Cucurbitacin B and Its Derivatives: A Review of Progress in Biological Activities.

The emergence of natural products has provided extremely valuable references for the treatment of various diseases. Cucurbitacin B, a tetracyclic triterpenoid compound isolated from cucurbitaceae and other plants, is the most abundant member of the cucurbitin family and exhibits a wide range of biological activities, including anti-inflammatory, anti-cancer, and even agricultural applications. Due to its high toxicity and narrow therapeutic window, structural modification and dosage form development are necessary to address these issues with cucurbitacin B. This paper reviews recent research progress in the pharmacological action, structural modification, and application of cucurbitacin B. This review aims to enhance understanding of advancements in this field and provide constructive suggestions for further research on cucurbitacin B.

Investigation of the effects of polyethylene microplastics at environmentally relevant concentrations on the plant-soil-microbiota system: A two-year field trial.

Microplastics are a potential threat to agricultural sustainability. However, the effects of microplastics at environmentally relevant concentrations on the plant-soil-microbiota system in realistic field conditions are largely unknown. Herein, we conducted a two-year field trial to study the effects of polyethylene (PE) microplastics at 0, 100, and 600 mg/kg on crop growth, soil properties, and the composition and function of microbial communities in a farmland with rice-wheat rotation. PE did not affect wheat growth but it increased the rice grain weight by 42.5 % at 600 mg/kg, and enhanced rice height by 35.4 % and 30.2 % at 100 and 600 mg/kg, respectively. The presence of PE significantly decreased soil available phosphorus during the wheat season, while it reduced soil total nitrogen, NH4+-N and available phosphorus during the rice season. There were five and sixteen bacterial orders identified changed by PE in wheat and rice soils, respectively. Specifically, PE at different concentrations differentially altered the abundances of sulfate-reducing bacteria Thermodesulfovibrionia, Thermoactinomycetales and Syntrophobacterales, and further modified soil sulfate respiration in wheat soils. During the rice season, PE (100 mg/kg) increased the abundance of Xanthomonadales by 98.0 % and enriched the functional groups of intracellular parasites, while PE (600 mg/kg) inhibited twelve cluster of orthologous group function classes and disturbed bacterial metabolism. This study suggests that PE exhibits a greater impact on the plant-soil-microbiota system during the rice season compared to the previous year's wheat season, highlighting the importance of crop type and cultivation practices in determining the environmental risks of microplastics in agroecosystems.

I n situ tumor vaccine with optimized nanoadjuvants and lymph node targeting capacity to treat ovarian cancer and metastases.

Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an in situ nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.

Design, synthesis, and evaluation of antitumor activity in Pseudolaric acid B Azole derivatives: Novel and potent angiogenesis inhibitor via regulation of the PI3K/AKT and MAPK mediated HIF-1/VEGF signaling pathway.

Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC50 value of 0.68 µM, outperforming the lead compound PAB (IC50 = 5.44 µM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis.

Alleviated cadmium toxicity in wheat (Triticum aestivum L.) by the coactive role of zinc oxide nanoparticles and plant growth promoting rhizobacteria on TaEIL1 gene expression, biochemical and physiological changes.

Cadmium (Cd) contamination in agricultural soil is a major global concern among the multitude of human health and food security. Zinc oxide nanoparticles (ZnO-NPs) and plant growth promoting rhizobacteria (PGPR) have been known to combat heavy metal toxicity in crops. Herein, the study intended to explore the interactive effect of treatments mediated by inoculation of PGPR and foliar applied ZnO-NPs to alleviate Cd induced phytotoxicity in wheat plants which is rarely investigated. For this purpose, TaEIL1 expression, morpho-physiological, and biochemical traits of wheat were examined. Our results revealed that Cd reduced growth and biomass, disrupted plant physiological and biochemical traits, and further expression patterns of TaEIL1. The foliar application of ZnO-NPs improved growth attributes, photosynthetic pigments, and gas exchange parameters in a dose-additive manner, and this effect was further amplified with a combination of PGPR. The combined application of ZnO-NPs (100 mg L-1) with PGPR considerably increased the catalase (CAT; 52.4%), peroxidase (POD; 57.4%), superoxide dismutase (SOD; 60.1%), ascorbate peroxidase (APX; 47.4%), leading to decreased malondialdehyde (MDA; 47.4%), hydrogen peroxide (H2O2; 38.2%) and electrolyte leakage (EL; 47.3%) under high Cd (20 mg kg-1) stress. Furthermore, results revealed a significant reduction in roots (56.3%), shoots (49.4%), and grains (59.4%) Cd concentration after the Combined treatment of ZnO-NPs and PGPR as compared to the control. Relative expression of TaEIL1 (two homologues) was evaluated under control (Cd 0), Cd, ZnO-NPs, PGPR, and combined treatments. Expression profiling revealed a differential expression pattern of TaEIL1 under different treatments. The expression pattern of TaEIL1 genes was upregulated under Cd stress but downregulated under combined ZnO-NPs and PGPR, revealing its crucial role in Cd stress tolerance. Inferentially, ZnO-NPs and PGPR showed significant potential to alleviate Cd toxicity in wheat by modulating the antioxidant defense system and TaEIL1 expression. By inhibiting Cd uptake, and facilitating their detoxification, this innovative approach ensures food safety and security.

Effect of biochar amendment on bacterial community and their role in nutrient acquisition in spinach (Spinacia oleracea L.) grown under elevated CO2.

Global climate change is anticipated to shift the soil bacterial community structure and plant nutrient utilization. The use of biochar amendment can positively influence soil bacterial community structure, soil properties, and nutrient use efficiency of crops. However, little is known about the underlying mechanism and response of bacterial community structure to biochar amendment, and its role in nutrient enhancement in soil and plants under elevated CO2. Herein, the effect of biochar amendment (0, 0.5, 1.5%) on soil bacterial community structure, spinach growth, physiology, and soil and plant nutrient status were investigated under two CO2 concentrations (400 and 600 µmol mol-1). Findings showed that biochar application 1.5% (B.2.E) significantly increased the abundance of the bacterial community responsible for growth and nutrient uptake i.e. Firmicutes (42.25%) Bacteroidetes (10.46%), and Gemmatimonadetes (125.75%) as compared to respective control (CK.E) but interestingly abundance of proteobacteria decreased (9.18%) under elevated CO2. Furthermore, the soil available N, P, and K showed a significant increase in higher biochar-amended treatments under elevated CO2. Spinach plants exhibited a notable enhancement in growth and photosynthetic pigments when exposed to elevated CO2 levels and biochar, as compared to ambient CO2 conditions. However, there was variability observed in the leaf gas exchange attributes. Elevated CO2 reduced spinach roots and leaves nutrient concentration. In contrast, the biochar amendment (B2.E) enhanced root and shoot Zinc (494.99%-155.33%), magnesium (261.15%-183.37%), manganese (80.04%-152.86%), potassium (576.24%-355.17%), calcium (261.88%-165.65%), copper (325.42%-282.53%) and iron (717.63%-177.90%) concentration by influencing plant physiology and bacterial community. These findings provide insights into the interaction between plant and bacterial community under future agroecosystems in response to the addition of biochar contributing to a deeper understanding of ecological dynamics.

Differential impacts of organic and inorganic phosphorus on the growth and phosphorus utilization of Microcystis aeruginosa.

Phytoplankton growth in freshwater is often limited by the availability of phosphorus (P), and thorough understandings of P availability are essential to prevent algal blooms. However, the differences in bioavailability and utilization mechanisms of different P forms remain unclear, especially whether organophosphorus could be used as P sources. This study investigated the effects of 0.5, 1.0, and 2.0 mg/L P on Microcystis aeruginosa, including dissolved organic P (DOP) (1-hydroxyethane 1,1-diphosphonic acid) and dissolved inorganic P (DIP) (dipotassium phosphate). Compared with DIP, intracellular P content absorbed in DOP treatment was significantly lower. DOP was more conducive to the synthesis of soluble protein and the release of extracellular polymeric substances. Alkaline phosphatase activity was generally enhanced in response to DIP deficiency. Both DIP and DOP promoted carbon uptake to the same extent. DOP groups absorbed carbon to synthesize energy and proteins in response to stress, while DIP groups were mainly used carbon for growth. They all reduced the content of microcystin releasing into the aquatic environment and therefore reduced ecological risk caused by microcystin. Compared with DIP, the expressions of photosynthesis-related genes were significantly down-regulated in DOP group, while the expressions of nucleoside phosphate catabolism, P transporter, and amino acid biosynthesis and metabolism were significantly up-regulated in response to P deficiency environment and the stress of 1.0 mg/L DOP concentration. In summary, the bioavailability of different P forms on cyanobacteria is different, so it is not sufficient to only use total P for assessing environmental risk. P forms should also be considered for risk management of freshwater ecosystems.

For aqueous/soil cadmium immobilization under acid attack, does the hydroxyapatite converted from Pseudochrobactrum sp. DL-1 induced vaterite necessarily show higher stability?

Microbial induced carbonate precipitation (MICP) technology was widely applied to immobilize heavy metals, but its long-term stability is tough to maintain, particularly under acid attack. This study successfully converted Pseudochrobactrum sp. DL-1 induced vaterite (a rare crystalline phase of CaCO3) to hydroxyapatite (HAP) at 30 â„ƒ. The predominant conversion mechanism was the dissolution of CdCO3-containing vaterite and the simultaneous recrystallization of Ca4.03Cd0.97(PO4)3(OH)-containing HAP. For aqueous Cd immobilization, stability test at pH 2.0-10.0 showed that the Cd2+ desorption rate of Cd-adsorbed vaterite (3.96-4.35 ‱) were 7.13-20.84 times greater than that of Cd-adsorbed HAP (0.19-0.61 ‱). For soil Cd immobilization under 60 days of acid-rain erosion, the highest immobilization rate (51.00 %) of exchangeable-Cd and the lowest dissolution rate (-0.18 %) of carbonate-Cd were achieved with 2 % vaterite, while the corresponding rates were 16.78 % and 1.31 % with 2 % HAP, respectively. Furthermore, vaterite outperformed HAP in terms of soil ecological thorough evaluation. In conclusion, for Cd immobilization by MICP under acid attack, DL-1 induced vaterite displayed direct application value due to its exceptional stability in soil and water, while the mineral conversion strategy we presented is useful for further enhancing the stability in water.

Multiscale spatiotemporal characteristics and influencing factors of ecosystem service value of groundwater in China.

Ecosystem services are fundamental to human survival on Earth, but studies on ecosystem service value of groundwater (ESV-G) are rare. The multiscale characteristics and influencing factors of ESV-G in China from 2000 to 2020 were analyzed in this study. The results showed that ESV-G decreased first and then increased, the average ESV-G was 130.30 thousand yuan/km2, and ESV-G tended to shift towards middle level (second to fourth class). The Hu Line was the dividing line between the first class (more than half area) and the others. The AI and FRAC values indicated that the patches of ESV-G were more concentrated, with simpler shapes that were more amenable to governance at the province scale. Hot spots and cold spots were mainly located in the eastern and western parts of Hu Line, respectively. The ESV-G of the cold spots per unit area at the province scale was higher than that at the city scale, which indicated that the province scale had the potential for higher ESV-G per unit area and cost advantage. Precipitation and temperature were the main factors affecting ESV-G; the influence of human activities on ESV-G increased on a larger scale as time went by. Combination of precipitation and Digital Elevation Model (DEM) had the greatest influence on ESV-G among the combinational influencing factors. The province scale was the optimal scale to manage ESV-G. Climate change had led to the expansion of hot and cold spots of ESV-G, northern and southern areas should combine existing policies to carry out differentiated governance. This study extended the scope of ecosystem service value studies from land surface to underground, providing a scientific basis for the management of groundwater ecosystem.

Exploring phytoremediation potential of willow NJU513 for cadmium-contaminated soil with and without epibrassinolide treatment.

There has been a growing concern over soil cadmium (Cd) pollution, underscoring the importance of finding effective remediation strategies. Willow trees have emerged as promising candidates for phytoremediation of Cd-contaminated soils. Nevertheless, the specific potential of a novel willow genotype, NJU513, in remediating Cd-polluted soil remains unexplored. Hence, the primary objectives of this study were twofold: firstly, to ascertain the suitability of the willow genotype NJU513 for remediating Cd-contaminated soil; and secondly, to elevate its remediation efficciency with the application of epibrassinolide (Brs). In the pot-culture experiment without Brs, its leaf and stem Cd concentrations were 203 mg kg-1 and 65.1 mg kg-1, with a bioaccumulation factor (BCF) of 20.8 and 6.68, respectively. In the pot-culture experiment with Brs, the corresponding Cd concentrations were 226 mg kg-1 and 59.2 mg kg-1, with a BCF of 23.1 and 6.06, respectively. In addition, the extracted Cd contents were higher in the Brs treatments (1.11-1.37 mg plant-1) than in the no-Brs treatments (0.78-0.96 mg plant-1) because Brs increased the plant biomass and leaf BCF. The mechanism underlying the Cd accumulation of NJU513 leaves with and without Brs was revealed by a transcriptome analysis. The expression levels of genes related to metal ion binding, channel activity, and transporters in leaves were up-regulated, which contributed to the high Cd accumulation and stress tolerance. Analyses of soil metabolites and bacteria in the presence and absence of Brs spraying on willow leaves indicated that soil organic compounds with carboxyl and amino groups may induce Cd activation and passivation, respectively. This study provides valuable insights for developing woody plant varieties that can be used for remediating Cd-contaminated soil.

A Tumor-Activatable Liposomal Nanoprobe for Selective Visualization of Metastatic Lymph Nodes.

The precise identification of sentinel lymph nodes (SLNs) during surgery and assessment of their benign status is crucial for accurate tumor staging and optimal treatment strategizing. Currently, a deficiency exists in non-invasive in vivo diagnostic techniques that can accurately pinpoint SLNs during surgery while simultaneously evaluating their benign status. Here, a tumor-activatable liposomal nanoprobe (nTAL) is developed, remotely loaded with clinically approved photosensitizer, methyl aminolevulinate (MAL), to noninvasively visualize the tumor metastasis lymph nodes (LNs) with precision. Benefited from the highly efficient LNs draining of nanosized liposome and tumor cell-specific transformation of the non-fluorescent MAL to fluorescent protoporphyrin IX (PPIX), nTAL succeeded in targeting the SLNs and differentiated the metastatic from the benign ones with a positive correlation between PPIX generation and tumor cell infiltration in LNs. Moreover, the nTAL technology is capable of probing the early metastatic stage with a primary tumor size of 50 mm3. This study provides a new strategy for intraoperative visualization of real-time sentinel node dissection.

Construction and validation of a prognostic model for overall survival time of patients with ovarian cancer by metabolism-related genes.

BACKGROUND: Ovarian cancer is a female-specific malignancy with high morbidity and mortality. The metabolic reprogramming of tumor cells is closely related to the biological behavior of tumors. METHODS: The prognostic signature of the metabolism-related gene (MRGs) was established by LASSO-Cox regression analysis. The prognostic signature of MRGs was also prognosticated in each clinical subgroup. These genes were subjected to functional enrichment analysis and tissue expression exploration. Analysis of the MRG prognostic signature in terms of immune cell infiltration and antitumor drug susceptibility was also performed. RESULTS: A MRG prognostic signature including 21 genes was established and validated. Most of the 21 MRGs were expressed at different levels in ovarian cancer than in normal ovarian tissue. The enrichment analysis suggested that MRGs were involved in lipid metabolism, membrane organization, and molecular binding. The MRG prognostic signature demonstrated the predictive value of overall survival time in various clinical subgroups. The monocyte, NKT, Tgd and Tex cell scores showed differences between the groups with high- and low-risk score. The antineoplastic drug analysis we performed provided information on ovarian cancer drug therapy and drug resistance. In vitro experiments verified that PLCH1 in 21 MRGs can regulate the apoptosis and proliferation of ovarian cancer cells. CONCLUSION: This metabolism-related prognostic signature was a potential prognostic factor in patients with ovarian cancer, demonstrating high stability and accuracy.

Design, synthesis, and in vivo and in vitro biological screening of pseudolaric acid B derivatives as potential anti-tumor agents.

Pseudolaric Acid B (PAB), a natural product with remarkable anti-tumor activity, is a starting point for new anticancer therapeutics. We designed and synthesized 27 PAB derivatives and evaluated their anti-proliferative activities against four cancer cell lines: MCF-7, HCT-116, HepG2, and A549. Compared with unmodified PAB, the PAB derivatives showed stronger anti-proliferative activity. The ability of compound D3 (IC50 = 0.21 µM) to inhibit HCT-116 cells was approximately 5.3 times that of PAB (IC50 = 1.11 µM) and the antiproliferative action was unrelated to cytotoxicity (SI=20.38), indicating its superior safety profile (PAB; SI=0.95). Compound D3 effectively suppressed the EdU-positive rate and reduced colony formation, arrested HCT-116 cells in the S and G2/M phases and induced apoptosis. In vivo experiments further demonstrated low toxicity of compound D3 while suppressing tumor growth in mice. In summary, given its strong anti-proliferative effect and relative safety, further development of compound D3 is warranted.

Ultrahigh Potassium Storage Capacity of Ca2Si Monolayer with Orderly Multilayered Growth Mechanism.

As the rising renewable energy demands and lithium scarcity, developing high-capacity anode materials to improve the energy density of potassium-based batteries (PBBs) is increasingly crucial. In this work, a unique orderly multilayered growth (OMLG) mechanism on a 2D-Ca2Si monolayer is theoretically demonstrated for potassium storage by first-principles calculations. The global-energy-minimum Ca2Si monolayer is a semiconductor with isotropic mechanical properties and remarkable electrochemical properties, such as a low potassium ion migration energy barrier of 0.07 eV and a low open circuit voltage ranging from 0.224 to 0.003 V. Most notably, 2D-Ca2Si demonstrates an ultrahigh theoretical specific capacity of 5459 mAh g-1 and a total specific capacity of 610 mAh g-1, reaching up to 89% of the capacity of a potassium metal anode. Remarkably, the OMLG mechanism facilitates stable, dendrite-free deposition of hcp-K metal layers on the 2D-Ca2Si surface, where the ultrahigh and gradually converging lattice match as the layers increase is the key to achieving theoretically near-infinite growth. The study theoretically demonstrates the Ca2Si monolayer a highly promising anode material, and offers a novel potassium storage strategy for designing 2D anode materials with high specific capacity, rapid potassium-ion migration, and good safety.

Prediction of Halogenated MXenes as Electrode Materials for Halide-Ion Batteries.

Exploring and developing new rechargeable halide-ion batteries plays an important role in the advancement and growth of the ion battery family. Here, we systematically explored the feasibility of single-layer MXenes and their hydrogenated derivatives as electrode materials for halide-ion batteries via first-principles theory. The calculated results indicate that halide ions (T ions) can be stably and efficiently adsorbed on the surfaces of M2X and M2XH2, with theoretical specific capacities ranging from 227 to 497 mAh g-1. The diffusion barriers of the T ion on MXenes are from 0.55 to 0.10 eV, comparable to those of the Li ion in graphite and LiCoO2. The electronegativity of halide anions displays significant impacts on their discharge voltage plateaus on M2X, with the highest voltage up to 5.60 V for the F ion. As a comparison, the hydrogenation of M2XH2 with less surface activity raises a 2-3 V voltage reduction. All MXene-based full cells of TxTi2C|TyTi2CH2 (where x = 0-2 and y = 2-0) and TxTi2N|TyTi2NH2 (where x = 0-2 and y = 2-0) demonstrated high full battery specific energies for F-, Cl-, and Br-ion batteries, up to 462 Wh kg-1. These results demonstrate the potential of new halide-ion battery designs, paving the way for future research and innovation in battery technology.

Effect of ultraviolet aged polytetrafluoroethylene microplastics on copper bioavailability and Microcystis aeruginosa growth.

Microplastics (MPs) are ubiquitous in aquatic environments, which can act as carriers to affect the bioavailability of heavy metals. The aging process in the environment changes the physicochemical properties of MPs, thereby affecting their environmental behavior and co-toxicity with other pollutants. However, relevant research is limited. In this study, we compared the properties and Cu2+ adsorption capacity of pristine and aged polytetrafluoroethylene (PTFE) MPs and further explored the influence on copper bioavailability and bio-effects on Microcystis aeruginosa. Aging process induced surface oxidation and cracks of PTFE MPs, and decreased the stability of MPs in water by increasing zeta potential. PTFE MPs had a strong adsorption capacity for Cu2+ and increased the bioavailability of copper to microalgae, which was not affected by the aging process. Pristine and aged PTFE MPs adhered to cyanobacterium surfaces and caused shrinkage and deformation of cells. Inhibition of cyanobacterium growth, photosynthesis and reduction of total antioxidant capacity were observed in the treatment of PTFE MPs. Combined exposure of pristine MPs and Cu2+ had stronger toxic effects to cyanobacterium, and increased Microcystin-LR release, which could cause harm to aquatic environment. Aging reduced the toxic effects of PTFE MPs on microalgae. Furthermore, soluble exopolysaccharide (EPS) content was significantly higher in co-exposure of aged MPs and Cu2+, which could reduce the toxicity to cyanobacterium cells. These results indicate that aging process alleviates the toxicity to microalgae and environmental risks caused by PTFE MPs. This study improves understanding of the combined toxicity of aged MPs and metals in freshwater ecosystems.

Mechanistic approach of tannery wastewater and sulfadiazine mutual toxicity in wheat (Triticum aestivum L.) and mitigation through exogenous application of gallic acid.

Excessive release of chromium (Cr) from the tanning industry and antibiotics from livestock caused severe hazards to humans. Gallic acid (GA 10 mM) alleviated alone/combined SDZ 30 mg kg-1 and TWW 40, 60, and 100% stress in wheat. GA (10 mM) decreased the TSP 12 and 13%, TFAA 8 and 10%, TSS 14 and 16%, RS 18 and 16%, and NRS 11 and 9% in shoots and grains under SDZ + TWW (30 mg kg-1+100%), compared without foliar. GA (10 mM) declined the MDA 20 and 31, EL 13 and 36%, H2O2 17 and 15%, O2•- 10 and 11% in leaves and roots, under combined SDZ + TWW (30 mg kg-1+100%), compared without foliar. GA (10 mM) improved the POD 106 and 30%, SOD 145 and 31%, CAT 78, and 35%, APX 100 and 25% in leaves and roots under combined SDZ + TWW (30 mg kg-1+100%), compared without foliar application. Considerably GA (10 mM) reduced total Cr 18, CrIII 20, and CrVI 50% in roots and shoots 19, 41, and 48%, and grains 15, 27, and 29% respectively, under combined SDZ + TWW (30 mg kg-1+100%) stress, compared without foliar. Overall, GA boosted the wheat growth, physiology, and defence system by inhibiting the combined SDZ + Cr toxicity.

A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.

Efficacy and Safety of 5-Aminolevulinic Acid Photodynamic Therapy for Treating Cervical and Vaginal Intraepithelial Neoplasia.

Persistent HPV infections may cause cervical and vaginal intraepithelial neoplasia (CIN and VaIN). Traditional methods might destroy the structure and function of the cervix. 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is a non-invasive targeted therapy. This study aims to evaluate the efficacy and safety of ALA-PDT for CIN and VaIN and the clearance of HPV. A retrospective study of 303 patients who confirmed CIN or VaIN and received ALA-PDT was conducted. All the patients were followed up at six and twelve months after treatment and then annually thereafter. The effect was evaluated through HPV genotyping, a cytology test, and colposcopy-directed biopsy if necessary. After ALA-PDT, the remission rates for CIN 2, CIN 3, VaIN 2, and VaIN 3 were 90.6%, 88.5%, 87.3%, and 77.8%. For CIN 1, the remission rate at the six-month follow-up was 93.1%. The total HPV clearance rates were 72.5% at the six-month follow-up and 85.7% at the 12-month follow-up. The most common adverse event was vaginal discharge. No severe adverse effect was observed. ALA-PDT is an effective and safe treatment for all grades of CIN and VaIN and is helpful in clearing HPV with minimal side effects. This treatment may not influence fertility and delivery.

Potential decoupling of CO2 and Hg uptake process by global vegetation in the 21st century.

Mercury (Hg), a potent neurotoxin posing risks to human health, is cycled through vegetation uptake, which is susceptible to climate change impacts. However, the extent and pattern of these impacts are largely unknown, obstructing predictions of Hg's fate in terrestrial ecosystems. Here, we evaluate the effects of climate change on vegetation elemental Hg [Hg(0)] uptake using a state-of-the-art global terrestrial Hg model (CLM5-Hg) that incorporates plant physiology. In a business-as-usual scenario, the terrestrial Hg(0) sink is predicted to decrease by 1870 Mg yr-1 in 2100, that is ~60% lower than the present-day condition. We find a potential decoupling between the trends of CO2 assimilation and Hg(0) uptake process by vegetation in the 21st century, caused by the decreased stomatal conductance with increasing CO2. This implies a substantial influx of Hg into aquatic ecosystems, posing an elevated threat that warrants consideration during the evaluation of the effectiveness of the Minamata Convention.