The nuclear receptor coactivator 4 regulates ferritinophagy induced by vibrio splendidus in coelomocytes of Apostichopus japonicus.

Iron homeostasis is vital for the host's defense against pathogenic invasion and the ferritinophagy is a crucial mechanism in maintaining intracellular iron homeostasis by facilitating the degradation and recycling of stored iron. The nuclear receptor coactivator 4 (NCOA4) serves as a ferritinophagy receptor, facilitating the binding and delivery of ferritin to the autophagosome and lysosome. However, NCOA4 of the sea cucumber Apostichopus japonicus (AjNCOA4) has not been reported until now. In this study, we identified and characterized AjNCOA4 in A. japonicus. This gene encodes a polypeptide containing 597 amino acids with an open reading frame of 1794 bp. The inferred amino acid sequence of AjNCOA4 comprises an ARA70 domain. Furthermore, a multiple sequence alignment demonstrated varying degrees of sequence homology between AjNCOA4 from A. japonicus and other NCOA4 orthologs. The phylogenetic tree of NCOA4 correlates with the established timeline of metazoan evolution. Expression analysis revealed that AjNCOA4 is expressed in all tested tissues, including the body wall, muscle, intestine, respiratory tree, and coelomocytes. Following challenge with Vibrio splendidus, the coelomocytes exhibited a significant increase in AjNCOA4 mRNA levels, peaking at 24 h. We successfully obtained recombinant AjNCOA4 protein through prokaryotic expression and prepared a specific polyclonal antibody. Immunofluorescence and co-immunoprecipitation experiments demonstrated an interaction between AjNCOA4 and AjFerritin in coelomocytes. RNA interference-mediated knockdown of AjNCOA4 expression resulted in elevated iron ion levels in coelomocytes. Bacterial stimulation enhanced ferritinophagy in coelomocytes, while knockdown of AjNCOA4 reduced the occurrence of ferritinophagy. These findings suggest that AjNCOA4 modulates ferritinophagy induced by V. splendidus in coelomocytes of A. japonicus.

AANAT1 regulates insect midgut detoxification through the ROS/CncC pathway.

Insecticide resistance has been a problem in both the agricultural pests and vectors. Revealing the detoxification mechanisms may help to better manage insect pests. Here, we showed that arylalkylamine N-acetyltransferase 1 (AANAT1) regulates intestinal detoxification process through modulation of reactive oxygen species (ROS)-activated transcription factors cap"n"collar isoform-C (CncC): muscle aponeurosis fibromatosis (Maf) pathway in both the oriental fruit fly, Bactrocera dorsalis, and the arbovirus vector, Aedes aegypti. Knockout/knockdown of AANAT1 led to accumulation of biogenic amines, which induced a decreased in the gut ROS level. The reduced midgut ROS levels resulted in decreased expression of CncC and Maf, leading to lower expression level of detoxification genes. AANAT1 knockout/knockdown insects were more susceptible to insecticide treatments. Our study reveals that normal functionality of AANAT1 is important for the regulation of gut detoxification pathways, providing insights into the mechanism underlying the gut defense against xenobiotics in metazoans.

A model for identifying potentially inappropriate medication used in older people with dementia: a machine learning study.

BACKGROUND: Older adults with dementia often face the risk of potentially inappropriate medication (PIM) use. The quality of PIM evaluation is hindered by researchers' unfamiliarity with evaluation criteria for inappropriate drug use. While traditional machine learning algorithms can enhance evaluation quality, they struggle with the multilabel nature of prescription data. AIM: This study aimed to combine six machine learning algorithms and three multilabel classification models to identify correlations in prescription information and develop an optimal model to identify PIMs in older adults with dementia. METHOD: This study was conducted from January 1, 2020, to December 31, 2020. We used cluster sampling to obtain prescription data from patients 65 years and older with dementia. We assessed PIMs using the 2019 Beers criteria, the most authoritative and widely recognized standard for PIM detection. Our modeling process used three problem transformation methods (binary relevance, label powerset, and classifier chain) and six classification algorithms. RESULTS: We identified 18,338 older dementia patients and 36 PIMs types. The classifier chain + categorical boosting (CatBoost) model demonstrated superior performance, with the highest accuracy (97.93%), precision (95.39%), recall (94.07%), F1 score (95.69%), and subset accuracy values (97.41%), along with the lowest Hamming loss value (0.0011) and an acceptable duration of the operation (371s). CONCLUSION: This research introduces a pioneering CC + CatBoost warning model for PIMs in older dementia patients, utilizing machine-learning techniques. This model enables a quick and precise identification of PIMs, simplifying the manual evaluation process.

[Sanshentongmai Mixture Improves Oxidative Damage in Rat Cardiomyocytes H9C2 via Upregulation of microRNA-146a]. / 三参通脉合剂通过上调microRNA-146aæ”¹å–„å¤§é¼ å¿ƒè‚Œç»†èƒžH9C2的氧化损伤.

Objective: To investigate the effect of Sanshentongmai (SSTM) mixture on the regulation of oxidative damage to rat cardiomyocytes (H9C2) through microRNA-146a and its mechanism. Methods: H9C2 were cultured in vitro, H2O2 was used as an oxidant to create an oxidative damage model in H9C2 cells. SSTM intervention was administered to the H9C2 cells. Then, the changes in H2O2-induced oxidative damage in H9C2 cells and the expression of microRNA-146a were observed to explore the protective effect of SSTM on H9C2 and its mechanism. H9C2 cells cultured i n vitro were divided into 3 groups, including a control group, a model group of H2O2-induced oxidative damage (referred to hereafter as the model group), and a group given H2O2 modeling plus SSTM intervention at 500 µg/L for 72 h (referred to hereafter as the treatment group). The cell viability was measured by CCK8 assay. In addition, the levels of N-terminal pro-brain natriuretic peptide (Nt-proBNP), nitric oxide (NO), high-sensitivity C-reactive protein (Hs-CRP), and angiotensin were determined by enzyme-linked immunosorbent assay (ELISA). The expression level of microRNA-146a was determined by real-time PCR (RT-PCR). Result: H9C2 cells were pretreated with SSTM at mass concentrations ranging from 200 to 1500 µg/L. Then, CCK8 assay was performed to measure cell viability and the findings showed that the improvement in cell proliferation reached its peak when the mass concentration of SSTM was 500 µg/L, which was subsequently used as the intervention concentration. ELISA was performed to measure the indicators related to heart failure, including Nt-proBNP, NO, Hs-CRP, and angiotensin Ⅱ. Compared with those of the control group, the expressions of Nt-proBNP and angiotensin Ⅱ in the treatment group were up-regulated (P<0.05), while the expression of NO was down-regulated (P<0.05). There was no significant difference in the expression of Hs-CRP between the treatment group and the control group. These findings indicate that SSTM could effectively ameliorate oxidative damage in H9C2 rat cardiomyocytes. Finally, according to the RT-PCR findings for the expression of microRNA-146a in each group, H2O2 treatment at 15 µmol/L could significantly reduce the expression of microRNA-146a, and the expression of microRNA-146a in the treatment group was nearly doubled compared with that in the model group. There was no significant difference between the treatment group and the control group. Conclusion: SSTM can significantly resist the H2O2-induced oxidative damage of H9C2 cells and may play a myocardial protective role by upregulating microRNA-146a.

A Prediction Rule for the Dystonic Spread of Blepharospasm: A 4-Year Prospective Cohort Study.

OBJECTIVE: Blepharospasm (BSP), focal dystonia with the highest risk of spread, lacks clear understanding of early spreading risk factors and objective prognostic indicators. We aimed to identify these risk factors through clinical and electrophysiological assessments, and to establish a predictive model for dystonic spread in BSP. METHODS: We prospectively followed BSP patients for 4 years, collecting data on dystonic spread, and conducting electrophysiological evaluations. The blink reflex, masseter inhibitory reflex, and trigeminal somatosensory evoked potential were assessed. Univariable and multivariable Cox proportional hazard regression models were used to assess clinical characteristics associated with BSP dystonic spread. A predictive model was constructed using a nomogram, and performance of the model was evaluated using the area under the receiver operating characteristic curve. RESULTS: A total of 136 enrolled participants (mean age 56.34 years) completed a 4-year follow-up. Among them, 62 patients (45.6%) showed spread to other body regions. Multivariable Cox regression analysis showed that a high Hamilton Anxiety Scale score (hazard ratio 1.19, 95% confidence interval 1.13-1.25, p < 0.001), prolonged trigeminal somatosensory evoked potential mandibular branch P1-N2 peak interval (hazard ratio 1.11, 95% confidence interval 1.02-1.21, p = 0.017), and elevated trigeminal somatosensory evoked potential mandibular branch P1-N2 peak amplitude (hazard ratio 1.26, 95% confidence interval 1.12-1.41, p < 0.001) were independent risk factors for BSP dystonic spread within 4 years. Combining these factors, the predictive models demonstrated excellent discriminative ability, with the receiver operating characteristic curve score being 0.797, 0.790, 0.847, and 0.820 at 1, 2, 3 and 4 years after enrollment, respectively. INTERPRETATION: We established a predictive model with significant value for anticipating dystonic spread in BSP, offering crucial evidence. These findings contribute essential insights into the early clinical identification of the development and evolution of BSP diseases. ANN NEUROL 2024.

Intermittent Fasting Targets Osteocyte Neuropeptide Y to Relieve Osteoarthritis.

Osteoarthritis is a highly prevalent progressive joint disease that still requires an optimal therapeutic approach. Intermittent fasting is an attractive dieting strategy for improving health. Here this study shows that intermittent fasting potently relieves medial meniscus (DMM)- or natural aging-induced osteoarthritic phenotypes. Osteocytes, the most abundant bone cells, secrete excess neuropeptide Y (NPY) during osteoarthritis, and this alteration can be altered by intermittent fasting. Both NPY and the NPY-abundant culture medium of osteocytes (OCY-CM) from osteoarthritic mice possess pro-inflammatory, pro-osteoclastic, and pro-neurite outgrowth effects, while OCY-CM from the intermittent fasting-treated osteoarthritic mice fails to induce significant stimulatory effects on inflammation, osteoclast formation, and neurite outgrowth. Depletion of osteocyte NPY significantly attenuates DMM-induced osteoarthritis and abolishes the benefits of intermittent fasting on osteoarthritis. This study suggests that osteocyte NPY is a key contributing factor in the pathogenesis of osteoarthritis and intermittent fasting represents a promising nonpharmacological antiosteoarthritis method by targeting osteocyte NPY.

Reduced serum CLCF1 levels in hyperthyroidism patients and T3-treated mice.

Characteristic symptoms of hyperthyroidism include weight loss, heart palpitation, and sweating. Thyroid hormones (TH) can stimulate thermogenesis through central and peripheral mechanisms. Previous studies have shown an association between dysfunction of cardiotrophin-like cytokine factor 1 (CLCF1) and cold-induced sweating syndrome, with recent research also indicating a link between CLCF1 and brown adipose tissue thermogenesis. However, it remains unclear whether CLCF1 and TH have synergistic or antagonistic effects on thermogenesis. This study aims to investigate the influence of thyroid hormone on circulating CLCF1 levels in humans and explore the potential possibilities of thyroid hormone in regulating energy metabolism by modulating Clcf1 in mice. By recruiting hyperthyroid patients and healthy subjects, we observed significantly lower serum CLCF1 levels in hyperthyroid patients compared to healthy subjects, with serum CLCF1 levels independently associated with hyperthyroidism after adjusting for potential confounders. Tissue analysis from mice treated with T3 revealed a decrease in CLCF1 expression in BAT and iWAT of C57BL/6 mice. These findings suggest that TH may play a role in regulating CLCF1 expression in adipose tissue.

Communication behavior recognition using CNN-based signal analysis.

This article explores the technology of recognizing non-cooperative communication behavior, with a specific emphasis on analyzing communication station signals. Conventional techniques for analyzing signal data frames to determine their identity, while precise, do not have the ability to operate in real-time. In order to tackle this issue, we developed a pragmatic architecture for recognizing communication behavior and a system based on polling. The method utilizes a one-dimensional convolutional neural network (CNN) to segment data, hence improving its ability to recognize various communication activities. The study assesses the reliability of CNN in several real-world scenarios, examining its accuracy in the presence of noise interference, varying lengths of interception signals, interferences at different frequency points, and dynamic changes in outpost locations. The experimental results confirm the efficacy and dependability of the convolutional neural network in recognizing communication behavior in various contexts.

Chlorogenic acid can improve spermatogenic dysfunction in rats with varicocele by regulating mitochondrial homeostasis and inhibiting the activation of NLRP3 inflammasomes by oxidative mitochondrial DNA and cGAS/STING pathway.

In recent years, Varicocele (VC) has been recognized as a common cause of male infertility that can be treated by surgery or drugs. How to reduce the damage of VC to testicular spermatogenic function has attracted extensive attention in recent years. Among them, overexpressed ROS and high levels of inflammation may play a key role in VC-induced testicular damage. As the key mediated innate immune pathways, cGAS-STING shaft under pathological conditions, such as in cell and tissue damage stress can be cytoplasmic DNA activation, induce the activation of NLRP3 inflammatory corpuscle, triggering downstream of the inflammatory cascade reaction. Chlorogenic acid (CGA), as a natural compound from a wide range of sources, has strong anti-inflammatory and antioxidant activities, and is a potential effective drug for the treatment of varicocele infertility. The aim of this study is to investigate the role of CGA in the spermatogenic dysfunction of the rat testis induced by VC and the potential mechanisms. The results of this study have shown that CGA gavage treatment ameliorated the pathological damage of seminiferous tubules, increased the number of sperm in the lumen, and increased the expression levels of Occludin and ZO-1, which indicated the therapeutic effect of CGA on spermatogenic dysfunction in the testis of VC rats. Meanwhile, the damage of mitochondrial structure was alleviated and the expression levels of ROS, NLRP3 and pro-inflammatory cytokines (IL-1ß, IL-6, IL-18) were significantly reduced in the testicular tissues of model rats after CGA treatment. In addition, we demonstrated for the first time the high expression status of cGAS and STING in testicular tissues of VC model rats, and this was ameliorated to varying degrees after CGA treatment. In conclusion, this study suggests that CGA can improve the spermatogenic function of the testis by reducing mitochondrial damage and inhibiting the activation of the cGAS-STING axis, inhibiting the activation of the NLRP3 inflammasome, and improving the inflammatory damage of the testis, highlighting the potential of CGA as a therapeutic agent for varicocele infertility.

Adenosine 5'-Monophosphate-to-Threonine Ratio Promotes Abdominal Aortic Aneurysms via Up-Regulation of HLA-DR on Natural Killer Cells: A Bidirectional Mendelian Randomized Analysis.

Objective: Immune-metabolic interactions may have causal and therapeutic impacts on abdominal aortic aneurysms (AAAs). However, due to the lack of research on the relationship between immune-metabolic interactions and AAAs, further exploration of the mechanism faces challenges. Methods: A two-sample, two-step mediation analysis with Mendelian randomization (MR) based on genome-wide association studies (GWASs) was performed to determine the causal associations among blood immune cell signatures, metabolites, and AAAs. The stability, heterogeneity, and pleiotropy of the results were verified using a multivariate sensitivity analysis. Results: After multiple two-sample MRs using the AAA data from two large-scale GWAS databases, we determined that the human leukocyte antigen-DR (HLA-DR) levels on HLA-DR + natural killer (NK) cells (HLA-DR/NK) were associated with the causal effect of an AAA, with consistent results in the two databases (FinnGen: odds ratio (OR) = 1.054, 95% confidence interval (CI): 1.003-1.067, p-value = 0.036; UK Biobank: OR = 1.149, 95% CI: 1.046-1.261, p-value = 0.004). The metabolites associated with the risk of developing an AAA were enriched to find a specific metabolic model. We also found that the ratio of adenosine 5'-monophosphate (AMP) to threonine could act as a potential mediator between the HLA/NK and an AAA, with a direct effect (beta effect = 0.0496) and an indirect effect (beta effect = 0.0029). The mediation proportion was 5.56%. Conclusions: Our study found that an up-regulation of HLA-DR on HLA-DR/NK cells can increase the risk of an AAA via improvements in the AMP-to-threonine ratio, thus providing a potential new biomarker for the prediction and treatment of AAAs.

W/O/W emulsion-filled sodium alginate hydrogel beads for co-encapsulation of vitamins C and E: Insights into the fabrication, lipolysis, and digestion behavior.

In this study, vitamins C and E were simultaneously encapsulated in water-in-oil-in-water (W/O/W) emulsion-filled sodium alginate (SA) hydrogel beads, as well as the effects of SA concentrations (0.5%, 1.0%, 1.5%, and 2.0%) on the structures and lipolysis the of hydrogel beads were investigated. With increasing SA concentration, the beads showed larger sizes, denser structures and better textures. The droplets tightly penetrated the gel network at high SA concentrations. Digestion behavior revealed the disintegrated intramolecular structure at low SA concentrations. The beads with 0.5% SA were fragmented, losing the initial shape during digestion in the intestinal fluid. Additionally, lipid phases were released as W/O/W and O/W emulsion droplets after digestion. However, the high SA concentration-containing beads exhibited a well-preserved morphological structure after digestion, and the release profiles of lipid phase were mainly O/W emulsion droplets. Furthermore, vitamins C and E encapsulated in the beads exhibited high bioaccessibility (vitamin C: 90.20% and vitamin E: 95.19%).

A Big Prospect for Hydrogel Nano-System in Glioma.

Patients diagnosed with glioma typically face a limited life expectancy (around 15 months on average), a bleak prognosis, and a high likelihood of recurrence. As such, glioma is recognized as a significant form of malignancy. Presently, the treatment options for glioma include traditional approaches such as surgery, chemotherapy, and radiotherapy. Regrettably, the efficacy of these treatments has been less than optimal. Nevertheless, a promising development in glioma treatment lies in the use of hydrogel nano-systems as sophisticated delivery systems. These nano-systems have demonstrated exceptional therapeutic effects in the treatment of glioma by various responsive ways, including temperature-response, pH-response, liposome-response, ROS-response, light-response, and enzyme-response. This study seeks to provide a comprehensive summary of both the therapeutic application of hydrogel nano-systems in managing glioma and the underlying immune action mechanisms.

Innovative Delivery System Combining CRISPR-Cas12f for Combatting Antimicrobial Resistance in Gram-Negative Bacteria.

Antimicrobial resistance poses a significant global challenge, demanding innovative approaches, such as the CRISPR-Cas-mediated resistance plasmid or gene-curing system, to effectively combat this urgent crisis. To enable successful curing of antimicrobial genes or plasmids through CRISPR-Cas technology, the development of an efficient broad-host-range delivery system is paramount. In this study, we have successfully designed and constructed a novel functional gene delivery plasmid, pQ-mini, utilizing the backbone of a broad-host-range Inc.Q plasmid. Moreover, we have integrated the CRISPR-Cas12f system into the pQ-mini plasmid to enable gene-curing in broad-host of bacteria. Our findings demonstrate that pQ-mini facilitates the highly efficient transfer of genetic elements to diverse bacteria, particularly in various species in the order of Enterobacterales, exhibiting a broader host range and superior conjugation efficiency compared to the commonly used pMB1-like plasmid. Notably, pQ-mini effectively delivers the CRISPR-Cas12f system to antimicrobial-resistant strains, resulting in remarkable curing efficiencies for plasmid-borne mcr-1 or blaKPC genes that are comparable to those achieved by the previously reported pCasCure system. In conclusion, our study successfully establishes and optimizes pQ-mini as a broad-host-range functional gene delivery vector. Furthermore, in combination with the CRISPR-Cas system, pQ-mini demonstrates its potential for broad-host delivery, highlighting its promising role as a novel antimicrobial tool against the growing threat of antimicrobial resistance.

Coronary CTA-based radiomic signature of pericoronary adipose tissue predict rapid plaque progression.

OBJECTIVES: To explore the value of radiomic features derived from pericoronary adipose tissue (PCAT) obtained by coronary computed tomography angiography for prediction of coronary rapid plaque progression (RPP). METHODS: A total of 1233 patients from two centers were included in this multicenter retrospective study. The participants were divided into training, internal validation, and external validation cohorts. Conventional plaque characteristics and radiomic features of PCAT were extracted and analyzed. Random Forest was used to construct five models. Model 1: clinical model. Model 2: plaque characteristics model. Model 3: PCAT radiomics model. Model 4: clinical + radiomics model. Model 5: plaque characteristics + radiomics model. The evaluation of the models encompassed identification accuracy, calibration precision, and clinical applicability. Delong' test was employed to compare the area under the curve (AUC) of different models. RESULTS: Seven radiomic features, including two shape features, three first-order features, and two textural features, were selected to build the PCAT radiomics model. In contrast to the clinical model and plaque characteristics model, the PCAT radiomics model (AUC 0.85 for training, 0.84 for internal validation, and 0.81 for external validation; p < 0.05) achieved significantly higher diagnostic performance in predicting RPP. The separate combination of radiomics with clinical and plaque characteristics model did not further improve diagnostic efficacy statistically (p > 0.05). CONCLUSION: Radiomic feature analysis derived from PCAT significantly improves the prediction of RPP as compared to clinical and plaque characteristics. Radiomic analysis of PCAT may improve monitoring RPP over time. CRITICAL RELEVANCE STATEMENT: Our findings demonstrate PCAT radiomics model exhibited good performance in the prediction of RPP, with potential clinical value. KEY POINTS: Rapid plaque progression may be predictable with radiomics from pericoronary adipose tissue. Fibrous plaque volume, diameter stenosis, and fat attenuation index were identified as risk factors for predicting rapid plaque progression. Radiomics features of pericoronary adipose tissue can improve the predictive ability of rapid plaque progression.

Impact of insulin resistance on IVF/ICSI outcomes in women with polycystic ovary syndrome: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of insulin resistance (IR) on in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcomes in patients with polycystic ovary syndrome (PCOS). STUDY DESIGN: PubMed, Google Scholar,Web of Science, Embase, Scopus and the Cochrane Library were searched to identify relevant studies. A total of 6,137 PCOS women undergoing IVF/ICSI with or without IR were included in the systematic review and meta-analysis. RESULTS: The systematic review and meta-analysis included twelve observational studies that were free from inherent bias. When comparing PCOS women undergoing IVF/ICSI, the IR and non-IR groups did not show significant differences in oocytes retrieved (WMD = -0.63, 95 % CI: -2.37 to 1.12, P = 0. 483), fertilization rate (WMD = 1.01, 95 % CI: -0.66 to 2.67, P = 0.236; OR = 0.97, 95 % CI: 0.79 to 1.19, P = 0.783), and live birth rate (OR = 1.02, 95 % CI: 0.78 to 1.33, P = 0.892). However, the group with IR had a lower number of MII oocytes (WMD = -1.07, 95 % CI: -1.54 to -0.59, P < 0.001), total embryos (WMD = -1.37, 95 % CI: -1. 78 to -0.95, P < 0.001), and clinical pregnancy rate (OR = 0.77, 95 % CI: 0.59 to 0.99, P = 0.042), as well as a higher miscarriage rate (OR = 1.11, 95 % CI: 1.02 to 1.22, P = 0.017) compared to the non-IR group. CONCLUSION: In women with PCOS, IR had a negative impact on IVF/ICSI outcomes. To obtain more favourable empirical support, larger studies are necessary.

Genetically determined dietary habits and risk of Alzheimer's disease: a Mendelian randomization study.

Background: Emerging evidence have suggested that dietary habits have potential implication on the development of Alzheimer's disease (AD). However, elucidating the causal relationship between specific dietary factors and AD risk remains a challenge. Therefore, our study endeavors to investigate the causal association between dietary habits and the risk of AD. Materials and methods: We analyzed data on 231 dietary habits sourced from the UK Biobank and MRC-IEU, and AD data obtained from the FinnGen database. Employing a framework based on the classic two-sample Mendelian randomization (MR) study, we utilized the inverse-variance weighted (IVW) method as the primary analysis. Additionally, we conducted Steiger filtering and other methods to mitigate horizontal pleiotropy. The robustness of our overall findings was confirmed through multiple sensitivity analysis methods, and forward MR and reverse MR to address potential reverse causality bias. Results: Our study evaluated the causal effect between 231 dietary habits involving over 500,000 participants of European ancestry, and 10,520 AD cases. Only oily fish intake demonstrated a significant protective causal relationship with AD following FDR correction (raw p-value = 1.28e-4, FDR p-value = 0.011, OR = 0.60, 95%CI: 0.47-0.78). Additionally, six dietary habits potentially influenced AD risk, with protective causal effects observed for average monthly intake of other alcoholic drinks (raw p-value = 0.024, FDR p-value = 0.574, OR = 0.57, 95%CI: 0.35-0.93) and tea intake (raw p-value = 0.047, FDR p-value = 0.581, OR = 0.78, 95%CI: 0.603-1.00). Conversely, detrimental causal effects were observed for the average weekly champagne plus white wine intake (raw p-value = 0.006, FDR p-value = 0.243, OR = 2.96, 95%CI: 1.37-6.38), Danish pastry intake (raw p-value = 0.036, FDR p-value = 0.574, OR = 13.33, 95%CI: 1.19-149.69), and doughnut intake (raw p-value = 0.039, FDR p-value = 0.574, OR = 7.41, 95%CI: 1.11-49.57). Moreover, the protective effect of goat's cheese intake phenotype exhibited statistical significance only in the IVW method (raw p-value<0.05). Conclusion: Our results provide genetic support for a protective causal effect of oily fish intake on AD risk. Additionally, average monthly intake of other alcoholic drinks and tea consumption were also related with a lower risk of AD. Conversely, average weekly champagne plus white wine intake, Danish pastry intake, and doughnut intake were causally associated with increased risk of AD.

Characterization of an agmatine N-acetyltransferase from Bactrocera dorsalis that modulates ovary development.

Agmatine N-acetyltransferase (AgmNAT), which catalyzes the formation of N-acetylagmatine from acetyl-CoA and agmatine, is a member of the GCN5-related N-acetyltransferase family. So far, knowledge of the physiological roles of AgmNAT in insects is limited. Here, we identified one gene encoding protein homologous to that of Drosophila AgmNAT using sequence information from an activity-verified Drosophila AgmNAT in a BLAST search of the Bactrocera dorsalis genome. We expressed and purified B. dorsalis AgmNAT in Escherichia coli and used the purified enzyme to define the substrate specificity for acyl-CoA and amine substrates. Our application of the screening strategy to BdorAgmNAT led to the identification of agmatine as the best amine substrate for this enzyme, with the highest kcat/Km value. We successfully obtained a BdorAgmNAT knockout strain based on a wild-type strain (WT) using the CRISPR/Cas9 technique. The ovary development of the BdorAgmNAT knockout mutants was delayed for 10 days compared with the WT specimens. Moreover, mutants had a much smaller mature ovary size and laid far fewer eggs than WT. Loss of function of BdorAgmNAT caused by RNAi with mature WT females did not affect their fecundity. These findings indicate that BdorAgmNAT is critical for oogenesis. Our data provide the first evidence for AgmNAT in regulating ovary development.

SIRT5 exacerbates eosinophilic chronic rhinosinusitis by promoting polarization of M2 macrophage.

BACKGROUND: Previous studies implied that local M2 polarization of macrophage promoted mucosal edema and exacerbated TH2 type inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the specific pathogenic role of M2 macrophages and the intrinsic regulators in the development of CRS remains elusive. OBJECTIVE: We sought to investigate the regulatory role of SIRT5 in the polarization of M2 macrophages and its potential contribution to the development of CRSwNP. METHODS: Real-time reverse transcription-quantitative PCR and Western blot analyses were performed to examine the expression levels of SIRT5 and markers of M2 macrophages in sinonasal mucosa samples obtained from both CRS and control groups. Wild-type and Sirt5-knockout mice were used to establish a nasal polyp model with TH2 inflammation and to investigate the effects of SIRT5 in macrophage on disease development. Furthermore, in vitro experiments were conducted to elucidate the regulatory role of SIRT5 in polarization of M2 macrophages. RESULTS: Clinical investigations showed that SIRT5 was highly expressed and positively correlated with M2 macrophage markers in eosinophilic polyps. The expression of SIRT5 in M2 macrophages was found to contribute to the development of the disease, which was impaired in Sirt5-deficient mice. Mechanistically, SIRT5 was shown to enhance the alternative polarization of macrophages by promoting glutaminolysis. CONCLUSIONS: SIRT5 plays a crucial role in promoting the development of CRSwNP by supporting alternative polarization of macrophages, thus providing a potential target for CRSwNP interventions.

Identification of a novel hypoglycemic small molecule, trans-2, 4-dimethoxystilbene by rectifying gut microbiota and activating hepatic AMPKα-PPARγ pathway through gut-liver axis.

With the increasing prevalence of metabolic disorders, hyperglycemia has become a common risk factor that endangers people's lives and the need for new drug solutions is burgeoning. Trans-2, 4-dimethoxystilbene (TDMS), a synthetic stilbene, has been found as a novel hypoglycemic small molecule from glucose consumption test. Normal C57BL/6 J mice, mouse models of type 1 diabetes mellitus and diet-induced obesity subjected to TDMS gavage were found with lower glycemic levels and better glycemic control. TDMS significantly improved the symptoms of polydipsia and wasting in type 1 diabetic mice, and could rise their body temperature at the same time. It was found that TDMS could promote the expression of key genes of glucose metabolism in HepG2, as do in TDMS-treated liver, while it could improve the intestinal flora and relieve intestinal metabolic dysbiosis in hyperglycemic models, which in turn affected its function in the liver, forming the gut-liver axis. We further fished PPARγ by virtual screening that could be promoted by TDMS both in-vitro and in-vivo, which was regulated by upstream signaling of AMPKα phosphorylation. As a novel hypoglycemic small molecule, TDMS was proven to be promising with its glycemic improvements and amelioration of diabetes symptoms. It promoted glucose absorption and utilization by the liver and improved the intestinal flora of diabetic mice. Therefore, TDMS is expected to become a new hypoglycemic drug that acts through gut-liver axis via AMPKα-PPARγ signaling pathway in improving glycemic metabolism, bringing new hope to patients with diabetes and glucose metabolism disorders.