Jaceosidin

• Anti-inflammatory
• Anticancer
• Antioxidant
• Neuroprotective

• Hepatoprotective
• Antimicrobial
• Antiallergic
• Antiasthmatic
• Immunomodulatory

Jaceosidin (5,7,4′-trihydroxy-3′,6-dimethoxyflavone) exerts its diverse biological effects through multiple molecular pathways. As a methoxyflavone with three hydroxyl groups and two methoxy groups, jaceosidin possesses a unique pharmacological profile that contributes to its various health benefits. One of jaceosidin’s most extensively studied mechanisms is its anticancer activity. In cancer cells, jaceosidin induces apoptosis (programmed cell death) 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). This leads to mitochondrial membrane permeabilization, cytochrome c release, and activation of caspase cascades, particularly caspase-3, -8, and -9. Jaceosidin also induces cell cycle arrest primarily at the G2/M phase by modulating the expression and activity of cell cycle regulators. It decreases the expression of cyclin B1 and cyclin-dependent kinase 1 (CDK1), while increasing the expression of p21 and p27, CDK inhibitors.

This disruption of cell cycle progression prevents cancer cells from dividing and proliferating. A particularly significant anticancer mechanism of jaceosidin is its ability to inhibit the signal transducer and activator of transcription 3 (STAT3) signaling pathway. STAT3 is constitutively activated in many cancer types and plays a crucial role in cancer cell survival, proliferation, angiogenesis, and immune evasion. Jaceosidin inhibits STAT3 phosphorylation and nuclear translocation, thereby suppressing the expression of STAT3 target genes involved in cancer progression.

As an anti-inflammatory agent, jaceosidin 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. Jaceosidin also modulates the mitogen-activated protein kinase (MAPK) pathway, including p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), further contributing to its anti-inflammatory properties. In allergic and asthmatic conditions, jaceosidin demonstrates significant antiallergic and antiasthmatic effects through multiple mechanisms.

It inhibits the release of histamine from mast cells by suppressing the degranulation process. Jaceosidin also inhibits the production of leukotriene C4 (LTC4) by blocking 5-lipoxygenase (5-LOX) activity. Additionally, it reduces the expression of Th2 cytokines (IL-4, IL-5, IL-13) and IgE production, which are key mediators in allergic responses. The antioxidant properties of jaceosidin are mediated through both direct and indirect mechanisms.

With its three hydroxyl groups, jaceosidin can directly scavenge reactive oxygen species (ROS) and free radicals. More significantly, jaceosidin activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, leading to increased expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1). In the central nervous system, jaceosidin exhibits neuroprotective effects through multiple mechanisms. It protects neurons from oxidative stress and excitotoxicity by reducing glutamate-induced calcium influx and maintaining mitochondrial function.

Jaceosidin also inhibits neuroinflammation by suppressing microglial activation and reducing the production of pro-inflammatory mediators in the brain. Additionally, it has been shown to inhibit acetylcholinesterase (AChE) activity, potentially enhancing cholinergic neurotransmission, which is beneficial for cognitive function. In the liver, jaceosidin demonstrates hepatoprotective effects by reducing oxidative stress, inflammation, and lipid accumulation. It activates AMP-activated protein kinase (AMPK), which enhances fatty acid oxidation and reduces lipogenesis, potentially benefiting conditions like non-alcoholic fatty liver disease (NAFLD).

Jaceosidin also induces phase II detoxification enzymes through Nrf2 activation, enhancing the liver’s capacity to metabolize and eliminate toxins. The balanced hydroxyl/methoxy structure of jaceosidin (three hydroxyl groups and two methoxy groups) contributes to its unique pharmacological profile. The methoxy groups enhance its lipophilicity and membrane permeability, while the hydroxyl groups maintain significant antioxidant capacity. This structural feature also influences its interaction with various molecular targets, contributing to its diverse biological activities.

Optimal dosage ranges for jaceosidin in humans have not been well established through clinical trials. Most research has focused on jaceosidin as a component of herbal extracts, particularly from Artemisia species, rather than as an isolated compound. Based on preclinical studies and limited human research with related compounds, estimated effective doses would range from 5-30 mg of jaceosidin daily. For Artemisia extracts, typical daily doses range from 2-9 grams of dried herb or 300-900 mg of standardized extract containing 0.1-1% jaceosidin.

This would correspond to approximately 0.3-9 mg of jaceosidin daily. It’s important to note that jaceosidin’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 jaceosidin.

Jaceosidin has moderate oral bioavailability, estimated at approximately 15-25% in animal studies. This is higher than many highly hydroxylated flavonoids due to its balanced hydroxyl/methoxy structure, which provides a good compromise between water solubility and lipophilicity. The two methoxy groups (at positions 3′ and 6) increase lipophilicity compared to more hydroxylated flavonoids, potentially enhancing passive diffusion across cell membranes. However, jaceosidin’s bioavailability is still limited by several factors, including first-pass metabolism in the liver, efflux by P-glycoprotein transporters in the intestine, and phase II metabolism (primarily glucuronidation and sulfation).

In animal studies, jaceosidin has demonstrated tissue distribution to various organs, including the liver, lungs, and kidneys, with moderate penetration into the brain. The presence of other compounds in herbal extracts, particularly from Artemisia species, may influence jaceosidin’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 jaceosidin 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 jaceosidin’s half-life, Nanoparticle formulations – improve stability and targeted delivery, particularly relevant for anticancer applications

Jaceosidin 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 jaceosidin’s bioavailability through competitive inhibition of metabolic enzymes or transporters. For anti-inflammatory and antioxidant effects, timing is less critical than consistency of use, though divided doses throughout the day may maintain more consistent blood levels due to jaceosidin’s relatively short half-life (approximately 3-5 hours in animal studies). For allergic conditions, taking jaceosidin before exposure to known allergens may help prevent or reduce allergic responses.

For asthma, consistent daily dosing is important for maintaining anti-inflammatory effects in the airways. 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 Artemisia species containing jaceosidin often involves preparing them as teas or decoctions, which may have different absorption characteristics compared to modern extract formulations. When consumed as a tea, the hot water extraction may not efficiently extract all the jaceosidin due to its limited water solubility, potentially reducing bioavailability compared to alcohol-based extracts or enhanced delivery systems.

• Gastrointestinal discomfort (mild to moderate)
• Nausea (uncommon)
• Diarrhea (uncommon)
• Headache (rare)
• Dizziness (rare)
• Allergic reactions (rare, but more common in individuals with allergies to plants in the Asteraceae family)
• Mild sedation (rare)
• Dry mouth (uncommon)

• Pregnancy and breastfeeding (due to insufficient safety data and potential effects on hormone levels)
• Individuals with known allergies to plants in the Asteraceae family (including ragweed, chrysanthemums, marigolds, and daisies)
• Scheduled surgery (discontinue 2 weeks before due to potential anticoagulant effects)
• Hormone-sensitive conditions (due to potential phytoestrogenic effects)
• Individuals taking medications metabolized by CYP enzymes (due to potential interactions)
• Individuals with severe liver or kidney disease (due to limited data on metabolism and excretion in these populations)
• Individuals with bleeding disorders (due to potential antiplatelet activity)

• Anticoagulant and antiplatelet medications (may enhance bleeding risk due to potential antiplatelet effects)
• Cytochrome P450 substrates (jaceosidin may affect the metabolism of drugs that are substrates for CYP enzymes, particularly CYP1A2, CYP2C9, and CYP3A4)
• P-glycoprotein substrates (may alter drug transport and absorption)
• Immunosuppressants (may interfere with therapeutic effects through immunomodulatory actions)
• Antiasthmatic medications (potential for additive effects or interactions with conventional asthma treatments)
• Antiallergic medications (potential for additive effects or interactions with antihistamines and other allergy medications)
• Hormone replacement therapy (potential interactions due to phytoestrogenic effects)
• Antidiabetic medications (may enhance blood glucose-lowering effects)
• Chemotherapeutic agents (potential interactions due to effects on cell cycle and apoptosis pathways, which could either enhance or reduce efficacy depending on the specific drug)

Due to limited human clinical data on isolated jaceosidin, a definitive upper limit has not been established. Based on safety data for Artemisia extracts (which contain jaceosidin) and animal toxicity studies, doses up to 30 mg of jaceosidin daily or 900 mg of standardized Artemisia 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 jaceosidin’s effects on hormone levels and potential phytoestrogenic activity suggest caution in individuals with hormone-sensitive conditions.

Additionally, the presence of other bioactive compounds in Artemisia extracts may contribute to the overall safety profile, making it difficult to establish precise upper limits for isolated jaceosidin.

Jaceosidin itself is not approved as a drug by the FDA and is not commonly available as an isolated supplement. Plant extracts containing jaceosidin, such as Artemisia 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 jaceosidin specifically.

Artemisia species are generally recognized as safe (GRAS) when used in traditional amounts as herbs or supplements.

China: In China, Artemisia argyi (Ai Ye) is officially listed in the Chinese Pharmacopoeia as a traditional Chinese medicine. It is approved for specific indications based on traditional use, including menstrual disorders, abdominal pain, and stopping bleeding. Various formulations containing Artemisia argyi are approved for medicinal use. Jaceosidin as an isolated compound is primarily used in research rather than as an approved therapeutic agent.

Korea: In South Korea, Artemisia argyi (Ssuk) is recognized as a traditional herbal medicine and is included in the Korean Pharmacopoeia. It is approved for similar indications as in China. Artemisia extracts are used in various approved herbal formulations.

Japan: In Japan, Artemisia species are included in various Kampo medicine formulations approved by the Ministry of Health, Labour and Welfare. They are used in traditional moxibustion therapy and in herbal preparations for various conditions.

Eu: In the European Union, jaceosidin is not approved as a medicinal product. Artemisia species extracts containing jaceosidin may be sold as food supplements, subject to the general food safety regulations. The European Food Safety Authority (EFSA) has not issued specific health claims for jaceosidin or Artemisia extracts. Some EU member states may have their own regulations regarding traditional herbal medicinal products containing Artemisia species.

Australia: The Therapeutic Goods Administration (TGA) regulates Artemisia 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. Jaceosidin as an isolated compound is not specifically regulated.

Canada: Health Canada regulates Artemisia 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 related to traditional use. Isolated jaceosidin is not specifically approved as a standalone ingredient.

Medium to high

Isolated jaceosidin is rarely available commercially for supplementation and is primarily sold as a research chemical at prices ranging from $300-$800 per 10-25 mg, making

it prohibitively expensive for regular supplementation. Standardized Artemisia extracts containing jaceosidin along with other flavonoids typically cost $0.50-$2.00 per day for basic extracts and $2.00-$5.00 per day for premium, highly standardized formulations. Dried Artemisia leaves for tea preparation are the most cost-effective option, typically costing $0.20-$0.80 per day, though

they provide less consistent and potentially lower amounts of jaceosidin.

The cost-effectiveness of jaceosidin must be evaluated in the context of herbal extracts containing it, as isolated jaceosidin is not practically available for regular supplementation due to its high cost and limited commercial availability. For anti-inflammatory and antiallergic effects, Artemisia extracts containing jaceosidin offer moderate value compared to other botanical anti-inflammatories. While not as potent as some pharmaceutical anti-inflammatories, they provide a broader spectrum of benefits at a lower cost and potentially fewer side effects for long-term use. For allergic conditions, particularly allergic rhinitis and asthma, Artemisia extracts may offer good value as adjunctive therapy, potentially reducing the need for higher doses of conventional medications.

However, they should not replace standard medical care for these conditions. For anticancer applications, the current state of research does not support the use of jaceosidin or Artemisia extracts as standalone cancer treatments, regardless of cost considerations. They may have potential value as adjunctive therapy, but this should only be considered under medical supervision as part of a comprehensive treatment plan. For general antioxidant benefits, there are likely more cost-effective options than jaceosidin-containing extracts, as many other botanical antioxidants have stronger clinical evidence and lower costs.

When comparing the cost-effectiveness of Artemisia extracts containing jaceosidin to other supplements with similar indications: For allergic conditions, they are comparably priced to other natural antiallergics like quercetin or butterbur, but with less clinical evidence supporting their use. For anti-inflammatory effects, they are moderately priced compared to alternatives like curcumin or boswellia, offering good but not exceptional value. For women’s health applications (based on traditional use), they offer good value compared to specialized women’s health supplements, though modern clinical evidence is limited. The most cost-effective way to consume jaceosidin is through traditional Artemisia leaf tea, which can be prepared from dried leaves at a fraction of the cost of processed extracts.

However, the concentration of jaceosidin 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.

Pure jaceosidin is moderately stable, with a typical shelf life of 2-3 years when properly stored. The balanced hydroxyl/methoxy structure (three hydroxyl groups and two methoxy groups) provides better stability compared to more hydroxylated flavonoids. Standardized herbal extracts containing jaceosidin, such as Artemisia extracts, typically have a shelf life of 1-2 years from the date of manufacture. Dried herb material (e.g., Artemisia leaves) properly stored can maintain acceptable jaceosidin 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 jaceosidin. Protect from moisture, heat, oxygen, and light exposure, which can accelerate degradation. For research-grade pure jaceosidin, storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability.

For dried herb material (e.g., Artemisia leaves), store in airtight containers away from light and moisture to preserve the jaceosidin 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 methoxy groups provide some protection compared to more hydroxylated flavonoids, High temperatures (above 30°C) – accelerates decomposition, Moisture – can promote hydrolysis and microbial growth, particularly in liquid formulations, Oxygen exposure – leads to oxidation, particularly of the hydroxyl groups, pH extremes – jaceosidin is most stable at slightly acidic to neutral pH (5-7), Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Enzymatic activity – may occur in improperly processed plant extracts, Incompatible excipients in formulations – certain preservatives or other ingredients may interact negatively with jaceosidin, Repeated freeze-thaw cycles – can destabilize enhanced delivery formulations such as nanoemulsions or liposomes

Synthesis Methods

Natural Sources

Quality Considerations

Jaceosidin 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 jaceosidin 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. Jaceosidin is primarily found in Artemisia species, particularly Artemisia argyi (Chinese mugwort), which has a rich history in traditional East Asian medicine. In Traditional Chinese Medicine (TCM), Artemisia argyi, known as ‘Ai Ye,’ has been used for over 2,000 years.

The first documented medicinal use of Artemisia argyi appears in the ‘Shennong Bencao Jing’ (Divine Farmer’s Classic of Materia Medica), compiled around 200-250 CE, where it was classified as a warming herb that dispels cold, stops bleeding, and regulates menstruation. It was traditionally used to treat conditions such as menstrual disorders, abdominal pain, uterine bleeding, and chronic diarrhea. The famous physician Li Shizhen further documented the medicinal properties of Artemisia argyi in his monumental work ‘Bencao Gangmu’ (Compendium of Materia Medica) in the 16th century, noting its effectiveness for ‘warming the meridians, dispersing cold, and stopping bleeding.’ In traditional Korean medicine, Artemisia argyi (known as ‘Ssuk’ or ‘Aeyeop’) was similarly used for gynecological conditions, digestive disorders, and as a hemostatic agent. It was also used in moxibustion, a therapeutic technique involving the burning of moxa (processed Artemisia) on or near the skin at specific acupuncture points.

This practice, which dates back at least 3,000 years, was believed to warm the meridians and expel cold pathogens. In Japanese Kampo medicine, Artemisia species (known as ‘Yomogi’ or ‘Gaiyou’) were used in various formulations for similar purposes as in Chinese and Korean medicine. The herb was also used in traditional Japanese moxibustion practices. In traditional Vietnamese medicine, Artemisia argyi (known as ‘Ngải cứu’) was used for treating menstrual disorders, stopping bleeding, relieving pain, and treating allergic conditions.

It was also commonly used in moxibustion therapy. Beyond East Asia, various Artemisia species have been used in traditional medicine systems worldwide. In European herbal medicine, different Artemisia species were used for their digestive, antiparasitic, and menstruation-regulating properties. In North American indigenous medicine, native Artemisia species were used for respiratory conditions, digestive disorders, and ceremonial purposes.

Jaceosidin 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 5,7,4′-trihydroxy-3′,6-dimethoxyflavone, identifying it as a partially methoxylated flavone. Modern scientific interest in jaceosidin began to grow in the late 20th and early 21st centuries as research revealed its anti-inflammatory, anticancer, and antiallergic properties. The discovery of jaceosidin’s effects on cell cycle regulation, apoptosis induction, and inflammatory signaling pathways has provided scientific explanations for some of the traditional uses of Artemisia species, particularly their applications in inflammatory and allergic conditions.

Today, Artemisia extracts containing jaceosidin are used in various herbal formulations, particularly in East Asian countries, for treating allergic conditions, inflammation, and as adjunctive therapy in cancer care. The traditional practice of moxibustion continues to be an important therapeutic technique in traditional East Asian medicine, though the specific contribution of jaceosidin to its effects remains an area of ongoing research.