Metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of sustained environmental exposure.*

Heavy metals are ubiquitous in the environment present, in our food air and water and with vast industrial, domestic, agricultural, medical and technological applications there are multifactorial harmful effects on human biological systems and vital organ function. The effects accumulate over a lifetime from various sources of exposure. Children and the foetus are most at risk of harm, with early exposures in utero and early childhood potentially predisposing to multisystem ailments, as well as lower IQ and dysfunctional behaviour. Chronic low level exposure is associated with cognitive deficits and behavioural changes in both children and adults.*

Systemic affects of cellular toxicity include symptoms of:*

Central nervous system

Cardiovascular system

Gastrointestinal system

Respiratory system

Endocrine system

Skeletal system

Vital Organ Function

Liver Detoxication Phases

Phase I (CYP450 Enzymes) takes toxic molecules and alters them slightly so that they can be bound to a carrier molecule. The side effect of these toxins being altered is that they are more toxic. CelDTX induces CYP450 enzymes and increases superoxide dismutase protecting the body from free radicals. Phase II (Conjugation) takes these free radicals and binds them up with a safe carrier molecule, like glutathione, making them less toxic and able to move out of the body. CelDTX enhances glutathione levels to ensure sufficient amount to bind to the toxic molecules so they can be transported out of the body. Heavy metals like lead, mercury, and arsenic are detoxified and removed. Phase III (Transportation) is about moving toxins to where they need to be in order to get physically out of the body: mostly through the cells of the kidney, liver, and intestines. CelDTX reduces intestinal inflammation, support digestion function and protect organs from toxins. Optimal phase II and III detoxification requires the activation of the “cellular master switch” which is known as the Nrf2 protein.[1] This protein turns on the intracellular production of several antioxidants, including glutathione, and glutathione-S-transferase, the phase II enzyme that serves to bind glutathione to toxins for subsequent elimination from the cell. There are many natural substances that can activate Nrf2 including lipoic acid, selenium, pine bark extract, and Vitis vinifera. In addition, intracellular levels of glutathione can be enhanced with R-lipoic acid.[2]*

Cysteine

Cysteine is a sulfur-containing amino acid indicated to meet the nutritional needs of patients with severe liver disease who may have impaired enzymatic processes. Glutathione (GSH) is the most abundant non-protein thiol in mammalian cells, reaching an intracellular concentration in mM range, whereas its plasma concentration does not exceed micromolar range. In the cell, 90% of GSH is located in the cytoplasm, 10–12% in the mitochondria, and a small percentage in the endoplasmic reticulum (ER). This small tripeptide is composed of glutamate, cysteine, and glycine. Its biosynthesis is a two-step enzymatic cascade, including first a specific γ-ligation of glutamate and cysteine by γ-glutamate-cysteine ligase (GCL) and then the formation of peptide bond between this dipeptide and glycine by glutathione synthetase (GS).*

Cysteine availability is the limiting factor of GSH synthesis. GSH is involved in many important cellular functions via its key role in antioxidant defense, protecting the cell against free radicals produced as metabolic by-products, either directly or indirectly. Numerous studies demonstrated that this small molecule is crucial in many different human diseases such as aging, diabetes, acquired immune deficiency syndrome (AIDS), as well as neurodegenerative and liver diseases. The importance of glutathione in tumor metabolism and particularly in resistance mechanisms has been widely studied during the last decades. One of the well-described roles played by GSH is the detoxification of xenobiotics such as different drugs, and thus it is fundamental for the resistance to chemo-, but also radiotherapy. Indeed, multidrug and radiation resistance in tumor cells have been associated with higher intracellular levels of GSH, and increased level of GSH is a poor prognostic factor in many types of cancer.[3]*

Glutamine

Glutamine has also been demonstrated as a conditional essential amino acid, which plays a central role in the response to injury; and GLN also supports acid-base homeostasis, maintains the function and morphology of the gastrointestinal epithelium, preserves the stores of antioxidants in tissues, enhances the immune response and augments host defences.*

Through normal metabolic pathways, glutamine is converted to glutamate, which is used in the intracellular synthesis of Glutathione. It has been proposed that glutamine most effectively increases GSH levels during times of Glutathione depletion.[4]*

Ageing is associated with declining activity of the growth hormone-insulin-like growth factor-1 (hGH and IGF-1) axis and with a decrease in cognitive function. The stimulatory effect of an orally administered nutritional supplement, mainly containing glycine, glutamine and niacin on the hGH-IGF-1 axis and on mood and cognition was investigated. Forty-two healthy subjects (14 men and 28 women, aged 40-76 years) were enrolled in a randomised, double blind, placebo-controlled trial. They received 5 g of a nutritional supplement or placebo, twice daily orally for a period of 3 weeks. At baseline and after 3 weeks, blood was collected for measurement of serum hGH and IGF-1 levels and mood and cognitive function were tested. The nutritional supplement ingestion for 3 weeks was found to increase serum hGH levels with 70% relatively to placebo, whereas circulating IGF-1 levels did not change. Mean hGH (+/- SD) increased in this group from 3.23 (+/- 4.78) to 4.67 mU/l (+/- 5.27) (p = 0.03). The hGH increase was not associated with improvement in mood or memory. Correlation analyses, however, revealed that individual increases in IGF-1, but not hGH, were associated with improved memory and vigour. It is concluded that an oral mixture of glycine, glutamine and niacin can enhance hGH secretion in healthy middle-aged and elderly subjects.[5]*

R-alpha Lipoic acid

R-alpha Lipoic acid enhances glutathione (GSH) levels. Glutathione is the most important water-soluble anti-oxidant and is linked to detoxification of xenobiotics, modulation of signal transduction, prostaglandin metabolism, regulation of immune response, control of enzyme activity, and peptide hormones, etc. The availability of the amino acid Cysteine is known as the rate-limiting factor in glutathione synthesis. Lipoic acid is taken up rapidly by the cell and reduced to DHLA, which in turn reduces cystine to cysteine and accelerates the biosynthesis of GSH.*

R-alpha Lipoic acid acts as a potent antioxidant on its own, serves to regenerate other antioxidants like vitamin E, vitamin C, and glutathione, and increases the production of glutathione.[6] Clinical studies with rats have demonstrated that supplementation with R Alpha Lipoic acid improved mitochondrial function, increases metabolic rate, and decreases oxidative damage.[7]*

Neurodegenerative conditions

Alpha-lipoic acid (α-LA) has been demonstrated to be protective against cerebral ischemia injury. α-LA significantly reduced the infarct volume, brain oedema, and oxidative damage and promoted neurologic recovery in rats. Pre-treatment of α-LA caused an obvious increase in cell viability and a decrease in intracellular reactive oxygen species. Western blot analyses and immunofluorescence staining demonstrated a distinct increase in Nrf2 and HO-1 protein expression. Conversely, knockdown of Nrf2 or HO-1 resulted in the down-regulation of HO-1 protein and inhibited the neuroprotective effect of α-LA.*

α-LA treatment is neuroprotective and promotes functional recovery after ischemic stroke by attenuating oxidative damage, which is partially mediated by the Nrf2/HO-1 pathway.[8]*

Oxidative damage caused by increased ROS in neurons is a consequence of a number of mechanisms associated with senescence, and the role of mitochondria seems to be crucial in the cascade of AD pathology events. Interventions for mitochondrial dysfunction have the potential to reduce cognitive decline in AD as a consequence of re-establishing glucose and lipid metabolism, calcium homeostasis, and the regulation of cell death signalling pathways. In this sense, antioxidants, such as α-LA, are potential candidates in the strategy of restoring mitochondrial function, with evident benefits on mitobiogenesis, besides acting as a cofactor of mitochondrial enzymatic complexes—an essential pathway for energy production and metabolic regulation and directly scavenging ROS. In addition, α-LA shows effects on inflammasomes, on the one hand by reducing proinflammatory mediators such as IL-2, IFN-γ, and TNF-α, and on the other hand by increasing anti-inflammatory cytokines, such as IL-10. Additionally, the effects of α-LA show high coverage of sites of action, being considered a regulator of the expression of some genes, for example, the genes that code for nuclear factors Nrf2 and NF-κB. Thus, α-LA is an agent with multiple actions on the cellular machinery, acting in several mechanisms that are involved in the pathology of AD.[9]*

Pinus radiata (Pine bark)

Pycnogenol (Pine bark) increased the intracellular GSH content and activities of GSH peroxidase and GSH disulfide reductase, indicating its ability to modulate the GSH redox cycle. The activity of antioxidant enzymes catalase and superoxide dismutase also increased with Pycnogenol treatment. These results suggest that the anti-inflammatory effect of Pycnogenol may at least in part be due to its ability to modulate the GSH redox cycle and activities of catalase and superoxide dismutase.[10]*

The extract from the pine bark consists of bioflavonoids, catechins, procyanidins and phenolic acids. It acts as powerful antioxidant, chelating agent; it stimulates the activities of some enzymes, like SOD, eNOS, and exhibits other biological activities. Attention deficit hyperactivity disorder (ADHD) belongs to the neurodevelopmental disorders characterised by impulsivity, distractibility and hyperactivity. In the pathogenesis of ADHD genetic and non-genetic factors play an important role. It is assumed that one of non-genetic factors should be oxidative stress caused a significant decrease in GSSG and a highly significant increase in GSH levels as well as improvement of GSH/GSSG ratio in comparison to a group of patients taking a placebo. Total Antioxidant Status (TAS) in children with ADHD was decreased in comparison with reference values.[11]*

Vitis vinifera (Grape seed extract)

We evaluated the role of grape seed extract on lipid peroxidation and antioxidant status in discrete regions of the central nervous system of young and aged rats. Male albino rats of Wistar strain were divided into four groups: Group I—control young rats, Group II—young rats treated with grape seed extract (100 mg/kg body weight) for 30 days, Group III—aged control rats and Group IV—aged rats supplemented with grape seed extract (100 mg/kg body weight) for 30 days. Age-associated increase in lipid peroxidation was observed in the spinal cord, cerebral cortex, striatum and the hippocampus regions of aged rats (Group III). Activities of antioxidant enzymes like superoxide dismutase; catalase, glutathione peroxidase and levels of non-enzymic antioxidants like reduced glutathione, Vitamin C and Vitamin E were found to be significantly decreased in all the brain regions studied in aged rats when compared to young rats. However, normalised lipid peroxidation and antioxidant defences were reported in the grape seed extract-supplemented aged rats. These findings demonstrated that grape seed extract enhanced the antioxidant status and decreased the incidence of free radical-induced lipid peroxidation in the central nervous system of aged rats.[12]*

Neuroprotective and Cognition

Co-administration of Vitis vinifera extract with aluminium (Al) caused significant improvement in the short-term memory, cognition, anxiety, locomotion and muscular activity. Al exposure led to a significant decrease in the acetylcholinesterase activity in the brain, increase in serum glucose, TG, TC, ALP and ALT. Anti-oxidant parameters-reduced glutathione, catalase and glutathione reductase levels were also found to be significantly decreased but the levels of lipid peroxidation was significantly increased in brain following Al treatment. V. vinifera extract supplementation to Al treated animals caused a significant improvement in the activity of enzyme acetylcholinesterase which was altered by Al. Serum glucose, TG, TC, ALP and ALT were brought back to normal levels. Further, V. vinifera extract when given along with Al was also able to regulate the levels of Anti-oxidant parameters in brain and the values were found close to the normal controls. This study strengthens the hypothesis that V. vinifera extract can be used as a neuroprotectant during Al induced neurotoxicity.[13]*

Lycium chinense (Gou qi zi)

Treatment with Lycium chinense polysaccharides (LBPs) in a D-galactose induced mouse aging model resulted in enhanced lymphocyte proliferation and interleukin (IL)-2 activity, learning and memory ability and SOD activity of erythrocytes.[14] LBPs increased SOD, CAT and GSH-Px levels and reduced MDA concentration in the blood. It also improved skin SOD activity, reduced skin MDA content, and increased Hyp content.[15] [16] LBPs administration also significantly increased antioxidant enzyme activities and decreased creatine kinase activities. Antioxidant activity of LBPs has also been seen in humans. Thirty days intake of LBPs increased antioxidant efficacy in humans.[17] In summary, LBPs can increase the contents of antioxidant enzymes and decrease the content of MDA in the model aging group, indicating that it can protect tissues from the attack of oxidants and free radicals, thereby exerting its anti-aging effect.*

Gou qi zi increases non-specific immunity and increases phagocytic activity of the macrophages and the total number of T cells.[18]*

The antioxidant activity of polysaccharides extracted from Lycium barbarum fruits was evaluated. Six established in vitro methods, including superoxide radical (O2 -) scavenging activity, reducing power, ß-carotene linoleate model, inhibition of mice erythrocyte haemolysis mediated by peroxyl free radicals, 1,1- diphenyl-2 picrylhydrazyl (DPPH) radical-scavenging, and metal chelating activity were used in our evaluation. The polysaccharides showed considerable inhibitory activity in the ß-carotene–linoleate model system in a concentration-dependent manner. Further, they exhibited moderate concentration-dependent inhibition of the DPPH radical. The multiple antioxidant activity of the polysaccharides was evidenced by significant reducing power, superoxide scavenging ability, inhibition of mice erythrocyte haemolysis mediated by peroxyl free radicals, and also ferrous ion chelating potency.[19]*

Research shows that dang shen has adaptogenic, anti-fatigue, and anti-ageing and anti-anoxic effects. Studies show that it improves learning and memory and improves immunity as well.[20] Dang Shen also inhibits cholinesterase activity or increases acetylcholine content.[21]*

Codonopsis pilosula (Dang Shen)

Codonopsis pilosula polysaccharides has been shown to significantly increase glutathione levels.[22] Xu et al. [58] found that after the oral administrated the polysaccharide from C. pilosula for 8 weeks, the polysaccharide was able to increase the thymus index and spleen index as well as the activities of SOD in serum and liver, glutathione peroxidase and nitric oxide synthase particularly in kidney, while decreasing MDA in serum and liver and lipofuscin in brain. Its postponement of senility might be related to raising immunity, eliminating free radicals and anti-lipoperoxidation.[23] [24]*

Cytotoxicity of Codonopsis pilosula against human hepatocellular carcinoma.

Two water-soluble polysaccharides named CPP1a and CPP1c were isolated from C. pilosula. Further, the cytotoxicity assay indicated that CPP1a and CPP1c were more sensitive to HepG2 cells than cervical carcinoma Hela cells and gastric carcinoma MKN45 cells. Both of CPP1a and CPP1c could influence cell morphology, inhibit the migration and induce apoptosis by affecting the G2/M phase of HepG2 cells. Preliminary mechanism studies confirmed that CPP1a and CPP1c could induce apoptosis through up-regulating the ratio of Bax/Bcl-2 and activating caspase-3. According to previous research, we might speculate that the reason for the stronger cytotoxicity and pro-apoptotic effect of CPP1c than that of CPP1a can be attributed to its high uronic acid content.[25]*

Selenium

Poor dietary selenium (Se) intake and status have been shown to be associated with an elevated risk for various diseases. Key role of Se in human metabolism is attributed to its presence in the glutathione peroxidase (GSH-Px) – an antioxidant enzyme which protects cells against harmful effects of free radicals. Se has an immunostimulant and anti-inflammatory effect [5] and it is highly dependent on dietary sources.[26]*

Selenium (Se) Stimulates Cadmium (Cd) Detoxification in Caenorhabditis Elegans Through Thiols-Mediated Nanoparticles Formation and Secretion. The Cd-Se interaction, mediated by multiple thiols, including glutathione and phytochelatin, resulted in the formation of less toxic cadmium selenide (CdSe)/cadmium sulfide (CdS) nanoparticles. The CdSe/CdS nanoparticles were mainly distributed in the pharynx and intestine of the nematodes, and continuously excreted from the body, which also benefitted the C. elegans survival.[27]*

References

[1] Keum YS. Regulation of Nrf2-mediated phase II detoxification and anti-oxidant genes. Biomol Ther. 2012;20(2):144-151.

[2] Packer L, et al. Alpha-lipoic acid as a biological antioxidant. Free Radical Bio Med. 1995;19:227-250.

[3] Daher B, Vučetić M, Pouysségur J. Cysteine Depletion, a Key Action to Challenge Cancer Cells to Ferroptotic Cell Death. Front Oncol. 2020;10:723. Published 2020 May 7. doi:10.3389/fonc.2020.00723

[4] Yu JC, Jiang ZM, Li DM. Glutamine: a precursor of glutathione and its effect on liver. World J Gastroenterol. 1999;5(2):143-146. doi:10.3748/wjg.v5.i2.143

[5] Nutr Neurosci. 2003 Oct; 6(5): 269-75.

[6] Biochem Mol Biol Int 1995; 37:591-597.

[7] Passwater, RA. "Lipoic Acid: The Metabolic Antioxidant". Keats Publishing, Inc; 1995:1-47.

[8] Lv C, Maharjan S, Wang Q, et al. α-Lipoic Acid Promotes Neurological Recovery After Ischemic Stroke by Activating the Nrf2/HO-1 Pathway to Attenuate Oxidative Damage. Cell Physiol Biochem. 2017;43(3):1273-1287. doi:10.1159/000481840

[9] Dos Santos SM, Romeiro CFR, Rodrigues CA, Cerqueira ARL, Monteiro MC. Mitochondrial Dysfunction and Alpha-Lipoic Acid: Beneficial or Harmful in Alzheimer's Disease?. Oxid Med Cell Longev. 2019;2019:8409329. Published 2019 Nov 30. doi:10.1155/2019/8409329

[10] Nutrition Research Volume 20, Issue 2, February 2000, Pages 249-259

[11] Redox Report, Volume 11, Number 4, August 2006, pp. 163-172(10)

[12] Neuroscience Letters Volume 383, Issue 3, 5 August 2005, Pages 295-300

[13] Lakshmi, B. V. S., Sudhakar, M., & Anisha, M. (2014). Neuroprotective role of hydroalcoholic extract of Vitis vinifera against aluminium-induced oxidative stress in rat brain. NeuroToxicology, 41, 73–79. doi:10.1016/j.neuro.2014.01.003

[14] Deng HB, Cui DP, Jiang JM, Feng YC, Cai NS, Li DD (2003). Inhibiting effects of Achyranthes bidentata polysaccharide and Lycium barbarum polysaccharide on nonenzyme glycation in D-galactose induced mouse aging model. Biomed Environ Sci, 16: 267-275

[15] Yi R, Liu XM, Dong Q (2013). A study of Lycium barbarum polysaccharides (LBP) extraction technology and its anti-aging effect. Afr J Tradit Complement Altern Med, 10: 171-174

[16] Niu AJ, Wu JM, Yu DH, Wang R (2008). Protective effect of Lycium barbarum polysaccharides on oxidative damage in skeletal muscle of exhaustive exercise rats. Int J Biol Macromol, 42: 447-449

[17] Amagase H, Sun B, Borek C (2009). Lycium barbarum (goji) juice improves in vivo antioxidant biomarkers in serum of healthy adults. Nutr Res, 29: 19-25

[18] Zhong Cao Yao (Chinese Herbal Medicine) 19(7): 25

[19] Medicinal Chemistry Research. Volume 15, Number 9 / December, 2007

[20] Jiangxi Journal of Traditional Chinese Medicine. 2004 Vol.35 No.3 P.60-61.

[21] Yang Jianhong, et al. Advance on acetylcholinesterase inhibitors from medicinal plants. Yun Nan Hua Gong. 2006; 33(6): 78-82.

[22] Xie Q et al. Antifatigue and antihypoxia activities of oligosaccharides and polysaccharides from Codonopsis pilosula in mice. Food & Function, June 2020 DOI: 10.1039/D0FO00468E

[23] Xu AX, Zhang ZM, Ge B, Pu JF. Study effect and its mechanism on resisting senility of Codonopsis pilosula Nannf. Chin J Mod Appl Pharm. 2006;23:729–731.

[24] He JY, Ma N, Zhu S, Komatsu K, Li ZY, Fu WM. The genus Codonopsis (Campanulaceae): a review of phytochemistry, bioactivity and quality control. J Nat Med. 2015;69(1):1-21. doi:10.1007/s11418-014-0861-9

[25] Bai R, Li W, Li Y, et al. Cytotoxicity of two water-soluble polysaccharides from Codonopsis pilosula Nannf. var. modesta (Nannf.) L.T.Shen against human hepatocellular carcinoma HepG2 cells and its mechanism. Int J Biol Macromol. 2018;120(Pt B):1544-1550. doi:10.1016/j.ijbiomac.2018.09.123

[26] Socha K, Kochanowicz J, Karpińska E, et al. Dietary habits and selenium, glutathione peroxidase and total antioxidant status in the serum of patients with relapsing-remitting multiple sclerosis. Nutr J. 2014;13:62. Published 2014 Jun 18. doi:10.1186/1475-2891-13-62

[27] Li LL, Cui YH, Lu LY, et al. Selenium Stimulates Cadmium Detoxification in Caenorhabditis elegans through Thiols-Mediated Nanoparticles Formation and Secretion. Environ Sci Technol. 2019;53(5):2344-2352. doi:10.1021/acs.est.8b04200

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.