Berberine behind the thriller of marked symptomatic bradycardia

Cannillo, Margherita

doi:10.4330/wjc.v5.i7.261

Cited by 18 publications

(11 citation statements)

References 19 publications

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“…Based on the finding that the QT interval was prolonged after 120 min, we speculate that the prolongation of the QT interval by BBR is a combination of acute and long-term effect (trafficking deficiency of hERG). BBR induced trafficking deficiency of hERG and prolongation of APD/QTc interval provide supports to an increasing number of studies demonstrating the pro-arrhythmic potential and genetic toxicity of BBR on heart [26,27]. …”

Section: Discussionmentioning

confidence: 99%

Berberine Induces hERG Channel Deficiency through Trafficking Inhibition

Zhang

Zhi

Huang

et al. 2014

Cell Physiol Biochem

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Aims: The human ether-a-go-go-related gene (hERG) encodes the α subunit of the IKr, which plays an essential role in repolarization of action potentials. hERG channels are targeted by various pro-arrhythmic drugs. Berberine (BBR) was previously found to acutely inhibit hERG currents and prolong action potential duration. The present study aimed to determine long-term effects of BBR on the expression of 135kDa/155kDa hERG and the mechanism. Methods and Results: hERG expression was assessed by western blot. Mature hERG (155 kDa) was reduced, whereas ER-located hERG (135 kDa) was increased by BBR. This indicated that hERG was restricted to the ER and that BBR disrupted channel trafficking. To determine the mechanism of trafficking inhibition, we performed western blot and immunoprecipitation to test folding of hERG by assessing interaction between hERG and Hsp90/Hsp70. Both the expression of Hsp90 and its interaction with hERG were strongly decreased by BBR. These data suggest that BBR reduces channel folding to induce trafficking inhibition. Western blot and confocal imaging were used to further detect whether the unfolded protein response (UPR) was activated. Active ATF6, a marker of the UPR, was activated by BBR. Calnexin and calreticulin, chaperones that are activated by ATF6 to assist channel folding, were also elevated and increasingly colocalized with hERG. These data also demonstrate that the UPR was activated. Immunoprecipitation and western blot assays were performed after BBR treatment to examine ubiquitination and degradation, common endpoints of the UPR. We found that the ER-restricted hERG was ubiquitinized and degraded in the lysosomes and proteasomes. Conclusion: Our study demonstrates that BBR induces hERG channel deficiency by inhibiting channel trafficking after incubation for 24h. Trafficking inhibition activated the UPR, and the ER-restricted hERG was ubiquitinized and degraded in lysosomes and proteasomes.

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Section: Discussionmentioning

confidence: 99%

Berberine Induces hERG Channel Deficiency through Trafficking Inhibition

Zhang

Zhi

Huang

et al. 2014

Cell Physiol Biochem

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“…In human clinical trials only a small percentage of patients reported nausea, vomiting, diarrhea, or constipation with BBR treatment and no severe side effects were observed with standard doses (Sabir and Bhide 1971;Zhang et al 2010). High doses of BBR resulted in rare adverse effects including headache, skin irritation and bradycardia (Cannillo et al 2013). BBR is excreted mainly through the hepatobiliary system and no adverse effect has been observed in hepatic function.…”

Section: Safety and Tolerability Of Berberinementioning

confidence: 99%

Berberine as a therapy for type 2 diabetes and its complications: From mechanism of action to clinical studies

Chang

Chen

Hatch

2015

Biochem. Cell Biol.

123

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The incidence of type 2 diabetes is increasing rapidly worldwide, and the development of novel anti-diabetic drugs is emerging. However, most anti-diabetic drugs cannot be used in patients with hepatic dysfunction, renal disease, and heart disease, which makes pharmacological therapy of type 2 diabetes complicated. Despite continued introduction of novel agents, the search for an ideal drug that is useful as both a hypoglycemic agent and to reduce diabetes-related complications remains elusive. Berberine is an isoquinoline alkaloid extract that has shown promise as a hypoglycemic agent in the management of diabetes in animal and human studies. Mechanistic studies have revealed beneficial effects of berberine on diabetes-related complications. Although there have been few clinical reports of the anti-diabetic effects of berberine, little documentation of adverse effects in humans positions it as a potential candidate drug to treat type 2 diabetes. In the present review, the anti-diabetic mechanism of berberine, its effect on diabetes-related complications, and its recent use in human clinical studies is highlighted. In addition, we summarize the different treatments for type 2 diabetes in adults and children.

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“…In a randomized controlled trial, Li et al reported that Tongxinluo Capsules, a TCM used to treat coronary disease and angina pectoris, caused an adverse reaction in the form of stomachaches in the treatment group (70). Berberine, an active compound extracted from the herb Berberis, may induce the onset of competitive junctional rhythm, causing a loss of atrioventricular synchronization, and reduce chronotropic competence with the onset of symptoms upon exertion (71). In fact, the present evidence of adverse reactions and toxicity is insufficient.…”

Section: Adverse Reactionsmentioning

confidence: 59%