Oct. 07, 2024
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Traditional Chinese medicine has long been instrumental in addressing various health concerns and gaining momentum in modern clinical practices. Conditions such as cardiovascular diseases, cerebrovascular incidents, atherosclerosis, and complications arising from diabetes have significantly impacted the quality of life for individuals, subsequently increasing the demand for effective health care solutions. Berberine, an alkaloid derived from Rhizoma coptidis, is a natural remedy widely utilized in China, recognized for its antibacterial and anti-inflammatory attributes. An expanding body of research indicates several cellular and molecular targets associated with berberine, underscoring its promise as a viable alternative treatment for vascular diseases. This review aims to systematically evaluate the evidence supporting berberine's utility as a therapeutic agent for vascular conditions, detailing its pharmacological effects, underlying mechanisms, and pharmacokinetic characteristics. Current findings reveal that berberine exhibits potent anti-inflammatory, antioxidant, anti-apoptotic, and autophagy-inhibiting properties through modulation of various signaling pathways, including AMP-activated protein kinase (AMPK), nuclear factor kappa B (NF-κB), silent information regulator 1 (SIRT-1), hypoxia-inducible factor 1 alpha (HIF-1α), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), janus kinase 2 (JAK-2), calcium channels, and endoplasmic reticulum stress. Furthermore, we address the limitations associated with berberine in the treatment of vascular diseases and propose possible remedial measures. We will also identify research challenges and perspectives, providing a solid groundwork for future investigations to discover innovative therapeutic agents derived from traditional Chinese medicinal sources.
In recent years, unique molecular structures originating from herbal medicine formulations containing berberine have garnered significant attention regarding the therapeutic potential of this compound for vascular diseases (Lee et al., Ren et al., Rajabi et al.). Thanks to advancements in pharmacological research, berberine has emerged as one of the most promising naturally sourced medications addressing numerous vascular-related ailments through modulation of multiple signaling pathways. However, there is a lack of systematic reviews that examine the pharmacological and pharmacokinetic properties of berberine in relation to vascular diseases. Thus, this review compiles published studies on berberine's effects in vascular diseases since 2010, utilizing databases like Web of Science, ScienceDirect, PubMed, Google Scholar, and China National Knowledge Infrastructure, summarizing findings to elucidate the potential application of berberine in treating vascular diseases.
Research has shown that berberine disperses quickly across various tissues, including the liver, kidneys, muscles, lungs, brain, heart, pancreas, and adipose tissues, with concentrations surpassing those found in plasma four hours post-oral intake of a 200 mg/kg dose in rats. Furthermore, berberine levels remain notably stable within the liver, heart, brain, muscle, and pancreas tissues (Tan et al.).
However, studies investigating the in vivo tissue distribution of berberine are quite limited, possibly due to its broad distribution after oral administration. The advent of new technologies, such as high-performance liquid chromatography electrospray ionization mass spectrometry (HPLC-ESIMS)/mass spectrometry (MS) and MS imaging, may facilitate a detailed exploration of berberine's tissue distribution (Jove et al.). This widespread distribution pattern can potentially be advantageous for treating certain diseases, thus broadening berberine’s clinical applications. For instance, oral administration of 100 mg/kg of berberine has been reported to enhance the excretion of cholesterol from the liver into bile (Li et al., b). Consequently, the distribution aspect of berberine warrants additional investigation in future studies.
One study utilized a sensitive HPLC-ESIMS/MS technique to identify the various metabolites of berberine present in human plasma, with the most notable being berberrubine, characterized by its high lipid solubility, discovered in individuals consuming 15 mg/kg of oral berberine chloride daily over three months (Spinozzi et al.). Evidence indicates that berberine displays a similar metabolic profile in both rats (100 mg/kg orally) and humans (300 mg administered orally thrice a day for two days), as shown via urine samples (Qiu et al.). Using liquid chromatography hybridized with ion trap time-of-flight mass spectrometry, Ma et al. identified 16 distinct metabolites in rat bile, urine, and feces following an oral intake of berberine (200 mg/kg). Following a single oral dose of berberine (48.2, 120, or 240 mg/kg), the levels of phase 2 metabolites were remarkably higher than those found in phase 1 metabolites based on the AUC0;48 h values. Additionally, nine primary metabolites of berberine (demethyleneberberine, jatrorrhizine-3-O-β-D-glucuronide, jatrorrhizine, berberrubine-9-O-β-D-glucuronide, jatrorrhizine-3-O-sulfate, berberrubine, thalifendine-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.). Moreover, the metabolism of berberine via oral intake is closely linked to liver functionality and the gut microbiome: for example, administration of 300 mg/kg berberine in mice revealed a decrease in mRNA and enzyme activity levels of cytochrome P3A11 (CYP3A11) and CYP3A25, alongside an increase in CYP1A2 mRNA levels (Guo et al.). Similarly, administering a 200 mg/kg dose of berberine in rats demonstrated its metabolism in the liver by the CYP450 isoenzyme, leading to oxidative demethylation at several positions (C2, C3, C9, and C10) and subsequent conjugation of the hydroxyl groups with glucuronic acid (Singh et al.). Additionally, the gut microbiome exhibits an influential role in modulating berberine metabolism following oral administration, as evidenced by its conversion into absorbable dihydroberberine through nitroreductases produced by gut microbiota, which possesses a nearly five-fold greater intestinal absorption rate compared to berberine. The dihydroberberine subsequently undergoes oxidation back to berberine after absorption into the intestinal tissue, allowing entry into the bloodstream (Feng et al.; Han et al., a). Furthermore, gut microbiota has shown the capacity to convert berberine into oxyberberine through both in vitro and in vivo oxidation reactions, demonstrating a more significant binding interaction with hemoglobin than plasma (Li et al., a; Chen et al.).
In conclusion, the liver and intestine serve as the primary sites of berberine metabolism when administered orally. Mitigating the first-pass effect may decrease berberine's metabolic rate, thereby enhancing its bioavailability. Interestingly, a comprehensive study examining the in vivo metabolism of berberine indicated that phase II metabolites were the primary metabolic derivatives, contrary to previous research findings (Ma et al.). Future investigations should focus on the role of nitroreductases from the gut microbiome and the overall metabolism of berberine, to fully elucidate the pharmacodynamic framework underpinning this traditional Chinese medicine.
Research shifting focus to the excretion pathways of berberine has shed light on its limited absorption in vivo. Following a single oral dose of 200 mg/kg, berberine was discovered in feces, with a recovery rate of 22.74% within 48 hours. Thalifendine emerged as the most prevalent metabolite found in the bile, urine, and feces of rats (Ma et al.). In another experiment, 18.6% of berberine was noted as berberrubine in feces after an oral dose of 48.2 mg/kg. The overall recovery of berberine and its metabolites across urine, bile, and feces amounted to 41.2% in rats (Feng et al.). Hence, berberine and its derivatives are primarily eliminated through renal (urine and feces) and biliary excretions in both rats and mice (Liu et al.).
Berberine is an isoquinoline alkaloid (phytochemicals found in a variety of plants) characterized by its bright yellow hue and bitter taste. It is predominantly extracted from the root, rhizome, and stem bark of the Chinese herb Coptis chinensis and various Berberis species.
Historically, berberine has been utilized in Ayurvedic and traditional Chinese medicine (TCM) for treating an array of ailments. Contemporary scientific investigations suggest that berberine may serve as a natural remedy for elevated cholesterol levels, mouth ulcers, and diabetes, among other health issues.
Herein, we will explore essential information regarding berberine, its advantages, applications, safety considerations, and potential side effects.
Several studies indicate numerous potential health advantages associated with berberine. Nonetheless, it appears particularly effective for managing conditions like diabetes, high cholesterol, canker sores, and polycystic ovary syndrome (PCOS).
Evidence suggests that berberine can aid in lowering blood sugar levels for individuals diagnosed with diabetes, particularly when used alongside conventional treatments.
A randomized controlled trial assessed 80 subjects with type 2 diabetes, administering either 480 milligrams of berberine or the standard treatment of 1,000 milligrams (mg) of metformin daily over a span of 12 weeks. The results indicated that berberine proved as effective as metformin in reducing blood glucose levels and managing type 2 diabetes, with no short-term adverse effects reported.
Moreover, a meta-analysis involving 46 randomized controlled trials scrutinized berberine's safety and efficacy for type 2 diabetes management and concluded that berberine, whether consumed in isolation or alongside oral glucose-lowering medications, substantially enhanced blood sugar levels, hemoglobin A1C, insulin sensitivity, and inflammatory markers, yielding even greater results when integrated with conventional therapies.
However, the review pointed out that the effectiveness of berberine tended to diminish with treatment durations exceeding 12 weeks, daily doses over 2 grams (g), or participants aged above 60 years.
Berberine may promote cardiovascular wellness through multiple mechanisms.
Clinical trials have established that berberine is effective in lowering blood lipid levels, which encompasses total cholesterol, triglycerides, and low-density lipoprotein (LDL or "bad" cholesterol)—all significant contributors to cardiovascular disease risk.
Additionally, findings from human and animal studies suggest that berberine could enhance cardiac function and mitigate heart failure by regulating specific physiological pathways.
Moreover, there is early evidence suggesting that berberine could lower blood pressure and protect against arterial wall hardening and damage to blood vessel linings that may result from hypertension.
Compromised arterial health can lead to restricted blood flow, contributing to severe complications such as heart attacks and strokes.
It is vital to recognize, however, that the empirical evidence regarding berberine's blood pressure-lowering effects is limited and of relatively low quality; hence, further clinical evaluations are essential.
Notably, an observational study indicated that a daily intake of 1.2 to 2.0 grams of berberine, spaced over 12 weeks, equaled the efficacy of amiodarone in controlling the heart rate of individuals experiencing atrial fibrillation (A-Fib).
A-Fib describes an irregular heart rhythm that could potentially provoke blood clots, cardiac insufficiency, stroke, and various cardiac-related health concerns.
Nonetheless, it is essential to remain mindful that observational studies cannot definitively establish causation, necessitating careful interpretation of these outcomes.
Canker sores, scientifically known as aphthous stomatitis, manifest as small yet painful lesions forming inside the oral cavity. While they typically resolve independently, available treatment alternatives tend to be limited.
An older randomized controlled trial involving 84 participants investigated the effects of a berberine gel on mild canker sores. Participants applied either berberine gel or a placebo onto the ulcer four times a day for five days. At the conclusion of the study, those utilizing the berberine gel reported notable reductions in pain, ulcer size, redness, and fluid discharge.
Polycystic ovary syndrome (PCOS) arises from hormonal imbalances that elevate the risk for numerous chronic ailments, contributing to symptoms such as infertility, weight gain, irregular menstrual cycles, and excessive hair growth.
A randomized controlled trial examined the effects of administering 500 mg of berberine hydrochloride twice daily, paired with 500 mg of metformin hydrochloride twice daily, in a cohort of 136 individuals with PCOS. While metformin improved multiple facets of the condition, berberine exhibited even greater enhancements in body composition, lipid profiles, and hormonal status, suggesting that it may be significantly beneficial in reducing the risk of cardiovascular conditions among PCOS patients.
A further review of various studies revealed that berberine, when compared against placebo or no treatment, shows potential efficacy in improving ovulation rates and live birth outcomes among PCOS patients, alongside effects such as reduced insulin resistance and lowered levels of androgens (male sex hormones), fasting blood sugar, and insulin.
Despite these encouraging findings, the limited body of research indicates a need for additional investigations to better understand berberine's impact on fertility and pregnancy outcomes for individuals experiencing PCOS.
Beyond the previously highlighted health advantages, some individuals utilize berberine for:
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Since berberine is not commonly found in regular dietary sources, supplementation is necessary to incorporate it into your nutrition plan.
Berberine supplements are available in several formats, including capsules, tablets, liquids, and powders. Less frequently, it can be found in topical gels and eye drops. These supplements can be acquired through health food stores, pharmacies, or online platforms.
There are currently no official guidelines regarding the appropriate means to consume berberine. Nevertheless, it’s advised that the total daily dosage be divided into three segments, taken before meals.
Upon following the suggested regimen, it can take several weeks to months before revealing noticeable health benefits.
An established dosage for berberine supplements has not yet been defined. Nevertheless, various studies have indicated that benefits are observable within daily doses ranging from 0.4 to 2 grams, sustained for up to two years.
Further research is warranted to identify optimal dosages tailored to various health conditions.
It is best to consult with your healthcare provider before commencing berberine supplementation to ensure the correct dosage aligns with your specific health requirements.
Generally, berberine is well-tolerated, boasting a favorable safety profile. It is deemed safe for most healthy adults, especially when employed topically or taken in quantities up to 1.5 grams daily over a six-month period.
Berberine is not recommended during pregnancy, as it has the potential to cross the placental barrier and adversely affect the developing fetus. Its use during breastfeeding is also discouraged, as it may transfer into breast milk.
In newborns, exposure to berberine may lead to jaundice (a yellowing of the skin) and could result in a form of brain damage known as kernicterus.
The available data is insufficient to determine berberine's safety in children.
Although research in this area remains limited, it is posited that berberine may interact with certain medications:
Additionally, berberine holds the potential to interact with herbal and dietary supplements that influence blood clotting, blood glucose, or blood pressure.
No food interactions with berberine have been reported.
If you are currently using prescription medications or dietary supplements, consult your healthcare provider to ensure no potential interactions arise.
It is noteworthy that the Food and Drug Administration (FDA) does not necessitate pre-market approval for the safety and effectiveness of dietary supplements.
Whenever possible, opt for supplements from manufacturers that employ third-party testing to validate purity and ascertain that the product includes the stated ingredients on its labeling.
Recognized third-party testing organizations encompass USP, ConsumerLab, and NSF.
It is advisable to steer clear of collecting berberine-containing plants from the wild due to the risks of misidentification or contamination with other potentially hazardous compounds.
Although berberine is acknowledged for its safety, excessive consumption could heighten the incidence of side effects and create concerns about safety.
Always adhere to the recommended intake instructions provided on the product label or those provided by your healthcare provider.
While adverse effects associated with berberine are relatively uncommon, some clinical trials have documented mild gastrointestinal side effects, which may include:
The majority of these side effects seem to dissipate within the first four weeks of usage.
Berberine is a natural compound found within various plant species that displays potential in the treatment of diabetes, elevated cholesterol, and PCOS, alongside other health-related issues. It may prove most beneficial when integrated with conventional treatment regimens.
While generally deemed safe, berberine has the potential to interact with specific medications and supplements. Thus, it is imperative to discuss with your healthcare provider before considering berberine, particularly for individuals with pre-existing health conditions or those taking prescription medications.
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