Oxidative stress and inflammation are proved to be critical for the pathogenesis of diabetes mellitus. Berberine (BBR) is a natural compound isolated from plants such as
For decades, diabetes mellitus especially type 2 diabetes mellitus (T2DM) has become a public health problem and threatened the people worldwide, not only in western countries, but also in the developing world like China. The pathogenesis and pathophysiological processes of T2DM are extreme complex and remain to be controversial. However, a growing number of evidences showed that oxidative stress and inflammation might play important roles in the development of T2DM [
In metabolic disorders, oxidative stress could be typically induced by excessive nutritional factors like glucose and free fatty acids (FFA) [
Recently, results from laboratory studies as well as clinical investigations have proved that diabetes is in fact an inflammatory disease [
There are a number of medications available in clinic to treat T2DM. In addition to chemical drugs, a number of natural products or traditional Chinese medicine (TCM) formulas were reported to have antidiabetic or insulin-sensitizing activities, and some of them have been used in clinic with a long history [
In general, BBR was safe and effective in the treatment of patients with T2DM [
Mechanisms of BBR in restoring insulin sensitivity and lowering blood glucose included inhibition of mitochondrial function and activation of AMP-activated protein kinase (AMPK), regulation of islet function, modulation of gut microenvironment, and upregulation of insulin receptor expression [
The inhibitory effect of BBR on oxidative stress was observed both in cells cultured with high glucose-containing media [
Effects of BBR on parameters of oxidative stress in animals with diabetes mellitus.
References | Diabetic animal model | Administration of BBR |
Tissues |
Effects of BBR | |||
---|---|---|---|---|---|---|---|
Oxidative stress markers | Antioxidant enzymes | ||||||
MDA | GSH | SOD | GSH-Px | ||||
[ |
Wistar rats, STZ 60 mg/kg, single i.p |
200 mg/kg/d, p.o. for 12 weeks | Serum |
|
ND |
|
ND |
|
|||||||
[ |
SD rats, STZ 60 mg/kg, single tail vein injection | 200 mg/kg/d, p.o. for 12 weeks | Serum |
|
ND |
|
ND |
|
|||||||
[ |
Wistar rats, STZ 35 mg/kg, single i.p |
75, 150, and 300 mg/kg/d, p.o. for 16 weeks | Serum and liver |
|
↑ |
|
|
|
|||||||
[ |
ddY mice, STZ 100 mg/kg, single i.p |
200 mg/kg/d, p.o. for 2 weeks | Liver | ND |
|
|
|
|
|||||||
[ |
SD rats, HFD for 2 weeks, then STZ 35 mg/kg, single i.p |
50, 100, and 150 mg/kg/d, p.o. for 6 weeks | Liver | — | — | — | ND |
|
|||||||
[ |
ICR mice, nicotinamide 1000 mg/kg + STZ 100 mg/kg, single i.p |
100 mg/kg/d, p.o. for 2 weeks | Liver and kidney |
|
ND |
|
ND |
|
|||||||
[ |
SD rats, HFD for 4 weeks, then STZ 40 mg/kg, single i.p |
100 and 200 mg/kg/d, p.o. for 8 weeks | Kidney |
|
ND |
|
ND |
|
|||||||
[ |
Wistar rats, STZ 35 mg/kg, single i.p |
75, 150 and 300 mg/kg/d, p.o. for 16 weeks | Pancreas |
|
ND |
|
ND |
|
|||||||
[ |
Wistar rats, alloxan 55 mg/kg, single tail vein injection, then on HFD | 100 and 200 mg/kg/d, p.o. for 21 days | Heart |
|
ND |
|
|
|
|||||||
[ |
Wistar rats, STZ 60 mg/kg, single i.p |
25, 50, and 100 mg/kg/d, p.o. for 30 days | Cortex and hippocampus |
|
|
ND | ND |
|
|||||||
[ |
Wistar rats, STZ 55 mg/kg, single i.p |
50 and 100 mg/kg/d, p.o. for 8 weeks | Hippocampus |
|
ND |
|
ND |
As summarized in Table
The antioxidant activity of BBR was associated with its inhibitory effect on the development of diabetes mellitus and insulin resistance induced by STZ/alloxan + HFD in animals [
Molecular mechanisms of BBR in reducing oxidative stress seem to be related with multiple cellular pathways and need further investigation. The schematic illustration of the pathways from available data was presented in Figure
Schematic illustration of the molecular mechanisms and pathways of BBR in reducing oxidative stress and inflammation. (1) BBR could inhibit oxidative stress by upregulation of SOD, UCP2 and downregulation of NADPH oxidase expression, which was possible to be mediated by the SIRT1/FOXO or AMPK pathway. (2) BBR administration induced the activation of the Nrf2 pathway, which was crucial for the antioxidant and anti-inflammatory activities of BBR. The effect of BBR on Nrf2 relied on the activation of AMPK, PI3K/Akt, and P38 pathways. (3) BBR could suppress inflammation by blocking the MAPK pathways in an AMPK-dependent manner, inhibiting the classic NF-
It was reported that BBR scavenged superoxide free radicals directly in vitro in a system containing alkaline dimethyl sulfoxide (DMSO) [
BBR could reduce oxidative stress by attenuating the expression level of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which was a major source of ROS production in cells [
Activation of NADPH oxidase is associated with the onset of diabetes, obesity and arthrosclerosis [
AMPK seemed to play a pivotal role in mediating the antioxidant activity of BBR. Besides NADPH oxidase downregulation, AMPK activation was linked to the upregulation of SOD expression [
The relationship between UCP2 and diabetes mellitus was complex. On the one hand, upregulation of UCP2 in adipose tissue or kidney could reduce ROS production and relieve diabetes or relevant complication; but on the other hand, increased UCP2 in islet
Recent studies revealed that BBR suppressed oxidative stress through induction of the nuclear factor erythroid-2-related factor-2 (Nrf2) pathway [
The anti-inflammatory activity of BBR was observed both in vitro and in vivo and was noted by the reduction of proinflammatory cytokines as well as acute phase proteins (Table
Effects of BBR on inflammatory cytokines and inflammation in cultured cells or animals with diabetes mellitus or insulin resistance.
References | Cell type, animal model | Administration of BBR | Samples examined | Effects of BBR |
---|---|---|---|---|
[ |
3T3-L1 adipocytes | 10 |
3T3-L1 adipocytes |
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[ |
HepG2 cells, palmitate induced insulin resistance | 0.1–10 |
Culture media |
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[ |
RAW 264.7 macrophages treated with LPS | 5 |
RAW 264.7 macrophages |
|
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||||
[ |
Mouse primary splenocytes treated with or without LPS | 0.8–3.3 |
Culture media |
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[ |
NIT-1 pancreatic |
1.25–5 |
Culture media |
|
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||||
[ |
KM mice, obesity and insulin resistance induced by HFD feeding for 13 weeks | 50 or 150 mg/kg/d, p.o. for 2 weeks | Serum |
|
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[ |
Wistar rats, STZ 50 mg/kg, single i.p. injection | 100 mg/kg/d, p.o. for 7 weeks | Serum |
|
|
||||
[ |
Wistar rats, NAFLD and insulin resistance induced by HFD for 8 weeks | 187.5 mg/kg/d, p.o. for 4 weeks | Liver |
|
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[ |
db/db mice | 5 mg/kg/d, i.p. for 4 weeks | White adipose tissue |
|
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||||
[ |
SD rats, STZ 60 mg/kg, single tail vein injection | 200 mg/kg/d, p.o. for 12 weeks | Kidney |
|
|
||||
[ |
NOD mice | 200 mg/kg/d, p.o. for 2 weeks | Supernatant from splenocytes, CD4+ T cells from spleen/lymph nodes |
|
|
||||
[ |
NOD mice | 50, 150 and 500 mg/kg/d, p.o. for 14 weeks | Supernatant from splenocytes |
|
Kidney and liver |
|
BBR could reduce proinflammatory cytokines, acute phase protein and infiltration of inflammatory cells in animals with diabetes mellitus or insulin resistance, either induced by STZ injection/HFD feeding or spontaneously happened (Table
Notably, BBR was proved to inhibit inflammation and relieve the development of type 1 diabetes mellitus in NOD mice [
Besides evidences from cultured cells and diabetic animal models, the anti-inflammatory effect of BBR was also observed in clinic [
BBR suppresses inflammation through complex mechanisms. Representative cellular pathways of BBR in inhibiting inflammation, which apparently shared in part with the antioxidant pathways, are summarized in Figure
In addition to antioxidant activity, the AMPK pathway was also crucial for the anti-inflammatory efficacy of BBR [
The anti-inflammatory activity of BBR was also associated with its inhibitory effect on the mitogen-activated protein kinase (MAPK) signaling pathways, which were activated by inflammatory stimuli [
There was discrepancy concerning the role of P38 in BBR-stimulated glucose metabolism as well. For example, BBR was shown to activate P38 and increase glucose uptake in L6 cells; and the effect of BBR on glucose metabolism could be partially blocked by a P38 inhibitor [
Besides antioxidant activity, the transcription factor of Nrf2 also played an important role in the anti-inflammatory activity of BBR (Figure
HO-1, an antioxidant enzyme whose expression was driven by Nrf2 [
The NF-
As inhibitory
Recent study proved that BBR could reduce renal inflammation in diabetic rats through inhibiting the Rho GTPase signaling pathway [
In addition to NF-
There were reports that the transcription stimulating activity of AP-1 and NF-
As a herbal compound, BBR was first reported to have glucose-lowering efficacy in 1986 in diabetic animals [
From the view of metabolic disorders, inflammation and oxidative stress closely relates each other [
BBR suppressed oxidative stress and inflammation through multiple mechanisms. In addition to what was mentioned above, recent studies indicated that the anti-inflammatory activity of BBR was also associated with its beneficial effects in the gut [
On the other hand, while BBR seemed poorly absorbed in the gut, recent pharmacokinetic study [
Some of the key issues of BBR in reducing oxidative stress and inflammation still need to be further studied. For example, conflicting results in the regulation of UCP2, MAPKs, and PPAR
In summary, natural compound BBR has antioxidant and anti-inflammatory activities which might contribute in part to its therapeutic efficacies against diabetes mellitus and insulin resistance. Multiple cellular kinases as well as signaling pathways such as AMPK, MAPKs, Nrf2/HO pathway, and NF-
Cerberine
Sirtuin 1
Forkhead box O
Nicotinamide adenine dinucleotide phosphate
Superoxide dismutase
AMP-activated protein kinase
Phosphatidylinositol 3-kinase
Nuclear factor erythroid-2-related factor-2
Uncoupling protein 2
Glutathione
NADPH quinine oxidoreductase-1
Heme oxygenase-1
Inducible nitric oxide synthase
Cyclooxygenase-2
Reactive oxygen species
Mitogen-activated protein kinase
I
Inhibitory
Nuclear factor-
Activator protein 1
Peroxisome proliferator-activated receptor
The authors have no conflict of interests in this paper.
This work was supported by the National Mega-Project for Innovative Drugs (2012ZX09301-002-001-015).