Danggui Shaoyao San Alleviates Early Cognitive Impairment in Alzheimer's Disease Mice Through IRS1/GSK3ß/Wnt3a-ß-Catenin Pathway.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease characterized by Amyloid plaques and neurofibrillary tangles. We explored the potential mechanism by which Danggui Shaoyao San (DSS) modulates central glucose metabolism via the insulin receptor substrate 1 (IRS1)/glycogen synthase kinase-3ß (GSK3ß)/Wnt3a-ß-catenin pathway, thereby exerting protective effects on cognitive functions. METHODS: In vitro, HT22 cells were induced with streptozotocin (STZ) to investigate the impact of GSK3ß on pathway transduction. The active components in the DSS stock solution were validated using mass spectrometry. Subsequently, an AD model in C57BL/6J mice was established through STZ injection into both ventricles. The success of the model was validated behaviorally and pathologically. The Morris Water Maze (MWM) test, immunohistochemistry, Western blotting, quantitative reverse transcription-PCR, and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) were employed to evaluate the influence of DSS on memory and pathological changes in AD. RESULTS: The DSS stock solution, rich in active components, ameliorated the memory deficits in AD mice in the MWM. In vitro, GSK3ß exhibited regulatory control over Wnt and ß-catenin, with GSK3ß inhibition mitigating ß-amyloid and tau redundancies at protein and gene levels, facilitating signal transduction. In vivo, DSS impacted key targets in the IRS1/GSK3ß/Wnt3a-ß-catenin pathway, mitigated senile plaques resulting from amyloid ß (Aß) deposition and neurofiber tangles induced by tau hyperphosphorylation, and alleviated the decline in central glucose metabolism observed in FDG-PET. CONCLUSIONS: Our findings suggest that DSS potentially confers cognitive protection by alleviating central hypoglycemia through the IRS1/GSK3ß/Wnt3a-ß-catenin pathway. This may serve as a promising therapeutic avenue for AD.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides.

Despite recent advancements in catalytic synthesis of axial chirality, reports on non-biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho-aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Rice false smut virulence protein subverts host chitin perception and signaling at lemma and palea for floral infection.

The flower-infecting fungus Ustilaginoidea virens causes rice false smut, which is a severe emerging disease threatening rice (Oryza sativa) production worldwide. False smut not only reduces yield, but more importantly produces toxins on grains, posing a great threat to food safety. U. virens invades spikelets via the gap between the 2 bracts (lemma and palea) enclosing the floret and specifically infects the stamen and pistil. Molecular mechanisms for the U. virens-rice interaction are largely unknown. Here, we demonstrate that rice flowers predominantly employ chitin-triggered immunity against U. virens in the lemma and palea, rather than in the stamen and pistil. We identify a crucial U. virens virulence factor, named UvGH18.1, which carries glycoside hydrolase activity. Mechanistically, UvGH18.1 functions by binding to and hydrolyzing immune elicitor chitin and interacting with the chitin receptor CHITIN ELICITOR BINDING PROTEIN (OsCEBiP) and co-receptor CHITIN ELICITOR RECEPTOR KINASE1 (OsCERK1) to impair their chitin-induced dimerization, suppressing host immunity exerted at the lemma and palea for gaining access to the stamen and pistil. Conversely, pretreatment on spikelets with chitin induces a defense response in the lemma and palea, promoting resistance against U. virens. Collectively, our data uncover a mechanism for a U. virens virulence factor and the critical location of the host-pathogen interaction in flowers and provide a potential strategy to control rice false smut disease.

Identification of NADPH Oxidase Genes Crucial for Rice Multiple Disease Resistance and Yield Traits.

Reactive oxygen species (ROS) act as a group of signaling molecules in rice functioning in regulation of development and stress responses. Respiratory burst oxidase homologues (Rbohs) are key enzymes in generation of ROS. However, the role of the nine Rboh family members was not fully understood in rice multiple disease resistance and yield traits. In this study, we constructed mutants of each Rboh genes and detected their requirement in rice multiple disease resistance and yield traits. Our results revealed that mutations of five Rboh genes (RbohA, RbohB, RbohE, RbohH, and RbohI) lead to compromised rice blast disease resistance in a disease nursery and lab conditions; mutations of five Rbohs (RbohA, RbohB, RbohC, RbohE, and RbohH) result in suppressed rice sheath blight resistance in a disease nursery and lab conditions; mutations of six Rbohs (RbohA, RbohB, RbohC, RbohE, RbohH and RbohI) lead to decreased rice leaf blight resistance in a paddy yard and ROS production induced by PAMPs and pathogen. Moreover, all Rboh genes participate in the regulation of rice yield traits, for all rboh mutants display one or more compromised yield traits, such as panicle number, grain number per panicle, seed setting rate, and grain weight, resulting in reduced yield per plant except rbohb and rbohf. Our results identified the Rboh family members involved in the regulation of rice resistance against multiple pathogens that caused the most serious diseases worldwide and provide theoretical supporting for breeding application of these Rbohs to coordinate rice disease resistance and yield traits.

Broad-spectrum resistance gene RPW8.1 balances immunity and growth via feedback regulation of WRKYs.

Arabidopsis RESISTANCE TO POWDERY MILDEW 8.1 (RPW8.1) is an important tool for engineering broad-spectrum disease resistance against multiple pathogens. Ectopic expression of RPW8.1 leads to enhanced disease resistance with cell death at leaves and compromised plant growth, implying a regulatory mechanism balancing RPW8.1-mediated resistance and growth. Here, we show that RPW8.1 constitutively enhances the expression of transcription factor WRKY51 and activates salicylic acid and ethylene signalling pathways; WRKY51 in turn suppresses RPW8.1 expression, forming a feedback regulation loop. RPW8.1 and WRKY51 are both induced by pathogen infection and pathogen-/microbe-associated molecular patterns. In ectopic expression of RPW8.1 background (R1Y4), overexpression of WRKY51 not only rescues the growth suppression and cell death caused by RPW8.1, but also suppresses RPW8.1-mediated broad-spectrum disease resistance and pattern-triggered immunity. Mechanistically, WRKY51 directly binds to and represses RPW8.1 promoter, thus limiting the expression amplitude of RPW8.1. Moreover, WRKY6, WRKY28 and WRKY41 play a role redundant to WRKY51 in the suppression of RPW8.1 expression and are constitutively upregulated in R1Y4 plants with WRKY51 being knocked out (wrky51 R1Y4) plants. Notably, WRKY51 has no significant effects on disease resistance or plant growth in wild type without RPW8.1, indicating a specific role in RPW8.1-mediated disease resistance. Altogether, our results reveal a regulatory circuit controlling the accumulation of RPW8.1 to an appropriate level to precisely balance growth and disease resistance during pathogen invasion.

Hsa-miR-877-5p Expression in Acute Ischemic Stroke Based on Bioinformatics Analysis and Clinical Validation.

Inflammation and immunity play important roles in the pathogenesis of ischemic stroke. This study aimed to explore key regulatory genes in acute ischemic stroke (AIS) and their underlying mechanisms to provide new research targets for the diagnosis and treatment of ischemic stroke. We searched for differentially expressed mRNAs and miRNAs in patients with AIS and healthy populations in GEO databases, constructed a miRNA-mRNA network, and screened key miRNAs using least absolute shrinkage and selection operator regression and the support vector machine-recursive feature elimination model. Correlations between key miRNAs and infiltrating immune cells and inflammatory factors were analyzed using CIBERSORT and immunoassays and verified using clinical experiments. Bioinformatics analysis identified hsa-miR-877-5p as a key regulatory miRNA in AIS that can modulate immune and inflammatory responses. In clinical studies, it was verified by quantitative PCR analysis that the expression of hsa-miR-877-5p in the blood of AIS patients was higher than that of the healthy group. Then, enzyme-linked immunosorbent assay revealed that the expression of IL-23 and TNF-α related to inflammation in AIS patients was higher than that of the healthy. Quantitative PCR further found that the relative mRNA expression of IL-23, CXCR3, and TNF-α in AIS group was higher than that of the healthy group. This study may provide a basis for a more comprehensive understanding of the potential mechanism of the occurrence and development of AIS, and hsa-miR-877-5p and its downstream effectors IL-23, CXCR3, and TNF-α may be potential intervention targets in AIS.

Variation in microbiological heterogeneity in Chinese strong-flavor Baijiu fermentation for four representative varieties of sorghum.

The quality and composition of strong-flavor Baijiu (SFB), a type of Chinese liquor, depends on the variety of sorghum used in fermentation. However, comprehensive in situ studies measuring the effects sorghum varieties on the fermentation are lacking and the underlying microbial mechanisms remains poorly understood. We studied the in situ fermentation of SFB by using metagenomic, metaproteomic, and metabolomic techniques across four sorghum varieties. Sensory characteristics were best for SFB made from glutinous variety Luzhouhong, followed by glutinous hybrid Jinnuoliang and Jinuoliang, and those made with non-glutinous Dongzajiao. In agreement with sensory evaluations, the volatile composition of SFB samples differed between sorghum varieties (P < 0.05). Fermentation of different sorghum varieties varied in microbial diversity, structure, volatile compounds, and physicochemical properties (pH, temperature, starch, reducing sugar, and moisture) (P < 0.05), with most changes occurring within the first 21 days. Additionally, the microbial interactions and their relationship with volatiles, as well as the physicochemical factors that govern microbial succession, differed between varieties of sorghum. The number of physicochemical factors affecting bacterial communities outweighed those affecting fungal communities, suggesting that bacteria were less resilient to the brewing conditions. This correlates with the finding that bacteria play a major role in the differences in microbial communities and metabolic functions during fermentation with the different varieties of sorghum. Metagenomic function analysis revealed differences in amino acid and carbohydrate metabolism between sorghum varieties throughout most of the brewing process. Metaproteomics further indicated most differential proteins were found in these two pathways, related to differences in volatiles between sorghum varieties of Baijiu and originating from Lactobacillus. These results provide insight into the microbial principles underlying Baijiu production and can be used to improve the quality of Baijiu by selecting the appropriate raw materials and optimizing fermentation parameters.

A natural allele of proteasome maturation factor improves rice resistance to multiple pathogens.

Crops with broad-spectrum resistance loci are highly desirable in agricultural production because these loci often confer resistance to most races of a pathogen or multiple pathogen species. Here we discover a natural allele of proteasome maturation factor in rice, UMP1R2115, that confers broad-spectrum resistance to Magnaporthe oryzae, Rhizoctonia solani, Ustilaginoidea virens and Xanthomonas oryzae pv. oryzae. Mechanistically, this allele increases proteasome abundance and activity to promote the degradation of reactive oxygen species-scavenging enzymes including peroxidase and catalase upon pathogen infection, leading to elevation of H2O2 accumulation for defence. In contrast, inhibition of proteasome function or overexpression of peroxidase/catalase-encoding genes compromises UMP1R2115-mediated resistance. More importantly, introduction of UMP1R2115 into a disease-susceptible rice variety does not penalize grain yield while promoting disease resistance. Our work thus uncovers a broad-spectrum resistance pathway integrating de-repression of plant immunity and provides a valuable genetic resource for breeding high-yield rice with multi-disease resistance.

Golovinomyces cichoracearum effector-associated nuclear localization of RPW8.2 amplifies its expression to boost immunity in Arabidopsis.

Arabidopsis RESISTANCE TO POWDERY MILDEW 8.2 (RPW8.2) is specifically induced by the powdery mildew (PM) fungus (Golovinomyces cichoracearum) in the infected epidermal cells to activate immunity. However, the mechanism of RPW8.2-induction is not well understood. Here, we identify a G. cichoracearum effector that interacts with RPW8.2, named Gc-RPW8.2 interacting protein 1 (GcR8IP1), by a yeast two-hybrid screen of an Arabidopsis cDNA library. GcR8IP1 is physically associated with RPW8.2 with its REALLY INTERESTING NEW GENE finger domain that is essential and sufficient for the association. GcR8IP1 was secreted and translocated into the nucleus of host cell infected with PM. Association of GcR8IP1 with RPW8.2 led to an increase in RPW8.2 in the nucleus. In turn, the nucleus-localized RPW8.2 promoted the activity of the RPW8.2 promoter, resulting in transcriptional self-amplification of RPW8.2 to boost immunity at infection sites. Additionally, ectopic expression or host-induced gene silencing of GcR8IP1 supported its role as a virulence factor in PM. Altogether, our results reveal a mechanism of RPW8.2-dependent defense strengthening via altered partitioning of RPW8.2 and transcriptional self-amplification triggered by a PM fungal effector, which exemplifies an atypical form of effector-triggered immunity.

Comprehensive Assessment of Eutrophication in Xiamen Bay and Its Implications for Management Strategy in Southeast China.

The eutrophication of coastal water has been a critical environmental problem in China's offshore areas. How to effectively assess the status of coastal waters is key for pollution treatment and environmental protection. In recent years, eutrophication-symptom-based and multi-indicator methods, termed "phase II" methods, have been gradually adopted to assess the eutrophication status in some coastal waters in China and have achieved success. The cumulative quantile is typically selected to determine the characteristic value of an indicator in "phase II" methods. The influence of small-scale damaged water bodies on eutrophication assessment may be exaggerated, which often leads to the overassessment of the eutrophication status. In this study, the area ratio method was integrated into the assessment of the estuarine trophic status (ASSETS) method in order to assess the eutrophication status of Xiamen Bay in 2016. The results indicated that, in 2016, the eutrophication status of Xiamen Bay coastal waters was moderate and exhibited spatiotemporal variation. The area ratio method can effectively reduce the effect of small-scale coastal waters with extremely high eutrophication on the overassessment of eutrophication at the broader scale, allowing the eutrophication status to be better reflected, even with limited observation data. The centralized distribution of pollution sources and poor hydrodynamic conditions are the main reasons for the aforementioned phenomenon. Controlling the pollution discharge from the Jiulong River in flood seasons is key to reducing eutrophication in Xiamen coastal waters.