Oct. 07, 2024
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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), Ca 2+ 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.
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.
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., ).
Berberine is an isoquinoline alkaloid (phytochemicals found in a number of plants) with a bright yellow color and bitter taste. It is commonly found in the root, rhizome, and stem bark of the Chinese herb Coptis chinensis and other Berberis plants.
For centuries, berberine has been used in Ayurvedic and traditional Chinese medicine (TCM) to treat various ailments. Modern research suggests it may be a natural remedy for high cholesterol, mouth sores, and diabetes, among other health conditions.
Here's everything you need to know about berberine, including its benefits, uses, safety, and side effects.
Design by Health
Benefits of Berberine
Berberine has many potential health benefits. However, it seems to be most effective for treating diabetes, high cholesterol, canker sores, and polycystic ovary syndrome (PCOS).
Lowers Blood Sugar in People with Diabetes
Berberine may help reduce blood sugar in people with diabetes. It appears to be most effective when combined with traditional therapies.
A randomized control trial gave 80 patients with type 2 diabetes 480 milligrams of berberine or traditional treatment with 1,000 milligrams (mg) of metformin daily for 12 weeks.
The study found that berberine was as effective as metformin at reducing blood sugar and controlling type 2 diabetes. No short-term side effects were reported.
Furthermore, a review of 46 randomized controlled trials examined berberine's safety and effectiveness for treating type 2 diabetes.
The review found that berberine, when consumed alone or combined with oral blood-sugar-lowering medications, significantly improved blood sugar levels, hemoglobin A1C, insulin resistance, and markers of inflammation. These improvements were more significant when combined with conventional treatment.
However, it's important to note that the review found that berberine's effectiveness decreased when treatment lasted more than 12 weeks, the daily dosage exceeded 2 grams (g), or the patients were over 60 years old.
May Support Heart Health
Berberine may support heart health through several mechanisms.
Clinical trials have found berberine effective at reducing blood lipid levels. This includes total cholesterol, triglycerides, and low-density lipoprotein (LDL or "bad") cholesterol, all of which are risk factors for heart disease.
Additionally, human and animal studies suggest that berberine may help improve heart function and prevent heart failure by regulating specific pathways in the body.
Berberine also shows promise in lowering blood pressure and protecting against the hardening of arterial walls and damage to blood vessel linings caused by high blood pressure.
When the arteries harden, it can eventually reduce or block blood flow, leading to various health complications, including heart attack and stroke.
However, it must be noted that evidence around berberine's effect on blood pressure is limited and of low quality, making it difficult to determine its effectiveness. Further human studies are needed.
Furthermore, a observational study showed that 1.2 to 2.0 g of berberine daily for 12 weeks was equally effective as amiodarone in controlling heart rate in people with atrial fibrillation (A-Fib).
A-fib is an irregular heartbeat that can lead to blood clots, heart failure, stroke, and other heart-related health complications.
Keep in mind, though, that observational studies cannot prove cause and effect, so results should be interpreted with caution.
May Treat Canker Sores
Canker sores, or aphthous stomatitis, are small, painful sores that develop inside your mouth. Although they generally go away on their own, effective treatment options are limited.
One older randomized control trial in 84 people examined the effects of a berberine gel on mild canker sores. Participants were instructed to apply either the berberine gel or a placebo to a mouth ulcer four times daily for five days.
At the end of the study, participants who used berberine gel experienced improvements in pain ulcer size, redness, and fluid discharge.
PCOS Symptom Relief
PCOS is a condition caused by a hormonal imbalance. It can increase the risk for several chronic diseases and cause infertility, weight gain, irregular periods, and excess hair growth.
One randomized control trial examined the effects of 500 mg of berberine hydrochloride twice daily, 500 mg of metformin hydrochloride twice daily, and milligrams of myoinositol twice daily in 136 PCOS patients.
While metformin improved all aspects of the condition, berberine showed greater improvements in body composition, lipid profile, and hormone status. This suggests it may be more beneficial than metformin for reducing the risk of heart disease in individuals with PCOS.
Furthermore, a review of studies noted that berberine, compared to a placebo or no treatment, appears promising for improving ovulation and live pregnancy rates in PCOS patients. It may also help lower insulin resistance and reduce androgen (male sex hormone) levels, fasting blood sugar, and insulin levels.
However, due to limited research, additional studies are needed to evaluate the effect of berberine in improving fertility and pregnancy outcomes in PCOS patients.
Other Potential Benefits
In addition to the potential health benefits listed above, some people use berberine to support:
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Featured content:How to Take Berberine
Berberine isn't found in everyday foods, so you must take a supplement if you want to add it to your diet.
Berberine supplements are sold in various forms, including capsules, tablets, liquid, and powder. Although less common, berberine can also be found in topical gels and eye drops. Berberine supplements can be purchased in health food stores, drug stores, or online.
There are no official recommendations on how to take berberine. However, most manufacturers recommend dividing the daily dose of berberine into three smaller doses, taken before meals.
When taken as recommended, it may take several weeks to several months to see health benefits.
Dosage
There is no established dosage for berberine supplements. However, most studies have shown benefits with doses between 0.4 and 2 g per day, taken for up to two years.
Further research is needed to determine the optimal for various health conditions.
Talk with your healthcare provider before taking berberine to ensure that the supplement and dosage are appropriate for your specific needs.
Is Berberine Safe?
Berberine is generally well-tolerated with a good safety profile. It is considered safe for most healthy adults when used topically and taken in doses of up to 1.5 g daily for six months.
Berberine is thought to be unsafe during pregnancy, as it may cross the placenta and harm the developing fetus. Berberine is also not recommended while breastfeeding because it may be transferred to the infant through breast milk.
In newborn infants, berberine may cause jaundice (yellowing of the skin) and lead to a type of brain damage called kernicterus.
There aren't enough studies to determine the safety of berberine in children.
Potential Drug Interactions
While research is limited, berberine may interact with the following medications:
Berberine also has the potential to interact with herbs and other supplements that affect blood clotting, blood sugar levels, or blood pressure.
Berberine does not appear to interact with any foods.
If you take prescription medications or dietary supplements, talk with your healthcare provider to ensure no potential interactions occur.
What to Look For
The Food and Drug Administration (FDA) does not approve dietary supplements for safety and effectiveness before being sold.
When possible, choose a supplement from a manufacturer that utilizes third-party testing to ensure purity and that the product contains the ingredients listed on its label.
Reputable third-party organizations include USP, ConsumerLab, and NSF.
Plants naturally containing berberine should be avoided in the wild as they may be misidentified or contain other potentially unsafe compounds.
Can You Take Too Much Berberine?
While berberine is generally considered safe, taking too much may increase the risk of side effects and safety concerns.
Always take berberine as instructed on the product label or as recommended by your healthcare provider.
Side Effects of Berberine
While side effects of berberine are relatively uncommon, some clinical trials have reported mild gastrointestinal side effects, including:
Most of these side effects seem to resolve within the first four weeks of use.
A Quick Review
Berberine is a compound found in various plant species that shows promise in treating diabetes, high cholesterol, and PCOS, among other health conditions. It may work best when combined with traditional treatment methods.
Although generally considered safe, berberine has the potential to interact with certain supplements and medications. Therefore, it is important to talk with your healthcare provider before using berberine, especially if you have any health conditions or are taking prescription medications.
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