Copper metabolism-related signature for prognosis prediction and MMP13 served as malignant factor for breast cancer.

Objectives: To comprehensively analyze the copper metabolism in Breast cancer, we established a prognostic signature for breast cancer (BC) related to copper metabolism. Methods: Copper metabolism-related genes were sourced from previous literatures and were selected by the Univariate Cox regression. Cu-enrichment scores were calculated via ssGSEA. Differentially expressed genes were identified with limma between high and low Cu-enrichment scores group, then we used the Random Survival Forest and LASSO to build the CuScore for BC. Kaplan-Meier analysis, ROC curves, and Cox regression were used to evaluate CuScore. Genomic mutations were analyzed with GISTIC. Immune cells were examined using ESTIMATE, ssGSEA and TIMER. Enrichment analysis used clusterProfiler and GSVA. The GDSC database and oncoPredict package analyzed chemotherapeutic sensitivity. MMP13 was selected for in vitro assays. Results: Four copper metabolism-related genes (UBE2D2, SLC31A1, ATP7A, and MAPK1) with prognostic value were identified. Higher expression levels of these genes were associated with higher Cu-enrichment scores, a factor of malignancy in breast cancer. Among 115 differentially expressed genes, 19 prognostic genes were identified, with three (CEACAM5, MMP13, and CRISP3) highlighted by Random Survival Forest and LASSO. Higher CuScores correlated with worse prognoses and were effective in predicting breast cancer outcomes. CuScore and metastasis were independent prognostic factors. Tumor-infiltrating immune cells were associated with lower CuScores. GO-GSEA analysis indicated six immune-related pathways might be regulated by CuScore. Patients with higher CuScores had lower TMB and were more sensitive to Sapitinib and LCL161, while those with lower CuScores might respond better to anti-PD1 therapy. High MMP13 expression in breast cancer was linked to malignancy, affecting cell proliferation and migration. Conclusion: The identified copper metabolism-related gene signature has the potential to predict prognosis and guide clinical treatment for BC. Among these genes, MMP13 may act as a malignant factor in BC.

Radiomics analysis of dual-layer spectral-detector CT-derived iodine maps for predicting tumor deposits in colorectal cancer.

OBJECTIVE: To investigate the value of radiomics analysis of dual-layer spectral-detector computed tomography (DLSCT)-derived iodine maps for predicting tumor deposits (TDs) preoperatively in patients with colorectal cancer (CRC). MATERIALS AND METHODS: A total of 264 pathologically confirmed CRC patients (TDs + (n = 80); TDs - (n = 184)) who underwent preoperative DLSCT from two hospitals were retrospectively enrolled, and divided into training (n = 124), testing (n = 54), and external validation cohort (n = 86). Conventional CT features and iodine concentration (IC) were analyzed and measured. Radiomics features were derived from venous phase iodine maps from DLSCT. The least absolute shrinkage and selection operator (LASSO) was performed for feature selection. Finally, a support vector machine (SVM) algorithm was employed to develop clinical, radiomics, and combined models based on the most valuable clinical parameters and radiomics features. Area under receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis were used to evaluate the model's efficacy. RESULTS: The combined model incorporating the valuable clinical parameters and radiomics features demonstrated excellent performance in predicting TDs in CRC (AUCs of 0.926, 0.881, and 0.887 in the training, testing, and external validation cohorts, respectively), which outperformed the clinical model in the training cohort and external validation cohorts (AUC: 0.839 and 0.695; p: 0.003 and 0.014) and the radiomics model in two cohorts (AUC: 0.922 and 0.792; p: 0.014 and 0.035). CONCLUSION: Radiomics analysis of DLSCT-derived iodine maps showed excellent predictive efficiency for preoperatively diagnosing TDs in CRC, and could guide clinicians in making individualized treatment strategies. CLINICAL RELEVANCE STATEMENT: The radiomics model based on DLSCT iodine maps has the potential to aid in the accurate preoperative prediction of TDs in CRC patients, offering valuable guidance for clinical decision-making. KEY POINTS: Accurately predicting TDs in CRC patients preoperatively based on conventional CT features poses a challenge. The Radiomics model based on DLSCT iodine maps outperformed conventional CT in predicting TDs. The model combing DLSCT iodine maps radiomics features and conventional CT features performed excellently in predicting TDs.

Causal association of blood cell traits with inflammatory bowel diseases: a Mendelian randomization study.

Background: Observational studies have found associations between blood cell traits and inflammatory bowel diseases (IBDs), whereas the causality and dose-effect relationships are still undetermined. Methods: Two-sample Mendelian randomization (MR) analyses using linear regression approaches, as well as Bayesian model averaging (MR-BMA), were conducted to identify and prioritize the causal blood cell traits for Crohn's disease (CD) and ulcerative colitis (UC). An observational study was also performed using restricted cubic spline (RCS) to explore the relationship between important blood cell traits and IBDs. Results: Our uvMR analysis using the random effects inverse variance weighted (IVW) method identified eosinophil (EOS) as a causal factor for UC (OR = 1.36; 95% CI: 1.13, 1.63). Our MR-BMA analysis further prioritized that high level of lymphocyte (LYM) decreased CD risk (MIP = 0.307; θ^MACE = -0.059; PP = 0.189; θ^λ = -0.173), whereas high level of EOS increased UC risk (MIP = 0.824; θ^MACE = 0.198; PP = 0.627; θ^λ = 0.239). Furthermore, the observational study clearly depicts the nonlinear relationship between important blood cell traits and the risk of IBDs. Conclusion: Using MR approaches, several blood cell traits were identified as risk factors of CD and UC, which could be used as potential targets for the management of IBDs. Stratified genome-wide association studies (GWASs) based on the concentration of traits would be helpful owing to the nonlinear relationships between blood cell traits and IBDs, as demonstrated in our clinical observational study. Together, these findings could shed light on the clinical strategies applied to the management of CD and UC.

Associations Between ABO Blood Groups and Diseases in the Digestive System and Vein.

Purpose: The ABO blood type system is crucial for human blood transfusions. However, the relationships between ABO blood groups and diseases in the digestive system and vein have not been elucidated. We investigated the relationships between ABO blood groups and diseases in the digestive system and vein in this study. Patients and Methods: A retrospective study on a Chinese population, including 1432 Crohn's disease (CD), 416 ulcerative colitis (UC), 1140 stomach cancer (SC), 841 colorectal cancer (CRC), 384 pancreatic cancer (PC), 520 liver cancer (LC), and 563 venous thrombosis (VT) patients, was performed. Furthermore, 896 healthy subjects were enrolled as normal controls (NC) in this study. The demographic characteristics of patients and NC were compared using the unpaired t-test and χ2 test. Multivariate logistic regression model was used to evaluate the association between ABO blood groups and CD and VT. Results: ABO blood groups distributions in UC, SC, CRC, PC, and LC patients did not differ from that of NC, but CD and VT patients had significant difference of ABO blood group distribution from that of NC (p = 0.015 and p = 0.002, respectively). Patients with CD and VT had considerably lower rates of type O blood (p = 0.011 and p = 0.001, respectively) and significantly higher rates of type AB blood (p = 0.013 and p = 0.022, respectively) than those with NC. Multivariate logistic regression analysis showed the association of CD and VT with non-O blood types was still significant with a higher risk than with blood group O after adjusting for age and gender (OR = 1.355, 95% CI = 1.100-1.670, p = 0.004 and OR = 1.465, 95% CI = 1.131-1.903, p = 0.004, respectively). Conclusion: ABO blood groups distributions in CD and VT patients significantly differed from that of NC. Non-O blood group could be a new predictor for CD and VT.

The role of IgG4 in systemic lupus erythematosus: Implications for pathogenesis and therapy.

Immunoglobulin (Ig) G4 has a distinctive nature, and its involvement in autoimmune disorders is a subject of ongoing debate and uncertainty. A growing body of evidence indicates that IgG4 may play a pathogenic role in the development of systemic lupus erythematosus (SLE). The IgG4 autoantibodies have the capability to bind autoantigens in a competitive manner with other Ig classes, thereby forming immune complexes (ICs) that are noninflammatory in nature. This is due to the low affinity of IgG4 for both the Fc receptors and the C1 complement molecule, which results in a diminished inflammatory response in individuals with SLE. The present study aims to elucidate the significance of IgG4 in SLE. The present discourse pertains to the nascent and suggested modalities through which IgG4 might participate in the pathogenesis of SLE and the potential ramifications for therapeutic interventions in SLE.

Platelet/Albumin ratio and plateletcrit levels are potential new biomarkers for assessing endoscopic inflammatory bowel disease severity.

BACKGROUND: Endoscopy is currently recognized as the gold standard for assessing inflammatory bowel disease (IBD) severity. However, because the procedure is costly and invasive, endoscopy is not suitable for frequently monitoring intestinal inflammation. In this study, our aim was to identify noninvasive, low cost, and convenient biomarkers for identifying endoscopic IBD activity. METHODS: In total, 246 patients with IBD (131 with Ulcerative colitis (UC) and 115 with Crohn's disease (CD)) and 369 healthy controls were recruited for this retrospective study. IBD activity was evaluated using endoscopic and clinical examinations. The potential of several inflammatory biomarkers, including platelets (PLT), plateletcrit (PCT), albumin (ALB), highly sensitive C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and platelet-to-albumin ratio (PLT/ALB) to assess endoscopic IBD activity was evaluated using receiver operating characteristic (ROC) analyses. RESULTS: PLT/ALB ratio, PLT, ALB, and hs-CRP levels were correlated with Mayo scores in UC patients, while PCT, PLT, fibrinogen (FIB), PLT/ALB ratio, hs-CRP, and ESR levels were correlated with Simple Endoscopic Scores for CD (SES-CD) in CD patients. ROC analyses showed that the area under the curve (AUC) value for the PLT/ALB ratio (0.705) was greater than hs-CRP (0.607) and ESR (0.552) values in UC patients. The AUC value for PCT (0.779) was greater than hs-CRP (0.698) and ESR (0.746) values in CD patients. CONCLUSION: PLT/ALB ratio and PCT biomarkers were the most appropriate of all tested inflammatory biomarkers for assessing endoscopic IBD activity in UC and CD patients, respectively.

Aggrephagy-related patterns in tumor microenvironment, prognosis, and immunotherapy for acute myeloid leukemia: a comprehensive single-cell RNA sequencing analysis.

Acute myeloid leukemia (AML) is a complex mixed entity composed of malignant tumor cells, immune cells and stromal cells, with intra-tumor and inter-tumor heterogeneity. Single-cell RNA sequencing enables a comprehensive study of the highly complex tumor microenvironment, which is conducive to exploring the evolutionary trajectory of tumor cells. Herein, we carried out comprehensive analyses of aggrephagy-related cell clusters based on single-cell sequencing for patients with acute myeloid leukemia. A total of 11 specific cell types (T, NK, CMP, Myeloid, GMP, MEP, Promono, Plasma, HSC, B, and Erythroid cells) using t-SNE dimension reduction analysis. Several aggrephagy-related genes were highly expressed in the 11 specific cell types. Using Monocle analysis and NMF clustering analysis, six aggrephagy-related CD8+ T clusters, six aggrephagy-related NK clusters, and six aggrephagy-related Mac clusters were identified. We also evaluated the ligand-receptor links and Cell-cell communication using CellChat package and CellChatDB database. Furthermore, the transcription factors (TFs) of aggrephagy-mediated cell clusters for AML were assessed through pySCENIC package. Prognostic analysis of the aggrephagy-related cell clusters based on R package revealed the differences in prognosis of aggrephagy-mediated cell clusters. Immunotherapy of the aggrephagy-related cell clusters was investigated using TIDE algorithm and public immunotherapy cohorts. Our study revealed the significance of aggrephagy-related patterns in tumor microenvironment, prognosis, and immunotherapy for AML.

A comprehensive insight into the role of molecular pathways affected by the Angiopoietin and Tie system involved in hematological malignancies' pathogenesis.

Angiogenesis has been recognized as a critical factor in developing solid tumors and hematological malignancies. How angiogenesis affects the molecular pathways in malignancies is still a mystery. The angiopoietin family, one of the known molecular mediators for angiogenesis, encourages angiogenesis by attaching to Tie receptors on cell surfaces. Angiopoietin, Tie, and particularly the molecular pathways they mediate have all been the subject of recent studies that have established their diagnostic, prognostic, and therapeutic potential. Here, we've reviewed the function of molecular pathways impacted by the Angiogenin and Tie system in hematological malignancies.

Causal Effects of Blood Lipid Traits on Inflammatory Bowel Diseases: A Mendelian Randomization Study.

Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), have become a global health problem with a rapid growth of incidence in newly industrialized countries. Observational studies have recognized associations between blood lipid traits and IBDs, but the causality still remains unclear. To determine the causal effects of blood lipid traits, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) on IBDs, two-sample Mendelian randomization (MR) analyses were conducted using the summary-level genome-wide association study (GWAS) statistics of blood lipid traits and IBDs. Our univariable MR using multiplicative random-effect inverse-variance weight (IVW) method identified TC (OR: 0.674; 95% CI: 0.554, 0.820; p < 0.00625) and LDL-C (OR: 0.685; 95% CI: 0.546, 0.858; p < 0.00625) as protective factors of UC. The result of our multivariable MR analysis further provided suggestive evidence of the protective effect of TC on UC risk (OR: 0.147; 95% CI: 0.025, 0.883; p < 0.05). Finally, our MR-BMA analysis prioritized TG (MIP: 0.336; θ^MACE: -0.025; PP: 0.31; θ^λ: -0.072) and HDL-C (MIP: 0.254; θ^MACE: -0.011; PP: 0.232; θ^λ: -0.04) for CD and TC (MIP: 0.721; θ^MACE: -0.257; PP: 0.648; θ^λ: -0.356) and LDL-C (MIP: 0.31; θ^MACE: -0.095; PP: 0.256; θ^λ: -0.344) for UC as the top-ranked protective factors. In conclusion, the causal effect of TC for UC prevention was robust across all of our MR approaches, which provide the first evidence that genetically determined TC is causally associated with reduced risk of UC. The finding of this study provides important insights into the metabolic regulation of IBDs and potential metabolites targeting strategies for IBDs intervention.

Population performance and detoxifying and protective enzyme activities of four thrips species feeding on flowers of Magnolia grandiflora (Ranunculales: Magnolia).

BACKGROUND: Different thrips species can co-occur on the same flowers with different dominance degrees. To accurately evaluate the population performance on different thrips species on Magnolia grandiflora flowers, we investigated the diversity of thrips species and their population dynamics both in the field and laboratory. In addition, the activities of detoxifying and protective enzymes in thrips were also measured. RESULTS: Field investigations revealed that four thrips species (Thrips hawaiiensis, Thrips flavidulus, Frankliniella occidentalis, and Thrips coloratus) coexisted on M. grandiflora flowers. They were ranked, from highest population density to lowest, as follows: T. hawaiiensis > T. flavidulus > F. occidentalis > T. coloratus. In laboratory investigations, the species were ranked, from fastest developmental rates to slowest, as follows: F. occidentalis > T. hawaiiensis > T. flavidulus > T. coloratus; and from largest population size to smallest, as follows: T. hawaiiensis > F. occidentalis > T. flavidulus > T. coloratus. Biochemistry assays showed that the four species differed in their activities of detoxifying enzymes (carboxylesterase, glutathione-S-transferase, and cytochrome P450) and protective enzymes (superoxide dismutase, peroxidase) in both laboratory and field strains. CONCLUSION: Differences in population performance among these four thrips on M. grandiflora may be related to their activity levels of physiological enzymes. The variations in thrips population performance between the field and the laboratory could be due to differences in environmental conditions. T. hawaiiensis showed a strong host preference for M. grandiflora, and thus it has the potential to be a dangerous pest in horticultural plants. © 2023 Society of Chemical Industry.

Daridorexant for the treatment of insomnia disorder: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Daridorexant is a novel dual orexin receptor antagonist that has shown efficacy as a treatment for insomnia in multiple randomized clinical trials. However, the efficacy and safety of daridorexant for treatment of insomnia disorder has not been characterized comprehensively in the literature. Therefore, we performed a meta-analysis of available studies. We performed a meta-analysis to systematically evaluate the efficacy and safety of daridorexant for treatment of insomnia disorder. METHODS: MEDLINE, Embase, Cochrane Library, and Clinicaltrials.gov for randomized controlled trials were systematically searched up to February 2022. Relative risk and standard mean difference were used to evaluate clinical outcomes. RESULTS: We pooled 2271 patients from 4 randomized clinical trials, and evaluated efficacy endpoints. We found that 50 mg of daridorexant was superior to placebo for 4 efficacy outcomes including wake time after sleep onset, latency to persistent sleep, subjective total sleep time, and Insomnia Daytime Symptoms and Impacts Questionnaire domain score (P < .05). In addition, there were no significant differences (P > .05) in adverse events between daridorexant and placebo. CONCLUSIONS: Different dosages of daridorexant were tested for treatment of insomnia; however, 5 and 10 mg are not available because of issues of suboptimal effectiveness. Daridorexant showed better efficacy and safety for treatment of insomnia disorder at doses of 25 and 50 mg.

Platelet-derived microvesicles (PMVs) in cancer progression and clinical applications.

Platelet-derived microvesicles (PMVs), the microvesicles with the highest concentration in the bloodstream, play a key role in the regulation of hemostasis, inflammation, and angiogenesis. PMVs have recently been identified as key factors in the link between platelets and cancer. PMVs bind to both cancer cells and nontransformed cells in the microenvironment of the tumor, and then transfer platelet-derived contents to the target cell. These contents have the potential to either stimulate or modulate the target cell's response. PMVs are encased in a lipid bilayer that contains surface proteins and lipids as well as components found inside the PMV. Each of these components participates in known and potential PMV roles in cancer. The complicated roles played by PMVs in the onset, development, and progression of cancer and cancer-related comorbidities are summarized in this study.

Time series analysis of COVID-19 infection curve: A change-point perspective.

In this paper, we model the trajectory of the cumulative confirmed cases and deaths of COVID-19 (in log scale) via a piecewise linear trend model. The model naturally captures the phase transitions of the epidemic growth rate via change-points and further enjoys great interpretability due to its semiparametric nature. On the methodological front, we advance the nascent self-normalization (SN) technique (Shao, 2010) to testing and estimation of a single change-point in the linear trend of a nonstationary time series. We further combine the SN-based change-point test with the NOT algorithm (Baranowski et al., 2019) to achieve multiple change-point estimation. Using the proposed method, we analyze the trajectory of the cumulative COVID-19 cases and deaths for 30 major countries and discover interesting patterns with potentially relevant implications for effectiveness of the pandemic responses by different countries. Furthermore, based on the change-point detection algorithm and a flexible extrapolation function, we design a simple two-stage forecasting scheme for COVID-19 and demonstrate its promising performance in predicting cumulative deaths in the U.S.

Platelet-related gene risk score: a predictor for pancreatic cancer microenvironmental signature, chemosensitivity and prognosis.

Recent studies have indicated that platelets may play a role in the advancement of pancreatic cancer by supporting tumor growth and increasing resistance to chemotherapy. This study aims to develop a prognostic model for pancreatic cancer using a platelet-related gene risk score. Prognostic platelet-related genes (PRGs) were identified from public databases and analyzed using cluster analysis. We investigated the microenvironment signatures and gene mutation patterns across different PRG-based molecular subtypes of pancreatic cancer. A prognostic model based on PRGs was developed using LASSO-Cox Regression Analysis. Additionally, we examined the correlation between the risk score and tumor clinical characteristics, as well as drug sensitivity. Two molecular subtypes, cluster C1 and C2, were identified. Cluster C2 was associated with a poorer prognosis compared to Cluster C1. The C1 group exhibited higher scores for activated CD8+ T cells, central memory CD4+ T cells, and natural killer T cells. The C2 group demonstrated a higher frequency of gene mutations. We established and validated a novel prognostic prediction model and platelet-related gene risk score for pancreatic cancer. The risk score was positively correlated with T stage, N stage, and tumor grade, and it presented a significant prognostic value compared to other clinical factors. In conclusion, a novel prognostic prediction model focusing on platelet involvement in pancreatic cancer has been developed, offering potential benefits for future drug therapies and clinical prognostic assessments.

Clinical efficacy and safety of low-dose doxepin in Chinese patients with generalized anxiety disorder: A before-after study.

Clinical and animal studies have reported that low-dose doxepin may have positive effects on generalized anxiety disorder (GAD); however, its effectiveness and clinical safety are less well understood. This study is a before-after study and aims to investigate the effectiveness and side effects of low-dose doxepin by evaluating Hamilton Anxiety Scale (HAMA) scores, hormones, blood glucose, serum lipids, body weight, and body mass index (BMI) in patients with GAD. Forty-nine patients (20 males and 29 females) with GAD were randomly assigned to receive low-dose doxepin (6.25 mg-12.5 mg per day) for 12 weeks between February 2015 and March 2016. HAMA scores, fasting blood glucose (FBG) body weight, BMI, and some serum biochemical indexes, such as adrenocorticotropic hormone (ACTH), free triiodothyronine (FT3), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDLC), and FBG, were assessed during pretreatment and post-treatment. Mean scores of HAMA decreased from 19.50 ±â€…1.22 to 8.50 ±â€…3.61 after low-dose doxepin treatment (P < .01). The serum levels of ACTH (4.33 ±â€…2.14 vs 6.12 ±â€…3.02 pmol/L), FT3 (4.78 ±â€…0.51 vs 5.15 ±â€…0.52 pg/mL), TC (4.55 ±â€…1.01 vs 5.93 ±â€…1.66 mmol/L), TG (1.69 ±â€…1.51 vs 3.39 ±â€…2.86 mmol/L), and LDLC (2.43 ±â€…0.88 vs 3.76 ±â€…1.25 mmol/L), and FBG (5.06 ±â€…0.43 vs 5.78 ±â€…0.81 mmol/L) were higher than that pretreatment with a significant difference (P < .01). Bodyweight (62.00 ±â€…7.45 vs 64.00 ±â€…6.44 kg, P = .23) and BMI (23.70 ±â€…2.35 vs 24.48 ±â€…2.11 kg/m2, P = .14) had no difference after treatment. These results suggest that low-dose doxepin has beneficial clinical efficacy and safety. Low-dose doxepin can ameliorate anxiety in GAD patients and has some effects on neuroendocrine systems and the metabolic activity of serum glucose and lipid.

B-Cell Lymphoma Producing IgM Anti-B Antibody: A Case Report.

ABO blood group system is the most important blood group system in transfusion and transplantation medicine. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphomas (NHLs) worldwide. There have been some studies that lymphoma could affect ABO blood group system and thus affect blood transfusion strategy. However, the mechanisms lymphoma affecting ABO blood group system have not been fully elucidated so far. Here, we report a case of a patient who was a 72-year-old Chinese man came to our hospital for medical advice because of cervical lymphadenophathy. The patient was subsequently diagnosed with diffuse large B-cell lymphoma by lymph-node biopsy. His ABO blood group was initially typed as B on November 7, 2020. He was transfusing B type leukocyte poor RBCs (LPR) before we found the patient's ABO blood group discrepancy on December 2, 2020 by forward and reverse typing methods, which the discrepancy was verified by genotyping. The patient began to transfuse O type washed RBCs (WRBC) since then. Compared to transfuse B type leukocyte poor RBCs (LPR), the efficiency of transfusing O type washed RBCs (WRBC) was better. Although hemoglobin level did not greatly improve, indirect bilirubin level evidently decreased. Furthermore, we found B-cell lymphoma affected blood transfusion strategy by producing IgM anti-B antibody in this case. Clinicians should need to be aware of the effect of B-cell lymphoma on blood transfusion strategy.

FGF21 facilitates autophagy in prostate cancer cells by inhibiting the PI3K-Akt-mTOR signaling pathway.

Fibroblast growth factor 21 (FGF21) plays an important role in regulating glucose and lipid metabolism, but its role in cancer is less well-studied. We aimed to investigate the action of FGF21 in the development of prostate cancer (PCa). Herein, we found that FGF21 expression was markedly downregulated in PCa tissues and cell lines. FGF21 inhibited the proliferation and clone formation of LNCaP cells (a PCa cell line) and promoted apoptosis. FGF21 also inhibited PCa cell migration and invasiveness. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that FGF21 was related to autophagy and the phosphatidylinositol 3-kinase-Akt kinase-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway. Mechanistically, FGF21 promoted autophagy in LNCaP cells by inhibiting the PI3K-Akt-mTOR-70S6K pathway. In addition, FGF21 inhibited PCa tumorigenesis in vivo in nude mice. Altogether, our findings show that FGF21 inhibits PCa cell proliferation and promoted apoptosis in PCa cells through facilitated autophagy. Therefore, FGF21 might be a potential novel target in PCa therapy.

Conditioned medium-preconditioned EPCs enhanced the ability in oligovascular repair in cerebral ischemia neonatal rats.

BACKGROUND: Oligovascular niche mediates interactions between cerebral endothelial cells and oligodendrocyte precursor cells (OPCs). Disruption of OPC-endothelium trophic coupling may aggravate the progress of cerebral white matter injury (WMI) because endothelial cells could not provide sufficient support under diseased conditions. Endothelial progenitor cells (EPCs) have been reported to ameliorate WMI in the adult brain by boosting oligovascular remodeling. It is necessary to clarify the role of the conditioned medium from hypoxic endothelial cells preconditioned EPCs (EC-pEPCs) in WMI since EPCs usually were recruited and play important roles under blood-brain barrier disruption. Here, we investigated the effects of EC-pEPCs on oligovascular remodeling in a neonatal rat model of WMI. METHODS: In vitro, OPC apoptosis induced by the conditioned medium from oxygen-glucose deprivation-injured brain microvascular endothelial cells (OGD-EC-CM) was analyzed by TUNEL and FACS. The effects of EPCs on EC damage and the expression of cytomokine C-X-C motif ligand 12 (CXCL12) were examined by western blot and FACS. The effect of the CM from EC-pEPCs against OPC apoptosis was also verified by western blot and silencing RNA. In vivo, P3 rat pups were subjected to right common carotid artery ligation and hypoxia and treated with EPCs or EC-pEPCs at P7, and then angiogenesis and myelination together with cognitive outcome were evaluated at the 6th week. RESULTS: In vitro, EPCs enhanced endothelial function and decreased OPC apoptosis. Meanwhile, it was confirmed that OGD-EC-CM induced an increase of CXCL12 in EPCs, and CXCL12-CXCR4 axis is a key signaling since CXCR4 knockdown alleviated the anti-apoptosis effect of EPCs on OPCs. In vivo, the number of EPCs and CXCL12 protein level markedly increased in the WMI rats. Compared to the EPCs, EC-pEPCs significantly decreased OPC apoptosis, increased vascular density and myelination in the corpus callosum, and improved learning and memory deficits in the neonatal rat WMI model. CONCLUSIONS: EC-pEPCs more effectively promote oligovascular remodeling and myelination via CXCL12-CXCR4 axis in the neonatal rat WMI model.

Conditional Deletion of Foxg1 Alleviates Demyelination and Facilitates Remyelination via the Wnt Signaling Pathway in Cuprizone-Induced Demyelinated Mice.

The massive loss of oligodendrocytes caused by various pathological factors is a basic feature of many demyelinating diseases of the central nervous system (CNS). Based on a variety of studies, it is now well established that impairment of oligodendrocyte precursor cells (OPCs) to differentiate and remyelinate axons is a vital event in the failed treatment of demyelinating diseases. Recent evidence suggests that Foxg1 is essential for the proliferation of certain precursors and inhibits premature neurogenesis during brain development. To date, very little attention has been paid to the role of Foxg1 in the proliferation and differentiation of OPCs in demyelinating diseases of the CNS. Here, for the first time, we examined the effects of Foxg1 on demyelination and remyelination in the brain using a cuprizone (CPZ)-induced mouse model. In this work, 7-week-old Foxg1 conditional knockout and wild-type (WT) mice were fed a diet containing 0.2% CPZ w/w for 5 weeks, after which CPZ was withdrawn to enable remyelination. Our results demonstrated that, compared with WT mice, Foxg1-knockout mice exhibited not only alleviated demyelination but also accelerated remyelination of the demyelinated corpus callosum. Furthermore, we found that Foxg1 knockout decreased the proliferation of OPCs and accelerated their differentiation into mature oligodendrocytes both in vivo and in vitro. Wnt signaling plays a critical role in development and in a variety of diseases. GSK-3ß, a key regulatory kinase in the Wnt pathway, regulates the ability of ß-catenin to enter nuclei, where it activates the expression of Wnt target genes. We then used SB216763, a selective inhibitor of GSK-3ß activity, to further demonstrate the regulatory mechanism by which Foxg1 affects OPCs in vitro. The results showed that SB216763 clearly inhibited the expression of GSK-3ß, which abolished the effect of the proliferation and differentiation of OPCs caused by the knockdown of Foxg1. These results suggest that Foxg1 is involved in the proliferation and differentiation of OPCs through the Wnt signaling pathway. The present experimental results are some of the first to suggest that Foxg1 is a new therapeutic target for the treatment of demyelinating diseases of the CNS.

Sfrp5 interacts with Slurp1 to regulate the accumulation of triglycerides in hepatocyte steatosis model.

Secreted frizzled-related protein 5 (Sfrp5), an anti-inflammatory adipocytokine secreted by adipocytes, plays an important role in energy metabolism. Studies have shown that Sfrp5 plays a salutary role in the regulation of lipid metabolism, but its specific mechanism needs further study. In this study, we showed a lower level of Sfrp5 in subjects with diet-induced obesity than in normal-diet C57BL/6J mice. To further investigate Sfrp5-associated proteins in HepG2 cells, the immunoprecipitation assay and silver staining assay were performed. By mass spectrometry analysis, secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide (Slurp-1) was found to interact with Sfrp5. Further verification was obtained through the positive and reverse immunoprecipitation assay. In this study, we found that the sole over-expression of Slurp1 promoted the expression of Sfrp5 in palmitate-induced HepG2 cells. In addition, our experimental evidence shows that the role of Slurp1 in decreasing TG level was greatly reduced in the case of suppression of expression of Sfrp5 in palmitate-induced model cells. Our study further found that Slurp1 regulates the synthesis pathway of triglyceride by interacting with Sfrp5 to alleviate triglyceride accumulation in palmitate-induced model cells. In summary, we are the first to discover the interaction between Sfrp5 and Slurp1, and we found that Slurp1 may regulate the accumulation of TG through Sfrp5.