Background and PurposeThe edible blue pigments produced by gardenia fruits have been used as value-added colorants for foods in East Asia for 20 years. However, the biological activity of the blue pigments derived from genipin has not been reported.Methodology/Principal FindingsThe anti-inflammatory effect of blue pigments was studied in lipopolysaccharide (LPS) stimulated RAW 264.7 macrophage in vitro. The secretions of nitric oxide (NO) and prostaglandin E2 (PGE2) were inhibited in concentration-dependent manner by blue pigments. Real-time reverse-transcription polymerase chain reaction (Real-time RT-PCR) analyses demonstrated that the mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α) was inhibited, moreover, ELISA results showed that the productions of IL-6 and TNF-α were inhibited. Cell-based ELISA revealed the COX-2 protein expression was inhibited. The proteome profiler array showed that 12 cytokines and chemokines involved in the inflammatory process were down-regulated by blue pigments. Blue pigments inhibited the nuclear transcription factor kappa-B (NF-κB) activation induced by LPS, and this was associated with decreasing the DNA-binding activity of p65 and p50. Furthermore, blue pigments suppressed the degradation of inhibitor of κB (IκB) α, Inhibitor of NF-κB Kinase (IKK) α, IKK-β, and phosphorylation of IκB-α. The anti-inflammatory effect of blue pigments in vivo was studied in carrageenan-induced paw edema and LPS-injecting ICR mice. Finally, blue pigments significantly inhibited paw swelling and reduced plasma TNF-α and IL-6 production in vivo.Conclusions and ImplicationsThese results suggest that the anti-inflammatory properties of blue pigments might be the results from the inhibition of iNOS, COX-2, IL-6, IL-1β, and TNF-α expression through the down-regulation of NF-κB activation, which will provide strong scientific evidence for the edible blue pigments to be developed as a new health-enhancing nutritional food for the prevention and treatment of inflammatory diseases.
Antibacterial hydrogels are attracting extensive attention in soft tissue repair and regeneration, including bacteria-infected-wound healing. The abuse of antibiotics leads to drug resistance. Recent developments have demonstrated that the delivery of inorganic bactericidal agents in hydrogels can drive the wound healing process; however, this approach is complicated by external light stimuli, cytotoxicity, nondegradability, and sophisticated fabrication. Herein, an inherent antibacterial, bioresorbable hydrogel was developed by the spontaneous self-aggregation of amphiphilic, oxadiazole-group-decorated quaternary ammonium salts (QAS)-conjugated poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC-QAS) micellar nanoantimicrobials for methicillin-resistant Staphylococcus aureus (MRSA)-infected cutaneous wound healing. The PCEC-QAS hydrogel showed a stable gel state within the temperature range of 5–50 °C and antibacterial efficacy against both Gram-negative and -positive bacteria in vitro and in vivo. Additionally, the PCEC-QAS hydrogel facilitated the cell spreading, proliferation, and migration without cytotoxicity. An in vivo degradation and skin defect healing study suggested the PCEC-QAS hydrogel was totally absorbed without local or systemic toxicity and could promote wound repair in the absence of drugs, cytokines, or cells. Significantly, this hydrogel accelerated the regeneration of a MRSA-infected full-thickness impaired skin wound by successfully reconstructing an intact and thick epidermis similar to normal mouse skin. Collectively, a self-assembling PCEC-QAS antibacterial hydrogel is a promising dressing material to promote skin regeneration and prevent bacterial infection without additional drugs, cells, light irradiation, or delivery systems, providing a simple but effective strategy for treating dermal wounds.
In this work, a novel starch-based zwitterionic copolymer, starch-graft-poly(sulfobetaine methacrylate) (ST-g-PSBMA), was synthesized via Atom Transfer Radical Polymerization. Starch, which formed the main chain, can be degraded completely in vivo, and the pendent segments of PSBMA endowed the copolymer with excellent protein resistance properties. This ST-g-PSBMA copolymer could self-assemble into a physical hydrogel in normal saline, and studies of the formation mechanism indicated that the generation of the physical hydrogel was driven by electrostatic interactions between PSBMA segments. The obtained hydrogels were subjected to detailed analysis by scanning electron microscopy, swelling ratio, protein resistance, and rheology tests. Toxicity and hemolysis analysis demonstrated that the ST-g-PSBMA hydrogels possess excellent biocompatibility and hemocompatibility. Moreover, the cytokine secretion assays (IL-6, TNF-α, and NO) confirmed that ST-g-PSBMA hydrogels had low potential to trigger the activation of macrophages and were suitable for in vivo biomedical applications. On the basis of these in vitro results, the ST-g-PSBMA hydrogels were implanted in SD rats. The tissue responses to hydrogel implantation and the hydrogel degradation in vivo were determined by histological analysis (Hematoxylin and eosin, Van Gieson, and Masson's Trichrome stains). The results presented in this study demonstrate that the physical cross-linking, starch-based zwitterionic hydrogels possess excellent protein resistance, low macrophage-activation properties, and good biocompatibility, and they are a promising candidate for an in vivo biomedical application platform.
Targeting activated macrophages using anti-inflammatory phytopharmaceuticals has been proposed as general therapeutic approaches for rheumatic diseases. Besides macrophages, chondrocytes are another promising target of anti-inflammatory agents. Tetrandrine is a major bisbenzylisoquinoline alkaloid isolated from Stephania tetrandrae S. Moore which has been used for 2,000 years as an antirheumatic herbal drug in China. Although, the anti-inflammatory effect of tetrandrine has been demonstrated, the mechanism has not been clearly clarified. In this study, we designed a comprehensive anti-inflammatory evaluation system for tetrandrine, including complete Freund's adjuvant (CFA)-induced arthritis rat, LPS-induced macrophage RAW 264.7 cells, and chondrogenic ATDC5 cells. The results showed that tetrandrine alleviated CFA-induced foot swelling, synovial inflammation, and proinflammatory cytokines secretion. Tetrandrine could inhibit IL-6, IL-1b, and TNF-a expression via blocking the nuclear translocation of nuclear factor (NF)-kB p65 in LPS-induced RAW 264.7 cells. Moreover, ATDC5 cells well responded to LPS induced proinflammatory mediators secretion and tissue degradation, and tetrandrine could also inhibit the production of nitric oxide and prostaglandin E 2 , as well as the expression of matrix metalloproteinase (MMP)-3 and tissue inhibitor of metalloproteinase (TIMP)-1 via inhibiting IkBa phosphorylation and degradation. In conclusion, the results showed that one of the anti-inflammatory mechanisms of tetrandrine was inhibiting IkBa and NF-kB p65 phosphorylation in LPS-induced macrophage RAW 264.7 cells and chondrogenic ATDC5 cells. Moreover, we introduce a vigorous in vitro cell screening system, LPS-induced murine macrophage RAW 264.7 cells coupling chondrogenic ADTC5 cells, for screening anti-rheumatic drugs. ß
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