To date, ACE2 receptor is the major known entry point for SARS-CoV-2 into human cells.^cxxxviii The main protease (Mpro) is an essential enzyme required for the multiplication of these SARS-VoV-2 in the host cells.^cxxxix

Among the different classes of natural products combined, flavonoids represent the largest group of ACE2 inhibitors. In fact, several studies have previously implicated some flavonoids to possess inhibitory properties against ACE2 activity.^{cxl,cxli,cxlii,cxliii,cxliv}

Supporting ingredients: epicatechin^cxlv, luteolin^cxlvi, quercetin dihydrate^cxlvii, dihydroquercetin (taxifolin)^cxlviii

AMPk is found in every cell in the body and serves as a “master regulating switch” in energy metabolism. It helps determine your body’s balance between energy consumption and production.

AMPK also plays a crucial role in the regulation of mitochondrial homeostasis, controlling major steps in mitochondrial biogenesis and degradation.^cxlix

Researchers believe that as we age, AMPK activity significantly decreases which is a reason why we experience changes in appetite, body weight and energy levels. AMPK activators are things we think of as beneficial “stressors.” These include calorie restriction, fasting and intense exercise.^cl

AMPK is an attractive therapeutic target for several human ailments, such as end-stage renal diseases, atherosclerosis, hepatitis, myocardial ischemia/re- perfusion injury, cancer and neurodegenerative disease. Activation of AMPK can facilitate bacterial eradication in sepsis and related inflammatory conditions associated with the inhibition of neutrophil activation and chemotaxis. Activation of AMPK also inhibits NF-κB signaling and inflammation although the mechanism is not direct; hence, it has a positive impact on health and lifespan.^cli

Supporting ingredients: curcumin^clii, dihydromyricetin^cliii, dihydroquercetin^cliv, epicatechin^clv, luteolin^clvi,clvii, quercetin dihydrate^clviii, thymoquinone^clix, betaine anhydrous^clx.

Apolipoprotein B, commonly known as ApoB, is the main protein found in low-density lipoproteins (LDL). When ApoB and cholesterol particles are trapped in the arterial wall, the deposits can build up as plaque and restrict blood flow, damaging the arteries and increasing the chances of blood clots.^clxi

Apolipoprotein (apo) E is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. ApoE participates in the distribution/redistribution of lipids among various tissues and cells of the body. In addition, intracellular apoE may modulate various cellular processes physiologically or pathophysiologically, including cytoskeletal assembly and stability, mitochondrial integrity and function, and dendritic morphology and function.^clxii

Epicatechin reduces the production of apolipoprotein B (ApoB), the main protein component of LDL.^clxiii,clxiv

Supporting ingredients: dihydromyricetin^clxv, epicatechin^clxvi, luteolin^clxvii, quercetin dihydrate^clxviii, thymoquinone^clxix, betaine anhydrous^clxx.

Interleukin-1β (IL-1β) is a critical regulator of the inflammatory response.^clxxi

Supporting ingredients: astaxanthin^clxxii, curcumin^clxxiii, dihydromyricetin^clxxiv, epicatechin^clxxv, quercetin dihydrate^clxxvi, dihydroquercetin (taxifolin)^clxxvii, thymoquinone^clxxviii, betaine anhydrous.^clxxix

Interleukin-6 (IL-6) is a pro-inflammatory cytokine, induces the expression of a variety of proteins responsible for acute inflammation, and plays an important role in the proliferation and differentiation of cells in our bodies.^clxxx

Supporting ingredients: astaxanthin^clxxxi, betaine anhydrous^clxxxii, curcumin^{clxxxiii,clxxxiv}, dihydromyricetin^clxxxv, epicatechin^clxxxvi, luteolin^clxxxvii, quercetin dihydrate^clxxxviii, dihydroquercetin (taxifolin)^clxxxix,thymoquinone.^cxc

Interleukin-18 (IL-18) acts not only on the immune system but also on other systems and physiological processes, such as the endocrine system, the nervous system, and bone metabolism. Under conditions of stress, IL-18 is released from the adrenal gland, suggesting the possible involvement of IL-18 in stress-induced systemic alterations.^ccxiv,ccxv

Additionally, IL-18 induces the production of IL-17.^ccxvi

Supporting ingredients: astaxanthin^ccxvii, curcumin^ccxviii, dihydromyricetin^ccxix, quercetin dihydrate^ccxx, dihydroquercetin (taxifolin)^ccxxi, thymoquinone.^ccxxii

Interleukin-10 (IL-10) is an anti-inflammatory cytokine that maintains the balance of the immune response, allowing the clearance of infection while minimizing damage to the host.^cxcix

Supporting ingredients: astaxanthin^cc, betaine anhydrous^cci, curcumin^ccii, dihydromyricetin^cciii, quercetin dihydrate^cciv, dihydroquercetin (taxifolin)^ccv, thymoquinone^ccvi.

Interleukin-18 (IL-18) acts not only on the immune system but also on other systems and physiological processes, such as the endocrine system, the nervous system, and bone metabolism. Under conditions of stress, IL-18 is released from the adrenal gland, suggesting the possible involvement of IL-18 in stress-induced systemic alterations.^ccxiv,ccxv

Additionally, IL-18 induces the production of IL-17.^ccxvi

Supporting ingredients: astaxanthin^ccxvii, curcumin^ccxviii, dihydromyricetin^ccxix, quercetin dihydrate^ccxx, dihydroquercetin (taxifolin)^ccxxi, thymoquinone.^ccxxii

CD38 is a molecule that can act as an enzyme, with NAD-depleting and intracellular signaling activity. The role of CD38 in immune cells ranges from modulating cell differentiation to effector functions during inflammation, where CD38 may regulate cell recruitment, cytokine release, and NAD availability. In line with a role in inflammation, CD38 appears to also play a critical role in inflammatory processes during autoimmunity.^ccxxiii

Reducing chronic inflammation is an aim of healthy aging. Inflammatory profiles of senescent cells are associated with heightened CD38 activation and resulting NAD+ degradation through compounding aging and inflammation processes.^ccxxiv

Supporting ingredients: luteolin^ccxxv,ccxxvi, quercetin dihydrate^ccxxvii

COX-2 inhibitors mostly block pain and inflammation. NSAIDs (like ibuprofen and naproxen) usually affect both COX-1 and COX -2 enzymes. For this reason, these medications are called nonselective NSAIDs.

Because COX-2 inhibitors more precisely target COX-2 enzymes, they’re called selective NSAIDs. Ingredients in ACEND inhibit COX-2 enzymes.^ccxxviii

Supporting ingredients: astaxanthin^ccxxix, betaine anhydrous^ccxxx, curcumin^ccxxxi, dihydromyricetin^ccxxxii, luteolin^ccxxxiii, quercetin dihydrate^ccxxxiv, dihydroquercetin (taxifolin)^ccxxxv, thymoquinone.^ccxxxvi

Forkhead box O1 (FOXO1), is a transcription factor that contributes to hepatic lipid metabolism.

FOXO1 is an important metabolic regulator which is inactivated by insulin. Physiologically it regulates metabolism in the fasting state and under caloric restriction when insulin levels are low. FOXO transcription factors appear to orchestrate many of the beneficial responses to caloric restriction and may therefore represent an interesting target for improving metabolism in the presence of obesity and increased insulin levels.^ccxxxvii

Supporting ingredients: Betaine Anhydrous^ccxxxviii, luteolin^ccxxxix

The gene FOXO3, one of only two for which genetic polymorphisms have exhibited consistent associations with longevity in diverse human populations.

FOXO’s are involved in energy metabolism, oxidative stress, proteostasis, apoptosis, cell cycle regulation, metabolic processes, immunity, inflammation, and stem cell maintenance.^ccxl

Supporting ingredients: curcumin^ccxli, dihydroquercetin (taxifolin)^ccxlii, luteolin^ccxliii, quercetin dihydrate.^ccxliv

IGF-1 (insulin-like growth factor 1) is an important hormone involved in the growth of cells and the tissues. It has similar functions to insulin, though it’s not as strong in respect to its ability to influence blood sugar, it does help manage and maintain blood sugar levels.^ccxlv,ccxlvi

Supporting ingredients: betaine anhydrous , dihydroquercetin (taxifolin) , quercetin dihydrate^ccxlvii

Computational docking assays show that dihydromyricetin binds to a novel binding site IKKβ-Cys46, which plays a pivotal role in the pathogenesis of inflammation.^ccl

Supporting ingredients: dihydromyricetin^ccli, epicatechin^cclii, quercetin dihydrate^ccliii

The expression of inducible NOS (iNOS) occurs in conditions of inflammation and ca n produce large amounts of nitric oxide (NO). In extreme conditions iNOS is regarded as a harmful enzyme and is proposed to be a major contributor to diseases.^ccliv

Supporting ingredients: astaxanthin^cclv, curcumin^cclvi, dihydromyricetin^cclvii, epicatechin^cclviii, thymoquinone^cclix, quercetin dihydrate^cclx, dihydroquercetin (taxifolin)^cclxi, betaine anhydrous^cclxii

JNK proteins have been shown to play several vital roles in organisms, involved in the regulation of cancer, inflammatory response, DNA repair, and even aging.^cclxiii

Supporting ingredients: astaxanthin^cclxiv, curcumin^cclxv, dihydromyricetin^cclxvi, luteolin^cclxvii, thymoquinone^cclxviii, quercetin dihydrate^cclxix , dihydroquercetin (taxifolin)^cclxx

The MAPK signaling pathway is essential in regulating many cellular processes including inflammation, cell stress response, cell differentiation, cell division, cell proliferation, metabolism, motility, and apoptosis.^cclxxvi

Supporting ingredients: astaxanthin^cclxxvii, dihydromyricetin^cclxxviii, epicatechin^cclxxix, luteolin^cclxxx, thymoquinone^cclxxxi, quercetin dehydrate^cclxxxii, dihydroquercetin (taxifolin)^cclxxxiii, betaine anhydrous.^cclxxxiv

According to the World Health Organization, major depression [was] recognized as the fourth extensive cause of the worldwide in incapacity balanced life-years and could turn into the second most critical cause by 2020 (from 2019).^cclxxi By 2030, experts report that major depressive disorder (MDD) will become the main contributor to disease burden globally.^cclxxii

Monoamine oxidase (MAO) inhibitors are considered as important targets for the treatment of depression, anxiety, and neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases.

Flavonoid scaffold showed notable antidepressant and neuroprotective properties as revealed by various and established preclinical trials.^cclxxiii

Supporting ingredients: curcumin^cclxxiv, epicatechin, luteolin, proanthocyanididns, quercetin dihydrate (all listed^cclxxv)

mTOR is a protein that tells cells when to grow, divide, and survive. mTOR often mutates in cancer cells, leading to uncontrolled tumor cell growth. The National Cancer Institute (NCI) supported the basic research that demonstrated the remarkable anticancer effects of mTOR inhibitors. mTOR also increases ATP production, creates new mitochondria, and increases mitochondrial metabolism by activating PGC1a.^{cclxxxvi,cclxxxvii}

Supporting ingredients: curcumin^cclxxxviii, epicatechin^ccxc, dihydromyricetin^ccxc, luteolin^ccxci, quercetin dihydrate^ccxcii, thymoquinone^ccxciii.

NF-κB regulates multiple aspects of our immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes and plays a critical role in regulating the survival, activation and differentiation of our immune cells and inflammatory T cells.^ccxciv

Nuclear factor-κB (NF-κB), a transcription factor that is essential for inflammatory responses, is one of the most important molecules linking chronic inflammation to cancer, and its activity is tightly regulated by several mechanisms. Inflammation has been recognized as a hallmark of cancer and all known hallmarks of cancer involve NF-κB activation.^ccxcv

Supporting ingredients: astaxanthin^ccxcvi, curcumin^ccxcvii, dihydromyricetin^ccxcviii, epicatechin^ccxcix, thymoquinone^ccc, quercetin dihydrate^ccci, dihydroquercetin (taxifolin)^cccii, betaine anhydrous.^ccciii

Abnormal activation of the NLRP3 inflammasome has been linked with multiple inflammatory disorders, which include cryopyrin-associated periodic syndromes, Alzheimer’s disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, and multiple molecular and cellular events, including mitochondrial dysfunction and the production of reactive oxygen species (ROS).^ccciv

Supporting ingredients: astaxanthin^cccv, curcumin^cccvi, dihydromyricetin^cccvii, thymoquinone^cccviii, quercetin dihydrate^cccix, betaine anhydrous^cccx

Nrf2 regulates the expression of antioxidant proteins and enzymes, increasing their production to help your body fight off molecules that attack cells. It’s known as the “master regulator” of our body’s antioxidant response. When Nrf2 is activated, it enters the nucleus and turns on several hundred genes, known collectively as “survival genes.” This, in turn, initiates the production of several of your body’s own powerful enzymes that fight free radicals. These enzymes include catalase, glutathione, and superoxide dismutase (SOD).^cccxi,cccxii

Supporting ingredients: astaxanthin^{cccxi,cccxiii}, dihydromyricetin^cccxiv, luteolin^cccxv, epicatechin^cccxvi, luteolin^cccxvii, quercetin dihydrate.^cccxviii

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. It is directly related to cellular quiescence, proliferation, cancer, and longevity.^cccxix

Supporting ingredients: astaxanthin^cccxx, curcumin^cccxxi, dihydromyricetin^cccxxii, epicatechin^cccxxiii, thymoquinone^cccxxiv, quercetin dihydrate.^cccxxv

A strong link has been established between the p38 pathway and inflammation. Rheumatoid arthritis, Alzheimer’s disease and inflammatory bowel disease are all postulated to be regulated in part by the p38 pathway.^cccxxvi A variety of viral infections are related to the p38 MAPK signaling pathway, and p38 is an important host factor in virus-infected cells.^cccxxvii

Supporting ingredients: astaxanthin^cccxxviii, dihydromyricetin^cccxxix, epicatechin^cccxxx, thymoquinone^cccxxxi, quercetin dihydrate.^cccxxxii

Disproportionate increase in activated p65 and subsequent transactivation of effector molecules is integral to the pathogenesis of many chronic diseases such as the rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and even neurodegenerative pathologies. Hence, the NF-κB p65 signaling pathway has been a pivotal point for intense drug discovery and development.

Supporting ingredients: betaine anhydrous^cccxxxiii, curcumin^cccxxxiv, dihydromyricetin^cccxxxv, epicatechin^cccxxxvi, quercetin dihydrate^cccxxxvii, luteolin^cccxxxviii, thymoquinone^cccxxxix

Evidence shows that inhibiting PCSK9 reduces cardiovascular events, such as cardiovascular disease (CVD). This is mainly related to the pivotal role of PCSK9 in controlling low-density lipoprotein (LDL) cholesterol levels.

The influence on PCSK9 by ingredients in ACEND, are often due to activation of related pathways. Example, an ingredient may influence the expression of the SREBP pathway and thereby downregulates the expression of PCSK9.^cccxl,cccxli

Supporting ingredients: curcumin^cccxlii, luteolin^cccxliii, quercetin dihydrate^cccxliv

Plant derived PPARγ modulators contribute to insulin sensitivity without detrimental side effects.^cccxlv

Supporting ingredients: astaxanthin^cccxlvi, curcumin^cccxlvii, luteolin^cccxlviii, quercetin dihydrate^cccxlix, vitamin E^cccl

‘Reactive oxygen species’ (ROS) represents a wide variety of oxidant molecules with vastly different properties and biological functions that range from signaling to causing cell damage.^cccli ROS-related disease can be either due to a lack of ROS (e.g., certain autoimmune disorders) or a surplus of ROS (e.g., cardiovascular, and neurodegenerative diseases).^ccclii

Supporting ingredients: astaxanthin^cccliii, curcumin^cccliv, dihydromyricetin^ccclv, epicatechin^ccclvi, luteolin, thymoquinone^ccclvii, quercetin dihydrate^ccclviii, dihydroquercetin (taxifolin).^ccclix

SIRT1 has been connected in gene expression, metabolism, and aging. SIRT enzymes are thought to “turn off” certain genes that promote aging, such as those involved in inflammation, fat synthesis and storage, and insulin resistance.^ccclx

Supporting ingredients: astaxanthin^ccclxi, curcumin^ccclxii, dihydromyricetin^ccclxiii, dihydroquercetin^ccclxiv, luteolin^ccclxv, thymoquinone^ccclxvi, quercetin dihydrate.^ccclxvii

SIRT3 has been shown to be involved in almost all aspects of mitochondrial metabolism and homeostasis, protecting mitochondria from damage. Accumulating evidence has recently documented that SIRT3 is associated with many types of human diseases, including age-related diseases, cancer, heart disease and metabolic diseases.^{ccclxviii,ccclxix,ccclxx}

Supporting ingredients: curcumin^ccclxxi, epicatechin^ccclxxii, dihydromyricetin.^ccclxxiii

The activation of the sirtuins — particularly SIRT6 — is associated with an increase in both median and maximum lifespan in several life forms, and a similar increase in health span. It is a target of several diseases such as cancer, neurodegenerative diseases, aging, diabetes, metabolic disorder, and heart disease.^ccclxxv

Supporting ingredients: curcumin^ccclxxvi, epicatechin^ccclxxvii, luteolin.^ccclxxviii

The STAT 1 protein plays a key role in the immune response against pathogens.^{ccclxxix,ccclxxx,ccclxxxi}

Supporting ingredients: luteolin^ccclxxxii

STAT-3 serves critical roles in several cellular processes, including the cell cycle, cell proliferation, cellular apoptosis and tumorigenesis.^{ccclxxxiii,ccclxxxiv}

Supporting ingredients: curcumin^ccclxxxv, quercetin dihydrate^ccclxxxvi, dihydroquercetin (taxifolin).^ccclxxxvii

STAT5 proteins regulate cellular functions such as proliferation, differentiation, and survival. STAT5 plays an important role in the maintenance of normal immune function and homeostasis,^ccclxxxviii

Supporting ingredients: dihydromyricetin.^ccclxxxix

TLR4 is the sensor that orchestrates inflammatory responses through a series of well-characterized downstream cascades. To ensure immunity, and yet limit pathology, inflammatory responses must be confined within the proverbial “Goldilocks zone” and TLR4 does this.^cccxc

Supporting ingredients: curcumin^cccxci, dihydromyricetin^cccxcii, quercetin dihydrate^cccxciii, betaine anhydrous.^cccxciv

TNFa (tumor necrosis factor alpha) is produced by cells in your immune system that has many effects in promoting the inflammatory process. It is produced chiefly by macrophages, a type of white blood cell, but can be produced by other cells as well. TNFa is a major cause of the excess inflammation that drives rheumatoid arthritis (RA).^cccxcv

Supporting ingredients: astaxanthin^cccxcvi, curcumin^cccxcvii, dihydromyricetin^cccxcviii, dihydroquercetin^cccxcix, luteolin^cd, thymoquinone^cdi, quercetin dihydrate^cdii, betaine anhydrous.^cdiii

VEGF is one of the most important inducers of angiogenesis (the formation of new blood vessels). It’s normally an important process that supports wound healing and supplies oxygen-rich blood to your organs and tissues. But in people with cancer, angiogenesis supports tumor growth and spread by feeding tumors with oxygen and nutrients. Blocking angiogenesis has led to great promise in the treatment of various cancers and inflammatory diseases.^cdiv,cdv

Supporting ingredients: curcumin^cdvi, dihydromyricetin^cdvii, epicatechin^cdviii, thymoquinone, dihydroquercetin (taxifolin)^cdix, quercetin dihydrate.^cdx