We identify berberine (BBR), a compound isolated from a Chinese herb, as a new cholesterol-lowering drug. Oral administration of BBR in 32 hypercholesterolemic patients for 3 months reduced serum cholesterol by 29%, triglycerides by 35% and LDL-cholesterol by 25%. Treatment of hyperlipidemic hamsters with BBR reduced serum cholesterol by 40% and LDL-cholesterol by 42%, with a 3.5-fold increase in hepatic LDLR mRNA and a 2.6-fold increase in hepatic LDLR protein. Using human hepatoma cells, we show that BBR upregBerberineulates LDLR expression independent of sterol regulatory element binding proteins, but dependent on ERK activation. BBR elevates LDLR expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the 5' proximal section of the LDLR mRNA 3' untranslated region responsible for the regulatory effect of BBR. These findings show BBR as a new hypolipidemic drug with a mechanism of action different from that of statin drugs.

Berberine, is an alkaloid from Hydrastis canadensis L., Chinese herb Huanglian, and many other plants. It is widely used in traditional Chinese medicine as an antimicrobial in the treatment of dysentery and infectious diarrhea. This manuscript describes cardiovascular effects of berberine and its derivatives, tetrahydroberberine and 8-oxoberberine. Berberine has positive inotropic, negative chronotropic, antiarrhythmic, and vasodilator properties. Both derivatives of berberine have antiarrhythmic activity. Some cardiovascular effects of berberine and its derivatives are attributed to the blockade of K+ channels (delayed rectifier and K(ATP)) and stimulation of Na+ -Ca(2+) exchanger. Berberine has been shown to prolong the duration of ventricular action potential. Its vasodilator activity has been attributed to multiple cellular mechanisms. The cardiovascular effects of berberine suggest its possible clinical usefulness in the treatment of arrhythmias and/or heart failure.

Memory impairment induced by ethanol in rats is a consequence of changes in the CNS that are secondary to impaired oxidative stress and cholinergic dysfunction. Treatment with antioxidants and cholinergic agonists are reported to produce beneficial effects in this model. Berberine, an isoquinoline alkaloid is reported to exhibit antioxidant effect and cholinesterase (ChE) inhibitor activity. However, no report is available on the influence of berberine on ethanol-induced memory impairment. Therefore, we tested its influence against cognitive dysfunction in ethanol-induced rats using Morris water maze paradigm. Lipid peroxidation and glutathione levels as parameter of oxidative stress and cholinesterase (ChE) activity as a marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Forty five days after ethanol treated rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased glutathione, and elevated ChE activity. In contrast, chronic treatment with berberine (25-100mg/kg, p.o., once a day for 45days) improved cognitive performance, and lowered oxidative stress and ChE activity in ethanol treated rats. In another set of experiments, berberine (100mg/kg) treatment during training trials also improved learning and memory, and lowered oxidative stress and ChE activity. Chronic treatment (45days) with vitamin C, and donepezil during training trials also improved ethanol-induced memory impairment and reduced oxidative stress and/or cholinesterase activity. In conclusion, the present study demonstrates that treatment with berberine prevents the changes in oxidative stress and ChE activity, and consequently memory impairment in ethanol treated rats.

To investigate the effect and possible mechanism of berberine (Ber) on myocardial injury induced by exhaustion exercise (Ee).Forty healthy male SPF Sprague-Dawley rats were randomly divided into 5 groups using the random unit group design method: control group, Ee group and Ee plus Ber group (low: 50 mg·kg(-1)·d(-1), medium: 100 mg·kg(-1)·d(-1) and high dose: 150 mg·kg(-1)·d(-1),8 each). Ber (1.5 ml) or equal volume saline was given per gavage for 14 days. Rats assigned to Ee groups underwent Ee swimming once daily and rats in control group remain sedentary. After 14 days, echocardiographic measurements were performed and left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), left ventricular diastolic diameter (LVIDd) and left ventricular systolic diameter (LVIDs) were obtained. The morphological structure of heart was detected by HE and Masson staining. Serum superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by enzyme-linked immunosorbent assay. Cardiomyocytes apoptosis was detected by TUNEL method. The protein expression of myocardial hypertrophy marker protein B-type natriuretic peptide (BNP) and apoptotic marker protein (Bcl-2, Bax) in rat myocardial tissue was detected by Western blot.(1) Both LVFS and LVEF were significantly lower, and LVIDs and LVIDd were significantly larger in Ee group than those in control group (all0.01). The LVFS and LVEF in medium dose of Ber and high-dose Ber groups were significantly higher, and the LVIDs and LVIDd were significantly smaller than those in Ee group (all0.01). (2) The results of HE staining showed that the myocardial cells in control group were closely arranged, regular, normal in morphology, clear in structure, and uniform in staining. The myocardial cells of rats in Ee group were disarranged, cell staining was uneven, and vacuoles appeared in the cytoplasm. The disorder of myocardial cell arrangement and unequal staining in the medium dose of Ber were attenuated than in Ee group. The Masson staining results showed that the myocardial cells in control group were closely arranged, regular, normal in shape, clear in structure, and rarely blue-stained (fibrosis). Myocardial cells in rats in Ee group showed obvious fibrosis. The myocardial cell fibrosis in rats with medium dose of Ber was significantly reduced than exercise group. (3) MDA content in myocardial tissue of rats in Ee group was significantly higher than that of control group, and MDA content in myocardial tissue of rats in medium dose of Ber group was significantly lower than in Ee group (0.01). The SOD activity of myocardial tissue in rats was significantly lower than that of control group, while that of rats with medium dose of Ber was significantly higher than that of rats in Ee group (0.01). (4) TUNEL staining results showed that only a small amount of apoptosis myocardial cells were seen in control group, and a large number of apoptosis myocardial cells were seen in rats in Ee group. However, the number of apoptotic cardiomyocytes in medium dose of Ber was significantly lower than that in Ee group. The AI of rat cardiomyocytes was significantly higher than that of control group (0.01), and the AI of rat cardiomyocytes in median dose of Ber group was significantly lower than in Ee group (0.01). (5) BNP and Bax protein expression in the myocardial tissues of rats in Ee group were significantly higher than in control group (0.01). BNP and Bax protein expression in the myocardial tissues in median dose of Ber group were significantly lower than that of Ee group (0.01). The myocardial protein expression level of Bax was significantly higher, and the myocardial protein level of Bcl-2 was significantly lower in Ee group than in control group (both0.01), treatment with median dose of Ber could partly reverse above changes (both0.01).Ber can attenuate exhaustion exercise induced myocardial injury and remodeling in rats, and the beneficial effects of Ber might possibly be mediated by reducing free radical release and cardiomyocytes apoptosis.

Huntington disease (HD) represents a family of neurodegenerative diseases that are caused by misfolded proteins. The misfolded proteins accumulate in the affected brain regions in an age-dependent manner to cause late-onset neurodegeneration. Transgenic mouse models expressing the HD protein, huntingtin, have been widely used to identify therapeutics that may retard disease progression. Here we report that Berberine (BBR), an organic small molecule isolated from plants, has protective effects on transgenic HD (N171-82Q) mice. We found that BBR can reduce the accumulation of mutant huntingtin in cultured cells. More importantly, when given orally, BBR could effectively alleviate motor dysfunction and prolong the survival of transgenic N171-82Q HD mice. We found that BBR could promote the degradation of mutant huntingtin by enhancing autophagic function. Since BBR is an orally-taken drug that has been safely used to treat a number of diseases, our findings suggest that BBR can be tested on different HD animal models and HD patients to further evaluate its therapeutic effects.

Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility. We directly validated this Doxycycline-induced glycolytic phenotype, by using metabolic flux analysis and label-free unbiased proteomics.Next, we identified two natural products (Vitamin C and Berberine) and six clinically-approved drugs, for metabolically targeting the Doxycycline-resistant CSC population (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol). This new combination strategy allows for the more efficacious eradication of CSCs with Doxycycline, and provides a simple pragmatic solution to the possible development of Doxycycline-resistance in cancer cells. In summary, we propose the combined use of i) Doxycycline (Hit-1: targeting mitochondria) and ii) Vitamin C (Hit-2: targeting glycolysis), which represents a new synthetic-lethal metabolic strategy for eradicating CSCs.This type of metabolic Achilles' heel will allow us and others to more effectively"starve"the CSC population.