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.
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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., ).
Step aside, Ozempic &#; there&#;s a trending, alternative weight-loss supplement on the scene.
The supplement berberine has been branded as &#;nature&#;s Ozempic&#; on social media. Ozempic is a type 2 diabetes drug known by the generic name semaglutide that also is used for weight loss. Semaglutide has skyrocketed in popularity as an often effective (albeit sometimes very expensive) weight-loss measure.
Tara A. Schmidt, M.Ed., RDN, LD, a registered dietitian with Mayo Clinic, thinks the term &#;nature&#;s Ozempic&#; for berberine is good marketing &#; but not necessarily honest or helpful.
Although research suggests some good uses for berberine, it&#;s not ready for prime time as an obesity treatment. And you should always take a beat to scrutinize a claim that a supplement is &#;natural,&#; Schmidt says.
&#;If you are looking at something that&#;s being considered a &#;natural&#; version of a medication, it can look really appealing,&#; says Schmidt. But the natural label does not guarantee a pure and unprocessed substance, and consumers may not realize that a supplement can seriously interfere with other medications they are taking.
And even if a supplement truly comes from natural sources, it&#;s still unlikely to provide a quick and easy fix for health conditions such as obesity.
&#;With weight loss and with diabetes management, even when (we offer) a prescription medication, we always, always, always also combine it with lifestyle interventions,&#; she says. &#;So when people get excited about supplements out there, even if there is some evidence, we can&#;t just assume that it&#;s magic &#; even Ozempic&#;s not magic in itself.&#;
Berberine is a type of plant substance known as an alkaloid, and is found in a variety of plants, including barberry, goldenseal, Oregon grapes and coptis. These plants have long been used in traditional medicines &#; including Native American and Chinese practices &#; to treat a wide variety of illnesses, including eye conditions, diarrhea, jaundice and acne.
Today, berberine is available in supplement form and taken orally, though it is sometimes delivered intravenously or topically.
According to TikTok, a whole lot. Alongside first-person online testimonials about weight loss, skim through social media and you&#;ll find people who are using berberine for ailments like high cholesterol, insulin resistance and polycystic ovary syndrome (PCOS).
While such a wide array of benefits seems too good to be true, a look at the research shows that berberine is indeed ripe with possibility. Researchers are exploring many possible uses of berberine including as a treatment for diabetes, obesity, cancer, PCOS, high cholesterol and more.
However, research is still limited, especially as some of the studies done thus far were small or performed on animals, Schmidt says. Even so, some of the most encouraging results for berberine thus far are for:
You may notice that obesity didn&#;t make the shortlist. That&#;s because there aren&#;t enough high-quality studies on the subject, though there has been some research showing that berberine supplementation may help reduce weight.
Berberine may be safe when taken in recommended amounts &#; with the exceptions that it should not be used by children or people who are pregnant or breastfeeding.
The main side effects are gastrointestinal (GI) and include nausea, constipation, diarrhea, gas and vomiting. But Schmidt sees a much more pressing potential risk than GI symptoms.
&#;The scary thing is that it interacts with a ton of medications. There is a very long list of meds that could possibly interact with the berberine,&#; Schmidt says. &#;Don&#;t take this unless you speak to your medical provider first.'&#;
For more information, please visit Berberine Hydrochloride Exporter.
Possible interactive medications include anti-clotting drugs, sedating medications such as zolpidem (Ambien, Edluar) and diabetes drugs including metformin.
It potentially works in a bunch of different ways. It&#;s considered antimicrobial and may alter the bacteria in your gut. In addition, berberine may affect a wide variety of body functions, and is thought to act as an anti-inflammatory, antioxidant and anti-cancer substance.
Berberine&#;s effects on insulin and gut microbiota may be partially responsible for potential weight loss, Schmidt says. And one animal study showed that it affected glucagon-like peptide 1 (GLP-1) &#; a hormone involved in insulin secretion &#; which semaglutide also affects.
Some people on social media are claiming that the supplement berberine is helping them lose weight by lessening their appetite.
&#;One week in. 3 pounds down. All the snack chatter in my head has disappeared,&#; one TikTok commenter wrote. Another chimed in, &#;Same thing happened to me! Food noise gone and hunger really reduced.&#;
Better blood sugar regulation may explain a more regulated appetite, Schmidt says.
&#;If you&#;re not having those highs and lows in your blood sugar, you might not feel that more extreme hunger,&#; she says.
It&#;s also possible that some people experience a reduced appetite due to berberine&#;s possible GI side effects such as nausea, she says. This can lead to the question, &#;Did the side effects impact my hunger, or is the supplement actually regulating my appetite?&#;
As with any supplement, it&#;s best not to take any berberine until you&#;ve talked with a member of your health care team, especially as berberine may interact with other medications or supplements. Definitely don&#;t drop a prescription drug such as metformin in favor of berberine without talking to your prescribing doctor or a pharmacist.
It&#;s thought that taking 1.5 grams of berberine every day &#; sometimes split into multiple doses &#; for six months or less is safe. The six-month limit is due to a lack of longer term data, Schmidt says.
Berberine shares some issues with all other supplements, Schmidt says. Supplements are not subject to the more-rigorous regulation that the U.S. Food and Drug Administration (FDA) applies to medications, and they are not proved to be safe or effective.
Because of this, medical professionals may shy away from taking a stand on a supplement, citing lack of research, Schmidt says. People looking for alternative solutions &#; maybe because they can&#;t afford prescription medications, maybe because they are looking for alternative solutions after being ignored or failed by the medical system &#; may then turn elsewhere for insight.
&#;We get TikTokkers &#; who are not physicians, who are not pharmacists, who are not registered dietitians &#; giving advice, and now we have consumers listening to people who are outside of the medical industry, because no one in the medical industry is comfortable enough to endorse it or not,&#; Schmidt says.
&#;We just have to wait sometimes for research to catch up. But research requires money. And research requires time.&#;
While research plays catch-up, there are many pharmaceutical and lifestyle evidence-based interventions backed up by years of research to help address the same issues berberine may help with, including gut health, blood sugar problems and weight loss, Schmidt says.
And although many supplements are touted as a natural solution, this is not always an accurate representation &#; whether due to manufacturer malfeasance (such as weight-loss supplements found to contain unlisted prescription drugs) or the realities of processing the supplement.
&#;(For example), people aren&#;t eating stevia leaves. Stevia is still an artificial sweetener unless you&#;re putting the leaf in your coffee. So natural or not, these are still processed supplements; they come out of a factory,&#; Schmidt says.
Finally, just because something is naturally occurring or seems beneficial does not necessarily mean consuming it in supplement form will be helpful. For example, it&#;s possible that supplemental vitamin E increases the risk of prostate cancer.
&#;(The assumption is) taking more vitamin E is going to be a good thing, right? It&#;s a vitamin,&#; Schmidt says. &#;You can&#;t assume anything is going to be beneficial until it&#;s studied.&#;
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