Friday Hope: Tangerine Peel (Hesperetin)

Potent Anti-Covid, Anti-Cancer, Anti-Diabetic, and Cardioprotective Activity

Hesperetin effects as an anti-SARS-CoV-2 and anti-COVID-19-associated cancer progression agent by targeting intracellular signaling pathways

In my continuing search for natural therapeutics to treat COVID and Spike related pathologies, I am ever impressed with the abundance that Nature has provided us. If SARS-CoV-2 has taught me anything, it is to underscore what Hippocrates wrote centuries ago:

“Let food be thy medicine and medicine be thy food.”

It also underscores what my Cardiologist (sadly now deceased) at Harvard told me in back in the 90s (I have paroxysmal Afib):

“The best drugs are no drugs.”

I am pleased to report that I have found yet another natural wonder-therapeutic - Tangerine Peel. The active component of the peel is Hesperetin. So, the best place to start is to understand what Hesperetin is.

Hesperetin is a flavanone, that is, mainly found in citruses, such as lemons, limes, tangerines, and other fruits, such as grapes. It has been observed that hesperetin and its metabolites have an important effect in the decrease of inflammatory responses through various mechanisms and several study models (Ren et al., 2016a; Yang et al., 2012) also present an anticarcinogenic effect (Devi et al., 2015) (Table 7.2). Glycosidic hesperetin is known as hesperidin and as neohesperidose, and as it is bound to glucose and to rhamnose, it can form isomeric configurations that can provide sweet and bitter flavors in fruits where they are found (Garg et al., 2001).

Natural and Artificial Flavoring Agents and Food Dyes
https://www.sciencedirect.com/science/article/abs/pii/B9780128115183000077

First, Hesperetin is, in itself, a powerful COVID therapeutic.

In vitro (Choi and Lee 2010; Ren et al. 2016) and in vivo investigations (Ye et al. 2019) have indicated that hesperetin has potential to inhibit IL-1β, IL-6, and TNF-α expression significantly via forbidding multiple signaling pathways such as MAPK, JNK, and NF-κB. In addition, based on a randomized, double‑blind, placebo‑controlled clinical trial by Zahra Yari et al. hesperidin could decrease systolic blood pressure, triglyceride, fasting glucose level and TNF-α in metabolic syndrome (MetS) patients. Furthermore, hesperidin significantly reduced insulin, low density lipoprotein cholesterol and total cholesterol in MetS patients’ group, however, in control group only insulin and glucose significantly reduced (Yari et al. 2020).Therefore, hesperetin can inhibit the secretion of pro-inflammatory cytokines with its high anti-inflammatory activities and also it has anti-adipogenic, anti-oxidant, and anti-hypercholesterolemic effects. Overall, hesperetin can be a potential treatment for inhibition of SARS-CoV-2 entry into host cells and by its pharmacological properties suppressing viral particles replication and pro-inflammatory overreaction.

Additionally, Hesperetin blocks the cancer progressing action of SARS-CoV-2 and its Spike Protein. The virus promotes angiogenesis and hypoxia, which “feeds” cancer: A major reason for turbocancers. Again, Hesperetin blocks this.

SARS-CoV-2 virus infection clearly causes regional hypoxia in the infected areas. This hypoxia may benefit the stabilization of hypoxia-inducible factor-1alpha (HIF-1α) and the overexpression of vascular endothelial growth factor (VEGF) in the endothelial and cancer cells (Fig. 1) (Serebrovska et al. 2020). So, SARS-CoV-2 virus infection causes hypoxia and promotes angiogenesis. Likewise, to prevent angiogenesis, an experiment on C6 glioma rat cells found that hesperetin blocks the HIF-1α/VEGF/VEGFR2 signaling pathway in glioma endothelial cells (Stanisic et al. 2018).

Hesperetin also has the ability to restore lost levels of the now famous p53 – the cancer suppressing “protector of the genome.”

Accordingly, p53, which was impaired in many cancer stem cells, reached significant levels in BCSC cells with hesperetin treatment (Hermawan et al. 2021).

Hesperetin as an anti-SARS-CoV-2 agent can inhibit COVID-19-associated cancer progression by suppressing intracellular signaling pathways
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9393098/

Beyond these two clinical benefits, Hesperetin is instrumental in treating other Spike and age related/metabolic pathologies.

HEART FAILURE AND FIBROSIS

In conclusion, we found that the orange flavonoid hesperetin protected against cardiac remodelling induced by pressure overload via inhibiting cardiac hypertrophy, fibrosis, oxidative stress and myocytes apoptosis. These findings suggest a potential therapeutic drug for cardiac remodelling and HF.

Hesperetin protects against cardiac remodelling induced by pressure overload in mice
https://pubmed.ncbi.nlm.nih.gov/23719775/

DIABETES

We investigated the hypoglycemic and hypolipidemic effects of two hesperertin glycosides, namely, hesperidin and cyclodextrin (CD)-clathrated hesperetin, in Goto-Kakizaki (GK) weanling rats with type 2 diabetes. We demonstrated that hesperidin and CD-hesperetin normalized glucose metabolism by altering the activities of glucose-regulating enzymes and reducing the levels of lipids in the serum and liver of the GK rats. These effects of hesperidin glycosides were partly produced by altering the expression of genes encoding the peroxisome proliferator-activated receptors, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, and the low-density lipoprotein receptor.

Hypoglycemic and Hypolipidemic Effects of Hesperidin and Cyclodextrin-Clathrated Hesperetin in Goto-Kakizaki Rats with Type 2 Diabetes
https://academic.oup.com/bbb/article/73/12/2779/5947974

Thank you for your readership and support. I will continue to find ways to treat and prevent illness and damage caused by SARS-CoV-2 and its Spike Protein. Seek and we shall find.

Blessings to all and best wishes for a wonderful weekend.