Search

Metastasis is the major cause of death in patients with pancreatic ductal adenocarcinoma (PDAC), and circulating tumor cells (CTCs) play an important role in the development of metastasis. However, few studies have uncovered the metastasis mechanism of PDAC based on CTCs. In this study, the existing bulk RNA-sequencing (bulk RNA-seq) and single-cell sequencing (scRNA-seq) data for CTCs in pancreatic cancer were obtained from the Gene Expression Omnibus (GEO) database. Analysis of tumor-infiltrating immune cells (TIICs) by CIBERSORT showed that the CTCs enriched from the peripheral blood of metastatic PDAC were found to contain a high proportion of T cell regulators (Tregs) and macrophages, while the proportion of dendritic cells (DCs) was lower than that enriched from localized PDAC. Through weighted gene co-expression network analysis (WGCNA) and the result of scRNA-seq, we identified the hub module (265 genes) and 87 marker genes, respectively, which were highly associated with metastasis. The results of functional enrichment analysis indicated that the two gene sets mentioned above are mainly involved in cell adhesion and cytoskeleton and epithelial–mesenchymal transition (EMT). Finally, we found that HMGB3 was the hub gene according to the Venn diagram. The expression of HMGB3 in PDAC was significantly higher than that in normal tissues (protein and mRNA levels). HMGB3 expression was significantly positively correlated with both EMT-related molecules and CTC cluster–related markers. Furthermore, it was also found that HMGB3 mutations were favorably related to tumor-associated immune cells through the TIMER2.0 online tool. We further demonstrated that PDAC patients with higher HMGB3 expression had significantly worse overall survival (OS) in multiple datasets. In summary, our study suggests that HMGB3 is a hub gene associated with EMT in CTCs, the formation of CTC clusters, and infiltration patterns of immune cells favorable for tumor progression and metastasis to distant organs.

When dealing with the complex deformation of free surface such as wave breaking, traditional mesh-based Computational Fluid Dynamics (CFD) methods often face problems arising alongside grid distortion and re-meshing. Therefore, the meshless method became robust for treating large displaced free surface and other boundaries caused by moving structures. The particle method, which is an important branch of meshless method, is mainly divided into the Smoothed Particle Hydrodynamics (SPH) and Moving Particle Semi-implicit (MPS) methods. Different from the SPH method, which involves continuity and treat density as a variable when building kernel functions, the kernel function in the MPS method is a weight function which treats density as a constant, and the spatial derivatives are discretized by establishing the gradient operator and Laplace operator separately. In other words, the first- or second-order continuity of the kernel functions in the MPS method is not a necessity as in SPH, though it might be desirable. At present, the MPS method has been successfully applied to various violent-free surface flow problems in ocean engineering and diverse applications have been comprehensively demonstrated in a number of review papers. This work will focus on algorithm developments of the MPS method and to provide all perspectives in terms of numerical algorithms along with their pros and cons.

Abstract Background Idiopathic pulmonary fibrosis is a persistent disease of the lung interstitium for which there is no efficacious pharmacological therapy. Protodioscin, a steroidal saponin, possesses diverse pharmacological properties; however, its function in pulmonary fibrosis is yet to be established. Hence, in this investigation, it was attempted to figure out the anti-pulmonary fibrosis influences of protodioscin and its pharmacological properties related to oxidative stress. Methods A mouse lung fibrosis model was generated using tracheal injections of bleomycin, followed by intraperitoneal injection of different concentrations of protodioscin, and the levels of oxidative stress and fibrosis were detected in the lungs. Multiple fibroblasts were treated with TGF-β to induce their transition to myofibroblasts. It was attempted to quantify myofibroblast markers’ expression levels and reactive oxygen species levels as well as Nrf2 activation after co-incubation of TGF-β with fibroblasts and different concentrations of protodioscin. The influence of protodioscin on the expression and phosphorylation of p62, which is associated with Nrf2 activation, were detected, and p62 related genes were predicted by STRING database. The effects of Nrf2 inhibitor or silencing of the Nrf2, p62 and NBR1 genes, respectively, on the activation of Nrf2 by protodioscin were examined. The associations between p62, NBR1, and Keap1 in the activation of Nrf2 by protodioscin was demonstrated using a co-IP assay. Nrf2 inhibitor were used when protodioscin was treated in mice with pulmonary fibrosis and lung tissue fibrosis and oxidative stress levels were detected. Results In vivo, protodioscin decreased the levels of fibrosis markers and oxidative stress markers and activated Nrf2 in mice with pulmonary fibrosis, and these effects were inhibited by Nrf2 inhibitor. In vitro, protodioscin decreased the levels of myofibroblast markers and oxidative stress markers during myofibroblast transition and promoted Nrf2 downstream gene expression, with reversal of these effects after Nrf2, p62 and NBR1 genes were silenced or Nrf2 inhibitors were used, respectively. Protodioscin promoted the binding of NBR1 to p62 and Keap1, thereby reducing Keap1-Nrf2 binding. Conclusion The NBR1-p62-Nrf2 axis is targeted by protodioscin to reduce oxidative stress and inhibit pulmonary fibrosis. Graphical Abstract

Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that lacks effective treatment modalities. Once patients are diagnosed with IPF, their median survival is approximately 3–5 years. PPARγ is an important target for the prevention and treatment of pulmonary fibrosis. Asarinin is a lignan compound that can be extracted from food plant Asarum heterotropoides. In this study, we investigated the therapeutic effects of asarinin in a pulmonary fibrosis model constructed using bleomycin in mice and explored the underlying mechanisms. Intraperitoneal administration of asarinin to mice with pulmonary fibrosis showed that asarinin effectively attenuated pulmonary fibrosis, and this effect was significantly inhibited by the PPARγ inhibitor GW9662. Asarinin inhibited TGF-β1-induced fibroblast-to-myofibroblast transition in vitro, while GW9662 and PPARγ gene silencing significantly inhibited this effect. In addition, asarinin inhibited not only the canonical Smad pathway of TGF-β but also the non-canonical AKT and MAPK pathways by activating PPARγ. Our study demonstrates that asarinin can be used as a therapeutic agent for pulmonary fibrosis, and that PPARγ is its key target.

ObjectiveAccording to the Global Tuberculosis Report for three consecutive years, tuberculosis (TB) is the second leading infectious killer. Primary pulmonary tuberculosis (PTB) leads to the highest mortality among TB diseases. Regretfully, no previous studies targeted the PTB of a specific type or in a specific course, so models established in previous studies cannot be accurately feasible for clinical treatments. This study aimed to construct a nomogram prognostic model to quickly recognize death-related risk factors in patients initially diagnosed with PTB to intervene and treat high-risk patients as early as possible in the clinic to reduce mortality.MethodsWe retrospectively analyzed the clinical data of 1,809 in-hospital patients initially diagnosed with primary PTB at Hunan Chest Hospital from January 1, 2019, to December 31, 2019. Binary logistic regression analysis was used to identify the risk factors. A nomogram prognostic model for mortality prediction was constructed using R software and was validated using a validation set.ResultsUnivariate and multivariate logistic regression analyses revealed that drinking, hepatitis B virus (HBV), body mass index (BMI), age, albumin (ALB), and hemoglobin (Hb) were six independent predictors of death in in-hospital patients initially diagnosed with primary PTB. Based on these predictors, a nomogram prognostic model was established with high prediction accuracy, of which the area under the curve (AUC) was 0.881 (95% confidence interval [Cl]: 0.777-0.847), the sensitivity was 84.7%, and the specificity was 77.7%.Internal and external validations confirmed that the constructed model fit the real situation well.ConclusionThe constructed nomogram prognostic model can recognize risk factors and accurately predict the mortality of patients initially diagnosed with primary PTB. This is expected to guide early clinical intervention and treatment for high-risk patients.

Abstract A differentiation switch of bone marrow mesenchymal stem/stromal cells (BMSCs) from osteoblasts to adipocytes contributes to age‐ and menopause‐associated bone loss and marrow adiposity. Here it is found that osteocytes, the most abundant bone cells, promote adipogenesis and inhibit osteogenesis of BMSCs by secreting neuropeptide Y (NPY), whose expression increases with aging and osteoporosis. Deletion of NPY in osteocytes generates a high bone mass phenotype, and attenuates aging‐ and ovariectomy (OVX)‐induced bone‐fat imbalance in mice. Osteocyte NPY production is under the control of autonomic nervous system (ANS) and osteocyte NPY deletion blocks the ANS‐induced regulation of BMSC fate and bone‐fat balance. γ‐Oryzanol, a clinically used ANS regulator, significantly increases bone formation and reverses aging‐ and OVX‐induced osteocyte NPY overproduction and marrow adiposity in control mice, but not in mice lacking osteocyte NPY. The study suggests a new mode of neuronal control of bone metabolism through the ANS‐induced regulation of osteocyte NPY.

Abstract Recently, the gut microbiota (GM) has been shown to be a regulator of bone homeostasis and the mechanisms by which GM modulates bone mass are still being investigated. Here, it is found that colonization with GM from children (CGM) but not from the elderly (EGM) prevents decreases in bone mass and bone strength in conventionally raised, ovariectomy (OVX)‐induced osteoporotic mice. 16S rRNA gene sequencing reveals that CGM reverses the OVX‐induced reduction of Akkermansia muciniphila (Akk). Direct replenishment of Akk is sufficient to correct the OVX‐induced imbalanced bone metabolism and protect against osteoporosis. Mechanistic studies show that the secretion of extracellular vesicles (EVs) is required for the CGM‐ and Akk‐induced bone protective effects and these nanovesicles can enter and accumulate into bone tissues to attenuate the OVX‐induced osteoporotic phenotypes by augmenting osteogenic activity and inhibiting osteoclast formation. The study identifies that gut bacterium Akk mediates the CGM‐induced anti‐osteoporotic effects and presents a novel mechanism underlying the exchange of signals between GM and host bone.

Oleanolic acid (OA) has recently become a research hotspot in the treatment of many human diseases, especially osteoporosis and arthritis. However, the mechanisms are not elucidated completely. We aimed to elucidate the target and the mechanism via which OA inhibited osteoclast differentiation. We used TRAP staining and toluidine blue dye to test OA effect on osteoclastogenesis and bone resorption respectively. We detected the expression level of osteoclast differentiation related genes, estrogen receptor alpha (ERα) and miR-503. We blocked ERα with its specific blocker, methylpiperidino pyrazole (MPP). We antagonized the function of miR-503 with antagomir-503-5p. RT-PCR and ELISA kits were used to investigate the effects of OA on miR-503 formation and maturation-relevant enzymes Dicer and Drosha at gene and protein levels. The data suggested that OA inhibited osteoclastogenesis and bone resorption. OA upregulated ERα and miR-503 expression levels, inhibited RANK expression. MPP significantly attenuated the OA effect including inhibiting osteoclastogenesis, inhibiting bone resorption and up-regulating miR-503 expression. It showed that ERα was the target of OA and OA up-regulated miR-503 expression through ERα. Antagomir-503-5p inhibited the function of miR-503 and attenuated the inhibition of OA on osteoclastogenesis, suggesting that OA inhibited osteoclast by up-regulating miR-503 expression. In addition, OA up-regulated miR-503 by up-regulating Dicer expression. In conclusion, OA inhibits RANKL-induced osteoclastogenesis via ERα/miR-503/RANK signaling pathway in RAW264.7 cells.

BACKGROUND: About 1 million people worldwide commit suicide each year, and college students with suicidal ideation are at high risk of suicide. The prevalence of suicidal ideation in college students has been estimated extensively, but quantitative syntheses of overall prevalence are scarce, especially in China. Accurate estimates of prevalence are important for making public policy. In this paper, we aimed to determine the prevalence of suicidal ideation in Chinese college students. OBJECTIVE AND METHODS: Databases including PubMed, Web of Knowledge, Chinese Web of Knowledge, Wangfang (Chinese database) and Weipu (Chinese database) were systematically reviewed to identify articles published between 2004 to July 2013, in either English or Chinese, reporting prevalence estimates of suicidal ideation among Chinese college students. The strategy also included a secondary search of reference lists of records retrieved from databases. Then the prevalence estimates were summarized using a random effects model. The effects of moderator variables on the prevalence estimates were assessed using a meta-regression model. RESULTS: A total of 41 studies involving 160339 college students were identified, and the prevalence ranged from 1.24% to 26.00%. The overall pooled prevalence of suicidal ideation among Chinese college students was 10.72% (95%CI: 8.41% to 13.28%). We noted substantial heterogeneity in prevalence estimates. Subgroup analyses showed that prevalence of suicidal ideation in females is higher than in males. CONCLUSIONS: The prevalence of suicidal ideation in Chinese college students is relatively high, although the suicide rate is lower compared with the entire society, suggesting the need for local surveys to inform the development of health services for college students.