MnO2-based dual channel surface plasmon resonance fiber sensor for trace glutathione and refractive index detection.

Glutathione (GSH) plays vital role in human biological systems, so its rapid and sensitive detection is necessary for health condition monitoring. In this work, a simple structure for dual channel GSH and refractive index (RI) detection is proposed. By introducing Au-MnO2 thin film coating on the fiber surface for the first time, GSH solution would lead to the dissolution of MnO2, the change in GSH levels could be monitored over a short period in channel 2. For channel 1, ITO-Ag thin film is applied for RI change detection. After optimization, the GSH detection sensitivity reached about -2.361 nm/mM in the range of 0.005-50 mM, and the RI sensitivity reached 1704.252 nm/RIU in the range of 1.331-1.3895 RIU. Channel 1 could also put into GSH detection in the high concentration scale to enlarge the sensor's range and 0.095 nm/mM of sensitivity is acquired within the range of 50-600 mM. With the presence of MnO2 film, the detection sensitivity increased 25.663 times. Neither channel interferes with the operation of the other. Proposed sensor provides stability, high selectivity and elevation in GSH detection sensitivity, which shows great potential for environmental and biological detection field and their applications.

Notopterol alleviates the progression of osteoarthritis: An in vitro and in vivo study.

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)-1ß, 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.

Hederagenin Suppresses Inflammation and Cartilage Degradation to Ameliorate the Progression of Osteoarthritis: An In vivo and In vitro Study.

Osteoarthritis (OA), a common degenerative joint disease, is characterized by the progressive degradation of articular cartilage and inflammation. Hederagenin (HE) is a pentacyclic triterpenoid saponin extracted from many herb plants. It has anti-inflammatory, anti-lipid peroxidative, anti-cancer, and neuroprotective activities. However, its effect on OA has not been investigated. Our study found that HE may be a potential anti-OA drug. In vitro, HE could suppress extracellular matrix (ECM) degradation via up-regulating aggrecan and Collagen II levels as well as downregulating MMPs and ADAMTS5 levels. It could also reduce proinflammatory and inflammatory cytokines or enzymes production, including TNF-α, IL-6, iNOS, COX-2, NO, and PGE2. Besides, HE markedly reduced IL-1ß-induced C28/I2 cell apoptosis and ROS accumulation. Mechanistically, HE exerted chondroprotective and anti-inflammatory effects by partly inhibiting JAK2/STAT3/MAPK signalling pathway and the crosstalk of the two pathways. Also, HE exhibited anti-apoptotic and anti-oxidative effect via targeting Keap1-Nrf2/HO-1/ROS/Bax/Bcl-2 axis. In vivo, HE significantly reduced monosodium iodoacetate (MIA) induced cartilage destruction of rats with a lower OARSI score and inflammatory cytokine levels, further demonstrating its protective effects in OA progression. These results suggest that HE is a potential compound for the development of drugs to treat OA.

Cyasterone inhibits IL-1ß-mediated apoptosis and inflammation via the NF-κB and MAPK signaling pathways in rat chondrocytes and ameliorates osteoarthritisin vivo.

Osteoarthritis is a prevalent global joint disease, which is characterized by inflammatory reaction and cartilage degradation. Cyasterone, a sterone derived from the roots of Cyathula officinalis Kuan, exerts protective effect against several inflammation-related diseases. However, its effect on osteoarthritis remains unclear. The current study was designed to investigate the potential anti-osteoarthritis activity of cyasterone. Primary chondrocytes isolated from rats induced by interleukin (IL)-1ß and a rat model stimulated by monosodium iodoacetate (MIA) were used for in vitro and in vivo experiments, respectively. The results of in vitro experiments showed that cyasterone apparently counteracted chondrocyte apoptosis, increased the expression of collagen II and aggrecan, and restrained the production of the inflammatory factors inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), metalloproteinase-3 (MMP-3), and metalloproteinase-13 (MMP-13) induced by IL-1ß in chondrocytes. Furthermore, cyasterone ameliorated the inflammation and degenerative progression of osteoarthritis potentially by regulating the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. For in vivo experiments, cyasterone significantly alleviated the inflammatory response and cartilage destruction of rats induced by monosodium iodoacetate, where dexamethasone was used as the positive control. Overall, this study laid a theoretical foundation for developing cyasterone as an effective agent for the alleviation of osteoarthritis.

Albumin-based drug carrier targeting urokinase receptor for cancer therapy.

Urokinase plasminogen activator receptor (uPAR) is a key participant in extracellular proteolysis, tissue remodeling and cell motility. uPAR overexpresses in most solid tumors and several hematologic malignancies, but has low levels on normal tissues, thus is advocated as a molecular target for cancer therapy. One of the obstacles for the evaluation of uPAR targeting agents in preclinical study is the species specificity, where targeting agents for human uPAR  usually not bind to murine uPAR. Here, we develop a targeting agent that binds to both murine and human uPAR. This targeting agent is genetically fused to human serum albumin, a commonly used drug carrier, and the final construct is named as uPAR targeting carrier (uPARTC). uPARTC binds specifically to uPAR-overexpressing 293T/huPAR and 293T/muPAR as demonstrated by flow cytometry. A cytotoxic compound, celastrol, is embedded into uPARTC non-covalently. The resulting macromolecular complex show effective proliferation inhibition on both murine and human uPAR overexpressing cells, and exhibit potent antitumor efficacy on hepatoma H22-bearing mice. This work demonstrates that uPARTC is a promising tumor targeting drug carrier, which address the species-specificity challenge of uPAR targeting agents and can be used to load other cytotoxic compounds.

Magnoflorine attenuates inflammatory responses in RA by regulating the PI3K/Akt/NF-κB and Keap1-Nrf2/HO-1 signalling pathways in vivo and in vitro.

BACKGROUND: As a prolonged autoimmune disorder, rheumatoid arthritis (RA) is characterised by synovial hyperplasia and the erosion of bone and cartilage. Magnoflorine (MAG) is the main component purified from Clematis manshurica Rupr. Recent studies have shown that MAG has anti-inflammatory, antioxidant, and immunosuppressive effects, which are relevant to anti-RA activities. OBJECTIVE: The current investigation was conducted to explore the anti-RA effects of MAG and to discover the possible molecular mechanisms. METHODS: In vitro experiments, CCK-8, wound healing, and transwell assays were utilized to evaluate the anti-proliferative, anti-migratory, and anti-invasive activities of MAG, respectively. The rate of cell distribution and cell apoptosis were evaluated by flow cytometry. ROS generation was detected by DCFH-DA staining. Western blotting, quantitative real-time polymerase chain reaction assay, and immunofluorescent staining were employed to test the anti-RA effect of MAG as well as to explore the potential mechanisms by evaluating related gene and protein expression. For in vivo experiments, an adjuvant-induced arthritis (AIA) rat model was established. The related parameters were measured in rats. Then, rats were sacrificed, and ankle joints were collected for histopathological analysis and observation. RESULTS: MAG significantly decreased the proliferation, migration, invasion, and reactive oxygen species levels in IL-1ß-treated MH7A cells. Furthermore, MAG promoted cell apoptosis by increasing Bax levels and decreasing Bcl-2 levels. MAG also induced cell cycle arrest. Inflammatory cytokines (iNOS, COX-2, IL-6, and IL-8) and MMPs (MMP-1, 2, 3, 9, and 13) were reduced by MAG treatment. Molecular analysis revealed that MAG exerted anti-RA effects by partly inhibiting the PI3K/Akt/NF-κB signalling axis and activating the Keap1-Nrf2/HO-1 signalling pathway. In vivo studies have revealed that MAG treatment substantially improved severe symptoms in AIA rats, and these curative effects were linked to the attenuation of inflammatory responses. CONCLUSION: These results first suggested that MAG exhibits anti-arthritic effects in IL-1ß-treated MH7A cells and AIA rat models. Thus, MAG may be used as a new drug to treat RA clinically.

Anti-proliferation and anti-inflammation effects of corilagin in rheumatoid arthritis by downregulating NF-κB and MAPK signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: The dried aboveground part of Geranium Wilfordii Maxim. (G. Wilfordii) is a traditional Chinese herbal medicine named lao-guan-cao. It has long been used for dispelling wind-dampness, unblocking meridians, and stopping diarrhea and dysentery. Previous investigations have revealed that 50% ethanolic extract of G. Wilfordii has anti-inflammatory and anti-proliferation activities on TNF-α induced murine fibrosarcoma L929 cells. Corilagin (COR) is a main compound in G. Wilfordii with the content up to 1.69 mg/g. Pharmacology study showed that COR has anti-inflammatory, anti-tumor, anti-microorganism, anti-oxidant, and hepatoprotective effects. However, there is no any investigation on its anti-proliferation and anti-inflammation effects in rheumatoid arthritis (RA). AIM OF THE STUDY: The present study aimed to evaluate the potential pharmacological mechanisms of anti-proliferation and anti-inflammation effects of COR in RA. MATERIALS AND METHODS: In vitro, MH7A cells model induced by IL-1ß was used. The anti-proliferation activity of COR was assessed by Cell Counting Kit-8 (CCK-8) assay, and the anti-migration and anti-invasion activity of COR was determined by wound healing assay and transwell assay, respectively. Furthermore, apoptosis assay by flow cytometer was used to measure the pro-apoptotic effect of COR. The mRNA expressions of Bax, Bcl-2, IL-6, IL-8, MMP-1, MMP-2, MMP-3, MMP-9, COX-2, and iNOS were measured by qRT-PCR, and related protein were further verified by ELISA kits or Western blot. Moreover, protein levels associated with NF-κB and MAPK signaling pathways of p65, P-p65, IκBα, P-IκBα, ERK1/2, P-ERK1/2, JNK, P-JNK1/2/3, p38, and P-p38 were determined by Western blot. The nuclear translocation of NF-κB-p65 was detected by immunofluorescent staining. In vivo, adjuvant-induced arthritis (AIA) rat model was used, and the body weight, paw swelling, and arthritis score during the entire period were measured. Histopathological analysis of joints of synovial tissues was also determined. The expression of pro-inflammatory cytokines in serum including IL-6, TNF-α, IL-1ß, and IL-17 were measured. RESULTS: The in vitro results showed that COR could dose-dependently inhibit the proliferation, migration, and invasion of IL-1ß-induced MH7A cells, as well as promote its apoptosis. Moreover, it also suppressed the over-expression of Bcl-2, IL-6, IL-8, MMP-1, MMP-2, MMP-3, MMP-9, COX-2, and iNOS while up-regulated the level of Bax. Besides, the ratios of P-p65/p65, P-IκBα/IκBα, P-ERK/ERK, P-JNK/JNK, and P-p38/p38 were decreased, and the nuclear translocation of p65 induced by IL-1ß was blocked by COR. In vivo results indicated that COR significantly reduced the paw swelling and arthritis score in AIA rats, and inhibited synovial tissue hyperplasia and erosion, as well as inflammatory cells infiltration. It also decreased the serum pro-inflammatory cytokines (IL-6, TNF-α, IL-1ß, and IL-17) production. CONCLUSION: These results revealed that COR exerted anti-rheumatoid arthritis effect, and its underlying mechanisms may be related to inhibiting the proliferation, migration, and invasion of synovial fibroblasts, enhancing cell apoptosis, and suppressing inflammatory responses via downregulating NF-κB and MAPK signaling pathways.

Chicoric acid attenuates tumor necrosis factor-α-induced inflammation and apoptosis via the Nrf2/HO-1, PI3K/AKT and NF-κB signaling pathways in C28/I2 cells and ameliorates the progression of osteoarthritis in a rat model.

Osteoarthritis (OA) is the most common arthritis, and is characterized by inflammation and cartilage degradation. Chicoric acid (CA), a bioactive caffeic acid derivative isolated from the root of Taraxacum mongolicumHand. - Mazz., has been reported to have anti-inflammatory effects. However, the therapeutic effects of CA on chondrocyte inflammation remain unknown. Our study aimed to explore the effect of CA on OA both in vivo and in vitro. In vitro, CA treatment significantly suppressed the overproduction of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and IL-12 in tumor necrosis factor alpha (TNF-α)-induced human C28/I2 chondrocytes. Moreover, CA attenuated TNF-α induced degradation of the extracellular matrix (ECM) by upregulating the expression of collagen Ⅱ and aggrecan, and downregulating ADAMTS-5 and matrix metalloproteinases (MMPs). Additionally, CA treatment inhibited apoptosis in C28/I2 cells by upregulating of Bcl-2 levels, downregulating Bax and ROS levels, and activating the Nrf2/HO-1 pathway. Mechanistically, CA exerted an anti-inflammatory effect by inhibiting the PI3K/AKT and NF-κB signaling pathways, enhancing Nrf-2/HO-1 to limit the activation of NF-κB. In vivo experiments also proved the therapeutic effects of CA on OA in rats. These findings indicate that CA may become a new drug for the treatment of OA.