Berberine can significantly inhibit the binding activity of NF-B and AP-1 at concentrations of 10-4 mol/L or higher

Berberine can significantly inhibit the binding activity of NF-B and AP-1 at concentrations of 10-4 mol/L or higher. activity. apoptosis and activate autophagy. Open in a separate window Physique 2 Structure of berberine. Several derivatives of berberine have been synthesized to improve bioactivity and bioavailability. Structural modifications have mainly focused on the C-8, C-9, C-10, C-12 and C-13 positions of berberine14, and some new skeleton analogs have been synthesized. Modification at C-8 or C-13 mainly increases its antimicrobial activity, which is also closely related to the length of the substituent chain. The substituent at the C-9 position of berberine may increase anti-tumor activity8. It is usually well known that berberine exerts its activity mainly in the gastrointestinal system, which is due to its low bioavailability15. Therefore, special attention should be paid to the bioactivity of this natural product in the gastrointestinal system. To the best of our knowledge, there is no systematic review of the pharmacological effects of berberine and its derivatives in the digestive system. Here, we review the main advances of berberine and its derivatives as anti-inflammatory and anti-tumor brokers in the digestive system to provide useful information for anticancer drug development based on berberine. Anti-inflammatory activity in the digestive system The anti-gastroenteritis effect and its mechanism Berberine has been used to treat inflammatory bowel disease (IBD), study exhibited that berberine has the ability to ameliorate proinflammatory cytokine-induced intestinal epithelia tight junction Teriparatide Acetate damage17,18. This process is regulated by cytokines15 such as the Th2 cytokine interleukin-13 (IL-13), as well as TNF- and IFN-19. IL-8 is an important cytokine for the recruitment and activation of polymorph nuclear neutrophil cells that are abundant in the intestinal lesions of IBD. Berberine is beneficial to the mucosal healing process, possibly by inhibiting IL-8 production. For example, IL-8 production in rectal mucosa is usually inhibited by berberine at a concentration of 10.0 nmol/L in trinitrobenzene sulfonic acid (TNB)-induced colitis in rats20. These effectors not only play important roles in inflammation but are also involved in the process of tumor development and dissemination17,18,19,20. The transcription factor activator protein 1 (AP-1) plays a critical role in inflammation and carcinogenesis. Berberine can significantly inhibit the binding activity of NF-B and AP-1 at concentrations of 10-4 mol/L or higher. Further study revealed that berberine inhibited LPS-induced MCP-1/CCL2 production an AP-1 and NF-B-dependent pathway21,22,23,24,25. It has been reported that berberine repressed proinflammatory responses through AMP-activated protein kinase (AMPK) activation in macrophages, significantly down-regulating the expression of proinflammatory genes such as TNF-, IL-1, IL-6, monocyte chemo-attractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Moreover, these inhibitory effects of berberine on proinflammatory responses were abrogated by an AMPK inhibitor, or dominant-negative AMPK, which indicated that berberine TTA-Q6(isomer) would down-regulate proinflammatory responses in macrophages AMPK stimulation26,27. In inflammatory responses, COX-2 plays an important role in the synthesis of prostaglandins (PGs) from arachidonic acid. An investigation revealed that berberine could inhibit COX-2 expression and prostaglandin E2 (PGE2) levels28. The anti-hepatic inflammatory effect and its mechanism Berberine can down-regulate several hepatic proinflammatory genes, including TNF-, IL-6 and serum amyloid A3 (SAA3), which are proposed to play important roles in the development of steatohepatitis29. This effect of berberine may occur the activation of AMPK and inhibition of NF-B30. The anti-inflammatory effect of berberine in hepatic cells has been observed in different animal models. Some and studies carried out in male albino rats have shown that berberine decreased the expression of both TNF- and COX-2 in a hepatotoxicity rat model induced by cyclophosphamide (CP)31. Berberine is able TTA-Q6(isomer) to effectively inhibit the production of IL-6 and TNF- in HepG2 cells. Its mechanism of action for anti-inflammation could be attributed to the inhibition of ERK1/2 activation32. This anti-inflammatory activity was similar to the data in a recent study reporting that berberine inhibited the LPS-induced inflammatory response in macrophages26. Other researchers studied the mechanism of the anti-hepatitis effect of berberine and found that berberine significantly decreased the expression of pro-/anti-inflammatory and/or Th1/Th2 cytokines, suggesting that berberine TTA-Q6(isomer) alleviated spontaneous inflammation in non-obese diabetic mice33. The anti-tumor activity of berberine in the digestive system The anti-tumor activity of berberine mainly includes inhibiting the growth of tumor cells, promoting TTA-Q6(isomer) tumor cell apoptosis, inducing the differentiation of tumor cells and inhibiting the expression and metastasis of tumor cells. As summarized in Physique 4, the mechanism of these effects is the down-regulation of the level of cyclin and growth factor receptors and the inhibition of some signaling.