The production of inflammatory cytokines and oxidative stress are linked to metabolic derangements that ultimately lead to an elevated risk of developing chronic disease. The novel investigation that links inflammation and oxidative stress with type 2 Diabetes Mellitus dig deeply into the metabolic and cellular pathways. Recent studies focused on the therapeutic effect of berberine, and metabolic outcomes have shown positive results. However, berberine’s inhibitory effects against oxidative stress and inflammation are complex and need to be featured.

Berberine is the alkaloidal bioactive compound found in Hydratis Canadensis and Coptis Chinensis. Its beneficial activities are related to its capacity to interact with multiple proteins in the body. Besides, berberine has many metabolites associated with different beneficial functions because they interact with different cellular pathways.

 

Berberine Metabolism

The metabolism of berberine is reported to have 2 phases. In the first phase, berberine goes through demethylation, dehydrogenation, and hydroxylation. Further, berberine’s 2^nd phase metabolism produces glucuronide conjugates and methylated conjugates. Nevertheless, feces and urine metabolites have been reported. Dihydroberberine (dhBBR) was found in mice feces and has been linked to the gut microbiota metabolism. On the other hand, demethylberberine-2-O-sulfate was the major berberine metabolite found in urine. Despite the ample variety of metabolites, berberine has a low plasma concentration, is poorly absorbed by the gut, and commonly remains in the gut lumen.

Common berberine metabolites

berberrubine

thalifendine

demethyleneberberine

jatrorrhizine

 

Uses of berberine

 

The efficacy of berberine to treat diabetes is comparable to metformin results. Besides, berberine is effective in reducing endothelial dysfunction, retinopathy, and kidney failure. Also, the use of berberine on hepatic pathologies and low toxicity are related to treatment efficacy.

• Lowers blood glucose.
• Improves insulin sensitivity.
• Modulated microbiota.
• Regulates B-cell.
• Activates AMPK.
• Upregulates insulin receptors.
• Works as an antioxidant.
• Reduces inflammation.

Antioxidant effect of berberine.

 

The supplementation of berberine in animal model studies resulted in increased levels of GHS and a higher activity of superoxide dismutase (SOD) and glutathione peroxidase (GHS-Px). On the other hand, berberine reduced malondialdehyde (MDA) levels. The results of such studies link berberine to the scavenging of superoxide free radicals, even in a glycemic environment.

 

The exerted effects on the upregulation of mRNA content of SOD are mediated by SIRT1 and FOXO overexpression. Also, it suppresses nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, resulting in less ROS. This can improve diabetic conditions. Concerning the downregulation of NADH oxidase, AMPK activation is linked to a reduced arterial oxidative stress.

UCP2

On the other hand, the upregulation effect of berberine over the expression of UCP2 (uncoupling protein 2) has yet to be clarified. UCP2 is located in the mitochondria membrane, and its presence is linked to reduced production of ROS and oxidative stress. Yet, more information is needed to understand the effects of UCP2 on islet B-cell. It has been reported that UCP2 could inhibit insulin secretion.

Another berberine’s antioxidant effect is related to the expression of Nrf2 (nuclear factor erythroid-2 related factor 2) pathway.

• Nfr2:

  is an antioxidant transcription factor that works via the expression of NQO-1 (NADPH quinone oxidoreductase 1) and HO-1 (heme oxygenase-1).

  • Balances energy metabolism.
  • Maintenance of redox potential in cells.
  • Nfr2 + berberine antioxidant effect depends on the activation of P38, AMPK, and P13K (phosphatidylinositol 3 kinase)/Akt pathways.
  • Nfr2+ berberine leads to an Nfr2 translocation to the nucleus that results in GSH and SOD expression.

Anti-inflammatory potential of berberine

Recent studies associate the suppression of proinflammatory cytokines with the presence of berberine. Indeed, some of these suppressed cytokines are MMP9 (matrix metalloprotease 9), TNF-α, COX2 (cyclooxygenase-2), iNOS (inducible nitric oxide synthase), MCP1 (monocyte chemoattractant protein 1), IL-6, IL-1β, CRP (C-reactive protein), and HP (hepatoglobin). Some of the berberine’s effects on downregulating cytokine production rely on its capacity to reduce serine phosphorylation while increasing tyrosine phosphorylation.

Multiple pathways mediate berberine’s antioxidant effect; the anti-inflammatory mechanisms are linked to various pathways, some of them shared with the antioxidant pathway.

AMPK

Not only the AMPK pathway is involved in the antioxidant effects of berberine. In fact, studies show that in the case of an AMPK blockage, berberine could not intervene with the synthesis of COX-2 and iNOS. Therefore, the expression of prostaglandins and excessive release of nitric oxide augmented IR’s development, contributing to the DM pathogenesis.

Another inflammation-induced pathway, MAPK (mitogen-activated protein kinase), could be downregulated by AMPK and berberine activation.

Nrf2 and P38

P38 is a mitogen-activated protein kinase with extensive effects in inflammatory pathways. Its conjugation with berberine has brought conflicting findings. In fact, some reports show that their combined actions could lead to glucose uptake by L6 cells, but other studies found that these results could not be reproduced.

However, the Nrf2 activation and nuclear translocation have been associated with berberine and the activation of P38 and AMPK pathways. Therefore, the expression of proinflammatory cytokines has been reduced by these actions.

NF-κB pathway

The NF-κB pathway can be stimulated by glucose, fatty acids, and TNF-a, as well as the activation of IκB kinase- β (IKK-β) through serine phosphorylation (ser181). However, the supplementation of berberine resulted in a decrease of IKK-β and further inhibited the nuclear transfer of NF-κB. Therefore, a reduction in the synthesis of proinflammatory cytokines like IL-6, iNOS, COX2, and TNF-α contributes to enhanced DM results.

Applied berberine supplementation

 

The most common berberine dosage used in clinical studies ranges between 0.2-10g/day. In fact, the intervention with these amounts of berberine resulted in a 20-40% reduction in blood glucose level. It has been reported that these results resemble the effects of metformin and rosiglitazone. Despite the clinical uses, anti-inflammatory, and antioxidant properties, berberine needs to be further explored.

 

SMOOTH(ie) Genes

References

Ma, Xueling, et al. “The pathogenesis of diabetes mellitus by oxidative stress and inflammation: its inhibition by berberine.” Frontiers in Pharmacology 9 (2018): 782.

Wang, Kun, et al. “The metabolism of berberine and its contribution to the pharmacological effects.” Drug metabolism reviews 49.2 (2017): 139-157.

Cicero, Arrigo FG, and Alessandra Baggioni. “Berberine and its role in chronic disease.” Anti-inflammatory Nutraceuticals and Chronic Diseases. Springer, Cham, 2016. 27-45.

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