Assessing the causal relationship between non-small cell lung cancer and sepsis: a Mendelian randomization study.

BACKGROUND: A Two-sample Mendelian randomization (MR) Analysis was used to assess the causal relationship between non-small cell lung cancer (NSCLC) and sepsis. METHOD: Single nucleotide polymorphisms (SNPs) closely associated with NSCLC were utilized as instrumental variables (IVs) in this study. The Inverse Variance Weighted (IVW) method was used as the primary method for MR analysis, supplemented by the Weighted median, Weighted model, and MR-Egger regression method. Sensitivity analysis was conducted to improve result robustness, and data from various sources were validated and integrated. Bonferroni tests were applied to adjust for multiple comparisons. RESULTS: After Bonferroni tests correcting the combined results, MR analysis revealed a significant association between genetically predicted NSCLC and an increased susceptibility to sepsis (odds ratios [OR]: 1.140, 95% confidence interval [CI]: 1.085-1.199, P = 2.61 × 10- 7). The combined results demonstrated that NSCLC is associated with a heightened risk of sepsis in patients under 75 years of age (OR: 1.085, 95%CI: 1.037-1.353, P = 3.84 × 10- 4). Furthermore, lung adenocarcinoma (LUAD) was found to be potentially associated with an increased susceptibility to sepsis (OR: 1.040, 95% CI: 1.009-1.073, P = 1.16 × 10- 2). These results withstood multiple sensitivity analyses, demonstrating their robustness. CONCLUSION: This study confirms that NSCLC can significantly increase susceptibility to sepsis at the genetic level, providing valuable insights for the early identification of individuals at risk for sepsis.

New flavonoid and their anti-A549 cell activity from the bi-directional solid fermentation products of Astragalus membranaceus and Cordyceps kyushuensis.

Astragalus membranaceus and Cordyceps kyushuensis were used to obtain Astragalus membranaceus-Cordyceps kyushuensis bi-directional solid fermentation products using the bi-directional solid fermentation technique. The fermentation products were isolated and purified to obtain 20 individual compounds, of which compound 1 was a novel isoflavane, and compounds 2, 3, and 4 were novel isoflavones, along with 16 known compounds. In vitro experiments demonstrated that compounds 4, 5, 8, 10, and 20 exhibited significant inhibitory activity against A549 lung cancer cells. Specifically, the IC50 value of the novel compound 4 was 53.4 µM, while the IC50 value of cordycepin was 9.0 µM.

Causality of genetically proxied immunophenotypes on cardiovascular diseases: a Mendelian randomization study.

Background: Cardiovascular diseases (CVDs) stand as the foremost global cause of mortality, prompting a growing interest in using the potential of immune cells for heart injury treatment. This study aims to assess the causal association between immune cells and CVDs. Methods: A total of 731 immune cells were derived from a previously published genome-wide association study (GWAS), which included approximately 22 million genetic variants among 3,757 individuals of Sardinian ancestry. Genetic associations with atrial fibrillation (AF), heart failure, coronary artery disease, myocardial infarction and stroke were extracted from large-scale GWAS. A two-sample Mendelian randomization (MR) analysis was used to assess the causal association between immune cells and CVDs. Replication MR analysis based on FinnGen dataset and meta-analysis are sequentially conducted to validate causal relationships. Results: Collectively, genetically predicted 4 immune cell traits were associated with AF and 5 immune cell traits were associated with stroke. Increased levels of IgD- CD38dim absolute count were associated with a higher susceptibility to AF, while increased expression of CD14+ CD16+ monocytes, CD62L on CD62L+ myeloid dendritic cells, and CD16 on CD14- CD16+ monocytes were linked to a decreased susceptibility to AF. Additionally, an elevated susceptibility to stroke was linked to an increase in the percentage of CD39+ resting Tregs and heightened CD27 expression on IgD- CD38+ cells. Conversely, a decreased susceptibility to stroke was associated with increased CD40 expression on monocytes, particularly on CD14+ CD16+ and CD14+ CD16- monocytes, with the latter two showing the most compelling evidence. Conclusion: This study identified several immune cell traits that have a causal relationship with CVDs, thus confirming that immune cells play an important role in the pathogenesis of these diseases.

Ligature induced periodontitis in rats causes gut dysbiosis leading to hepatic injury through SCD1/AMPK signalling pathway.

AIMS: Previous studies have demonstrated that chronic periodontitis (CP) is closely associated with the occurrence and development of a variety of systemic diseases. In this study, we successfully constructed a rat CP model through dental silk ligation, and the corresponding inflammatory reactions and fatty lesions were observed in the liver. MAIN METHODS: Sprague-Dawley rats (n = 6) underwent tooth ligation at the bilateral first molars with silk thread to induce CP and were sacrificed 8 weeks later and compared to non-ligated rats (n = 6). RNA sequencing and 16S rRNA analysis were performed to determine the molecular mechanisms of CP involved in inducing liver disease. Alveolar bone loss, liver enzymes, mandible and liver histopathology, and inflammatory responses were compared between groups. KEY FINDINGS: RNA sequencing of liver tissue showed that the expression of SCD1 increased significantly in CP rats compared to controls. KEGG enrichment analysis showed that the AMPK signalling pathway may be involved in liver steatosis. The intestinal flora of faecal samples of rats were analysed by 16S rRNA sequencing, and the results indicated that the intestinal flora of the CP group was evidently imbalanced. The expression levels of tight junction proteins (ZO-1, occludin, and claudin-1) were significantly reduced in CP rats. Meanwhile, increases in serum IL-1ß and lipopolysaccharide in CP rats reflected a systemic inflammatory response. SIGNIFICANCE: CP may be involved in the occurrence and development of hepatic injury and liver steatosis, and its mechanism may be related to the oral-gut-liver axis and SCD1/AMPK signal activation in the liver.

Serological investigation and genotyping of Mycobacterium avium subsp. paratuberculosis in sheep and goats in Inner Mongolia, China.

Paratuberculosis a contagious and chronic disease in domestic and wild ruminants, is caused by Mycobacterium avium subspecies paratuberculosis (MAP). Typical clinical signs include intractable diarrhea, progressive emaciation, proliferative enteropathy, and mesenteric lymphadenitis. Paratuberculosis is endemic to many parts of the world and responsible for considerable economic losses. In this study, different types of paratuberculosis and MAP in sheep and goats were investigated in Inner Mongolia, a northern province in China contiguous with two countries and eight other provinces. A total of 4434 serum samples were collected from six cities in the western, central, and eastern regions of Inner Mongolia and analyzed using the ELISA test. In addition, tissue samples were collected from seven animals that were suspected to be infected with MAP. Finally, these tissues samples were analyzed by histopathological examination followed by polymerase chain reaction (PCR), IS1311 PCR-restriction enzyme analysis (PCR-REA), and a sequence analysis of five genes. Among all 4434 ruminant serum samples collected from the six cities in the western, central, and eastern regions of Inner Mongolia, 7.60% (337/4434) measured positive for the MAP antibody. The proportions of positive MAP antibody results for serum samples collected in the western, central, and eastern regions were 5.10% (105/2058), 6.63% (85/1282), and 13.44% (147/1094), respectively. For the seven suspected infected animals selected from the herd with the highest rate of positivity, the gross pathology and histopathology of the necropsied animals were found to be consistent with the pathological features of paratuberculosis. The PCR analysis further confirmed the diagnosis of paratuberculosis. The rest of the results demonstrated that herds of sheep and goats in Inner Mongolia were infected with both MAP type II and type III. To the best of our knowledge, this is the first study of the two subtypes of MAP strains in sheep and goats in Inner Mongolia.

Transcriptome sequencing reveals fibrotic associated-genes involved in bovine mammary fibroblasts with Staphylococcus aureus.

Bovine mammary fibrosis represents a considerable health problem of cows, primarily indicated by lactation failure. Staphylococcus aureus (S. aureus) can cause mammary damage, this multifactorial disease necessitates to identify how and to what extent molecular pathogen defense mechanisms prevent bacterial infections in bovine mammary gland. In this study, we have aimed to determine the transcriptional responses in bovine mammary fibroblasts (BMFBs) induced by S. aureus using bioinformatics analysis to determine whether mRNA expression profile changes between BMFBs activation and quiescence. Established primary BMFBs obtained from healthy Holstein bovine were induced 106 CFU/mL heat-inactivated S. aureus and total RNA was isolated 6 h after treatment. The 574 DEGs were involved in gene ontology (GO) that were immune response, apoptotic process, extracellular region, receptor binding, endopeptidase activity and protein kinase activity et al. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, distinct pathway contained signaling molecules common to various inflammatory and fibrotic pathways were Pathways in cancer, Cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, TNF signaling pathway, MAPK signaling pathway and Toll-like receptor signaling pathway. The BMFBs was treated with heat-inactivated S. aureus (106 CFU/mL) and also with pharmacological inhibitors of ERK1/2, P38 MAPK and JNK. The MMP-2 activity were examined gelatin zymography, MMP-2, TIMP-1, -2 and PLAU/PAI-1 protein expression were examined in vitro by western blot. The MMP-2 activity was significantly inhibited by simultaneous inhibition of ERK1/2, P38 MAPK and JNK, and MMP-2, TIMP-1,-2 and PLAU/PAI-1 protein expression were significantly decreased by inhibiting ERK1/2, P38 MAPK or JNK. This suggested a crosstalk between the ERK1/2, P38 MAPK or JNK signaling pathways in regulating extracellular matrix metabolism in the BMFBs with S. aureus. Our study complement our initial study on S. aureus-induced responses by fibrosis-associated genes in BMFBs. This may lead to development of novel therapeutic targets to control bovine mammary fibrosis induced by S. aureus.

Ameliorating effect of luteolin on memory impairment in an Alzheimer's disease model.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorder. It is characterized by the formation of amyloid plaques and neurofibrillary tangles in the brain, the degeneration of cholinergic neurons and neuronal cell death. The present study aimed to investigate the effect of luteolin, a flavonoid compound, on memory impairment in a streptozotocin (STZ)­induced Alzheimer's rat model. Morris water maze and probe tests were performed to examine the effect of luteolin treatment on cognition and memory. The effect of luteolin on CA1 pyramidal layer thickness was also examined. The results demonstrated that luteolin significantly ameliorated the spatial learning and memory impairment induced by STZ treatment. STZ significantly reduced the thickness of CA1 pyramidal layer and treatment of luteolin completely abolished the inhibitory effect of STZ. Our results suggest that luteolin has a potentially protective effect on learning defects and hippocampal structures in AD.