Dr. Ron’s Research Review – June 25, 2014

© 2014

This week’s research review is an update on berberine research.

A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients with a diagnosis of metabolic syndrome. Berberine (500 mg 3x/day before meals for 3 months) in 12 patients had a remission of 36% (P=0.037) in the presence of metabolic syndrome and a significant decrease in waist circumference in females (106+/-4 vs. 103+/-3 cm, P<0.05), systolic blood pressure (SBP) (123+/-7 vs. 115+/-9 mmHg, P<0.01), triglycerides (2.4+/-0.7 vs. 1.4+/-0.5 mmol/L, P<0.01), area under the curve (AUC) of glucose (1182.1+/-253.6 vs. 1069.5+/-172.4 mmol/l, P<0.05), AUC of insulin (92,056+/-72,148 vs. 67,407+/-46,441 pmol/L, P<0.01), and insulinogenic index (0.78+/-0.69 vs. 0.62+/-0.46, P<0.05), as well as an increase in the Matsuda index (2.1+/-1.0 vs. 3.1+/-1.6, P<0.01). (Perez-Rubio et al., 2013)

A recent double-blind, placebo-controlled study examined the effect berberine (500 mg 2x/day for 3 months) on the lipid profile in 144 subjects with low cardiovascular risk. Berberine reduced total cholesterol, triglycerides and LDL cholesterol and increased HDL cholesterol when compared with placebo. (Derosa et al., 2013)

Berberine, was shown to attenuate glucose neurotoxicity and promote Nrf2-related neurite outgrowth. (Hsu et al., 2013)

Fluconazole assists berberine to kill fluconazole-resistant Candida albicans. (Li et al., 2013)

Dr. Ron


 

Articles

Effects of berberine on lipid profile in subjects with low cardiovascular risk.
            (Derosa et al., 2013) Download
OBJECTIVE: To evaluate the efficacy as antihypercholesterolemic agent of berberine in patients with low cardiovascular risk. RESEARCH DESIGN AND METHODS: 144 Caucasian subjects were enrolled. After a 6-month run-in period following diet and practicing physical activity, patients were randomized to take placebo or berberine 500 mg twice a day, for 3 months, in a double-blind, placebo-controlled design. Berberine and placebo were then interrupted for 2 months (washout period), and all patients continued with only diet and physical activity. At the end of the washout period, patients restarted berberine or placebo twice a day for further 3 months. Anthropometric and metabolic parameters were assessed during the run-in period, at randomization, before and after the washout period. RESULTS: A decrease of body weight and BMI was observed after the run-in period. Berberine reduced total cholesterol, triglycerides and LDL cholesterol and increased HDL cholesterol after 3 months from randomization and compared with placebo. After the washout period, lipid profile worsened; afterward, when berberine was reintroduced, lipid profile improved again both compared with the washout period, and with placebo. CONCLUSIONS: Berberine is effective and safe to mildly improve lipid profile in subjects with low risk for cardiovascular disease.

Berberine, a natural antidiabetes drug, attenuates glucose neurotoxicity and promotes Nrf2-related neurite outgrowth.
            (Hsu et al., 2013) Download
Reactive oxygen intermediates production and apoptotic damage induced by high glucose are major causes of neuronal damage in diabetic neuropathy. Berberine (BBR), a natural antidiabetes drug with PI3K-activating activity, holds promise for diabetes because of its dual antioxidant and anti-apoptotic activities. We have previously reported that BBR attenuated H2O2 neurotoxicity via activating the PI3K/Akt/Nrf2-dependent pathway. In this study, we further explored the novel protective mechanism of BBR on high glucose-induced apoptotic death and neurite damage of SH-SY5Y cells. Results indicated BBR (0.1-10 nM) significantly attenuated reactive oxygen species (ROS) production, nucleus condensation, and apoptotic death in high glucose-treated cells. However, AG1024, an inhibitor of insulin growth factor-1 (IGF-1) receptor, significantly abolished BBR protection against high glucose-induced neuronal death. BBR also increased Bcl-2 expression and decreased cytochrome c release. High glucose down-regulated IGF-1 receptor and phosphorylation of Akt and GSK-3beta, the effects of which were attenuated by BBR treatment. BBR also activated nuclear erythroid 2-related factor 2 (Nrf2), the key antioxidative transcription factor, which is accompanied with up-regulation of hemeoxygenase-1 (HO-1). Furthermore, BBR markedly enhanced nerve growth factor (NGF) expression and promoted neurite outgrowth in high glucose-treated cells. To further determine the role of the Nrf2 in BBR neuroprotection, RNA interference directed against Nrf2 was used. Results indicated Nrf2 siRNA abolished BBR-induced HO-1, NGF, neurite outgrowth and ROS decrease. In conclusion, BBR attenuated high glucose-induced neurotoxicity, and we are the first to reveal this novel mechanism of BBR as an Nrf2 activator against glucose neurotoxicity, providing another potential therapeutic use of BBR on the treatment of diabetic complications.

Fluconazole assists berberine to kill fluconazole-resistant Candida albicans.
(Li et al., 2013) Download
It was found in our previous study that berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. The aim of the present study was to clarify how BBR and FLC worked synergistically and the underlying mechanism. Antifungal time-kill curves indicated that the synergistic effect of the two drugs was BBR dose dependent rather than FLC dose dependent. In addition, we found that BBR accumulated in C. albicans cells, especially in the nucleus, and resulted in cell cycle arrest and significant change in the transcription of cell cycle-related genes. Besides BBR, other DNA intercalators, including methylene blue, sanguinarine, and acridine orange, were all found to synergize with FLC against FLC-resistant C. albicans. Detection of intracellular BBR accumulation by fluorescence measurement showed that FLC played a role in increasing intracellular BBR concentration, probably due to its effect in disrupting the fungal cell membrane. Similar to the case with FLC, other antifungal agents acting on the cell membrane were able to synergize with BBR. Interestingly, we found that the efflux of intracellular BBR was FLC independent but strongly glucose dependent and associated with the drug efflux pump Cdr2p. These results suggest that BBR plays a major antifungal role in the synergism of FLC and BBR, while FLC plays a role in increasing the intracellular BBR concentration.

Effect of Berberine Administration on Metabolic Syndrome, Insulin Sensitivity, and Insulin Secretion
         (Perez-Rubio et al., 2013) Download
Abstract Background: The aim of this study was to evaluate the effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Methods: A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients with a diagnosis of metabolic syndrome. Glucose and insulin levels after a dextrose load were measured. Triglycerides and high-density lipoprotein cholesterol concentrations at baseline were also measured. Twelve patients received berberine hydrochloride (500 mg) three times daily before meals for 3 months. The remaining 12 patients received placebo. Area under the curve (AUC) of glucose and insulin, total insulin secretion, first-phase of insulin secretion, and insulin sensitivity were assessed. Results: After berberine administration, patients had a remission of 36% (P=0.037) in the presence of metabolic syndrome and a significant decrease in waist circumference in females (106+/-4 vs. 103+/-3 cm, P<0.05), systolic blood pressure (SBP) (123+/-7 vs. 115+/-9 mmHg, P<0.01), triglycerides (2.4+/-0.7 vs. 1.4+/-0.5 mmol/L, P<0.01), area under the curve (AUC) of glucose (1182.1+/-253.6 vs. 1069.5+/-172.4 mmol/l, P<0.05), AUC of insulin (92,056+/-72,148 vs. 67,407+/-46,441 pmol/L, P<0.01), and insulinogenic index (0.78+/-0.69 vs. 0.62+/-0.46, P<0.05), as well as an increase in the Matsuda index (2.1+/-1.0 vs. 3.1+/-1.6, P<0.01). Conclusions: Administration of berberine leads to remission of metabolic syndrome and decreases in waist circumference, SBP, triglycerides, and total insulin secretion, with an increase in insulin sensitivity.

 

References

Derosa, G, et al. (2013), ‘Effects of berberine on lipid profile in subjects with low cardiovascular risk.’, Expert Opin Biol Ther, 13 (4), 475-82. PubMedID: 23441841
Hsu, YY, YT Tseng, and YC Lo (2013), ‘Berberine, a natural antidiabetes drug, attenuates glucose neurotoxicity and promotes Nrf2-related neurite outgrowth.’, Toxicol Appl Pharmacol, 272 (3), 787-96. PubMedID: 23954465
Li, DD, et al. (2013), ‘Fluconazole assists berberine to kill fluconazole-resistant Candida albicans.’, Antimicrob Agents Chemother, 57 (12), 6016-27. PubMedID: 24060867
Perez-Rubio, K. G., et al. (2013), ‘Effect of Berberine Administration on Metabolic Syndrome, Insulin Sensitivity, and Insulin Secretion’, Metab Syndr Relat Disord, PubMedID: 23808999