13-Methylberberine

Sci Rep. 2016 Dec 5;6:38129.

13-Methylberberine, a berberine analogue with stronger anti-adipogenic effects on mouse 3T3-L1 cells.[Pubmed: 27917887 ]

Lipid metabolism modulation is a main focus of metabolic syndrome research, an area in which many natural and synthetic chemicals are constantly being screened for in vitro and in vivo activity. Berberine, a benzylisoquinoline plant alkaloid, has been extensively investigated for its anti-obesity effects and as a potential cholesterol and triglyceride-lowering drug.
METHODS AND RESULTS:
We screened 11 protoberberine and 2 benzophenanthridine alkaloids for their anti-adipogenic effects on 3T3-L1 adipocytes and found that 13-Methylberberine exhibited the most potent activity. 13-Methylberberine down-regulated the expression of the main adipocyte differentiation transcription factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT enhancer binding protein alpha (C/EBPα), as well as their target genes. PPARγ, C/EBPα, and sterol regulatory element binding protein 1 (SREBP-1) protein levels were reduced, and this lipid-reducing effect was attenuated by an AMP-activated protein kinase (AMPK) inhibitor, indicating that the effect of this compound requires the AMPK signaling pathway. Decreased Akt phosphorylation suggested reduced de novo lipid synthesis. C-13 methyl substitution of berberine increased its accumulation in treated cells, suggesting that 13-Methylberberine has improved absorption and higher accumulation compared to berberine.
CONCLUSIONS:
Our findings suggest that 13-Methylberberine has potential as an anti-obesity drug.

Int Immunopharmacol. 2016 Nov;40:269-276.

13-Methylberberine reduces HMGB1 release in LPS-activated RAW264.7 cells and increases the survival of septic mice through AMPK/P38 MAPK activation.[Pubmed: 27632705 ]

High mobility group box 1 (HMGB1), a late phase cytokine of sepsis, is viewed as a potential target for the treatment of sepsis. The authors considered that 13-Methylberberine (13-MB) might reduce circulating HMGB1 levels and increase survival in a mouse model of sepsis by activating AMP-activated protein kinase (AMPK).
METHODS AND RESULTS:
Western blot analysis and vascular contraction testing were performed using RAW264.7 cells and rat thoracic aorta, respectively. The mechanisms responsible were investigated using various signal inhibitors and small interfering RNA techniques. 13-MB significantly reduced HMGB1 release by LPS-activated RAW264.7 cells, and this was prevented by silencing AMPK or p38, or by pretreating cells with p38 MAPKinase inhibitor, suggesting that the activations of p38 and AMPK were responsible for the observed reduction in HMGB1 release. As was expected, 13-MB increased the phosphorylations of p38 and AMPK. Interestingly, phosphorylations of p38 by 13-MB were inhibited by AMPKsiRNA, indicating that AMPK lies upstream of p38. Furthermore, 13-MB concentration-dependently inhibited IκB phosphorylation in LPS-activated RAW264.7 cells, and in aortic rings, co-treatment with 13-MB and LPS for 8h, in vitro, significantly restored the isometric contraction induced by phenylephrine. Importantly, 13-MB significantly increased the survival rate of LPS-induced endotoxemic mice.
CONCLUSIONS:
These results suggest 13-MB may be useful for treating diseases in which HMGB1 is viewed as a target.

Life Sci. 2003 Aug 1;73(11):1401-12.

Effects of 13-alkyl-substituted berberine alkaloids on the expression of COX-II, TNF-alpha, iNOS, and IL-12 production in LPS-stimulated macrophages.[Pubmed: 12850501]

Berberine, a major alkaloidal component of Coptidis Rhizoma, has antibacterial activity, anti-inflammatory effect, antitumor and antimotility actions. We suggested that one of possible mechanisms of anti-bacterial activity of berberine may be based on the production of interleukin (IL)-12. Recently 13-alkyl-substituted berberines were shown to be better activity than berberine against certain bacteria species and human cancer cell lines.
METHODS AND RESULTS:
In the present study, therefore, the effects of 13-Methylberberine (13-MB) and 13-ethylberberine (13-EB) on the production of IL-12 and expression of iNOS, TNF-alpha and COX-II were investigated using macrophages in culture. In LPS-stimulated RAW 264.7 cells, these alkaloids decreased the nitrites, concentration-dependently. The concentration of 50% inhibition of NO production (IC50) by 13-MB and 13-EB was 11.64 and 9.32 microM, respectively. The suppressed expression of iNOS protein was responsible for the reduction of NO production. Neither the expression of mRNA of iNOS, COX-II and TNF- alpha nor protein of COX-II and TNF-alpha was affected by both 13-MB and 13-EB, but production of PGE2 in LPS-stimulated RAW 264.7 cells was significantly reduced. Another striking finding of the present study is that 13-MB and 13-EB increased production of IL-12 in LPS-treated splenic macrophages.
CONCLUSIONS:
These results indicate that posttranscriptional regulatory mechanism of iNOS gene expression by 13-MB and 13-EB is involved, and COX-II activity is inhibited by 13-MB and 13-EB, respectively. In conclusion, the present study demonstrates that 13-methyl- and 13-ethylberberine alkaloids can be useful as an immunotherapeutic compound for induction of IL-12, which is potentially applicable for tumors, infectious disease, and airway inflammation.