence in living cells and three-dimensional multicellular tumor spheroids. This work may offer a valuable tool for a basic understanding of cellular senescence in cancer biology and interventions.

Correlation between fat-to-muscle mass ratio and cognitive impairment in elderly patients with type 2 diabetes mellitus: a cross-sectional study.

BACKGROUND: Fat to muscle mass ratio (FMR), a novel index integrating fat and muscle composition, has garnered attention in age-related conditions such as type 2 diabetes mellitus (T2DM) and neurodegenerative diseases. Despite this research on the relationship between FMR and cognitive impairment (CI) in T2DM remains scarce. This study aimed to investigate the sex-specific association between FMR and CI in elderly T2DM patients. METHODS: A total of 768 elderly (> 60 years) T2DM in-patients (356 men and 412 women) were recruited from the Department of Endocrinology at Tianjin Nankai University affiliated hospital. Bioelectrical Impedance Analysis (BIA) was used to assess body composition, and Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive performance. T2DM patients were categorized into normal cognitive function (NC) and cognitive impairment (CI) groups based on MoCA scores and stratified by sex. Binary logistic regression was employed to examine the association between FMR and CI. RESULTS: Among the participants, 42.7% of men and 56.3% of women experienced cognitive deterioration. Women with CI exhibited lower body mass index (BMI) and skeletal muscle mass index (SMI), while men with cognitive disorders showed lower SMI, FMR, and higher fat mass index (FMI). FMR was consistently unrelated to cognition in females, irrespective of adjustment made. However, in males, FMR was significantly associated with an increasing risk of cognitive dysfunction after adjusting for demographic and clinical variables (OR: 1.175, 95% CI: 1.045-1.320, p = 0.007). Furthermore, for each 0.1 increase in FMR, the incidence of CI rose by 31.1% after additional adjustment for BMI. In males, the prevalence of CI increased sequentially across FMR quartiles (p < 0.05). CONCLUSION: Elderly T2DM men with high FMR had unfavorable cognitive function. FMR is independently associated with an increased risk of CI in male T2DM patients regardless of BMI.

Topological Single-stranded DNA Encoding and Programmable Assembly of Molecular Nanostructures for NIR-II Cancer Theranostics.

Molecular nanotechnology promises to offer privileged access to developing NIR-II materials with precise structural and functional manipulation for transformable theranostic applications. However, the lack of an affordable, yet general, method makes this goal currently inaccessible. By virtue of the intriguing nucleic acid chemistry, here we present an artificial base-directed topological single-strand DNA encoding design that enables one-step synthesis of valence-controlled NIR-II molecular nanostructures and spatial assembly of these nanostructures to modulate their behaviors in living systems. As proof-of-concept studies, we construct ultrasmall Ag2 S quantum dots and pH-responsive, size-tunable CuS assemblies for in vivo NIR-II fluorescence imaging and deep tumor photothermal therapy. This work paves a new way for creating functionally diversified architectures and broadens the scope of DNA-encoded material engineering.

Dual-Parameter Recognition-Directed Design of the Activatable Fluorescence Probe for Precise Imaging of Cellular Senescence.

Specific imaging of cellular senescence emerges as a promising strategy for early diagnosis and treatment of various age-related diseases. The currently available imaging probes are routinely designed by targeting a single senescence-related marker. However, the inherently high heterogeneity of senescence makes them inaccessible to achieve specific and accurate detection of broad-spectrum cellular senescence. Here, we report the design of a dual-parameter recognition fluorescent probe for precise imaging of cellular senescence. This probe remains silent in non-senescent cells, yet produces bright fluorescence after sequential responses to two senescence-associated markers, namely, SA-ß-gal and MAO-A. In-depth studies reveal that this probe allows for high-contrast imaging of senescence, independent of the cell source or stress type. More impressively, such dual-parameter recognition design further allows it to distinguish senescence-associated SA-ß-gal/MAO-A from cancer-related ß-gal/MAO-A, compared to commercial or previous single-marker detection probes. This study offers a valuable molecular tool for imaging cellular senescence, which is expected to significantly expand the basic studies on senescence and facilitate advances of senescence-related disease theranostics.

Recent Advances in Strategies for Imaging Detection and Intervention of Cellular Senescence.

Cellular senescence is a stable cell cycle arrest state that can be triggered by a wide range of intrinsic or extrinsic stresses. Increased burden of senescent cells in various tissues is thought to contribute to aging and age-related diseases. Thus, the detection and interventions of senescent cells are critical for longevity and treatment of disease. However, the highly heterogeneous feature of senescence makes it challenging for precise detection and selective clearance of senescent cells in different age-related diseases. To address this issue, considerable efforts have been devoted to developing senescence-targeting molecular theranostic strategies, based on the potential biomarkers of cellular senescence. Herein, we review recent advances in the field of anti-senescence research and highlight the specific visualization and elimination of senescent cells. Additionally, the challenges in this emerging field are outlined.

Mechanisms of autophagy and endoplasmic reticulum stress in the reversal of platinum resistance of epithelial ovarian cancer cells by naringin.

OBJECTIVE: Our previous studies showed that naringin (Nar) can effectively reverse the cisplatin resistance of ovarian cancer cells. This study aims to explore the potential mechanism by which Nar reverses cisplatin resistance in ovarian cancer. METHODS: The proliferative activity of cells was evaluated using CCK8 and cell clone formation assays. Autophagic flux in cells was evaluated via LC3B immunofluorescence and monodansylcadaverine (MDC) staining. The expression levels of autophagy, endoplasmic reticulum (ER) stress, and apoptosis-related proteins were detected via Western blotting. Autophagy and ER stress were regulated using siATG5, siLC3B, rapamycin (Rap), chloroquine (CQ), 4-phenylbutyric acid (4-PBA), and thapsigargin (TG). siATG5 and siLC3B are short interfering RNAs (siRNAs) used to knock down the expression of ATG5 and LC3B genes, respectively. RESULTS: Nar inhibited autophagy in SKOV3/DDP cells by activating the PI3K/AKT/mTOR pathway. And Nar increased the levels of ER stress-related proteins, namely, P-PERK, GRP78, and CHOP, and promoted apoptosis in SKOV3/DDP cells. Moreover, treatment with the inhibitor of ER stress alleviated apoptosis induced by Nar in SKOV3/DDP cells. In addition, compared to cisplatin or naringin alone, the combination of Nar and cisplatin significantly reduced the proliferative activity of SKOV3/DDP cells. And siATG5, siLC3B, CQ or TG pretreatment further inhibited the proliferative activity of SKOV3/DDP cells. Conversely, Rap or 4-PBA pretreatment alleviated the cell proliferation inhibition caused by Nar combined with cisplatin. CONCLUSION: Nar not only inhibited the autophagy in SKOV3/DDP cells by regulating the PI3K/AKT/mTOR signalling pathway, but also promoted apoptosis in SKOV3/DDP cells by targeting ER stress. Nar can reverse the cisplatin resistance in SKOV3/DDP cells through these two mechanisms.

Engineering Hierarchical Recognition-Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti-Atherosclerosis Therapy.

Precise regulation of vascular senescence represents a far-reaching strategy to combat age-related diseases. However, the high heterogeneity of senescence, alongside the lack of targeting and potent senolytics, makes it very challenging. Here we report a molecular design to tackle this challenge through multidimensional, hierarchical recognition of three hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state. Its potential for in vivo treatment of vascular diseases is successfully illustrated in a model of atherosclerosis, with effective suppression of the plaque progression yet negligible side effects.

Reduced ecosystem resilience quantifies fine-scale heterogeneity in tropical forest mortality responses to drought.

Sensitivity of forest mortality to drought in carbon-dense tropical forests remains fraught with uncertainty, while extreme droughts are predicted to be more frequent and intense. Here, the potential of temporal autocorrelation of high-frequency variability in Landsat Enhanced Vegetation Index (EVI), an indicator of ecosystem resilience, to predict spatial and temporal variations of forest biomass mortality is evaluated against in situ census observations for 64 site-year combinations in Costa Rican tropical dry forests during the 2015 ENSO drought. Temporal autocorrelation, within the optimal moving window of 24 months, demonstrated robust predictive power for in situ mortality (leave-one-out cross-validation R2  = 0.54), which allows for estimates of annual biomass mortality patterns at 30 m resolution. Subsequent spatial analysis showed substantial fine-scale heterogeneity of forest mortality patterns, largely driven by drought intensity and ecosystem properties related to plant water use such as forest deciduousness and topography. Highly deciduous forest patches demonstrated much lower mortality sensitivity to drought stress than less deciduous forest patches after elevation was controlled. Our results highlight the potential of high-resolution remote sensing to "fingerprint" forest mortality and the significant role of ecosystem heterogeneity in forest biomass resistance to drought.

Spatially Confined Intervention of Cellular Senescence by a Lysosomal Metabolism Targeting Molecular Prodrug for Broad-Spectrum Senotherapy.

Specific intervention of senescent cells (SnCs) is emerging as a powerful means to counteract aging and age-related diseases. Canonical methods are generally designed to target SnC-associated signaling pathways, which are however dynamically changing and highly heterogeneous in SnCs, significantly limiting the effectiveness. Here, we present a tailor-made molecular prodrug targeting lysosome dysfunction, a unique feature shared by virtually all types of SnCs. The prodrug comprises three modules all targeting the altered lysosomal programs in SnCs, namely, a recognizing unit towards the elevated lysosome content, a linker cleavable by the activated lysosomal enzyme, and a lysosomotropic agent targeting the increased lysosomal membrane sensitivity. This spatially confined design enables killing broad-spectrum SnCs, with high specificity over non-SnCs. Along with in vivo benefits, this work offers a way to significantly expand the applicability of senotherapy in a wide range of diseases.

Detecting forest response to droughts with global observations of vegetation water content.

Droughts in a warming climate have become more common and more extreme, making understanding forest responses to water stress increasingly pressing. Analysis of water stress in trees has long focused on water potential in xylem and leaves, which influences stomatal closure and water flow through the soil-plant-atmosphere continuum. At the same time, changes of vegetation water content (VWC) are linked to a range of tree responses, including fluxes of water and carbon, mortality, flammability, and more. Unlike water potential, which requires demanding in situ measurements, VWC can be retrieved from remote sensing measurements, particularly at microwave frequencies using radar and radiometry. Here, we highlight key frontiers through which VWC has the potential to significantly increase our understanding of forest responses to water stress. To validate remote sensing observations of VWC at landscape scale and to better relate them to data assimilation model parameters, we introduce an ecosystem-scale analog of the pressure-volume curve, the non-linear relationship between average leaf or branch water potential and water content commonly used in plant hydraulics. The sources of variability in these ecosystem-scale pressure-volume curves and their relationship to forest response to water stress are discussed. We further show to what extent diel, seasonal, and decadal dynamics of VWC reflect variations in different processes relating the tree response to water stress. VWC can also be used for inferring belowground conditions-which are difficult to impossible to observe directly. Lastly, we discuss how a dedicated geostationary spaceborne observational system for VWC, when combined with existing datasets, can capture diel and seasonal water dynamics to advance the science and applications of global forest vulnerability to future droughts.

Oxygen Vacancy-Driven Reversible Free Radical Catalysis for Environment-Adaptive Cancer Chemodynamic Therapy.

Amplifying free radical production by chemical dynamic catalysis to cause oxidative damage to cancer cells has received extensive interest for cancer-specific therapy. The major challenge is inevitable negative modulation on the tumor microenvironment (TME) by these species, hindering durable effectiveness. Here we show for the first time an oxygen vacancy-rich Bi-based regulator that allows environment-adaptive free radical catalysis. Specifically, the regulator catalyzes production of highly toxic O2.- and . OH in cancer cells via logic enzymatic reactions yet scavenges accumulation of free radicals and immunosuppressive mediators in TME-associated noncancerous cells. Atomic-level mechanistic studies reveal that such dual-modal regulating behavior is dominated by oxygen vacancies that well fit for free radical catalytic kinetics, along with distinguished cellular fates of this regulator. With this smart regulator, a "two birds with one shot" cancer dynamic therapy can be expected.

Decoding the Complex Free Radical Cascade by Using a DNA Framework-Based Artificial DNA Encoder.

DNA-based molecular communications (DMC) are critical for regulating biological networks to maintain stable organismic functions. However, the complicated, time-consuming information transmission process involved in genome-coded DMC and the limited, vulnerable decoding activity generally lead to communication impairment or failure, in response to external stimuli. Herein, we present a conceptually innovative DMC strategy mediated by the DNA framework-based artificial DNA encoder. With the free-radical cascade as a proof-of-concept study, the artificial DNA encoder shows active sensing and real-time actuation, in situ and broad free radical-decoding efficacy, as well as robust resistance to environmental noise. It can also block undesirable short-to-medium-range communications between free radicals and inflammatory networks, leading to a synergistic anti-obesity effect. The artificial DNA encoder-based DMC may be generalized to other communication systems for a variety of applications.

An Acidity-Unlocked Magnetic Nanoplatform Enables Self-Boosting ROS Generation through Upregulation of Lactate for Imaging-Guided Highly Specific Chemodynamic Therapy.

Chemodynamic therapy is an emerging tumor therapeutic strategy. However, the anticancer effects are greatly limited by the strong acidity requirements for effective Fenton-like reaction, and the inevitably "off-target" toxicity. Herein, we develop an acidity-unlocked nanoplatform (FePt@FeOx @TAM-PEG) that can accurately perform the high-efficient and tumor-specific catalysis for anticancer treatment, through dual pathway of cyclic amplification strategy. Notably, the pH-responsive peculiarity of tamoxifen (TAM) drug allows for the catalytic activity of FePt@FeOx to be "turn-on" in acidic tumor microenvironments, while keeping silence in neutral condition. Importantly, the released TAM within cancer cells is able to inhibit mitochondrial complex I, leading to the upregulated lactate content and thereby the accumulated intracellular H+ , which can overcome the intrinsically insufficient acidity of tumor. Through the positive feedback loop, large amount of active FePt@FeOx nanocatalyzers are released and able to access to the endogenous H2 O2 , exerting the improved Fenton-like reaction within the more acidic condition. Finally, such smart nanoplatform enables self-boosting generation of reactive oxygen species (ROS) and induces strong intracellular oxidative stress, leading to the substantial anticancer outcomes in vivo, which may provide a new insight for tumor-specific cascade catalytic therapy and reducing the "off-target" toxicity to surrounding normal tissues.

Molecular Self-Assembly of Bioorthogonal Aptamer-Prodrug Conjugate Micelles for Hydrogen Peroxide and pH-Independent Cancer Chemodynamic Therapy.

Chemodynamic therapy (CDT) has demonstrated new possibilities for selective and logical cancer intervention by specific manipulation of dysregulated tumorous free radical homeostasis. Current CDT methods largely rely on conversion of endogenous hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals via classical Fenton or Haber-Weiss chemistry. However, their anticancer efficacies are greatly limited by the requirement of strong acidity for efficient chemical reactions, insufficient tumorous H2O2, and upregulated antioxidant defense to counteract free radical-caused oxidative damage. Here, we present a new concept whereby bioorthogonal chemistry and prodrug are combined to create a new type of aptamer drug conjugate (ApDC): aptamer-prodrug conjugate (ApPdC) micelle for improved and cancer-targeted CDT. The hydrophobic prodrug bases can not only promote self-assembly of aptamers but also act as free radical generators via bioorthogonal chemistry. In depth mechanistic studies reveal that, unlike traditional CDT systems, ApPdC micelles enable in situ activation and self-cycling generation of toxic C-centered free radicals in cancer cells through cascading bioorthogonal reactions, with no dependence on either H2O2 or pH, yet concurrently with diminished cancerous antioxidation by GSH depletion for a synergistic CDT effect. We expect this work to provide new insights into the design of targeted cancer therapies and studies of free radical-related molecular mechanisms.

Transducing Complex Biomolecular Interactions by Temperature-Output Artificial DNA Signaling Networks.

The requirement of special expensive instruments for quantitative information readout has significantly restricted sustainable development, from ideation to execution, of advanced artificial networks. Here we present a step toward a paradigm of evolutionary signaling networks that enable translating complex signaling information into easy-to-read temperature output. Combining DNA molecular engineering with basic optical mechanisms, a DNA/Hemin complex-derived versatile temperature-output transducer is established, which can be coupled with other functional modules to fabricate diverse portable DNA signaling networks by dynamic programming of DNA chemical reactions. Its versatility is successfully demonstrated by constructing self-amplified and logic-circuit-based DNA signaling networks to monitor trace and multibit nucleic acid interactions using a thermometer. This affordable yet powerful DNA signaling network design may portend an era of point-of-care signaling network methodology.

Forecasting semi-arid biome shifts in the Anthropocene.

Shrub encroachment, forest decline and wildfires have caused large-scale changes in semi-arid vegetation over the past 50 years. Climate is a primary determinant of plant growth in semi-arid ecosystems, yet it remains difficult to forecast large-scale vegetation shifts (i.e. biome shifts) in response to climate change. We highlight recent advances from four conceptual perspectives that are improving forecasts of semi-arid biome shifts. Moving from small to large scales, first, tree-level models that simulate the carbon costs of drought-induced plant hydraulic failure are improving predictions of delayed-mortality responses to drought. Second, tracer-informed water flow models are improving predictions of species coexistence as a function of climate. Third, new applications of ecohydrological models are beginning to simulate small-scale water movement processes at large scales. Fourth, remotely-sensed measurements of plant traits such as relative canopy moisture are providing early-warning signals that predict forest mortality more than a year in advance. We suggest that a community of researchers using modeling approaches (e.g. machine learning) that can integrate these perspectives will rapidly improve forecasts of semi-arid biome shifts. Better forecasts can be expected to help prevent catastrophic changes in vegetation states by identifying improved monitoring approaches and by prioritizing high-risk areas for management.

Increasing atmospheric humidity and CO2 concentration alleviate forest mortality risk.

Climate-induced forest mortality is being increasingly observed throughout the globe. Alarmingly, it is expected to exacerbate under climate change due to shifting precipitation patterns and rising air temperature. However, the impact of concomitant changes in atmospheric humidity and CO2 concentration through their influence on stomatal kinetics remains a subject of debate and inquiry. By using a dynamic soil-plant-atmosphere model, mortality risks associated with hydraulic failure and stomatal closure for 13 temperate and tropical forest biomes across the globe are analyzed. The mortality risk is evaluated in response to both individual and combined changes in precipitation amounts and their seasonal distribution, mean air temperature, specific humidity, and atmospheric CO2 concentration. Model results show that the risk is predicted to significantly increase due to changes in precipitation and air temperature regime for the period 2050-2069. However, this increase may largely get alleviated by concurrent increases in atmospheric specific humidity and CO2 concentration. The increase in mortality risk is expected to be higher for needleleaf forests than for broadleaf forests, as a result of disparity in hydraulic traits. These findings will facilitate decisions about intervention and management of different forest types under changing climate.

Naked-Eye Readout of Analyte-Induced NIR Fluorescence Responses by an Initiation-Input-Transduction Nanoplatform.

Fluorescence visualization (FV) in the near-infrared (NIR) window promises to break through the signal-to-background ratio (SBR) bottleneck of traditional visible-light-driven FV methods. However, straightforward NIR-FV has not been realized, owing to the lack of methods to readily transduce NIR responses into instrument-free, naked eye-recognizable outputs. Now, an initiation-input-transduction platform comprising a well-designed NIR fluorophore as the signal initiator and lanthanide-doped nanocrystals as the transducer for facile NIR-FV is presented. The analyte-induced off-on NIR signal serves as a sensitizing switch of transducer visible luminescence for naked-eye readout. The design is demonstrated for portable, quantitative detection of phosgene with significantly improved SBR and sensitivity. By further exploration of initiators, this strategy holds promise to create advanced NIR-FV probes for broad sensing applications.