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Rationale: Consumption of a high-fat diet (HFD) has been implicated in cognitive deficits and gastrointestinal dysfunction in humans, with the gut microbiota emerging as a pivotal mediator of these diet-associated pathologies. The introduction of plant-based polysaccharides into the diet as a therapeutic strategy to alleviate such conditions is gaining attention. Nevertheless, the mechanistic paradigm by which polysaccharides modulate the gut microbiota remains largely undefined. This study investigated the mechanisms of action of Eucommiae cortex polysaccharides (EPs) in mitigating gut dysbiosis and examined their contribution to rectifying diet-related cognitive decline. Methods: Initially, we employed fecal microbiota transplantation (FMT) and gut microbiota depletion to verify the causative role of changes in the gut microbiota induced by HFD in synapse engulfment-dependent cognitive impairments. Subsequently, colonization of the gut of chow-fed mice with Escherichia coli (E. coli) from HFD mice confirmed that inhibition of Proteobacteria by EPs was a necessary prerequisite for alleviating HFD-induced cognitive impairments. Finally, supplementation of HFD mice with butyrate and treatment of EPs mice with GW9662 demonstrated that EPs inhibited the expansion of Proteobacteria in the colon of HFD mice by reshaping the interactions between the gut microbiota and colonocytes. Results: Findings from FMT and antibiotic treatments demonstrated that HFD-induced cognitive impairments pertaining to neuronal spine loss were contingent on gut microbial composition. Association analysis revealed strong associations between bacterial taxa belonging to the phylum Proteobacteria and cognitive performance in mice. Further, introducing E. coli from HFD-fed mice into standard diet-fed mice underscored the integral role of Proteobacteria proliferation in triggering excessive synaptic engulfment-related cognitive deficits in HFD mice. Crucially, EPs effectively counteracted the bloom of Proteobacteria and subsequent neuroinflammatory responses mediated by microglia, essential for cognitive improvement in HFD-fed mice. Mechanistic insights revealed that EPs promoted the production of bacteria-derived butyrate, thereby ameliorating HFD-induced colonic mitochondrial dysfunction and reshaping colonocyte metabolism. This adjustment curtailed the availability of growth substrates for facultative anaerobes, which in turn limited the uncontrolled expansion of Proteobacteria. Conclusions: Our study elucidates that colonocyte metabolic disturbances, which promote Proteobacteria overgrowth, are a likely cause of HFD-induced cognitive deficits. Furthermore, dietary supplementation with EPs can rectify behavioral dysfunctions associated with HFD by modifying gut microbiota-colonocyte interactions. These insights contribute to the broader understanding of the modulatory effects of plant prebiotics on the microbiota-gut-brain axis and suggest a potential therapeutic avenue for diet-associated cognitive dysfunction.
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Disfunción Cognitiva , Dieta Alta en Grasa , Disbiosis , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Polisacáridos , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Dieta Alta en Grasa/efectos adversos , Ratones , Disfunción Cognitiva/terapia , Polisacáridos/farmacología , Masculino , Disbiosis/terapia , Colon/microbiología , Escherichia coli , Butiratos/metabolismo , Proteobacteria/aislamiento & purificación , Proteobacteria/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: The associations of gut microbial metabolites, such as trimethylamine N-oxide (TMAO), its precursors, and phenylacetylglutamine (PAGln), with the risk of gestational diabetes mellitus (GDM) remain unclear. METHODS: Serum samples of 201 women with GDM and 201 matched controls were collected and then targeted metabolomics was performed to examine the metabolites of interest. Multivariable conditional logistic regression was applied to investigate the relationship between metabolites and GDM. Meta-analysis was performed to combine our results and four similar articles searched from online databases, and Mendelian randomization (MR) analysis was eventually conducted to explore the causalities. RESULTS: In the case-control study, after dichotomization and comparing the higher versus the lower group, the adjusted odds ratio and 95% confidence interval of choline and L-carnitine with GDM were 2.124 (1.186-3.803) and 0.293 (0.134-0.638), respectively; but neutral relationships between TMAO, betaine, and PAGln with GDM were observed. The following meta-analysis consistently revealed that L-carnitine was negatively associated with GDM. However, MR analyses showed no evidence of causalities. CONCLUSIONS: Maternal levels of L-carnitine were related to the risk of GDM in both the original case-control study and meta-analysis. However, we did not observe any genetic evidence to establish a causal relationship between this metabolite and GDM.
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Atrazine, a commonly employed herbicide for corn production, can leave residues in soil, resulting in photosynthetic toxicity and impeding growth in subsequent alfalfa (Medicago sativa L.) crops within alfalfa-corn rotation systems. The molecular regulatory mechanisms by which atrazine affects alfalfa growth and development, particularly its impact on the microbial communities of the alfalfa rhizosphere, are not well understood. This study carried out field experiments to explore the influence of atrazine stress on the biomass, chlorophyll content, antioxidant system, and rhizosphere microbial communities of the atrazine-sensitive alfalfa variety WL-363 and the atrazine-resistant variety JN5010. The results revealed that atrazine significantly reduced WL-363 growth, decreasing plant height by 8.58 cm and root length by 5.42 cm (p < 0.05). Conversely, JN5010 showed minimal reductions, with decreases of 1.96 cm in height and 1.26 cm in root length. Chlorophyll content in WL-363 decreased by 35% under atrazine stress, while in JN5010, it was reduced by only 10%. Reactive oxygen species (ROS) accumulation increased by 60% in WL-363, compared to a 20% increase in JN5010 (p < 0.05 for both). Antioxidant enzyme activities, such as superoxide dismutase (SOD) and catalase (CAT), were significantly elevated in JN5010 (p < 0.05), suggesting a more robust defense mechanism. Although the predominant bacterial and fungal abundances in rhizosphere soils remained generally unchanged under atrazine stress, specific microbial groups exhibited variable responses. Notably, Promicromonospora abundance declined in WL-363 but increased in JN5010. FAPROTAX functional predictions indicated shifts in the abundance of microorganisms associated with pesticide degradation, resistance, and microbial structure reconstruction under atrazine stress, displaying different patterns between the two varieties. This study provides insights into how atrazine residues affect alfalfa rhizosphere microorganisms and identifies differential microbial responses to atrazine stress, offering valuable reference data for screening and identifying atrazine-degrading bacteria.
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BACKGROUND: Idiopathic inflammatory myopathy (IIM) is a systemic autoimmune disease characterized by skeletal muscle involvement. This study aimed to investigate the role of adenosine receptor signalling pathways in the development of experimental autoimmune myositis (EAM). METHODS: An ecto-5'-nucleotidase (CD73) inhibitor, adenosine receptor agonists, a hypoxia-inducible factor-1α (HIF-1α) inhibitor or a vehicle were administered to control and EAM mice. Murine splenic CD4+ or regulatory T cells (Tregs) were isolated using magnetic beads and subsequently stimulated with an adenosine A2B receptor agonist, a HIF-1α inhibitor, or vehicle in vitro. In cross-sectional studies, we collected 64 serum samples (69% female, 49 ± 9 years), 63 peripheral blood samples (70% female, 50 ± 11 years), and 34 skeletal muscle samples (71% female, 63 ± 6 years) from patients with IIM. Additionally, 35 serum samples and 30 peripheral blood samples were obtained from age- and sex-matched healthy controls, and six quadriceps muscle samples were collected from patients with osteoarthritis to serve as the normal group. RESULTS: Patients with IIM exhibited increased CD73 [dermatomyositis (DM), polymyositis (PM): P < 0.01; immune-mediated necrotizing myopathy (IMNM): P < 0.0001] and adenosine deaminase (ADA) expression (DM: P < 0.001; PM, IMNM: P < 0.0001) in the skeletal muscles, and serum ADA levels [56.7 (95% CI: 53.7, 58.7) vs. 198.8 (95% CI: 186.2, 237.3) ng/µL, P < 0.0001]. Intervention with a CD73 inhibitor exacerbated (P = 0.0461), whereas adenosine receptor agonists (A1: P = 0.0009; A2B: P < 0.0001; A3: P = 0.0001) and the HIF-1α inhibitor (P = 0.0044) alleviated skeletal muscle injury in EAM mice. Elevated expression of programmed cell death protein-1 (PD1: P = 0.0023) and T-cell immunoglobulin and mucin-domain containing-3 (TIM3: P < 0.0001) in skeletal muscles of patients with IIM were correlated with creatine kinase levels (PD1, r = 0.7072, P < 0.0001; TIM3, r = 0.4808, P = 0.0046). PD1+CD4+ (r = 0.3243, P = 0.0115) and PD1+CD8+ (r = 0.3959, P = 0.0017) T cells were correlated with Myositis Disease Activity Assessment Visual Analogue Scale scores (muscle) in IIM. The exhausted Tregs were identified in the skeletal muscles of patients with IIM. Activation of the A2B adenosine receptor downregulated HIF-1α (protein or mRNA level, P < 0.01), resulting in decreased T helper cell 17 (Th17) (13.58% vs. 5.43%, P = 0.0201) and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3)+ Th17 (16.32% vs. 6.73%, P = 0.0029), decreased exhausted Tregs (PD1+ Tregs: 53.55% vs. 40.28%, P = 0.0005; TIM3+ Tregs: 3.93% vs. 3.11%, P = 0.0029), and increased Tregs (0.45% vs. 2.89%, P = 0.0006) in EAM mice. CONCLUSIONS: The exhausted T cells may be pathogenic in IIM, and the activation of adenosine A2B receptor signalling pathway can regulate Th17/Treg balance and inhibit Tregs exhaustion, thereby slowing EAM disease progression.
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OBJECTIVES: Idiopathic inflammatory myopathy (IIM) is a group of systemic autoimmune diseases characterised by muscle involvement. This study aims to reveal the characteristics of IIM subtypes and explore the molecular mechanisms underlying IIM. METHODS: The STRING database was utilised to construct a protein-protein interaction network of differentially expressed genes obtained from the GSE128470, GSE3112, and GSE39454 datasets. The immune cell infiltration level was assessed by CIBERSORT in polymyositis (PM). Experimental autoimmune myositis (EAM) model mice were constructed for experimental verification. Serum levels of soluble CD44 (sCD44) were measured using enzyme-linked immunosorbent assay. RESULTS: The upregulated hub gene CD44 was highly expressed in inflammatory cells infiltrating the skeletal muscle of patients with PM and in EAM mice. CD44 was correlated with both M1 macrophages (r=0.57, p<0.0001) and M2 macrophages (r=0.57, p<0.0001) in PM. Additionally, CD44+F4/80+ macrophages in skeletal muscle were increased (p<0.0001) and CD44 showed a stronger association with markers of M1 macrophage in EAM mice. Moreover, serum sCD44 levels were elevated in patients with IIM (p=0.0024), PM (p=0.0332) and dermatomyositis (p=0.0001) notably in the anti-melanoma differentiation-associated gene 5 antibody positive subtype (p=0.0007). sCD44 levels also positively correlated with visual analogue score (r=0.4424, p=0.0013), myositis intention to treat activity index (r=0.3938, p=0.0047), skin damage score (r=0.3796, p=0.0101) and skin activity score (r=0.4625, p=0.0014) in patients with IIM. CONCLUSIONS: This study suggests that macrophages expressing CD44 may be involved in the pathogenesis of PM, and sCD44 could serve as a potential marker for skin damage and activity in IIM.
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The dynamic balance between the self-renewal and differentiation of stem cells in plants is precisely regulated by a series of developmental regulated genes that exhibit spatiotemporal-specific expression patterns. Several studies have demonstrated that the WOX family transcription factors play critical roles in maintaining the identity of stem cells in Arabidopsis thaliana. In this study, we obtained amiR-WOX9 transgenic plants, which displayed terminating prematurely of shoot apical meristem (SAM) development, along with alterations in inflorescence meristem and flower development. The phenotype of amiR-WOX9 plants exhibited similarities to that of wus-101 mutant, characterized by a stop-and-go growth pattern. It was also found that the expression of WUS in amiR-WOX9 lines was decreased significantly, while in UBQ10::WOX9-GFP transgenic plants, the WUS expression was increased significantly despite no substantial alteration in meristem size compared to Col. Therefore, these data substantiated the indispensable role of WOX9 in maintaining the proper expression of WUS. Further investigations unveiled the direct binding of WOX9 to the WUS promoter via the TAAT motif, thereby activating its expression. It was also found that WUS recognized identical the same TAAT motif cis-elements in its own promoter, thereby repress self-expression. Next, we successfully identified a physical interaction between WOX9 and WUS, and verified that it was harmful to the expression of WUS. Finally, our experimental findings demonstrate that WOX9 was responsible for the direct activating of WUS, which however was interfered by the ways of WUS binding its own promoter and the interaction of WUS and WOX9, thereby ensuring the appropriate expression pattern of WUS and then the stem cell stability. This study contributes to an enhanced comprehension of the regulatory network of the WOX9-WUS module in maintaining the equilibrium of the SAM.
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BACKGROUND: Baryscapus dioryctriae (Chalcidodea: Eulophidae) is a parasitic wasp that parasitizes the pupae of many Pyralidae members and has been used as a biological control agent against Dioryctria pests of pinecones. RESULTS: This B. dioryctriae assembly has a genome size of 485.5 Mb with a contig N50 of 2.17 Mb, and scaffolds were assembled onto six chromosomes using Hi-C analysis, significantly increasing the scaffold N50 to 91.17 Mb, with more than 96.13% of the assembled bases located on chromosomes, and an analysis revealed that 94.73% of the BUSCO gene set. A total of 54.82% (279.27 Mb) of the assembly was composed of repetitive sequences and 24,778 protein-coding genes were identified. Comparative genomic analysis demonstrated that the chemosensory perception, genetic material synthesis, and immune response pathways were primarily enriched in the expanded genes. Moreover, the functional characteristics of an odorant-binding protein (BdioOBP45) with ovipositor-biased expression identified from the expanded olfactory gene families were investigated by the fluorescence competitive binding and RNAi assays, revealing that BdioOBP45 primarily binds to the D. abietella-induced volatile compounds, suggesting that this expanded OBP is likely involved in locating female wasp hosts and highlighting a direction for future research. CONCLUSIONS: Taken together, this work not only provides new genomic sequences for the Hymenoptera systematics, but also the high-quality chromosome-level genome of B. dioryctriae offers a valuable foundation for studying the molecular, evolutionary, and parasitic processes of parasitic wasps.
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Genoma de los Insectos , Receptores Odorantes , Avispas , Animales , Avispas/fisiología , Avispas/genética , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Señales (Psicología) , Cromosomas de Insectos/genética , Femenino , Interacciones Huésped-ParásitosRESUMEN
OBJECTIVE: The objective of this study is to search for hydroxysafflor yellow A (HSYA) and Idiopathic sudden sensorineural hearing loss (ISSNHL)-related target genes and to study the treatment effects of HSYA on lipopolysaccharide (LPS)-induced endothelial cell injury. METHODS: We used network pharmacology to screen molecules related to HSYA and ISSNHL, then analyzed these molecules and their enriched biological processes and signaling pathways via Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). We selected inflammation-related hub genes for molecular docking determination by protein-protein interaction (PPI) analysis, and further verified them with in vitro experiments. RESULTS: Thirty-four HSYA-ISSNHL-related differential genes were obtained using drug-disease differential gene screening using online tools. Three key proteins, NF-κB, CASP3, and MAPK1, were selected according to Degree > 20. Among them, NF-κB is closely related to inflammation and ISSNHL. In in vitro experiments, HSYA reduced inflammatory (IL-6, TNF- α) and oxidative stress (ROS, SOD and MDA) indicators after LPS intervention, and the expression of NF-κB-related signaling pathway genes. CONCLUSION: HSYA may reduce inflammation and oxidative stress by inhibiting the expression of the TLR4 / NF-κB-related signaling pathway, therefore protecting endothelial cells, which might be a potential mechanism of HSYA in ISSNHL treatment.
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Introduction. Cytotoxin-associated gene A (CagA) from Helicobacter pylori is highly related to chronic gastritis. Tyrosine phosphorylation of Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs from CagA determines the pathogenicity of H. pylori.Gap statement. The precise amino acid variations surrounding the EPIYA motifs and their correlation with clinical outcomes have been poorly explored.Aim. The purpose of this study was to examine the CagA 3' region polymorphism of H. pylori and its association with chronic gastritis in the Chinese population.Method. A total of 86 cagA-positive H. pylori strains were isolated from patients with chronic gastritis in two different hospitals in Beijing, PR China. Genomic DNA was extracted commercial kits, and the cagA 3' variable region of H. pylori was amplified by polymerase chain reaction (PCR). The PCR products were sequenced and analysed using the CLC Sequence Viewer, BioEdit, and WebLogo 3.Results. Two hundred and fifty-nine EPIYA motifs were identified from cagA-positive H. pylori strains. Notably, EPIYA-B exhibited a higher frequency of variation in comparison to EPIYA-A, EPIYA-C, and EPIYA-D. The prevalent sequences for East-Asian-type CagA were QVNK and TIDF, while KVNK and TIDD were most commonly observed for Western-type CagA. The CRPIA motifs of East-Asian-type CagA and Western-type CagA varied at positions 4, 6, 7, 8, and 10. CagA-ABD (73.2%) was the most prevalent type, followed by CagA-ABC (18.6%) and CagA-AB (3.4%). The ratio of CagA-ABD was observed to be higher in cases of chronic non-atrophic gastritis with erosive (NAGE) or chronic atrophic gastritis (AG) compared to chronic non-atrophic gastritis (NAG), and the difference was found to be statistically significant (χ2=59.000/64.000, P<0.001).Conclusions. The EPIYA segments of Western-type CagA and East-Asian-type CagA differ significantly and the presence of CagA-ABD may be associated with severe chronic gastritis from this study.
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Antígenos Bacterianos , Proteínas Bacterianas , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Polimorfismo Genético , Humanos , Antígenos Bacterianos/genética , Helicobacter pylori/genética , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/patogenicidad , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Gastritis/microbiología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/epidemiología , Masculino , Femenino , China/epidemiología , Enfermedad Crónica , Persona de Mediana Edad , Adulto , Anciano , Pueblo Asiatico/genética , Secuencias de Aminoácidos , Pueblos del Este de AsiaRESUMEN
OBJECTIVE: To study the effect of long snake moxibustion intervention on gut microbiota of patients with ankylosing spondylitis (AS) by 16S rDNA sequencing technology. METHODS: 30 AS patients and 30 healthy volunteers were recruited and treated with long snake moxibustion once a week for 12 weeks. AS patients were divided into pre-treatment and post-treatment groups. VAS, BASDAI and BASFI scores of AS patients before and after treatment were collected. 16S rDNA high-throughput sequencing technology was used to analyze the characteristics and differences of gut microbiota in AS patients before and after treatment and in healthy volunteers. RESULTS: VAS, BASDAI and BASFI scores of AS patients after long snake moxibustion treatment were lower than those of pre-treatment group (P<0.05). The results of gut microbiota Alpha diversity showed that ace and chao1 index of the post-treatment group were higher than those of the healthy group (P<0.05), but there was no statistical significance in ace and chao1 index between the pre-treatment group and the post-treatment group (P>0.05). Beta diversity analysis showed that mild classification aggregation occurred between the healthy group and the pre-treatment group , but did not reach a significant level, and there was no significant difference between the the pre-treatment group and the post-treatment group. The results of species abundance showed that, at the phylum level, compared with the healthy group, the relative abundance of Firmicutes and Proteobacteria decreased in the pre-treatment group, while the relative abundance of Bacteroidetes and Actinobacteria increased. Compared with the pre-treatment group, the relative abundance of Firmicutes increased and the relative abundance of Actinobacteria decreased in the post-treatment group, but there were no statistically significant differences in the above changes (P>0.05). At the genus level, compared with the healthy group, the relative abundances of Subdoligranulum in the pre-treatment group were increased (P<0.05), while the relative abundances of Bifidobacterium and Streptococcus were decreased (P<0.05). Compared with the pre-treatment group, the relative abundance of Romboutsia in the post-treatment group was increased (P<0.05). CONCLUSION: Long snake moxibustion can obviously improve the clinical symptoms of AS patients. The possible mechanism of action is related to regulating the abundance of gut microbiota, increasing beneficial bacteria and restoring the homeostasis of gut microorganisms.
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OBJECTIVE: Previous cementless total knee arthroplasty (TKA) designs faced challenges with insufficient initial fixation on tibial side, resulting in inferior functional outcomes and survival rates. The Zoned Trabecular Bone Cementless Knee is a novel implant designed for cementless TKA which aims to achieve excellent initial fixation, promoting effective osseointegration. The aim of this research was to compare the early clinical and radiographic results of this cementless TKA with cemented TKA. METHODS: Between September 2021 and April 2022, 64 patients (64 knees) were recruited in this prospective randomized controlled trial to receive either cementless 3D-printed trabecular metal TKA or a cemented posterior stabilized TKA. Preoperative and postoperative clinical evaluations, including the range of motion (ROM), Knee Society Score (KSS), and the Reduced Western Ontario and MacMaster Universities Score (WOMAC), were conducted and analyzed for comparison. Radiographs and computed tomography scans were utilized to assess the initial fixation. The complications between the two groups were also recorded and compared. Continuous data were analyzed for significance using independent-samples t-test or the Mann-Whitney U test and categorical data were analyzed using chi-squared or Fisher's exact test. RESULTS: Both groups demonstrated significant enhancement at 12 months follow-up in the ROM compared with baseline (ROM: 94.7 ± 23.4 vs. 113.1 ± 12.3 in cementless group and 96.5 ± 14.7 vs. 111.0 ± 12.8 in cemented group, p < 0.05). However, no statistical differences were observed between the two groups in postoperative ROM, KSS, or WOMAC score. The radiographs and computed tomography scans showed similar results, including radiolucent lines and osteolysis in either femoral or tibial. Additionally, there was no statistical difference in the overall complication rate between the two groups. Notably, one patient in the cementless TKA group required revision for periprosthetic infection as the end point. CONCLUSIONS: This novel 3D-printed trabecular metal cementless TKA achieved comparable clinical outcomes and initial fixation to cemented TKA in early stage. Longer-term examination is necessary to validate these results.
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BACKGROUND: We previously reported that the HMGB1/TLR4 axis promoted inflammation during the acute phase of intracerebral hemorrhage. Given that this phase is known to involve neuronal pyroptosis and neuroinflammation, here we explore whether HMGB1/TLR signaling activate inflammasome and pyroptosis after intracerebral hemorrhage. METHODS: Autologous blood was injected into Sprague-Dawley rats to induce intracerebral hemorrhage. Neurological deficits were assessed using a modified neurological severity score. These expression and localization of NLRP1 and NLRP3 inflammasomes, as well as the levels of pyroptosis and pyroptosis-associated proteins were assessed using Western blot or immunocytochemistry. These experiments were repeated in animals that received treatment with short interfering RNAs against NLRP1 or NLRP3, with HMGB1 inhibitor ethyl pyruvate or TLR4 inhibitor TAK-242. RESULTS: Intracerebral hemorrhage upregulated NLRP1 and NLRP3 in the ipsilateral striatum and increased the proportions of these cells that were pyroptosis-positive. Additionally, the levels of caspase protein family (e.g., pro-caspase-1 and caspase-1), apoptosis-associated speck-like protein (ASC), pro-interleukin-1ß (IL-1ß), and IL-1ß were also elevated. These effects on pyroptosis and associated neurological deficit, were partially reversed by knockdown of NLRP1 or NLRP3, or by inhibition of HMGB1 or TLR4. Inhibition of HMGB1 or TLR4 resulted in the downregulation NLRP3 but not NLRP1. CONCLUSIONS: The HMGB1/TLR4 signaling may activate the NLRP3 inflammasome during the acute phase of intracerebral hemorrhage, resulting in the inflammatory process known as pyroptosis. These insights suggest potential therapeutic targets for the mitigation tissue injury and associated neurological deficits following hemorrhagic stroke.
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Hemorragia Cerebral , Proteína HMGB1 , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Ratas Sprague-Dawley , Receptor Toll-Like 4 , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis/fisiología , Piroptosis/efectos de los fármacos , Proteína HMGB1/metabolismo , Ratas , Receptor Toll-Like 4/metabolismo , Masculino , Hemorragia Cerebral/metabolismo , Inflamasomas/metabolismo , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Proteínas del Tejido NerviosoRESUMEN
Cardiovascular diseases, mainly caused by atherosclerosis, are the leading causes of morbidity and mortality worldwide. Despite the discrepancies in clinical manifestations between different abnormalities, atherosclerosis shares similar pathophysiological processes, such as mitochondrial dysfunction. Cardiolipin (CL) is a conserved mitochondria-specific lipid that contributes to the cristae structure of the inner mitochondrial membrane (IMM). Alterations in the CL, including oxidative modification, reduced quantity, and abnormal localization, contribute to the onset and progression of atherosclerosis. In this review, we summarize the knowledge that CL is involved in the pathogenesis of atherosclerosis. On the one hand, CL and its oxidative modification promote the progression of atherosclerosis via several mechanisms, including oxidative stress, apoptosis, and inflammation in response to stress. On the other hand, CL externalizes to the outer mitochondrial membrane (OMM) and acts as the pivotal "eat-me" signal in mitophagy, removing dysfunctional mitochondria and safeguarding against the progression of atherosclerosis. Given the imbalance between proatherogenic and antiatherogenic effects, we provide our understanding of the roles of the CL and its oxidative modification in atherosclerotic cardiovascular diseases, in addition to potential therapeutic strategies aimed at restoring the CL. Briefly, CL is far more than a structural IMM lipid; broader significances of the evolutionarily conserved lipid need to be explored.
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Aterosclerosis , Cardiolipinas , Estrés Oxidativo , Humanos , Cardiolipinas/metabolismo , Aterosclerosis/metabolismo , Animales , Mitocondrias/metabolismo , Mitofagia , Apoptosis , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológicoRESUMEN
BACKGROUND AND PURPOSE: Toll-like receptors (TLRs) are involved in innate immunity and inflammatory responses in various diseases. Our study aimed to investigate the association between the levels of soluble TLR4 (sTLR4) and soluble TLR2 (sTLR2) and clinical outcomes following intracerebral hemorrhage (ICH). METHODS: Patients admitted to department of Neurology with acute ICH were included. Plasma levels of sTLR4 and sTLR2 after ICH were measured by enzyme-linked immunosorbent assay. Poor clinical outcome was defined as a modified Rankin score (mRS) of 3-6 at 3-month and 12-month after onset. RESULTS: All 207 patients with ICH and 100 non-stroke controls were included in our analysis. The mean sTLR4 level was 4.53±1.51â¯ng/ml and mean sTLR2 level was 3.65±0.72â¯ng/ml. There was significant trend towards worse clinical outcomes with increasing sTLR4 and sTLR2 terciles at 3 and 12 months. According to receiver operating curve (ROC), the sTLR4 was reliable predictor for poor clinical outcome at 3 months (ROC=0.75) and 12 months (ROC=0.74). The sTLR2 was less reliable predictor for poor clinical outcome at 3 months (ROC=0.64) and 12 months (ROC=0.65). The level of sTLR4 was an independent predictor of poor clinical outcome at 12-month (OR 1.24, 95â¯% CI 1.16-1.80; P=0.019). CONCLUSIONS: The sTLR4 quantification may provide accurate prognostic information after ICH.
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Hemorragia Cerebral , Receptor Toll-Like 2 , Receptor Toll-Like 4 , Humanos , Receptor Toll-Like 2/sangre , Hemorragia Cerebral/sangre , Masculino , Femenino , Anciano , Receptor Toll-Like 4/sangre , Persona de Mediana Edad , Resultado del Tratamiento , Anciano de 80 o más Años , Pronóstico , Biomarcadores/sangreRESUMEN
PURPOSE: To investigate the effect of reducing Lysyl oxidase (LOX) overexpression on retinal ganglion cells (RGCs) apoptosis in an acute ocular hypertension (AOH) rat model. METHODS: AOH rat model was performed by anterior chamber perfusion and either received an intravitreal injection with ß-aminopropionitrile (BAPN) or normal saline. After 2wk, Quantification of survival RGCs in the retina was performed using Retrograde FluoroGold labeling. The mRNA expression levels of LOX, LOXL1-4, collagen 1a1 (Col1a1), collagen 3a1 (Col3a1), collagen4a1 (Col4a1), elastin (Eln), fibronectin1 (Fbn1), fibronectin4 (Fbn4) were determined by RT-qPCR. LOX expression was determined by Western blot (WB) analysis and immunohistochemistry. The RNA expression of LOX, Eln and Col1a1 in RGCs retrograde-labeled with 1,1'-dioctadecyl-3,3,3',3' tetra-methylindocarbocyanine perchlorate(DiI)that selected through FACS sorting were determined by RT-qPCR analysis. Changes of the retinal function were detected by Electroretinogram (ERG) analysis. RESULTS: Results showed that significant LOX overexpression and loss of RGCs related to IOP exposure in AOH retinas. PCR analysis indicated significant increased mRNA level of Col1a1, Col3al and Eln in AOH retinas. Significant increase mRNA expression of LOX, Col1a1 and Eln in the RGCs were observed in AOH group compared with CON group. AOH rats injected with BAPN showed a significant decrease in LOX expression, reduced the loss of RGCs and retinal function damage. CONCLUSIONS: The results demonstrated that changes of LOX and specific ECM components in retina were correlated with AOH. Findings from this study indicated that preventing LOX over-expression may be protective against RGCs loss and retinal function damage in AOH animal model.
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The pervasive issue of cheating in educational tests has emerged as a paramount concern within the realm of education, prompting scholars to explore diverse methodologies for identifying potential transgressors. While machine learning models have been extensively investigated for this purpose, the untapped potential of TabNet, an intricate deep neural network model, remains uncharted territory. Within this study, a comprehensive evaluation and comparison of 12 base models (naive Bayes, linear discriminant analysis, Gaussian process, support vector machine, decision tree, random forest, Extreme Gradient Boosting (XGBoost), AdaBoost, logistic regression, k-nearest neighbors, multilayer perceptron, and TabNet) was undertaken to scrutinize their predictive capabilities. The area under the receiver operating characteristic curve (AUC) was employed as the performance metric for evaluation. Impressively, the findings underscored the supremacy of TabNet (AUC = 0.85) over its counterparts, signifying the profound aptitude of deep neural network models in tackling tabular tasks, such as the detection of academic dishonesty. Encouraged by these outcomes, we proceeded to synergistically amalgamate the two most efficacious models, TabNet (AUC = 0.85) and AdaBoost (AUC = 0.81), resulting in the creation of an ensemble model christened TabNet-AdaBoost (AUC = 0.92). The emergence of this novel hybrid approach exhibited considerable potential in research endeavors within this domain. Importantly, our investigation has unveiled fresh insights into the utilization of deep neural network models for the purpose of identifying cheating in educational tests.
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OBJECTIVE: To investigate the mechanism of endothelial cell specific molecule 1 (ESM1) promoting cervical cancer cell proliferation and EMT characteristics through zinc finger E-box binding homeobox 1 (ZEB1)/EMT pathway. METHODS: The correlation between ESM1 expression and prognosis of cervical cancer patients was analyzed by bioinformatics. SiHa, HeLa cell lines and corresponding control cell lines with stable ESM1 expression were obtained. Cell proliferation ability was detected by CCK-8 assay. The invasion and migration ability of Hela and SiHa cells were detected by Transwell assay and scratch closure assay. Expressions of EMT-related markers E-cadherin and Vimentin were detected by real-time PCR. The ability of silenced ESM1 to tumor formation in vivo was detected by tumor formation in nude mice. The effects of aloe-emodin on inhibit ESM1 expression and its inhibitory effect on cervical cancer cells in vitro and in vivo were analyzed by the same method. RESULTS: ESM1 was highly expressed in cervical cancer, and the high expression of ESM1 was associated with poor prognosis of cervical cancer patients. CCK-8 results showed that the proliferation, invasion and migration of Hela and SiHa cells were significantly reduced after siRNA interfered with ESM1 expression. Overexpression of ESM1 promoted the proliferation and migration of cervical cancer cells. Mechanism studies have shown that the oncogenic effect of ESM1 is realized through the ZEB1/PI3K/AKT pathway. High throughput drug screening found that aloe-emodin can target ESM1. Inhibitory effect of aloe emodin on ESM1/ZEB1/EMT signaling pathway and cervical cancer cells. CONCLUSION: The silencing of ESM1 expression may inhibit the proliferation, invasion, metastasis and epithelial-mesenchymal transformation of cervical cancer cells by inhibiting ZEB1/PI3K/AKT. Aloe-emodin is a potential treatment for cervical cancer, which can play an anti-tumor role by inhibiting ESM1/ZEB1.
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Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Proteínas de Neoplasias , Proteoglicanos , Neoplasias del Cuello Uterino , Homeobox 1 de Unión a la E-Box con Dedos de Zinc , Humanos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Femenino , Animales , Proliferación Celular/efectos de los fármacos , Ratones , Movimiento Celular/efectos de los fármacos , Células HeLa , Proteoglicanos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Ratones Desnudos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Invasividad Neoplásica , Pronóstico , Ratones Endogámicos BALB CRESUMEN
Staphylococcus aureus (SA) poses a serious risk to human and animal health, necessitating a low-cost and high-performance analytical platform for point-of-care diagnostics. Cellulose paper-based field-effect transistors (FETs) with RNA-cleaving DNAzymes (RCDs) can fulfill the low-cost requirements, however, its high hydrophilicity and lipophilicity hinder biochemical modification and result in low sensitivity, poor mechanical stability and poor fouling performance. Herein, we proposed a controllable self-cleaning FET to simplify biochemical modification and improve mechanical stability and antifouling performance. Then, we constructed an RCD-based DNA nanotree to significantly enhance the sensitivity for SA detection. For controllable self-cleaning FET, 1 H,1 H,2 H,2 H-perfluorodecyltrimethoxysilane based-polymeric nanoparticles were synthesized to decorate cellulose paper and whole carbon nanofilm wires. O2 plasma was applied to regulate to reduce fluorocarbon chain density, and then control the hydrophobic-oleophobic property in sensitive areas. Because negatively charged DNA affected the sensitivity of semiconducting FETs, three Y-shaped branches with low-cost were designed and applied to synthesize an RCD-based DNA-Nanotree based on similar DNA-origami technology, which further improved the sensitivity. The trunk of DNA-Nanotree was composed of RCD, and the canopy was self-assembled using multiple Y-shaped branches. The controllable self-cleaning FET biosensor was applied for SA detection without cultivation, which had a wide linear range from 1 to 105 CFU/mL and could detect a low value of 1 CFU/mL.
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Técnicas Biosensibles , ADN Catalítico , Staphylococcus aureus , ADN Catalítico/química , ADN Catalítico/metabolismo , Técnicas Biosensibles/métodos , Transistores Electrónicos , ARN/metabolismo , Límite de Detección , Celulosa/química , Papel , Nanopartículas/química , HumanosRESUMEN
BACKGROUND: Heat stress (HS) commonly occurs as a severe pathological response when the body's sensible temperature exceeds its thermoregulatory capacity, leading to the development of chronic brain inflammation, known as neuroinflammation. Emerging evidence suggests that HS leads to the disruption of the gut microbiota, whereas abnormalities in the gut microbiota have been demonstrated to affect neuroinflammation. However, the mechanisms underlying the effects of HS on neuroinflammation are poorly studied. Meanwhile, effective interventions have been unclear. ß-Hydroxybutyric acid (BHBA) has been found to have neuroprotective and anti-inflammatory properties in previous studies. This study aims to explore the modulatory effects of BHBA on neuroinflammation induced by HS and elucidate the underlying molecular mechanisms. METHODS: An in vivo and in vitro model of HS was constructed under the precondition of BHBA pretreatment. The modulatory effects of BHBA on HS-induced neuroinflammation were explored and the underlying molecular mechanisms were elucidated by flow cytometry, WB, qPCR, immunofluorescence staining, DCFH-DA fluorescent probe assay, and 16S rRNA gene sequencing of colonic contents. RESULTS: Heat stress was found to cause gut microbiota disruption in HS mouse models, and TM7 and [Previotella] spp. may be the best potential biomarkers for assessing the occurrence of HS. Fecal microbiota transplantation associated with BHBA effectively reversed the disruption of gut microbiota in HS mice. Moreover, BHBA may inhibit microglia hyperactivation, suppress neuroinflammation (TNF-α, IL-1ß, and IL-6), and reduce the expression of cortical endoplasmic reticulum stress (ERS) markers (GRP78 and CHOP) mainly through its modulatory effects on the gut microbiota (TM7, Lactobacillus spp., Ruminalococcus spp., and Prevotella spp.). In vitro experiments revealed that BHBA (1 mM) raised the expression of the ERS marker GRP78, enhanced cellular activity, and increased the generation of reactive oxygen species (ROS) and anti-inflammatory cytokines (IL-10), while also inhibiting HS-induced apoptosis, ROS production, and excessive release of inflammatory cytokines (TNF-α and IL-1ß) in mouse BV2 cells. CONCLUSION: ß-Hydroxybutyric acid may be an effective agent for preventing neuroinflammation in HS mice, possibly due to its ability to inhibit ERS and subsequent microglia neuroinflammation via the gut-brain axis. These findings lay the groundwork for future research and development of BHBA as a preventive drug for HS and provide fresh insights into techniques for treating neurological illnesses by modifying the gut microbiota.
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Ácido 3-Hidroxibutírico , Eje Cerebro-Intestino , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias , Animales , Ratones , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/fisiología , Eje Cerebro-Intestino/fisiología , Eje Cerebro-Intestino/efectos de los fármacos , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Masculino , Ácido 3-Hidroxibutírico/farmacología , Trastornos de Estrés por Calor/metabolismo , Chaperón BiP del Retículo Endoplásmico , Fármacos Neuroprotectores/farmacología , Respuesta al Choque Térmico/fisiología , Respuesta al Choque Térmico/efectos de los fármacosRESUMEN
BACKGROUND: Silicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it's unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear. METHODS: To evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions. RESULTS: In vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO2-induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-ß/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts. CONCLUSION: In summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis.