Received Aug 24; Accepted Oct 20; Collection date .
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PMCID: PMC PMID:Traditional Chinese medicine plays a significant role in the treatment of various diseases and has attracted increasing attention for clinical applications. Vascular diseases affecting vasculature in the heart, cerebrovascular disease, atherosclerosis, and diabetic complications have compromised quality of life for affected individuals and increase the burden on health care services. Berberine, a naturally occurring isoquinoline alkaloid form Rhizoma coptidis, is widely used in China as a folk medicine for its antibacterial and anti-inflammatory properties. Promisingly, an increasing number of studies have identified several cellular and molecular targets for berberine, indicating its potential as an alternative therapeutic strategy for vascular diseases, as well as providing novel evidence that supports the therapeutic potential of berberine to combat vascular diseases. The purpose of this review is to comprehensively and systematically describe the evidence for berberine as a therapeutic agent in vascular diseases, including its pharmacological effects, molecular mechanisms, and pharmacokinetics. According to data published so far, berberine shows remarkable anti-inflammatory, antioxidant, antiapoptotic, and antiautophagic activity via the regulation of multiple signaling pathways, including AMP-activated protein kinase (AMPK), nuclear factor κB (NF-κB), mitogen-activated protein kinase silent information regulator 1 (SIRT-1), hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), janus kinase 2 (JAK-2), Ca2+ channels, and endoplasmic reticulum stress. Moreover, we discuss the existing limitations of berberine in the treatment of vascular diseases, and give corresponding measures. In addition, we propose some research perspectives and challenges, and provide a solid evidence base from which further studies can excavate novel effective drugs from Chinese medicine monomers.
Keywords: berberine, cardiovascular disease, cerebrovascular disease, diabetes mellitus, pharmacokinetics
The global health burden of vascular diseases, such as atherosclerosis, cerebrovascular disease, hypertension, and complications of diabetes, is rapidly increasing (Al Rifai et al., ; Ji et al., ; Riccardi et al., ). Epidemiological surveys have shown that the increasing cost of vascular diseases worldwide compromises quality of life for individuals (Liss et al., ). In addition, a broad variety of factors, including inflammation, vascular dysplasia, oxidative stress, and abnormal lipid metabolism, cause vascular diseases (Guzik and Touyz, ; Feng et al., ). Hence, strategies aiming to reduce inflammation and oxidative stress and normalize the lipid metabolism are generally used to treat and prevent the vascular diseases, and statins, nonsteroidal anti-inflammatory drugs, and novel biological agents are common therapeutic agents (Oesterle et al., ; Lu et al., ; Doña et al., ). However, the high cost and side effect profiles of these drugs make finding cheaper alternatives with fewer side effects and similar or better therapeutic outcomes a matter of urgency. Therapies used in traditional Chinese medicines (TCM) have long been used as complementary and alternative medicines for the treatment of vascular disease in China (Cheng et al., ; Li et al., b). Recently, these have garnered research interest owing to fewer adverse reactions and lower toxicities of these compounds compared with those identified and used in western medicine (Xie et al., ; Oduro et al., ; Atanasov et al., ). Undeniably, TCM has made an indelible contribution to human health and is considered a potential source of therapies derived from natural, rather than synthetic, sources. Therefore, there is an increased emphasis on the use of medicinal plants such as those used in TCM in the development of novel drugs.
Berberine (C20H18NO4 +, CAS no: &#;83-1, Figure 1), a naturally occurring benzylisoquinoline alkaloid, has a long history of medical applications in TCM (Li et al., ). As a natural bioactive ingredient, berberine mainly exists naturally in the roots, rhizomes, and stem bark of various medicinal plants from the Ranunculaceae (Wang et al., ), Rutaceae (Ryuk et al., ), and Berberidaceae families (Gawel et al., ). Berberine was reportedly used in China as a folk medicine by Shennong at approximately BC, and the first recorded use of berberine is described in the ancient Chinese medical book The Divine Farmer&#;s Herb-Root Classic (Neag et al., ). The hydrochloride salt of berberine, listed as an oral antibacterial agent in Pharmacopoeia of the People&#;s Republic of China, is a common over-the-counter medication; dosage is usually 0.1 g in pill form taken 1&#;3 times per day for gastrointestinal infections (Zhang et al., b). Colloquially, it is known as Huangliansu (Chinese: &#;&#;&#;; literally translated into English: &#;the essence of Chinese goldthread&#;). Modern pharmacological studies have confirmed that berberine exhibits various clinically useful biological properties, including anticardiovascular disease and anticancer properties (Feng et al., ; Hu et al., ). A growing body of evidence has shown that berberine has poor bioavailability due to first-pass effects in the intestinal lumen, leading to limitations in its clinical application (Xu et al., ; Habtemariam, b). However, berberine is currently being evaluated in clinical trials for its important clinical benefits, lower toxicity and side effects compared with currently available therapies in western medicine, with its active metabolites exerting similar bioactive properties as berberine itself (Kumar et al., ; Imenshahidi and Hosseinzadeh, ). Further studies on berberine&#;s mechanism of action as well as new applications and novel formulations are therefore warranted.
In recent years, novel unique molecular entities derived from herbal medicines containing berberine have led to increased attention to the potential of this compound in the treatment of vascular diseases (Lee et al., ; Ren et al., ; Rajabi et al., ). Along with advances in pharmacological research, berberine was considered one of the most promising naturally derived drugs for the treatment of numerous human vascular diseases through the modulation of multiple signaling pathways. However, no systematic reviews on the pharmacological and pharmacokinetic properties of berberine in the context of vascular disease have been published. Therefore, in this review, we screened articles on berberine treatment in vascular diseases published in the years &#; using Web of Science, ScienceDirect, PubMed, Google Scholar and China National Knowledge Infrastructure online databases and summarized the findings to provide insights into the potential application of berberine in vascular diseases.
Berberine is a yellow solid, with a melting point of 145.1&#;146.7°C; it is soluble in hot water, slightly soluble in cold water or ethanol, and insoluble in benzene, ether, chloroform, and other organic solvents (Zhang et al., a). The structure of berberine comprises a dihydroisoquinoline ring and an isoquinoline ring with planar characteristics (Figure 1). The skeleton can be divided into four rings, A, B, C, and D, with the C2 and C3 of the A ring forming a methylenedioxy group responsible for most of the biological activities of berberine, such as anticancer activity (Leyva-Peralta et al., ). The &#;C&#; ring contains a quaternary ammonium structure (with N+ in the aromatic ring), which is necessary for the antibacterial activity (Gaba et al., ). In the &#;D&#; ring, C9 and C10 are each attached to a methoxy group. At present, structural modification studies of berberine mainly focus on the &#;C&#; and &#;D&#; rings (Xiao et al., ; Habtemariam a); available evidence suggests that alkylation or acylation in the &#;D&#; ring resulted in hypoglycemic activity (Cheng et al., ; Shan et al., ). The introduction of cinnamic acid at 9-O position exerted strong hypoglycemic effects (Zhang et al., b). C8 and C13 alkylation were shown to enhance cytotoxicity (Singh et al., ). Similarly, positions N7 and C13 are prone to modifications that enhance anticellular proliferative activity of berberine (Gaba et al., ). Moreover, berberine is fluorescent, with a maximum absorption wavelength of 350 nm and an emission wavelength of 530 nm in 0.01 mol/L sodium dodecyl sulfate solution. Thus, liquid chromatography&#;mass spectrometry and isotope labeling can be used to measure the content of berberine as part of a TCM or drugs (Chang et al., ; Ai et al., ).
Berberine exerts superior therapeutical effects on the vascular diseases, such as atherosclerosis; however, its effects are limited in clinic due to poor oral absorption and low bioavailability (Han et al., b). Previous research has reported that the absolute bioavailability of berberine is 0.37% when administered in a single oral administration (48.2, 120, or 240 mg/kg body weight) in rats (Feng et al., ). Oral treatment with 100 mg/kg berberine has an absolute bioavailability of 0.68% as measured in rat plasma samples, with a mean maximum plasma concentration (Cmax) of 9.48 ng/ml and an area under the curve (AUC)0&#;36 h of 46.5 ng h/ml (Chen et al., ). Sahibzada et al. () found that after a single oral dose of 50 mg/kg berberine in rabbits, the Cmax was 0.411 μg/ml.
Some studies have also reported the absorption of berberine in humans. In one study, the mean Cmax at 8 h post-administration was reported to be approximately 0.4 ng/ml for 400 mg berberine administered orally (n = 20) (Hua et al., ). Another study reported that the Cmax of berberine in 10 healthy individuals given 500 mg berberine orally was extremely low, at 0.07 nM (Spinozzi et al., ). It is thought that the lower in vivo bioavailability of berberine is closely related to extensive intestinal first-pass elimination, in which the drug is filtered out of the circulation by the liver resulting in a low level of systemic circulation (Guan et al., ). After orally administrated with 100 mg/kg berberine to rats, approximately half of berberine ran intact through the gastrointestinal tract and another half was disposed of by the small intestine, resulting in an extremely low extent of absolute oral bioavailability (0.36%) (Liu et al., b). Additionally, a caco-2 cell monolayer model was used to confirm that berberine is the substrate for the drug transporter P glycoprotein, which may contribute to the lower absorption of berberine in small intestinal epithelial cells by passive diffusion (Zhang et al., ; Cui et al., ).
With its remarkable pharmacological activity, berberine has been used for a variety of diseases in the clinic. However, due to its low in vivo bioavailability, exploring methods that increase the concentration of berberine in blood is key to improving its usefulness in this context. Although intravenous administration provides a direct approach that may improve the bioavailability of berberine, this can lead to serious side effects including respiratory arrest (Han et al., b). Therefore, berberine is often administered orally in clinic. Conversion of biological small molecules into salt compounds may be a method to improve its bioavailability in vivo. The bioavailability of berberine organic acid salts, especially berberine fumarate and berberine succinate, is higher than that of berberine hydrochloride (Cui et al., ). Moreover, chemical structure modification can be used to improve bioavailability of this drug. Long-chain alkylation (C5-C9) may enhance hydrophobicity, which has been shown to improve bioavailability; for example, 9-O-benzylation further enhances lipophilicity and imparts neuroprotective effect (Lin et al., ; Singh et al., ).
It has been demonstrated that berberine is rapidly distributed through tissues in the liver, kidneys, muscle, lungs, brain, heart, pancreas, and fat, in descending order of amount, while the concentration of berberine in most of these tissues was higher than that in plasma 4 h after oral administration at a dose of 200 mg/kg in rats. Moreover, berberine concentrations remained relatively stable in liver, heart, brain, muscle, and pancreas tissue in rats (Tan et al., ).
However, recent studies on the distribution of berberine in vivo are rare, which may be attributed to the broad tissue distribution in vivo after oral administration. The availability of new technologies such as component analysis by high-performance liquid chromatography electrospray ionization mass spectrometry (HPLC&#;ESIMS)/mass spectrometry (MS) and MS imaging may permit improved exploration of the berberine tissue distribution (Jove et al., ). The fact that berberine is widely distributed in tissues may be useful in the treatment of some diseases, which may broaden the scope of its clinical application. For example, with the character of enrichment in the liver, oral treatment with 100 mg/kg berberine may promote the excretion of cholesterol from the liver to the bile (Li et al., b). Thus, distribution of berberine may be an important pharmacokinetic property requiring further study in future.
One study used a sensitive HPLC-ESIMS/MS method to identify the metabolites of berberine in human plasma, of which berberrubine was most abundant, with high lipid solubility in individuals who received 15 mg/kg oral berberine chloride per day for 3 months (Spinozzi et al., ). Evidence showed that berberine had a similar metabolic profile in rats (100 mg/kg administered orally) and humans (300 mg administered orally three times a day for 2 days) via the urine (Qiu et al., ). Using liquid chromatography coupled with ion trap time-of-flight mass spectrometry, Ma et al. () revealed that 16 separate metabolites could be identified in rat bile, urine, and feces samples after oral administration of berberine (200 mg/kg). After a single oral administration (48.2, 120, or 240 mg/kg) of berberine in rats, the levels of phase 2 metabolites were much higher than those of phase 1 metabolites for the AUC0&#;48 h values. Simultaneously, nine major metabolites of berberine (demethyleneberberine, jatrorrhizine-3-O-β-D-glucuronide, jatrorrhizine, berberrubine-9-O-β-D-glucuronide, jatrorrhizine-3-O-sulfate, berberrubine, thalfendine-10-O-β-D-glucuronide, demethyleneberberine-2-O-sulfate, and demethyleneberberine-2-O-β-D-glucuronide) were detected in rat serum using a LC&#;MS/MS method (Feng et al., ). Additionally, it was demonstrated that the metabolism of berberine by oral is closely related to liver function and gut microbiota. After oral administration of 300 mg/kg berberine in mice, cytochrome P3A11 (CYP3A11) and CYP3A25 mRNA and CYP3A11 and CYP2D22 enzyme activity levels were all found to be decreased, while the level of CYP1A2 mRNA was increased (Guo et al., ). Similarly, on oral administration of 200 mg/kg berberine in rats, the drug was shown to be metabolized in the liver by the CYP450 isoenzyme via oxidative demethylation at C2, C3, C9, and C10, followed by conjugation of the hydroxyl groups with glucuronic acid (Singh et al., ). Furthermore, gut microbiota can also affect the metabolism of berberine after oral administration. It was demonstrated that 200 mg/kg berberine administered orally could be converted into absorbable dihydroberberine by nitroreductases produced by gut microbiota, which showed a nearly 5-fold higher intestinal absorption rate than berberine in rats; the dihydroberberine is then oxidized back to berberine after absorption into the intestinal tissue, and enters the blood (Feng et al., ; Han et al., a). Also, gut microbiota was shown to convert berberine into oxyberberine through an oxidation reaction in vitro and in vivo, which exerted a much stronger binding interaction with hemoglobin than plasma (Li et al., a; Chen et al., ).
To summarize this section, the liver and intestine are the main metabolizing organs of berberine by oral administration. Inhibiting the first-pass effect may reduce the metabolism of berberine and improve its bioavailability. Interestingly, according to an in-depth study on the metabolism of berberine in vivo, it found that phase II metabolites are the major metabolic products of berberine (Feng et al., ), whereas the opposite was true in previous studies (Ma et al., ). In addition, particular attention should be paid to nitroreductases produced by gut microbiota, and berberine metabolism in general, in future studies, in order to fully establish the pharmacodynamic basis of this TCM.
To better understand the poor absorption of berberine in vivo, some researchers have paid more attention to the excretion of berberine via the digestive tract. Berberine was found in feces with a recovery rate of 22.74% after a single oral dose (200 mg/kg) in 48 h, and thalifendine was the most abundant berberine metabolite excreted in the bile, urine, and feces in rats (Ma et al., ). In another study, 18.6% of the berberine was excreted in feces as berberrubine after intragastric administration at a single dose of 48.2 mg/kg. The total recovery of berberine and its metabolites from the urine, bile, and feces was 41.2% in rats (Feng et al., ). To summarize, berberine and its metabolites are mainly excreted by the kidneys (urine and feces) and bile in rats and mice (Liu et al., ).
Recently, vascular protective effects of berberine have been reported in experimental studies of diverse vascular diseases. Berberine has shown promising vascular protection against atherosclerosis, cerebrovascular disease, hypertension, diabetes mellitus (DM), and intestinal vascular diseases. The pharmacological properties and molecular pathways of berberine are presented in Figure 2.
Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide (Huang et al., ). Studies indicate that the abnormal proliferation of vascular smooth muscle cells (VSMCs) is involved in the pathogenesis of CVD (Xiang et al., ; Zhang et al., a). It has also been demonstrated that berberine (10, 30 and 100 μmol/L) could inhibit angiotensin IV-induced proliferation in cultured VSMCs by targeting the peroxisome proliferator-activated receptor α (PPAR-α)&#;nitric oxide (NO) signaling pathway (Qiu et al., ).
Inflammation is one of the most observed cardiovascular conditions, and has a significant role in the progression of CVD (Golia et al., ; Lockshin et al., ). Aggravating inflammation may induce vascular remodeling after myocardial ischemia (MI), contributing to reduction of the ejection fraction and subsequent heart failure (Lu et al., ; Chong et al., ). It has been suggested that 50 mg/kg berberine may improve vascular inflammation and remodeling by inhibiting p38 mitogen-activated protein kinase (MAPK) activation, and activating transcription factor 2 phosphorylation (p-ATF-2) and matrix metalloprotease 2 (MMP-2) expression in rats (Li et al., a). Protein hyperacetylation is associated with the development of MI (Treviño-Saldaña and García-Rivas, ; Aggarwal et al., ). Accumulating studies have demonstrated that silent information regulator 1 (SIRT-1) can regulate oxidative stress and inflammation to inhibit the development and progression of cardiac dysfunction in myocardial ischemia/reperfusion (MI/R) injury (Xue et al., ; Chang et al., ). Owing to its strong antioxidative and anti-inflammatory activities, oral administration of berberine (200 mg/kg) conferred cardioprotective effects in rats by improving post-MI/R cardiac function recovery and reducing infarct size after MI/R injury; the mechanism of action was found to be associated with the regulation of the SIRT-1 signaling pathway (Yu et al., ). As a selective barrier between tissue and blood, endothelial cells play a potential role in the control of inflammatory responses and homeostasis (Krüger-Genge et al., ). Endothelial cell dysfunction and/or injury can disrupt the integrity of the endothelial lining and subsequently lead to vascular disease, such as MI (Monteiro et al., ). Additionally, large experimental studies suggest that excessive inflammation can directly lead to endothelial cell apoptosis (Bravo-San Pedro et al., ; Henning et al., ). Lipopolysaccharide (LPS)-induced inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs) were found to be inhibited by pretreatment with 5 μM berberine, mediated by inhibition of c-Jun N-terminal kinase (JNK) phosphorylation, and increased myeloid cell leukemia 1 (MCL-1) expression and superoxide dismutase (SOD) activity (Guo et al., ).
Angiogenesis, the formation of new blood vessels from preexisting ones, is indispensable for revascularization and cardiac remodeling following MI (Mathiyalagan et al., ; Chong et al., ; Tang et al., ). Ischemic heart disease is a leading cause of mortality and results from vascular cavity stenosis and occlusion (Garry et al., ). Rehabilitation of the myocardial ischemic region involves the activation of several stimulatory and inhibitory modulators of angiogenesis; the most notable of which are vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF-2), and thrombospondin 1 (TSP-1) (Detillieux et al., ; Frangogiannis et al., ; Martinez et al., ; Garikipati et al., ). Treatment with 10 mg/kg of berberine-rich extract (5 days a week by gavage) remarkably reduced heart infarct size, and increased the expression of angiogenesis-promoting factors in rats with MI/R injury, including VEGF, FGF-2 and TSP-1 (Banaei et al., ). In addition, microRNA plays a key role in many cardiac pathological processes, including MI (Parikh et al., ). Treatment with berberine in mice with MI injury was shown to lead to elevated miR-29b can activate the protein kinase B (Akt) signaling pathway, thus promoting angiogenesis and cell proliferation and migration to improve heart function (Zhu et al., ). A study in zebrafish embryos revealed that the level of VEGF-aa mRNA was up-regulated by berberine, which interfered with the angiogenic process, promoting bradycardia and reducing the cardiac output, atrial shortening fraction percentage, and atrial stroke volume (Martini et al., ). A complex hemodynamic pathological phenomenon exists in ischemia and reperfusion injury that can engage the metabolic and inflammatory machinery in the development of various disorders, including heart failure (Raza et al., ). Interestingly, intragastric administration of 100 mg/kg berberine daily for 14 days attenuated ischemia&#;reperfusion injury via hemodynamic improvements and inhibition of AMPK activity in both non-ischemic and ischemic areas of rat heart tissue (Chang et al., ).
Recent evidence has confirmed that endoplasmic reticulum (ER) stress is correlated with the development and progression of various heart diseases including cardiac hypertrophy, ischemic heart diseases, and heart failure (Wang et al., ). Prolonged ER stress, however, can become a leading cause of vascular endothelial cell dysfunction and apoptosis in CVD (Chen et al., ; Fatima et al., ). Oral administration of 200 mg/kg berberine daily for 2 weeks was reported to protect the heart from MI/R injury in rats by activating the janus kinase 2 (JAK-2)/signal transducer and activator of transcription 3 (STAT-3) signaling pathway, as well as by attenuating ER stress-induced apoptosis (Zhao et al., ). Alternatively, apoptosis and inflammation are correlated with anoxia-reoxygenation injury in CVD, which typically occurs during MI (Huang et al., ; Gan et al., ). The decreased inflammatory cytokines and myocardial cell apoptosis resulting from berberine administration may alleviate anoxia-reoxygenation injury by downregulating p38 MAPK-mediated nuclear factor κB (NF-κB) signaling pathway (Zhao et al., c). In conclusion, given its robust anti-inflammatory, antioxidative stress, antiapoptotic, and anti-ER stress effects, berberine may effectively improve CDV and MI by inhibiting the MAPK, AMPK and NF-κB pathways and activating PPARα-NO, VEGF, and JAK-2/STAT-3 pathways (Figure 3 and Table 1).
Atherosclerosis is a leading cause of death worldwide, and is characterized by lipid deposition, chronic inflammatory injury, smooth muscle cell proliferation, and plaque formation (Insull, ; Wolf and Ley, ). The pathological process of atherosclerosis begins with endothelial damage, accompanied by abnormal migration of VSMCs, leading to vascular remodeling (Sitia et al., ; Liang et al., ). Administration of 25, 50 and 100 μM berberine may suppress the expression of MMP-2, MMP-9 and urokinase-type plasminogen activator (u-PA) to significantly inhibit fetal bovine serum-induced human aortic smooth muscle cell (HASMC) migration, which may act to interrupt the activator protein 1 (AP-1) and NF-κB signaling pathways (Liu et al., ). Dysregulation of lipid metabolism is considered another major risk factor for atherosclerosis (Agrawal et al., ). An expert committee published the National Cholesterol Education Program in United States, emphasizing that low density lipoprotein (LDL) should be the primary target of cholesterol-lowering therapy in atherosclerosis (Tavares et al., ). In particular, clinical trials have demonstrated that lowering LDL levels can reduce the risk of atherosclerosis (Ference et al., ; Ji and Lee, ). Notably, the increased lipid in the serum and liver was reduced with the administration of berberine, which improved intima-media thickening, restored aortic endothelium-dependent vasodilatation, and alleviated atherosclerotic lesions in APOE(&#;/&#;) mice fed a western-type diet for 12 weeks (Tan et al., ). Similarly, berberine ameliorated high-fat diet (HFD)-induced hyperlipidemia and lipid accumulation in liver and adipose tissue, alleviated endothelial lesions and reduced the expression of inflammatory cytokines in the plasma of APOE(&#;/&#;) mice; it also reduced cholesteryl ester gathering in the aortic arch, resulting in ameliorated arterial plaque build-up via altered AMPK and NF-κB gene expression, and interrupted crosstalk between adipocytes and macrophages (Ma et al., ).
Tumor necrosis factor α (TNF-α) is a major proinflammatory factor in the development of vascular inflammation (Jang et al., ). Aberrant inflammatory responses may result in the ablation of macrophages, aggravation of vascular endothelial injury, and abnormal tissue proliferation in atherosclerosis (Hui et al., ; Brown et al., ). In vitro studies have indicated that TNF-α-induced inflammation, which causes excessive expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1) could be decreased by berberine in human aortic endothelial cells; this may be associated with inhibition of the NF-κB and AMPK pathways (Liu et al., b). Oxidized LDL (ox-LDL) can act as an antigen to activate the immune inflammatory response, increasing the infiltration of inflammatory cells and the secretion of inflammatory factors in atherosclerosis (Lundberg et al., ). Ox-LDL-induced HUVEC proliferation and inflammatory responses were reversed with berberine, which lowered the expression of proliferating cell nuclear antigen (PCNA), NF-&#;B, and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), and inhibited the phosphoinositide 3-kinase (PI3K)/Akt, extracellular signal-regulated kinase 1/2 (ERK-1/2), and p38 MAPK pathways (Xu et al., ). Ox-LDL has also been shown to injure endothelial cells directly, and contributes to endothelial dysfunction via overexpression of LOX-1, which induces a further rise in intracellular reactive oxygen species (ROS) (Kattoor et al., ; Akhmedov et al., ). Orally administrated at 156 mg/kg, berberine improved endothelial dysfunction by reducing aortic ROS generation and the release of inflammatory cytokines in the serum of a mouse model of atherosclerosis (Tan et al., ). Additionally, platelet&#;endothelial cell interactions potentiated by oxidative stress are thought to contribute to early atherosclerosis (Brown et al., ). Existing inflammatory and oxidative suppression of berberine prevented the development of the atherosclerotic plaque area by inhibiting translocation of NF-κB to the nucleus (Feng et al., ). Uncoupling protein 2 (UCP-2) is an inner mitochondrial membrane protein that belongs to the UCP family and plays an important role in lowering mitochondrial membrane potential and dissipating metabolic energy, preventing the accumulation of oxidative stress (Pierelli et al., ). Amazingly, treatment with 1 mmol/L berberine in drinking water led to suppression of oxidative stress and vascular inflammation by stimulating AMPK-dependent UCP-2 expression in mice with atherosclerosis (Wang et al., ). Moreover, recent studies found that the gut microbiota played a crucial role in atherosclerosis (Jonsson and Bäckhed, ; Verhaar et al., ). Another study emphasized that the modulation of gut microbiota, specifically the abundance of the Akkermansia bacterial genus, contributed to the antiatherosclerotic and metabolic protective effects of berberine by suppressing intestinal inflammation and promoting intestinal epithelial barrier integrity (Zhu et al., ).
Prolonged activation of the ER stress pathway can lead to aggravated oxidative stress and endothelial cell apoptosis (Tabas, ; Linton et al., ). Kawasaki disease (KD) is an acute febrile illness characterized by systemic vasculitis, especially in coronary arteries (de Ferranti et al., ). Berberine exerted its protective effects on KD-induced apoptosis of human coronary artery endothelial cells by inhibiting oxidative and ER stress (Xu et al., ). Endothelial cell apoptosis induced by ER stress is closely linked with plaque progression, which can contribute to unstable atherosclerotic plaques, perhaps in response to thrombosis in atherosclerosis (Yang et al., ). Homocysteine increases damage to vascular endothelial cells, thereby reducing vasodilation factors released by endothelial cells and impairing vasodilation in the endothelium, resulting in vascular endothelial apoptosis and inducing oxidation (Salvio et al., ). Nevertheless, an in vivo experiment has shown that berberine increased the stability of atherosclerotic plaques and mitigated detrimental effects of vascular endothelial cell activity experimentally induced by 50 mg/kg homocysteine thiolactone, and similar results are found in vitro study induced by 1 mM homocysteine thiolactone (Li et al., a). Collectively, the studies presented here (Table 2) indicate that berberine may improve vascular endothelial damage, abnormal lipid metabolism, chronic inflammation, plaque formation, and cell apoptosis, thereby alleviating atherosclerosis (Figure 4).
Alzheimer&#;s disease (AD) is a complex, aging-related, neurodegenerative disease, and the pathology process mainly involves β-amyloid (Aβ) overproduction and accumulation, tau hyperphosphorylation, and neuronal loss (Lian et al., ; Spangenberg et al., ; Gao et al., ). Administration of 0.5 μM berberine significantly suppressed Aβ-induced production of interleukin 6 (IL-6) and MCP-1 by inhibiting the activation of NF-κB and blocking the PI3K/Akt and MAPK pathways (Jia et al., ). Accumulated Aβ can result from abnormal processing of amyloid precursor protein (APP) in AD (O'Brien and Wong, ). APP C-terminal fragment levels and APP and tau hyperphosphorylation were decreased with 100 mg/kg berberine, administered by oral gavage for 4 months, via the Akt/glycogen synthase kinase 3 (GSK-3) pathway in rats with AD (Durairajan et al., ). Similarly, berberine modulates Aβ generation through activation of the AMPK pathway in N2a mouse neuroblastoma cells (Zhang et al., ). Moreover, elevated Aβ can mediate synaptic loss and dysfunction, another pathological hallmark of AD, by targeting mitochondria (Hong et al., ). Pretreatment with 1 μM berberine alleviated axonal mitochondrial abnormalities by preserving the mitochondrial membrane potential and preventing decreases in ATP, increasing axonal mitochondrial density and length, and improving mitochondrial motility and trafficking in 0.5 μM Aβ cultured hippocampal mouse neurons (Zhao et al., a). Additionally, neuronal loss and cerebral blood flow contributed to dysfunction in memory and reward systems in AD (Dai et al., ; Nobili et al., ). Studies found that drinking water containing 100 mg/L berberine exerted a strong neuroprotective effect, improving cognitive deficits, inhibiting the apoptosis of neurons, and promoting the formation of micro-vessels by restoring cerebral blood flow and reducing Aβ accumulation in an APP/tau/PS-1 mouse model of AD (Ye et al., ). As shown in Table 3, the potential effects of berberine observed in the study suggest that it may effectively prevent AD by reducing accumulated Aβ. Few studies have focused on the improvement of tau hyperphosphorylation and neuronal loss in AD, which should thus be a focus of future research.
Vascular dementia (VD) is the second most common form of dementia and is caused by vascular pathologies causing brain injury (Poh et al., ). In a rat model of VD induced by cerebral ischemia&#;reperfusion injury, increased angiogenesis was observed with berberine chloride (50 mg/kg) treatment, which may be due to the activation of hypoxia-inducible factor 1α (HIF-1α)/VEGF signal pathway (Liu et al., ). In general, few studies have focused on the relationship between berberine and vascular in VD. According to the development of new biological in recent years, imaging technology is conducive to strengthen the study of berberine and cerebrovascular diseases. Second near-infrared II (NIR-II) imaging, a kind of biomedical imaging technology with characteristics of high sensitivity, high resolution, and real-time imaging, can visualize the vasculature in the brain (Guo et al., a). Therefore, we can directly utilize the NIR-II to observe the improvement of the vascular in the brain by treatment with berberine.
An epidemiological investigation showed that the incidence of hypertension increases with age across all countries, regions, or ethnicities, and is generally higher in industrialized countries than developing countries (Zhou et al., ). Hypertension is more common in the elderly, and mostly manifests as simple systolic hypertension; however, it is increasing in younger age groups (James et al., ; Zhang and Moran, ). Among the many mechanisms underlying arterial stiffness, endothelial dysfunction is believed to be a critical determinant for its onset and progression (Kostov and Halacheva, ; Safar, ). Owing to arterial stiffness, elevated arterial blood pressure can contribute to both extracellular matrix (ECM) deposition and remodeling or enhanced contractility or stiffness of VSMCs (Bertorello et al., ). In vitro, berberine (at concentrations of 1.25, 2.5, and 5 μM) considerably inhibited aortic endothelial cells in spontaneous hypertensive rats (SHRs) by suppressing cell proliferation, apoptosis, and down-regulating the expression of Toll-like receptor 4 (TLR-4), myeloid differentiation protein 88 (MYD-88), NF-κB, IL-6, and TNF-α (Wang and Ding, ). Numerous studies have verified that vascular endothelial cell dysfunction and lncRNA activity may together be associated with hypertension (Lorenzen and Thum, ; Konukoglu and Uzun, ). The levels of five lncRNAs were found to be modulated by the administration of 100 mg/kg berberine in mice with hypertention, which may preserve vascular endothelial cell function (Tan et al., ). Endothelial microparticles (EMPs) are extracellular vesicles that are shed by the endothelium as a result of activation, injury, or apoptosis of endothelial cells, and are considered important biomarkers of the status of endothelial cells and vascular function (Sun et al., ). Endothelial progenitor cells (EPCs) mobilized from bone marrow can migrate to the peripheral blood and differentiate into mature endothelial cells, contributing to endothelial recovery (Pyšná et al., ). One study found that EPC number and activity was significantly reduced among people with hypertension when compared to healthy individuals, and low circulating levels of EPCs may contribute to endothelial dysfunction (Waclawovsky et al., ). Abnormal circulating EMPs and EPCs in SHRs were ameliorated by berberine treatment associated with endothelial dysfunction and arterial stiffness in SHRs (Zhang et al., ). Moreover, the production of NO caused by oxidative stress, aging, and spontaneous hypertension increases endothelium-dependent contractions (EDCs), contributing to blunted endothelium-dependent vasodilation (Vanhoutte et al., ; Vanhoutte et al., ). Continuous ER stress can exert detrimental effects through a maladaptive, unfolded protein response, resulting in cellular defects and disturbed vascular function (Ren et al., ). However, incubation with 1 μM berberine has been shown to reduce EDCs by activating the AMPK pathway, thus inhibiting ER stress and ROS generation, leading to cyclo-oxygenase 2 (COX-2) downregulation in SHR carotid arteries (Liu et al., ).
Ca2+ signals regulate vascular function in endothelial cells; Ca2+ release from the ER and/or Ca2+ influx through ion channels at the endothelial cell membrane results in endothelium-dependent vasodilation and diminished vascular resistance (Cook et al., ; Ottolini et al., ; Wang et al., ). Notably, endothelial transient receptor potential vanilloid 4 (TRPV-4) channels are associated with hypertension, as they regulate Ca2+ concentrations (Ottolini et al., ). Long-term administration of berberine has been shown to directly induce vasorelaxation, decreasing blood pressure and vascular stiffness, by suppressing the activity of TRPV-4 channels (Wang et al., ). Additionally, mechanical stretching forces increase the proliferation and apoptosis of VSMCs by activating the protein disulfide isomerase (PDI) redox system. Berberine has been shown to inhibit the PDI ER system and the MAPK pathway, thereby attenuating the simultaneous increases in VSMC proliferation and apoptosis observed in response to mechanical stretching during hypertension (Wang et al., ). Collectively, these results demonstrate that berberine may effectively ameliorate endothelial dysfunction, arterial stiffness, and vascular remodeling, resulting in reduced hypertension, and which the mechanism may be related to the inhibition of ER stress and activation of the AMPK pathway. An increasing number of studies on hypertension have focused on the Ca2+ and TRPV-4 pathways in recent years (Table 4).
Pulmonary arterial hypertension (PAH) is closely associated with extensive vascular remodeling, especially pulmonary arterial medial hypertrophy and muscularization, due to aberrant proliferation of pulmonary artery smooth muscle cells (PASMCs) resulting from hypoxia (Bisserier et al., ; Sharifi Kia et al., ). Hemodynamic and pulmonary pathological data showed that chronic hypoxia notably elevated the median width of pulmonary arterioles (Choudhary et al., ; Khoramzadeh et al., ). However, berberine substantially decreased pulmonary vascular remodeling in mice with hypoxia-induced PAH by inhibiting Akt/mammalian target of rapamycin (mTOR)/HIF-1α and transforming growth factor β (TGF-β) pathways, and activating bone morphogenetic protein type 2 (BMPR-2) receptor (Chen et al., ; Liu et al., ). Wande et al. () demonstrated substantial proliferative activities in hypoxia-induced human PASMCs, were possibly mediated by berberine (at concentrations of 10 μM) via inhibiting the thioredoxin (TRX-1) and β-catenin pathways. Activation of protein phosphatase 2A (PP2A) has been shown to induce apoptosis of PASMCs in people with PAH (Ferron et al., ). Berberine may prominently attenuate proliferation and migration of PASMCs induced by norepinephrine, alleviating PAH via PP2A pathway (Luo et al., ). These results together show that berberine significantly suppresses pulmonary vascular remodeling and proliferation of vascular endothelial cells in PAH; the antiproliferative and antiapoptotic effects may be mediated by inhibition of the Akt/mTOR/HIF-1α and PP2A pathways (Table 4).
The main cause of DM and associated complications is a low level or lack of pancreatic islet function, including insulin resistance, resulting in disordered glucose metabolism in the body (Pearson, ; Han et al., b). Sustained hyperglycemia progresses to various diabetic microangiopathies, including diabetic cardiovascular disease, nephropathy, neuropathy and retinopathy (Reddy et al., ; Montero et al., ; Tang and Yiu, ). Chronic inflammation caused by hyperglycemia is a major feature of DM (Saltiel and Olefsky, ). Adipose tissue macrophages (ATMs), including M1 ATMs, can induce inflammatory responses by producing pro-inflammatory cytokines such as TNF-α and IL-6, thus contributing to the induction of insulin resistance in DM (Russo and Lumeng, ). Oral berberine (50 mg/kg/day) markedly improved insulin resistance, reduced the inflammation and JNK, IKK-β, and NF-κB p65 phosphorylation by inhibiting M1 macrophage activation in adipose tissue (Ye et al., ). Owing to increased aldose reductase (AR) and NADPH oxidase (NOX) activities, platelet hyperreactivity and apoptosis during DM accounts for the accumulation of ROS (Vara et al., ; Ajjan et al., ). It was demonstrated that 50 mM glucose induced platelet aggregation, apoptosis and superoxide production, which was neutralized by 25 and 50 μM berberine via inhibiting of AR, NOX and GSH reductase activities (Paul et al., ). Similarly, 25 μM berberine had protective effects against endothelial injury by attenuating the generation of ROS, cellular apoptosis, NF-κB activation, and expression of adhesion molecules, which were induced by high glucose levels; it also enhanced the endothelium-dependent vasodilatation through the activation of the AMPK pathway (Wang et al., ).
Advanced glycation end products (AGEs) are produced via the nonenzymatic glycation reaction and are considered major pathogenic factors that trigger vascular complications in diabetes (Azegami et al., ). Incubation with 5 or 10 μg/ml berberine significantly inhibited AGE formation in high-glucose-AGEs-induced micro-endothelial injuries (Hao et al., ). Diabetic peripheral neuropathy, characterized by perivascular neuropathy, is reported to be involved in vascular disorders associated with diabetes (Olesen et al., ). The mesenteric artery, a part of the splanchnic circulation system, is involved in the regulation of arterial pressure (van Dijk et al., ). The iliac artery is mainly responsible for blood supply to the lower extremities and pelvic organs (Maier et al., ). Both of these sites are predisposed to large vascular lesions in diabetes. Oral administration of 200 mg/kg berberine markedly enhanced the nitrergic neural activity in the superior mesenteric artery and diminished the adrenergic function in the iliac artery, resulting in vasodilatation in diabetic rats (Geng et al., ; Zhao et al., b).
Intracellular Ca2+, which is tightly controlled by Ca2+ channels and transporters, is an important messenger in VSMC dedifferentiation (Nagel et al., ). Elevated concentrations of intracellular Ca2+ is a primary stimulus for smooth muscle contraction; it is reported that diabetic vascular dysfunction is tightly coupled to the impairment of intracellular Ca2+ processing in VSMCs (Searls et al., ; Yang et al., ). Impaired cerebral arterial vasodilation can be alleviated by berberine in a diabetic rat model via down-regulation of the intracellular Ca2+ processing of VSMCs (Ma et al., ). Hyperglycemia and hypertension are the two primary risk factors for vascular disease in diabetic patients (Cryer et al., ; Petrie et al., ). Increases in intracellular Ca2+ along with decreases in K+ can lower the membrane potential and enhance the vasoconstriction response and the proliferation of VSMCs, leading to hypertension (Seki et al., ; Sun et al., ). Chronic administration of 100 mg/kg berberine reduced blood pressure and improved vasodilation in diabetic rats by activating the Ca2+-activated K+ channel (Ma et al., ). Aberrant miR-133a expression in endothelial cells induces endothelial dysfunction and impaired endothelium-dependent vasodilation, aggravating the pathogenesis of cerebrovascular diseases (Li et al., b). Administration of berberine (1.0 g/kg for 8 weeks) reduced miR-133a expression and impairments in learning and memory, increasing the vasodilation in the middle cerebral artery to improve VD associated with diabetes (Yin et al., ). Furthermore, existing evidence suggests that hyperglycemia and hypoxia can trigger cerebrovascular dysfunction (Lefferts et al., ; Jin et al., ). Berberine at a concentration of 30 μM counteracted the attenuating effects of hypoxic/high-glucose conditions on the proliferation and migration of rat brain microvascular endothelial cells, which was in part mediated by the SIRT-1/HIF-1α/VEGF pathway (Mi et al., ). According to these studies, berberine had a hypoglycemic effect through improving insulin resistance, and has robust anti-inflammatory, antiapoptotic and antiendothelial injury effects in DM. Berberine appears to improve endothelial dysfunction by regulating Ca2+ and K+ channels in DM (Table 5).
Diabetic retinopathy (DR) is a retinal microvascular disease caused by chronic hyperglycemia leading to angiogenesis in retina (Ai et al., ). In recent years, improvement of disordered glucolipid metabolism is considered one of the most effective strategies for the treatment of DM and its complications (Zhao et al., b). Berberine has been shown to block DR development by modulating the glucolipid metabolism and inhibiting the HIF-1α/VEGF/NF-κB pathway (Yin et al., ). The pathological processes involved in DR may be related to increased levels of pro-inflammatory factors, leading to oxidative stress and the apoptotic cascade (Ai et al., ; Robles-Rivera et al., ; Gong et al., ). Berberine may deactivate the NF-κB pathway, thus suppressing oxidative stress and cell apoptosis in DR (Zhai et al., ). As a major energy receptor and metabolic regulator, AMPK is one of the therapeutic targets for metabolic and vascular diseases (Lu et al., ). 10 or 20 μM berberine was shown to have therapeutic effects, protecting Müller cells from 30 mM glucose-induced apoptosis by enhancing autophagy and activating the AMPK/mTOR pathway in DR (Chen et al., ). These results together indicate that berberine could attenuate the pathogenesis of DR, mainly through regulating the HIF-1α/VEGF/NF-κB and AMPK/mTOR pathways to inhibit microvascular proliferation, oxidative stress and apoptosis (Table 5).
Diabetic nephropathy (DN), one of the most serious microvascular complications of DM, is the leading cause of end-stage renal failure (Lai et al., ). The early stage of DN is mainly characterized by abnormal renal hemodynamics, which mainly manifests as decreased vascular resistance in the glomerulus (Toledo et al., ). Research has shown that accumulation of ECM production in the glomerular mesangial membrane may be related to NF-κB pathway (Gong et al., ). The ameliorative effects of berberine (300 mg/kg) on ECM accumulation may be due to decreased TGF-β1 and ICAM-1 resulting from inhibition of the NF-κB pathway, as shown in a rat model of DN (Liu et al., a). Recent studies have shown that abnormal levels of β-arrestins, including β-arrestins 1 and 2, have a role in microvascular permeability by regulating the production and function of ICAM-1 and vascular cell adhesion molecule 1 (VCAM-1) in the kidneys of a rat model of DN (Noh et al., ; Zhang et al., ). Orally administration of 100 or 200 mg/kg berberine had renoprotective effects owing to decreased ICAM-1 and VCAM-1 levels and increased β-arrestin 1 and 2 in kidneys of a rat model of DN (Tang et al., ). Additionally, inflammation in the kidney is another aggravating factor renal vascular damage in DN (Moreno et al., ). Berberine may attenuate LPS-induced inflammation and extracellular matrix accumulation via the NF-κB signaling pathway (Jiang et al., ). Given its robust antihyperglycemic and anti-inflammatory activities, and its inhibitory effect on angiogenesis, berberine should be considered a candidate drug for DN (Table 5).
The intestinal mucosal microvasculature is located underneath the intestinal epithelial layer and accurately regulates the passage of molecules across the gut-vascular barrier (GVB) (Zhong et al., ). The rat cecal ligation and puncture (CLP) sepsis model was orally treated with berberine (25 and 50 mg/kg for 5 days) showed a protective effect on GVB function in sepsis through the reduction of gut vascular permeability and the suppression of WNT/β-catenin pathways (He et al., ). High-density lipoprotein (HDL) particles are related to apoprotein M (ApoM) which is the main carrier of plasma sphingosine-1-phosphate (S1P) (Tavernier et al., ). Though only a small proportion of HDL contains ApoM, ApoM-bound S1P is important in maintaining vascular integrity and inhibiting vascular inflammation (Galvani et al., ). In a model of polymicrobial sepsis, berberine removed damaged GVB resulting from TLR4-mediated hyperglycemia, insulin resistance and proinflammatory molecule production, thus enriching ApoM gene expression and plasma ApoM via activating the ApoM/S1P pathway (Li et al., b). A previous study showed that the neonatal small intestine is prone to necrotizing enterocolitis (NEC), a severe acquired disease characterized by inflammation (MohanKumar et al., ). However, these changes were notably reversed by treatment with berberine; the anti-inflammatory mechanism of berberine in this context may act via suppression of the PI3K/Akt pathway (Fang et al., ). Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and are a major cause of postsurgical morbidity (Tsai et al., ). In the normal healing process, ECM can be completely degraded by the proenzyme MMP (Altoé et al., ). Berberine prevented adhesion reformation, promoting the activation of MMP-3 and MMP-8 by directly blocking tissue inhibitor of metalloproteinase-1 (TIMP-1) activation in fibroblasts (Liu et al., ). To summarize, berberine can inhibit endothelial and gut vascular permeability, inflammation and adhesion reformation in intestine; it may act through several pathways, including the WNT/β-catenin, ApoM/S1P and PI3K/Akt pathway (Table 6).
Angiogenesis is a process in which new blood vessels form and grow from pre-existing vessels; this process occurs under healthy and pathological conditions, such as cancer (Fang et al., ). VEGF promotes angiogenesis in endothelial cells. Berberine has been shown to suppress angiogenic action, HUVEC proliferation and migration, by inhibiting VEGF, against cancerous Meth A cells and hepatocellular carcinoma (Jie et al., ; Yahuafai et al., ). VEGF-2 is a major mediator of the biological effects of VEGF, and therefore plays an important role in tumor angiogenesis (Sharaky et al., ). Berberine was shown to inhibit angiogenesis in glioblastoma xenografts by targeting the VEGFR-2/ERK pathway (Jin et al., ). In tumor development, chronic inflammation leads to a sharp increase in VEGF expression (Crusz and Balkwill, ). Elevated inflammatory cytokine levels and epithelial&#;mesenchymal transition in glioma cells were shown to be reversed by 100 μM berberine; the mechanism for this may be via suppressing ERK-1/2 signaling and production of IL-1β and IL-18 (Tong et al., ). VEGFR-3 in lymphatic endothelial cells were essential for the development of VSMCs (Antila et al., ). Clinically, elevated levels of VEGFR-3 are thought to be correlated with cancers resulting from metastasis via the lymph nodes, such as renal carcinoma (Guida et al., ). Following an inflammatory stimulus, the production of ROS by oxidative stress and energy deficit at mitochondrial, lysosomal, or ER loci can directly lead to irreversible damage of tumor cells and initiate cell apoptosis and autophagy (Reuter et al., ). Combined with photodynamic therapy, 20 μM berberine triggered metabolite changes in renal carcinoma cells, resulting in inhibited cell proliferation, tumorigenesis, and angiogenesis, and inducing autophagy and apoptosis via increased ROS generation (Lopes et al., ). Another study implied that 12-O-tetradecanoyl phorbol-13-acetate (TPA) significantly increased the level of VEGF and fibronectin in both MCF7 and T47D breast cancer cells (Kim et al., ). TPA-induced VEGF and fibronectin expression was decreased by berberine treatment, via inhibition of the PI3K/A pathway, in breast cancer cells (Kim et al., ). Taken together, these results show that berberine may effectively inhibit the proliferation and angiogenesis of tumor cells by inhibiting VEGF, ERK and PI3K/Akt pathways and promote the apoptosis of tumor cells (Table 7).
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that may involve angiogenesis, particularly during the earliest stages of the disease (Yang et al., ; Lyu et al., ). Angiogenesis is strictly regulated by several pro- and antiangiogenic factors including VEGF, which have been suggested to be involved in neovascularization in RA joints (Li et al., a). Berberine was shown to have anti-inflammatory and antiangiogenic effects in a rat model of RA by decreasing the level of inflammatory factors, and suppressing p-ERK, p-p38 and p-JNK activation (Wang et al., ). Additionally, it is reported that doxorubicin-induced vascular congestion and inflammatory cell infiltration in the liver were largely attenuated by berberine pretreatment (Zhao et al., ).
Berberine is a multifunctional, natural product with therapeutic potential in vascular diseases, including cardiovascular disease, atherosclerosis, hypertension, cerebrovascular disease, diabetes and associated complications, intestinal vascular disease and cancer (Zhu et al., ; Martini et al., ; Yin et al., ). The present review has shown the excellent protective effect of berberine in diverse vascular diseases by preserving vascular endothelial cells, improving vascular remodeling and vasoconstriction, and suppressing inflammation, oxidative stress, autophagy, and apoptosis, based on recent in vitro and in vivo experimental reports (Figure 2). Moreover, berberine also modulates the concentration of Na+, Ca2+ and lipid metabolism in the VSMCs (Table 4). What is more, the network diagram of &#;vascular diseases-target-pathways&#; was shown in Figure 5, and the underlying mechanism of berberine in the treatment of vascular diseases mentioned in this paper may be related to multiple pathways, including HIF-1α/VEGF, STAT, MAPK, NF-κB, SIRT, PI3K/Akt, AMPK and TRPV-4.
Pharmacokinetics is principally to quantitatively assess the absorption, distribution, metabolism, and excretion (ADME) properties of drugs within a living organism that determine the safety and effective of drugs. Berberine is widely distributed in multiple tissues and organs after entering circulation, and can still accumulate in plasma despite keeping a low-rise concentration (Han et al., a; Chen et al., ). According to our review, there are still many issues to overcome regarding the use of berberine to treat the vascular diseases. First, the bioavailability of orally-administered berberine in vivo is low due to first-pass elimination. It is therefore imperative to investigate alternative modes and methods of drug delivery with the aim of increasing the bioavailability of berberine. Numerous studies have showed that the strategic use of nanotechnology, including nanocarriers, liposomes, and microfluidic technology-assisted preparation methods, may increase the bioavailability of berberine for use in cardiovascular and metabolic diseases (Allijn et al., ; Guo et al., b; Dewanjee et al., ). Structural modification of berberine may also improve bioavailability and efficacy and reduce adverse drug reactions (Mbese et al., ; Luo et al., ). Han et al. (); synthesized, water-soluble berberine derivatives with modified 9-O-monosaccharide (administered at concentrations of 0.2, 1 and 5 μg/ml) were shown to have antidiabetic effects, with lower cytotoxicity and a half-maximal inhibitory concentration (IC50) nearly 1.5 times than that of unmodified berberine in HepG2 liver cancer cells. Additionally, this review found that the toxicity of berberine and its derivatives have been rarely investigated. Considering the long-term development for berberine prevention and treatment of vascular diseases, comprehensive toxicity investigations, especially potentially cumulative toxicity in vivo studies, need to be carried out. It is also necessary to explain the efficacy and toxicity of berberine for use in human pharmacokinetic studies, and the identification of the ideal dosage are of enormous significance if side effects associated with drug accumulation are to be avoided. Relatively newly developed biological techniques, including microfluidic technology, computational toxicological methods, hepatoid cell models, and high-throughput chip models, could be employed to explore the toxicity of berberine (Banerjee et al., ; Kimura et al., ). In addition, single-cell in vitro models, as reported in the literature reviewed here, may not adequately reflect the pathogenesis of diseases in vivo. A multi-organ in vitro model based on microfluidic technology may be more helpful models of vascular diseases for the evaluation of the safety and efficacy of berberine (Rothbauer et al., ; Malik et al., ). For the clinical trial of berberine on vascular disease, many factors limit its clinical application, including the low methodological quality and drug&#;drug interactions (Imenshahidi and Hosseinzadeh, ). Therefore, the development of a standardized dosage, administration route, duration and adverse reaction of berberine could also be pursued in clinical settings for better therapeutic efficacy and safety.
Concurrently, we should strengthen the mechanism of berberine in the treatment of vascular diseases. Novel technologies that could be employed to explore the mechanism of action of berberine in the treatment of vascular diseases include CRISPR&#;CAS-9 gene editing, metabolomics, proteomics, and genomics. Most importantly, recently published investigations of the pharmacological mechanisms of berberine may provide new insights into the treatment of vascular diseases by berberine. For example, Zhao and others demonstrated that 560 mg/kg berberine administered orally in Coptis chinensis can significantly increase insulin secretion via the potassium voltage-gated channel subfamily H member 6 (KCNH-6) potassium channel in mice with HFD-induced hyperglycemia (Zhao et al., a). Overall, this study comprehensively reviewed and summarized the pharmacokinetics properties and therapeutic potentials of berberine in diverse vascular diseases, thus providing experimental evidence for future research to discover novel drugs from Chinese medicine monomers.
XM, FL, and XA conceived the study; XA, PY, LL, SL, and XL collected, analyzed, and interpreted the relevant literatures; XA, LP, and JL drew all the figures and tables; XA wrote the manuscript; XM and FL supervised the study and revised the manuscript. The final version of the manuscript was read and approved by all authors.
This work was supported by the National Natural Science Foundation of China ( and ), the National Key R&D Program of China (YFC), the Regional Innovation and Cooperation Project of the Science and Technology Department of Sichuan Province (YFQ), the Major Science and Technology Project of Sichuan Science and Technology Department (YFSY), and the Key R&D and Transformation Program of the Science and Technology Department of Qinghai Province (-SF-C33).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Articles from Frontiers in Pharmacology are provided here courtesy of Frontiers Media SA
Nine of the top ten causes of death in the United States in were diseases. Preventable diseases kill hundreds of thousands of people annually and cause years of pain and suffering for hundreds of thousands more. About 10% of Americans have type 2 diabetes, and nearly half of all American adults have some form of cardiovascular disease, according to a report.
Berberine, a golden yellow compound found in several plants, might play a role in preventing or slowing the progression of both heart disease and diabetes, among several other medical conditions. In this guide, we&#;ll investigate the pros and cons of adding berberine to your daily diet, explore the safety and quality measures of different supplements, and spotlight our top eight picks for the best berberine supplement in .
If you&#;re in a hurry, check out our top recommendations below.
Not every herbal supplement is created equally, and there can be a lot of misinformation out there. We&#;ve spent over 70 hours researching berberine to gain a thorough understanding of what this supplement is, how it works, and how it can be beneficial. We also took note of who would not be a good candidate for taking berberine. For this guide alone, we read over 50 scientific studies analyzing the efficacy of berberine supplementation and put this information to use when considering our top product recommendations.
Like all health-related content on this website, this review was thoroughly vetted by one or more members of our Medical Review Board for accuracy. We&#;ll keep an eye on the latest science and evolving product options for berberine supplements to ensure this guide stays up-to-date.
Over the past two decades, Innerbody Research has helped tens of millions of readers make more informed decisions to live healthier lifestyles.
We considered three major criteria when comparing berberine supplements: product safety, efficacy, and cost.
Since supplements aren&#;t regulated by the Food and Drug Administration (FDA) the same way that food and prescription medications are, it&#;s essential that companies do the right thing and are thorough with product testing. We consider product safety and transparent testing to be the highest priority.
While almost all of our top picks had the same effective main ingredient (berberine hydrochloride (HCl)), there were a couple of products that stood out for their potent formulas and addition of elements that may significantly aid with berberine absorption. These products have exciting potential, but we also consider possible downsides to a highly potent supplement &#; if a formula is potentially stronger and not as well studied, research becomes less predictive, and negative side effects could outweigh health benefits. Instead, at this time, we reserve our highest recommendation for a form and dosage that are most supported by current research.
Cost is also an important consideration, but we found that because the price of berberine supplements didn&#;t vary too significantly per milligram (and almost all of our top picks offer savings through subscription programs and free shipping), the other factors at play were more crucial.
Winner: Double Wood
While berberine has many powerful benefits, it also has some drawbacks. It can be rough on the digestive system, and there haven&#;t been many studies on its long-term safety. A berberine supplement that&#;s been through extensive third-party testing will be safer than most. Likewise, we look to ensure it was manufactured in a facility that is compliant with Good Manufacturing Practices (GMP or cGMP) and registered with the FDA.
Double Wood makes its GMP-compliant facility status known right off the bat, and the company includes links to both a certificate of analysis and third-party testing results near the top of the berberine supplement&#;s webpage. These results back up the company&#;s ingredient claims on the label, instilling confidence that you&#;re receiving the berberine you seek. This is especially important considering that one study found that 60% of berberine supplements do not meet the 90-110% potency standard of what is printed on their label.39 Double Wood clearly explains how often you should take the supplement to avoid the worst side effects and provides allergen notices, contraindications with other medications, and other safety tips. While other companies in our top picks also perform rigorous testing, we liked Double Wood&#;s easy-to-locate results, combined with its competitive pricing and free shipping.
Winner: Double Wood
We consider the method of administration, effective dosing, and other ingredients that could improve efficacy. An effective supplement should deliver the benefits we want to see without completely undermining safety or affordability. We found that most clinical research has demonstrated that doses of 500-1,500mg of berberine daily provide therapeutic benefits.12 Common side effects of taking too much berberine can include nausea, bloating, diarrhea, or constipation, so we recommend taking a supplement that allows you to safely stay within this dosage range.
Double Wood comes in 500mg capsules, allowing you to easily adjust your dosage if you find yourself experiencing gastrointestinal distress. Clinical research has reliably shown that berberine is extremely difficult for the body to digest. Less than 1% of all berberine that we take orally ends up circulating in our bloodstream.40 And while some other formulas in our top picks, like those from Toniiq and Renue by Science, boast greater potency or absorption, we like that Double Wood allows you to stay consistent with dosing that has been studied the most; there&#;s no guessing how much you are really absorbing from each capsule. Also, the company&#;s certificate of analysis on the webpage is current and demonstrates that its dosage claims are accurate.
Winner: Puritan&#;s Pride
Determining the cost of a supplement requires more than looking at the listed price. Subscription or bulk deals, shipping costs, the number of servings, and the price per serving of a supplement all determine how much you&#;ll pay. We also consider a supplement&#;s customer service policies for things like returns when evaluating a supplement&#;s cost, so you can rest assured knowing you can get your money back in case it doesn&#;t agree with you.
Puritan&#;s Pride has centered its brand on its unique way of getting you low prices, and the company&#;s berberine supplement is no exception. For every bottle you purchase, you&#;ll get two of the same size for free. While it looks like Puritan&#;s Pride charges roughly as much as competitors, slicing this price into thirds reveals excellent savings. You can join its subscription program for an additional 5% off, and the company has one the longest return windows on our list at 90 days. There are tradeoffs that come with the lower price tag, but if you&#;re on a tight budget and don&#;t have a kitchen scale for measuring powders, Puritan&#;s Pride is a solid pick.
To help you break down the differences between our top products, we&#;ve put together a chart mapping all of their most important features. Check it out below.
Berberine is an alkaloid found in the roots, bark, and other structures of many plants, including the Oregon grape (Mahonia aquifolium), goldenseal (Hydrastis canadensis), Indian barberry (Berberis aristata), and European barberry (Berberis vulgaris). It has a long history of therapeutic uses in Ayurvedic and traditional Chinese medicine and an equally expansive list of potential benefits within the framework of contemporary medicine.
Berberine has both antimicrobial and anti-inflammatory properties. It may play a role in defending the body against harmful bacterial overgrowth and even promote growth of beneficial organisms in the gut microbiome, which in turn affects a variety of disease processes.2 While there is still much to uncover in terms of the mechanisms of how exactly berberine works, researchers do know it impacts a host of medical conditions, such as:
A literature review even discussed berberine&#;s potential for antitumor effects against a few types of cancer.13 However, at this time, the most extensive research has revolved around berberine&#;s impacts on diabetes and cholesterol management.
Most of berberine&#;s physiological effects are still under investigation, but let&#;s take a look at some of its most recognized mechanisms of action.
Berberine activates AMP-activated protein kinase (AMPK), the primary enzyme that monitors and regulates our cellular energy levels. Increasing the amount of AMPK in our bodies gets nutrients where they need to be, effectively controlling our metabolism. This process of AMPK activation is the link to berberine&#;s benefits for diabetic patients, as well as other conditions like obesity and high cholesterol. AMPK is thought to be a tumor suppressor, too, essentially starving cells while they attempt to form cancerous tumors (though after cancer has developed, AMPK can sometimes promote tumor growth instead).14
We know that berberine has long been used as an antimicrobial agent in traditional Chinese medicine. But exactly how this compound is effective hasn&#;t been explored until more recently. A study investigating berberine&#;s antimicrobial properties found that it slows bacterial metabolism, stops them from creating new cell walls and amino acids, and lowers their antioxidant levels.15 Historically, berberine has been used to treat diarrhea from both bacterial infections and noninfectious conditions.16 (Ironically, diarrhea and stomach pain are sometimes side effects when you start taking berberine.) Much of the research on berberine&#;s impact on intestinal and gut microbiome health is still in progress, but studies have backed up the anecdotal evidence that berberine may be a potent anti-diarrheal agent.2
Berberine&#;s anti-inflammatory effects come into play through the modulation of multiple signaling pathways. In this regard, most studies look at berberine&#;s effects on non-alcoholic fatty liver disease, but inflammation is also a critical part of conditions like heart disease and diabetes.12 17 Notably, a meta-analysis found significant reductions in CRP (C-reactive protein, a major marker of inflammation) in patients taking berberine.18
One of the few things we can almost conclusively say berberine supports is diabetic care. Specifically, it improves HbA1c levels (an indicator of long-term blood sugar control) and insulin resistance (meaning your cells can use insulin more effectively, leading to less glucose storage and lower blood glucose levels).19 According to a animal study, berberine supplementation can slow the progression from prediabetes to type 2 diabetes.20 Some studies also suggest that taking berberine in addition to prescription medication like metformin could result in greater glycemic control, but more definitive research is needed to support this theory.21 It&#;s worth noting that berberine could potentially be a good alternative for those that can&#;t take diabetes medication due to liver, kidney, or heart disease.
Another significant benefit of berberine is its protection against heart disease.22 While we don&#;t know for sure if it can stop heart failure, we do know that it can decrease the likelihood of:
Berberine plays a role in decreasing total cholesterol, LDL cholesterol, and blood triglycerides while increasing HDL cholesterol.24 25 It also lowers high blood pressure, supporting good heart health from every angle. The positive impacts berberine has on obesity and blood sugar could also work hand-in-hand to help prevent heart disease. And interestingly, berberine appears to have an anti-apoptotic effect on heart cells, which can keep the cells from dying prematurely.
Berberine dosages have not been formally established, but clinical studies use a dose range between 500mg and 2,000mg daily. However, one study found that high cholesterol levels start to improve at 300mg daily.26 Berberine has a relatively short half-life, so most people report seeing success with three 500mg capsules daily (1,500mg total).
Generally speaking, berberine is a safe supplement for healthy adults. There aren&#;t a lot of side effects associated with berberine at the aforementioned doses, but you might experience some stomach upset when getting started. Specifically, berberine can cause:
The company is the world’s best Berberine Hydrochloride Exporter supplier. We are your one-stop shop for all needs. Our staff are highly-specialized and will help you find the product you need.
The more berberine you take, the more likely you are to experience these side effects. Higher doses also mean you might feel stronger side effects for a longer time. If you know you have a sensitive stomach, starting on a low dose of berberine and slowly increasing how much you take over time might make sense. As with any supplement, talk to your doctor before adding berberine to your daily regimen.
There aren&#;t many studies looking at how well berberine works long-term, nor are there many investigating any potential safety hazards associated with taking berberine for years. Some of the longest-running studies looked at berberine as a dietary supplement for colorectal cancer over two years and found only a few adverse reactions, but pay attention to your body.27 Because we don&#;t know what could happen, taking berberine long-term is not typically recommended.
Berberine is an herbal supplement that the FDA doesn&#;t regulate the same way as food and prescription medication. It can&#;t be used to diagnose, treat, cure, or prevent any diseases, including type 2 diabetes, high cholesterol, insulin resistance, and everything else that research explores but hasn&#;t confirmed. Always talk to your doctor before trying a new supplement, and don&#;t stop taking prescription medication to try berberine without their approval.
Berberine interacts with several liver enzymes called cytochromes (specifically CYP2D6, CYP2C9, and CYP3A4, all of which come from cytochrome P450). These enzymes break down medications and help our bodies build cholesterol and certain steroids. While berberine isn&#;t the only supplement that interacts with cytochrome P450, it&#;s important to note because it can influence how much of your prescription medication gets absorbed. If your medication has a warning not to eat grapefruit while taking it, you shouldn&#;t take berberine with it either. (This is why it&#;s essential to check with your doctor before starting berberine, as the list of potential cytochrome P450 interactions is quite long.)
Several other medications interact poorly with berberine. These include:
If you have diabetes and take insulin, be careful while taking berberine. Since it can lower your insulin resistance, you might need to use less insulin than before to stabilize your blood sugar. Keep an eye out for low or dropping blood sugar levels, as hypoglycemia can be extremely dangerous. It&#;s best to check in with your endocrinologist beforehand if you want to try berberine supplements.
Berberine is particularly unsafe for pregnant and lactating individuals. Babies and fetuses that ingest berberine are more likely to have jaundice &#; a condition in which the liver doesn&#;t function as expected, leading to a buildup of bilirubin and jaundice&#;s hallmark yellow skin. This could lead to jaundice-induced brain damage called kernicterus, a rare disorder in which bilirubin is deposited in the brain, leading to vision and hearing loss which may be permanent. Likewise, children under 18 should not take berberine supplements.
Best overall
Double Wood creates a simple and high-quality berberine supplement. There isn&#;t much to it, but there doesn&#;t have to be. Double Wood combines the best traits of a successful supplement &#; a relatively low cost, transparent testing and safety measures, and a dose high enough to make a difference in small enough capsules to provide flexibility.
Each capsule contains 500mg of pure berberine HCl, and on its website, Double Wood encourages you to take anywhere from 2-4 capsules daily, each three hours apart with food. Following these instructions, you might find that a bottle lasts anywhere from two weeks to one month since there are 60 capsules in every bottle.
However, the product label on the bottle states to simply take one 500mg capsule daily. This discrepancy is confusing, and while 500mg of berberine may be enough for some, most research studies use doses closer to what the Double Wood website suggests. It&#;s also a little misleading when it comes to how many servings are actually present in a bottle of Double Wood berberine. Despite this, the company&#;s pricing is still competitive per serving. If you think you&#;ll need closer to 1,500mg of berberine daily, we&#;d recommend purchasing the Double Pack, which ships two bottles of berberine at a slightly reduced price.
One of the biggest reasons that Double Wood stands out as our top pick for berberine supplements is its commitment to transparency. You won&#;t have to look far to find out that it was made in GMP-compliant facilities in the U.S., and its allergen notice is prominently displayed. The company also links directly to a current certificate of analysis and independent third-party testing results on the webpage, revealing that its berberine capsules contain exactly what is claimed on the label. Currently, each capsule contains berberine, hypromellose (veggie capsule), and silicon dioxide (a common anti-caking agent). This is slightly different from the previous formula, which included berberine with just microcrystalline cellulose. If one of your goals is avoiding additives, and you have a kitchen scale handy, PureBulk might be a better fit for you.
Double Wood sells its berberine capsules at several different price points depending on the number of bottles you&#;re ordering and whether or not you&#;re joining the subscription program. Double and triple packs have a bigger discount up front, but you&#;ll save less per order when joining the subscription program (10% as opposed to 15% for a single bottle). Ultimately, you do still save a significant amount by bundling or subscribing &#; or both. We&#;ve put together a quick chart to help you figure out how much you&#;ll pay.
Subscriptions are all processed through the third-party service Recharge. You can choose how frequently you&#;d like to have a new bottle delivered:
All orders ship for free from Double Wood and generally arrive within five to seven business days. If you aren&#;t happy with your berberine supplement, you can get a refund even if you&#;ve already opened the bottle. After placing the order, you&#;ll have 30 days to initiate a refund, and you&#;ll need to ship the bottle back whether or not you&#;ve opened it. Despite the company&#;s free shipping policy, you will need to pay for return shipping yourself. Double Wood will still accept refunds after the 30 days are up but won&#;t guarantee it; after 30 days, Double Wood will provide refunds only at its discretion. While this return policy isn&#;t as long as some of our other top picks &#; like Puritan&#;s Pride or PureBulk, which offer 90-day policies &#; we appreciate that Double Wood will accept a return even if the product has been opened.
Best budget pick
Each bottle of Puritan&#;s Pride&#;s Berberine contains 60 capsules of 500mg berberine sourced from Indian barberry. However, because you get bottles in sets of three for every order, Puritan&#;s Pride&#;s berberine capsules allow for much more flexibility in your dosing schedule. You can take anywhere from 500mg to 2,000mg daily without worrying about whether or not you&#;ll run out in less than a month.
Puritan&#;s Pride also offers berberine mixed with several other ingredients (such as turmeric and black pepper, cinnamon, and silymarin), so you can pick a combination that&#;ll support your specific health goals if you&#;re focused on decreasing inflammation, increasing metabolism, or supporting liver health.30 However, we think that pure berberine capsules are best for most people.
We confirmed that Puritan&#;s Pride berberine supplements are vegan-friendly, and a small amount of vegetable magnesium stearate and silica are included, which are common fillers. This won&#;t hurt your health, but if you&#;re looking for a completely clean supplement, this one might not quite fit the bill.
All Puritan&#;s Pride supplements are manufactured in GMP-certified facilities and tested multiple times throughout their creation. However, the company doesn't specify whether the supplements are tested in-house or by independent third parties and doesn&#;t provide any test results. This is somewhat disappointing; transparency is key when looking for a health supplement since they aren&#;t closely regulated by the FDA. If safety is essential in your decision-making process, you may wish to consider another option on our list, such as Double Wood or Toniiq, which provide testing results right on their product websites.
Puritan&#;s Pride uses one of the most unusual pricing strategies in the field. Every single order &#; no matter what it is you&#;re getting &#; comes in sets of three bottles. The company has increased its prices by a few dollars since our last review, but thanks to its bulk deals, these supplements are still our top budget pick. The chart below lays out exactly how much you&#;ll pay in different circumstances.
Joining the subscription program saves you only 5%, but it does unlock free shipping for orders of $30 or more. Otherwise, you can get free shipping when purchasing $49 or more of Puritan&#;s Pride products. If you don&#;t quite meet that $49 requirement, you&#;ll be charged $4.95, and some U.S. states and territories are subject to an additional $5.99 surcharge.
You can try Puritan&#;s Pride&#;s berberine supplement risk-free. Puritan&#;s Pride offers a 90-day money-back guarantee, meaning that you can try it and return it as long as it&#;s within three months of purchase. That said, you can&#;t have tried all three (or six) bottles; if you opt for a return, Puritan&#;s Pride will only offer a full refund if just one bottle has been opened. However, you&#;ll need to include them all in a return package when you send the product back.
If you&#;re curious about what the rest of Puritan&#;s Pride catalog holds, check out our full review.
Best powder
Taking a supplement capsule (or three) every day isn&#;t for everyone. For those who dislike swallowing pills or who want to avoid additives, PureBulk offers an additive-free Berberine HCl powder that makes it easy to consume berberine in the way that you prefer. Also, you might know that you love berberine and want to buy it in bulk without paying hand over fist. This is where PureBulk excels: you can buy its Berberine HCl powder (made exclusively from Phellodendron amurense bark) in six different sizes, from 25g all the way up to 1kg.
There are downsides to this approach. You&#;ll have to do the math to figure out how many servings are in each bag of powder, but PureBulk recommends you take 500mg daily. You&#;ll also need to have a kitchen scale or an extremely accurate scoop at the ready to ensure you&#;re taking a consistent amount every time. This can be inconvenient and requires you to use caution in order to avoid unwanted side effects from taking too much. However, because it&#;s a powder, you can personalize your dose to exactly the right amount that works for you.
All PureBulk products are made in GMP-certified facilities and are independently tested by a qualified third-party laboratory. If you want to read the test results, PureBulk provides a link for you to request a copy of the certificate of analysis.
PureBulk offers its berberine supplement in ten sizes and three forms, so you can get as much &#; or as little &#; as you need. These include:
We noticed that PureBulk has increased its prices in all sizes since our last review, with a change of just a dollar or two in the smaller quantities but more significant changes in the larger quantities (like $297 vs. $270 for the 1 kg option). PureBulk also offers a true bulk option of 15kg for $2,244.55. This berberine powder comes in a large drum and is best suited for situations where you&#;re sharing your berberine with many other people. (15kg will likely start to lose its efficacy before you can finish it yourself.)
Because the company sells its berberine powder in such large quantities, PureBulk doesn&#;t offer any subscription programs. And while PureBulk can accept PayPal as a payment method for many of its items, if you&#;re buying berberine, you&#;ll have to use a debit or credit card.
If you&#;re in the military, a teacher, or a first responder, PureBulk offers a 15% discount. You&#;ll need to verify your identity through VerifyPass, a third-party platform, and upon approval, you&#;ll get a one-time discount code valid for 24 hours. You&#;ll need to repeat this process to get another code each time you shop with PureBulk.
PureBulk offers free shipping on orders over $49 going to the United States unless your order contains a bulk tub (20kg or 25kg) or a heavy parcel (3kg or more per individual item or 10kg total) going to Alaska or Hawaii. Otherwise, shipping costs vary depending on where you live and how much you&#;re purchasing.
If you decide berberine isn&#;t right for you (or find out you don&#;t have a kitchen scale as you thought), you have 90 days from when it first shipped to return your powder or capsules to PureBulk. This is one of the most generous return policies we&#;ve found among our top berberine picks, alongside Puritan&#;s Pride and Renue By Science. However, be aware that for a full refund, the berberine must be returned unopened, and you&#;ll need to pay for return shipping. The company does consider refunds for opened products; in that case, it will issue a refund equal to the cost of the smallest size it offers in that particular product. Returns for bulk orders are not accepted.
Most potent
Known mostly for its excellent NAD+ supplements, Renue By Science steps out of its usual arena with LIPO Berberine. This supplement adds sunflower lecithin as a liposomal barrier &#; two phospholipid layers arranged in a sphere &#; to a traditional berberine supplement. Because the human body uses phospholipid bilayers to create our cells, it notices, bonds to, and processes the liposomal supplement much faster and more effectively than if it just went through your digestive system.
This liposomal technology is particularly important for a berberine supplement. Less than 1% of any given oral berberine supplement gets put to use in the body, but a animal study showed that liposomal berberine is stored, absorbed, and used 16 times more than berberine on its own, meaning that there could indeed be more of it to help you for longer.1 31 In theory, your body will get more use out of this berberine supplement than alternatives, although more (human) clinical studies are needed to back this claim up.
The dose you'll find in each serving of LIPO Berberine is considerably less than competitors. Each capsule (equivalent to one serving) only contains 150mg of berberine. You can triple the dose (to 450mg) and still only need to order one bottle a month since there are 90 capsules per bottle. Still, the increased absorption from its liposomal format means it&#;s harder to pin down exactly how much of it you&#;re getting and using.
When you consider the results of the animal study mentioned above, there&#;s a chance you are absorbing a significant amount more berberine than in another supplement. If you assume that the animal study accurately predicts the greater absorption rate in humans, then a 150mg dose of LIPO Berberine might be equivalent to something like 2,500mg of traditionally formulated berberine HCl, which is a high dose. While there is potential for taking fewer capsules per day due to the increased absorption, there&#;s no way to divide that 150mg dose into something smaller. This brings up the concern of possible negative GI side effects. If you would rather take a supplement with a higher berberine content and less of a guess as to how much you are absorbing, an option like Double Wood or Puritan&#;s Pride (both have 500mg capsules) might be a better fit.
Renue By Science is transparent with its testing and quality assurance. The company includes a copy of the certificate of analysis directly on the webpage. Without having to ask, you can see exactly how an independent third party scored LIPO Berberine &#; and, interestingly, the batch at the time of writing contained 167mg per capsule, 17mg more than is listed on the label.
Renue By Science only sells LIPO Berberine in one size and form: a bottle of 90 capsules for $49.95. The company doesn't offer any bundle deals but has added a subscription program since our last review. You can save 5% if you subscribe and can choose to have your product delivered every one, two, or three months.
If you order more than $50 &#; by adding literally anything else from the catalog alongside one bottle of LIPO Berberine &#; you&#;ll unlock free USPS First Class shipping to the United States. Renue also offers free shipping to the United Kingdom and Australia (orders over $89), as well as most other countries (orders over $250). If you don&#;t want to add anything else to your purchase, there&#;s a flat shipping charge:
Renue By Science will not ship to Mexico, Spain, Russia, Ukraine, or the United Arab Emirates, but it will send its products to any other country.
The website is not clear on the company&#;s return policy but states that it guarantees 100% customer satisfaction. After reaching out to the company&#;s customer support, we were told that there is no defined return window and that any unopened product can be returned for a refund. We suggest contacting the customer support team via or live chat if you have questions regarding your purchase. But given the uncertainty about the greater absorption of liposomal berberine, you won&#;t know how it makes you feel until you try it.
Runner-up for best overall
A study found that 60% of tested berberine supplements failed to meet the potency standards of 90-110% of what is claimed on the label.39 Toniiq uses an extraction process that aims to ensure a highly purified product. Toniiq&#;s Berberine 97% is produced from Himalayan Berberis aristata root (Indian barberry). Each serving contains a scientifically supported dose of 500mg, and the company claims it is an 82:1 concentrated product, promising to deliver more of the berberine that you are seeking. Something to consider is whether or not such a highly concentrated product would be more likely to cause some of the undesirable GI side effects of berberine. If you know you are sensitive to berberine, you may want to keep that in mind when considering your options. The uncertainty here is partly why Toniiq didn&#;t become our overall top pick for most people.
One downside is that while the berberine is thoughtfully sourced for purity, the capsules themselves do contain some additives (microcrystalline cellulose, vegetable magnesium stearate, and silicon dioxide). While none of these additives are unusual, there are other options out there if you are seeking a 100% berberine, additive-free product, such as the PureBulk Berberine HCl Powder.
We like that Toniiq products are made in a cGMP- and NSF- certified lab and that the company is transparent about its testing protocols. It utilizes a randomized third-party testing program and has a certificate of analysis for every lot produced. The berberine certificate of analysis is available and easy to find on the product page, and the company is willing to share third-party lab results upon request.
Toniiq&#;s Berberine 97% comes in just one size option, a 90-capsule bottle for $24, which is one of the more affordable options among our top picks. (Our top budget pick, Puritan&#;s Pride, is $0.20 per serving versus Toniiq&#;s $0.27 per serving.) A serving size is one 500mg capsule, but the suggested use is one capsule up to three times a day. This means one bottle can last you anywhere from one to three months, depending on your preferred dosing schedule.
Toniiq offers a subscribe and save program that allows you to save 15%. You can choose between 30-, 60-, or 90-day delivery. The company also offers a 60-day money-back guarantee &#; refund requests are limited to three individual products and must be after two weeks of use. Toniiq doesn't require you to ship the product back if you decide it&#;s not going to work for you; instead, it asks that you pass it on to someone else who might benefit from using it.
The biggest downside with Toniiq (and the chief reason why it is only the runner-up for best overall berberine supplement) is its shipping policy. The company only offers free shipping for purchases over $99, which is pretty steep. So unless you are stocking up on multiple supplements or several bottles of berberine, you will be absorbing the shipping cost. We found that orders are shipped via USPS, DHL, or UPS, depending on your location, and the cost is not a flat rate. Our reviewer&#;s shipping cost was $13, so it&#;s definitely something to consider when exploring your berberine options.
Best organic
Oregon grape root is one of the best plant sources of berberine. It&#;s widely used in oral and topical formulas, addressing everything from an upset stomach to irritation-related rashes. Oregon&#;s Wild Harvest bundled Oregon grape root into a capsule to capitalize on the plant&#;s berberine content, providing you with a supplement made exclusively from natural sources.
Each plant-sourced capsule contains 1,140mg of organic Oregon grape root and nothing else. You&#;ll need to take three capsules daily for one serving, and there are 30 servings (90 capsules) per container.
The biggest downside of this supplement is that there&#;s no listed berberine content. Similar plants like barberry and goldenseal have anywhere from 0.5% to 13% berberine, putting the estimated berberine range per serving between 5mg and 150mg. This is a wide range and also a relatively low dosage, but you may find that other antioxidants and phytochemicals in the Oregon grape root make up the difference. Oregon&#;s Wild Harvest is aware of this flaw and has said that the company is actively working on testing and measuring the berberine content per serving. If you would prefer to know exactly how much berberine you are consuming in a clean formula, our other top pick that doesn&#;t contain additives (PureBulk) might be a better option for you.
Oregon&#;s Wild Harvest performs every step of the manufacturing process in-house, from growing the herbs and packaging to testing and shipping. While it does not appear that the company uses third-party quality testing, it does verify quality and potency on every batch and processes its herbs in facilities compliant with USDA standards.
These Organic Oregon Grape Capsules are sold in one size, containing 90 capsules (30 servings). You can purchase it as a one-time order or join the company&#;s subscription program to save 15% on every order. For each bottle, you&#;ll pay the following prices:
With the subscription program, you can choose exactly when you want your new bottle delivered and how often. You can also skip refills and cancel the subscription altogether with little hassle. You can choose your delivery frequency to be every 1, 2, 3, 4, 8, 13, or 26 weeks, depending on your needs.
Free shipping kicks in when you spend $50 or more. If you&#;re just looking for one (or two) bottles of Organic Oregon Grape Capsules, you&#;ll be charged depending on how much you order and where it&#;s shipping. On average, expect to pay about $6 in shipping (slightly less if you live on the West Coast and slightly more if you live on the East Coast).
If you aren&#;t happy with your order, you can return it for a refund or exchange it within 60 days of purchase. But the amount you&#;ll get back (or in credit) depends on the quantity you return unopened; if you want a full refund, send your supplements back unopened in the original container.
Nutricost has an extensive catalog and a history of well-performing supplements. The company&#;s Berberine Capsules continue this trend, offering 600mg of Indian-barberry-derived berberine in every capsule. The serving size is two capsules, giving you a dose of mg of berberine. However, when the cost is broken down, at $0.90 per mg serving, Nutricost is not quite as cost-effective as some of our top picks. For example, Toniiq Berberine 97% is $0.27 per one 500mg serving, and some quick math tells us that a mg dose (equivalent to Nutricost) would be just $0.65.
This berberine supplement also includes silica, magnesium stearate, and microcrystalline cellulose, so if you&#;re looking for a completely clean supplement, you may want to look elsewhere. However, these ingredients are relatively common in supplements, so it&#;s not anything alarming; instead, it just means there&#;s a little more than just berberine inside.
Nutricost&#;s supplements are all manufactured in a GMP-certified facility and are tested for purity, potency, and quality by a third party, although the certificates are not readily available, unlike some of our other top picks.
Nutricost berberine was formerly our top pick for most potent due to its 600mg-per-capsule dosing. However, Nutricost is eclipsed by Renue by Science, thanks to its liposomal formula and subsequently more robust absorption. If a person absorbs one percent of Nutricost&#;s 600mg dose, that&#;s 6mg absorbed. But if clinical research is a valid indicator and the liposomal berberine from Renue by Science does indeed absorb at a rate 16 times higher than average berberine absorption, then the smaller 150mg dose from Renue by Science would result in absorption of 24mg of berberine (four times the amount you get from a dose of Nutricost). Nutricost also fell down the ranks due to its pricing per dosage and apparent change in return policy from a 90-day to a 60-day time window.
Like its other supplements, Nutricost keeps its berberine purchasing options simple and streamlined; the company only offers one size bottle containing 30 servings for $26.95. Since our last review, Nutricost has added a subscribe and save option, allowing you to save 15%. The subscription is run through Recharge, a third-party service that allows you to choose exactly when you want your new bottle delivered and how often. You can also skip refills and cancel the subscription altogether with little hassle. All subscriptions automatically refill once a month, but it&#;s easy to space it out (or push deliveries closer together) depending on your needs.
You can get free shipping in the U.S. if you order $59 or more worth of Nutricost products. Otherwise, standard shipping costs $7; prices vary for international orders. And if you aren&#;t happy with your berberine capsules, reach out to Nutricost to get your refund started. You can get your money back (minus the cost of shipping and handling) within 60 days of purchase.
Thorne&#;s Berberine (formerly known as Berberine-500) is a clinically refined, potent berberine supplement. One serving of Thorne&#;s berberine is two capsules containing a total of 1,000mg of berberine from Indian barberry extract. Each bottle holds 60 capsules (30 servings). This provides flexibility while ensuring you&#;ll have enough berberine to get you through the month. That said, if you anticipate needing more than 1,000mg daily, you may want to order more than one bottle at a time or join Thorne&#;s subscription program.
Thorne also offers a second berberine supplement for those who need less than 1,000mg per serving. Berberine-200 (formerly Berbercap) offers 60 capsules of a 200mg dose with the same high quality at a slightly lower price ($25). However, it is worth noting that Berberine-200 contains slightly different ingredients, including leucine, and would not be appropriate for vegans.
Though not labeled as such, the 500mg berberine supplement option has no additional animal-based ingredients (just a hypromellose capsule and calcium laurate), making it vegan-friendly. It&#;s also gluten-, dairy-, and soy-free. Thorne uses NSF and cGMP-certified facilities to manufacture its berberine supplements. Thorne was the first supplement manufacturer from the United States to earn an A rating from Australia&#;s Therapeutic Goods Administration, which is well known for having some of the highest standards in the world. All Thorne supplements are rigorously tested in-house four times at various stages of manufacturing, although test results are not readily available on the product website.
One bottle of Thorne&#;s Berberine Capsules costs $38 if you purchase it once. This breaks down into a steep $1.27 per serving, even though you are getting 1,000mg per dose. In comparison, our top budget pick, Puritan&#;s Pride, is only $0.20 per 500mg serving, which equates to $0.40 per 1,000mg. However, you can unlock savings by joining Thorne&#;s subscription program. You&#;ll save 10% on each item and 20% on subscription orders containing three or more products. However, those subscription savings only kick in after your first order. We&#;ve put together a chart below to clarify how much you&#;ll pay.
You can set up your subscription to send you a new bottle every:
Thorne offers free shipping to all orders within the contiguous United States. Orders shipping to Alaska or Hawaii and international orders can expect a steep variable shipping fee. And if you aren&#;t satisfied with your berberine capsules for any reason, you can return them within 60 days of purchase for a full refund.
In addition to its impacts on diabetes and its antimicrobial properties, some of berberine&#;s greatest assets lie in its effects on heart health and inflammation. But despite its far-reaching potential health benefits, taking a berberine supplement may not be right for everyone. We&#;ve laid out some alternative options to berberine if you are seeking out a different answer for these issues.
There is much research supporting berberine&#;s positive impacts on heart health, but luckily, there are several other options out there, too, if berberine isn&#;t right for you. Omega-3 fatty acids have anti-inflammatory properties, are known to lower triglyceride levels, and are easy-to-find supplements. You can also consume omega-3s in foods like fish and nuts; a healthy diet is one of the best things you can do for your heart health. Check out our guides on fish oil and krill oil if an omega-3 supplement sounds like something you might be interested in.
Coenzyme Q10 (CoQ10) is a naturally occurring enzyme and another popular supplement that can help prevent heart failure with long-term therapy.42 CoQ10 is also sometimes used to treat side effects from statins (which can lower the amount of CoQ10 the body makes). Folic acid is another supplement you can take that has strong evidence for heart benefits. This B vitamin helps to break down homocysteine, a known risk factor for heart disease.
Inflammation is at the root of many chronic diseases. Berberine appears to have benefits for many health conditions, like heart disease and obesity, and some believe that its anti-inflammatory effects are responsible. However, if you can&#;t tolerate berberine or are looking for another solution, there are many other options out there for you.
Similar to heart disease, one of the fastest and easiest ways to fight inflammation is through your diet. Refined carbohydrates, sodas, margarine, and red meat are known to be more inflammatory foods. Adding foods like berries, avocado, green tea, and fish to your diet can be a great first step. You can also supplement your diet with turmeric, ginger, fish oil, and vitamin D &#; all of which are proven anti-inflammatories that are easy to find.
Want more information on Green Tea Extract Powder? Feel free to contact us.