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Inflammatory bowel disease (IBD) is generally characterized by chronic inflammatory disorders of the gastrointestinal tract that are known as ulcerative colitis (UC) or Crohn's disease (CD). Although the underlying mechanism of action of IBD is unclear and because of the lack of satisfactory treatment, increasing evidence has indicated that pro-inflammatory cytokines that activate JAK-STAT signaling pathway regulate the differentiation of naïve T cells towards T helper (Th)1 and Th17 cell subsets and contribute to the development of IBD. ZT01 is a newly obtained triptolide derivative with strong anti-inflammatory effects and low toxicity. In this study, we evaluated the effects of ZT01 on DSS-induced colitis and investigated the underlying mechanism of action involved. Mice with DSS-induced acute or chronic colitis were used to assess the efficacy of ZT01 treatment, and T cells were cultured to analyze the differentiation of Th1 and Th17 cell by flow cytometry. In addition, intestinal epithelial barrier function, macrophage polarization, activation of the JAK-STAT signaling pathway, and the expression of cytokines and transcription factors were measured to assess the possible mechanisms of ZT01. We found that ZT01 had an obviously beneficial effect on DSS-induced colitis by improving the symptoms of bloody diarrhea, weight loss, and a shortened colon, thereby preserving the epithelial barrier function in the mouse colon. Furthermore, ZT01 significantly inhibited T cell differentiation into Th1 and/or Th17 cell subsets and macrophage polarization towards into an inflammatory phenotype via regulating the JAK-STAT signaling pathway. Thus, our findings suggested that ZT01 might be a potential pharmaceutical candidate that deserves to be further investigated as a treatment for IBD patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sepsis is a main reason for death in intensive care units, inflammation is closely related to sepsis. Anti-inflammation plays an important role in treating of sepsis. ZT01 is a triptolide derivative with strong anti-inflammatory activity and low toxicity. The purpose of this study is to evaluate the anti-inflammatory activity of ZT01 under the sepsis condition and explore the underlying molecular mechanisms. Two in vivo model of sepsis, caecal ligation and puncture or intraperitoneal injection of LPS in C57BL/6, were used to evaluate the therapeutic effects of ZT01. In vitro, the anti-inflammatory properties of ZT01 were assessed in IFN-γ or LPS-induced macrophages by ELISA, RT-PCR, western blotting and co-immunoprecipitation. Macrophages were used to investigate the polarization phenotype by flow cytometry. The results showed, ZT01 significantly attenuated inflammatory response of sepsis in serum or lung tissue by inhibiting production of pro-inflammatory factors and improved the survival rate of septic mice in vivo. In cultured macrophages, ZT01 not only decreased the levels of TNF-α and IL-6 but also prevented the TKA1-TAB1 complex formation, thereby inhibiting the phosphorylation expression of MKK4 and JNK, which were all stimulated by LPS. Moreover, ZT01 inhibited the LPS-induced polarization of macrophages into pro-inflammatory phenotype. Adoptive transfer ZT01 pretreated bone marrow-derived macrophages obviously reduced the pro-inflammatory factors in mice after LPS challenge. Our findings suggested that ZT01 exhibited anti-inflammation activity via preventing the pro-inflammatory phenotype of macrophages by blocking the formation of the TAK1-TAB1 complex and subsequently phosphorylation of MKK4 and JNK., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A series of novel triptolide/furoxans hybrids were designed and synthesized as analogues of triptolide, which is a naturally derived compound isolated from the thunder god vine (Tripterygium wilfordii Hook. F). Some of these synthesized compounds exhibited antiproliferative activities in the nanomolar range. Among them, compound 33 exhibited both good antiproliferative activity and NO-releasing ability and the acute toxicity of compound 33 decreased more than 160 times (LD 50  = 160.9 mg/kg) than triptolide. Moreover, compound 33 significantly inhibited the growth of melanoma at a low dose (0.3 mg/kg) and showed strong anti-inflammatory activity in vitro and in vivo. These results indicate that compound 33 could be a promising candidate for further study., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Methyl salicylate 2-O-β-D-lactoside (MSL) is a derivative of natural salicylate isolated from Gaultheria yunnanensis (Franch.) Rehder, which is widely used for treating rheumatoid arthritis (RA), swelling and pain. The aim of the present study was to investigate the effect of MSL on the progression of adjuvant-induced arthritis (AIA) in rat in vivo and explore the anti-inflammatory effects and mechanism of MSL in lipopolysaccharide (LPS)-treated murine macrophages RAW264.7 cells in vitro. Our results showed that MSL significantly inhibited the arthritis progression in AIA rats, decreasing the right hind paw swelling and ankle diameter, attenuating histopathological changes and suppressing the plasma levels of TNF-α and IL-1β in AIA rats. Besides, MSL had potent anti-inflammatory effects on the LPS-activated RAW264.7. MSL dose-dependently inhibited the activity of COX-1, and COX-2. Moreover, MSL prominently inhibited LPS-induced activation of MAPK in RAW264.7 cells by blocking phosphorylation of p38 and ERK. Our study suggests that MSL may be effective in the treatment of inflammatory diseases by inhibiting the pro-inflammatory cytokine production and regulating the MAPK signal pathway., (Copyright © 2015. Published by Elsevier B.V.)

Methyl salicylate 2-O-β-D-lactoside (DL0309), is a molecule chemically related to salicylic acid that is isolated from Gaultheria yunnanensis (FRANCH.) REHDER (G. yunnanensis). G. yunnanensis, a traditional Chinese herbal medicine, is widely used for treating rheumatoid arthritis, swelling, pain, trauma, and chronic tracheitis. In the present study, we explored the mechanism whereby DL0309 exerts anti-inflammatory effects, using the model of lipopolysaccharide (LPS)-treated RAW264.7 cells. We examined the effects of DL0309 on LPS-induced nuclear factor-kappaB (NF-κB) activity by Western blot analysis, cell imaging analysis and an electrophoretic mobility shift assay (EMSA). Production of pro-inflammatory cytokines was also measured. Our observations indicate that DL0309 suppressed production of nitric oxide (NO), reactive oxygen species (ROS) and the pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), in a concentration-dependent manner. The phosphorylation of IKK-β and degradation of IκB-α by LPS were both inhibited by DL0309 in the cytoplasm. The increased protein level of NF-κB by LPS in the nucleus was also reduced by DL0309. Consistent with these results, we found that DL0309 prevents the nuclear translocation and DNA binding activity of NF-κB. Finally, our results demonstrate that DL0309 exerts anti-inflammatory effects, by inhibiting the production of pro-inflammatory cytokines and suppressing of the activation of the NF-κB signaling pathway in LPS-treated macrophage cells. Therefore, DL0309 may have therapeutic potential for treating inflammatory diseases by regulating the NF-κB pathway and pro-inflammatory cytokine production.

Background: Neuroinflammation has been known to play a critical role in the pathogenesis of Alzheimer's disease (AD). Activation of microglia and astrocytes is a characteristic of brain inflammation. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) delays the onset of AD and suppresses its progression. Methyl salicylate-2-O-β-D-lactoside (DL0309) is a new molecule chemically related to salicylic acid. The present study aimed to evaluate the anti-inflammatory effects of DL0309., Findings: Our studies show that DL0309 significantly inhibits lipopolysaccharide (LPS)-induced release of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α; and the expression of the inflammation-related proteins iNOS, COX-1, and COX-2 by microglia and astrocytes. At a concentration of 10 μM, DL0309 prominently inhibited LPS-induced activation of NF-κB in glial cells by blocking phosphorylation of IKK and p65, and by blocking IκB degradation., Conclusions: We demonstrate here for the first time that DL0309 exerts anti-inflammatory effects in glial cells by suppressing different pro-inflammatory cytokines and iNOS/NO. Furthermore, it also regulates the NF-κB signaling pathway by blocking IKK and p65 activation and IκB degradation. DL0309 also acts as a non-selective COX inhibitor in glial cells. These studies suggest that DL0309 may be effective in the treatment of neuroinflammatory disorders, including AD.

Abstract: Ethyl salicylate 2-O-β-d-glucoside (ESG) is a derivative of natural salicylate isolated from Gaultheria yunnanensis (Franch.) Rehder, it has been used for the treatments of rheumatoid arthritis, swelling and pain. The aim of this study was to evaluate the anti-inflammatory effects of ESG and explore the anti-inflammatory mechanisms. We found that ESG had potent anti-inflammatory effects on the lipopolysaccharide (LPS)-activated murine macrophages RAW264.7. ESG exerted a dose-dependent inhibition of the LPS-stimulated release of the pro-inflammatory cytokines TNF-α and IL-1β. Moreover, it significantly inhibited LPS-stimulated the production of NO and PGE2 by repressing the expression of iNOS and COX protein respectively. Western blot analysis showed that ESG prominently inhibited LPS-induced activation of NF-κB in RAW264.7 cells by blocking phosphorylation of inhibitor IκBα and p65. Consistent with these results, we found that ESG prevented the nuclear translocation of NF-κB induced by LPS. Our study suggests that ESG may be effective in the treatment of inflammatory diseases by inhibiting the pro-inflammatory cytokine production and regulating the NF-κB signal pathway. [Copyright &y& Elsevier]