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Natural Yellows - For Obesity and Non-Alcoholic Liver Disease

Excess body weight is associated with many health concerns, and is rapidly  becoming the number one health problem worldwide. among the health risks are diabetes, cardiovascular disease, cancer and premature death. (1)  Individuals of the obese classification are especially subject to deleterious health implications. Obesity results in:

• Visceral Fat. Excessive adipose tissue, especially dangerous visceral fat surrounding internal organs, and
• Non-alcoholic fatty liver disease (NAFLD) is the most ubiquitous cause of liver disorder worldwide and is attributed to obesity and diabetes. NAFLD affects approximately 25% of the global population.(22). Insulin resistance is a major contributor to NAFLD. Ultimately, NAFLD may lead to liver cirrhosis and liver failure.

Visceral Fat - Obesity results in increases of visceral fat. Visceral fat (also known as belly fat) is the fat that accumulates around organs in the abdominal cavity and is linked to serious diseases, including type 2 diabetes. metabolic syndrome and those affecting organ functioning. Significant levels of inflammatory proteins are generated by visceral fat. In fact, inflammation of the liver which precedes HDLF, is mediated by visceral fat inflammatory proteins.(2)

• Heart visceral fat - Accumulation of fat surrounding the heart may have profound effects on the myocardium and functioning of the heart. In obese lab animals, the heart visceral fat (white fat) increased inflammation of the heart, including hypertrophy of the cardiomyocytes and fibrosis. Further, these changes to the heart are significantly related to increased rates of heart failure.(3) Such changes were not seen in lean animals which had a significant amount of brown fat adjacent to the heart muscle.
• Kidney visceral fat - Visceral fat deposits around the kidney are associated with both chronic kidney disease as well as cardiovascular disease.(4)
• Pancreatic Visceral Fat - Increased levels of pancreatic fat coincide with pancreatic cancer and pre-cancer lesions.(5)

Nonalcoholic fatty liver disease (NAFLD) - Obesity is a significant risk factor in the development of NAFLD.  Most noteworthy, is the excessive buildup of triglycerides in the liver which causes metabolic disturbances throughout the body. As a result, fatty acid metabolism becomes impaired, which may lead to fatty acid intermediates which causes insulin resistance and cardiovascular disease. 

Adipose Tissue and Aging - White adipose tissue, associated with obesity,  is the most affected tissue in aging. As the adipose tissue ages, there is a significant increase in oxidative stress and the generation of  inflammatory proteins resulting in  chronic low grade inflammation. In turn, this further damages tissue and accelerates aging. (6) 

• Telomere Shortening - Telomere shortening is a marker of aging. (7) Appears to be associated with obesity and increased insulin resistance.
• Insulin Resistance - Insulin resistance prevents blood sugar from being removed from the blood. The result is hyperglycemia which damages structures in the body. Eventually this become diabetes.
• Diminishes Immune Response - Increased inflammation from adipose tissue contributes to loss of innate immunity response during aging.(8)
• Impairs Stem Cell Regenerative Ability - Adipose tissue stem cells are impacted by adipose tissue inflammation. The result is the senescence of the stem cells and loss of tissue repair and regeneration.(9).
• Loss of Healthy Fat Cell (Stromal Cells) Renewal - Healthy adipose tissue requires renewal of adipose stromal cells. The stromal cells ensure the production of new healthy adipose cells. Obesity contributes to the loss of the stromal cells.(10)

INGREDIENTS:

• Berberine - Inhibits the inflammation of the liver associated NAFLD. Inflammation is a key event in the progression of NAFLD. (11) Also enhances brown adipose fat activity, which promotes thermogenesis, which dissipates harmful white adipose tissue,(12) Furthermore, berberine inhibits the proliferation of white fat adipocytes, thereby suppressing the formation of fat associated with obesity.(13) Berberine also reduces insulin resistance which improves glucose tolerance and NAFLD.(14).
• Apigenin - Reduces abdominal visceral obesity and weight. Abdominal visceral fat promotes metabolic syndrome including inhibition of adipocytes  (fat cells). Does not affect subcutaneous fat, which lies just under the skin.(15) Apigenin also improves NAFLD and Insulin resistance.(16) 
• Saffron - Improves insulin sensitivity,(16) Possesses a protective effect against NAFLD and fatty liver induced damage.(17)
• Curcumin - Reduces insulin resistance by enhancing GLUT4 gene expression (the receptor for Glucose transport into the cell).(18)
• Fisetin - Offers protection to suppress NAFLD initiation and progression.(19)
• Rosmarinic Acid - Ameliorates liver damage by NAFLD, by increasing antioxidant enzymes and activating AMPK. inhibiting hepatic fibosis and inflammation of the liver.(20) Rosmarinic acid also acts as an anti-obesity agent by inhibiting adipogenesis (the formation of fat tissue), and increasing lipolysis (the breakdown of fat), Also reduced adipocyte associated inflammation.(21)
• Pterostilbene -  Enhances brown adipose tissue activation. Increases thermogenesis and promotes browning of white adipose tissue,(23) Offers protective effect on liver steatosis.(24)
• Ursolic Acid - Targets insulin resistance and mitigating the effects of liver fibrosis. (25,26) Obesity disrupts insulin signaling, thereby promoting insulin resistance. Furthermore, visceral fat in obesity sets off cascading generation of proinflammatory cytokines. Ursolic acid may improve these conditions. 

YELLOW LONGEVITY® (Berberine | Apigenin | Saffron)

VASCULAR VX™

 CURCUMIN PXC™(Curcumin | Fisetin | Pterostilbene) 

 HYPER LONGEVITY™ (Ursolic Acid | Rosmarinic Acid)

REFERENCES:

(1)  Unamuno Xm et al. Adipokine dysregulation and adipose tissue inflammation in human obesity. Eur J Clin Invest. 2018 Sep

(2)  Casagrande BP, et al. Hepatic inflammation precedes steatosis and is mediated by visceral fat accumulation.  J Endocrinol. 2020 Mar 1

(3) Conceição G, et al. Fat Quality Matters: Distinct Proteomic Signatures Between Lean and Obese Cardiac Visceral Adipose Tissue Underlie its Differential Myocardial Impact. Cell Physiol Biochem. 2020 Apr 23

(4) Huang N, et al. Novel insight into perirenal adipose tissue: A neglected adipose depot linking cardiovascular and chronic kidney disease. World J Diabetes, 2020 Apr 15

(5) Sreedhar UL, et al. A Systematic Review of Intra-pancreatic Fat Deposition and Pancreatic Carcinogenesis. J Gastrointest Surg. 2019 Nov 20

(6) Yu Q, et al. Sample multiplexing for targeted pathway proteomics in aging mice. Proc Natl Acad Sci USA. 2020 Apr 24

(7) Mangge H, et al. Telomere shortening associates with elevated insulin and nuchal fat accumulation. Sci Rep. 2020 Apr 22

(8) Goldberg EL, et al. How Inflammation Blunts Innate Immunity in Aging. Interdiscip Top Gerontol Geiatr.  2020

(9) Conley SM, et al. Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells. Front Cell Dev Biol. 2020 Mar 26

(10) Eckel-Mahan K, et al. Adipose Stromal Cell Expansion and Exhaustion: Mechanisms and Consequences. Cells 2020 Apr 2

(11) Wang Y, et al. Berberine inhibits free fatty acid and LPS-induced inflammation via modulating ER stress response in macrophages and hepatocytes. PLoS One. 2020 May 1

(12) Horvath C, et al. Feeding brown fat: dietary phytochemicals targeting non-shivering thermogenesis to control body weight. Proc Nutr Soc, 2020 Apr 

(13) Wang C, et al. Berberine inhibits adipocyte differentiation, proliferation and adiposity through down-regulating galectin-3.

(14) Yu SJ, et al. Berberine alleviates insulin resistance by reducing peripheral branched-chain amino acids.  Am J Physiol Endocrinol Metab. 2019 Jan

(15) Su T, et al. Apigenin inhibits STAT3/CD36 signaling axis and reduces visceral obesity.  Pharmacol Res. 2020 Feb

(16) Jung UJ, et al. Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice.  Nutrients. 2016 May

(16) Yaribeygi H, et al.  Antidiabetic potential of saffron and its active constituents. J Cell Physiol, 2019 Jun

(17) Mashmoul M, et al. Protective effects of saffron extract and crocin supplementation on fatty liver tissue of high-fat diet-induced obese rats. BMC Complement Altern Med. 2016 Oct

(18) Al-Saud NBS.  Impact of curcumin treatment on diabetic albino rats. Saudi J Biol Sci. 2020 Feb;27

(19) Gaballah HH, et al, Mitigative effects of the bioactive flavonol fisetin on high-fat/high-sucrose induced nonalcoholic fatty liver disease in rats. 

(20) Kim M, et al.  Lemon Balm and Its Constituent, Rosmarinic Acid, Alleviate Liver Damage in an Animal Model of Nonalcoholic Steatohepatitis. Nutrients. 2020 Apr 22

(21) Rui Y, et al. Rosmarinic acid suppresses adipogenesis, lipolysis in 3T3-L1 adipocytes, lipopolysaccharide-stimulated tumor necrosis factor-α secretion in macrophages, and inflammatory mediators in 3T3-L1 adipocytes. Food Nutr Res. 2017 Jun

(22) Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology, 2016 Jul;

(23) Milton-Laskibar L, et al.  Effects of resveratrol and its  derivative pterostilbene on brown adipose tissue thermogenic activation and on white adipose tissue browning process. J Physiol Biochem. 2020 Mar 13

 (24) Gomez-Zorita S, et al. Effects of Pterostilbene on Diabetes, Liver Steatosis and Serum Lipids. Curr Med Chem. 2019 Oct 29

(25) Gonzales-Garibay AS, et al,  Effect of Ursolic Acid on Insulin Resistance and Hyperinsulinemia in Rats with Diet-Induced Obesity: Role of Adipokines Expression.  J Med Food. 2020 Mar;23

(26) 

Two times Power of Anti-Aging Resveratrol - Ursolic Acid and Rosmarinic Acid

Resveratrol has long been known as an natural anti-aging gene activator. The target of this activation is SIRT1. Research now indicates that another extract  (ursolic acid) is even more powerful than resveratrol in the activation SIRT1. Furthermore, the extracts ursolic acid and rosmarinic acid promote anti-aging in other ways,, including preservation of the functioning of the hypothalamus (implicated as playing a significant role in the aging process), inhibiting fibrosis (amyloid and tau) and inhibiting NOX2 and NOX4.

URSOLIC ACID

• SIRT1 Activator - Ursolic acid is a powerful activator of anti-aging protein SIRT1. In fact, when compared to resveratol, ursolic acid is double the power of activating SIRT1 versus resveratol.(1)

• Hypothalamus Anti-Aging - Recent research indicates that the hypothalamus is an important determinant in longevity, Dysregulation of the hypothalamus during aging affects the neuroendocrine system, and contributes to the exhaustion of stem cells, and the loss of proteostasis.(2) Ursolic acid beneficially supports health of the hypothalamus by enhancing levels of anti-aging SIRT1, SIRT6, PGC-1β and α-Klotho.(3)

• Nrf2 Preservation - Nrf2 is the master protein activator of the endogenous antioxidant system in the body, and is related to increased longevity. Ursolic acid is a potent inhibitor of the degradation of Nrf2, which supports increased level of Nrf2. (4)

ROSMARINIC ACID

• Longevity Extender -  In experimental studies with c. elegans, rosmarinic acid significantly extended lifespan by increasing anti-aging gene expression of daf-16 and other proteins.(5) 

• NOX2 and NOX4 (NADPH oxidases) Inhibitor - NOX2 and NOX4 play critical roles in aging.
• NOX2 - involved in hypertension, atherosclerosis, cardiac hypertrophy, diabetes and aging. The inhibition of NOX-2 is proposed for maintaining cardiovascular homeostasis.(6)
• NOX4 - involved in cellular senescence. The inhibition of NOX-4 may support anti-aging in body, which is expressed in many organs in the body.(7)
• Both NOXs are viewed as potential therapeutic targets to block.
• Rosmarinic acid inhibits both NOX2 and NOX4.(7)

• Amyoid Aggregation Inhibitor  -  An important hallmark of aging, both in the brain (Alzheimers Disease) and throughout the body, is the formation of amyloid fibril aggregates.
• While resveratrol has been shown to be inactive in the inhibition of aggregate formation,  rosmarinic acid, is shown as a powerful inhibitor.(8)
• Tau Aggregation Inhibitor - Insoluble tau protein is another protein abnormality (in conjunction with amyloid) associated with Alzheimer's Disease in the brain. Aging and chronic stress may induce tau aggregation. In lab animals, rosmarinic acid was shown to reduce tau protein aggregation. (9)

• Glycation Inhibitor - Supports Elastic Arteries and Skin. Glycation is the damaging of protein structure, accelerating aging of all protein structures in the body. Includes loss of elasticity of skin and arterial function.
• Glycation results in stiffness of the skin (and old appearance) and arteries. All indicators of significant aging. Rosmarinic acid was shown to improve the parameters of skin and arterial elasticity in human test subjects.(10)

• Insulin Resistance - AMPK. Rosmarinic acid significantly reduced skeletal muscle insulin resistance in insulin resistant lab animals. Rosmarinic acid activated AMPK in the muscle, which resulted in increased mitochondrial biogenesis,(11)

HYPER LONGEVITY  (Ursolic Acid | Rosmarinic Acid)

REFERENCES:

(1) Bakhtian N, et al. Mounting evidence validates Ursolic Acid directly activates SIRT1: A powerful STAC which mimic endogenous activator of SIRT1. Arch Biochem Biophys. 2018 Jul

(2) Kim K, et al. Role of hypothalamus in aging and its underlying cellular mechanisms. Mech. Ageing Dev. 2018. May.

(3) Bahrami SA, et al Ursolic acid regulates aging process through enhancing of metabolic sensor proteins level. Biomed Pharmacother, 2016 Aug

(4) Kamble SM, et al. In silico Evidence for Binding of Pentacyclic Triterpenoids to Keap1-Nrf2 Protein-Protein Binding Site. Comb Chem High Throughput Screen. 2017

(5) Wang F, et al. The Molecular Mechanism of Rosmarinic Acid Extending the Lifespan of Caenorhabditis elegans. Applied Mechanics and Materilals. 2011.

(6) Forte M, et al. The Pathophysiological Role of NOX2 in Hypertension and Organ Damage. High Blood Press. Cardiovasc Prev. 2016 Dec

(7) Revoltella S, et al. Identification of the NADPH Oxidase 4 Inhibiting Principle of Lycopus europaeus. Molecules. 2018 Mar.

(8) Ramazzotti M, et al, Mechanism for the inhibition of amyloid aggregation by small ligands.Biosci Rep. 2016 Sept.

(9) Shan Y, et al. Aging as a Precipitating Factor in Chronic Restraint Stress-Induced Tau Aggregation Pathology, and the Protective Effects of Rosmarinic Acid.  J Alzheimers Dis. 2016

(10) Yui S, et al. Beneficial Effects of Lemon Balm Leaf Extract on In Vitro Glycation of Proteins, Arterial Stiffness, and Skin Elasticity in Healthy Adults. J Nutr Sci Vitaminol (Tokyo) 2017

(11) Jayanthy G, et al, Rosmarinic Acid Mediates Mitochondrial Biogenesis in Insulin Resistant Skeletal Muscle Through Activation of AMPK. J Cell Biochem. 2017 Jul