Targeting KPNB1 with genkwadaphnin suppresses gastric cancer progression through the Nur77-mediated signaling pathway.

Gastric cancer (GC) remains a global challenge due to the lack of early detection and precision therapies. Genkwadaphnin (DD1), a natural diterpene isolated from the bud of Flos GenkWa (Thymelaeaceae), serves as a Karyopherin ß1 (KPNB1) inhibitor. In this study, we investigated the anti-tumor effect of DD1 in both cell culture and animal models. Our findings reveal that KPNB1, a protein involved in nuclear import, was highly expressed in GC tissues and associated with a poor prognosis in patients. We demonstrated that DD1, alongside the established KPNB1 inhibitor importazole (IPZ), inhibited GC cell proliferation and tumor growth by enhancing both genomic and non-genomic activity of Nur77. DD1 and IPZ reduced the interaction between KPNB1 and Nur77, resulting in Nur77 cytoplasmic accumulation and triggering mitochondrial apoptosis. The inhibitors also increased the expression of the Nur77 target apoptotic genes ATF3, RB1CC1 and PMAIP1, inducing apoptosis in GC cell. More importantly, loss of Nur77 effectively rescued the inhibitory effect of DD1 and IPZ on GC cells in both in vitro and in vivo experiments. In this study, we for the first time explored the relationship between KPNB1 and Nur77, and found KPNB1 inhibition could significantly increase the expression of Nur77. Moreover, we investigated the function of KPNB1 in GC for the first time, and the results suggested that KPNB1 could be a potential target for cancer therapy, and DD1 might be a prospective therapeutic candidate.

Pharmacologic and Nutritional Interventions for Early Alzheimer's Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Background: Early intervention is essential for meaningful disease modification in Alzheimer's disease (AD). Objective: We aimed to determine the efficacy and safety of pharmacologic and nutritional interventions for early AD. Methods: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from database inception until 1 September 2023. We included randomized controlled trials that evaluated the efficacy of interventions in early AD. Only interventions that demonstrated efficacy compared to placebo were included in the network meta-analysis (NMA). Then we performed frequentist fixed-effects NMA to rank the interventions. GRADE criteria were used to evaluate the level of evidence. Results: Fifty-eight trials including a total of 33,864 participants and 48 interventions were eligible for inclusion. Among the 48 interventions analyzed, only 6 (12.5%) treatments- ranging from low to high certainty- showed significant improvement in cognitive decline compared to placebo. High certainty evidence indicated that donanemab (standardized mean difference [SMD] -0.239, 95% confidence interval [CI] -0.343 to -0.134) and lecanemab (SMD -0.194, 95% CI -0.279 to -0.108) moderately slowed the clinical progression in patients with amyloid pathology. Additionally, methylphenidate, donepezil, LipiDiDiet, and aducanumab with low certainty showed significant improvement in cognitive decline compared to placebo. However, there was no significant difference in serious adverse events as reported between the six interventions and placebo. Conclusions: Only 12.5% of interventions studied demonstrated efficacy in reducing cognitive impairment in early AD. Donanemab and lecanemab have the potential to moderately slow the clinical progression in patients with amyloid pathology. Further evidence is required for early intervention in AD.

Tumor mitochondrial oxidative phosphorylation stimulated by the nuclear receptor RORγ represents an effective therapeutic opportunity in osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1ß and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.

Uptake of polycyclic aromatic hydrocarbons (PAHs) from PAH-contaminated soils to carrots and Chinese cabbages under the greenhouse and field conditions.

Polycyclic aromatic hydrocarbons (PAHs) with the properties of structural stability, semi-volatility, and hydrophobicity are toxic and persistent in environments; thus, their transport and fate in agroecosystems is essential for reducing PAH accumulation in the edible parts of crops. Here, we cultivated cabbages (Brassica pekinensis L.) and carrots (Daucus carota L.) in PAH-contaminated soils under the greenhouse and field conditions. After harvesting, we observed a 9.5-46% reduction in soil ∑PAH concentrations. There were 37% of bioconcentration factors (BCFbs) > 1 and 93% of translocation factors (TFab) > 1, while low-molecular-weight (LMW) PAHs had higher BCFbs than high-molecular-weight (HMW) PAHs. The PAH concentrations showed significant and positive correlations among soils, the belowground parts, and the aboveground parts. The toxicity equivalent concentration (TEQBaP) followed the order of cabbage (greenhouse) > cabbage (field) > carrot (greenhouse) > carrot (field), suggesting potentially higher health risks in cabbage relative to carrot and vegetables under the greenhouse relative to field condition. Our study suggested growing carrots under field conditions as a management strategy for reducing the risks of vegetables grown in PAH-contaminated soils.

Molecular-level carbon traits underlie the multidimensional fine root economics space.

Carbon influences the evolution and functioning of plants and their roots. Previous work examining a small number of commonly measured root traits has revealed a global multidimensionality of the resource economics traits in fine roots considering carbon as primary currency but without considering the diversity of carbon-related traits. To address this knowledge gap, we use data from 66 tree species from a tropical forest to illustrate that root economics space co-varies with a novel molecular-level traits space based on nuclear magnetic resonance. Thinner fine roots exhibit higher proportions of carbohydrates and lower diversity of molecular carbon than thicker roots. Mass-denser fine roots have more lignin and aromatic carbon compounds but less bioactive carbon compounds than lighter roots. Thus, the transition from thin to thick fine roots implies a shift in the root carbon economy from 'do-it-yourself' soil exploration to collaboration with mycorrhizal fungi, while the shift from light to dense fine roots emphasizes a shift from acquisitive to conservative root strategy. We reveal a previously undocumented role of molecular-level carbon traits that potentially undergird the multidimensional root economics space. This finding offers new molecular insight into the diversity of root form and function, which is fundamental to our understanding of plant evolution, species coexistence and adaptations to heterogeneous environments.

Photo-methanification of aquatic dissolved organic matters with different origins under aerobic conditions: Non-negligible role of hydroxyl radicals.

Lingering inconsistencies in the global methane (CH4) budget and ambiguity in CH4 sources and sinks triggered efforts to identify new CH4 formation pathways in natural ecosystems. Herein, we reported a novel mechanism of light-induced generation of hydroxyl radicals (•OH) that drove the production of CH4 from aquatic dissolved organic matters (DOMs) under ambient conditions. A total of five DOM samples with different origins were applied to examine their potential in photo-methanification production under aerobic conditions, presenting a wide range of CH4 production rates from 3.57 × 10-3 to 5.90 × 10-2 nmol CH4 mg-C-1 h-1. Experiments of •OH generator and scavenger indicated that the contribution of •OH to photo-methanificaiton among different DOM samples reached about 4∼42 %. In addition, Fourier transform infrared spectroscopy and Fourier transform ion cyclotron resonance mass spectrometry showed that the carbohydrate- and lipid-like substances containing nitrogen-bonded methyl groups, methyl ester, acetyl groups, and ketones, were the potential precursors for light-induced CH4 production. Based on the experimental results and simulated calculations, the contribution of photo-methanification of aquatic DOMs to the diffusive CH4 flux across the water-air interface in a typical eutrophic shallow lake (e.g., Lake Chaohu) ranged from 0.1 % to 18.3 %. This study provides a new perspective on the pathways of CH4 formation in aquatic ecosystems and a deeper understanding on the sources and sinks of global CH4.

A ß-Galactosidase-Activated Fluorogenic Reporter for the Detection of Gastric Cancer In Vivo and in Urine.

Although gastric cancer (GC) is one of the most frequent malignant tumors in the digestive tract with high morbidity and mortality, it remains a diagnostic dilemma due to its reliance on invasive biopsy or insensitive assays. Herein, we report a fluorescent gastric cancer reporter (FGCR) with activatable near-infrared fluorescence (NIRF) signals and high renal-clearance efficiency for the detection of orthotopic GC in a murine model via real-time imaging and remote urinalysis. In the presence of gastric-tumor-associated ß-galactosidase (ß-Gal), FGCR can be fluorescently activated for in vivo NIRF imaging. Relying on its high renal-clearance efficiency (∼95% ID), it can be rapidly excreted through kidneys to urine for the ultrasensitive detection of tumors with a diameter down to ∼2.1 mm and for assessing the prognosis of oxaliplatin-based chemotherapy. This study not only provides a new approach for noninvasive auxiliary diagnosis and prognosis of GC but also provides guidelines for the development of fluorescence probes for cancer diagnosis.

Interaction of reed litter and biochar presences on performances of constructed wetlands.

Constructed wetlands (CWs) are frequently used for effective biological treatment of nitrogen-rich wastewater with external carbon source addition; however, these approaches often neglect the interaction between plant litter and biochar in biochar-amended CW environments. To address this, we conducted a comprehensive study to assess the impacts of single or combined addition of common reed litter and reed biochar (pyrolyzed at 300 and 500 °C) on nitrogen removal, greenhouse gas emission, dissolved organic matter (DOM) dynamics, and microbial activity. The results showed that combined addition of reed litter and biochar to CWs significantly improved nitrate and total nitrogen removal compared with biochar addition alone. Compared to those without reed litter addition, CWs with reed litter addition had more low-molecular-weight and less aromatic DOM and more protein-like fluorescent DOM, which favored the enrichment of bacteria associated with denitrification. The improved nitrogen removal could be attributed to increases in denitrifying microbes and the relative abundance of functional denitrification genes with litter addition. Moreover, the combined addition of reed litter and 300 °C-heated biochar significantly decreased nitrous oxide (30.7 %) and methane (43.9 %) compared to reed litter addition alone, while the combined addition of reed litter and 500 °C-heated biochar did not. This study demonstrated that the presences of reed litter and biochar in CWs could achieve both high microbial nitrogen removal and relatively low greenhouse gas emissions.

DHODH inhibition represents a therapeutic strategy and improves abiraterone treatment in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is an aggressive disease with poor prognosis, and there is an urgent need for more effective therapeutic targets to address this challenge. Here, we showed that dihydroorotate dehydrogenase (DHODH), an enzyme crucial in the pyrimidine biosynthesis pathway, is a promising therapeutic target for CRPC. The transcript levels of DHODH were significantly elevated in prostate tumors and were negatively correlated with the prognosis of patients with prostate cancer. DHODH inhibition effectively suppressed CRPC progression by blocking cell cycle progression and inducing apoptosis. Notably, treatment with DHODH inhibitor BAY2402234 activated androgen biosynthesis signaling in CRPC cells. However, the combination treatment with BAY2402234 and abiraterone decreased intratumoral testosterone levels and induced apoptosis, which inhibited the growth of CWR22Rv1 xenograft tumors and patient-derived xenograft organoids. Taken together, these results establish DHODH as a key player in CRPC and as a potential therapeutic target for advanced prostate cancer.

Reassessing the Quantum Yield and Reactivity of Triplet-State Dissolved Organic Matter via Global Kinetic Modeling.

Measuring the quantum yield and reactivity of triplet-state dissolved organic matter (3DOM*) is essential for assessing the impact of DOM on aquatic photochemical processes. However, current 3DOM* quantification methods require multiple fitting steps and rely on steady-state approximations under stringent application criteria, which may introduce certain inaccuracies in the estimation of DOM photoreactivity parameters. Here, we developed a global kinetic model to simulate the reaction kinetics of the hv/DOM system using four DOM types and 2,4,6-trimethylphenol as the probe for 3DOM*. Analyses of residuals and the root-mean-square error validated the exceptional precision of the new model compared to conventional methods. 3DOM* in the global kinetic model consistently displayed a lower quantum yield and higher reactivity than those in local regression models, indicating that the generation and reactivity of 3DOM* have often been overestimated and underestimated, respectively. The global kinetic model derives parameters by simultaneously fitting probe degradation kinetics under different conditions and considers the temporally increasing concentrations of the involved reactive species. It minimizes error propagation and offers insights into the interactions of different species, thereby providing advantages in accuracy, robustness, and interpretability. This study significantly advances the understanding of 3DOM* behavior and provides a valuable kinetic model for aquatic photochemistry research.

Targeting RORγ inhibits the growth and metastasis of hepatocellular carcinoma.

Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), highlighting an essential role of ECM in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor RORγ is highly expressed and amplified in HCC tumors. RORγ functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. Elevated RORγ increases fibronectin-1 deposition, cell-matrix adhesion, and collagen production, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, RORγ antagonists effectively inhibit tumor growth and metastasis in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, elevated RORγ expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify RORγ as a key player of ECM remodeling in HCC and as an attractive therapeutic target for advanced HCC.

Spatiotemporal evolution of deformation and LSTM prediction model over the slope of the deep excavation section at the head of the South-North Water Transfer Middle Route Canal.

Slope deformation is one of the focal issues of concern during the normal operation and maintenance of the South-North Water Transfer Middle Route Project. To study the slope deformation evolution in the deep excavation section at the head of the canal, we applied 88 views of Sentinel-1A ascending image data from 2017 to 2019 and MT-InSAR(Multi-temporal InSAR) deformation monitoring technology to obtain long-time series deformation rates and cumulative deformation fields over the slope in the study area. Based on the analysis of the time-series monitoring data of the deformation field sample points, a LSTM (Long Short Term Memory Network) slope deformation predictive model was constructed to predict the slope deformation for the next 12 months at 12 sample points of the deep excavation slope. The impact of rainfall on slope deformation was investigated, and the reliability of the LSTM model was verified by using the measured data. The results show that the average annual deformation rate of the slope ranges from 10mm/a to 25mm/a, the maximum cumulative deformation is about 60 mm, and the slope of the excavated section is generally in an uplifted state. The rainfall-induced repeated uplift or subsidence of the canal slopes together with the peak deformation was closely related to the amount of rainfall during the wet season, and the longer the duration of the wet season, the more obvious the crest. Among the12 sample sites, the minimum and maximum deformation predicted using the LSTM model were 51.7 mm and 73.9 mm respectively, with the lowest correlation coefficient of 0.994 and the highest of 0.999. The maximum and minimum values of RMSE (Root Mean Square Error) were 4.4 mm and 3.6 mm respectively, indicating reliable prediction results. The results of the study can provide reference for the prevention and control of geological hazards in the South-North Water Transfer Canal.

Discovery of the First-in-Class RORγ Covalent Inhibitors for Treatment of Castration-Resistant Prostate Cancer.

Nuclear receptor receptor-related orphan receptor γ (RORγ) is a ligand-dependent transcription factor and has been established as a key player in castration-resistant prostate cancers (CRPC) by driving androgen receptor (AR) overexpression, representing a potential therapeutical target for advanced prostate cancers. Here, we report the identification of the first-in-class RORγ covalent inhibitor 29 via the structure-based drug design approach following structure-activity relationship (SAR) exploration. Mass spectrometry assay validated its covalent inhibition mechanism. Compound 29 significantly inhibited RORγ transcriptional activity and remarkably suppressed the expression levels of AR and AR-targeted genes. Compound 29 also exhibited much superior activity in inhibiting the proliferation and colony formation and inducing apoptosis of the CRPC cell lines relative to the positive control 2 and noncovalent control 33. Importantly, it markedly suppressed the tumor growth in a 22Rv1 mouse tumor xenograft model with good safety. These results clearly demonstrate that 29 is a highly potent and selective RORγ covalent inhibitor.

π-Electron Fluctuation-Induced P+ /C- Ambiphilic Interaction for Intramolecular CAr -H Bond Activation.

Herein, we describe how computational mechanistic understanding has led directly to the discovery of new 2H-phosphindole for C-CAr bond activation and dearomatization reaction. We uncover an unexpected intramolecular C-H bond activation with a 2H-phosphindole derivative. This new intriguing experimental observation and further theoretical studies led to an extension of the reaction mechanism with 2H-phosphindole. Through DFT calculations, we confirm that within a five-membered ring, the polarizable PC3 unit orchestrates the formation of an electrophilic phosphorus atom (P+ ) and a nucleophilic carbon atom (C- ). This kinetically accessible ambiphilic phosphorus/carbon couple is spatially separated by geometric constraints, and their reactivity is modulated through structural resonance.

The origin of bi-dimensionality in plant root traits.

Plant roots show extraordinary diversity in form and function in heterogeneous environments. Mounting evidence has shown global bi-dimensionality in root traits, the root economics spectrum (RES), and an orthogonal dimension describing mycorrhizal collaboration; however, the origin of the bi-dimensionality remains unresolved. Here, we propose that bi-dimensionality arises from the cylindrical geometry of roots, allometry between root cortex and stele, and independence between root cell wall thickness and cell number. Root geometry and mycorrhizal collaboration may both underlie the bi-dimensionality. Further, we emphasize why plant roots should be cylindrical rather than flat. Finally, we highlight the need to integrate organ-, cellular-, and molecular-level processes driving the bi-dimensionality in plant roots to fully understand plant diversity and functions.

Enhanced landfill leachate treatment performance by adsorption-assisted membrane distillation.

Membrane fouling and high-strength membrane concentrate production are two limitations of membrane distillation (MD) for landfill leachate treatment. In this study, activated carbon- and biochar-based adsorption processes were integrated into a conventional MD system to overcome these limitations. The organic matter fractionations of the leachate were thoroughly investigated during the treatment. Membrane-reversible and irreversible foulants differed remarkably from the inlet leachate in the non-assisted MD system. Specifically, reversible foulants were characterized by a high abundance of humic-like fluorescent components, high-molecular-weight humic-size constituents, peptides, and unsaturated compounds. In contrast, irreversible foulants were enriched with fulvic-like fluorescent components, low-molecular-weight neutrals, unsaturated compounds, and polyphenols. The adsorption-based pre-treatment effectively removed foulant precursors from landfill leachate, with a relatively higher (20%) adsorption performance for specific biochar used in this study than for activated carbon. Compared with the non-assisted MD system, the biochar-assisted MD system showed improved performance, achieving 40% overall membrane flux recovery, 42% higher filtration fluxes, and 53% lower concentrate production. In addition, a 15% higher removal of irreversible foulants was observed as compared to the reversible foulants, which can potentially increase the membrane lifespan. This study demonstrates the effectiveness of an adsorption-assisted MD system supported by increased filtration, membrane fouling alleviation, and low-strength leachate concentrate generation.

Discovery of a highly potent and orally available importin-ß1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer.

Nuclear transporter importin-ß1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-ß1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-ß1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-ß1.