Estrogen receptor ß activation alleviates inflammatory bowel disease by suppressing NLRP3-dependent IL-1ß production in macrophages via downregulation of intracellular calcium level.

INTRODUCTION: Although several estrogen receptor ß (ERß) agonists have been reported to alleviate IBD, the pivotal mechanism remains obscure. OBJECTIVES: To examine the effects and mechanisms of ERß activation on cytokine/chemokine networks in colitis mice. METHODS: Dextran sulfate sodium salt (DSS) and trinitro-benzene-sulfonic acid (TNBS) were used to induce mouse colitis model. Multiple molecular biological methods were employed to evaluate the severity of mouse colitis and the level of cytokine and/or chemokine. RESULTS: Bioinformatics analysis, ELISA and immunofluorescence results showed that the targeted cytokines and/or chemokines associated with ERß expression and activation is IL-1ß, and the anti-colitis effect of ERß activation was significantly attenuated by the overexpression of AAV9-IL-1ß. Immunofluorescence analysis indicated that ERß activation led to most evident downregulation of IL-1ß expression in colonic macrophages as compared to monocytes and neutrophils. Given the pivotal roles of NLRP3, NLRC4, and AIM2 inflammasome activation in the production of IL-1ß, we examined the influence of ERß activation on inflammasome activity. ELISA and WB results showed that ERß activation selectively blocked the NLRP3 inflammasome assembly-mediated IL-1ß secretion. The calcium-sensing receptor (CaSR) and calcium signaling play crucial roles in the assembly of the NLRP3 inflammasome. WB and immunofluorescence results showed that ERß activation reduced intracellular CaSR expression and calcium signaling in colonic macrophages. Combination with CaSR overexpression plasmid reversed the suppressive effect of ERß activation on NLRP3 inflammasome assembly, and counteracting the downregulation of IL-1ß secretion. CONCLUSION: Our research uncovers that the anti-colitis effect of ERß activation is accomplished through the reduction of IL-1ß levels in colonic tissue, achieved by specifically decreasing CaSR expression in macrophages to lower intracellular calcium levels and inhibit NLRP3 inflammasome assembly-mediated IL-1ß production.

ARDS and aging: TYMS emerges as a promising biomarker and therapeutic target.

Background: Acute Respiratory Distress Syndrome (ARDS) is a common condition in the intensive care unit (ICU) with a high mortality rate, yet the diagnosis rate remains low. Recent studies have increasingly highlighted the role of aging in the occurrence and progression of ARDS. This study is committed to investigating the pathogenic mechanisms of cellular and genetic changes in elderly ARDS patients, providing theoretical support for the precise treatment of ARDS. Methods: Gene expression profiles for control and ARDS samples were obtained from the Gene Expression Omnibus (GEO) database, while aging-related genes (ARGs) were sourced from the Human Aging Genomic Resources (HAGR) database. Differentially expressed genes (DEGs) were subjected to functional enrichment analysis to understand their roles in ARDS and aging. The Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning pinpointed key modules and marker genes, with ROC curves illustrating their significance. The expression of four ARDS-ARDEGs was validated in lung samples from aged mice with ARDS using qRT-PCR. Gene set enrichment analysis (GSEA) investigated the signaling pathways and immune cell infiltration associated with TYMS expression. Single-nucleus RNA sequencing (snRNA-Seq) explored gene-level differences among cells to investigate intercellular communication during ARDS onset and progression. Results: ARDEGs are involved in cellular responses to DNA damage stimuli, inflammatory reactions, and cellular senescence pathways. The MEmagenta module exhibited a significant correlation with elderly ARDS patients. The LASSO, RRF, and XGBoost algorithms were employed to screen for signature genes, including CKAP2, P2RY14, RBP2, and TYMS. Further validation emphasized the potential role of TYMS in the onset and progression of ARDS. Immune cell infiltration indicated differential proportion and correlations with TYMS expression. SnRNA-Seq and cell-cell communication analysis revealed that TYMS is highly expressed in endothelial cells, and the SEMA3 signaling pathway primarily mediates cell communication between endothelial cells and other cells. Conclusion: Endothelial cell damage associated with aging could contribute to ARDS progression by triggering inflammation. TYMS emerges as a promising diagnostic biomarker and potential therapeutic target for ARDS.

Preparation and Oil Adsorption of Cellulose-graft-poly(butyl acrylate-N,N'-methylene Bisacrylamide).

With the advancement of industrial economies, incidents involving spills of petroleum products have become increasingly frequent. The resulting pollutants pose significant threats to air, water, soil, plant and animal survival, as well as human health. In this study, microcrystalline cellulose served as the matrix and benzoyl peroxide (BPO) as the initiator, while butyl acrylate (BA) and N,N'-methylene bisacrylamide (MBA) were employed as graft monomers. Through free radical graft polymerization, cellulose-graft-poly(butyl acrylate-N,N'-methylene bisacrylamide) [Cell-g-P(BA-MBA)], possessing oil-adsorbing properties, was synthesized. The chemical structure, elemental composition, surface morphology and wetting properties of the graft polymerization products have been characterized, using infrared spectroscopy, elemental analysis, scanning electron microscopy and contact angle testing. The adsorption properties of Cell-g-P(BA-MBA) for various organic solvents and oils were then assessed. The experimental results demonstrated that Cell-g-P(BA-MBA) exhibited a maximum adsorption capacity of 37.55 g/g for trichloromethane. Adsorption kinetics experiments indicated a spontaneous and exothermic process involving physical adsorption, conforming to the Freundlich isotherm model. Furthermore, adsorption kinetics experiments revealed that Cell-g-P(BA-MBA) displayed favorable reuse and regeneration performance, maintaining its adsorption capacity essentially unchanged over fifteen adsorption-desorption cycles.

Arctigenin promotes mucosal healing in ulcerative colitis through facilitating focal adhesion assembly and colonic epithelial cell migration via targeting focal adhesion kinase.

Colonic mucosal defect constitutes the major reason of recurrence and deterioration of ulcerative colitis (UC), and mucosal healing has become the therapeutic endpoint of UC. Unfortunately, specific promoter of mucosal healing is still absent. Our previous researches demonstrated that arctigenin could alleviate colitis symptoms in mice, but whether it has a positive impact on colonic mucosal healing remains unclear. This study explores whether and how arctigenin promotes mucosal healing. Orally administered arctigenin was shown to alleviate colitis in mice primarily by enhancing mucosal healing. In vitro, arctigenin was shown to promote the wound healing by accelerating colonic epithelial cell migration but not proliferation. Acceleration of the focal adhesion turnover, especially assembly, is crucial for arctigenin promoting the cell migration. Arctigenin was able to activate focal adhesion kinase (FAK) in colonic epithelial cells through directly binding with Tyr251 site of FAK, as evidenced by surface plasmon resonance assay and site-directed mutagenesis experiment. In the colonic epithelial cells of UC patients and colitis mice, FAK activation was significantly down-regulated compared with the controls. Arctigenin promoted colonic epithelial cell migration and mucosal healing in dextran sulphate sodium (DSS)-induced colitis mice dependent on activating FAK, as confirmed by combined use with FAK inhibitor. In summary, arctigenin can directly promote mucosal healing in colitis mice through facilitating focal adhesion turnover, especially assembly, and consequent migration of epithelial cells via targeting FAK. Arctigenin may be developed as a mucosal healing promoter, and FAK is a potential therapeutic target for UC and other mucosal defect-related diseases.

Mitochondrial fusion induced by transforming growth factor-ß1 serves as a switch that governs the metabolic reprogramming during differentiation of regulatory T cells.

Although metabolic reprogramming during the differentiation of regulatory T cells (Treg cells) has been extensively studied, the molecular switch to alter energy metabolism remains undefined. The present study explores the critical role of mitochondrial dynamics in the reprogramming and consequent generation of Treg cells. The results showed that during Treg cell differentiation, mitochondrial fusion but not fission led to elevation of oxygen consumption rate values, facilitation of metabolic reprogramming, and increase of number of Treg cells and expression of Foxp3 in vitro and in vivo. Mechanistically, mitochondrial fusion favored fatty acid oxidation but restricted glycolysis in Treg cells through down-regulating the expression of HIF-1α. Transforming growth factor-ß1 (TGF-ß1) played a crucial role in the induction of mitochondrial fusion, which activated Smad2/3, promoted the expression of PGC-1α and therefore facilitated the expression of mitochondrial fusion proteins. In conclusion, during Treg cell differentiation, TGF-ß1 promotes PGC-1α-mediated mitochondrial fusion, which drives metabolic reprogramming from glycolysis to fatty acid oxidation via suppressing HIF-1α expression, and therefore favors the generation of Treg cells. The signals and proteins involved in mitochondrial fusion are potential therapeutic targets for Treg cell-related diseases.

Lycorine induces apoptosis of acute myeloid leukemia cells and inhibits triglyceride production via binding and targeting FABP5.

Acute myeloid leukemia (AML) is the most common hematopoietic malignancy with abnormal lipid metabolism. However, currently available information on the involvement of the alterations in lipid metabolism in AML development is limited. In this study, we demonstrate that FABP5 expression facilitates AML cell viability, protects AML cells from apoptosis, and maintains triglyceride production. Our bioinformatics analysis revealed that FABP5 expression was upregulated and correlated with unfavorable overall survival of AML patients. FABP5 expression may be used to distinguish normal and AML with high accuracy. FABP5-based risk score was an independent risk factor for AML patients. AML patients with highly expressed FABP5 predicted resistance to drugs. In vitro study showed that FABP5 expression was remarkably elevated in primary AML blasts and an AML cell line. Silencing FABP5 expression attenuated AML cell viability, reduced triglyceride production and lipid droplet accumulation, and induced apoptosis. We utilized AutoDock online tool to identify lycorine as an FABP5 inhibitor by binding FABP5 at amino acid residues Ile54, Thr56, Thr63, and Arg109. Lycorine treatment downregulated the expression levels of FABP5 and its target PPARγ, impaired AML cell viability, triggered apoptosis, and reduced triglyceride production in AML cells. These results demonstrate that FABP5 is critical for AML cell survival and highlight a novel metabolic vulnerability for AML.

MiRNA-181b-5p Modulates Cell Proliferation, Cell Cycle, and Apoptosis by Targeting SSX2IP in Acute Lymphoblastic Leukemia

Objective: Accumulating evidence indicates that miRNAs can negatively influence the expression of their downstream genes, thereby affecting the development of human cancers. The pathogenesis of acute lymphoblastic leukemia (ALL) is complex and more biomarkers and functional molecules need to be found. We attempted to reveal the specific mechanisms and functions of miRNA-181b-5p in ALL and investigated the effects of the miRNA-181b-5p/SSX2IP axis on ALL. Materials and Methods: Bioinformatics analyses were initially performed to screen out differentially expressed miRNAs in ALL and determine the research subject. qRT-PCR and western blotting were applied to evaluate the expression levels of target genes. Cell function experiments and mouse experiments were conducted to analyze the roles of the target genes in ALL. Results: miRNA-181b-5p was highly and differentially expressed in ALL and may target SSX2IP. The upregulation of miRNA-181b-5p and downregulation of SSX2IP were observed in ALL cells. miRNA-181b-5p could control multiple pathological processes of ALL, including cell proliferation, the cell cycle, and apoptosis, and miRNA-181b-5p could also facilitate tumor growth in vivo. Conclusion: miRNA-181b-5p promoted the malignant progression of ALL by downregulating SSX2IP. The miRNA-181b-5p/SSX2IP axis may be a promising target for intervention against the malignant behaviors of ALL.

Predictive value of integrin α7 for acute myeloid leukemia risk and its correlation with prognosis in acute myeloid leukemia patients.

BACKGROUND: This study aimed to explore the predictive value of integrin α7 (ITGA7) for acute myeloid leukemia (AML) risk and subsequently investigate its correlation with risk stratification and prognosis in AML patients. METHODS: Bone marrow samples were obtained from 196 de novo AML patients prior to initiation of treatment and from 50 subjects underwent bone marrow donation or bone marrow biopsy for non-hematologic malignant disease (as controls). ITGA7 mRNA and protein expressions were detected by real-time quantitative polymerase chain reaction and Western blot assays, respectively. In AML patients, the risk stratification was assessed, and complete remission (CR), event-free survival (EFS), and overall survival (OS) were evaluated. RESULTS: Both ITGA7 mRNA and protein expressions were increased in AML patients compared with controls, and their expressions were correlated with poorer risk stratification. For prognosis, ITGA7 mRNA expression and protein expression were declined in CR patients compared to non-CR patients. Meanwhile, both EFS and OS were shorter in ITGA7 mRNA high expression patients compared to ITGA7 mRNA low expression patients, as well as ITGA7 protein high expression patients compared to ITGA7 protein low expression patients. CONCLUSION: Integrin α7 might serve as a potential biomarker for predicting increased AML risk and worse prognosis in AML patients.

Platelet-to-Lymphocyte Ratio (PLR) Is Associated with Immune Thrombocytopenia (ITP) Recurrence: A Retrospective Cohort Study.

BACKGROUND Current guidelines are inadequate for use in predicting ITP recurrence. Therefore, our primary goal in this study was to investigate the association of platelet-to-lymphocyte ratio (PLR) at diagnosis with ITP recurrence in Chinese patients. MATERIAL AND METHODS We performed a historical cohort study and non-selectively enrolled 233 patients with newly-identified ITP from March 2013 to June 2017. The independent variable was PLR recorded at diagnosis and the dependent variable was recurrence-free survival (RFS) at 6 months. Data on the following variables were also collected for establishing a multivariate Cox regression model: demographic details, general details, and variables found to be closely related to PLR in previous studies, as well as risk factors for ITP recurrence. RESULTS During follow-up, 85 patients had an event within 6 months. At the range of 0.86-9.7 of PLR, a 1-unit increase in PLR was associated with a 13% decrease in ITP recurrence (hazard ratio: 0.87; 95% confidence interval: 0.78-0.97), whereas no association was detected at the range of 9.7-33.75 of PLR (hazard ratio: 0.99; 95% confidence interval: 0.95-1.04). An interaction test indicated that patients with HP infection (0.91 (0.86-1.97)) or diabetes history (0.86 (0.78-0.96)) showed a stronger association compared with patients without HP infection (1.01 (0.95-1.04) and those without diabetes (1.01 (0.97-1.04)). CONCLUSIONS Our findings suggest that PLR is a useful parameter to consider when hematologists attempt to assess the risk of recurrence in ITP patients receiving first-line therapy, and the nonlinearity of PLR and ITP recurrence risk must be fully considered when constructing predictive models.

Platelet to Lymphocyte Ratio and Glucocorticoid Resistance in Newly Diagnosed Primary Immune Thrombocytopenia: A Retrospective Cohort Study.

BACKGROUND In China, evidence regarding to the association between platelet to lymphocyte ratio (PLR) and glucocorticoid (GC) resistance in participants with primary newly identified immune thrombocytopenia (ITP) is limited. We aimed to investigate whether PLR is independently linked with GC-resistant ITP. MATERIAL AND METHODS We non-selectively and consecutively collected 154 newly diagnosed ITPs. The start enrollment time and the end enrollment time were from March 2013 to June 2017. The independent and dependent variables were PLR measured at diagnosis and GC non-response. Other variables involved in the present work can be summarized as demographic data and factors that were correlated with PLR reported by published studies. Univariate and multivariate binary logistic regression model and sensitivity analysis were used to evaluate the associations between PLR and GC resistance. RESULTS After adjusting covariates, PLR level was negatively associated with GC non-response [odds ratio (OR)=0.89, 95% confidence intervals (CI): 0.80 to 0.98], and supported by propensity score matching model (OR=0.74, 95%CI: 0.57 to 0.96]. Nonlinearity of PLR and GC resistance was observed whose inflection point was 5.08 (by 2-piecewise model). The OR and 95%CI on both sides of inflection point were 3.14 (0.81 to 12.21) and 0.81 (0.69 to 0.95), respectively. Subgroup analysis showed no significant differences from subgroups. CONCLUSIONS Threshold effect on PLR and GC resistance is observed. When PLR is larger than 5.08, a unit increase of PLR is independently associated with 19% reduction of GC resistance.

Three mutations of adult type 1 Gaucher disease found in a Chinese patient: A case report.

RATIONALE: Gaucher disease (GD), characterized by glucosylceramide accumulation in the macrophage-monocyte system, is caused by glucosidase b acid (GBA) gene mutations which lead to the deficiency of lysosomal enzyme glucocerebrosidase. The mutation spectrum of GBA in Chinese patients is quite different from those seen in Jewish and non-Jewish Caucasian patients. Thus, it is relatively hard to diagnose GD in Chinese. PATIENT CONCERNS: A 24-year-old Chinese female with intermittent abdominal distension and progressive decrease in strength but without neurologic symptoms was initially referred for femoral head necrosis on the right feet. Laboratory examinations results indicated panhematopenia. Bone marrow aspiration smear and biopsy specimen found typical "wrinkled" Gaucher cells. Molecular-genetic testing of GBA gene revealed 3 mutations including R159W (c. 475 C > T), V1230G (c. 689T > G), and G241A (c. 721G > A). DIAGNOSES: On the basis of these findings and clinical manifestations, the final diagnosis of type 1 GD was made. INTERVENTIONS: Enzyme replacement therapy (ERT) with velaglucerase α was carried out after the diagnosis of type 1 GD. OUTCOMES: The platelet and hemoglobin levels were restored by ERT. LESSONS: To our knowledge, this is the first report of GD patient carrying 3 mutations in Chinese. These mutations in GBA in the present case imply a potential pool of patients with GD with this mutation in Chinese.

Mean platelet volume at baseline and immune thrombocytopenia relapse in Chinese newly-diagnosed patients: a retrospective cohort study.

OBJECTIVE: In China, the ability of the current immune thrombocytopenia (ITP) guideline to stratify recurrent risk at diagnosis is limited. This study aimed to investigate whether mean platelet volume at diagnosis (MPV) is a risk factor for ITP relapse in Chinese. METHODS: The present study was a retrospective cohort study. Two hundred thirty-three adult patients with newly diagnosed ITP were consecutively and nonselectively collected from March 2013 to June 2017. The exposure and outcome variable were MPV at baseline and relapse-free survival at 6 months. Other covariants included demographic data, general information, variables that can affect MPV reported by previous literature and risk factors of ITP relapse. RESULTS: After adjusting potential confounders, the non-linear relationship was detected between MPV and ITP relapse, and inflection point was 21. The effect sizes and the confidence intervals on the left and right sides of inflection point were 1.30 (1.22-1.39) and 0.89 (0.76-1.04), respectively. Subgroup analysis showed, in subjects with hyperuricemia (1.54 (1.24, 1.90)), MPV showed significant differences from non-hyperuricemia (1.19 (1.13, 1.25)), and the p for interaction was less than 0.05. CONCLUSION: The relationship between MPV and ITP relapse is non-linear. MPV is an independent risk factor of ITP relapse when MPV is less than 21 fl.

Overexpression of heme oxygenase-1 induced by constitutively activated NF-κB as a potential therapeutic target for activated B-cell-like diffuse large B-cell lymphoma.

There is an urgent requirement for a new therapeutic target for activated B-cell-like lymphoma (ABC-DLBCL), which is known to have dismal outcome and constitutive activation of NF-κB. Heme oxygenase-1 (HO-1) can inhibit apoptosis and promote proliferation in many cancers. To our knowledge, no studies have been performed on the correlation between HO-1 and DLBCL. In this study, immunohistochemical analysis of 31 tumor tissues from DLBCL patients [20 of ABC subtype and 11 of germinal center B-cell-like (GCB) subtype] and 11 normal lymph nodes revealed that HO-1 overexpression was characteristic of ABC-DLBCL. In addition, HO-1 mRNA expression levels were consistent with the immunohistochemistry results. High levels of HO-1 expression were significantly correlated with the involvement of more than 1 extranodal site (p=0.025), with a high positivity rate of Ki-67 (p<0.01). Similar to its anti-apoptotic role in other malignancies, HO-1 upregulation suppressed apoptosis of the ABC-DLBCL cell line OCI-ly10, whereas its downregulation sensitized the tumor cells to chemotherapeutic drugs. Further study demonstrated that the HO-1 overexpression was mediated by constitutively activated NF-κB which together played an anti-apoptotic role in ABC-DLBCL. Combination of the NF-κB inhibitor Bay11­7082 and the lentivirus vector Lenti-siHO-1 significantly decreased HO-1 protein expression and increased apoptosis in OCI-ly10 cells. However, in GCB-DLBCL cells with low levels of NF-κB expression, the TNF-α-mediated activation of NF-κB leading to HO-1 upregulation rescued the cells from apoptosis caused by HO-1 silencing. These results indicated that HO-1 can be a potential target for the treatment of ABC-DLBCL.