Long-Term High-Fat Diet Impairs AQP4-Mediated Glymphatic Clearance of Amyloid Beta.

As a risk factor for Alzheimer's disease (AD), studies have demonstrated that long-term high-fat diet (HFD) could accelerate the deposition of amyloid beta (Aß) in the brain. The glymphatic system plays a critical role in Aß clearance from the brain. However, studies investigating the effects of long-term HFD on glymphatic function have reported paradoxical outcomes, and whether glymphatic dysfunction is involved in the disturbance of Aß clearance in long-term HFD-fed mice has not been determined. In the present study, we injected fluorescently labeled Aß into the hippocampus and found that Aß clearance was decreased in HFD-fed mice. We found that long-term HFD-fed mice had decreased glymphatic function by injecting fluorescent tracers into the cisterna magna and corpus striatum. In long-term HFD-fed mice, aquaporin-4 (AQP4) polarization in the cortex was disrupted, and glymphatic clearance activity was positively correlated with the AQP4 polarization index. In HFD-fed mice, the disturbance of Aß clearance from the hippocampus was exacerbated by TGN-020, a specific inhibitor of AQP4, whereas TGN-073, an enhancer of AQP4, ameliorated it. These findings suggest that long-term HFD disrupts Aß clearance by inhibiting AQP4-mediated glymphatic function. The underlying mechanism may involve the disruption of AQP4 polarization.

Predictive value of neutrophil-to-lymphocyte ratio in coronary chronic total occlusion patients.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) has been reported as a novel predictor for atherosclerosis and cardiovascular outcomes. This study aimed to determine the effects of NLR on long-term clinical outcomes of chronic total occlusion (CTO) patients. METHODS: A total of 670 patients with CTO who met the inclusion criteria were included at the end of the follow-up period. Patients were divided into tertiles according to their baseline NLR levels at admission: low (n = 223), intermediate (n = 223), and high (n = 224). The incidence of major adverse cardiac events (MACEs) during the follow-up period, including all-cause death, nonfatal myocardial infarction (MI), or ischemia-driven revascularization, were compared among the three groups. RESULTS: Major adverse cardiac events were observed in 27 patients (12.1%) in the low tertile, 40 (17.9%) in the intermediate tertile, and 61 (27.2%) in the high NLR tertile (P < 0.001). Kaplan-Meier analysis demonstrated a significantly higher incidence of MACE, ischemia-driven coronary revascularization, non-fatal MI, and mortality in patients within the high tertile than those in the low and intermediate groups (all P < 0.001). Multivariable COX regression analysis showed that the high tertile of baseline NLR level showed a strong association with the risk of MACE (hazard ratio [HR] = 2.21; 95% confidence interval [CI]: 1.21-4.03; P = 0.009), ischemia-driven coronary revascularization (HR = 3.19; 95% CI: 1.56-6.52; P = 0.001), MI (HR = 2.61; 95% CI: 1.35-5.03; P = 0.043) and mortality (HR = 3.78; 95% CI: 1.65-8.77; P = 0.001). CONCLUSION: Our findings suggest that NLR is an inexpensive and readily available biomarker that can independently predict cardiovascular risk in patients with CTO.

Impact of additional cytogenetic aberrations at diagnosis on prognosis of adults patients with Philadelphia chromosome positive acute lymphoblastic leukemia undergoing allogeneic hematopoietic cell transplantation: a retrospective analysis.

Additional chromosomal abnormalities(ACAs) at diagnosis are associated with inferior prognosis in chronic myeloid leukemia. However, the prognostic significance of ACAs in adult patients with Philadelphia Chromosome Positive acute lymphoblastic leukemia (Ph + ALL) receiving TKI-targeted drugs and allogeneic hematopoietic stem cell transplantation(HSCT) is unknown. One hundred thirty-six adult patients with Ph + ALL were included in the study and retrospectively analysed, evaluating the effect of ACAs on outcomes of transplantation. ACAs are observed in 60 cases (44%). ACAs detected in more than 5% of cases were defined as major-route and encompass: +der(22), +der(9), + 8, -7 and complex karyotype. The median follow-up was 26.4 months. In the subgroup analyses of major route ACAs, three-year cumulative incidence of relapse (CIR) and progression-free survival(PFS) are statistically significant in + 8[66.7% vs.23.7%, P = 0.024; 77.8% vs. 23.7%, P = 0.0087], -7[53.8% vs. 23.7%, P = 0.035%; 61.5% vs. 32.9%, P = 0.033], and complex karyotypes[42.9% vs. 23.7%, P = 0.027; 47.6% vs. 23.7%] compared with t(9;22) sole. Additionally, the 3-year CIR for Ph + ALL with + der(22) is 44% vs. 23.7% for t(9;22) sole(P = 0.045). The 3-year overall survival (OS) in the - 7 group is 46.5%, which is statistically significant compared with the other groups(P = 0.001). In multivariate analyses, three years CIR and PFS are statistically significant in + der(22), + 8, -7 and complex karyotype compared with t(9;22) sole(P < 0.05). More importantly, Ph + ALL with - 7 was negatively associated with the rate of 3-year OS(P = 0.012). Thus, ACAs at diagnosis appear to have a significant prognostic impact on transplantation outcomes in patients with Ph + ALL.

Enhancement of cadmium uptake in Sedum alfredii through interactions between salicylic acid/jasmonic acid and rhizosphere microbial communities.

The focus on phytoremediation in soil cadmium (Cd) remediation is driven by its cost-effectiveness and eco-friendliness. Selecting suitable hyperaccumulators and optimizing their growth conditions are key to enhance the efficiency of heavy metal absorption and accumulation. Our research has concentrated on the role of salicylic acid (SA) and jasmonic acid (JA) in facilitating Cd phytoextraction by "Sedum alfredii (S. alfredii)" through improved soil-microbe interactions. Results showed that SA or JA significantly boosted the growth, stress resistance, and Cd extraction efficiency in S. alfredii. Moreover, these phytohormones enhanced the chemical and biochemical attributes of the rhizosphere soil, such as pH and enzyme activity, affecting soil-root interactions. High-throughput sequencing analysis has shown that Patescibacteria and Umbelopsis enhanced S. alfredii's growth and Cd extraction by modifying the bioavailability and the chemical conditions of Cd in soil. Structural Equation Model analysis further verified that phytohormones significantly enhanced the interaction between S. alfredii, soil, and microbes, leading to a marked increase in Cd accumulation in the plant. These discoveries emphasized the pivotal role of phytohormones in modulating the hyperaccumulators' response to environmental stress and offered significant scientific support for further enhancing the potential of hyperaccumulators in ecological restoration technologies using phytohormones.

Molecular epizootiology of porcine reproductive and respiratory syndrome virus in the Xinjiang Uygur Autonomous Region of China.

Rapid evolution of porcine reproductive and respiratory syndrome virus (PRRSV) is the bottleneck for effective prevention and control of PRRS. Thus, understanding the prevalence and genetic background of PRRSV strains in swine-producing regions is important for disease prevention and control. However, there is only limited information about the epizootiological situation of PRRS in the Xinjiang Uygur Autonomous Region, China. In this study, blood or lung tissue samples were collected from 1,411 PRRS-suspected weaned pigs from 9 pig farms in Changji, Shihezi, and Wujiaqu cities between 2020 and 2022. The samples were first tested by RT-quantitative PCR, yielding a PRRSV-2 positive rate of 53.6%. Subsequently, 36 PRRSV strains were isolated through initial adaptation in bone marrow-derived macrophages followed by propagation in grivet monkey Marc-145 cells. Furthermore, 28 PRRSV-positive samples and 20 cell-adapted viruses were selected for high-throughput sequencing (HTS) to obtain the entire PRRSV genome sequences. Phylogenetic analysis based on the nucleotide sequences of the ORF5 gene of the PRRSV strains identified in this study grouped into sub-lineages 1.8 and 8.7 the former being the dominant strain currently circulating in Xinjiang. However, the NSP2 proteins of the Xinjiang PRRSV strains shared the same deletion patterns as sub-lineage 1.8 prototype strain NADC30 with the exception of 4 strains carrying 2-3 additional amino acid deletions. Further analysis confirmed that recombination events had occurred in 27 of 37 PRRSVs obtained here with the parental strains belonging to sub-lineages 1.8 and 8.7, lineages 3 and 5, with the recombination events having occurred most frequently in the 5' and 3' termini of ORF1a and 5' terminus of ORF1b.

Integrating Clinical Data and Radiomics and Deep Learning Features for End-to-End Delayed Cerebral Ischemia Prediction on Noncontrast CT.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia is hard to diagnose early due to gradual, symptomless development. This study aimed to develop an automated model for predicting delayed cerebral ischemia following aneurysmal SAH on NCCT. MATERIALS AND METHODS: This retrospective study included 400 patients with aneurysmal SAH (156 with delayed cerebral ischemia) who underwent NCCT. The study used ATT-Deeplabv3+ for automatically segmenting hemorrhagic regions using semisupervised learning. Principal component analysis was used for reducing the dimensionality of deep learning features extracted from the average pooling layer of ATT-DeepLabv3+. The classification model integrated clinical data, radiomics, and deep learning features to predict delayed cerebral ischemia. Feature selection involved Pearson correlation coefficients, least absolute shrinkage, and selection operator regression. We developed models based on clinical features, clinical-radiomics, and a combination of clinical, radiomics, and deep learning. The study selected logistic regression, Naive Bayes, Adaptive Boosting (AdaBoost), and multilayer perceptron as classifiers. The performance of segmentation and classification models was evaluated on their testing sets using the Dice similarity coefficient for segmentation, and the area under the receiver operating characteristic curve (AUC) and calibration curves for classification. RESULTS: The segmentation process achieved a Dice similarity coefficient of 0.91 and the average time of 0.037 s/image. Seventeen features were selected to calculate the radiomics score. The clinical-radiomics-deep learning model with multilayer perceptron achieved the highest AUC of 0.84 (95% CI, 0.72-0.97), which outperformed the clinical-radiomics model (P = .002) and the clinical features model (P = .001) with multilayer perceptron. The performance of clinical-radiomics-deep learning model using AdaBoost was significantly superior to its clinical-radiomics model (P = .027). The performance of the clinical-radiomics-deep learning model and the clinical-radiomics model with logistic regression notably exceeded that of the model based solely on clinical features (P = .028; P = .046). The AUC of the clinical-radiomics-deep learning model with multilayer perceptron (P < .001) and the clinical-radiomics model with logistic regression (P = .046) were significantly higher than the clinical model with logistic regression. Of all models, the clinical-radiomics-deep learning model with multilayer perceptron showed best calibration. CONCLUSIONS: The proposed 2-stage end-to-end model not only achieves rapid and accurate segmentation but also demonstrates superior diagnostic performance with high AUC values and good calibration in the clinical-radiomics-deep learning model, suggesting its potential to enhance delayed cerebral ischemia detection and treatment strategies.

Risk factors of falls in rural elderly of Ningxia in China: a prospective cohort study.

OBJECTIVES: To identify risk factors associated with falls in older people in rural China. METHODS: A prospective cohort study was conducted across 27 villages in the rural areas of Ningxia, China. After excluding individuals younger than 60 years, a total of 758 out of the initial 822 participants were ultimately included for the collection of baseline information. Participants were followed up through telephone calls or face-to-face interviews at 3rd, 6th and 12th months following the baseline investigation. The Cox proportional hazards regression model was used to examine risk factors of falls. RESULTS: A total of 758 participants underwent baseline information surveys, and all samples were included in the Cox model analysis. The study found that being woman (RR=1.879, 95% CI: 1.313 to 2.668), smoking (RR=1.972, 95% CI: 1.238 to 3.143), use of painkillers (RR=1.700, 95% CI: 1.226 to 2.356) and higher systolic blood pressure (SBP) (RR=1.081, 95% CI: 1.013 to 1.154) were associated with higher risk of falls among the elderly in rural China. After excluding those who were lost to follow-up or deceased, 738 participants completed the follow-up. There were 341 men (46.2%) and 397 women (53.8%), with an average age of 66.8±5.0 years. The fall rate in study area was 23.8% during the follow-up period. CONCLUSIONS: The fall rate among the elderly in rural China was higher than other areas. Our findings revealed that being woman, smoking, medication usage, elevated SBP and people with a higher body mass index were risk factors for developing falls.

Short leukocyte telomere length and high plasma phospholipid fatty acids increase the risk of type 2 diabetes.

In the last forty years, there has been a notable rise in the occurrence of diabetes within China, leading to the country now having the highest number of individuals affected by this condition globally. This prospective observational study examined the effect of different baseline relative leukocyte telomere length (RTL) and the combined effect of baseline RTL and plasma phospholipid fatty acid (PPFA) on the risk of developing diabetes. Adults from Ningxia Province who underwent baseline and follow-up surveys were included in the study. The correlation between the baseline RTL and PPFA was investigated using a multiple linear regression model. The combined effect of baseline RTL and PPFA levels on the risk of developing type 2 diabetes mellitus (T2DM) were investigated using a cox regression model with time as the covariate. A total of 1461 study subjects were included in this study. 141 subjects developed T2DM during the follow-up period. The baseline age was negatively correlated with RTL.Multiple linear regression analysis showed that C16:0 and MUFA concentrations influenced RTL. Subjects with shorter RTL at baseline had a higher risk of developing diabetes than those with longer RTL. Subjects with shorter RTL and higher C16:0 and MUFA concentrations at baseline had a higher risk of developing T2DM than those with longer RTL and lower C16:0 and MUFA concentrations. Our findings indicated that PPFA affects changes in RTL. In addition, RTL and PPFA are associated with the occurrence of T2DM.

Epigenetic mechanism of RBM15 in affecting cisplatin resistance in laryngeal carcinoma cells by regulating ferroptosis.

Laryngeal carcinoma (LC) is a common cancer of the respiratory tract. This study aims to investigate the role of RNA-binding motif protein 15 (RBM15) in the cisplatin (DDP) resistance of LC cells. LC-DDP-resistant cells were constructed. RBM15, lysine-specific demethylase 5B (KDM5B), lncRNA Fer-1 like family member 4 (FER1L4), lncRNA KCNQ1 overlapping transcript 1 (KCNQ1OT1), glutathione peroxidase 4 (GPX4), and Acyl-CoA synthetase long-chain family (ACSL4) was examined. Cell viability, IC50, and proliferation were assessed after RBM15 downregulation. The enrichment of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and N6-methyladenosine (m6A) on KDM5B was analyzed. KDM5B mRNA stability was measured after actinomycin D treatment. A tumor xenograft assay was conducted to verify the role of RBM15 in LC. Results showed that RBM15 was upregulated in LC and its knockdown decreased IC50, cell viability, proliferation, glutathione, and upregulated iron ion content, ROS, malondialdehyde, ACSL4, and ferroptosis. Mechanistically, RBM15 improved KDM5B stability in an IGF2BP3-dependent manner, resulting in FER1L4 downregulation and GPX4 upregulation. KDM5B increased KCNQ1OT1 and inhibited ACSL4. KDM5B/KCNQ1OT1 overexpression or FER1L4 knockdown promoted DDP resistance in LC by inhibiting ferroptosis. In conclusion, RBM15 promoted KDM5B expression, and KDM5B upregulation inhibited ferroptosis and promoted DDP resistance in LC by downregulating FER1L4 and upregulating GPX4, as well as by upregulating KCNQ1OT1 and inhibiting ACSL4. Silencing RBM15 inhibited tumor growth in vivo.

Key miRNAs of chicken seminal plasma extracellular vesicles related with sperm motility regulation.

MicroRNAs (miRNAs) are bio-active elements cargoed by seminal plasma extracellular vesicles extracellular vesicles (SPEVs) which are crucial for sperm function and fertility modulation. This study aimed to isolate, characterize, and identify the miRNA expression profiles in the SPEVs from high (HSM) and low sperm motility (LSM) groups that could serve as fertility biomarkers and explain the underlying mechanisms. The isolated SPEVs were round spherical structures of approximately 50-200 nm in diameter expressing molecular markers. A total of 1006 and 1084 miRNAs were detected in HSM and LSM, respectively, with 34 being differentially expressed. Their targeted genes involved in SNARE interactions in vesicular transport, Metabolic pathways, and Apelin signaling pathway, etc. The joint analysis with mRNAs of sperm and sperm storage tubules cells highlighted the cellular communication mediated by SPEVs miRNAs, where they may rule fertility by affecting sperm maturation and amino acid metabolism. SPEVs as additives could improve fertility of fresh and frozen sperm, while the knockdown of one of the differentially expressed miRNAs, miR-24-3p, diminished this effect, indicating its crucial roles. This study expands our understanding of SPEVs miRNAs mediated sperm maturation and fertility modulation, and may help to develop new therapeutic strategies for infertility and sperm storage.

High-resolution diffusion magnetic resonance imaging and spatial-transcriptomic in developing mouse brain.

Brain development is a highly complex process regulated by numerous genes at the molecular and cellular levels. Brain tissue exhibits serial microstructural changes during the development process. High-resolution diffusion magnetic resonance imaging (dMRI) affords a unique opportunity to probe these changes in the developing brain non-destructively. In this study, we acquired multi-shell dMRI datasets at 32 µm isotropic resolution to investigate the tissue microstructure alterations, which we believe to be the highest spatial resolution dMRI datasets obtained for postnatal mouse brains. We adapted the Allen Developing Mouse Brain Atlas (ADMBA) to integrate quantitative MRI metrics and spatial transcriptomics. Diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and neurite orientation dispersion and density imaging (NODDI) metrics were used to quantify brain development at different postnatal days. We demonstrated that the differential evolutions of fiber orientation distributions contribute to the distinct development patterns in white matter (WM) and gray matter (GM). Furthermore, the genes enriched in the nervous system that regulate brain structure and function were expressed in spatial correlation with age-matched dMRI. This study is the first one providing high-resolution dMRI, including DTI, DKI, and NODDI models, to trace mouse brain microstructural changes in WM and GM during postnatal development. This study also highlighted the genotype-phenotype correlation of spatial transcriptomics and dMRI, which may improve our understanding of brain microstructure changes at the molecular level.

[Effect and mechanism of EtOAc extract of Draconis Sanguis onimproving atherosclerosis in ApoE~(-/-) mice].

This study aims to investigate the effect and mechanism of the EtO Ac extract of Draconis Sanguis(DSE) on improving athero sclerosis in ApoE gene knockout(ApoE~(-/-)) mice. The ApoE~(-/-) mice were randomly divided into five groups: control group, mo delgroup, positive group treated with ezetimibe of 5 mg·kg~(-1)(EG), and low(100 mg·kg~(-1)) and high dose(200 mg·kg~(-1)) groups ofDSE. xcept for the control group, all other groups were fed a high-fat diet and administered drugs for 16 successive weeks. After 16 weeks of Eadministration, the body weight, liver, and epididymal fat mass of the mice were measured; the level of blood lipid and the plaquearea of the aortic outflow tract were detected to evaluate the efficacy of DSE in vivo. In addition, in vitro cultures of human umbilical v ein endothelial cell(HUVEC) were conducted. Oxidative stress of endothelial cells was induced by oxidized low-density lipoprot ein(ox-LDL), and the effects of DSE on oxidative stress-related proteins in endothelial cells were examined. The results sho wedthat both doses of DSE significantly improved the epididymal fat mass and index of ApoE~(-/-) mice with atherosclerosis, lowered thelevels of plasma cholesterol, triglyceride, and non-high density lipoprotein cholesterol, and reduced the plaque area of the aortic ou tflow tract. totIn alvitro experiments confirmed that ox-LDL significantly increased the level of lipid peroxidation marker 4-HNE in HUVECcells, confirming that DSE improved the degree of atherosclerotic lesions in ApoE~(-/-) mice by inhibiting ox-LDL-induced oxidative stress in vascular endothelial cells.

TP53 and KMT2D mutations associated with worse prognosis in peripheral T-cell lymphomas.

There are limited studies on mutation profiling for Peripheral T-cell lymphomas (PTCL) in the Chinese population. We retrospectively analyzed the clinical and genetic landscape of 66 newly diagnosed Chinese patients. Targeted next-generation sequencing (NGS) was performed for tissues from these patients. At least one mutation was detected in 60 (90.9%) patients, with a median number of 3 (0-7) mutations, and 32 (48.5%) cases detected with more than 4 mutations. The genes with higher mutation frequencies were TET2, RHOA, DNMT3A, IDH2, TP53, STAT3, and KMT2D respectively. When mutant genes are classified by functional group, the most prevalent mutations are related to epigenetics and signal transduction. IPI ≥2, PIT ≥2, and failure to achieve partial remission (PR) were factors for inferior progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed TP53 was an adverse factor for PFS (HR, 3.523; 95% CI, 1.262-9.835; p = 0.016), and KMT2D was an adverse factor for OS (HR, 10.097; 95% CI, 1.000-101.953; p = 0.048). Mutation profiling could help differentiate distinct types of PTCL and serve as a useful tool for determining treatment options and prognoses.

Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors.

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.

Personalized drug screening using patient-derived organoid and its clinical relevance in gastric cancer.

The efficacy of chemotherapy varies significantly among patients with gastric cancer (GC), and there is currently no effective strategy to predict chemotherapeutic outcomes. In this study, we successfully establish 57 GC patient-derived organoids (PDOs) from 73 patients with GC (78%). These organoids retain histological characteristics of their corresponding primary GC tissues. GC PDOs show varied responses to different chemotherapeutics. Through RNA sequencing, the upregulation of tumor suppression genes/pathways is identified in 5-fluorouracil (FU)- or oxaliplatin-sensitive organoids, whereas genes/pathways associated with proliferation and invasion are enriched in chemotherapy-resistant organoids. Gene expression biomarker panels, which could distinguish sensitive and resistant patients to 5-FU and oxaliplatin (area under the dose-response curve [AUC] >0.8), are identified. Moreover, the drug-response results in PDOs are validated in patient-derived organoids-based xenograft (PDOX) mice and are consistent with the actual clinical response in 91.7% (11/12) of patients with GC. Assessing chemosensitivity in PDOs can be utilized as a valuable tool for screening chemotherapeutic drugs in patients with GC.

Dissecting the antitumor effects of Scutellaria barbata: Initial insights into the metabolism of scutellarin and luteolin by gut microbiota.

The high prevalence of cancer and detrimental side effects associated with many cancer treatments necessitate the search for effective alternative therapies. Natural products are increasingly being recognized and investigated for their potential therapeutic benefits. Scutellaria barbata D. Don (SBD), a plant with potent antitumor properties, has attracted significant interest from oncology researchers. Its primary flavonoid components-scutellarin and luteolin-which have limited oral bioavailability due to poor absorption. This hinders its application for cancer treatment. The gut microbiota, which is considered a metabolic organ, can modulate the biotransformation of compounds, thereby altering their bioavailability and efficacy. In this study, we employed liquid chromatography tandem mass spectrometry (LC-MS/MS 8060) and ion trap-time of flight (LC-MSn-IT-TOF) analysis to investigate the ex vivo metabolism of scutellarin and luteolin by the gut microbiota. Five metabolites and one potential metabolite were identified. We summarized previous studies on their antitumor effects and performed in vitro tumor cell line studies to prove their antitumor activities. The possible key pathway of gut microbiota metabolism in vitro was validated using molecular docking and pure enzyme metabolic experiments. In addition, we explored the antitumor mechanisms of the two components of SBD through network pharmacology, providing a basis for subsequent target identification. These findings expand our understanding of the antitumor mechanisms of SBD. Notably, this study contributes to the existing body of knowledge regarding flavonoid biotransformation by the gut microbiota, highlighting the therapeutic potential of SBD in cancer treatment. Moreover, our results provide a theoretical basis for future in vivo pharmacokinetic studies, aiming to optimize the clinical efficacy of SBD in oncological applications.

Regulation of winter wheat-originated antifreeze glycoprotein on rooster spermatozoa freezability.

The freezability of chicken spermatozoa is low, therefore, effective cryoprotectants is desiderated. Antifreeze proteins (AFPs) are widely found in cold-tolerant species and help them to survive in freezing environments. This study was the first to evaluate the effects of different concentrations of plant-originated antifreeze glycoprotein (AFGP) (0, 0.1, 1, and 5 µg/mL) on post-thawed sperm motion characteristics, morphology, mitochondrial function, antioxidant activity, and fertilizing potential in chickens. Results showed that the total motility of 0.1 to 1 µg/mL AFGP groups were significantly higher than those of the 5 µg/mL AFGP group (P < 0.05). The post-thawed sperm viability of 0.1 µg/mL AFGP group was significantly higher than any of test groups (P < 0.05). Higher abnormal morphology rate of post-thawed sperm was observed in the control group (0 µg/mL AFGP) than in the 0.1, 1, and 5 µg/mL AFGP groups (P < 0.05). The concentrations of malondialdehyde (MDA) decreased gradually with the increase of AFGP concentration. ATP was significantly higher in the 0.1 and 1 µg/mL AFGP groups than those of control and any of test groups (P < 0.05). The 0.1 to 1 µg/mL AFGP groups had increased mitochondrial membrane potential (MMP) level (P > 0.05). The 0.1 µg/mL AFGP group had the highest average fertility (61.36%) compared with control group (57.02%) and any of test groups of chickens at 31 wk of age, and the 1 µg/mL AFGP group had the highest average fertility (37.72%) compared with control group (21.73%) and any of test groups of chickens at 65 wk of age. In conclusion, the results from this study suggest lower concentration of AFGP (0.1-1 µg/mL) showed positive effect for sperm function. This study inspires the continuous evaluation and seeking right way of adopting different kinds of AFPs in rooster semen cryopreservation.

The biochemical characterization of a TatD nuclease from Thermus thermophilus.

Nucleases play pivotal roles in DNA repair and apoptosis. Moreover, they have various applications in biotechnology and industry. Among nucleases, TatD has been characterized as an exonuclease with various biological functions in different organisms. Here, we biochemically characterized the potential TatD nuclease from Thermus thermophilus. The tatD gene from T. thermophilus was cloned, then the recombinant TatD nuclease was expressed and purified. Our results revealed that the TthTatD nuclease could degrade both single-stranded and double-stranded DNA, and its activity is dependent on the divalent metal ions Mg2+ and Mn2+. Remarkably, the activity of TthTatD nuclease is highest at 37 °C and decreases with increasing temperature. TthTatD is not a thermostable enzyme, even though it is from a thermophilic bacterium. Based on the sequence similarity and molecular docking of the DNA substrate into the modeled TthTatD structure, several key conserved residues were identified and their roles were confirmed by analyzing the enzymatic activities of the site-directed mutants. The residues E86 and H149 play key roles in binding metal ions, residues R124/K126 and K211/R212 had a critical role in binding DNA substrate. Our results confirm the enzymatic properties of TthTatD and provide a primary basis for its possible application in biotechnology.

PDCD2 as a prognostic biomarker in glioma correlates with malignant phenotype.

Programmed cell death 2 (PDCD2) is related to cancer progression and chemotherapy sensitivity. The role of PDCD2 in solid cancers (excluding hematopoietic malignancies) and their diagnosis and prognosis remains unclear. The TCGA, CGGA, GEPIA, cBioPortal, and GTEx databases were analyzed for expression, prognostic value, and genetic modifications of PDCD2 in cancer patients. Functional enrichment analysis, CCK8, colony formation assay, transwell assay, and xenograft tumor model were undertaken to study the PDCD2's biological function in glioma (GBMLGG). The PDCD2 gene was associated with solid cancer progression. In the functional enrichment analysis results, PDCD2 was shown to participate in several important GBMLGG biological processes. GBMLGG cells may be inhibited in their proliferation, migration, invasion, and xenograft tumor growth by knocking down PDCD2. Our research can provide new insights into solid cancer prognostic biomarkers of PDCD2.

Sophora subprostrate polysaccharide targets LncRNA MSTRG.5823.1 to suppress PCV2-mediated immunosuppression via TNF/NF-κB signaling.

Current evidence suggests that porcine circovirus type 2 (PCV2) infection induces immunosuppression in piglets. Sophora subprostrate polysaccharide (SSP) exhibits various pharmacological activities, including immunoregulatory, anti-inflammatory, antiviral, and antioxidant properties. However, the acts of lncRNAs in regulating the therapeutic effects of SSP on PCV2-infected RAW264.7 cells remains poorly understood. This study aimed to investigate the molecular mechanisms by which lncRNAs regulate PCV2-induced immunosuppression during SSP treatment. Our findings revealed that 1699 mRNAs, 373 lncRNAs, and 129 miRNAs were differentially expressed in PCV2-infected RAW264.7 cells. Additionally, 359 mRNAs, 271 lncRNAs, and 79 miRNAs exhibited differential expression in SSP-treated PCV2-infected RAW264.7 cells. GO and KEGG analyses indicated that the candidate genes were enriched in the TNF/NF-κB signaling pathway. Furthermore, based on GO and KEGG pathway analysis, a ceRNA network involving chemokine (C-X-C motif) ligand 2 (CXCL2), miR-217-x, and MSTRG.5823.1 was constructed. We demonstrated that lncRNA MSTRG.5823.1 localized to the cytoplasm. Moreover, we found that silencing or overexpressing lncRNA MSTRG.5823.1 significantly modulated PCV2-induced immunosuppression by regulating the activation of the TNF/NF-κB signaling pathway. Specifically, lncRNA MSTRG.5823.1 overexpression increased the expression of TNF/NF-κB signaling pathway-related genes and proteins in PCV2-infected RAW264.7 cells. Conversely, silencing lncRNA MSTRG.5823.1 decreased their expression. Rescue assays further revealed that the suppressive effects of miR-217-x overexpression on TNF/NF-κB signaling pathway-related genes and proteins could be reversed by MSTRG.5823.1 overexpression. These findings highlight the critical role of lncRNA MSTRG.5823.1 in PCV2 infection progression and suggest a new strategy for the prevention and treatment of PCV2 infection.