Repetitive traumatic brain injury-induced complement C1-related inflammation impairs long-term hippocampal neurogenesis.

JOURNAL/nrgr/04.03/01300535-202503000-00027/figure1/v/2024-06-17T092413Z/r/image-tiff Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus, leading to long-term cognitive impairment. However, the mechanism underlying this neurogenesis impairment remains unknown. In this study, we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury. Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development, delayed neuronal maturation, and reduced the complexity of neuronal dendrites and spines. Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval. Moreover, following repetitive traumatic brain injury, neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased, C1q binding protein levels were decreased, and canonical Wnt/ß-catenin signaling was downregulated. An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function. These findings suggest that repetitive traumatic brain injury-induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.

Uncovering the mechanism of Clostridium butyricum CBX 2021 to improve pig health based on in vivo and in vitro studies.

Introduction: As a symbiotic probiotic for the host, Clostridium butyricum (CB) has the potential to strengthen the body's immune system and improve intestinal health. However, the probiotic mechanism of CB is not completely understood. The Clostridium butyricum CBX 2021 strain isolated by our team from a health pig independently exhibits strong butyric acid production ability and stress resistance. Therefore, this study comprehensively investigated the efficacy of CBX 2021 in pigs and its mechanism of improving pig health. Methods: In this study, we systematically revealed the probiotic effect and potential mechanism of the strain by using various methods such as microbiome, metabolites and transcriptome through animal experiments in vivo and cell experiments in vitro. Results: Our in vivo study showed that CBX 2021 improved growth indicators such as daily weight gain in weaned piglets and also reduced diarrhea rates. Meanwhile, CBX 2021 significantly increased immunoglobulin levels in piglets, reduced contents of inflammatory factors and improved the intestinal barrier. Subsequently, 16S rRNA sequencing showed that CBX 2021 treatment implanted more butyric acid-producing bacteria (such as Faecalibacterium) in piglets and reduced the number of potentially pathogenic bacteria (like Rikenellaceae RC9_gut_group). With significant changes in the microbial community, CBX 2021 improved tryptophan metabolism and several alkaloids synthesis in piglets. Further in vitro experiments showed that CBX 2021 adhesion directly promoted the proliferation of a porcine intestinal epithelial cell line (IPEC-J2). Moreover, transcriptome analysis revealed that bacterial adhesion increased the expression of intracellular G protein-coupled receptors, inhibited the Notch signaling pathway, and led to a decrease in intracellular pro-inflammatory molecules. Discussion: These results suggest that CBX 2021 may accelerate piglet growth by optimizing the intestinal microbiota, improving metabolic function and enhancing intestinal health.

Catalytic Fast Pyrolysis of Tar-Rich Coal with a Bauxite Residue for Upgrading High-Value Products: Product Distribution and Kinetic Analysis.

Fast pyrolysis technology can reduce the secondary reactions, improve the volatile product yield, and reduce the semicoke yield. Still, the high proportion of heavy tar components affects the development of fast pyrolysis industrialization. Therefore, this paper put forward a catalytic upgrading method of coal based on the solid waste bauxite residue (BR) as a catalyst. This study investigated the impact of varying particle sizes of pulverized coal and the addition of the BR catalyst on the product distribution and kinetics of coal fast pyrolysis. The results found that the tar yield was the highest at 600 °C when the particle size of pulverized coal was 75-150 µm, which was 19.44%. In the range of 550-650 °C, the relative content of benzene and toluene xylene (BTX) in liquid products increased with the temperature. With the increase of the proportion of the BR catalyst, the yield of semicoke in coal pyrolysis products increased, the yield of the gas phase also increased, and the yield of the liquid phase decreased.

Research progress on Alpinia oxyphylla in the treatment of diabetic nephropathy.

Diabetic nephropathy (DN) constitutes a major microvascular complication of diabetes and is a primary cause of mortality in diabetic individuals. With the global rise in diabetes, DN has become an urgent health issue. Currently, there is no definitive cure for DN. Alpinia oxyphylla, a Chinese herbal medicine traditionally used, exhibits a wide range of pharmacological effects and is frequently used in the prevention and management of DN. This paper offers an extensive review of the biological mechanisms by which A. oxyphylla delivers therapeutic advantages in DN management. These mechanisms include activating podocyte autophagy, regulating non-coding RNA, modulating gut microbiota, alleviating lipotoxicity, counteracting oxidative stress, and diminishing inflammatory responses, underscoring the therapeutic potential of A. oxyphylla in DN treatment.

SMARCA4 mutation induces tumor cell-intrinsic defects in enhancer landscape and resistance to immunotherapy.

Cancer genomic studies have identified frequent alterations in components of the SWI/SNF (SWItch/Sucrose Non- Fermenting) chromatin remodeling complex including SMARCA4 and ARID1A . Importantly, clinical reports indicate that SMARCA4 -mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. However, the mechanistic basis of immunotherapy resistance is unknown. Here, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, we show that SMARCA4 loss caused decreased response to anti-PD1 immunotherapy associated with significantly reduced infiltration of dendritic cells (DCs) and CD4+ T cells into the tumor microenvironment (TME). Mechanistically, we show that SMARCA4 loss in tumor cells led to profound downregulation of STING, IL1ß and other components of the innate immune system as well as inflammatory cytokines that are required for efficient recruitment and activity of immune cells. We establish that this deregulation of gene expression is caused by cancer cell-intrinsic reprogramming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in innate immune response such as STING, IL1ß, type I IFN and inflammatory cytokines. Interestingly, we observed that transcription factor NF-κB binding motif was highly enriched in enhancers that lose accessibility upon SMARCA4 deficiency. Finally, we confirmed that SMARCA4 and NF-κB co-occupy the same genomic loci on enhancers associated with STING and IL1ß, indicating a functional interplay between SMARCA4 and NF-κB. Taken together, our findings provide the mechanistic basis for the poor response of SMARCA4 -mutant tumors to anti-PD1 immunotherapy and establish a functional link between SMARCA4 and NF-κB on innate immune and inflammatory gene expression regulation.

Novel mRNA adjuvant ImmunER enhances prostate cancer tumor-associated antigen mRNA therapy via augmenting T cell activity.

Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8+T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.

Identifying early language predictors: A replication of Gasparini et al. (2023) confirming applicability in a general population cohort.

BACKGROUND: Identifying language disorders earlier can help children receive the support needed to improve developmental outcomes and quality of life. Despite the prevalence and impacts of persistent language disorder, there are surprisingly no robust predictor tools available. This makes it difficult for researchers to recruit young children into early intervention trials, which in turn impedes advances in providing effective early interventions to children who need it. AIMS: To validate externally a predictor set of six variables previously identified to be predictive of language at 11 years of age, using data from the Longitudinal Study of Australian Children (LSAC) birth cohort. Also, to examine whether additional LSAC variables arose as predictive of language outcome. METHODS & PROCEDURES: A total of 5107 children were recruited to LSAC with developmental measures collected from 0 to 3 years. At 11-12 years, children completed the Clinical Evaluation of Language Fundamentals, 4th Edition, Recalling Sentences subtest. We used SuperLearner to estimate the accuracy of six previously identified parent-reported variables from ages 2-3 years in predicting low language (sentence recall score ≥ 1.5 SD below the mean) at 11-12 years. Random forests were used to identify any additional variables predictive of language outcome. OUTCOMES & RESULTS: Complete data were available for 523 participants (52.20% girls), 27 (5.16%) of whom had a low language score. The six predictors yielded fair accuracy: 78% sensitivity (95% confidence interval (CI) = [58, 91]) and 71% specificity (95% CI = [67, 75]). These predictors relate to sentence complexity, vocabulary and behaviour. The random forests analysis identified similar predictors. CONCLUSIONS & IMPLICATIONS: We identified an ultra-short set of variables that predicts 11-12-year language outcome with 'fair' accuracy. In one of few replication studies of this scale in the field, these methods have now been conducted across two population-based cohorts, with consistent results. An imminent practical implication of these findings is using these predictors to aid recruitment into early language intervention studies. Future research can continue to refine the accuracy of early predictors to work towards earlier identification in a clinical context. WHAT THIS PAPER ADDS: What is already known on the subject There are no robust predictor sets of child language disorder despite its prevalence and far-reaching impacts. A previous study identified six variables collected at age 2-3 years that predicted 11-12-year language with 75% sensitivity and 81% specificity, which warranted replication in a separate cohort. What this study adds to the existing knowledge We used machine learning methods to identify a set of six questions asked at age 2-3 years with ≥ 71% sensitivity and specificity for predicting low language outcome at 11-12 years, now showing consistent results across two large-scale population-based cohort studies. What are the potential or clinical implications of this work? This predictor set is more accurate than existing feasible methods and can be translated into a low-resource and time-efficient recruitment tool for early language intervention studies, leading to improved clinical service provision for young children likely to have persisting language difficulties.

Polyketides from the mangrove-derived fungus Penicillium robsamsonii HNNU0006.

Seven polyketides, including an undescribed depsidone (1) and six previously reported 3,6,8-trihydroxy-1-methylxanthone (2), 7-hydroxy-2-(2-hydroxypropyl)-5-methylchromone (3), methyl3-chloro-6-hydroxy-2-(4-hy-droxy-2-methoxy-6-methylphenoxy)-4- methoxybenzoate (4), xylarianin A (5), 4,5-dihydroxy-6-(6'-methylsalicyloxy)-2-hydro-xymethyl-2-cyclohexen-1-one (6) and alternariol (7), have been isolated from cultures of the mangrove-derived fungus Penicillium robsamsonii HNNU0006. The structure of compound 1 was elucidated by extensive spectroscopic analysis and X-ray crystallography. Furthermore, all the compounds were evaluated their cytotoxic activities, and compounds 1 and 7 showed weak cytotoxicity against two cell lines Vero and A549 with IC50 values ranging from 95.6 and 296.5 µM, relative to the positive control Etoposide phosphate with IC50 values of 24.5 and 18.7 µM, respectively.

Analysis of Adverse Events Post-13-Valent Pneumococcal Vaccination among Children in Hangzhou, China.

With the widespread use of the 13-valent pneumonia vaccine (PCV13) in China, monitoring adverse events following immunization (AEFIs) is critical. We conducted a descriptive analysis of the AEFI occurrences reported within Hangzhou between the years 2020 and 2023, including the temporal trend of case reports and variables such as sex, age, type of PCV13, dose number, type of reporter, cause-specific classification, severity, and onset from vaccination. Vaccine safety signals were analyzed using reporting odds ratios (RORs). Over the 4 years analyzed in the study, 2564 AEFI cases were reported, including seven severe cases. Most AEFIs occurred within 0-1 days after vaccination (2398, 93.53%), with over half affecting infants aged 1.5-6 months of age. No statistically significant difference was observed between PCV13-TT and PCV-CRM197. Seasonal differences in AEFI reports were noted. Positive signals were detected for fever (ROR-1.96SE: 1.64) and persistent crying (ROR-1.96SE: 1.61). Four serious AEFI cases were coincidental events, while three others were considered vaccine-related cases (including one case each of allergic reaction, febrile seizure, and thrombocytopenia). The safety and tolerability of PCV13 are good, and attention should be paid to severe AEFIs, as well as long-term safety disparities between different types of PCV13.

Genetic-informed proteome-wide scan reveals potential causal plasma proteins for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease for which there are no reliable biomarkers or disease-modifying drugs. Here, we integrated human genomics and proteomics to investigate the causal associations between 2769 plasma proteins and IPF. Our Mendelian randomisation analysis identified nine proteins associated with IPF, of which three (FUT3, ADAM15 and USP28) were colocalised. ADAM15 emerged as the top candidate, supported by expression quantitative trait locus analysis in both blood and lung tissue. These findings provide novel insights into the aetiology of IPF and offer translational opportunities in response to the clinical challenges of this devastating disease.

Multi-feature Fusion Network on Gray Scale Ultrasonography: Effective Differentiation of Adenolymphoma and Pleomorphic Adenoma.

RATIONALE AND OBJECTIVES: to develop a deep learning radiomics graph network (DLRN) that integrates deep learning features extracted from gray scale ultrasonography, radiomics features and clinical features, for distinguishing parotid pleomorphic adenoma (PA) from adenolymphoma (AL) MATERIALS AND METHODS: A total of 287 patients (162 in training cohort, 70 in internal validation cohort and 55 in external validation cohort) from two centers with histologically confirmed PA or AL were enrolled. Deep transfer learning features and radiomics features extracted from gray scale ultrasound images were input to machine learning classifiers including logistic regression (LR), support vector machines (SVM), KNN, RandomForest (RF), ExtraTrees, XGBoost, LightGBM, and MLP to construct deep transfer learning radiomics (DTL) models and Rad models respectively. Deep learning radiomics (DLR) models were constructed by integrating the two features and DLR signatures were generated. Clinical features were further combined with the signatures to develop a DLRN model. The performance of these models was evaluated using receiver operating characteristic (ROC) curve analysis, calibration, decision curve analysis (DCA), and the Hosmer-Lemeshow test. RESULTS: In the internal validation cohort and external validation cohort, comparing to Clinic (AUC=0.767 and 0.777), Rad (AUC=0.841 and 0.748), DTL (AUC=0.740 and 0.825) and DLR (AUC=0.863 and 0.859), the DLRN model showed greatest discriminatory ability (AUC=0.908 and 0.908) showed optimal discriminatory ability. CONCLUSION: The DLRN model built based on gray scale ultrasonography significantly improved the diagnostic performance for benign salivary gland tumors. It can provide clinicians with a non-invasive and accurate diagnostic approach, which holds important clinical significance and value. Ensemble of multiple models helped alleviate overfitting on the small dataset compared to using Resnet50 alone.

N-Carbamylglutamate in ovo feeding improves carcass yield, muscle fiber development, and meat quality in broiler chickens.

BACKGROUND: Insufficient endogenous nutrients in the broiler embryo can lead to muscle gluconeogenesis, which ultimately affects the post-hatching performance of chicks. This study investigated the effects of in ovo feeding (IOF) of N-carbamylglutamate (NCG) on the growth hormones, carcass yield, and meat quality in broilers. Fertile eggs from a 30-week-old Ross 308 breeder flock were divided into three treatment groups: NC (non-injection), SC (100 µL saline-injection), and NCG (2 mg NCG injection). Each group had six replicates, with 70 eggs per replicate during incubation. Injections were administered on the 17.5th day of embryonic development. After hatching, 270 chicks were selected for 42-day rearing for further sampling. RESULTS: Chicks in the NCG group had significantly higher body weight (BW) and average daily gain (ADG) at the growing phase, increased growth and testosterone hormone in both feeding phases (21 and 42 days), and improved average daily gain (ADG) and food conversion ratio (FCR) in both grower and entire feeding phases (P < 0.05). Triiodothyronine (T3) and tetraiodothyronine (T4) levels, carcass yield, dressing, drum weight, breast muscle weight, drumstick weights, thighs, pectoralis major, and their part percentage of carcass were improved in the NCG group (P < 0.05), these effects were varied along feeding phases. Moreover, IOF of the NCG also improved pectoralis breast muscle color values at 24 h post mortem (P < 0.05). CONCLUSION: These results suggest that NCG injection at the late embryonic age of broiler enhances growth performance and meat quality throughout the lifespan and this can probably be attributed to an increase in thyroid and testosterone hormones, indicating potential involvement in metabolic and nutrient partitioning pathway regulation. © 2024 Society of Chemical Industry.

Predictive nomogram model for severe coronary artery calcification in end-stage kidney disease patients.

INTRODUCTION: The Agatston coronary artery calcification score (CACS) is an assessment index for coronary artery calcification (CAC). This study aims to explore the characteristics of CAC in end-stage kidney disease (ESKD) patients and establish a predictive model to assess the risk of severe CAC in patients. METHODS: CACS of ESKD patients was assessed using an electrocardiogram-gated coronary computed tomography (CT) scan with the Agatston scoring method. A predictive nomogram model was established based on stepwise regression. An independent validation cohort comprised of patients with ESKD from multicentres. RESULTS: 369 ESKD patients were enrolled in the training set, and 127 patients were included in the validation set. In the training set, the patients were divided into three subgroups: no calcification (CACS = 0, n = 98), mild calcification (0 < CACS ≤ 400, n = 141) and severe calcification (CACS > 400, n = 130). Among the four coronary branches, the left anterior descending branch (LAD) accounted for the highest proportion of calcification. Stepwise regression analysis showed that age, dialysis vintage, ß-receptor blocker, calcium-phosphorus product (Ca × P), and alkaline phosphatase (ALP) level were independent risk factors for severe CAC. A nomogram that predicts the risk of severe CAC in ESKD patients has been internally and externally validated, demonstrating high sensitivity and specificity. CONCLUSION: CAC is both prevalent and severe in ESKD patients. In the four branches of the coronary arteries, LAD calcification is the most common. Our validated nomogram model, based on clinical risk factors, can help predict the risk of severe coronary calcification in ESKD patients who cannot undergo coronary CT analysis.

Trimerized S expressed by modified vaccinia virus Ankara (MVA) confers superior protection against lethal SARS-CoV-2 challenge in mice.

The reoccurrence of successive waves of SARS-CoV-2 variants suggests the exploration of more vaccine alternatives is imperative. Modified vaccinia virus Ankara (MVA) is a virus vector exhibiting excellent safety as well as efficacy for vaccine development. Here, a series of recombinant MVAs (rMVAs) expressing monomerized or trimerized S proteins from different SARS-CoV-2 variants are engineered. Trimerized S expressed from rMVAs is found predominantly as trimers on the surface of infected cells. Remarkably, immunization of mice with rMVAs demonstrates that S expressed in trimer elicits higher levels of binding IgG and IgA, as well as neutralizing antibodies for matched and mismatched S proteins than S in the monomer. In addition, trimerized S expressed by rMVA induces enhanced cytotoxic T-cell responses than S in the monomer. Importantly, the rMVA vaccines expressing trimerized S exhibit superior protection against a lethal SARS-CoV-2 challenge as the immunized animals all survive without displaying any pathological conditions. This study suggests that opting for trimerized S may represent a more effective approach and highlights that the MVA platform serves as an ideal foundation to continuously advance SARS-CoV-2 vaccine development. IMPORTANCE: MVA is a promising vaccine vector and has been approved as a vaccine for smallpox and mpox. Our analyses suggested that recombinant MVA expressing S in trimer (rMVA-ST) elicited robust cellular and humoral immunity and was more effective than MVA-S-monomer. Importantly, the rMVA-ST vaccine was able to stimulate decent cross-reactive neutralization against pseudoviruses packaged using S from different sublineages, including Wuhan, Delta, and Omicron. Remarkably, mice immunized with rMVA-ST were completely protected from a lethal challenge of SARS-CoV-2 without displaying any pathological conditions. Our results demonstrated that an MVA vectored vaccine expressing trimerized S is a promising vaccine candidate for SARS-CoV-2 and the strategy might be adapted for future vaccine development for coronaviruses.

Construction of nursing-sensitive quality indicators for acute poisoning in emergency departments: An e-Delphi study.

AIMS: The aim of the study was to develop a set of nursing-sensitive quality indicators for acute poisoning in emergency departments. DESIGN: A two-round e-Delphi study was conducted from July to November 2023. METHODS: Subject-matter experts from 19 tertiary hospitals across four provinces of China participated in the survey. Potential indicators identified through a literature review were rated on a 5-point Likert scale and comments solicited. Descriptive statistics were used to demonstrate convergence of expert opinion, and consensus was reached in two rounds. Weights of each indicator were determined by analytic hierarchy process. There were 20 expert responses in Round 1 and 18 in Round 2. RESULTS: After two rounds, experts reached a consensus on definitions, calculation formulas, and data collection methods for these indicators. Three primary and 11 secondary indicators were included in the final nursing-sensitive quality indicators for acute poisoning in the emergency department. CONCLUSION: A set of indicators about acute poisoning care, applicable to the Chinese context, was developed in collaboration with emergency nurse specialists. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: The lack of supervision of the nursing quality for acute poisoning leads to great variability in clinical practice in different medical institutions. The results can help in their standardization in China and in other countries lacking regulation. Our study also offers nursing managers a concrete and operable evaluation tool for quality supervision. Normative nursing behaviours are conducive to increase safety and enhance patients' experience of medical treatment. IMPACT: The indicators identified in this study closely approach clinical practice and exhibit the characteristics of sensitivity and practicality. Although developed in the Chinese healthcare system, there is potential for adoption or adaption in other healthcare settings. REPORTING METHOD: This study was reported in line with the Conducting and REporting of DElphi studies (CREDE) guidance on Delphi studies. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution in this study. CONTRIBUTION TO THE WIDER GLOBAL CLINICAL COMMUNITY: The nursing quality of acute poisoning in emergency departments remains a growing attention, but the relevant assessment tools are lack. This study provides a set of nursing-sensitive quality indicators for acute poisoning to guide the quality monitoring of nursing managers. Study recommendations have broad applicability to all healthcare professionals who are engaged in emergency nursing.

The cellular response and molecular mechanism of superoxide dismutase interacting with superparamagnetic iron oxide nanoparticles.

This study explored the response of superoxide dismutase (SOD) under superparamagnetic iron oxide nanoparticles (SPIONs)-induced oxidative stress using combined cellular and molecular methods. Results found that SPIONs induced the inhibition of catalase activity, the U-inverted change of SOD activity and the accumulation of reactive oxygen species (ROS), leading to oxidative damage and cytotoxicity. The change of intracellular SOD activity was resulted from the increase of molecular activity induced by directly interacting with SPIONs and ROS-inhibition of activity. The increase of molecular activity could be attributed to the structural and conformational changes of SOD, which were caused by the direct interaction of SOD with SPIONs. The SOD-SPIONs interaction and its interacting mechanism were explored by multi-spectroscopy, isothermal titration calorimetry and zeta potential assays. SOD binds to SPIONs majorly via hydrophobic forces with the involvement of electrostatic forces. SPIONs approximately adsorb 11 units of SOD molecule with the binding affinity of 2.99 × 106 M-1. The binding sites on SOD were located around Tyr residues, whose hydrophilicity increased upon interacting with SPIONs. The binding to SPIONs loosened the peptide chains, changed the secondary structure and reduced the aggregation state of SOD.

Effect of alternating nicotinamide phosphoribosyltransferase expression levels on mitophagy in Alzheimer's disease mouse models.

AD is the abbreviation for Alzheimer's Disease, which is a neurodegenerative disorder that features progressive dysfunction in cognition. Previous research has reported that mitophagy impairment and mitochondrial dysfunction have been crucial factors in the AD's pathogenesis. More recently, literature has emerged which offers findings suggesting that the nicotinamide adenine dinucleotide (short for NAD+) augmentation eliminates the defective mitochondria and restores mitophagy. Meanwhile, as an enzyme which is rate-limiting, the Nicotinamide phosphoribosyltransferase, or NAMPT, is part of the salvage pathway of NAD+ synthesis. Therefore, the aim of the research project has been to produce proof for how the NAMPT-NAD +-silent information-regulated transcription factors1/3 (short for SIRT1/3) axis function in mediating mitophagy in APP/PS1 mice aged six months. The results revealed that the NAMPT-NAD+-SIRT1/3 axis in the APP/PS1 mice's hippocampus was considerably declined. Surprisingly, P7C3 (an NAMPT activator) noticeably promoted the NAD+-SIRT1/3 axis, improved mitochondrial structure and function, enhanced mitophagy activity along with the ability of learning and memory. While FK866 (an NAMPT inhibitor) reversed the decreased NAD+-SIRT1/3 axis, and even exacerbated Aß plaque deposition level in the APP/PS1 mice's hippocampus. The findings observed in this study indicate two main points: avoiding downregulation of the NAMPT activity can prevent AD-related mitophagy impairment; on the other hand, NAMPT characterizes a potential therapeutic intervention regarding AD pathogenesis.

Bioorthogonal Labeling and Enrichment of Histone Monoaminylation Reveal Its Accumulation and Regulatory Function in Cancer Cell Chromatin.

Histone monoaminylation (i.e., serotonylation and dopaminylation) is an emerging category of epigenetic mark occurring on the fifth glutamine (Q5) residue of H3 N-terminal tail, which plays significant roles in gene transcription. Current analysis of histone monoaminylation is mainly based on site-specific antibodies and mass spectrometry, which either lacks high resolution or is time-consuming. In this study, we report the development of chemical probes for bioorthogonal labeling and enrichment of histone serotonylation and dopaminylation. These probes were successfully applied for the monoaminylation analysis of in vitro biochemical assays, cells, and tissue samples. The enrichment of monoaminylated histones by the probes further confirmed the crosstalk between H3Q5 monoaminylation and H3K4 methylation. Finally, combining the ex vivo and in vitro analyses based on the developed probes, we have shown that both histone serotonylation and dopaminylation are highly enriched in tumor tissues that overexpress transglutaminase 2 (TGM2) and regulate the three-dimensional architecture of cellular chromatin.

CUX1 attenuates the apoptosis of renal tubular epithelial cells induced by contrast media through activating the PI3K/AKT signaling pathway.

OBJECTIVE: Contrast media (CM) is a commonly applied drug in medical examination and surgery. However, contrast-induced acute kidney injury (CIAKI) poses a severe threat to human life and health. Notably, the CUT-like homeobox 1 (CUX1) gene shows protective effects in a variety of cells. Therefore, the objective of this study was to provide a new target for the treatment of CIAKI through exploring the role and possible molecular mechanism of CUX1 in CIAKI. METHOD: Blood samples were collected from 20 patients with CIAKI and healthy volunteers. Human kidney 2 (HK-2) cells were incubated with 200 mg/mL iohexol for 6 h to establish a contrast-induced injury model of HK-2 cells. Subsequently, qRT-PCR was used to detect the relative mRNA expression of CUX1; CCK-8 and flow cytometry to assess the proliferation and apoptosis of HK-2 cells; the levels of IL(interleukin)-1ß, tumor necrosis factor alpha (TNF-α) and malondialdehyde (MDA) in cells and lactate dehydrogenase (LDH) activity in cell culture supernatant were detect; and western blot to observe the expression levels of CUX1 and the PI3K/AKT signaling pathway related proteins [phosphorylated phosphoinositide 3-kinase (p-PI3K), PI3K, phosphorylated Akt (p-AKT), AKT]. RESULTS: CUX1 expression was significantly downregulated in blood samples of patients with CIAKI and contrast-induced HK-2 cells. Contrast media (CM; iohexol) treatment significantly reduced the proliferation of HK-2 cells, promoted apoptosis, stimulated inflammation and oxidative stress that caused cell damage. CUX1 overexpression alleviated cell damage by significantly improving the proliferation level of HK-2 cells induced by CM, inhibiting cell apoptosis, and reducing the level of LDH in culture supernatant and the expression of IL-1ß, TNF-α and MDA in cells. CM treatment significantly inhibited the activity of PI3K/AKT signaling pathway activity. Nevertheless, up-regulating CUX1 could activate the PI3K/AKT signaling pathway activity in HK-2 cells induced by CM. CONCLUSION: CUX1 promotes cell proliferation, inhibits apoptosis, and reduces inflammation and oxidative stress in CM-induced HK-2 cells to alleviate CM-induced damage. The mechanism of CUX1 may be correlated with activation of the PI3K/AKT signaling pathway.