Naturally Occurring Diosmetin
Also known as: 3',5,7-trihydroxy-4'-methoxyflavone, Naturally occurring diosmetin, Methylated flavonoid, Diosmetin
Overview
Diosmetin is a naturally occurring flavonoid, specifically a flavone subclass, found predominantly in citrus fruits and various medicinal plants. Structurally, it is closely related to luteolin but features a methoxy group at the 4' position. This compound is being investigated for a range of potential therapeutic applications, including cardiovascular benefits (such as antihypertensive effects), neuroprotection, anticancer properties, and hepatoprotection. Its biological activities are attributed to its potent antioxidant, anti-inflammatory, antiplatelet, and enzyme-modulating properties. While promising, the research on diosmetin is primarily in the preclinical and early clinical stages, with most studies conducted in animal models and cell cultures. Human trials are limited, indicating that the overall quality of evidence is moderate, with a need for more large-scale randomized controlled trials and meta-analyses to confirm its efficacy and safety in humans.
Benefits
Diosmetin exhibits several evidence-based benefits, primarily derived from preclinical studies. It has shown significant antihypertensive effects, reducing mean arterial pressure (MAP) in both normotensive and hypertensive rat models in a dose-dependent manner, with statistically significant reductions (p < 0.001). This suggests a strong potential for managing high blood pressure. In neuroprotection, diosmetin has demonstrated the ability to protect neuroblastoma cells from advanced glycation end products (AGEs)-induced endoplasmic reticulum (ER) stress and apoptosis, indicating its relevance in conditions like Alzheimer's disease. Its anticancer properties include inhibiting the proliferation and metastasis of hepatocellular carcinoma cells by modulating autophagy and downregulating matrix metalloproteinases (MMP-2, MMP-9). Furthermore, related compounds like diosmin (a diosmetin glycoside) have shown liver-protective effects, suggesting similar potential for diosmetin itself. Secondary benefits stem from its anti-inflammatory and antioxidant actions, which contribute to its overall cardiovascular and neuroprotective profiles. While these effects are promising, human data are currently lacking, and the clinical significance and population-specific benefits remain to be fully elucidated.
How it works
Diosmetin exerts its biological effects through several distinct molecular mechanisms. Its antihypertensive action is partly mediated by stimulating muscarinic receptors, a pathway independent of nitric oxide synthase. For neuroprotection, diosmetin activates PPARγ, which in turn reduces markers of endoplasmic reticulum (ER) stress such as ATF4 and CHOP, and inhibits caspase-12-dependent apoptosis. In the context of cancer, diosmetin's anticancer activity involves the inhibition of the mTOR pathway and the downregulation of matrix metalloproteinases (MMP-2 and MMP-9), which are crucial for tumor proliferation and metastasis. These actions collectively influence cardiovascular, nervous, and hepatic systems by interacting with specific molecular targets like muscarinic receptors, PPARγ, mTOR, and various ER stress proteins. While its mechanisms are being uncovered, human pharmacokinetic data, including absorption and bioavailability, are limited, though complexation with γ-cyclodextrin has shown promise in improving its bioavailability.
Side effects
The safety profile of diosmetin in humans is not well-established due to the limited number of clinical trials. Preclinical data from animal studies suggest that diosmetin is generally well tolerated, with no common or uncommon side effects extensively documented in human subjects. Consequently, information regarding potential drug interactions, contraindications, or specific considerations for special populations (e.g., pregnant women, children, or individuals with pre-existing conditions) is largely unknown. Given its potential to modulate cytochrome P450 enzymes and various receptor pathways, there is a theoretical possibility of drug interactions, but no definitive clinical evidence supports this. Caution is advised when considering diosmetin supplementation, especially for individuals on other medications, until more comprehensive human safety data become available. Without robust clinical trials, the full spectrum of adverse effects, their severity, and frequency cannot be accurately determined.
Dosage
The optimal and safe dosage of diosmetin for human use has not yet been established due to the limited number of clinical trials. Most available data are derived from animal studies, where acute intravenous administration has shown significant effects on mean arterial pressure. However, these findings cannot be directly extrapolated to human oral dosing. There is no defined minimum effective dose, optimal dosage range, or maximum safe dose for humans. Timing considerations for administration are also unclear, as acute effects have been observed in animal models, but the impact of chronic dosing remains unknown. Diosmetin has poor water solubility, which affects its absorption and bioavailability. Research suggests that complexation with cyclodextrins, such as diosmetin-7-glucoside complexed with γ-cyclodextrin, may enhance its oral bioavailability. However, specific recommendations for different forms or required cofactors are not available. Until robust human clinical trials are conducted, any use of diosmetin should be approached with caution, and dosage should not be self-determined.
FAQs
Is diosmetin safe for human use?
The safety of diosmetin in humans is not well established. While preclinical data suggest it is well tolerated, more extensive clinical trials are needed to confirm its safety profile and identify any potential side effects or contraindications in humans.
Can diosmetin lower blood pressure in humans?
Animal studies have shown promising antihypertensive effects, with significant reductions in blood pressure. However, human evidence is currently lacking, and further clinical research is required to determine if these effects translate to humans.
Does diosmetin have anticancer effects?
In vitro and animal studies suggest that diosmetin possesses anticancer potential, particularly in hepatocellular carcinoma cells, by inhibiting proliferation and metastasis. However, these findings need to be validated through human clinical trials.
How quickly does diosmetin work?
Acute effects have been observed in animal models, indicating a relatively rapid onset of action in those contexts. However, the time course of effects in humans, especially with chronic administration, is currently unknown and requires further study.
Research Sources
- https://pmc.ncbi.nlm.nih.gov/articles/PMC9416473/ – This in vivo study in normotensive and hypertensive rats demonstrated that diosmetin significantly reduced mean arterial pressure in a dose-dependent manner. The research indicated that this antihypertensive effect is mediated via muscarinic receptor stimulation, independently of the nitric oxide pathway, providing mechanistic insights into its cardiovascular benefits.
- https://japsonline.com/abstract.php?article_id=3321&sts=2 – This research, including in vitro studies on HepG2 hepatocellular carcinoma cells, investigated diosmetin's anticancer properties. It found that diosmetin inhibits the proliferation and metastasis of these cancer cells by modulating the mTOR pathway and downregulating matrix metalloproteinases (MMP-2 and MMP-9), suggesting its potential as an anticancer agent.
- https://pmc.ncbi.nlm.nih.gov/articles/PMC9183070/ – This in vitro cell study on SH-SY5Y neuroblastoma cells exposed to advanced glycation end products (AGEs) showed that diosmetin offers neuroprotection. It effectively reduced endoplasmic reticulum (ER) stress markers and apoptosis by activating PPARγ, highlighting its potential relevance in neurodegenerative conditions like Alzheimer's disease.
- https://link.springer.com/article/10.1007/s00210-024-03297-z – This article discusses the hepatoprotective effects of diosmin, a glycoside of diosmetin, against various hepatic injuries. While not directly on diosmetin, it suggests related liver-protective potential for diosmetin itself, indicating a broader therapeutic scope for this class of compounds.
- https://academic.oup.com/bbb/article/87/7/771/7150672 – This study investigated methods to improve the bioavailability of diosmetin, specifically focusing on diosmetin-7-glucoside complexed with γ-cyclodextrin. It found that this complexation significantly enhanced the compound's solubility and absorption, addressing a key challenge for its potential oral administration and therapeutic efficacy.
Supplements Containing Naturally Occurring Diosmetin
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