Citrus sinensis L. Fruit Extract (40% nobiletin)

Citrus sinensis L. Fruit Extract Common Name

Sweet Orange | Blood orange

Top Benefits of Citrus bioflavonoids

  • Supports body clock function (i.e., circadian system)*
  • Supports healthy weight*
  • Supports mitochondrial biogenesis, structure, and function*
  • Supports healthy metabolism and insulin signaling*
  • Supports cellular responses and antioxidant defenses*
  • Supports brain function*
  • Supports the protection of organs and systems *
  • Supports healthy gut microbiota*  

What are Citrus bioflavonoids?

Citrus × sinensis, which includes sweet oranges and blood oranges, is regularly consumed in the diet. The peels and fruit are a rich source of the polymethoxylated flavones nobiletin and tangeretin. They also contain the flavanone hesperidin and lesser amounts of other citrus bioflavonoids. Citrus bioflavonoids were once called vitamin P and have been used to support healthy blood vessels and veins. Flavonoids tend to promote antioxidant defenses and a balanced cellular response. Citrus flavonoids share these properties. This citrus bioflavonoid extract has been concentrated for the unique polymethoxylated flavone nobiletin, a clock-enhancing small molecule used to support body clock function and metabolic health.

Neurohacker’s Citrus bioflavonoids Sourcing

A Citrus × sinensis extract standardized for 40% nobiletin was selected because this unique polymethoxylated flavone is a modulator of clock function (i.e., circadian system). 

The immature dried fruit of Citrus × sinensis is used as a source for nobiletin. In addition to a standardized amount of this polymethoxylated bioflavonoid, the dried fruit contains a range of other citrus bioflavonoids.

This standardized extract is supplied by Brewster Nutrition, a leader in citrus bioflavonoids since 1950. The 40% standardized extract is their highest concentration for nobiletin. It’s an expensive ingredient, but worth it.

Citrus bioflavonoids Dosing Principles and Rationale

Many flavonoid molecules are part of plants’ protective responses to mild environmental stress. Consuming them tends to produce adaptive functional responses, upregulating pathways that provide stress resistance. We think of polymethoxylated flavones like nobiletin and citrus bioflavonoids in general as having threshold effects. When combined with other flavonoids we think it’s better to use them following hormetic dosing principles (see Neurohacker Dosing Principles). Flavonoids are additive, and often synergistic with other polyphenol compounds, so the combination of all polyphenols in a formulation should be considered when determining dosage (not the amount of a single polyphenol molecule in isolation). When we dose Citrus × sinensis we consider the content of other polyphenols in the formulation and adjust the dose accordingly.

Citrus bioflavonoids Key Mechanisms

Circadian rhythms

  • Nobiletin and tangeretin are clock amplitude-enhancing small molecules (CEM) — modulate the circadian system (1, 2)
  • Nobiletin and tangeretin upregulate circadian rhythm protein Period 2 (PER2) (1–3)
  • Promotes metabolic function through a circadian-dependent mechanism (1, 4)

Mitochondrial biogenesis

  • Upregulates peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1α) (4–7)
  • Upregulates nuclear transcription factors of mitochondrial biogenesis (nuclear respiratory factor 1 [NRF1], NRF2, mitochondrial transcription factor A [TFAM]) (6, 8–10)

Mitochondrial structure and function

  • Protects from mitochondrial dysfunction (11, 12)
  • Protects from complex I-V inhibition (4, 13)
  • Upregulates ATP production (14)
  • Supports mitochondrial membrane potential (11)

Signaling pathways

  • Upregulates AMP-activated protein kinase (AMPK) signaling (4, 8, 15, 16)
  • Upregulates peroxisome proliferator-activated receptor alpha (PPARα) and delta PPARδ (6, 8, 17–19)
  • Regulates PPARγ signaling (6, 15, 17–20)
  • Downregulates glycogen synthase kinase 3 beta (GSK-3β) (4, 13, 21)
  • Downregulates mTOR signaling (21)
  • Upregulates SIRT-1 signaling (4, 6)

Metabolism

  • Supports healthy blood glucose levels (1, 5, 7, 17, 18, 22)
  • Supports healthy insulin sensitivity (1, 4, 5, 7, 18, 19, 22)
  • Upregulates GLUT-1 and GLUT-4 (17, 18)
  • Balances the respiratory quotient (1)
  • Regulates the urea cycle (23)

Body weight 

  • Supports healthy body weight (1, 5, 7, 17, 22)
  • Downregulates fat accumulation in the blood and liver (1, 5, 7, 19, 22, 24)
  • Supports healthy blood triglyceride and cholesterol levels  (7, 19, 24, 25)
  • Upregulates adiponectin levels (17, 18)
  • Promotes the differentiation of brown adipose tissue (6, 22)
  • Upregulates UCP-1 and UCP-2 (6, 7, 17, 22)
  • Promotes thermogenesis (22)

Cellular signaling

  • Downregulates the expression of proinflammatory mediators – cyclooxygenase-2 (COX-2), nitric oxide (NO) inducible NO synthase (iNOS), tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), IL-6, nuclear factor-kappa B (NF-κB), interferon-gamma (IFN-ɣ) (7–10, 17–21, 26–28)
  • Regulates immune cell activity (7, 29)

Antioxidant defenses

  • Upregulates antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx])  (8, 9, 12, 27)
  • Downregulates the generation of reactive oxygen species (4, 8, 11, 12, 27)
  • Replenishes glutathione (GSH) levels (8, 9, 12, 27)
  • Upregulates heme oxygenase-1 (HO-1) (10, 20)

Brain function

  • Neuroprotective against ischemia/hypoxia (9, 21, 30, 31)
  • Neuroprotective against neurotoxic agents (11, 12, 32)
  • Protects cognitive function (3, 13, 33)
  • Supports emotional memory (34)
  • Regulates neural cytokine signaling (26, 28)
  • Supports hippocampal mitochondrial bioenergetics (14)
  • Upregulates BDNF signaling (31, 35)

Protection of organs and systems

  • Protects cardiovascular structure and function (5, 7, 36–38)
  • Protects liver structure and function (8)
  • Protects gastrointestinal structure and function  (27)

Gut microbiota

  • Regulates the composition of the gut microbiota (39–42)
  • Regulates gut microbial metabolism (41)
  • Supports gut barrier function (39)

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*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.