Protease-activated receptor 2 signaling upregulates angiogenic growth factors in renal cell carcinoma

Renal cell carcinoma (RCC) is a highly vascular tumor associated with expression of various angiogenic growth factors. The precise process of how these growth factors are regulated in RCC is not fully understood. Recent evidence suggests that protease activated receptors (PARs), a new family of G-protein coupled receptors, play a crucial role in vascular development and tumor progression through a variety of mechanisms. However, the nature of PAR expression in human RCC tissues and its function in regulating angiogenesis in RCC are largely unknown. In this study, we investigated the expression and function of PAR-2 in RCC. RT-PCR and immunohistochemistry assays show that PAR-2 expression is significantly increased in human RCC tissue compared with the adjacent non-neoplastic kidney tissue. In RCC derived cells, PAR-2 is functional as evidenced by robust signaling through MAP kinases including ERK1/2 and JNK. Furthermore, activation of PAR-2 significantly upregulates several angiogenic cytokines, including interleukin-6 (IL-6), IL-8, monocytes chemotactic protein-1 (MCP-1) and growth-related oncogene (GRO). To our knowledge, this is the first report that characterized PAR-2 expression in RCC tissue and further demonstrated that PAR-2 has a critical role in regulating angiogenesis in RCC.     

Effects of Matrine on JAK-STAT Signaling Transduction Pathways in Bleomycin-Induced Pulmonary Fibrosis

The current study aims to investigate the effects of matrine on the JAK-STAT signaling transduction pathways in bleomycin (BLM)-induced pulmonary fibrosis (PF) and to explore its action mechanism. A total of 72 male C57BL/6 mice were randomized into the control, model, and treatment groups. PF models were established by instilling BLM intratracheally. The treatment group was given daily matrine through gastric lavage. Six mice were sacrificed in each group at 3, 7, 14, and 28 days. The lung tissues were observed using hematoxylin-eosin staining. The expression of JAK, STAT1, and STAT3 was observed using immunohistochemistry and then determined using real-time polymerase chain reaction. Alveolitis and PF significantly improved in the treatment group compared with the model group (P < 0.05). The expression of JAK, STAT1, and STAT3 in the model group increased at day 7, peaked at day 14 and then decreased, but the expression was still higher than that in the control group at day 28 (P < 0.05). The three indices in the treatment group were significantly lower than those in the model group at any detection time point (P < 0.05). PF causes high expression of JAK, STAT1, and STAT3. Matrine exerts an anti-PF effect by inhibiting the JAK-STAT signaling transduction pathways.     

Establishment of Dental Epithelial Cell Line (HAT-7) and the Cell Differentiation Dependent on Notch Signaling Pathway

Rat incisors grow continuously throughout life. Producing a variety of dental epithelial cells is performed by stem cells located in the cervical loop of the incisor apex. To study the mechanisms for cell differentiation, we established a dental epithelial cell line (HAT-7) originating from a cervical loop epithelium of a rat incisor. Immunochemical studies showed that HAT-7 produced the cells expressing amelogenin, ameloblastin, or alkaline phosphatase (ALP). To illustrate a role of Notch signaling in the determinant of the cell fate, we examined expression patterns of Notch1 and Jagged1 in HAT-7 density dependently. At lower cell density, Notch1- or Jagged1-expressing cells were not seen. However, when they were fully confluent, cells began to express Notch1 or Jagged1 strongly. Some ALP-positive cells were almost consistent with Notch1-expressing cells but not Jagged1-expressing cells. These results suggested that the determinant of direction of differentiation was associated with Notch signaling pathway.     

Gut microbiome in Schizophrenia: Altered functional pathways related to immune modulation and atherosclerotic risk

Emerging evidence has linked the gut microbiome changes to schizophrenia. However, there has been limited research into the functional pathways by which the gut microbiota contributes to the phenotype of persons with chronic schizophrenia. We characterized the composition and functional potential of the gut microbiota in 48 individuals with chronic schizophrenia and 48 matched (sequencing plate, age, sex, BMI, and antibiotic use) non-psychiatric comparison subjects (NCs) using 16S rRNA sequencing. Patients with schizophrenia demonstrated significant beta-diversity differences in microbial composition and predicted genetic functional potential compared to NCs. Alpha-diversity of taxa and functional pathways were not different between groups. Random forests analyses revealed that the microbiome predicts differentiation of patients with schizophrenia from NCs using taxa (75% accuracy) and functional profiles (67% accuracy for KEGG orthologs, 70% for MetaCyc pathways). We utilized a new compositionally-aware method incorporating reference frames to identify differentially abundant microbes and pathways, which revealed that Lachnospiraceae is associated with schizophrenia. Functional pathways related to trimethylamine-N-oxide reductase and Kdo₂-lipid A biosynthesis were altered in schizophrenia. These metabolic pathways were associated with inflammatory cytokines and risk for coronary heart disease in schizophrenia. Findings suggest potential mechanisms by which the microbiota may impact the pathophysiology of the disease through modulation of functional pathways related to immune signaling/response and lipid and glucose regulation to be further investigated in future studies.     

Nuclear Factor-κB: Fine-Tuning a Central Integrator of Diverse Biologic Stimuli

The nuclear factor (NF)-κ B family of proteins is a key regulator of inflammation, innate immunity, and cell survival and differentiation. Components of these pathways are potential targets of intervention for inflammation, infectious diseases, and cancer. However, therapeutic interventions that dampen the host response to infection and injury must also recognize the autoregulatory loops in the “resolution” phase of inflammation and infection. A more precise fine-tuning of these pathways leading to NF-κB activation will require dissecting temporally the different phases of activation and endogenous autoregulatory deactivation programs in diseases and redefining end-points after drug/inhibitor treatment to correlate changes in these stages.     

Ras-MAPK通路在食管癌中的研究进展

Ras is best known for the ability of regulating cell growth, proliferation and differentiation. Mutations in Ras are associated with abnormal cell proliferation, resulting in the incidence of all human cancers. Mitogen-activated protein kinase (MAPK) signaling pathways are the most well described pathways in carcinogenesis, which has been identified as a key downstream effector in Ras signaling as well as playing important roles in prognosis of tumors. Recently, evidence has gradually accumulated to demonstrate that mutation in Ras or aberrant expression of MAPK has profound effects on the incidence of esophageal carcinoma, and applications of some chemotherapeutic drugs can not lead to the expectant function. Further understanding of the relevant molecular mechanisms of Ras-MAPK signaling pathways will be helpful for development of efficient targeting therapeutic approaches to the treatment of esophageal cancer. In this article, the advances of Ras-MAPK signaling pathways in esophageal carcinoma are reviewed.     

Enriched environment boosts the post-stroke recovery of neurological function by promoting autophagy

Autophagy is crucial for maintaining cellular homeostasis, and can be activated after ischemic stroke. It also participates in nerve injury and repair. The purpose of this study was to investigate whether an enriched environment has neuroprotective effects through affecting autophagy. A Sprague-Dawley rat model of transient ischemic stroke was prepared by occlusion of the middle cerebral artery followed by reperfusion. One week after surgery, these rats were raised in either a standard environment or an enriched environment for 4 successive weeks. The enriched environment increased Beclin-1 expression and the LC3-II/LC3-I ratio in the autophagy/lysosomal pathway in the penumbra of middle cerebral artery-occluded rats. Enriched environment-induced elevations in autophagic activity were mainly observed in neurons. Enriched environment treatment also promoted the fusion of autophagosomes with lysosomes, enhanced the lysosomal activities of lysosomal-associated membrane protein 1, cathepsin B, and cathepsin D, and reduced the expression of ubiquitin and p62. After 4 weeks of enriched environment treatment, neurological deficits and neuronal death caused by middle cerebral artery occlusion/reperfusion were significantly alleviated, and infarct volume was significantly reduced. These findings suggest that neuronal autophagy is likely the neuroprotective mechanism by which an enriched environment promotes recovery from ischemic stroke. This study was approved by the Animal Ethics Committee of the Kunming University of Science and Technology, China(approval No. 5301002013855) on March 1, 2019.     

消肿止痛合剂对大鼠随意皮瓣血管再生的影响

目的:观察消肿止痛合剂对大鼠随意皮瓣血管再生及血管内皮生长因子(VEGF)-Dll4/Notch信号通路的影响。方法:将240只健康SD大鼠随机分为6组,分别为空白组、假手术组、模型组、消肿止痛合剂组(消肿组)、消肿止痛合剂+Notch阻断剂MK-0752(MK)组(消肿+MK组)和消肿止痛合剂组+VEGF受体抑制剂axitinib(AXI)组(消肿+AXI组)。观察皮瓣毛细血管充盈时间;HE染色观察皮瓣组织新生毛细血管的数量、微血管密度、微血管管径及血管成活面积;ELISA法检测血清中VEGF的含量;RT-qPCR检测大鼠皮瓣组织中VEGFA、Notch和Dll4的mRNA表达水平。结果:与模型组相比,消肿组第10天毛细血管充盈时间降低(P<0.05);与消肿组相比,消肿+AXI组的毛细血管充盈时间增加(P<0.05)。模型组大鼠皮瓣组织细胞排列紊乱,细胞核稀疏,可见明显水肿和大量白细胞浸润;消肿组和消肿+MK组水肿明显减轻,组织间隙炎症细胞浸润减少,其中消肿+MK组减轻更为明显。与模型组相比,消肿组微血管数量、密度和面积均显著增加,VEGF的含量显著增加,VEGFA、Notch和Dll4的mRNA表达量显著升高(P<0.05);与消肿组相比,AXI干预后微血管数量、密度和面积均显著减少,VEGF的含量降低,VEGFA、Notch和Dll4的mRNA表达量降低(P<0.05);MK干预后,VEGFA的mRNA表达水平升高,而Notch和Dll4 mRNA表达增加的趋势被有效抑制(P<0.05)。结论:消肿止痛合剂能够促进皮瓣术后血管的再生,从而增强了随意型皮瓣的成活率,可能与影响VEGF-Dll4/Notch信号转导通路有关。     

Myeloid-derived suppressor cells and regulatory T cells share common immunoregulatory pathways-related microRNAs that are dysregulated by acute lymphoblastic leukemia and chemotherapy

BackgroundRelapse remains a critical challenge in children with acute lymphoblastic leukemia (ALL). The emergence of immunoregulatory cells, including myeloid-derived suppressor cells (MDSCs), and T regulatory (T_reg) cells, has been considered one potential mechanism of relapse in children with ALL.AimThis study aimed to address the microRNAs (miRNAs) related to MDSCs and T_reg cells and to explore their targeted immunoregulatory pathways.MethodsAffymetrix microarray was used for global miRNA profiling in B-ALL pediatric patients before, during, and after induction of chemotherapy. Bioinformatics analysis was performed on MDSCs and T_reg cells-related dysregulated miRNAs, and miR-Pathway analysis was performed to explore their targeted immunoregulatory pathways.Results516 miRNAs were dysregulated in ALL patients as compared to the healthy donor. Among them, 13 miRNAs and 8 miRNAs related to MDSCs and T_reg cells, respectively, were common in all patients. Besides, 12 miRNAs were shared between MDSCs and T_reg cells; 4 of them were common in all patients. Four immune-related pathways; TNF, TGF-β, FoxO, and Hippo were found implicated.ConclusionOur pilot study concluded certain miRNAs related to MDSCs and T_reg cells, these miRNAs were linked to immunoregulatory pathways. Our results open avenues for testing those miRNA as molecular biomarkers for the immunosuppressive tumor microenvironment.     

State of the art of bacterial chemotaxis

Bacterial chemotaxis is a biased movement of bacteria toward the beneficial chemical gradient or away from a toxic chemical gradient. This movement is achieved by sensing a chemical gradient by chemoreceptors. In most of the chemotaxis studies, Escherichia coli has been used as a model organism. E. coli have about 4–6 flagella on their surfaces, and the motility is achieved by rotating the flagella. Each flagellum has reversible flagellar motors at its base, which rotate the flagella in counterclockwise and clockwise directions to achieve “run” and “tumble.” The chemotaxis of bacteria is regulated by a network of interacting proteins. The sensory signal is processed and transmitted to the flagellar motor by cytoplasmic proteins. Bacterial chemotaxis plays an important role in many biological processes such as biofilm formation, quorum sensing, bacterial pathogenesis, and host infection. Bacterial chemotaxis can be applied for bioremediation, horizontal gene transfer, drug delivery, or maybe some other industry in near future. This review contains an overview of bacterial chemotaxis, recent findings of the physiological importance of bacterial chemotaxis in other biological processes, and the application of bacterial chemotaxis.