Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors.

The development of tumors relies on lactate metabolic reprogramming to facilitate their unchecked growth and evade immune surveillance. This poses a significant challenge to the efficacy of antitumor immunity. To address this, a tumor-selective nano-dispatcher, PIMDQ/Syro-RNP, to enforce the immunotherapeutic effect through regulation of lactate metabolism and activation of toll-like receptors is developed. By using the tumor-targeting properties of c-RGD, the system can effectively deliver monocarboxylate transporters 4 (MCT4) inhibitor (Syro) to inhibit lactate efflux in tumor cells, leading to decreased lactate levels in the tumor microenvironment (TME) and increased accumulation within tumor cells. The reduction of lactate in TME will reduce the nutritional support for regulatory T cells (Tregs) and promote the effector function of T cells. The accumulation of lactate in tumor cells will lead to tumor death due to cellular acidosis. In addition, it will also reduce the uptake of glucose by tumor cells, reduce nutrient plunder, and further weaken the inhibition of T cell function. Furthermore, the pH-responsive release of Toll-like receptors (TLR) 7/8 agonist IMDQ within the TME activates dendritic cells (DCs) and promotes the infiltration of T cells. These findings offer a promising approach for enhancing tumor immune response through targeted metabolic interventions.

Pilose Antler Protein Relieves UVB-Induced HaCaT Cells and Skin Damage.

Extended exposure to UVB (280-315 nm) radiation results in oxidative damage and inflammation of the skin. Previous research has demonstrated that pilose antler extracts have strong anti-inflammatory properties and possess antioxidant effects. This study aimed to elucidate the mechanism of pilose antler protein in repairing photodamage caused by UVB radiation in HaCaT cells and ICR mice. Pilose antler protein (PAP) was found to increase the expression of type I collagen and hyaluronic acid in HaCaT cells under UVB irradiation while also inhibiting reactive oxygen species (ROS) production and oxidative stress in vitro. In vivo, the topical application of pilose antler protein effectively attenuated UVB-induced skin damage in ICR mice by reducing interleukin-1ß (IL-ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and inhibiting skin inflammation while alleviating UVB-induced oxidative stress. It was shown that pilose antler protein repaired UVB-induced photodamage through the MAPK and TGF-ß/Smad pathways.

Cynomorium songaricum Rupr. flavonoids improve cyclophosphamide-induced reproductive function damage by regulating the testosterone synthesis pathway.

Introduction: The prevalence of male infertility has been increasing globally, necessitating the search for safe and nontoxic active compounds to alleviate reproductive dysfunction. Although the precise mechanism remains unknown, Cynomorium songaricum Rupr. (CS) extract has protective effects on the reproductive system. The effect of C. songaricum Rupr. flavonoids (CSF) on reproductive injury and testicular mesenchymal stem cell viability in male mice and TM3 cells was investigated. Methods: We explored the possible association between these effects and the testosterone (T) synthesis pathway. Mice were administered cyclophosphamide to induce reproductive damage, followed by CSF administration. Body mass and organ index were recorded. Pathological changes in T and the epididymis were observed using hematoxylin-eosin staining. ELISA measured the serum levels of T, luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and estradiol (E2) in mice. Fructose and zinc ion levels in the seminal plasma were measured. TM3 cells were treated with Bisphenol A (BPA) and different concentrations of CSF, followed by proliferative evaluations using the CCK-8 assay and T and LH level assessments using ELISA. Furthermore, the expression of steroidogenic enzyme genes and proteins was investigated using western blotting and RT-PCR. Results: CSF exhibited a notable reduction in reproductive damage and improved pathological changes in testicular and epididymal tissues. CSF group demonstrated substantially higher levels of seminal plasma fructose and zinc ions; markedly elevated serum levels of T, LH, GnRH, and FSH; and lower levels of E2 than those of the model group. Intracellular T content and secretion of T and LH increase with CSF while effectively mitigating BPA-induced damage to TM3 cells. CSF group exhibited substantially higher gene and protein expression of steroidogenic enzymes than those of the model group, both in vivo and in vitro. CSF ameliorates reproductive impairment by enhancing the expression of pivotal enzymes involved in synthesizing T. Discussion: CSF ameliorates cyclophosphamide-induced reproductive impairment and bisphenol A-induced TM3 cell damage in mice by regulating sex hormone levels in the Hypothalamic-Pituitary-Gonadal Axis (HPG axis) and upregulating the expression of steroidogenic enzymes. Therefore, CS is a potential treatment for male reproductive impairment.

Coat Proteins of the Novel Victoriviruses FaVV1 and FaVV2 Suppress Sexual Reproduction and Virulence in the Pathogen of Fusarium Head Blight.

Fusarium head blight (FHB), a disease inflicted by Fusarium graminearum and F. asiaticum, poses a growing threat to wheat in China, particularly in the face of climate change and evolving agricultural practices. This study unveiled the discovery of the victorivirus FgVV2 from the F. asiaticum strain F16176 and comprehensively characterized the function of the two victoriviruses FaVV1 and FaVV2 in virulence. Through comparative analysis with a virus-free strain, we established that these mycoviruses markedly repress the sexual reproduction and pathogenicity of their fungal hosts. Furthermore, we synthesized the coat protein (CP) genes CP1 from FaVV1 and CP2 from FaVV2, which were fused with the green fluorescent protein (GFP) gene and successfully expressed in Fusarium strains in wild-type isolates of F. asiaticum and F. graminearum. Similar to virus-infected strains, the transformed strains expressing CPs showed a significant decrease in perithecia formation and pathogenicity. Notably, CP2 exhibited a stronger inhibitory effect than CP1, yet the suppression of sexual reproduction in F. graminearum was less pronounced than that in F. asiaticum. Additionally, the pathogenicity of the F. asiaticum and F. graminearum strains expressing CP1 or CP2 was substantially diminished against wheat heads. The GFP-tagged CP1 and CP2 revealed distinct cellular localization patterns, suggesting various mechanisms of interaction with the host. The findings of this study provide a significant research foundation for the study of the interaction mechanisms between FaVV1 and FaVV2 with their hosts, as well as for the exploration and utilization of fungal viral resources.

Adipose tissue senescence: Biological changes, hallmarks and therapeutic approaches.

Adipose tissue (AT), the largest energy storage reservoir and endocrine organ, plays a crucial role in regulating systemic energy metabolism. As one of the most vulnerable tissues during aging, the plasticity of AT is impaired. With age, AT undergoes redistribution, characterized by expansion of visceral adipose tissue (VAT) and reduction of peripheral subcutaneous adipose tissue (SAT). Additionally, age-related changes in AT include reduced adipogenesis of white adipocytes, decreased proliferation and differentiation capacity of mesenchymal stromal/stem cells (MSCs), diminished thermogenic capacity in brown/beige adipocytes, and dysregulation of immune cells. Specific and sensitive hallmarks enable the monitoring and evaluation of the biological changes associated with aging. In this study, we have innovatively proposed seven characteristic hallmarks of AT senescence, including telomere attrition, epigenetic alterations, genomic instability, mitochondrial dysfunction, disabled macroautophagy, cellular senescence, and chronic inflammation, which are intricately interconnected and mutually regulated. Finally, we discussed anti-aging strategies targeting AT, offering insights into mitigating or delaying metabolic disturbances caused by AT senescence.

Unsupervised Transfer Learning Method via Cycle-Flow Adversarial Networks for Transient Fault Detection under Various Operation Conditions.

The efficient fault detection (FD) of traction control systems (TCSs) is crucial for ensuring the safe operation of high-speed trains. Transient faults (TFs) can arise due to prolonged operation and harsh environmental conditions, often being masked by background noise, particularly during dynamic operating conditions. Moreover, acquiring a sufficient number of samples across the entire scenario presents a challenging task, resulting in imbalanced data for FD. To address these limitations, an unsupervised transfer learning (TL) method via federated Cycle-Flow adversarial networks (CFANs) is proposed to effectively detect TFs under various operating conditions. Firstly, a CFAN is specifically designed for extracting latent features and reconstructing data in the source domain. Subsequently, a transfer learning framework employing federated CFANs collectively adjusts the modified knowledge resulting from domain alterations. Finally, the designed federated CFANs execute transient FD by constructing residuals in the target domain. The efficacy of the proposed methodology is demonstrated through comparative experiments.

Prediction of 90 day readmission in heart failure with preserved ejection fraction by interpretable machine learning.

AIMS: Certain critical risk factors of heart failure with preserved ejection fraction (HFpEF) patients were significantly different from those of heart failure with reduced ejection fraction (HFrEF) patients, resulting in the limitations of existing predictive models in real-world situations. This study aimed to develop a machine learning model for predicting 90 day readmission for HFpEF patients. METHODS AND RESULTS: Data were extracted from electronic health records from 1 August 2020 to 1 August 2021 and follow-up records of patients with HFpEF within 3 months after discharge. Feature extraction was performed by univariate analysis combined with the least absolute shrinkage and selection operator (LASSO) algorithms. Machine learning models like eXtreme Gradient Boosting (XGBoost), random forest, neural network and logistic regression were adopted to construct models. The discrimination and calibration of each model were compared, and the Shapley Additive exPlanations (SHAP) method was used to explore the interpretability of the model. The cohort included 746 patients, of whom 103 (13.8%) were readmitted within 90 days. XGBoost owned the best performance [area under the curve (AUC) = 0.896, precision-recall area under the curve (PR-AUC) = 0.868, sensitivity = 0.817, specificity = 0.837, balanced accuracy = 0.827]. The Kolmogorov-Smirnov (KS) statistic was 0.694 at 0.468 in the XGBoost model. SHAP identified the top 12 risk features, including activities of daily living (ADL), left atrial dimension (LAD), left ventricular end-diastolic diameter (LVDD), shortness, nitrates, length of stay, nutritional risk, fall risk, accompanied by other symptoms, educational level, anticoagulants and edema. CONCLUSIONS: Our model could help medical agencies achieve the early identification of 90 day readmission risk in HFpEF patients and reveal risk factors that provide valuable insights for treatments.

Identification and Characterization of High-Molecular-Weight Proteins Secreted by Plasmodiophora brassicae That Suppress Plant Immunity.

Plasmodiophora brassicae is an obligate intracellular parasitic protist that causes clubroot disease on cruciferous plants. So far, some low-molecular-weight secreted proteins from P. brassicae have been reported to play an important role in plant immunity regulation, but there are few reports on its high-molecular-weight secreted proteins. In this study, 35 putative high-molecular-weight secreted proteins (>300 amino acids) of P. brassicae (PbHMWSP) genes that are highly expressed during the infection stage were identified using transcriptome analysis and bioinformatics prediction. Then, the secretory activity of 30 putative PbHMWSPs was confirmed using the yeast signal sequence trap system. Furthermore, the genes encoding 24 PbHMWSPs were successfully cloned and their functions in plant immunity were studied. The results showed that ten PbHMWSPs could inhibit flg22-induced reactive oxygen burst, and ten PbHMWSPs significantly inhibited the expression of the SA signaling pathway marker gene PR1a. In addition, nine PbHMWSPs could inhibit the expression of a marker gene of the JA signaling pathway. Therefore, a total of 19 of the 24 tested PbHMWSPs played roles in suppressing the immune response of plants. Of these, it is worth noting that PbHMWSP34 can inhibit the expression of JA, ET, and several SA signaling pathway marker genes. The present study is the first to report the function of the high-molecular-weight secreted proteins of P. brassicae in plant immunity, which will enrich the theory of interaction mechanisms between the pathogens and plants.

Metabolic Crosstalk between Liver and Brain: From Diseases to Mechanisms.

Multiple organs and tissues coordinate to respond to dietary and environmental challenges. It is interorgan crosstalk that contributes to systemic metabolic homeostasis. The liver and brain, as key metabolic organs, have their unique dialogue to transmit metabolic messages. The interconnected pathogenesis of liver and brain is implicated in numerous metabolic and neurodegenerative disorders. Recent insights have positioned the liver not only as a central metabolic hub but also as an endocrine organ, capable of secreting hepatokines that transmit metabolic signals throughout the body via the bloodstream. Metabolites from the liver or gut microbiota also facilitate a complex dialogue between liver and brain. In parallel to humoral factors, the neural pathways, particularly the hypothalamic nuclei and autonomic nervous system, are pivotal in modulating the bilateral metabolic interplay between the cerebral and hepatic compartments. The term "liver-brain axis" vividly portrays this interaction. At the end of this review, we summarize cutting-edge technical advancements that have enabled the observation and manipulation of these signals, including genetic engineering, molecular tracing, and delivery technologies. These innovations are paving the way for a deeper understanding of the liver-brain axis and its role in metabolic homeostasis.

Iron oxide nanozymes enhanced by ascorbic acid for macrophage-based cancer therapy.

In recent years, using pharmacological ascorbic acid has emerged as a promising therapeutic approach in cancer treatment, owing to its capacity to induce extracellular hydrogen peroxide (H2O2) production in solid tumors. The H2O2 is then converted into cytotoxic hydroxyl free radicals (HO˙) by redox-active Fe2+ inside cells. However, the high dosage of ascorbic acid required for efficacy is hampered by adverse effects such as kidney stone formation. In a recent study, we demonstrated the efficient catalytic conversion of H2O2 to HO˙ by wüstite (Fe1-xO) nanoparticles (WNPs) through a heterogenous Fenton reaction. Here, we explore whether WNPs can enhance the therapeutic potential of ascorbic acid, thus mitigating its dose-related limitations. Our findings reveal distinct pH dependencies for WNPs and ascorbic acid in the Fenton reaction and H2O2 generation, respectively. Importantly, WNPs exhibit the capability to either impede or enhance the cytotoxic effect of ascorbic acid, depending on the spatial segregation of the two reagents by cellular compartments. Furthermore, our study demonstrates that treatment with ascorbic acid promotes the polarization of WNP-loaded macrophages toward a pro-inflammatory M1 phenotype, significantly suppressing the growth of 4T1 breast cancer cells. This study highlights the importance of orchestrating the interplay between ascorbic acid and nanozymes in cancer therapy and presents a novel macrophage-based cell therapy approach.

Person-centered exploration of work-related stress patterns, predictors, and their association with subhealth in midwives: A cross-sectional study.

BACKGROUND: Midwives experience elevated levels of work-related stress. However, there is limited understanding of the patterns of this stress, its sociodemographic and work-related determinants, and its association with sub-health. METHOD: This multi-center cross-sectional study, conducted in 21 hospitals in Zhuhai City, Guangdong Province, China, involved 300 midwives. Work-related stress levels in midwives were evaluated using the Chinese version of the Nursing Stress Scale, while social, physical and mental sub-health status was measured with the Sub-Health Measurement Scale. Utilizing latent profile analysis, the study aimed to categorize midwives into homogeneous profiles based on patterns of work-related stress. RESULTS: Among the 300 midwives examined, three distinct profiles were identified: profile 1 (n=57, 19 %), characterized by low work-related stress; profile 2 (n=149, 50 %), representing the moderate work-related stress class; and profile 3 (n=94, 31 %), indicative of high work-related stress. Midwives in the high work-related stress profile tended to be younger, with lower monthly income, lower professional titles, and a higher likelihood of night shift work (all P<0.01). Significant and noteworthy trends were observed in sociodemographic characteristics (age, monthly income, and professional title) and work-related characteristics (night shift status). After controlling for confounders, the work-related stress profile demonstrated a negative association with social, physical and mental sub-health status. CONCLUSION: This study highlights integrating stress domains and adopting a person-centered approach to examine midwives' work-related stress. Identifying predictors of profile membership and their relationship with sub-health can inform tailored interventions to reduce stress and improve midwives' well-being.

A cross-tissue transcriptome-wide association study reveals novel susceptibility genes for migraine.

BACKGROUND: Migraine is a common neurological disorder with a strong genetic component. Despite the identification of over 100 loci associated with migraine susceptibility through genome-wide association studies (GWAS), the underlying causative genes and biological mechanisms remain predominantly elusive. METHODS: The FinnGen R10 dataset, consisting of 333,711 subjects (20,908 cases and 312,803 controls), was utilized in conjunction with the Genotype-Tissue Expression Project (GTEx) v8 EQTls files to conduct cross-tissue transcriptome association studies (TWAS). Functional Summary-based Imputation (FUSION) was employed to validate these findings in single tissues. Additionally, candidate susceptibility genes were screened using Gene Analysis combined with Multi-marker Analysis of Genomic Annotation (MAGMA). Subsequent Mendelian randomization (MR) and colocalization analyses were conducted. Furthermore, GeneMANIA analysis was employed to enhance our understanding of the functional implications of these susceptibility genes. RESULTS: We identified a total of 19 susceptibility genes associated with migraine in the cross-tissue TWAS analysis. Two novel susceptibility genes, REV1 and SREBF2, were validated through both single tissue TWAS and MAGMA analysis. Mendelian randomization and colocalization analyses further confirmed these findings. REV1 may reduce the migraine risk by regulating DNA damage repair, while SREBF2 may increase the risk of migraine by regulating cholesterol metabolism. CONCLUSION: Our study identified two novel genes whose predicted expression was associated with the risk of migraine, providing new insights into the genetic framework of migraine.

Adipocyte secreted NRG4 ameliorates age-associated metabolic dysfunction.

With the progressive aging of society, there is an increasing prevalence of age-related diseases that pose a threat to the elderly's quality of life. Adipose tissue, a vital energy reservoir with endocrine functions, is one of the most vulnerable tissues in aging, which in turn influences systematic aging process, including metabolic dysfunction. However, the underlying mechanism is still poorly understood. In this study, we found that NRG4, a novel adipokine, is obviously decreased in adipocyte tissues and serums during aging. Moreover, delivered recombinant NRG4 protein (rNRG4) into aged mice can ameliorate age-associated insulin resistance, glucose disorders and other metabolic disfunction. In addition, rNRG4 treatment alleviates age-associated hepatic steatosis and sarcopenia, accompanied with altered gene signatures. Together, these results indicate that NRG4 plays a key role in the aging process and is a therapeutic target for the treatment of age-associated metabolic dysfunction.

Signal Modulation Induced by a Hole Transfer Layer Participant Photoactive Gate: A Highly Sensitive Organic Photoelectrochemical Transistor Sensing Platform.

It is urgent to pursue appropriate gate photoactive materials for gate-to-channel signal modulation to achieve superior transconductance performances of organic photoelectrochemical transistor (OPECT) sensors. Notably, a hole transfer layer (HTL) participant CdZnS/sulfur-doped Ti3C2 MXene (S-MXene) gate was designed and developed in this work, which exhibited a remarkable signal modulation performance by up to 3 orders of magnitude. Because of the incorporation of S-MXene with an enhanced electrical conductivity as the effective HTL, the signal modulation capabilities of the CdZnS/S-MXene photoactive gate were superior to those of CdZnS and CdZnS/MXene. This incorporation inhibited the recombination of the interfacial charge and facilitated the transfer of photogenerated holes, thus enhancing the photoelectric conversion performance. This enhancement facilitated fast electron transfer with a larger effective photovoltage to augment the dedoping ability of channel ions. Based on these findings, an aptasensing platform that exhibited good performance was constructed using the proposed OPECT device, with ofloxacin as a model target and an aptamer for specific recognition. The developed OPECT aptasensor had various advantages, including a high sensitivity, good linear range (1.0 × 10-13 to 1.0 × 10-6 M), and low limit of detection (3.3 × 10-15 M). This study provided a proof-of-concept for the generalized development of HTL participant gates for OPECT sensors and other related applications.

The critical roles of the Zn2Cys6 transcription factor Fp487 in the development and virulence of Fusarium pseudograminearum: A potential target for Fusarium crown rot control.

Fusarium crown rot (FCR) caused by Fusarium pseudograminearum poses a significant threat to wheat production in the Huang-Huai-Hai region of China. However, the pathogenic mechanism of F. pseudograminearum is still poorly understood. Zn2Cys6 transcription factors, which are exclusive to fungi, play pivotal roles in regulating fungal development, drug resistance, pathogenicity, and secondary metabolism. In this study, we present the functional characterization of a Zn2Cys6 transcription factor F. pseudograminearum, designated Fp487. In F. pseudograminearum, Fp487 is shown to be required for mycelial growth through gene knockout and phenotypic analyses. Compared with wild-type CF14047, the ∆Fp487 mutant displayed a slight reduction in growth rate but a significant decrease in conidiogenesis, pathogenicity and 3-acetyl-deoxynivalenol (3AcDON) production. Moreover, the mutant exhibited heightened sensitivity to oxidative and cytomembrane stress. Furthermore, we synthesized dsRNA from the Fp487 gene in vitro, resulting in a reduction in the growth rate of F. pseudograminearum and its virulence on barley leaves through spray-induced gene silencing (SIGS). Notably, this study makes the first instance of inducing the expression of abundant dsRNA from F. pseudograminearum by engineering the Escherichia coli strain HT115 (DE3) and utilizing the SIGS technique to evaluate the virulence effect of dsRNA on F. pseudograminearum. In conclusion, our findings revealed the crucial role of Fp487 in regulating pathogenicity, stress responses, DON production, and conidiogenesis in F. pseudograminearum. Furthermore, Fp487 is a potential RNAi-based target for FCR control.

Efficacy and action mechanisms of compound Shen Chan decoction on experimental models of atopic dermatitis.

Shen chan decoction (SCD) as a significant Traditional Chinese medicine (TCM) to treat atopic dermatitis (AD), but its mechanism of action has not been clarified, so we started the present study, first possible effects of SCD on AD were predicted using network pharmacology. Next, dinitrochlorobenzene was used to establish a mouse model of AD. After successful modelling, the SCD were administered intragastrically to treat the mice. Eventually, the KEGG pathway enrichment analysis indicated that SCD improved AD mainly through effects on inflammation and the gut microbiota. The experimental findings revealed that SCD treatment attenuated AD symptoms and downregulate the characteristic immune factors, namely IL-4, IL-6 and IgE. Moreover, it promoted a balance between Th1/Th2 cells. Furthermore, the itch signaling pathways involving H1R/PAR-2/TRPV1 were inhibited. The 16S rRNA sequencing results indicated that SCD administration influenced the Firmicutes/Bacteroidetes ratio at the phylum level by augmenting the relative proportions of Lactobacillaceae and Muribaculaceae at the family and genus levels, while decreasing the abundances of Lactococcus and Ruminococcus. These findings suggest that internal administration of SCD is an effective therapeutic approach for AD. We suggest that SCD may be an alternative therapy for the treatment of AD.Additionally, it could offer valuable insights into the pathogenesis of AD and the development of innovative therapeutic agents.

Development of CO2-switchable deep eutectic solvent-based liquid-liquid microextraction approach: Application in urinary excretion and tissue distribution studies.

BACKGROUND: Pharmacokinetic studies are pivotal in drug development, focusing on absorption, distribution, and excretion of active compounds. Effective sample preparation methods play a crucial role in these studies. Traditional techniques like protein precipitation and liquid-liquid extraction often involve toxic solvents and are time-consuming. Recently, deep eutectic solvent (DES) has emerged as an eco-friendly alternative due to its high efficiency, low cost, and low toxicity. This study introduces a novel sample pretreatment method using CO2-switchable DES in liquid-liquid microextraction (LLME) to enhance speed, accuracy, and sensitivity in complex biological samples analysis. RESULTS: A liquid-liquid microextraction sample pretreatment method based on switchable DES combined with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was established for the analysis of urine and tissue samples. The method was optimized through systematic investigation of key parameters, including DES type, volume, molar ratio, pH, vortex time, gas purge time, and salt addition. The resulting procedure exhibited satisfying linearity (r2 ≥ 0.9958), good precision (RSD ≤6.01 %), desirable recovery (52.44%-98.12 %) and matrix effect (86.22%-119.30 %), and the accuracy and precision of stability were within the ±15 % limit. The proven methods were further applied to urinary excretion study and tissue distribution study of Nelumbinis plumula (NP) extract. The results indicated that the total cumulative excretion of liensinine, isoliensinine and neferine in urine within 240 h was 4.96 %, 0.66 % and 0.44 %, respectively. The tissue distribution study showed that alkaloids mainly distribute in liver, kidney, and spleen. SIGNIFICANCE: This research introduces a groundbreaking technique distinguished by its simplicity, speed, cost-effectiveness, and environmental friendliness. This approach, utilizing CO2-switchable DES as an extraction solvent for LLME, integrates deproteinization and removal of interfering molecules into a single step. This integration showcases its efficiency and convenience, demonstrating significant promise for various applications in the analysis of biological samples. Additionally, this study provides the first report on urinary excretion and tissue distribution of alkaloids from NP using a DES-LLME method. These findings offer valuable insights into the in vivo behavior of herbal medicine, enhancing understanding of pharmacological actions and facilitating clinical rational administration.

Protective effects of docosahexaenoic acid supplementation on cognitive dysfunction and hippocampal synaptic plasticity impairment induced by early postnatal PM2.5 exposure in young rats.

PM2.5 exposure is a challenging environmental issue that is closely related to cognitive development impairment; however, currently, relevant means for prevention and treatment remain lacking. Herein, we determined the preventive effect of docosahexaenoic acid (DHA) supplementation on the neurodevelopmental toxicity induced by PM2.5 exposure. Neonatal rats were divided randomly into three groups: control, PM2.5, and DHA + PM2.5 groups. DHA could ameliorate PM2.5-induced learning and memory dysfunction, as well as reverse the impairment of hippocampal synaptic plasticity, evidenced by enhanced long-term potentiation, recovered synaptic ultrastructure, and increased expression of synaptic proteins. Moreover, DHA increased CREB phosphorylation and BDNF levels and attenuated neuroinflammation and oxidative stress, reflected by lower levels of IBA-1, IL-1ß, and IL-6 and increased levels of SOD1 and Nrf2. In summary, our findings demonstrated that supplementation of DHA effectively mitigated the cognitive dysfunction and synaptic plasticity impairment induced by early postnatal exposure to PM2.5. These beneficial effects may be attributed to the upregulation of the CREB/BDNF signaling pathway, as well as the reduction of neuroinflammation and oxidative stress.

The Analysis of ceRNA Networks and Tumor Microenvironment in Endometrial Cancer.

Background: Endometrial carcinoma is a life-threatening and aggressive tumor that affects women worldwide. ceRNAs and carcinoma-infiltrating immunocytes can be associated with tumor formation and progression. Therefore, investigating the unique mechanisms underlying endometrial carcinoma is crucial. Methods: Prognostic nomograms were constructed based on the differentially expressed genes between normal and tumor tissues. Twenty types of tumor immune infiltrating cells in uterine corpus endometrial carcinoma (UCEC) were examined using CIBERSORT. To identify the potential signaling pathways, the associations among essential ceRNA network genes and important immunocytes were investigated using the co-expression assay. Results: Differential analysis identified 3636 mRNAs, 249 miRNAs, and 252 lncRNAs unique to UCEC. The ceRNA network was constructed using the interplays between 19 lncRNA-miRNA pairs and 434 miRNA-mRNA pairs. Furthermore, CIBERSORT and ceRNA integration analysis revealed that immune cells, including dendritic cells and natural killer cells, and associated ceRNAs such as LRP8, HDGF, PPARGC1B, and TEAD1 can appropriately predict prognosis. A receiver operating characteristic curve was constructed to predict patient outcomes. Conclusions: Using a nomogram, we predicted the outcomes of patients with UCEC Furthermore, we revealed its significance in improving clinical management.

FgGmtB Plays an Important Role in Growth, Reproduction, Virulence and Deoxynivalenol Biosynthesis of Fusarium graminearum.

GDP-mannose transporters (GMTs) have been implicated in the virulence of some important pathogenic fungi, and guanosine diphosphate (GDP) mannose transporters transport GDP-mannose from the cytosol to the Golgi lumen prior to mannosylation, where mannose attaches to the modified protein. GMTs could be potential targets for new antifungal drugs, as disruption of any step in GDP-mannose biosynthesis can affect fungal viability, growth, or virulence. To date, the GDP-mannose transporter has been extensively studied in yeast, but its biological function in fungi, particularly F. graminearum, is still unclear. In this experimental study, the role of the GDP-mannose transporter in F. graminearum was investigated by analysing the VRG4 gene. FgGmtA and FgGmtB were blastp-derived from their Scvrg4 protein sequences and proved to be their functional homologues. The mutant and complementary strains of FgGmtA, FgGmtB and FgGmtA&B genes were generated and used to evaluate the effect of the two GMTs genes on mycelial growth, asexual reproduction, sexual reproduction, cell wall sensitivity, glyphosate synthesis and drug susceptibility. Only in the FgGmtB and FgGmtA&B mutants was the rate of mycelial growth slowed, conidium production increased, sexual reproduction impaired, cell wall sensitivity increased, glycemic content decreased, and drug sensitivity reduced. The results of the pathogenicity assessment of GMTs showed that only FgGmtB affects the patogenicity of F. graminearum. At the same time, the effect of GMTs on the ability of rhinoceros to synthesise DON toxins was investigated and the results showed that the ability of ΔFgGmtB and ΔFgGmtA&B mutants to produce the DON toxin was significantly reduced, and the expression of toxin-related genes was also reduced.