Nobiletin
Specifically for Oxidative Stress
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Why it works for Oxidative Stress:
Multi-pathway antioxidant + anti-inflammatory actions (cell/animal data, mechanistic reviews):
- Upregulates endogenous antioxidant defenses (Nrf2/ARE axis). Nobiletin increases Nrf2 activity and downstream enzymes (HO-1, NQO1, SOD, catalase, GPx), which is a canonical way to counter ROS and re-establish redox balance. This has been shown across liver-injury and NAFLD models and summarized in recent reviews. Frontiers
- Downregulates pro-oxidant/pro-inflammatory signaling (NF-κB, MAPKs). It inhibits IκBα phosphorylation/degradation and NF-κB p65 nuclear translocation; it also suppresses NF-κB/MAPK in multiple tissues—mechanisms tightly linked to oxidative stress and inflammatory cascades. ScienceDirect
- Mitochondrial & metabolic support via the circadian clock. Nobiletin is a RORα/γ agonist and clock-amplitude enhancer that improves metabolic gene expression and mitochondrial respiration in muscle and liver in vivo—mechanisms that indirectly reduce oxidative injury from metabolic overload. Europe PMC
- Neuroprotection under oxidative stress. Reviews and experiments in neural systems report reduced ROS, protection against Aβ-induced oxidative toxicity, and improved antioxidant capacity—relevant where oxidative stress drives pathology. BioMed Central
How to use for Oxidative Stress:
There’s no approved medical dosing for treating “oxidative stress” itself. What we know comes from food-based or supplement trials aimed at related outcomes:
Mixture of nobiletin + tangeretin (NoT):
- Dose used: 50 mg once daily (as a standardized NoT capsule) for 6 weeks in a randomized, double-blind, placebo-controlled human trial (nocturia). It reduced night-time voids (secondary endpoints) and was well-tolerated. This shows a feasible daily capsule regimen, though the endpoint wasn’t “oxidative stress.” MDPI
Nobiletin-rich citrus peel powder combined with perilla oil (food-based):
- Dose used: 2.91 mg nobiletin/day delivered via air-dried immature ponkan powder, alongside 1.47 mL perilla oil, for 12 months in older adults; this increased biological antioxidant potential and improved some cognitive outcomes vs. perilla oil alone. RSC Publishing
General supplement guidance (what’s actually on shelves):
- Authoritative monographs note no established clinical dose for nobiletin alone and that human trials of nobiletin by itself are lacking; combinations or enriched extracts are what’s been tested. Drugs.com
Absorption/bioavailability tips (from formulation research):
- Nobiletin is poorly water-soluble; taking with food (especially some fat) is reasonable to aid absorption. Formulations like emulsions, micelles or amorphous solid dispersions improve bioavailability in vivo (animal/PK work). Europe PMC
A pragmatic, evidence-aligned way people use it:
- If you choose to try it for general antioxidant support (not as disease treatment), a standardized citrus-peel extract supplying ~50 mg/day of polymethoxyflavones (nobiletin+tangeretin) mirrors the human NoT RCT; or a lower, food-based amount (~3 mg/day) as in the ponkan-powder study if you prefer dietary forms. Start low, take with meals, and review your meds for interactions (see §4). (Again: this is not medical advice—talk to your clinician first.) MDPI
Scientific Evidence for Oxidative Stress:
Human trials (related endpoints; limited but growing):
- NoT (nobiletin + tangeretin) 50 mg/day for 6 weeks in older adults with nocturia (RCT, double-blind crossover): decreased night-time frequency; no significant adverse events. Mechanism likely circadian/renal fluid handling; not a direct oxidative stress readout but shows clinical activity and tolerability. MDPI
- Nobiletin-rich ponkan powder (≈2.91 mg/day) + perilla oil for 12 months in healthy elderly (RCT): improved cognitive index, raised biological antioxidant potential (BAP) and serum BDNF, suggesting enhanced systemic antioxidant status. RSC Publishing
- Reviews/monographs emphasize that trials of nobiletin alone are sparse and endpoints vary; more targeted human oxidative-stress trials are needed. Drugs.com
Key mechanistic & preclinical evidence (oxidative stress focus):
- Nrf2/HO-1/NQO1 activation; SOD, CAT, GPx increases in liver and metabolic models; reduction of lipid peroxidation/ROS in NAFLD and acute liver injury. Frontiers
- NF-κB inhibition and anti-inflammatory effects across tissues; reduced oxidative stress markers in LPS/D-gal and other models. ScienceDirect
- Circadian RORα/γ agonism that enhances metabolic fitness and mitochondrial respiration (skeletal muscle), likely reducing oxidative burden from metabolic overload. Europe PMC
- Neuroprotection under oxidative challenges (Aβ models, neuronal oxidative assays). SpringerLink
Specific Warnings for Oxidative Stress:
Not a proven medical treatment for any disease. Human data for “oxidative stress” per se are limited; benefits are mostly preclinical or indirect (circadian/metabolic, cognitive proxies). Drugs.com
Antiplatelet effects (bleeding risk):
Nobiletin inhibits platelet activation/aggregation (in vitro/in vivo). Avoid or use cautiously with anticoagulants/antiplatelets (e.g., warfarin, DOACs, clopidogrel, aspirin), bleeding disorders, or before surgery. Europe PMC
Cytochrome P450 interactions:
Citrus polymethoxyflavones (including nobiletin) can affect CYP1A2 and, in citrus matrices, contribute to CYP3A4 effects (induction/inhibition varies by compound and mixture). Clinical significance is uncertain, but caution is warranted with sensitive CYP1A2/CYP3A4 substrates (e.g., theophylline, tizanidine; some statins, calcium-channel blockers). ScienceDirect
Herb-herb/compound interactions:
Preclinical work shows CYP3A4-mediated interactions when co-administered with other botanicals (example: anemarsaponin BII). This underscores a potential for DDIs with multi-ingredient supplements. Europe PMC
Pregnancy/lactation, pediatrics:
Safety is not established; reputable monographs advise avoiding use during pregnancy/breastfeeding and in young children due to lack of data. Drugs.com
General tolerability:
Short-term human supplementation in RCTs noted no serious adverse events; animal studies suggest a favorable toxicity profile at high doses, but these do not substitute for human safety data. MDPI
Formulation/bioavailability:
Because nobiletin is poorly soluble, erratic absorption is possible; formulations (emulsions/solid dispersions) can change exposure—another reason to avoid stacking with other CYP-active botanicals or drugs. Europe PMC
General Information (All Ailments)
What It Is
Chemical identity / source
- Nobiletin is a polymethoxyflavone (a type of flavonoid) with six methoxy (–OCH₃) groups; its full IUPAC name is 3′,4′,5,6,7,8-hexamethoxyflavone (or sometimes referenced in the 2-phenylchromen-4-one series).
- It is naturally found in the peels of citrus fruits (especially certain mandarins, oranges, and related species).
Physical / chemical properties
- Because of its multiple methoxy groups, nobiletin is relatively lipophilic (fat-soluble), which aids membrane penetration but presents challenges in aqueous solubility and bioavailability.
- In the body, it undergoes metabolism (especially demethylation by cytochrome P450 enzymes) to produce metabolites (notably 4′-demethylated nobiletin) that may themselves be bioactive.
Pharmacokinetics / distribution
- After oral ingestion, nobiletin is absorbed in the intestine (likely via passive permeability or proton-linked transport mechanisms) and then subject to first-pass metabolism.
- Studies show that nobiletin (or its metabolites) can reach the brain, crossing the blood-brain barrier, with brain half-life longer than in plasma. BioMed Central
- Its bioavailability is limited, and various formulation strategies (nanoemulsions, solid dispersions, etc.) have been explored to enhance its absorption and tissue delivery.
How It Works (Mechanisms of Action)
Nobiletin appears to influence many biological pathways. The multiplicity of effects is both a promise and a complication (i.e. pleiotropy). Below are some of the proposed and observed mechanisms from in vitro and animal studies:
Anti-oxidant / radical scavenging effects
- Nobiletin can neutralize reactive oxygen species (ROS) and reactive nitrogen species, reducing oxidative stress. Its structural groups (particularly methoxy groups) enable it to scavenge free radicals.
- It may also upregulate endogenous antioxidant defenses (e.g. via Nrf2 / antioxidant response elements) in some contexts. ScienceDirect
Anti-inflammatory / immunomodulation
- Nobiletin has been observed to inhibit inflammatory signaling cascades, such as NF-κB, reduce expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and suppress proinflammatory cytokines (TNF-α, IL-6, etc.) in cellular and animal models. Drugs.com
- It also modulates upstream receptors or adaptor pathways (e.g. TLR4) and associated kinases to blunt inflammatory responses. MDPI
Metabolic regulation / insulin sensitivity
- In animal and cellular models, nobiletin improves glucose tolerance, lowers insulin resistance, and can reduce hepatic steatosis (fat accumulation in the liver). MDPI
- It influences lipid metabolism (cholesterol, triglycerides) and the expression of lipid regulatory genes (e.g. via PPARs, SREBPs) in liver and adipose tissue. ScienceDirect
- It may activate AMPK (AMP-activated protein kinase), a central energy sensor, which can drive beneficial changes in metabolic pathways (glucose uptake, fatty acid oxidation). salispharm.com
Neuroprotection / cognitive effects
- Nobiletin exerts protective effects in various neurological and neurodegenerative models. For example, it can reduce neuroinflammation and oxidative stress, inhibit apoptosis of neurons, enhance synaptic plasticity, and modulate pathways like cAMP/PKA/ERK/CREB that support memory formation. BioMed Central
- In Alzheimer’s disease–type models, nobiletin may inhibit β-secretase (BACE1) activity, reduce amyloid-β production, and promote clearance mechanisms (e.g. via neprilysin). BioMed Central
- It can also affect the expression of synaptic receptors (e.g. AMPA receptor phosphorylation) and promote neuronal survival.
Circadian regulation / mitochondrial energetics
- More recently, nobiletin has been shown to influence circadian clock genes (e.g. RORs) and mitochondrial respiration in skeletal muscle, potentially aligning metabolic function with biological rhythms and improving energy efficiency. BioMed Central
- By enhancing mitochondrial function and reducing metabolic “inefficiencies,” it may help in age-related metabolic decline. BioMed Central
Anti-cancer / anti-proliferative effects
- In multiple cancer cell lines and animal tumor models, nobiletin has shown inhibition of cell proliferation, induction of cell cycle arrest and apoptosis, inhibition of angiogenesis, suppression of metastasis, and modulation of oncogenic signaling (e.g. NF-κB, EMT, PI3K/Akt) pathways. Drugs.com
- It can act synergistically with other compounds (e.g. statins) in cancer prevention models. Wikipedia
Bone health / anti-osteoporosis effects
- Some animal studies suggest that nobiletin can suppress osteoclastogenesis (the bone-resorbing cells), reduce bone loss, and thereby could have relevance in osteoporosis or arthritis models. Drugs.com
Thus, nobiletin acts via a network of pathways rather than a single “magic bullet” mechanism.
Why It’s Important / Potential Benefits
Given its multifaceted biological effects, nobiletin is of interest in various health domains:
Metabolic syndrome, diabetes, cardiovascular risk
- Because it can improve insulin sensitivity, reduce hepatic fat accumulation, and favorably modulate lipid profiles, nobiletin may have value in preventing or mitigating type 2 diabetes, nonalcoholic fatty liver disease, dyslipidemia, and related cardiovascular risks. MDPI
- In diabetic animal models, nobiletin improved hemodynamics (blood pressure, heart function) and myocardial metrics. Drugs.com
Neurodegenerative diseases and cognitive aging
- Its neuroprotective, anti-inflammatory, and synaptic enhancement effects make nobiletin a promising molecule in the context of Alzheimer’s disease, Parkinson’s disease, age-related cognitive decline, and memory disorders. BioMed Central
- One small human trial combining nobiletin with another agent (perilla seed oil) in older adults found some stabilization or improvement in cognitive measures vs control. Drugs.com
Cancer prevention / adjunct therapy
- Because nobiletin can inhibit tumor-promoting pathways, suppress inflammation, and induce apoptosis in cancer cells, it is studied as a possible chemopreventive agent or adjunct to conventional therapies. Drugs.com
Anti-inflammatory / general cell protection
- Chronic, low-level inflammation underlies many chronic diseases (atherosclerosis, metabolic syndrome, neurodegeneration). Nobiletin’s ability to temper inflammatory signaling may contribute to “healthspan” benefits. ScienceDirect
- By protecting cells against oxidative stress, nobiletin may help preserve tissue integrity over time.
Bone and musculoskeletal health
- If its anti-osteoclast and bone-preservation effects are validated in humans, nobiletin may help in osteoporosis, bone loss, or joint health contexts. Drugs.com
Aging / longevity
- Because many of its effects (metabolic optimization, anti-inflammation, mitochondrial support, circadian alignment) intersect with mechanisms of aging, some researchers consider nobiletin a candidate for nutraceutical approaches to healthspan extension. MDPI
However, it is very important to emphasize: none of these potential benefits are yet established in humans via robust clinical trials. The promising signals come heavily from cells, rodents, and limited pilot human work.
Considerations / Cautions / Unknowns
When evaluating nobiletin’s potential as a health-targeted supplement or therapeutic, several caveats and unknowns must be kept in mind:
Lack of large-scale human clinical trials
- As of now, no well-powered, randomized, placebo-controlled trials have been published that definitively establish safety, optimal dosing, efficacy, or long-term effects of nobiletin alone in humans. Drugs.com
- The one human trial cited combined nobiletin with another compound, making it hard to isolate the effect of nobiletin alone. Drugs.com
Bioavailability and dosing challenges
- Because of its lipophilicity and sometimes low aqueous solubility, absorption in humans is limited. There’s uncertainty regarding what dose is needed to achieve tissue levels seen in animal studies. ScienceDirect
- Formulation strategies (nanoemulsions, solid dispersions, encapsulation) may improve delivery but add complexity and variability. ScienceDirect+1
Metabolism / interactions
- Because nobiletin is metabolized by liver cytochrome P450 enzymes (via demethylation), there is potential for drug–flavonoid interactions (e.g. affecting levels of co-administered drugs metabolized by CYPs). BioMed Central
- Interactions with other dietary flavonoids or supplements may modulate its effects in unpredictable ways.
Safety / toxicity
- To date, there is limited data on long-term safety in humans. In animal studies, high doses over periods have not shown dramatic toxicity, changes in organ weights, behavior, or overt adverse effects in many cases. MDPI
- However, absence of evidence is not evidence of absence. Potential unknown adverse effects (e.g. genotoxicity, liver stress, idiosyncratic toxicity) remain a concern.
Dose, standardization, and purity
- Because it is a natural phytochemical, supplement preparations may vary widely in purity, dosage, and presence of contaminants. Without regulation, batches might not deliver what is claimed. Biomedicus
- The “right” dose to produce beneficial effects without harm is not established in humans.
Translatability from animal models
- Many observed effects exist in rodents or cell cultures under controlled conditions; human physiology is more complex. What works in mice may not translate to humans in terms of magnitude, safety, or feasibility.
Possible off-target / paradoxical effects
- Because nobiletin modulates multiple pathways, in certain disease states or in combination with certain medications, its effects might be maladaptive or interfere with other interventions. For example, in one UV radiation study, nobiletin protected cells from UVB but worsened the effects of UVA in some cells. Drugs.com
Regulatory status
- Depending on jurisdiction, nobiletin might be sold as a “dietary supplement,” “nutraceutical,” or undergo stricter regulation if claimed to treat disease. Its status, permissible claims, quality controls, and testing requirements vary.
Helps with these conditions
Nobiletin is most effective for general wellness support with emerging research . The effectiveness varies by condition based on clinical evidence and user experiences.
Detailed Information by Condition
Type 2 Diabetes
Circadian-clock modulation (ROR agonist): Nobiletin acts on the body’s molecular clock (enhancing ROR activity), which in turn regulates glucose and l...
Oxidative Stress
Multi-pathway antioxidant + anti-inflammatory actions (cell/animal data, mechanistic reviews):Upregulates endogenous antioxidant defenses (Nrf2/ARE ax...
Cellular Aging
Circadian-clock activation (via RORα/γ): Nobiletin is a clock-amplitude enhancer that directly targets RORα/γ in the circadian oscillator. In animals...
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