Effect of barley yellow dwarf virus (BYDV) on barley: A precise assessment of reductions in yield components under variable disease severities.

Understanding the effects of barley yellow dwarf virus (BYDV) on crop agronomic traits and yield performance helps breeders balance their selection criteria and farmers decide if pesticides should be applied to control aphids that distribute the virus. To precisely assess the deterioration of different agronomic traits and yield components caused by different levels of BYDV infection, seeds of a BYDV-sensitive barley variety cv. RGT Planet were space sown in a field plot with 10 cm between seeds and 20 cm between rows under two consecutive years. When BYDV symptoms were shown, plants with different levels (0 - 5) of BYDV infection were tagged. For accurate comparisons, the neighbouring non/less-infected plants were also tagged. At maturity, different agronomic traits and yield components were measured on those tagged plants. Results showed a strong linear correlation between BYDV severity and the performance of agronomic traits and yield components. The yield reductions ranged from 30% for the least affected (score of 1) to 90% for the severely affected (score of 5). Our research confirmed previous findings that BYDV seriously affects crop yield and the prediction of yield loss due to BYDV infection should use the percentage of plants with different BYDV symptoms.

Tumor microenvironment-responsive macrophage-mediated immunotherapeutic drug delivery.

Immunotherapy, as a promising treatment strategy for cancer, has been widely employed in clinics, while its efficiency is limited by the immunosuppression of tumor microenvironment (TME). Tumor-associate macrophages (TAMs) are the most abundant immune cells infiltrating the TME and play a crucial role in immune regulation. Herein, a M0-type macrophage-mediated drug delivery system (PR-M) was designed for carrying Toll-like receptors (TLRs) agonist-loaded nanoparticles. When TLR agonist R848 was released by responding to the TME, the PR-Ms were polarized from M0-type to M1-type and TAMs were also stimulated from M2-type to M1-type, which eventually reversed the immunosuppressive states of TME. By synergizing with the released R848 agonists, the PR-M significantly activated CD4+ and CD8+ T cells in the TME and turned the 'cold' tumor into 'hot' tumor by regulating the secretion of cytokines including IFN-γ, TNF-α, IL-10, and IL-12, thus ultimately promoting the activation of antitumor immunity. In a colorectal cancer mouse model, the PR-M treatment effectively accumulated at the tumor site, with a 5.47-fold increase in M1-type and a 65.08 % decrease in M2-type, resulting in an 85.25 % inhibition of tumor growth and a 87.55 % reduction of tumor volume compared with the non-treatment group. Our work suggests that immune cell-mediated drug delivery systems can effectively increase drug accumulation at the tumor site and reduce toxic side effects, resulting in a strong immune system for tumor immunotherapy. STATEMENT OF SIGNIFICANCE: The formation of TME and the activation of TAMs create an immunosuppressive network that allows tumor to escape the immune system and promotes its growth and spread. In this study, we designed an M0-type macrophage-mediated drug delivery system (PR-M). It leverages the synergistic effect of macrophages and agonists to improve the tumor immunosuppressive micro-environment by increasing M1-type macrophages and decreasing M2-type macrophages. As part of the treatment, the drug-loaded macrophages endowed the system with excellent tumor targeting. Furthermore, loading R848 into TME-responsive nanoparticles could protect macrophages and reduce the potential toxicity of agonists. Further investigations demonstrated that the designed PR-M could be a feasible strategy with high efficacy in tumor targeting, drug loading, autoimmunity activation, and lower side effects.

Nuclear receptor 4A1 ameliorates renal fibrosis by inhibiting vascular endothelial growth factor A induced angiogenesis in UUO rats.

INTRODUCTION: Angiogenesis is closely related to renal fibrosis; however, its basic mechanism remains unclear. In our study, we found that nuclear receptor 4A1 (NR4A1) inhibits vascular endothelial growth factor A (VEGFA)-induced angiogenesis, ameliorating renal fibrosis. METHODS: We prepared a renal fibrosis animal model with unilateral ureteral obstruction (UUO) and NR4A1 knockdown UUO mice model, Using Human umbilical vein endothelial cells (HUVECs) to conduct all in vitro experiments. We then detected and analyzed the expression levels of NR4A1 and other genes related to angiogenesis and fibrosis. RESULTS: The angiogenesis related genes, such as VEGFA, vascular endothelial growth factor receptor-2 (VEGFR-2), endoglin (CD105), as well as the expression of fibrosis related genes that included, α-smooth muscle actin (α-SMA), Vimentin, and Collagen I are all significantly increased in the UUO rat model. In addition, the expression of NR4A1 of the kidney tissue of UUO rats was significantly reduced. Therefore, according to the above results, we speculated that angiogenesis may exacerbate renal fibrosis and NR4A1 may repress renal fibrosis by inhibiting angiogenesis. To further verify the above results, we used VEGFA to stimulate HUVECs with (or without) overexpression or knockdown of NR4A1. The results showed that with prolonged stimulation using VEGFA, the expression of NR4A1 decreases. Overexpression of NR4A1 significantly inhibits the expression of related indicators of angiogenesis and renal fibrosis. Furthermore, knockdown of NR4A1 induces endothelial cell proliferation and migration; therefore, exacerbating angiogenesis and fibrosis. Finally, the results of NR4A1 knockdown UUO mice showed that knockdown of NR4A1 can aggravating kidney damage and induce the expression of angiogenesis and renal fibrosis related indicators, while UUO can significantly induce kidney damage, angiogenesis and renal fibrosis. When knockdown of NR4A1, renal kidney damage, angiogenesis and fibrosis becomes more severe than UUO. Thus, all of these results indicate that NR4A1 can ameliorate renal fibrosis by inhibiting angiogenesis. CONCLUSIONS: NR4A1 can inhibit angiogenesis to ameliorate renal fibrosis.

The Role of Oxidative Stress in Hypomagnetic Field Effects.

The geomagnetic field (GMF) is crucial for the survival and evolution of life on Earth. The weakening of the GMF, known as the hypomagnetic field (HMF), significantly affects various aspects of life on Earth. HMF has become a potential health risk for future deep space exploration. Oxidative stress is directly involved in the biological effects of HMF on animals or cells. Oxidative stress occurs when there is an imbalance favoring oxidants over antioxidants, resulting in cellular damage. Oxidative stress is a double-edged sword, depending on the degree of deviation from homeostasis. In this review, we summarize the important experimental findings from animal and cell studies on HMF exposure affecting intracellular reactive oxygen species (ROS), as well as the accompanying many physiological abnormalities, such as cognitive dysfunction, the imbalance of gut microbiota homeostasis, mood disorders, and osteoporosis. We discuss new insights into the molecular mechanisms underlying these HMF effects in the context of the signaling pathways related to ROS. Among them, mitochondria are considered to be the main organelles that respond to HMF-induced stress by regulating metabolism and ROS production in cells. In order to unravel the molecular mechanisms of HMF action, future studies need to consider the upstream and downstream pathways associated with ROS.

Vertical Barrier Heterostructures for Reliable and High-Performance Self-Powered Infrared Detection.

With their fascinating properties, emerging two-dimensional (2D) materials offer innovative ways to prepare high-performance infrared (IR) detectors. However, the current performance of 2D IR photodetectors is still below the requirements for practical application owing to the severe interfacial recombination, sharply raised contact resistance, and deteriorated metal conductivity at nanoscale. Here, we introduce a vertical barrier heterojunction with a structure of PtSe2/GaAs that combines the excellent optoelectronic properties of transition metal sulfides with topological semi-metals, which allows for an adjustable bandgap and high carrier mobility. The heterojunction was fabricated using the wet transfer method. The heterostructures show significant rectification behaviors and photovoltaic effects, which allow it to operate as a self-driven photodetector at zero bias. The photoresponse parameters at 850 nm with zero bias voltage are 67.2 mA W-1, 6.7 × 1012 Jones, 9.8%, 3.8 × 105, 164 µs, and 198 µs for the responsivity, specific detectivity, external quantum efficiency, Ilight/Idark ratio, rise time, and fall time, respectively. Moreover, the heterojunction is highly sensitive to a wide spectral band from ultraviolet to near-infrared (360-1550 nm). At the same time, this heterostructure demonstrates significant potential for applications in IR polarized light detection and room-temperature high-resolution IR imaging. The excellent properties of the heterojunction make it well-suited for high-performance, self-powered IR detection.

Functional analysis on the role of HvHKT1.4 in barley (Hordeum vulgare L.) salinity tolerance.

High-affinity potassium transporters (HKTs) are well known proteins that govern the partitioning of Na+ between roots and shoots. Six HvHKTs were identified in barley and designated as HvHKT1.1, HvHKT1.3, HvHKT1.4, HvHKT1.5, HvHKT2.1 and HvHKT2.2 according to their similarity to previously reported OsHKTs. Among these HvHKTs, HvHKT1.4 was highly up-regulated under salinity stress in both leaves and roots of Golden Promise. Subcellular localization analysis showed that HvHKT1.4 is a plasma-membrane-localized protein. The knockout mutants of HvHKT1.4 showed greater salinity sensitivity and higher Na+ concentration in leaves than wild-type plants. Haplotype analysis of HvHKT1.4 in 344 barley accessions showed 15 single nucleotide substitutions in the CDS region, belonging to five haplotypes. Significant differences in mean salinity damage scores, leaf Na+ contents and Na+/K+ were found between Hap5 and other haplotypes with Hap5 showing better salinity tolerance. The results indicated that HvHKT1.4 can be an effective target in improving salinity tolerance through ion homeostasis.

Thymol improves ischemic brain injury by inhibiting microglia-mediated neuroinflammation.

BACKGROUND: Microglia-mediated inflammation is a critical factor in the progression of ischemic stroke. Consequently, mitigating excessive microglial activation represents a potential therapeutic strategy for ischemic injury. Thymol, a monophenol derived from plant essential oils, exhibits diverse beneficial biological activities, including anti-inflammatory and antioxidant properties, with demonstrated protective effects in various disease models. However, its specific effects on ischemic stroke and microglial inflammation remain unexplored. METHODS: Rodent transient middle cerebral artery occlusion (tMCAO) model was established to simulate ischemic stroke. TTC staining, modified neurological function score (mNSS), and behavioral tests were used to assess the severity of neurological damage. Then immunofluorescence staining and cytoskeleton analysis were used to determine activation of microglia. Lipopolysaccharide (LPS) was utilized to induce the inflammatory response of primary microglia in vitro. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and enzyme-linked immunosorbent assay (ELISA) were performed to exam the expression of inflammatory cytokines. And western blot was used to investigate the mechanism of the anti-inflammatory effect of thymol. RESULTS: In this study, we found that thymol treatment could ameliorate post-stroke neurological impairment and reduce infarct volume by mitigating microglial activation and pro-inflammatory response (IL-1ß, IL-6, and TNF-α). Mechanically, thymol could inhibit the phosphorylation of phosphatidylinositol-3-kinase (PI3K), sink serine/threonine kinase (Akt), and mammalian target of rapamycin (mTOR), thereby suppressing the activation of nuclear factor-κB (NF-κB). CONCLUSIONS: Our study demonstrated that thymol could reduce the microglial inflammation by targeting PI3K/Akt/mTOR/NF-κB signaling pathway, ultimately alleviating ischemic brain injury. These findings suggest that thymol is a promising candidate as a neuroprotective agent against ischemic stroke.

The roles of orphan nuclear receptor 4 group A1 and A2 in fibrosis.

Fibrosis is not a disease but rather an outcome of the pathological tissue repair response. Many myofibroblasts are activated which lead to the excessive accumulation of extracellular matrix components such as collagen and fibronectin with fibrosis. A variety of organs, including kidney, liver, lung, heart and skin, can undergo fibrosis under the stimulation of exogenous or endogenous pathogenic factors. The orphan nuclear receptor 4 group A1 (NR4A1) and nuclear receptor 4 group A2（NR4A2）are belong to the nuclear receptor subfamily and inhibit the occurrence and development of fibrosis. NR4A1 is an inhibitory factor of TGF-ß signaling transduction. Overexpression of NR4A1 in fibroblasts can reduce TGF-ß induced collagen deposition and fibrosis related gene expression. Here, we summarize the current research progress on the NR4A1/2 and fibrosis, providing reference for the treatment of fibrosis.

Facile Synthesis of Organic-Inorganic Hybrid Heterojunctions of Glycolated Conjugated Polymer-TiO2-X for Efficient Photocatalytic Hydrogen Evolution.

The utilization of the organic-inorganic hybrid photocatalysts for water splitting has gained significant attention due to their ability to combine the advantages of both materials and generate synergistic effects. However, they are still far from practical application due to the limited understanding of the interactions between these two components and the complexity of their preparation process. Herein, a facial approach by combining a glycolated conjugated polymer with a TiO2-X mesoporous sphere to prepare high-efficiency hybrid photocatalysts is presented. The functionalization of conjugated polymers with hydrophilic oligo (ethylene glycol) side chains can not only facilitate the dispersion of conjugated polymers in water but also promote the interaction with TiO2-X forming stable heterojunction nanoparticles. An apparent quantum yield of 53.3% at 365 nm and a hydrogen evolution rate of 35.7 mmol h-1 g-1 is achieved by the photocatalyst in the presence of Pt co-catalyst. Advanced photophysical studies based on femtosecond transient absorption spectroscopy and in situ, XPS analyses reveal the charge transfer mechanism at type II heterojunction interfaces. This work shows the promising prospect of glycolated polymers in the construction of hybrid heterojunctions for photocatalytic hydrogen production and offers a deep understanding of high photocatalytic performance by such heterojunction photocatalysts.

Association between weight-adjusted waist index and periodontitis: A population-based study.

OBJECTIVE: This study aims to examine the association between the Weight-adjusted Waist Circumference Index (WWI) and the prevalence of periodontitis, providing novel evidence on the link between central obesity and periodontal health. METHODS: A cross-sectional study was conducted with 10,289 participants enrolled from NHANES 2009 to 2014. WWI was calculated by dividing waist circumference by the square root of weight. We employed a multivariate logistic regression model and smoothed curve fitting method to evaluate the relationship between WWI and periodontitis. We also compared different subgroups and analyzed the interaction effects. RESULTS: A significant positive association between WWI and periodontitis was observed in 10,289 participants aged ≥30 (OR: 1.20, 95% CI: 1.12-1.28). Upon categorizing WWI into quartiles, the top quartile group exhibited a 27% increased prevalence of periodontitis compared to the bottom quartile (OR: 1.27, 95% CI: 1.10-1.46; P for trend = 0.001). Among individuals aged 30 to 60, the strength of this positive correlation is more pronounced than in those aged 60 and above. CONCLUSIONS: WWI demonstrates a positive correlation with periodontitis with a particularly pronounced impact on moderate periodontitis, suggesting its potential to improve periodontitis prevention in a broad population.

Untargeted metabonomics and TLR4/ NF-κB signaling pathway analysis reveals potential mechanism of action of Dendrobium huoshanense polysaccharide in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is marked by hepatic steatosis accompanied by an inflammatory response. At present, there are no approved therapeutic agents for NAFLD. Dendrobium Huoshanense polysaccharide (DHP), an active ingredient extracted from the stems of Dendrobium Huoshanense, and exerts a protective effect against liver injury. However, the therapeutic effects and mechanisms of action DHP against NAFLD remain unclear. DHP was extracted, characterized, and administered to mice in which NAFLD had been induced with a high-fat and high-fructose drinking (HFHF) diet. Our results showed that DHP used in this research exhibits the characteristic polysaccharide peak with a molecular weight of 179.935 kDa and is composed primarily of Man and Glc in a molar ratio of 68.97:31.03. DHP treatment greatly ameliorated NAFLD by significantly reducing lipid accumulation and the levels of liver function markers in HFHF-induced NAFLD mice, as evidenced by decreased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and total triglyceride (TG). Furthermore, DHP administration reduced hepatic steatosis, as shown by H&E and Oil red O staining. DHP also inhibited the Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway expression, thereby reducing levels of hepatic proinflammatory cytokines. Besides, untargeted metabolomics further indicated that 49 metabolites were affected by DHP. These metabolites are strongly associated the metabolism of glycine, serine, threonine, nicotinate and nicotinamide, and arachidonic acid. In conclusion, DHP has a therapeutic effect against NAFLD, whose underlying mechanism may involve the modulation of TLR4/NF-κB, reduction of inflammation, and regulation of the metabolism of glycine, serine, threonine, nicotinate and nicotinamide metabolism, and arachidonic acid metabolism.

Molecular Mechanism Underlying ROS-Mediated AKH Resistance to Imidacloprid in Whitefly.

Synthetic insecticides used to control Bemisia tabaci include organophosphorus, pyrethroids, insect growth regulators, nicotinoids, and neonicotinoids. Among these, neonicotinoids have been used continuously, which has led to the emergence of high-level resistance to this class of chemical insecticides in the whitefly, making whitefly management difficult. The adipokinetic hormone gene (AKH) and reactive oxygen species (ROS) play roles in the development of insect resistance. Therefore, the roles of AKH and ROS in imidacloprid resistance in Bemisia tabaci Mediterranean (MED; formerly biotype Q) were evaluated in this study. The expression level of AKH in resistant B. tabaci MED was significantly lower than that in sensitive B. tabaci (MED) (p < 0.05). AKH expression showed a decreasing trend. After AKH silencing by RNAi, we found that ROS levels as well as the expression levels of the resistance gene CYP6CM1 and its upstream regulatory factors CREB, ERK, and P38 increased significantly (p < 0.05); additionally, whitefly resistance to imidacloprid increased and mortality decreased (p < 0.001). These results suggest that AKH regulates the expression of resistance genes via ROS in Bemisia tabaci.

Molecular Basis of Plant-Pathogen Interactions in the Agricultural Context.

Biotic stressors pose significant threats to crop yield, jeopardizing food security and resulting in losses of over USD 220 billion per year by the agriculture industry. Plants activate innate defense mechanisms upon pathogen perception and invasion. The plant immune response comprises numerous concerted steps, including the recognition of invading pathogens, signal transduction, and activation of defensive pathways. However, pathogens have evolved various structures to evade plant immunity. Given these facts, genetic improvements to plants are required for sustainable disease management to ensure global food security. Advanced genetic technologies have offered new opportunities to revolutionize and boost plant disease resistance against devastating pathogens. Furthermore, targeting susceptibility (S) genes, such as OsERF922 and BnWRKY70, through CRISPR methodologies offers novel avenues for disrupting the molecular compatibility of pathogens and for introducing durable resistance against them in plants. Here, we provide a critical overview of advances in understanding disease resistance mechanisms. The review also critically examines management strategies under challenging environmental conditions and R-gene-based plant genome-engineering systems intending to enhance plant responses against emerging pathogens. This work underscores the transformative potential of modern genetic engineering practices in revolutionizing plant health and crop disease management while emphasizing the importance of responsible application to ensure sustainable and resilient agricultural systems.

Establishment of a chip digital PCR detection method for canine circovirus.

Canine circovirus (CanineCV), which is a new mammalian circovirus first reported in the United States in 2012, mainly causes diarrhea and vomiting in dogs. As CanineCV evolves and new subtypes emerge, there is an urgent need for new detection technologies to improve the sensitivity and detection rates of viruses in complex scenarios. A chip digital PCR(cdPCR) assay was established for the detection of CanineCV in this study. The results showed good reproducibility, specificity and a linear relationship; the minimum detection limit of CanineCV by cdPCR was 6.62 copies/µL, which is 10 times more sensitive than quantitative real-time PCR (qPCR). The qPCR-positive detection rate was 1 %, while CanineCV cdPCR (2.1 %) exhibited a greater positive detection rate. Fifteen complete genomes were sequenced and subdivided into CanineCV-1 and CanineCV-3. In conclusion, we developed a rapid, reliable, and specific cdPCR method for screening and monitoring canine CV.

Genetically Edited Cascade Nanozymes for Cancer Immunotherapy.

Immune checkpoint blockade (ICB) has brought tremendous clinical progress, but its therapeutic outcome can be limited due to insufficient activation of dendritic cells (DCs) and insufficient infiltration of cytotoxic T lymphocytes (CTLs). Evoking immunogenic cell death (ICD) is one promising strategy to promote DC maturation and elicit T-cell immunity, whereas low levels of ICD induction of solid tumors restrict durable antitumor efficacy. Herein, we report a genetically edited cell membrane-coated cascade nanozyme (gCM@MnAu) for enhanced cancer immunotherapy by inducing ICD and activating the stimulator of the interferon genes (STING) pathway. In the tumor microenvironment (TME), the gCM@MnAu initiates a cascade reaction and generates abundant cytotoxic hydroxyl (•OH), resulting in improved chemodynamic therapy (CDT) and boosted ICD activation. In addition, released Mn2+ during the cascade reaction activates the STING pathway and further promotes the DC maturation. More importantly, activated immunogenicity in the TME significantly improves gCM-mediated PD-1/PD-L1 checkpoint blockade therapy by eliciting systemic antitumor responses. In breast cancer subcutaneous and lung metastasis models, the gCM@MnAu showed synergistically enhanced therapeutic effects and significantly prolonged the survival of mice. This work develops a genetically edited nanozyme-based therapeutic strategy to improve DC-mediated cross-priming of T cells against poorly immunogenic solid tumors.

Managing Super Pests: Interplay between Pathogens and Symbionts Informs Biocontrol of Whiteflies.

Bemisia tabaci is distributed globally and incurs considerable economic and ecological costs as an agricultural pest and viral vector. The entomopathogenic fungus Metarhizium anisopliae has been known for its insecticidal activity, but its impacts on whiteflies are understudied. We investigated how infection with the semi-persistently transmitted Cucurbit chlorotic yellows virus (CCYV) affects whitefly susceptibility to M. anisopliae exposure. We discovered that viruliferous whiteflies exhibited increased mortality when fungus infection was present compared to non-viruliferous insects. High throughput 16S rRNA sequencing also revealed significant alterations of the whitefly bacterial microbiome diversity and structure due to both CCYV and fungal presence. Specifically, the obligate symbiont Portiera decreased in relative abundance in viruliferous whiteflies exposed to M. anisopliae. Facultative Hamiltonella and Rickettsia symbionts exhibited variability across groups but dominated in fungus-treated non-viruliferous whiteflies. Our results illuminate triangular interplay between pest insects, their pathogens, and symbionts-dynamics which can inform integrated management strategies leveraging biopesticides This work underscores the promise of M. anisopliae for sustainable whitefly control while laying the groundwork for elucidating mechanisms behind microbe-mediated shifts in vector competence.

Losartan ameliorates renal fibrosis by inhibiting tumor necrosis factor signal pathway.

Losartan is widely used in the treatment of chronic kidney disease (CKD) and has achieved good clinical efficacy, but its exact mechanism is not clear. We performed high-throughput sequencing (HTS) technology to screen the potential target of losartan in treating CKD. According to the HTS results, we found that the tumor necrosis factor (TNF) signal pathway was enriched. Therefore, we conducted in vivo and in vitro experiments to verify it. We found that TNF signal pathway was activated in both unilateral ureteral obstruction (UUO) rats and human proximal renal tubular epithelial cells (HK-2) treated with transforming growth factor-ß1 (TGF-ß1), while losartan can significantly inhibit TNF signal pathway as well as the expression of fibrosis related genes (such as COL-1, α-SMA and Vimentin). These data suggest that losartan may ameliorate renal fibrosis through modulating the TNF pathway.

Losartan ameliorates renal fibrosis by inhibiting tumor necrosis factor signal pathway / Losartán mejora la fibrosis renal al inhibir la vía de señalización del factor de necrosis tumoral

Losartan is widely used in the treatment of chronic kidney disease (CKD) and has achieved good clinical efficacy, but its exact mechanism is not clear. We performed high-throughput sequencing (HTS) technology to screen the potential target of losartan in treating CKD. According to the HTS results, we found that the tumor necrosis factor (TNF) signal pathway was enriched. Therefore, we conducted in vivo and in vitro experiments to verify it. We found that TNF signal pathway was activated in both unilateral ureteral obstruction (UUO) rats and human proximal renal tubular epithelial cells (HK-2) treated with transforming growth factor-β1 (TGF-β1), while losartan can significantly inhibit TNF signal pathway as well as the expression of fibrosis related genes (such as COL-1, α-SMA and Vimentin). These data suggest that losartan may ameliorate renal fibrosis through modulating the TNF pathway.(AU)

El Losartán es ampliamente utilizado en el tratamiento de la enfermedad renal crónica (CKD) y ha logrado buenos resultados clínicos, pero su mecanismo exacto aún no está claro. Utilizamos la técnica de secuenciación de alto rendimiento (HTS) para detectar posibles dianas de losartán para el tratamiento de la CKD. Según los resultados de HTS, encontramos un enriquecimiento de la vía de señalización del factor de necrosis tumoral (TNF). Así, realizamos experimentos in vivo e in vitro para verificar esto. Encontramos que, tanto en ratas con obstrucción ureteral unilateral (uuo) como en células epiteliales tubulares renales proximal humanas (HK-2) tratadas con factor de crecimiento transformador β1 (TGF-β1), se activó la vía de señalización del TNF. El losartán inhibe significativamente la expresión de las vías de señalización del TNF y genes relacionados con la fibrosis, como COL-1, α-SMA y vicentin. Estos datos sugieren que el losartán puede mejorar la fibrosis renal regulando la vía del TNF.(AU)

Aluminium tolerance and stomata operation: Towards optimising crop performance in acid soil.

Stomatal operation is crucial for optimising plant water and gas exchange and represents a major trait conferring abiotic stress tolerance in plants. About 56% of agricultural land around the globe is classified as acidic, and Al toxicity is a major limiting factor affecting plant performance in such soils. While most of the research work in the field discusses the impact of major abiotic stresses such as drought or salinity on stomatal operation, the impact of toxic metals and, specifically aluminium (Al) on stomatal operation receives much less attention. We aim to fill this knowledge gap by summarizing the current knowledge of the adverse effects of acid soils on plant stomatal development and operation. We summarised the knowledge of stomatal responses to both long-term and transient Al exposure, explored molecular mechanisms underlying plant adaptations to Al toxicity, and elucidated regulatory networks that alleviate Al toxicity. It is shown that Al-induced stomatal closure involves regulations of core stomatal signalling components, such as ROS, NO, and CO2 and key elements of ABA signalling. We also discuss possible targets and pathway to modify stomatal operation in plants grown in acid soils thus reducing the impact of Al toxicity on plant growth and yield.

Neutrophil Membrane-Camouflaged Polyprodrug Nanomedicine for Inflammation Suppression in Ischemic Stroke Therapy.

Neuroinflammation has emerged as a major concern in ischemic stroke therapy because it exacebates neurological dysfunction and suppresses neurological recovery after ischemia/reperfusion. Fingolimod hydrochloride (FTY720) is an FDA-approved anti-inflammatory drug which exhibits potential neuroprotective effects in ischemic brain parenchyma. However, delivering a sufficient amount of FTY720 through the blood-brain barrier into brain lesions without inducing severe cardiovascular side effects remains challenging. Here, a neutrophil membrane-camouflaged polyprodrug nanomedicine that can migrate into ischemic brain tissues and in situ release FTY720 in response to elevated levels of reactive oxygen species. This nanomedicine delivers 15.2-fold more FTY720 into the ischemic brain and significantly reduces the risk of cardiotoxicity and infection compared with intravenously administered free drug. In addition, single-cell RNA-sequencing analysis identifies that the nanomedicine attenuates poststroke inflammation by reprogramming microglia toward anti-inflammatory phenotypes, which is realized via modulating Cebpb-regulated activation of NLRP3 inflammasomes and secretion of CXCL2 chemokine. This study offers new insights into the design and fabrication of polyprodrug nanomedicines for effective suppression of inflammation in ischemic stroke therapy.