notopterol and Inflammation

Over the past few decades, clinicians and experts applied kinds of therapies for patients with malignant gliomas such as chemotherapy, radiation or surgical extraction. However, they used to ignore the real seriousness of neuropsychiatric symptoms after glioma, including cognitive dysfunction, anxiety, and depression, which severely impeded patients' recovery and prognosis. Interestingly, one of our previous clinical studies have found some behavioral symptoms in glioma patients were associated with systemic inflammation. Notopterol is one of the principal extracts of the traditional Chinese medicinal herb Notopterygium incisum having anti-tumour and anti-inflammatory activity. However, whether notopterol is beneficial to the treatment of glioma has not been reported. In this study, we found that notopterol inhibited growth and increased apoptosis of glioma via inhibiting STAT3 activity. In addition, notopterol treatment improved cognitive impairment and depression-like behavior in GL261 cell-based glioma mice via preventing the loss of dendritic spines and the reduction of synapse related proteins (PSD95 and Synapsin-1) in hippocampal neurons. Notopterol significantly reduced the levels of cytokines (iNOS, TNF-α, IL-6, and IL-β) and the activity of STAT3/NF-kB signalling pathway in peritumoural brain tissues and GL261 conditioned medium (GCM) treated microglial cell line (BV2 cells). These results demonstrated that notopterol not only exerted anti-glioma effects via inhibiting STAT3 activity, but improved neuropsychiatric symptoms via inhibiting tumour associated inflammation through modulation of the STAT3/NF-kB pathway in glioma-bearing mice.

Topics: Animals; Cognitive Dysfunction; Depression; Glioma; Inflammation; Mice; NF-kappa B; STAT3 Transcription Factor

Accumulating research has indicated that inordinate activation of microglia releases inflammatory cytokines, damages neurons, and causes neuroinflammation, which eventually could lead to neurodegenerative diseases such as Parkinson's disease and Huntington's disease, etc. Notopterol (NOT) has anti-inflammatory and anti-oxidant functions in boundary tissues, but the effects of NOT on neuroinflammation have not been covered. Therefore, this study attempts to investigate the effect of NOT on neuroinflammation and the underlying mechanisms. According to the findings, NOT dramatically decreased the expression of pro-inflammatory mediators (interleukin-6 (IL-6), inducible nitric-oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and Cyclooxygenase-2 (COX-2)) in LPS-exposed BV-2 cells. Western blot analysis revealed that NOT could promote the activation of AKT/Nrf2/HO-1 signaling pathway. Further studies have shown that anti-inflammatory property of NOT was inhibited by MK2206 (an AKT inhibitor), RA (an Nrf2 inhibitor), and SnPP IX (an HO-1 inhibitor). In addition, it was also discovered that NOT could weaken the damage of LPS to BV-2 cells and improve their survival rate. As a result, our results imply that NOT inhibits the inflammatory response of BV-2 cells through the AKT/Nrf2/HO-1 signaling axis and exerts a neuroprotective effect by inhibiting the activation of BV-2 cells.

Topics: Anti-Inflammatory Agents; Humans; Inflammation; Lipopolysaccharides; Microglia; Neuroinflammatory Diseases; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide Synthase Type II; Proto-Oncogene Proteins c-akt; Signal Transduction

Osteoarthritis (OA) is a prevalent degenerative joint disorder caused by the progressive destruction of cartilage and inflammation in the articular cavity. Studies have proved that the inhibition of articular cartilage destruction and generation of inflammatory factors can be effective strategies for treating OA. Notopterol (NOT) is a quality control index of Notopterygium incisum Ting ex H. T. Chang (N. incisum) with anti-inflammatory, antioxidant, and analgesic activities. Moreover, NOT has been used for many years to treat joint diseases. A study using human C28/I2 cells suggested that NOT down-regulated the hypersecretion of inflammatory mediators and alleviated the degradation of the extracellular matrix (ECM). In addition, NOT decreased the overproduction of reactive oxygen species (ROS) and chondrocyte apoptosis through the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway. NOT exerted a chondroprotective effect by partly inhibiting the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathways and regulating the nuclear factor Nrf2/heme oxygenase-1(HO-1) signaling pathway. In vivo, NOT improved the destruction of articular cartilage in a rat OA model, which may be related to the inhibition of tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6, and IL-12 expressions in synovial fluid. In summary, these results showed that NOT alleviated the progression of OA and is expected to become a new therapy for treating OA clinically.

Topics: Animals; Cartilage, Articular; Chondrocytes; Humans; Inflammation; Interleukin-1beta; NF-E2-Related Factor 2; Osteoarthritis; Phosphatidylinositol 3-Kinases; Rats

The traditional Chinese medicinal herb Notopterygium incisum Ting ex H.T. Chang has anti-rheumatism activity, and a mass spectrometry assay of patients' serum after administration of the herb revealed that notopterol is the most abundant component enriched. However, the functions of notopterol and its molecular target in rheumatoid arthritis (RA) treatment remain unknown. Here, we show in different RA mouse strains that both oral and intraperitoneal administration of notopterol result in significant therapeutic effects. Mechanistically, notopterol directly binds Janus kinase (JAK)2 and JAK3 kinase domains to inhibit JAK/signal transducers and activators of transcription (JAK-STAT) activation, leading to reduced production of inflammatory cytokines and chemokines. Critically, combination therapy using both notopterol and tumor necrosis factor (TNF) blocker results in enhanced therapeutic effects compared to using TNF blocker alone. We demonstrate that notopterol ameliorates RA pathology by targeting JAK-STAT signaling, raising the possibility that notopterol could be effective in treating other diseases characterized by aberrant JAK-STAT signaling pathway.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Biological Products; Chemokines; Coumarins; Etanercept; Inflammation; Inflammation Mediators; Interferon-gamma; Janus Kinase 2; Janus Kinase 3; Lipopolysaccharides; Macrophages; Mice, Inbred C57BL; Mice, Inbred DBA; Protein Domains; STAT Transcription Factors; Tumor Necrosis Factor-alpha