Psoriasin overexpression confers drug resistance to cisplatin by activating ERK in gastric cancer

Psoriasin, a member of the S100 multigenic family, which is aberrantly expressed in a variety of human tumors, is considered as an attractive molecular target for cancer treatment. The present study aimed to characterize the role of psoriasin in gastric cancer (GC), the associated pathways through which it contributes to cancer development and progression, and the effect of psoriasin on cellular response to pre-operative chemotherapy in patients with GC. Expression of psoriasin mRNA and protein were analyzed using quantitative polymerase chain reaction and immunohistochemistry of gastric cancer cohorts, respectively. Gastric cancer cell models with differential expression of psoriasin were generated using stable cell lines that overexpressed psoriasin. The in vitro biological functions of the cells in response to psoriasin overexpression and to chemotherapeutic agents were assessed using various cell-based assays. Psoriasin was overexpressed in patients with advanced GC, and high psoriasin levels led to poor clinical outcomes. Increasing psoriasin expression in GC cell lines promoted cell proliferation, migration and invasion in vitro. Furthermore, psoriasin overexpression caused alterations in the levels of epithelial-mesenchymal transition-associated proteins, and activated the extracellular signal-regulated kinase signaling pathway. Additionally, higher levels of psoriasin expression were significantly associated a lack of response to neoadjuvant chemotherapy in patients with GC. Psoriasin overexpression tended to decrease the sensitivity of GC cells to cisplatin, potentially by inhibiting apoptosis or increasing the S-phase population. Taken together, these results indicate that psoriasin may be a promising therapeutic target for GC treatment, and a potential molecular marker to predict patient response to pre-operative chemotherapy

Novel compounds in fruits of coriander (Coşkuner & Karababa) with anti-inflammatory activity

© 2020 Coriander, Coriandrum Sativum L., is one of the commonest food and medicinal plants in many countries, but its chemical ingredients and pivotal role in anti-inflammatory activity have not been fully explored. The present study aimed to identify new compounds in the fruits of coriander and explore their anti-inflammatory activity. The compounds were isolated by chromatographic seperations and identified using spectroscopic and spectrometric methods. RAW264.7 macrophage cells were used to detect the anti-inflammatory activity of the compounds via Griess assay, western blotting, ELISA, and flow cytometry methods. The study resulted in the discovery of four new compounds, which were identified as: 4α-(furo[2,3-d]pyrimidin-6′-ylmethyl)-9α-propylnonolactone (1), 4-(formyloxy)-4-(6′-methylcyclohex-1-en-1-yl)butanoate(2), (7α,8α)-3α-hydroxyl-12,13α-dimethyl-5(6)-en-bicyclo[5,3,0]caprolactone (3), 7-methoxy-4-methyl-5,6-dihydro-7H-(2-hydroxypropan-2-yl)furo[2,3-f] coumarin (4). Compound 3 showed the highest anti-inflammatory activity with IC50 of 6.25 μM for an inhibitory effect on nitrite oxide (NO) level. In addition, compound 3 decreased the lipopolysaccharides-stimulated generations of ROS and the inflammatory cytokines (IL-6 and TNF-α). Mechanism exploration indicated that compound 3 suppressed inflammatory mediators’ expression, like iNOS and COX-2. Furthermore, the NF-κB and MAPK pathways were involved in the anti-inflammatory process of compound 3

Modularly engineering Rhodotorula toruloides for α-terpineol production

α-Terpineol is a monoterpenoid alcohol that has been widely used in the flavor, fragrance, and pharmaceutical industries because of its sensory and biological properties. However, few studies have focused on the microbial production of α-terpineol. The oleaginous yeast Rhodotorula toruloides is endowed with a natural mevalonate pathway and is a promising host in synthetic biology and biorefinery. The primary objective of this work was to engineer R. toruloides for the direct biosynthesis of α-terpineol. The improvement in monoterpenoid production was achieved through the implementation of modular engineering strategies, which included the enhancement of precursor supply, blocking of downstream pathways, and disruption of competing pathways. The results of these three methods showed varying degrees of favorable outcomes in enhancing α-terpineol production. The engineered strain 5L6HE5, with competitive pathway disruption and increased substrate supply, reached the highest product titer of 1.5 mg/L, indicating that reducing lipid accumulation is an efficient method in R. toruloides engineering for terpenoid synthesis. This study reveals the potential of R. toruloides as a host platform for the synthesis of α-terpineol as well as other monoterpenoid compounds

The distribution of heterophilic antigens and their relationship with autoimmune diseases

IntroductionMicrobial infections are associated with the occurrence of autoimmune diseases, but the mechanisms of microbial infection inducing autoimmune diseases are not fully understood. The existence of heterophilic antigens between microorganisms and human tissues may explain part of the pathogenesis of autoimmune diseases. Here, we investigate the distribution of heterophilic antigens and its relationship with autoimmune diseases.MethodsMonoclonal antibodies against a variety of microorganisms were prepared. The titer, subclass and reactivity of antibodies with microorganisms were identified, and heterophilic antibodies that cross-reacted with human tissues were screened by human tissue microarray. The reactivity of these heterophilic antibodies with different individuals and different species was further examined by immunohistochemistry.ResultsIn this study, 21 strains of heterophilic antibodies were screened. The results showed that these heterophilic antibodies were produced due to the existence of heterophilic antigens between microorganism and human body and the distribution of heterophilic antigens had individual, tissue and species differences.ConclusionOur study showed that heterophilic antigens exist widely between microorganisms and human body, and the heterophilic antigens carried by microorganisms may break the immune tolerance of the body through carrier effect and initiate immune response, which may be one of the important mechanisms of infection inducing autoimmune diseases

Unraveling the transcriptome-based network of tfh cells in primary sjogren syndrome: insights from a systems biology approach

BackgroundPrimary Sjogren Syndrome (pSS) is an autoimmune disease characterized by immune cell infiltration. While the presence of follicular T helper (Tfh) cells in the glandular microenvironment has been observed, their biological functions and clinical significance remain poorly understood.MethodsWe enrolled a total of 106 patients with pSS and 46 patients without pSS for this study. Clinical data and labial salivary gland (LSG) biopsies were collected from all participants. Histological staining was performed to assess the distribution of Tfh cells and B cells. Transcriptome analysis using RNA-sequencing (RNA-seq) was conducted on 56 patients with pSS and 26 patients without pSS to uncover the underlying molecular mechanisms of Tfh cells. To categorize patients, we employed the single-sample gene set enrichment analysis (ssGSEA) algorithm, dividing them into low- and high-Tfh groups. We then utilized gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and deconvolution tools to explore functional and immune infiltration differences between the low- and high-Tfh groups.ResultsPatients with pSS had a higher positive rate of the antinuclear antibody (ANA), anti-Ro52, anti-SSA, anti-SSB and hypergammaglobulinaemia and higher levels of serum IgG compared to the non-pSS. Histopathologic analyses revealed the presence of Tfh cells (CD4+CXCR5+ICOS+) in germinal centers (GC) within the labial glands of pSS patients. GSEA, WGCNA, and correlation analysis indicated that the high-Tfh group was associated with an immune response related to virus-mediated IFN response and metabolic processes, primarily characterized by hypoxia, elevated glycolysis, and oxidative phosphorylation levels. In pSS, most immune cell types exhibited significantly higher infiltration levels in the high-Tfh group compared to the low-Tfh group. Additionally, patients in the Tfh-high group demonstrated a higher positive rate of the ANA, rheumatoid factor (RF), and hypergammaglobulinaemia, as well as higher serum IgG levels.ConclusionOur study suggests that Tfh cells may play a crucial role in the pathogenesis of pSS and could serve as potential therapeutic targets in pSS patients

Characterisation of macrophage infiltration and polarisation based on integrated transcriptomic and histological analyses in Primary Sjögren’s syndrome

BackgroundPrimary Sjögren’s syndrome (pSS) is a progressive inflammatory autoimmune disease. Immune cell infiltration into glandular lobules and ducts and glandular destruction are the pathophysiological hallmarks of pSS. Macrophages are one of the most important cells involved in the induction and regulation of an inflammatory microenvironment. Although studies have reported that an abnormal tissue microenvironment alters the metabolic reprogramming and polarisation status of macrophages, the mechanisms driving macrophage infiltration and polarisation in pSS remain unclear.MethodsImmune cell subsets were characterised using the single-cell RNA sequencing (scRNA-seq) data of peripheral blood mononuclear cells (PBMCs) from patients with pSS (n = 5) and healthy individuals (n = 5) in a public dataset. To evaluate macrophage infiltration and polarisation in target tissues, labial salivary gland biopsy tissues were subjected to histological staining and bulk RNA-seq (pSS samples, n = 24; non-pSS samples, n = 12). RNA-seq data were analysed for the construction of macrophage co-expression modules, enrichment of biological processes and deconvolution-based screening of immune cell types.ResultsDetailed mapping of PBMCs using scRNA-seq revealed five major immune cell subsets in pSS, namely, T cells, B cells, natural killer (NK) cells, dendritic cells (DCs) and monocyte-macrophages. The monocyte-macrophage subset was large and had strong inflammatory gene signatures. This subset was found to play an important role in the generation of reactive oxygen species and communicate with other innate and adaptive immune cells. Histological staining revealed that the number of tissue-resident macrophages was high in damaged glandular tissues, with the cells persistently surrounding the tissues. Analysis of RNA-seq data using multiple algorithms demonstrated that the high abundance of pro-inflammatory M1 macrophages was accompanied by the high abundance of other infiltrating immune cells, senescence-associated secretory phenotype and evident metabolic reprogramming.ConclusionMacrophages are among the most abundant innate immune cells in PBMCs and glandular tissues in patients with pSS. A bidirectional relationship exists between macrophage polarisation and the inflammatory microenvironment, which may serve as a therapeutic target for pSS

The Volume of Hippocampal Subfields in Relation to Decline of Memory Recall Across the Adult Lifespan

Background: The hippocampus is an important limbic structure closely related to memory function. However, few studies have focused on the association between hippocampal subfields and age-related memory decline. We investigated the volume alterations of hippocampal subfields at different ages and assessed the correlations with Immediate and Delayed recall abilities.Materials and Methods: A total of 275 participants aged 20–89 years were classified into 4 groups: Young, 20–35 years; Middle-early, 36–50 years; Middle-late, 51–65 years; Old, 66–89 years. All data were acquired from the Dallas Lifespan Brain Study (DLBS). The volumes of hippocampal subfields were obtained using Freesurfer software. Analysis of covariance (ANCOVA) was performed to analyze alterations of subfield volumes among the 4 groups, and multiple comparisons between groups were performed using the Bonferroni method. Spearman correlation with false discovery rate correction was used to investigate the relationship between memory recall scores and hippocampal subfield volumes.Results: Apart from no significant difference in the left parasubiculum (P = 0.269) and a slight difference in the right parasubiculum (P = 0.022), the volumes of other hippocampal subfields were significantly different across the adult lifespan (P < 0.001). The hippocampal fissure volume was increased in the Old group, while volumes for other subfields decreased. In addition, Immediate recall scores were associated with volumes of the bilateral molecular layer, granule cell layer of the dentate gyrus (GC-DG), cornus ammonis (CA) 1, CA2/3, CA4, left fimbria and hippocampal amygdala transition area (HATA), and right fissure (P < 0.05). Delayed recall scores were associated with the bilateral molecular layer, GC-DG, CA2/3 and CA4; left tail, presubiculum, CA1, subiculum, fimbria and HATA (P < 0.05).Conclusion: The parasubiculum volume was not significantly different across the adult lifespan, while atrophy in dementia patients in some studies. Based on these findings, we speculate that volume changes in this region might be considered as a biomarker for dementia disorders. Additionally, several hippocampal subfield volumes were significantly associated with memory scores, further highlighting the key role of the hippocampus in age-related memory decline. These regions could be used to assess the risk of memory decline across the adult lifespan

Characterization of an aspartate aminotransferase encoded by YPO0623 with frequent nonsense mutations in Yersinia pestis

Yersinia pestis, the causative agent of plague, is a genetically monomorphic bacterial pathogen that evolved from Yersinia pseudotuberculosis approximately 7,400 years ago. We observed unusually frequent mutations in Y. pestis YPO0623, mostly resulting in protein translation termination, which implies a strong natural selection. These mutations were found in all phylogenetic lineages of Y. pestis, and there was no apparent pattern in the spatial distribution of the mutant strains. Based on these findings, we aimed to investigate the biological function of YPO0623 and the reasons for its frequent mutation in Y. pestis. Our in vitro and in vivo assays revealed that the deletion of YPO0623 enhanced the growth of Y. pestis in nutrient-rich environments and led to increased tolerance to heat and cold shocks. With RNA-seq analysis, we also discovered that the deletion of YPO0623 resulted in the upregulation of genes associated with the type VI secretion system (T6SS) at 26°C, which probably plays a crucial role in the response of Y. pestis to environment fluctuations. Furthermore, bioinformatic analysis showed that YPO0623 has high homology with a PLP-dependent aspartate aminotransferase in Salmonella enterica, and the enzyme activity assays confirmed its aspartate aminotransferase activity. However, the enzyme activity of YPO0623 was significantly lower than that in other bacteria. These observations provide some insights into the underlying reasons for the high-frequency nonsense mutations in YPO0623, and further investigations are needed to determine the exact mechanism