Plasma IL-6 levels and their association with brain health and dementia risk: A population-based cohort study.

BACKGROUND: Recent studies have associated immune abnormalities with dementia. IL-6 is a crucial cytokine in inflammatory responses, and recent evidence has linked elevated IL-6 levels to changes in brain structure and cognitive decline. However, the connection between IL and 6 levels, cognition, brain volumes, and dementia risk requires exploration in large prospective cohorts. METHODS: This study utilized a longitudinal cohort from the UK Biobank to analyze the correlation between IL and 6 expression levels, cognitive performance, and cortical and subcortical brain volumes through linear regression. Additionally, we assessed the association between IL and 6 levels and long-term dementia risk using Cox regression analysis. We also used one-sample Mendelian randomization to analyze the impact of genetic predisposition of dementia on elevated IL-6 levels. RESULTS: A total of 50,864 participants were included in this study, with 1,391 new cases of all-cause dementia identified. Higher plasma IL-6 levels are associated with cortical and subcortical atrophy in regions such as the fusiform, thalamus proper, hippocampus, and larger ventricle volumes. IL-6 levels are negatively associated with cognitive performance in pair matching, numeric memory, prospective memory, and reaction time tests. Furthermore, elevated IL-6 levels are linked to a 23-35 % increased risk of all-cause dementia over an average follow-up period of 13.2 years. The one-sample Mendelian randomization analysis did not show associations between the genetic predisposition of dementia and elevated IL-6 levels. CONCLUSIONS: Increased IL-6 levels are associated with worse cognition, brain atrophy, and a heightened risk of all-cause dementia. Our study highlights the need to focus on the role of peripheral IL-6 levels in managing brain health and dementia risk.

Y-STR analysis of highly degraded DNA from skeletal remains over 70 years old.

The goal of the following study is to clarify whether the skeletal remains over 70 years old from missing persons and their alleged relatives shared identical Y-STR loci. Nowadays, advances in ancient DNA extraction techniques and approaches of using multiple different Y-STRs have significantly increased the possibility of obtaining DNA profiles from highly degraded skeletal remains. Given the ages and conditions of the skeletal remains, ancient DNA extraction methods can be used to maximize the probability of DNA recovery. Considering that information about distant relatives is more relevant for long-term missing persons and alleged family members are male, Y-STR loci analysis is considered the most appropriate and informative approach for determining paternal lineage relationship. In this study, Y-STR genotypes obtained from these alleged relatives were identical to each other and to the alleles of missing persons' consensus profiles at more than 22 loci examined, whilst not being found in Y-STR population database from Y-Chromosome STR Haplotype Reference Database. Therefore, Missing Person No.7 and Missing Person No.18 have a patrilineal relationship with reference samples from Family1 and Family2, respectively. In addition, the fact that Y-STR haplotypes obtained from skeletal remains of missing persons and reference samples are not found in the Han Chinese people from East Asian demonstrates its rarity and further supports a paternal lineage relationship amongst them.

The Idesia polycarpa genome provides insights into its evolution and oil biosynthesis.

The deciduous tree Idesia polycarpa can provide premium edible oil with high polyunsaturated fatty acid contents. Here, we generate its high-quality reference genome, which is ∼1.21 Gb, comprising 21 pseudochromosomes and 42,086 protein-coding genes. Phylogenetic and genomic synteny analyses show that it diverged with Populus trichocarpa about 16.28 million years ago. Notably, most fatty acid biosynthesis genes are not only increased in number in its genome but are also highly expressed in the fruits. Moreover, we identify, through genome-wide association analysis and RNA sequencing, the I. polycarpa SUGAR TRANSPORTER 5 (IpSTP5) gene as a positive regulator of high oil accumulation in the fruits. Silencing of IpSTP5 by virus-induced gene silencing causes a significant reduction of oil content in the fruits, suggesting it has the potential to be used as a molecular marker to breed the high-oil-content cultivars. Our results collectively lay the foundation for breeding the elite cultivars of I. polycarpa.

Naringenin attenuated airway cilia structural and functional injury induced by cigarette smoke extract via IL-17 and cAMP pathways.

BACKGROUND: Cigarette smoke impairs mucociliary clearance via mechanisms such as inflammatory response and oxidative injury, which in turn induces various respiratory diseases. Naringenin, a naturally occurring flavonoid in grapes and grapefruit, has exhibited pharmacological properties such as anti-inflammatory, expectorant, and antioxidant properties. However, it is still unclear whether naringenin protects airway cilia from injury caused by cigarette smoke. PURPOSE: This study aimed to investigate the effect of naringenin on cigarette smoke extract (CSE)-induced structural and functional abnormalities in airway cilia and highlight the potential regulatory mechanism. METHODS: Initially, network pharmacology was used to predict the mechanism of action of naringenin in ciliary disease. Next, HE staining, immunofluorescence, TEM, qRT-PCR, western blot, and ELISA were performed to assess the effects of naringenin on airway cilia in tracheal rings and air-liquid interface (ALI) cultures of Sprague Dawley rats after co-exposure to CSE (10% or 20%) and naringenin (0, 25, 50, 100 µM) for 24 h. Finally, transcriptomics and molecular biotechnology methods were conducted to elucidate the mechanism by which naringenin protected cilia from CSE-induced damage in ALI cultures. RESULTS: The targets of ciliary diseases regulated by naringenin were significantly enriched in inflammation and oxidative stress pathways. Also, the CSE decreased the number of cilia in the tracheal rings and ALI cultures and reduced the ciliary beat frequency (CBF). However, naringenin prevented CSE-induced cilia damage via mechanisms such as the downregulation of cilia-related genes (e.g., RFX3, DNAI1, DNAH5, IFT88) and ciliary marker proteins such as DNAI2, FOXJ1, and ß-tubulin IV, the upregulation of inflammatory factors (e.g., IL-6, IL-8, IL-13), ROS and MDA. IL-17 signaling pathway might be involved in the protective effect of naringenin on airway cilia. Additionally, the cAMP signaling pathway might also be related to the enhancement of CBF by naringenin. CONCLUSION: In this study, we first found that naringenin reduces CSE-induced structural disruption of airway cilia in part via modulation of the IL-17 signaling pathway. Furthermore, we also found that naringenin enhances CBF by activating the cAMP signaling pathway. This is the first report to reveal the beneficial effects of naringenin on airway cilia and the potential underlying mechanisms.

Durable protective efficiency provide by mRNA vaccines require robust immune memory to antigens and weak immune memory to lipid nanoparticles.

The Pegylated lipids in lipid nanoparticle (LNPs) vaccines have been found to cause acute hypersensitivity reactions in recipients, and generate anti-LNPs immunity after repeated administration, thereby reducing vaccine effectiveness. To overcome these challenges, we developed a new type of LNPs vaccine (SAPC-LNPs) which was co-modified with sialic acid (SA) - lipid derivative and cleavable PEG - lipid derivative. This kind of mRNA vaccine can target dendritic cells (DCs) and rapidly escape from early endosomes (EE) and lysosomes with a total endosomal escape rate up to 98 %. Additionally, the PEG component in SAPC-LNPs was designed to detach from the LNPs under the catalysis of carboxylesterase in vivo, which reduced the probability of PEG being attached to LNPs entering antigen-presenting cells. Compared with commercially formulated vaccines (1.5PD-LNPs), mice treated with SAPC-LNPs generated a more robust immune memory to tumor antigens and a weaker immune memory response to LNPs, and showed lower side effects and long-lasting protective efficiency. We also discovered that the anti-tumor immune memory formed by SAPC-LNPs mRNA vaccine was directly involved in the immune cycle to rattack tumor. This immune memory continued to strengthen with multiple cycles, supporting that the immune memory should be incorporated into the theory of tumor immune cycle.

MucLiPred: Multi-Level Contrastive Learning for Predicting Nucleic Acid Binding Residues of Proteins.

Protein-molecule interactions play a crucial role in various biological functions, with their accurate prediction being pivotal for drug discovery and design processes. Traditional methods for predicting protein-molecule interactions are limited. Some can only predict interactions with a specific molecule, restricting their applicability, while others target multiple molecule types but fail to efficiently process diverse interaction information, leading to complexity and inefficiency. This study presents a novel deep learning model, MucLiPred, equipped with a dual contrastive learning mechanism aimed at improving the prediction of multiple molecule-protein interactions and the identification of potential molecule-binding residues. The residue-level paradigm focuses on differentiating binding from non-binding residues, illuminating detailed local interactions. The type-level paradigm, meanwhile, analyzes overarching contexts of molecule types, like DNA or RNA, ensuring that representations of identical molecule types gravitate closer in the representational space, bolstering the model's proficiency in discerning interaction motifs. This dual approach enables comprehensive multi-molecule predictions, elucidating the relationships among different molecule types and strengthening precise protein-molecule interaction predictions. Empirical evidence demonstrates MucLiPred's superiority over existing models in robustness and prediction accuracy. The integration of dual contrastive learning techniques amplifies its capability to detect potential molecule-binding residues with precision. Further optimization, separating representational and classification tasks, has markedly improved its performance. MucLiPred thus represents a significant advancement in protein-molecule interaction prediction, setting a new precedent for future research in this field.

Naringenin regulates cigarette smoke extract-induced extracellular vesicles from alveolar macrophage to attenuate the mouse lung epithelial ferroptosis through activating EV miR-23a-3p/ACSL4 axis.

BACKGROUND: Alveolar macrophages are one of the momentous regulators in pulmonary inflammatory responses, which can secrete extracellular vesicles (EVs) packing miRNAs. Ferroptosis, an iron-dependent cell death, is associated with cigarette smoke-induced lung injury, and EVs have been reported to regulate ferroptosis by transporting intracellular iron. However, the regulatory mechanism of alveolar macrophage-derived EVs has not been clearly illuminated in smoking-related pulmonary ferroptosis. Despite the known anti-ferroptosis effects of naringenin in lung injury, whether naringenin controls EVs-mediated ferroptosis has not yet been explored. PURPOSE: We explore the effects of EVs from cigarette smoke-stimulated alveolar macrophages in lung epithelial ferroptosis, and elucidate the EV miRNA-mediated pharmacological mechanism of naringenin. STUDY DESIGN AND METHODS: Differential and ultracentrifugation were conducted to extract EVs from different alveolar macrophages treatment groups in vitro. Both intratracheal instilled mice and treated epithelial cells were used to investigate the roles of EVs from alveolar macrophages involved in ferroptosis. Small RNA sequencing analysis was performed to distinguish altered miRNAs in EVs. The ferroptotic effects of EV miRNAs were examined by applying dual-Luciferase reporter assay and miRNA inhibitor transfection experiment. RESULTS: Here, we firstly reported that EVs from cigarette smoke extract-induced alveolar macrophages (CSE-EVs) provoked pulmonary epithelial ferroptosis. The ferroptosis inhibitor ferrostatin-1 treatment reversed these changes in vitro. Moreover, EVs from naringenin and CSE co-treated alveolar macrophages (CSE+Naringenin-EVs) markedly attenuated the lung epithelial ferroptosis compared with CSE-EVs. Notably, we identified miR-23a-3p as the most dramatically changed miRNA among Normal-EVs, CSE-EVs, and CSE+Naringenin-EVs. Further experimental investigation showed that ACSL4, a pro-ferroptotic gene leading to lipid peroxidation, was negatively regulated by miR-23a-3p. The inhibition of miR-23a-3p diminished the efficacy of CSE+Naringenin-EVs. CONCLUSION: Our findings firstly provided evidence that naringenin elevated the EV miR-23a-3p level from CSE-induced alveolar macrophages, thereby inhibiting the mouse lung epithelial ferroptosis via targeting ACSL4, and further complemented the mechanism of cigarette-induced lung injury and the protection of naringenin in a paracrine manner. The administration of miR-23a-3p-enriched EVs has the potential to ameliorate pulmonary ferroptosis.

Simultaneous dendritic cells targeting and effective endosomal escape enhance sialic acid-modified mRNA vaccine efficacy and reduce side effects.

mRNA vaccines are attractive prospects for the development of DC-targeted vaccines; however, no clinical success has been realized because, currently, it is difficult to simultaneously achieve DC targeting and efficient endosomal/lysosomal escape. Herein, we developed a sialic acid (SA)-modified mRNA vaccine that simultaneously achieved both. The SA modification promoted DCs uptake of lipid nanoparticles (LNPs) by 2 times, >90% of SA-modified LNPs rapidly escaped from early endosomes (EEs), avoided entering lysosomes, achieved mRNA simultaneously translated in ribosomes distributed in the cytoplasm and endoplasmic reticulum (ER), significantly improved the transfection efficiency of mRNA LNPs in DCs. Additionally, we applied cleavable PEG-lipids in mRNA vaccines for the first time and found this conducive to cellular uptake and DC targeting. In summary, SA-modified mRNA vaccines targeted DCs efficiently, and showed significantly higher EEs/lysosomal escape efficiency (90% vs 50%), superior tumor treatment effect, and lower side effects than commercially formulated mRNA vaccines.

Forensic characteristics and genetic substructure analysis of the Handan Han population, Northern China.

We analysed the forensic characteristics and substructure of the Handan Han population based on 36 Y-STR (short tandem repeat) and Y-SNP (single nucleotide polymorphism) markers. The two most dominant haplogroups in Handan Han, O2a2b1a1a1-F8 (17.95%) and O2a2b1a2a1a (21.51%), and their abundant downstream branches, reflected the strong expansion of the precursor of the Hans in Handan. The present results enrich the forensic database and explore the genetic relationships between Handan Han and other neighbouring and/or linguistically close populations, which suggests that the current concise overview of the Han intricate substructure remains oversimplified.

Sex differences in islet stress responses support female ß cell resilience.

OBJECTIVE: Pancreatic ß cells play a key role in maintaining glucose homeostasis; dysfunction of this critical cell type causes type 2 diabetes (T2D). Emerging evidence points to sex differences in ß cells, but few studies have examined male-female differences in ß cell stress responses and resilience across multiple contexts, including diabetes. Here, we address the need for high-quality information on sex differences in ß cell and islet gene expression and function using both human and rodent samples. METHODS: In humans, we compared ß cell gene expression and insulin secretion in donors with T2D to non-diabetic donors in both males and females. In mice, we generated a well-powered islet RNAseq dataset from 20-week-old male and female siblings with similar insulin sensitivity. Our unbiased gene expression analysis pointed to a sex difference in the endoplasmic reticulum (ER) stress response. Based on this analysis, we hypothesized female islets would be more resilient to ER stress than male islets. To test this, we subjected islets isolated from age-matched male and female mice to thapsigargin treatment and monitored protein synthesis, cell death, and ß cell insulin production and secretion. Transcriptomic and proteomic analyses were used to characterize sex differences in islet responses to ER stress. RESULTS: Our single-cell analysis of human ß cells revealed sex-specific changes to gene expression and function in T2D, correlating with more robust insulin secretion in human islets isolated from female donors with T2D compared to male donors with T2D. In mice, RNA sequencing revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was physiologically significant, as islets isolated from female mice were more resilient to ER stress induction with thapsigargin. Specifically, female islets showed a greater ability to maintain glucose-stimulated insulin production and secretion during ER stress compared with males. CONCLUSIONS: Our data demonstrate sex differences in ß cell gene expression in both humans and mice, and that female ß cells show a greater ability to maintain glucose-stimulated insulin secretion across multiple physiological and pathological contexts.

The Typical Damage Form and Mechanism of a Railway Prestressed Concrete Sleeper.

Prestressed concrete sleepers are an important track component that is widely used in railway ballast track. Prestressed concrete sleepers have high strength, strong stability, and good durability; thus, their operation and use in railways are beneficial. However, in different countries and regions, certain damage to sleepers typically appears. Existing research on concrete sleepers focuses primarily on the structural design method, the application of new materials, theoretical analysis, and bearing strength test research, while ignoring sleeper damage. There are a few sleeper damage studies, but they look at only one type of damage; thus, there is no comprehensive study of prestressed concrete sleeper damage. The damage forms of prestressed concrete sleeper damage are thus summarized in this study, and the theory of the causes of prestressed concrete sleepers is analyzed based on the limit state method for the first time. The findings indicate that sleeper structure design is the primary cause of its operation and use status, and that special measures should be considered based on sleeper use conditions. In addition to meeting design requirements, materials, curing systems, product inspection, and other factors must be considered during manufacturing to improve the sleepers' long-term performance. Keeping the track in good condition, including but not limited to the state of fasteners, ballast bed, and track geometry is also an important aspect of preventing sleeper damage. The outcomes of this study provide better insights into the influences of damage to railway prestressed concrete sleepers and can be used to improve track maintenance and inspection criteria.

Naringenin attenuates inflammation, apoptosis, and ferroptosis in silver nanoparticle-induced lung injury through a mechanism associated with Nrf2/HO-1 axis: In vitro and in vivo studies.

With the wide application of silver nanoparticles (AgNPs), their potential damage to human health needs to be investigated. Lung is one of the main target organs after inhalation of AgNPs. Naringenin has been reported to have anti-inflammatory and anti-oxidative properties. This study aims to evaluate the protective effects of naringenin against AgNPs-induced lung injury and determine the underlying mechanism. In in vivo experiments, AgNPs were intratracheally instilled into ICR mice (l mg/kg) to establish a lung injury model. These mice were then treated with naringenin by oral gavage (25, 50, 100 mg/kg) for three days. Naringenin treatment decreased the levels of white blood cells, neutrophils, and lymphocytes in the blood, ameliorated lung injury, suppressed the release of pro-inflammatory cytokines, normalized ferroptotic markers and prevented oxidative stress with elevating Nrf2 and HO-1 protein expressions in lung. In in vitro experiments, BEAS-2B cells were firstly treated with AgNPs (320 µg/mL) and then naringenin (25, 50, and 100 µM), respectively. Naringenin attenuated AgNPs-induced oxidative stress and inflammatory response. Moreover, naringenin attenuated AgNPs-induced apoptosis with modulated low BAX, CytC, cleaved Caspase9, cleaved Caspase3 but high Bcl2. Furthermore, naringenin effectively decreased ferroptotic markers and increased the protein expressions of Nrf2 and HO-1, as well as increased the nuclear translocation of Nrf2. Importantly, the anti-apoptotic and anti-ferroptotic effects of naringenin in BEAS-2B cells were found to be at least partially Nrf2-dependent. These results indicated that naringenin exerted anti-inflammation, anti-apoptosis, and anti-ferroptosis effects and protected against AgNPs-induced lung injury at least partly via activating Nrf2/HO-1 signaling pathway.

The effect of a low dose hydrogen-oxygen mixture inhalation in midlife/older adults with hypertension: A randomized, placebo-controlled trial.

Objective: To explore the effect of a low-dose hydrogen-oxygen (H2-O2) mixture inhalation in midlife/older adults with hypertension. Methods: This randomized, placebo-controlled trial included 60 participants with hypertension aged 50-70 years who were randomly divided into Air group (inhaled placebo air) or H2-O2 group [inhaled H2-O2 mixture (66% H2/33% O2)]. Participants in both groups were treated 4 h per day for 2 weeks. Four-limb blood pressure and 24-h ambulatory blood pressure were monitored before and after the intervention, and levels of plasma hormones related to hypertension were determined. Results: A total of 56 patients completed the study (27 in the Air group and 29 in the H2-O2 group). The right and left arm systolic blood pressure (SBP) were significantly decreased in H2-O2 group compared with the baseline levels (151.9 ± 12.7 mmHg to 147.1 ± 12.0 mmHg, and 150.7 ± 13.3 mmHg to 145.7 ± 13.0 mmHg, respectively; all p < 0.05). Meanwhile, the H2-O2 intervention significantly decreased diastolic nighttime ambulatory blood pressure by 2.7 ± 6.5 mmHg (p < 0.05). All blood pressures were unaffected in placebo group (all p > 0.05). When stratified by age (aged 50-59 years versus aged 60-70 years), participants in the older H2-O2 group showed a larger reduction in right arm SBP compared with that in the younger group (p < 0.05). In addition, the angiotensin II, aldosterone, and cortisol levels as well as the aldosterone-to-renin ratio in plasma were significantly lower in H2-O2 group compared with baseline (p < 0.05). No significant differences were observed in the Air group before and after the intervention. Conclusion: Inhalation of a low-dose H2-O2 mixture exerts a favorable effect on blood pressure, and reduces the plasma levels of hormones associated with hypertension on renin-angiotensin-aldosterone system and stress in midlife/older adults with hypertension.

Microbial Metabolism of Naringin and the Impact on Antioxidant Capacity.

Naringin is a dietary flavonoid glycoside with broad bioactivities, and it has been found to undergo extensive microbial metabolism in human gut. Microbial metabolites are believed to play an important role in the overall bioactivity of naringin. However, knowledge is scarce about its microbial metabolism in laboratory rats, which are the most commonly used animal model for naringin-related biomedical studies. Herein, we profiled the microbial metabolism of naringin in rat by an in vitro anaerobic fermentation combined with LC-MS/MS methods. A total of 35 microbial metabolites were identified, and corresponding metabolic pathways were proposed. Naringin and its metabolites were further quantified in fermentation samples. Rhoifolin, neoeriocitrin, neohesperidin, naringenin, methylated naringin, and hydroxylated naringin were detected as the primary microbial metabolites. Moreover, antioxidant capacity assays suggested that fermentation-associated microbial metabolites exhibited higher antioxidant activity than original naringin. Obtained results contribute to a more comprehensive understanding of the microbial metabolism and antioxidant capacity of naringin.

Naringenin suppresses BEAS-2B-derived extracellular vesicular cargoes disorder caused by cigarette smoke extract thereby inhibiting M1 macrophage polarization.

Extracellular vesicles (EVs)-mediated epithelium-macrophage crosstalk has been proved to maintain lung homeostasis in cigarette smoke-induced lung diseases such as chronic obstructive pulmonary disease (COPD). In our previous study, we found that EVs derived from cigarette smoke extract (CSE) treated BEAS-2B promoted M1 macrophage polarization, which probably accelerated the development of inflammatory responses. Naringenin has been proved to suppress M1 macrophage polarization, but whether naringenin regulates macrophage polarization mediated by EVs has not been reported. In this study, we firstly found that EVs derived from naringenin and CSE co-treated BEAS-2B significantly inhibited the expression of CD86 and CD80 and the secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, inducible nitric oxide synthase (iNOS), and IL-12 in macrophage induced by EVs derived from CSE-treated BEAS-2B. Further research revealed that naringenin downregulated BEAS-2B-derived EVs miR-21-3p which targeted phosphatase and tensin homolog deleted on chromosome ten/protein kinase B (PTEN/AKT) cascade in macrophages and then suppressed M1 macrophage polarization. Subsequent proteomics suggested that naringenin decreased BEAS-2B-derived EVs poly ADP-ribose polymerase (PARP)1 expression thereby suppressing M1 macrophage polarization probably. Our study provides novel pharmacological references for the mechanism of naringenin in the treatment of cigarette smoke-induced lung inflammatory diseases.

Bioinformatics-based screening of key genes between maternal preeclampsia and offspring schizophrenia.

Converging lines of evidence suggest an association between schizophrenia and prenatal neurodevelopmental disorders. Preeclampsia is a multisystem disease based on the coexistence of pregnancy and elevated blood pressure, which increases the risk for offspring abnormal neurodevelopment. Previous studies have showed maternal preeclampsia is associated with an increased risk of offspring schizophrenia, but the molecular mechanism remains unclear. In this study, we sought to identify key protein-coding genes between maternal preeclampsia and offspring schizophrenia. GSE53987 and GSE166846 datasets from Gene Expression Omnibus (GEO) database were analysed to obtain common differentially expressed genes (DEGs) between preeclampsia and schizophrenia. GSE62105 dataset was analysed to identify the DEGs' expressions in neural cells from one control and one schizophrenic patient. GSE92845 dataset was analysed to describe the changes of the DEGs in human neural stem cells. In total, we obtained ten common DEGs. All of them expressed differently in neural cells of the control and schizophrenic patient. We chose the six DEGs that had similar trend in both neural cells and UCB from preeclampsia patients and analysed their expressions in human neural stem cells over time. We found the expressions of CKAP5 and SAT1 in day 30 had significant difference comparing with those in day 0. The KEGG pathway analysis of their interaction proteins showed they were involved with metabolism. Our results may provide a new insight for genetic basis of relationship between maternal preeclampsia and offspring schizophrenia.

Multi-Omics Analysis Reveals the Systematic Relationship Between Oral Homeostasis and Chronic Sleep Deprivation in Rats.

Sleep disorders were associated with oral health. Inflammation has especially been thought to be a key factor in linking oral diseases and sleep deficiency. However, how chronic sleep deprivation (CSD) affects oral homeostasis, particularly oral inflammation and oral microbiota, is still unknown. This study aimed to uncover the systematic relationship between oral homeostasis and CSD in rats. The metabolomics in serum, proteomics in the tongue tissues, and microbiome analysis in the oral cavity in CSD rats were performed. Multi-omics data integration analysis was performed to uncover the systematic relationship between oral homeostasis and CSD through the weighted correlation network analysis. We found that CSD could lead to oral inflammation in rats. CSD significantly increased systemic inflammation by enhancing the serum levels of IL-1ß, IL-6 and inhibiting the serum level of IL-10. Serum levels of adrenocorticotropin hormone, corticosterone, and triiodothyronine were increased in CSD rats, and the steroid hormone biosynthesis pathway was also found to be involved in the perturbation resulting from CSD, together suggesting the activation of the hypothalamic-pituitary-adrenocortical and hypothalamic-pituitary-thyroid axis. CSD led to changes of oral microbiota composition, and g_Acinetobacter, Candidatus Chryseobacterium massiliae, and g_Moraxella were significantly correlated with multiple proteins in bacterial invasion of epithelial cells pathway, which may partially responsible for oral inflammation resulting from CSD. The changes of proteomic profiling expression caused by CSD in tongue tissues were mainly enriched in neurodegenerative diseases pathways and immune/inflammation-related pathways. Multi-omics analysis indicated that the inflammatory response-related modules were significantly correlated with the neurodegenerative disease-related module suggesting a possible link between neurodegenerative diseases and oral inflammation. Together, CSD induced oral inflammation and subtle changes on oral microbiota. Our study is helpful to further understand the role that oral homeostasis plays in the process by which CSD affects human health and disease.

Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia-associated insulin resistance.

Hyperinsulinemia is commonly viewed as a compensatory response to insulin resistance, yet studies have demonstrated that chronically elevated insulin may also drive insulin resistance. The molecular mechanisms underpinning this potentially cyclic process remain poorly defined, especially on a transcriptome-wide level. Transcriptomic meta-analysis in >450 human samples demonstrated that fasting insulin reliably and negatively correlated with INSR mRNA in skeletal muscle. To establish causality and study the direct effects of prolonged exposure to excess insulin in muscle cells, we incubated C2C12 myotubes with elevated insulin for 16 h, followed by 6 h of serum starvation, and established that acute AKT and ERK signaling were attenuated in this model of in vitro hyperinsulinemia. Global RNA-sequencing of cells both before and after nutrient withdrawal highlighted genes in the insulin receptor (INSR) signaling, FOXO signaling, and glucose metabolism pathways indicative of 'hyperinsulinemia' and 'starvation' programs. Consistently, we observed that hyperinsulinemia led to a substantial reduction in Insr gene expression, and subsequently a reduced surface INSR and total INSR protein, both in vitro and in vivo. Bioinformatic modeling combined with RNAi identified SIN3A as a negative regulator of Insr mRNA (and JUND, MAX, and MXI as positive regulators of Irs2 mRNA). Together, our analysis identifies mechanisms which may explain the cyclic processes underlying hyperinsulinemia-induced insulin resistance in muscle, a process directly relevant to the etiology and disease progression of type 2 diabetes.

Long-Term Physical and Mechanical Properties and Microstructures of Fly-Ash-Based Geopolymer Composite Incorporating Carbide Slag.

The long-term property development of fly ash (FA)-based geopolymer (FA-GEO) incorporating industrial solid waste carbide slag (CS) for up to 360 d is still unclear. The objective of this study was to investigate the fresh, physical, and mechanical properties and microstructures of FA-GEO composites with CS and to evaluate the effects of CS when the composites were cured for 360 d. FA-GEO composites with CS were manufactured using FA (as an aluminosilicate precursor), CS (as a calcium additive), NaOH solution (as an alkali activator), and standard sand (as a fine aggregate). The fresh property and long-term physical properties were measured, including fluidity, bulk density, porosity, and drying shrinkage. The flexural and compressive strengths at 60 d and 360 d were tested. Furthermore, the microstructures and gel products were characterized by scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS). The results show that the additional 20.0% CS reduces the fluidity and increases the conductivity of FA-GEO composites. Bulk densities were decreased, porosities were increased, and drying shrinkages were decreased as the CS content was increased from 0.0% to 20.0% at 360 d. Room temperature is a better curing condition to obtain a higher long-term mechanical strength. The addition of 20.0% CS is more beneficial to the improvement of long-term flexural strength and toughness at room temperature. The gel products in CS-FA-GEO with 20.0% CS are mainly determined as the mixtures of sodium aluminosilicate (N-A-S-H) gel and calcium silicate hydration (C-S-H) gel, besides the surficial pan-alkali. The research results provide an experimental basis for the reuse of CS in various scenarios.

miRNAomics analysis reveals the promoting effects of cigarette smoke extract-treated Beas-2B-derived exosomes on macrophage polarization.

Inhalation of cigarette smoke induces airway and parenchyma inflammation that predisposes smokers to multiple lung diseases such as COPD. Macrophage polarization, an important specifying feature of inflammation, is involved in the progression of pulmonary inflammation. Exosomes and their loaded miRNAs provide a medium for cross-talk between alveolar macrophages and lung epithelial cells to maintain lung homeostasis. In this study, we treated Beas-2B with CSE to speculate the effects of Beas-2B-derived exosomes on macrophage polarization and performed exosomal miRNAomics analysis to explore the mechanism. We found that CSE-treated Beas-2B-derived exosomes could not only increase the percentages of CD86+, CD80+ CD163+, and CD206+ cells but also induce the secretion of TNF-α, IL-6, iNOS, IL-10, Arg-1, and TGF-ß, indicating both M1 and M2 polarization of RAW264.7 macrophages were promoting. We performed miRNAomics analysis to identify 27 differentially expressed exosomal miRNAs such as miR-29a-3p and miR-1307-5p. Next, we obtained 14942 target genes of these miRNAs such as SCN1A and PLEKHA1 through the prediction of TargetScan and miRanda. We utilized KEGG enrichment analysis for these targets to identify potential pathways such as the PI3K-Akt signaling pathway and the MAPK signaling pathway on the regulation of macrophage polarization. We further found that miR-21-3p or miR-27b-3p may play critical roles in the promotion of CSE-Exo on macrophage polarization by miRNA interference. Collectively, this study provided novel information for diagnostic and therapeutic tactics of cigarette smoke-related lung diseases.