Prostaglandin E3 attenuates macrophage-associated inflammation and prostate tumour growth by modulating polarization

Alternative polarization of macrophages regulates multiple biological processes. While M1-polarized macrophages generally mediate rapid immune responses, M2-polarized macrophages induce chronic and mild immune responses. In either case, polyunsaturated fatty acid (PUFA)-derived lipid mediators act as both products and regulators of macrophages. Prostaglandin E₃ (PGE₃) is an eicosanoid derived from eicosapentaenoic acid, which is converted by cyclooxygenase, followed by prostaglandin E synthase successively. We found that PGE₃ played an anti-inflammatory role by inhibiting LPS and interferon-γ-induced M1 polarization and promoting interleukin-4-mediated M2 polarization (M2a). Further, we found that although PGE₃ had no direct effect on the growth of prostate cancer cells in vitro, PGE₃ could inhibit prostate cancer in vivo in a nude mouse model of neoplasia. Notably, we found that PGE₃ significantly inhibited prostate cancer cell growth in a cancer cell-macrophage co-culture system. Experimental results showed that PGE₃ inhibited the polarization of tumour-associated M2 macrophages (TAM), consequently producing indirect anti-tumour activity. Mechanistically, we identified that PGE₃ regulated the expression and activation of protein kinase A, which is critical for macrophage polarization. In summary, this study indicates that PGE₃ can selectively promote M2a polarization, while inhibiting M1 and TAM polarization, thus exerting an anti-inflammatory effect and anti-tumour effect in prostate cancer.     

Development and validation of glycolysis-related prognostic score for prediction of prognosis and chemosensitivity of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with aggressive biological behaviour. Its rapid proliferation and tumour growth require reprogramming of glucose metabolism or the Warburg effect. However, the association between glycolysis-related genes with clinical features and prognosis of PDAC is still unknown. Here, we used the meta-analysis to correlate the hazard ratios (HR) of 106 glycolysis genes from MSigDB by the cox proportional hazards regression analysis in 6 clinical data sets of PDAC patients to form a training cohort, and a single group of PDAC patients from the TCGA, ICGC, Arrayexpress and GEO databases to form the validation cohort. Then, a glycolysis-related prognosis (GRP) score based on 29 glycolysis prognostic genes was established in 757 PDAC patients from the training composite cohort and validated in 267 ICGC-CA validation cohort (all P < .05). In addition, including PADC, the prognostic value was also confirmed in other 7 out of 30 pan-cancer cohorts. The GRP score was significantly related to specific metabolism pathways, immune genes and immune cells in the patients with PADC (all P < .05). Finally, by combining with immune cells, the GRP score also well-predicted the chemosensitivity of patients with PADC in the TCGA cohort (AUC = 0.709). In conclusion, this study developed a GRP score for patients with PDAC in predicting prognosis and chemosensitivity for PDAC.     

The detrimental effect of iron on OA chondrocytes: Importance of pro-inflammatory cytokines induced iron influx and oxidative stress

Iron overload is common in elderly people which is implicated in the disease progression of osteoarthritis (OA), however, how iron homeostasis is regulated during the onset and progression of OA and how it contributes to the pathological transition of articular chondrocytes remain unknown. In the present study, we developed an in vitro approach to investigate the roles of iron homeostasis and iron overload mediated oxidative stress in chondrocytes under an inflammatory environment. We found that pro-inflammatory cytokines could disrupt chondrocytes iron homeostasis via upregulating iron influx transporter TfR1 and downregulating iron efflux transporter FPN, thus leading to chondrocytes iron overload. Iron overload would promote the expression of chondrocytes catabolic markers, MMP3 and MMP13 expression. In addition, we found that oxidative stress and mitochondrial dysfunction played important roles in iron overload-induced cartilage degeneration, reducing iron concentration using iron chelator or antioxidant drugs could inhibit iron overload-induced OA-related catabolic markers and mitochondrial dysfunction. Our results suggest that pro-inflammatory cytokines could disrupt chondrocytes iron homeostasis and promote iron influx, iron overload-induced oxidative stress and mitochondrial dysfunction play important roles in iron overload-induced cartilage degeneration.     

Molecular probes for the human adenosine receptors

Adenosine receptors, G protein–coupled receptors (GPCRs) that are activated by the endogenous ligand adenosine, have been considered potential therapeutic targets in several disorders. To date however, only very few adenosine receptor modulators have made it to the market. Increased understanding of these receptors is required to improve the success rate of adenosine receptor drug discovery. To improve our understanding of receptor structure and function, over the past decades, a diverse array of molecular probes has been developed and applied. These probes, including radioactive or fluorescent moieties, have proven invaluable in GPCR research in general. Specifically for adenosine receptors, the development and application of covalent or reversible probes, whether radiolabeled or fluorescent, have been instrumental in the discovery of new chemical entities, the characterization and interrogation of adenosine receptor subtypes, and the study of adenosine receptor behavior in physiological and pathophysiological conditions. This review summarizes these applications, and also serves as an invitation to walk another mile to further improve probe characteristics and develop additional tags that allow the investigation of adenosine receptors and other GPCRs in even finer detail.

     

Targeting P2 receptors in purinergic signaling: a new strategy of active ingredients in traditional Chinese herbals for diseases treatment

Adenosine triphosphate (ATP) and its metabolites adenosine diphosphate, adenosine monophosphate, and adenosine in purinergic signaling pathway play important roles in many diseases. Activation of P2 receptors (P2R) channels and subsequent membrane depolarization can induce accumulation of extracellular ATP, and furtherly cause kinds of diseases, such as pain- and immune-related diseases, cardiac dysfunction, and tumorigenesis. Active ingredients of traditional Chinese herbals which exhibit superior pharmacological activities on diversified P2R channels have been considered as an alternative strategy of disease treatment. Experimental evidence of potential ingredients in Chinese herbs targeting P2R and their pharmacological activities were outlined in the study.

     

Astragaloside IV attenuates inflammatory response mediated by NLRP-3/calpain-1 is involved in the development of pulmonary hypertension

Inflammation eventually leads to pulmonary arterial hypertension (PAH). Astragaloside IV(AS-IV) has a protective effect on pulmonary hypertension, but the specific protective mechanism has been unclear until now. Therefore, in this study, our aim was to investigate the mechanisms underlying the effects of AS-IV on PAH. In vivo, male Sprague-Dawley (SD) rats were injected intraperitoneally with monocrotaline (MCT, 60 mg/kg) and treated with AS-IV (40 mg/kg, 80 mg/kg), MCC950 and MDL-28170. In vitro, human pulmonary artery endothelial cells (HPAECs) were treated with monocrotaline pyrrole (MCTP, 60 μg/mL). The protein expression levels of NLRP-3, caspase-1, ASC, IL-18, IL-1β and calpain-1 were measured in vivo and/or in vitro. The results showed that AS-IV decreased the protein expression levels of NLRP-3, caspase-1, ASC, IL-18, IL-1β and calpain-1 in vivo and/or vitro. In conclusion, in this study the results suggested that AS-IV could inhibit monocrotaline-induced pulmonary arterial hypertension via the NLRP-3/calpain-1 pathway.     

Implications of seed germination ecology for conservation of Camptotheca acuminata,a rare,endemic, and endangered species in China

Plant Ecology - Seed germination and seedling recruitment are among the most critical stages for plant population persistence and development, which may be influenced by habitat fragmentation and...     

Stream Water Chemistry in Mixed-Conifer Headwater Basins: Role of Water Sources,Seasonality, Watershed Characteristics,and Disturbances

Ecosystems - Understanding the transport of dissolved organic carbon (DOC) and nitrogen (N) as water flows through headwater basins is important for predicting downstream water quality. With...