Apigenin / Parsley / Celery

 

GENERAL SUMMARY:

• Apigenin is a natural bioflavonoid found in a variety of plants such as parsley, celery, chamomile and artichokes. It is a yellow crystalline solid and is part of the flavone class of flavonoids, which are responsible for the color and flavor of many plants.

• Research has shown that consuming foods high in apigenin is associated with protection against various diseases, including cardiovascular disease, neurodegenerative disorders, and certain types of cancer. 

• Apigenin sources: Dried parsley contains the highest apigenin concentration at 45,035 μg/g, followed by dried chamomile flowers (3,000-5,000 μg/g), celery seeds (786.5 μg/g), vine spinach (622 μg/g), and Chinese celery (240.2 μg/g).

ANTI-CANCER EFFECTS:

• Apigenin was reported to suppress various human cancers in vitro and in vivo by multiple biological effects, such as triggering cell apoptosis and autophagy, inducing cell cycle arrest, suppressing cell migration and invasion, and stimulating an immune response (2017).

• In a 2008 study, long-term flavonoid treatment (daily 20 mg apigenin and 20 mg EGCG) treatment of 87 patients with resected colorectal cancer led to a 7% neoplasia recurrence rate compared to 47% in controls, suggesting that flavonoids could effectively reduce colon cancer recurrence (P = 0.027).

• A 2010 study demonstrated that apigenin can inhibit leukemia cell proliferation and induce cell-cycle arrest, but may also reduce chemotherapy sensitivity in certain cell types, suggesting caution in its consumption during treatment.

• Apigenin induced apoptosis in human leukemia cells by inactivating Akt, activating JNK, and downregulating Mcl-1 and Bcl-2, while in vivo apigenin administration led to attenuation of tumor growth in U937 xenografts, highlighting its potential for incorporation in leukemia treatment regimens (2012).

• Apigenin acts as a cell-signaling pathway modulator in cancer prevention and treatment, reducing the expression of STAT3, STAT5, and JAK2 in breast cancer cell lines (SKBR3 and MDA-MB-453,HER2) and inhibiting tumor proliferation and growth. (2021)

• Apigenin potentiates the inhibitory effect of interferon-α on cancer cell viability by inhibiting 26S proteasome-mediated interferon receptor degradation and activating JAK/STAT signaling pathway, providing a novel mechanism for increasing the efficacy of type I interferons (2016).

• Apigenin enhances the IFN-α/β-induced activation of the JAK/STAT pathway by increasing ISRE luciferase reporter expression and the tyrosine phosphorylation of STAT1 and STAT2, ultimately leading to increased mRNA expression of IFN-α-responsive genes PKR and 2’,5’-OAS1. (2016)

• Apigenin suppressed Renal Cell Carcinoma (RCC) cell proliferation, induced DNA damage, G2/M phase cell cycle arrest, and p53-dependent apoptosis, leading to reduced tumor growth in a xenograft mouse model, showing promise for RCC treatment (2017)

OTHER METABOLIC EFFECTS:

• A 2022 study found that a specific CD38 inhibitor, 78c,  increased mice lifespan (+10%) and healthspan in a model of chronological aging, raising the hopes that apigenin too might improve mice lifespan. 

• Apigenin may inhibit CD38, a major NAD+ consumer, thereby potentially boosting NAD+ levels, which could offer an alternative approach to taking NAD+ precursors for addressing age-related NAD+ depletion. (2013)

• Apigenin inhibits platelet adhesion and thrombus formation, synergizing with aspirin in suppressing the arachidonic acid pathway (2008).

• Anti-diabetic effects: Celery seeds contain an anti-microbial compound that effectively blocks gastric H. pylori growth, a bacterium linked to a nearly three-fold increased risk of type II diabetes (2012).

DEEPER DIVE:

Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence (link)

Aim: To investigate biological prevention with flavonoids the recurrence risk of neoplasia was studied in patients with resected colorectal cancer and after adenoma polypectomy.

Methods: Eighty-seven patients, 36 patients with resected colon cancer and 51 patients after polypectomy, were divided into 2 groups: one group was treated with a flavonoid mixture (daily standard dose 20 mg apigenin and 20 mg epigallocathechin-gallat, n = 31) and compared with a matched control group (n = 56). Both groups were observed for 3-4 years by surveillance colonoscopy and by questionnaire.

Results: Of 87 patients enrolled in this study, 36 had resected colon cancer and 29 of these patients had surveillance colonoscopy. Among the flavonoid-treated patients with resected colon cancer (n = 14), there was no cancer recurrence and one adenoma developed. In contrast the cancer recurrence rate of the 15 matched untreated controls was 20% (3 of 15) and adenomas evolved in 4 of those patients (27%). The combined recurrence rate for neoplasia was 7% (1 of 14) in the treated patients and 47% (7 of 15) in the controls (P = 0.027).

Conclusion: Sustained long-term treatment with a flavonoid mixture could reduce the recurrence rate of colon neoplasia in patients with resected colon cancer.

How much apigenin in parsley?

Dried parsley can contain about 45 mg/gram ... The apigenin content of fresh parsley is reportedly 215.5 mg …

Mike Lusgarten’s diet: (Parsley = 47g/day, only 13% is dry mass… around 6g)

Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy, 2009

Natural-food-based compounds show substantial promise for prevention and biotherapy of cancers including leukemia. In general, their mechanism of action remains unclear, hampering rational use of these compounds. Herein we show that the common dietary flavonoid apigenin has anticancer activity, but also may decrease chemotherapy sensitivity, depending on the cell type. We analyzed the molecular consequences of apigenin treatment in two types of leukemia, the myeloid and erythroid subtypes. Apigenin blocked proliferation in both lineages through cell-cycle arrest in G2/M phase for myeloid HL60 and G0/G1 phase for erythroid TF1 cells. In both cell lines the JAK/STAT pathway was one of major targets of apigenin. Apigenin inhibited PI3K/PKB pathway in HL60 and induced caspase-dependent apoptosis. In contrast, no apoptosis was detected in TF1 cells, but initiation of autophagy was observed. The block in cell cycle and induction of autophagy observed in this erythroleukemia cell line resulted in a reduced susceptibility toward the commonly used therapeutic agent vincristine. Thus, this study shows that although apigenin is a potential chemopreventive agent due to the induction of leukemia cell-cycle arrest, caution in dietary intake of apigenin should be taken during disease as it potentially interferes with cancer treatment. 

Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in vivo (link)

In this study, we investigated the functional role of Akt and c-jun-NH(2)-kinase (JNK) signaling cascades in apigenin-induced apoptosis in U937 human leukemia cells and anti-leukemic activity of apigenin in vivo. Apigenin induced apoptosis by inactivation of Akt with a concomitant activation of JNK, Mcl-1 and Bcl-2 downregulation, cytochrome c release from mitochondria, and activation of caspases. Constitutively active myristolated Akt prevented apigenin-induced JNK, caspase activation, and apoptosis. Conversely, LY294002 and a dominant-negative construct of Akt potentiated apigenin-induced apoptosis in leukemia cells. Interruption of the JNK pathway showed marked reduction in apigenin-induced caspase activation and apoptosis in leukemia cells. Furthermore, in vivo administration of apigenin resulted in attenuation of tumor growth in U937 xenografts accompanied by inactivation of Akt and activation of JNK. Attenuation of tumor growth in U937 xenografts by apigenin raises the possibility that apigenin may have clinical implications and can be further tested for incorporating in leukemia treatment regimens.

Apigenin Inhibits Platelet Adhesion and Thrombus Formation and Synergizes with Aspirin in the Suppression of the Arachidonic Acid Pathway (link)

Quercetin induces apoptosis by activating caspase-3 and regulating Bcl-2 and cyclooxygenase-2 pathways in human HL-60 cells (acute leukemia) (link)

Dietary apigenin potentiates the inhibitory effect of interferon-α on cancer cell viability through inhibition of 26S proteasome-mediated interferon receptor degradation, 2016 (link)

Background

Type I interferons (IFN-α/β) have broad and potent immunoregulatory and antiproliferative activities. However, it is still known whether the dietary flavonoids exhibit their antiviral and anticancer properties by modulating the function of type I IFNs.

Objective

This study aimed at determining the role of apigenin, a dietary plant flavonoid abundant in common fruits and vegetables, on the type I IFN-mediated inhibition of cancer cell viability.

Design

Inhibitory effect of apigenin on human 26S proteasome, a known negative regulator of type I IFN signaling, was evaluated in vitro. Molecular docking was conducted to know the interaction between apigenin and subunits of 26S proteasome. Effects of apigenin on JAK/STAT pathway, 26S proteasome-mediated interferon receptor stability, and cancer cells viability were also investigated.

Results

Apigenin was identified to be a potent inhibitor of human 26S proteasome in a cell-based assay. Apigenin inhibited the chymotrypsin-like, caspase-like, and trypsin-like activities of the human 26S proteasome and increased the ubiquitination of endogenous proteins in cells. Results from computational modeling of the potential interactions of apigenin with the chymotrypsin site (β5 subunit), caspase site (β1 subunit), and trypsin site (β2 subunit) of the proteasome were consistent with the observed proteasome inhibitory activity. Apigenin enhanced the phosphorylation of signal transducer and activator of transcription proteins (STAT1 and STAT2) and promoted the endogenous IFN-α-regulated gene expression. Apigenin inhibited the IFN-α-stimulated ubiquitination and degradation of type I interferon receptor 1 (IFNAR1). Apigenin also sensitized the inhibitory effect of IFN-α on viability of cervical carcinoma HeLa cells.

Conclusion

These results suggest that apigenin potentiates the inhibitory effect of IFN-α on cancer cell viability by activating JAK/STAT signaling pathway through inhibition of 26S proteasome-mediated IFNAR1 degradation. This may provide a novel mechanism for increasing the efficacy of IFN-α/β.

Apigenin enhances the IFN-α/β-induced activation of the JAK/STAT pathway (2016)

Considering the important role of 26S proteasome in the attenuation of JAK/STAT pathway signaling, we hypothesize that apigenin may enhance the activation of JAK/STAT pathway by inhibiting 26S proteasome. To test this, we first examined the effect of apigenin on IFNα/β-induced JAK/STAT signaling. As shown in Fig. 4a, apigenin potently increased ISRE luciferase reporter expression induced by IFN-α or IFN-β in a concentration-dependent manner. Apigenin at 10 µM alone significantly increased ISRE reporter expression, as previously reported (17). We then examined the effect of apigenin alone on tyrosine phosphorylation of STAT1, the key factor mediating ISRE gene transcription. However, no obvious tyrosine phosphorylation of STAT1 was observed, possibly owing to the limitation of detection using anti-phospho-STAT1 antibody (data not shown). To further determine the effect of apigenin on type I IFNs, we examined the phosphorylation state of STATs in response to IFN-α. Apigenin increased the tyrosine phosphorylation of STAT1 and STAT2 in a concentration-dependent manner over that observed with IFN-α alone (Fig. 4b). The tyrosine phosphorylation of STAT1 was also increased in combination with luteolin and various concentrations of IFN-α (Supplementary Fig. 3). PKR and 2’,5’-OAS1 are IFN-α-responsive genes that contain an ISRE consensus sequence in their promoter regions. We examined the effect of apigenin on the mRNA expression of these two genes in combination with IFN-α. As shown in Fig. 4c, the mRNA expression of both IFN-regulated genes significantly increased after treatment with a combination of apigenin and IFN-α over that accompanying IFN-α treatment alone. These results indicate that apigenin enhances the activation of type I IFNs-induced JAK/STAT signaling.

Apigenin role as cell-signaling pathways modulator: implications in cancer prevention and treatment, 2021

By preventing the STAT3 phosphorylation, apigenin prevents the activation of MMPs, TWIST1 and VEGF [23]. It has been evidenced from cell lines experiments conducted on Breat Cancer cell lines (SKBR3 and MDA-MB-453,HER2), that apigenin successfully reduces the expression of STAT3, STAT5 and JAK2 thus preventing tumor proliferation and growth.

Mike Lustgarten

Apigenin also inhibits CD38, thereby boosting NAD:

https://www.youtube.com/watch?v=5-2YoGctcCk&t=5s

May Inhibit CD38 in Vivo (2013)

Apigenin is actually gaining popularity because of the possibility that it may inhibit CD38, a major NAD+ consumer which increases with age, causing the noted depletion of NAD+. Rise in CD38 may be due to any number of factors further upstream, such as inflammation. Take care that your diet is not inflammatory first. Depending on your age, diet and other factors you may notice different results with this product. That said, rather than taking NAD+ precursors, this may be a better, and relatively cheaper alternative. Until studies show us more, or until recent drugs targeting CD38 pass phase III trials, this is all we have.

CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging, 2022

Nicotinamide adenine dinucleotide (NAD) levels decline during aging, contributing to physical and metabolic dysfunction. The NADase CD38 plays a key role in age-related NAD decline. Whether the inhibition of CD38 increases lifespan is not known. Here, we show that the CD38 inhibitor 78c increases lifespan and healthspan of naturally aged mice. In addition to a 10% increase in median survival, 78c improved exercise performance, endurance, and metabolic function in mice. The effects of 78c were different between sexes. Our study is the first to investigate the effect of CD38 inhibition in naturally aged animals.

Apigenin has a great anxiolytic effect!

Within minutes after taking this product, I could experience a positive effect. I started to feel more relaxed and less nervous. I have started to take it because I read that it has this type of effect on the nervous system and the brain. Nevertheless the effect is rather on the mild side. But only one capsule a day is enough. Half life of this product in our bodies is more than 90 hours. Therefore it has a relatively long term effect. I also read that if we take a higher dosage of Apigenin it may have a sedative effect. I took two capsules a day but saw no difference, however, I still noticed a good relaxing and anxiolytic effect. Therefore, I continue with only one capsule a day. I also noticed that physically and mentally I feel less tired: I think that this is due to the fact that such flavonoids are good for strengthening for the blood vessels; thus the blood can circulate better and nurture the muscles and brain more easily. Furthermore, I read that Apigenin has a destructive effect on the proliferation of cancer cells. With so many benefits, I am surprised that Apigenin is not better known and that not more manufacturers are selling this anti-aging product.

* Sleeping better. Kind of relaxes the thoughts.

Apigenin Inhibits Renal Cell Carcinoma Cell Proliferation (2017)

We found that apigenin suppressed ACHN, 786-0, and Caki-1 RCC cell proliferation in a dose- and time-dependent manner. A comet assay suggested that apigenin caused DNA damage in ACHN cells, especially at higher doses, and induced G2/M phase cell cycle arrest through ATM signal modulation. Small interfering RNA (siRNA)-mediated p53 knockdown showed that apigenin-induced apoptosis was likely p53 dependent. Apigenin anti-proliferative effects were confirmed in an ACHN cell xenograft mouse model. Apigenin treatment reduced tumor growth and volume in vivo, and immunohistochemical staining revealed lower Ki-67 indices in tumors derived from apigenin-treated mice. These findings suggest that apigenin exposure induces DNA damage, G2/M phase cell cycle arrest, p53 accumulation and apoptosis, which collectively suppress ACHN RCC cell proliferation in vitro and in vivo. Given its antitumor effects and low in vivo toxicity, apigenin is a highly promising agent for treatment of RCC.

Dried parsley has been reported to have the maximum quantity of apigenin, at 45,035 μg/g. Additional sources of apigenin are dried flower of chamomile, containing 3,000 to 5,000 μg/g; celery seeds, containing 786.5 μg/g; and vine spinach and Chinese celery, containing 622 μg/g and 240.2 μg/g [16].

Time to Celebrate Celery (link)

It is believed apigenin works by decreasing the expression of vascular endothelial growth factor (VEGF), a protein that stimulates the formation of new blood vessels that are vital for tumor growth. In a study published in the journal Pharmacology Magazine, scientists found that rats supplemented with celery seed extract daily for 60 days significantly reduced triglycerides levels by 22% and LDL cholesterol by 27%, along with a 28% increase in beneficial HDL cholesterol.14 The lipid lowering effects of celery are due to the increased conversion of cholesterol into bile acids, which are eliminated in feces.15

In addition to its beneficial effects on lipid levels, celery also shows promise in lowering blood pressure. In the laboratory, celery seeds exhibited potent inhibition of angiotensin converting enzyme (ACE), a protein responsible for constricting blood vessels and elevating blood pressure. This may partially explain the results reported in a study published in the Tehran University Medical Journal in which 37 hypertensive patients between the ages of 45 and 65 administered 6 grams of celery seed powder significantly lowered mean systolic and diastolic readings by 17.1 and 4.4 mmHg, respectively.17

The anti-diabetic benefits of celery can also be attributed to its unique ability to fight Helicobacter pylori (H. pylori), a bacterium that leads to a near three-fold increase in the risk of type II diabetes. In a study reported in the Journal of Pharmacy and Pharmacology, researchers identified an anti-microbial compound in celery seeds that is highly effective in blocking the growth of gastric H. pylori.21