The overlooked fruit with big health benefits

By Naveed Saleh, MD, MS
Published June 5, 2020

Key Takeaways

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Nothing is more mundane than the sight of an orange, lemon, lime, or grapefruit. Citrus is literally everywhere—grown in more than 140 countries. In fact, in 2012, global production of citrus fruits tipped the scales at 131 million tons. (That’s a lot of pulp!) However mundane and ubiquitous citrus fruit may be, their multifarious health benefits may be less apparent. Citrus fruits are packed with health-boosting bioactive ingredients including essential oils, alkaloids, flavonoids, limonoids, coumarins, carotenoids, and phenolic acids that have been intently studied for their contributions to chemotherapeutics and complementary medicine. 

Here’s a more detailed look at the anti-inflammatory, anticancer, neuroprotective, metabolic, and cardioprotective properties associated with citrus fruits.

Anti-inflammatory properties

Inflammation is an intricate response mediated by various cytokines—including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α)—along with a cascade of molecular mediators, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). These inflammatory cytokines play key roles in chronic inflammatory conditions like Parkinson disease, Alzheimer disease, multiple sclerosis, and colon cancer.

In a review article published in the Chemistry Central Journal, orange peel extract suppressed UVB-induced COX-2 expression and PGE2 production in HaCaT cells, a type of skin cell widely used in scientific research. Furthermore, coumarin, flavonoids, and volatile oil found in citrus fruits were shown to harbor anti-inflammatory properties and may, thus, be used as supplements to protect against or improve chronic inflammatory conditions.

Anticancer properties

The flavonoids, coumarins, and limonoids found in citrus fruits are linked to lower risk of gastric cancer, breast cancer, liver cancer, lung cancer, colon cancer, blood cancer, and more. Moreover, common flavonoids found in citrus—including didymin, eriocitrin, hesperidin, naringin, narirutin, neohesperidin, and rutin—have demonstrated antioxidant and anti-inflammatory properties.

Citrus peel, for instance, contains a special class of flavonoid, according to the authors of a review article published in Food Science and Human Wellness. “Citrus peels are also the sole and rich source of polymethoxylated flavonoids, which were found to exert many biological properties, particularly anti-cancer and anti-inflammatory activity,” wrote the authors. 

“Recent studies have also demonstrated potent anti-carcinogenic and anti-inflammatory efficacy of 5-demethylated polymethoxyflavones in single molecules or in multiple 5-demethylated polymethoxyflavones. The natural content of 5-demethylated polymethoxyflavones in citrus peels is low in percentage, but it has been confirmed that they have more potent biological activity than their non-demethylated counterparts, such as anticancer activity,” they added.

Metabolic health

Various studies have shown that the flavonoids found in citrus decrease blood cholesterol and triglyceride levels. In fact, full methoxylation of the A-ring constituting citrus flavonoids could be the perfect structure for moderate metabolism of liver fat, according to some researchers.

Flavonoids improve lipid metabolism as well as other metabolic derangements inherent in metabolic syndrome, as explained in a review published in Current Opinion in Lipidology. “Citrus flavonoids, including naringenin, hesperidin, nobiletin and tangeretin, have emerged as promising therapeutic agents for the treatment of metabolic dysregulation,” wrote the review authors. 

They continued: “Epidemiological studies report that intake of citrus flavonoid-containing foods attenuates cardiovascular diseases. Experimental and a limited number of clinical studies reveal lipid-lowering, insulin-sensitizing, antihypertensive and anti-inflammatory properties. In animal models, citrus flavonoid supplements prevent hepatic steatosis, dyslipidemia and insulin sensitivity primarily through inhibition of hepatic fatty acid synthesis and increased fatty acid oxidation. Citrus flavonoids blunt the inflammatory response in metabolically important tissues including liver, adipose tissue, kidney and the aorta.”

Cardiovascular functions

Flavonoids found in citrus fruits may also exert beneficial effects in the setting of coronary heart disease. Naringenin and hesperetin, in particular, may exert anti-atherogenic effects, in part, by activating the peroxisome proliferator-activated receptor and up-regulating adiponectin expression in adipocytes. With respect to hypertension, results from human trials have been mixed. But, the findings from one of these trials showed that intake of high-flavonoid citrus juice for 5 weeks lowered diastolic blood pressure measures by 3.7 mmHg.

Neuroprotective functions

The citrus flavanones hesperidin, neohesperidin, and hesperetin are antioxidants that can cross the blood-brain barrier. (Of note, flavanones are a subgroup of flavonoids.) In a preclinical study, researchers showed that these flavanones at physiological concentrations exhibited neuroprotective effects against H2O2-induced cytotoxicity in PC12 cells, a cell line derived from rats. 

According to the study authors, at test concentrations, these flavones “inhibited the decrease of cell viability (MTT reduction), prevented membrane damage (LDH release), scavenged ROS formation, increased catalase activity, and attenuated the elevation of intracellular free Ca2+, the decrease of mitochondrial membrane potential (except those of 0.8 µM neohesperidin-treated cells) and the increase of caspase-3 activity in H2O2-induced PC12 cells. Meanwhile, hesperidin and hesperetin attenuated decreases of glutathione peroxidase and glutathione reductase activities and decreased DNA damage in H2O2-induced PC12 cells.” 

Caspase-3 activity is activated in apoptosis, and glutathione peroxidase and glutathione reductase play a role in determining susceptibility to oxidative stress. Furthermore, mitochondrial activity peaks in oncogenesis and contributes to apoptosis and necrosis. Indeed, mitochondria provide building blocks for tumor growth, moderate transcription, control redox, and calcium homeostasis.

Kidney stone prevention

Finally, although a primary metabolite—and not secondary—citric acid has an interesting health benefit that bears mentioning: It helps prevent kidney stones.

According to the UW Metabolic Stone Clinic: “Citric acid makes urine less favorable for the formation of stones. In its natural form, such as from citrus fruits, citric acid does not alkalinize the urine as citrate (from medication) does. Rather, it prevents small stones from becoming ‘problem stones’ by coating them and preventing other material from attaching and building onto the stones.”

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