Vitexin

• Antioxidant
• Anti-inflammatory
• Neuroprotective
• Cardioprotective

• Anxiolytic
• Antidiabetic
• Hepatoprotective
• Anticancer
• Antimicrobial

Vitexin (apigenin-8-C-glucoside) exerts its diverse biological effects through multiple molecular pathways. As a C-glycosylflavone, vitexin possesses a unique structural feature where a glucose molecule is directly attached to the C-8 position of the apigenin backbone via a carbon-carbon bond, rather than through an oxygen atom as in O-glycosides. This C-glycosidic bond is resistant to hydrolysis by glycosidases, contributing to vitexin’s distinct pharmacokinetic profile and biological activities. One of vitexin’s most extensively studied mechanisms is its antioxidant activity.

Vitexin scavenges reactive oxygen species (ROS) and free radicals through its hydroxyl groups, particularly those on the A and B rings of the flavone structure. It neutralizes superoxide anions, hydroxyl radicals, and peroxynitrite, preventing oxidative damage to cellular components including lipids, proteins, and DNA. Beyond direct scavenging, vitexin enhances endogenous antioxidant defenses by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. By promoting Nrf2 nuclear translocation and binding to antioxidant response elements (AREs), vitexin upregulates the expression of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1).

This dual approach to antioxidant protection—direct scavenging and enhancement of endogenous antioxidant systems—provides comprehensive defense against oxidative stress. As an anti-inflammatory agent, vitexin inhibits the nuclear factor-kappa B (NF-κB) signaling pathway by preventing IκB kinase (IKK) activation and subsequent nuclear translocation of NF-κB, thereby reducing the expression of pro-inflammatory genes. It suppresses the production of inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), while inhibiting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Vitexin also modulates the mitogen-activated protein kinase (MAPK) signaling pathways, including p38 MAPK, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), further contributing to its anti-inflammatory properties.

In the cardiovascular system, vitexin demonstrates protective effects through multiple mechanisms. It improves endothelial function by enhancing nitric oxide (NO) production through activation of endothelial nitric oxide synthase (eNOS) via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Vitexin also inhibits platelet aggregation and thrombus formation by reducing thromboxane A2 production and calcium mobilization in platelets. Additionally, it protects cardiomyocytes from ischemia/reperfusion injury by preserving mitochondrial function, reducing calcium overload, and inhibiting apoptosis.

In the central nervous system, vitexin exhibits neuroprotective effects through multiple mechanisms. It protects neurons from oxidative stress and excitotoxicity by reducing glutamate-induced calcium influx and maintaining mitochondrial function. Vitexin also inhibits neuroinflammation by suppressing microglial activation and reducing the production of pro-inflammatory mediators in the brain. Furthermore, it has been shown to enhance brain-derived neurotrophic factor (BDNF) expression and activate the PI3K/Akt/glycogen synthase kinase-3β (GSK-3β) pathway, promoting neuronal survival and synaptic plasticity.

Vitexin’s anxiolytic effects are mediated through modulation of the gamma-aminobutyric acid (GABA) system. It enhances GABAergic neurotransmission by binding to the benzodiazepine site of GABAA receptors, though with a different binding profile compared to classical benzodiazepines. This interaction increases chloride ion influx into neurons, resulting in hyperpolarization and reduced neuronal excitability, which contributes to its anxiolytic and mild sedative properties. In metabolic regulation, vitexin improves insulin sensitivity and glucose metabolism through multiple mechanisms.

It enhances glucose uptake in skeletal muscle and adipose tissue by activating AMP-activated protein kinase (AMPK) and increasing glucose transporter 4 (GLUT4) translocation to the cell membrane. Vitexin also protects pancreatic β-cells from oxidative stress and inflammation, preserving insulin secretion capacity. Additionally, it inhibits α-glucosidase and α-amylase, enzymes involved in carbohydrate digestion, potentially reducing postprandial glucose levels. In cancer cells, vitexin demonstrates antiproliferative and pro-apoptotic effects.

It induces cell cycle arrest primarily at the G0/G1 or G2/M phases by modulating the expression and activity of cell cycle regulators, including cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. Vitexin also triggers apoptosis through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways. It modulates the expression of Bcl-2 family proteins, decreasing anti-apoptotic proteins (Bcl-2, Bcl-xL) and increasing pro-apoptotic proteins (Bax, Bad), leading to mitochondrial membrane permeabilization, cytochrome c release, and activation of caspase cascades. Furthermore, vitexin has been shown to inhibit angiogenesis by reducing vascular endothelial growth factor (VEGF) expression and signaling, potentially limiting cancer progression and metastasis.

The C-glycosidic bond in vitexin contributes to its unique pharmacological profile compared to its aglycone apigenin. This structural feature affects its bioavailability, metabolism, and tissue distribution, potentially leading to different biological activities and therapeutic applications. The glucose moiety enhances water solubility while maintaining some of the lipophilicity of the flavone backbone, creating a balanced structure that can interact with various molecular targets.

Optimal dosage ranges for vitexin in humans have not been well established through clinical trials. Most research has focused on vitexin as a component of herbal extracts, particularly from hawthorn (Crataegus species) and passion flower (Passiflora species), rather than as an isolated compound. Based on preclinical studies and limited human research with herbal extracts containing vitexin, estimated effective doses would range from 10-50 mg of vitexin daily. For hawthorn extracts, typical daily doses range from 160-900 mg of standardized extract containing 1.5-3% vitexin and vitexin derivatives.

This would correspond to approximately 2.4-27 mg of vitexin and related compounds daily. For passion flower extracts, typical daily doses range from 300-800 mg of standardized extract containing 0.5-2% vitexin, corresponding to approximately 1.5-16 mg of vitexin daily. It’s important to note that vitexin’s bioactivity may be influenced by other compounds present in herbal extracts, potentially leading to synergistic effects that allow for lower effective doses compared to isolated vitexin.

Vitexin has relatively low oral bioavailability, estimated at approximately 3-8% in animal studies. This limited bioavailability is primarily due to its C-glycosidic structure, which affects its absorption and metabolism. Unlike O-glycosides, the C-glycosidic bond in vitexin (where the glucose is directly attached to the C-8 position of apigenin via a carbon-carbon bond) is resistant to hydrolysis by intestinal and hepatic glycosidases. This means that vitexin is primarily absorbed intact rather than being converted to its aglycone (apigenin) in the gastrointestinal tract.

The glucose moiety enhances water solubility but reduces passive diffusion across cell membranes due to its hydrophilicity. Absorption occurs primarily through active transport mechanisms, including sodium-dependent glucose transporters (SGLTs) and possibly other transporters. Once absorbed, vitexin undergoes limited phase II metabolism, primarily glucuronidation and sulfation, though to a lesser extent than many other flavonoids due to its already glycosylated structure. The C-glycosidic bond also makes vitexin less susceptible to efflux by P-glycoprotein transporters in the intestine, which may partially compensate for its limited passive diffusion.

In animal studies, vitexin has demonstrated tissue distribution to various organs, including the liver, kidneys, and brain, though brain penetration is limited due to its hydrophilicity. The presence of other compounds in herbal extracts, particularly from hawthorn and passion flower, may influence vitexin’s bioavailability through various mechanisms, including competitive inhibition of metabolic enzymes or transporters.

Nanoemulsion formulations – can increase bioavailability by 3-10 fold by improving solubility and enhancing intestinal permeability, Liposomal encapsulation – protects vitexin from degradation and enhances cellular uptake, Self-emulsifying drug delivery systems (SEDDS) – improve dissolution and absorption in the gastrointestinal tract, Phospholipid complexes – enhance lipid solubility and membrane permeability, Microemulsions – provide a stable delivery system with enhanced solubility, Combination with piperine – inhibits P-glycoprotein efflux and intestinal metabolism, Cyclodextrin inclusion complexes – improve aqueous solubility while maintaining stability, Solid dispersion techniques – enhance dissolution rate and solubility, Co-administration with other flavonoids that may compete for metabolic enzymes, potentially extending vitexin’s half-life, Nanoparticle formulations – improve stability and targeted delivery, particularly relevant for cardiovascular and neuroprotective applications

Vitexin is best absorbed when taken with meals containing some fat, which can enhance solubility and stimulate bile secretion, improving dissolution and absorption. The presence of other flavonoids may enhance vitexin’s bioavailability through competitive inhibition of metabolic enzymes or transporters. For cardiovascular benefits, consistent daily dosing is important, with some evidence suggesting that divided doses (morning and evening) may maintain more consistent blood levels due to vitexin’s relatively short half-life (approximately 2-4 hours in animal studies). For anxiety and stress, taking vitexin 30-60 minutes before stressful situations may help manage acute symptoms, while consistent daily dosing is recommended for chronic anxiety.

For antioxidant and anti-inflammatory effects, timing is less critical than consistency of use, though divided doses throughout the day may maintain more consistent blood levels. For metabolic support, taking vitexin before meals may enhance its effects on postprandial glucose levels through α-glucosidase and α-amylase inhibition. Enhanced delivery formulations like nanoemulsions or liposomes may have different optimal timing recommendations based on their specific pharmacokinetic profiles, but generally follow the same principles of taking with food for optimal absorption. Traditional use of hawthorn and passion flower containing vitexin often involves preparing them as teas or tinctures, which may have different absorption characteristics compared to modern extract formulations.

When consumed as a tea, the hot water extraction efficiently extracts vitexin due to its good water solubility, but the absence of lipids may limit absorption compared to when taken with a meal.

• Gastrointestinal discomfort (mild, uncommon)
• Nausea (rare)
• Dizziness (rare)
• Headache (rare)
• Mild sedation (uncommon, primarily with higher doses)
• Allergic reactions (rare)
• Mild hypotension (uncommon, primarily in individuals with already low blood pressure)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Scheduled surgery (discontinue 2 weeks before due to potential cardiovascular effects)
• Individuals with severe hypotension (due to potential blood pressure-lowering effects)
• Individuals taking medications for cardiovascular conditions (due to potential interactions)
• Individuals with known allergies to plants in the Rosaceae family (for hawthorn-derived vitexin) or Passifloraceae family (for passion flower-derived vitexin)
• Individuals with severe liver or kidney disease (due to limited data on metabolism and excretion in these populations)

• Antihypertensive medications (may enhance blood pressure-lowering effects)
• Cardiac glycosides (potential for additive effects on cardiac function)
• Benzodiazepines and other sedatives (potential for additive sedative effects due to vitexin’s mild GABAA receptor modulation)
• Anticoagulant and antiplatelet medications (may enhance antiplatelet effects, though this interaction appears to be mild)
• Cytochrome P450 substrates (limited evidence suggests potential mild inhibition of certain CYP enzymes)
• Antidiabetic medications (may enhance blood glucose-lowering effects)
• Antioxidant medications (potential for additive effects with other antioxidants)
• Phosphodiesterase-5 inhibitors (potential for additive effects on vasodilation)

Due to limited human clinical data on isolated vitexin, a definitive upper limit has not been established. Based on safety data for hawthorn and passion flower extracts (which contain vitexin) and animal toxicity studies, doses up to 50 mg of vitexin daily or 900 mg of standardized extract daily appear to be well-tolerated in most individuals. For general supplementation, doses exceeding these levels are not recommended without medical supervision due to potential drug interactions and limited long-term safety data at higher doses. It’s important to note that vitexin has demonstrated a favorable safety profile in both preclinical and limited clinical studies, with a wide therapeutic window.

Acute toxicity studies in animals have shown very low toxicity, with LD50 values well above any reasonable supplemental dose. The presence of other bioactive compounds in herbal extracts may contribute to the overall safety profile, making it difficult to establish precise upper limits for isolated vitexin. Traditional use of hawthorn and passion flower in moderate doses has a long history of safe use, further supporting the generally favorable safety profile of vitexin-containing preparations.

Vitexin itself is not approved as a drug by the FDA and is not commonly available as an isolated supplement. Plant extracts containing vitexin, such as hawthorn and passion flower extracts, are regulated as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Manufacturers cannot make specific disease treatment claims but may make general structure/function claims with appropriate disclaimers. The FDA has not evaluated the safety or efficacy of vitexin specifically.

Hawthorn and passion flower are generally recognized as safe (GRAS) when used in traditional amounts as herbs or supplements.

Eu: In the European Union, vitexin is not approved as a medicinal product. However, hawthorn and passion flower extracts containing vitexin are regulated as traditional herbal medicinal products under Directive 2004/24/EC in several EU countries, allowing them to be sold with specific health claims related to traditional use. The European Medicines Agency (EMA) has published community herbal monographs on both hawthorn and passion flower, recognizing their traditional medicinal use.

Germany: In Germany, hawthorn extracts are approved by Commission E (the German regulatory authority for herbs) for the treatment of New York Heart Association (NYHA) stage II heart failure. Passion flower extracts are approved for nervousness and sleep disorders. Both are available as registered herbal medicinal products with specific therapeutic indications.

Uk: In the United Kingdom, hawthorn and passion flower products may be registered as Traditional Herbal Medicinal Products (THMPs) under the Traditional Herbal Medicines Registration Scheme, allowing them to be sold with specific health claims based on traditional use.

Canada: Health Canada regulates hawthorn and passion flower extracts as Natural Health Products (NHPs). Several products containing these extracts have been issued Natural Product Numbers (NPNs), allowing them to be sold with specific health claims. For hawthorn, these include ‘helps support cardiovascular health’ and ‘traditionally used in Herbal Medicine to help maintain cardiovascular health.’ For passion flower, claims include ‘traditionally used in Herbal Medicine as a sleep aid’ and ‘helps relieve restlessness and nervousness.’ Isolated vitexin is not specifically approved as a standalone ingredient.

Australia: The Therapeutic Goods Administration (TGA) regulates hawthorn and passion flower extracts as complementary medicines. Several products containing these extracts are listed on the Australian Register of Therapeutic Goods (ARTG). Traditional use claims are permitted with appropriate evidence of traditional use. Vitexin as an isolated compound is not specifically regulated.

China: In China, hawthorn (Shan Zha) is officially listed in the Chinese Pharmacopoeia as a traditional Chinese medicine. It is approved for improving digestion and treating food stagnation. Various formulations containing hawthorn are approved for medicinal use. Vitexin as an isolated compound is primarily used in research rather than as an approved therapeutic agent.

Japan: In Japan, hawthorn and passion flower are recognized as medicinal plants and are included in some traditional Japanese medicine formulations. Vitexin as an isolated compound is not specifically regulated for therapeutic use.

Medium

Isolated vitexin is rarely available commercially for supplementation and is primarily sold as a research chemical at prices ranging from $200-$600 per 10-25 mg, making

it prohibitively expensive for regular supplementation. Standardized hawthorn extracts containing vitexin along with other flavonoids typically cost $0.30-$1.50 per day for basic extracts and $1.50-$3.00 per day for premium, highly standardized formulations. Standardized passion flower extracts containing vitexin typically cost $0.25-$1.00 per day for basic extracts and $1.00-$2.50 per day for premium formulations. Dried hawthorn or passion flower for tea preparation is the most cost-effective option, typically costing $0.15-$0.50 per day, though

it provides less consistent and potentially lower amounts of vitexin.

The cost-effectiveness of vitexin must be evaluated in the context of herbal extracts containing it, as isolated vitexin is not practically available for regular supplementation due to its high cost and limited commercial availability. For cardiovascular support, hawthorn extracts containing vitexin offer good value compared to many pharmaceutical interventions for mild to moderate heart conditions. Clinical studies have demonstrated significant improvements in exercise tolerance, symptoms, and quality of life in patients with NYHA stage II heart failure, with minimal side effects and at a fraction of the cost of many conventional medications. The long-term benefits for cardiovascular health may justify the moderate cost of high-quality extracts.

For anxiety and sleep support, passion flower extracts containing vitexin offer good value compared to both pharmaceutical anxiolytics and many other herbal alternatives. The anxiolytic effects are generally milder than benzodiazepines but come with significantly fewer side effects and no risk of dependence, making them a cost-effective option for mild to moderate anxiety and sleep disturbances. For antioxidant and anti-inflammatory benefits, there are likely more cost-effective options than vitexin-containing extracts, as many other botanical antioxidants have similar potency at lower costs. For neuroprotective effects, the value proposition is promising based on preclinical studies, but clinical evidence is still lacking.

The long-term benefits for neurodegenerative conditions would need to be substantial to justify ongoing supplementation costs. When comparing the cost-effectiveness of hawthorn and passion flower extracts containing vitexin to other supplements with similar indications: For cardiovascular support, hawthorn extracts are comparably priced to CoQ10 and fish oil supplements, with stronger clinical evidence for mild heart failure but less evidence for other cardiovascular conditions. For anxiety and sleep, passion flower extracts are generally less expensive than many specialized anti-anxiety supplements like L-theanine or specific adaptogenic herbs, while offering comparable benefits for mild to moderate anxiety. The most cost-effective way to consume vitexin is through traditional hawthorn or passion flower tea, which can be prepared from dried herb at a fraction of the cost of processed extracts.

However, the concentration of vitexin and other active compounds may be lower and less consistent in tea preparations compared to standardized extracts. Enhanced delivery systems such as nanoemulsions, liposomes, or SEDDS offer better bioavailability and potentially superior therapeutic outcomes, which may justify their higher cost for specific health conditions, particularly those affecting the cardiovascular system where clinical benefits have been well-documented.

Pure vitexin is moderately stable, with a typical shelf life of 2-3 years when properly stored. The C-glycosidic bond (where the glucose is directly attached to the C-8 position of apigenin via a carbon-carbon bond) provides better stability compared to O-glycosides, as it is resistant to hydrolysis by acids and enzymes. Standardized herbal extracts containing vitexin, such as hawthorn or passion flower extracts, typically have a shelf life of 1-2 years from the date of manufacture. Dried herb material (e.g., hawthorn leaves or flowers, passion flower) properly stored can maintain acceptable vitexin content for 1-2 years.

Tea preparations have a much shorter shelf life, with optimal potency maintained for only a few hours after preparation. Enhanced delivery formulations such as nanoemulsions or liposomes generally have shorter shelf lives of 1-2 years, depending on the specific formulation and preservative system.

Store in a cool, dry place away from direct sunlight in airtight, opaque containers. Refrigeration is recommended for liquid formulations and can extend shelf life of extracts containing vitexin. Protect from moisture, heat, oxygen, and light exposure, which can accelerate degradation. For research-grade pure vitexin, storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability.

For dried herb material (e.g., hawthorn, passion flower), store in airtight containers away from light and moisture to preserve the vitexin content. The addition of antioxidants such as vitamin E or ascorbic acid to formulations can help prevent oxidation and extend shelf life. Enhanced delivery formulations may have specific storage requirements provided by the manufacturer, which should be followed carefully to maintain stability and potency. Avoid repeated freeze-thaw cycles, particularly for liquid formulations, as this can destabilize the product.

Exposure to UV light and sunlight – causes photodegradation, though the C-glycosidic bond provides better stability compared to O-glycosides, High temperatures (above 30°C) – accelerates decomposition, Moisture – can promote hydrolysis (though to a lesser extent than with O-glycosides) and microbial growth, particularly in liquid formulations, Oxygen exposure – leads to oxidation, particularly affecting the hydroxyl groups, pH extremes – vitexin is most stable at slightly acidic to neutral pH (5-7), with increased degradation in strongly acidic or alkaline conditions, Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Enzymatic activity – while the C-glycosidic bond is resistant to glycosidases, other enzymes may affect the flavone structure, Incompatible excipients in formulations – certain preservatives or other ingredients may interact negatively with vitexin, Repeated freeze-thaw cycles – can destabilize enhanced delivery formulations such as nanoemulsions or liposomes

Synthesis Methods

Natural Sources

Quality Considerations

Vitexin itself was not identified or isolated until the modern era, but it is a constituent of several plants that have been used in traditional medicine systems for centuries. While the specific contribution of vitexin to the traditional uses of these plants was unknown to ancient practitioners, it is now recognized as one of the bioactive compounds in these historically important medicinal materials. Vitexin is primarily found in hawthorn (Crataegus species) and passion flower (Passiflora species), both of which have rich histories in traditional medicine across various cultures. Hawthorn has been used in traditional medicine systems worldwide for thousands of years.

In Traditional Chinese Medicine (TCM), hawthorn (Shan Zha) has been used since at least the 1st century CE, as documented in the ‘Shennong Bencao Jing’ (Divine Farmer’s Classic of Materia Medica). It was traditionally used to improve digestion, particularly of meat and fatty foods, and to treat food stagnation, abdominal pain, and diarrhea. By the Tang Dynasty (618-907 CE), hawthorn was also being used for cardiovascular conditions, with the famous physician Sun Simiao recommending it for ‘blood stasis’ and chest pain. In European herbal medicine, hawthorn has been used since at least the Middle Ages.

The Greek physician Dioscorides mentioned hawthorn in his De Materia Medica in the 1st century CE, noting its astringent properties. In medieval Europe, hawthorn was considered a sacred tree associated with protection and hope, and its berries were used to treat heart conditions, insomnia, and digestive disorders. By the 19th century, hawthorn had become a popular remedy for various heart conditions in European and American medical practice. The Irish physician Dr.

Green is credited with introducing hawthorn as a cardiac tonic to modern Western medicine in the late 19th century. Passion flower has a more recent but still significant history in traditional medicine. Native to the Americas, passion flower was used by indigenous peoples, particularly in North and South America, for its calming and sedative properties. The Aztecs used passion flower as a sedative and to treat insomnia and nervousness.

When European explorers arrived in the Americas in the 16th century, they quickly learned about passion flower from indigenous peoples and brought it back to Europe. By the 17th century, passion flower was being used in European herbal medicine for its calming and sleep-promoting effects. In the 19th and early 20th centuries, passion flower was included in various pharmacopeias and was commonly prescribed for nervousness, insomnia, and epilepsy. It was officially listed in the United States National Formulary from 1916 to 1936.

Bamboo leaves, another source of vitexin, have been used in traditional Asian medicine, particularly in China, Korea, and Japan, for thousands of years. In TCM, bamboo leaves (Zhu Ye) were used to clear heat, resolve phlegm, and calm the spirit. They were traditionally used to treat fevers, coughs, and irritability. Pearl millet and mung bean, which also contain vitexin, have been staple foods in various cultures for thousands of years and were also used in traditional medicine systems for their cooling and detoxifying properties.

Vitexin was first isolated and characterized in the mid-20th century as part of the scientific investigation into the active components of these traditional medicinal plants. Its structure was elucidated as apigenin-8-C-glucoside, identifying it as a C-glycosylflavone with a unique carbon-carbon bond between the flavone backbone and the glucose moiety. Modern scientific interest in vitexin began to grow in the late 20th and early 21st centuries as research revealed its antioxidant, anti-inflammatory, cardioprotective, and neuroprotective properties. The discovery of vitexin’s effects on cardiac function, oxidative stress, and neuroinflammation has provided scientific explanations for some of the traditional uses of hawthorn and passion flower, particularly their applications in cardiovascular and nervous system conditions.

Today, hawthorn and passion flower extracts containing vitexin are used in various herbal formulations, particularly in Europe and North America, for treating cardiovascular conditions, anxiety, and insomnia. Hawthorn extracts are approved in Germany for the treatment of mild heart failure, while passion flower extracts are approved for nervousness and sleep disorders.

Several clinical trials investigating hawthorn extracts (containing vitexin) for cardiovascular conditions, including heart failure, hypertension, and coronary artery disease, Preclinical studies investigating vitexin’s potential in neurodegenerative diseases, particularly focusing on its neuroprotective properties in Alzheimer’s and Parkinson’s disease models, Research on vitexin’s antidiabetic effects in various animal models of diabetes and metabolic syndrome, Investigations into vitexin’s anxiolytic and antidepressant effects in animal models and small human trials, Studies on novel delivery systems to enhance vitexin’s bioavailability and targeted delivery