Atp 622 1: Fill & Download for Free

What is Ras?Ras is any protein part of the Ras superfamily of proteins related in structure. Ras is a ubiquitous protein expressed in all cells in our body. Ras proteins are part of a group of proteins termed the small GTPase class.Ras proteins are general involved in cell growth, differentiation, and survival. As you can see this makes the Ras superfamily of proteins the perfect candidate for contributing to cancer growth (unregulated proliferation and growth of cells). Ras specifically is involved in roughly 30% of human cancers[1].Ras proteins are part of complex, multifaceted signal transduction pathways that eventually lead to a these growth and proliferation signals which are transmitted via the nucleus.What exactly does signal transduction involve?Signal transduction is essentially the transmission of a signal from the outside of a cell to the nucleus inside. This signal results in alterations in cell metabolism, gene transcription (protein expression), and/or cell shape.There is generally a large amplification in signal as the agonist (binding signal) initially either binds on the outside of a cell membrane (as is the case for large hydrophilic molecules that will not be able to cross the hydrophobic phospholipid cell membrane) or on the inside of the cell (as is the case for hydrophobic steroid molecules that can cross the membrane with ease). This agonist causes a signal to be transmitted all the way to the nucleus. A signal agonist can cause an amplification in signal up to a million fold with ease.These pathways can be executed through a myriad of different cell receptors and pathways, some with higher levels of complexities and amplifications than others.For the purpose of our discussion, there are two main types of receptors: GPCR (G-protein coupled receptors) and RTK (receptor tyrosine kinases). The latter are much more heavily involved in growth, cell differentiation, etc. Both are involved in Ras activation.After the initial agonist binding to the receptor there is a few steps that are required for this signal to be transmitted which different slightly based on GPCR/RTK activation:Ligand --> Receptor --> Transducer/Effector --> Effector --> 2nd Messenger/Protein Kinase1) Ligand (agonist) binds to receptor. This can be done with an extra or intracellular receptor as previously described depending on the hydrophilic or hydrophobic characteristics of the ligand. In GPCRs this is a simple protein receptor, but with RTKs there can be an enzymatic activation of two protein receptors that causes them to link together and activate themselves and form one enzymatically linked receptor.2) Receptor sends the message to the transducer/effector, which then binds some sort of messenger to send the signal along. This is usually done by the phosphorylation of a protein that will carry this message forward. The point is that an activation must occur. Ras is activated by a protein called GEF and inactivated by a protein called GAP.This activation is reversed rather quickly in normal circumstances. In GPCRs this involves activation of a three subunit protein, whereas in RTKs it involves adaptor proteins that recruit the next protein required in the pathway.3) The transducer/effector (in this case Ras) sends the message to the last step of the pathway before the signal reaches the nucleus, the protein kinase pathway. This pathway (in this case the Raf/MEK/ERK pathway, also known as the MAP KKK pathway) will transduce the signal to the nucleus.Where do the problems arise?As you know, Ras is a small GTPase class of protein, and is a part of the signal transduction pathway which activates the protein kinase pathway and leads to the signal ultimately being transmitted. This activation is initially carried out through the GPCR or RTK and is turned off through a negative feedback loop from the products of the Ras pathway at the receptor/adaptor level. This normally stops the activation of the transducer/effector Ras.The problem arises when mutations in Ras occur - and they occur quite often in cancer patients. Once a mutation in Ras has occurred, it becomes permanently turned on and the pathway does not cease to stop. Even if the adaptor proteins or receptors receive the signal to stop activity it does not matter because Ras itself has mutated to decrease its own GTPase activity. As the exchange of GTP for GDP and the subsequent GTP hydrolysis stops due to the mutation, GTP stays bound to the Ras protein and unregulated cell proliferation and growth ensues.Not only does GTPase activity decrease, but the Ras protein loses sensitivity to GAP (one of the regular inhibitors of Ras)[2][3][4] and is exposed to a larger quantity of GEF (one of the regular activators of Ras through GTP binding)[5][6].Thus, we can say that the problems arise through 3 main mechanisms:1) Mutations in the Ras protein itself that lead to decrease GTPase activity, and therefore a constantly bound GTP molecule and permanent activation of Ras.2) Overactivation of the wild-type protein that leads to the production of GEF.3) Loss of GAP function due to the decreased sensitivity of the Ras protein.So why can't we inhibit Ras once it has mutated?Pharmaceutical companies have been spending billions of dollars in trying to inhibit Ras once it has been mutated. However, these companies have had only minimal success, if any at all.The first approach has been taken in regards to the disrupting the Ras to GTP binding, but none have succeeded.1) Using competitive inhibitors for the enzymatic active site of Ras. This actually backfired because any molecule that could function to do this would actually further impede any potential GTPase activity. This inactivity gives Ras its oncogenic activity in the first place. Regardless, the only molecules that have been found to achieve this function are clostridial cytotoxins (a type of bacterial toxin), and these toxins work enzymatically to create a Ras protein that is covalently modified, causing Ras to become resistant to GAP entirely. Using an molecule to do the opposite, creating an agonist, would be very difficult (restoring GAP sensitivity or GTPase activity) and it has been shown that it may not be feasible at all[7].2) Developing a drug in attempt to displace GTP from Ras. This has proven a dead end road due despite its promising nature. Due to the high kinetic affinity between the binding of Ras to GTP, the ATP binding site drug competitors on the market cannot compete (micro molar vs nano molar affinities).Disrupting the Ras to GTP high affinity binding has been characterized as "undruggable" in a recent 2010 study[8]. There is still enthusiastic chatter in this arena but so far no one has further succeeded in this task.Some have also tried to disrupt the upstream GEF activator protein (SOS in the previous image)[9][10]. However, nothing yet has been developed to show major promise.This has left us with the absence of an obvious molecule on the level of Ras to target. The next focus has been involved in the construction of Ras itself.Post-translation covalent protein modifications are essential to the formation of Ras, and so it has been suggested that it may be a good target to go after the tools involved in those modifications - specifically farnesyl transferase. Theoretically, disruption of the proteins post-translational modifications would result in a non-functional protein. Furthermore, it was hypothesized that the presence of inactive Ras would act as an inhibitor to previously active Ras signalling through the sequestering of molecules to the proper sub cellular locations involved in its signalling pathways.This approach has involved using farnesyl transferase inhibitors (FTIs). A couple of these FTIs actually made it all the way to phase 3 clinic trials after showing promising results before it was shown to lack the anticipated anticancer activity[11].So why did this not work? Most likely because they drugs were developed using a mutated version of an isoform of Ras. The belief was that all isoforms of Ras would respond similarly, but that unfortunately is not the case. It has been shown that the active in vivo isoforms of Ras become geranylgeranylated in cells in the presence of FTIs, which allows them to bypass the action of the FTIs and develop fully. Nothing further has been developed in this area, but it is possible that FTIs will produce benefits in the future.Another focus has been on Ras at the expression level. In other words, scientists have been trying to reduce the expression of particularly harmful isoforms.Targets for this approach include promoters of specific isoforms of Ras such as the guanine-rich sequence forming a G-quadruplex structure which has been confirmed in human DNA[12]. Many drugs are already available on the market which can bind and stabilize these G-quadruplex DNA structures and can regulate expression of Ras in vitro.However, regulatory activity of these structures can be negative or positive in vivo depending on the isoform of Ras. Also the sequences that are compatible with these structures are widespread within human DNA. Therefore it is unlikely that this will provide a proper mechanism for stopping Ras.Pieces of regulatory RNA called microRNAs (specifically microRNA-622) are also being tested which have been shown to decrease specific isoforms of Ras. It is unknown how efficacious this path will turn out to beThe last major focus has been with the protein kinase pathway. Inactivating the MAP KKK pathway you have previously learned about would cause the Ras signal to cease before it could cause any damage. A major problem with this approach is that it is so far downstream from the source of the problem.Since the oncogenic signal from Ras is transmitted through multiple pathways it has been speculated that this will not prove to be very effective[14][15][16][17][18][19][20]. Despite this, FDA approval of one of these inhibitors (trametinib) has been granted. Another MAP KKK inhibitor, MEK162, has shown promising results also in melanoma patients[13].For this approach to be effective the MAP KKK signally pathway would have to predominate the signal transduction pathway from Ras. Another problem with this approach is that resistance could easily emergence with these inhibitors.There are other newer methods being developed of Ras, but it's unclear if any will prove to be useful at this point. Scientists are continually still working to stop Ras and will most likely continue to do so until they find a way as the benefits of such a discover would have a very high payoff for humanity.What happens if we do block Ras?There will still be complications even if we do find a way to simply block the actions of Ras, as Ras is involved in widespread functions in the human body.To give one example, it has been shown that Ras is part of an important pathway for synaptic remodelling in the human brain (the very process that underlies memory)[21]. Mutations in regulators of Ras in neutrons are found in patients with non syndromic mental retardation[22]. There is also evidence that the H-Ras isoform is involved in control of synaptic plasticity[23].This is just one more example in the challenges that we still have yet to face in blocking Ras.References:A. T. Baines, D. Xu, and C. J. Der, “Inhibition of Ras for cancer treatment: the search continues,” Future Medicinal Chemistry, vol. 3, no. 14, pp. 1787–1808, 2011.J. B. Gibbs, I. S. Sigal, M. Poe, and E. M. Scolnick, “Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules,” Proceedings of the National Academy of Sciences of the United States of America, vol. 81, no. 18, pp. 5704–5708, 1984.G. Bollag and F. McCormick, “Differential regulation of rasGAP and neurofibromatosis gene product activities,” Nature, vol. 351, no. 6327, pp. 576–579, 1991.U. Krengel, I. Schlichting, A. Scherer et al., “Three-dimensional strucutures of H-ras p21 mutants: molecular basis for their inability to function as signal switch molecules,” Cell, vol. 62, no. 3, pp. 539–548, 1990.K. Zhang, A. G. Papageorge, and D. R. Lowy, “Mechanistic aspects of signaling through Ras in NIH 3T3 cells,” Science, vol. 257, no. 5070, pp. 671–674, 1992.R. R. Mattingly and I. G. Macara, “Phosphorylatlon-dependent activation of the Ras-GRF/CDC25(Mm) exchange factor by muscarinic receptors and G-protein βγ subunits,” Nature, vol. 382, no. 6588, pp. 268–272, 1996.K. Scheffzek, M. R. Ahmadian, W. Kabsch et al., “The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic ras mutants,” Science, vol. 277, no. 5324, pp. 333–338, 1997.T. Tanaka and T. H. Rabbitts, “Interfering with RAS-effector protein interactions prevent RAS-dependent tumour initiation and causes stop-start control of cancer growth,” Oncogene, vol. 29, no. 45, pp. 6064–6070, 2010.T. Maurer, L. S. Garrenton, A. Oh et al., “Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 14, pp. 5299–5304, 2012.Q. Sun, J. P. Burke, J. Phan et al., “Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation,” Angewandte Chemie International Edition, vol. 51, pp. 6140–6143, 2012.A. M. Tsimberidou, C. Chandhasin, and R. Kurzrock, “Farnesyltransferase inhibitors: where are we now?” Expert Opinion on Investigational Drugs, vol. 19, no. 12, pp. 1569–1580, 2010.G. Biffi, D. Tannahill, J. McCafferty, and S. Balasubramanian, “Quantitative visualization of DNA G-quadruplex structures in human cells,” Nature Chemistry, vol. 5, pp. 182–186, 2013.P. A. Ascierto, D. Schadendorf, C. Berking et al., et al., “MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study,” The Lancet Oncology, vol. 14, pp. 249–256, 2013.K. R. Stengel and Y. Zheng, “Essential role of Cdc42 in Ras-induced transformation revealed by gene targeting,” PLoS ONE, vol. 7, Article ID e37317, 2012.N. Mitin, K. L. Rossman, and C. J. Der, “Signaling interplay in ras superfamily function,” Current Biology, vol. 15, no. 14, pp. R563–R574, 2005.A. V. Patel, D. Eaves, W. J. Jessen et al., et al., “Ras-driven transcriptome analysis identifies aurora kinase A as a potential malignant peripheral nerve sheath tumor therapeutic target,” Clinical Cancer Research, vol. 18, pp. 5020–5030, 2012.S. Eser, N. Reiff, M. Messer et al., et al., “Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer,” Cancer Cell, vol. 23, pp. 406–420, 2013.H. Y. Chow, A. M. Jubb, J. N. Koch et al., et al., “p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model,” Cancer Research, vol. 72, pp. 5966–5975, 2012.R. E. Menard and R. R. Mattingly, “Cell surface receptors activate p21-activated kinase 1 via multiple Ras and PI3-kinase-dependent pathways,” Cellular Signalling, vol. 15, no. 12, pp. 1099–1109, 2003.Q. Li and R. R. Mattingly, “Restoration of E-cadherin cell-cell junctions requires both expression of E-cadherin and suppression of ERK MAP kinase activation in ras-transformed breast epithelial cells,” Neoplasia, vol. 10, no. 12, pp. 1444–1458, 2008.E. J. Weeber and J. D. Sweatt, “Molecular neurobiology of human cognition,” Neuron, vol. 33, no. 6, pp. 845–848, 2002.L. B. Rosen, D. D. Ginty, M. J. Weber, and M. E. Greenberg, “Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras,” Neuron, vol. 12, no. 6, pp. 1207–1221, 1994.K. A. Rauen, “HRAS and the Costello syndrome,” Clinical Genetics, vol. 71, no. 2, pp. 101–108, 2007.

Many of the answers provided do not address the subset of brain aging. The brain, akin to the rest of the human body degrades over time and without proper care, tuning, or consideration of routines / activities we have come to find a degradation in performance.Many folks overlook or forgo delving into areas of brain care at the onset of their anti-aging discovery process. Alas, marketing dollars and advertising spend leverages our vanity, directing discretionary dollars in ways that may not be most advantageous for our ever growing community of older adults.For individuals suffering from Alzheimer's (early onset thru advanced stages), or those that experience small hiccups in mental functioning, these products have been studied and researched across the world and are now just beginning to find traction in the mainstream.For those individuals who are lacking mental (or physical) energy as the aging process ensues, there are opportunities to regain your stamina and focus to levels that would appear to turn the clock back 5 or 10 years!If you have not heard of nootropics until now, let me be the first to welcome you to wonderfully wide world of natural and synthetic agents that may drastically improve your outlook and ability to function in an aging world.You very likely have encountered some of the 138 most common Nootropics just never knew what they were or what they did to your brain and body!Screenshot of our Nootropic Periodic Table BelowNootropics better support your body and mind, reducing oxidative stress, balancing or regulating biological responses to stressful situations, increasing alertness, improving cognition and memory, facilitating greater physical exertion and recovery, and aiding in absorption and digestion of nutrients and foods, etc…Synthetic Nootropics crucial for your brain (and body)PhenylpiracetamFirst synthesized in 1983, Phenylpiracetam is a modification of the nootropic Piracetam[1]. The primary alteration to Phenylpiracetam from its predecessor is the addition of a phenyl group– a small change that has made phenylpiracetam significantly more potent than Piracetam, even at much smaller dosages [2]. Phenylpiracetam’s cognitive enhancing effects are reportedly achieved by increasing the density and number of acetylcholine, dopamine, GABA, and glutamate receptors in the brain [3]. Through this mechanism, research suggests that Phenylpiracetam increases functional activity at the neurotransmitter binding sites most important for memory and cognition. While Phenylpiracetam is commonly used by nootropic users to enhance alertness, mental clarity, and learning– it is officially recognized as a psychostimulant, and, as such, it is a banned by WADA for use in competitive sports[2][4].REFERENCESMalykh, A. G., & Sadaie, M. R. (2010). Piracetam and piracetam-like drugs.Drugs,70(3), 287-312.Zvejniece, L., Svalbe, B., Veinberg, G., Grinberga, S., Vorona, M., Kalvinsh, I., et al. (2011). Investigation into stereoselective pharmacological activity of phenotropil.Basic & clinical pharmacology & toxicology,109(5), 407-412.Firstova, Y. Y., Abaimov, D., Kapitsa, I., Voronina, T., & Kovalev, G. (2011). The effects of scopolamine and the nootropic drug phenotropil on rat brain neurotransmitter receptors during testing of the conditioned passive avoidance task. Neurochemical Journal, 5(2), 115-125.Docherty, J. (2008). Pharmacology of stimulants prohibited by the World Anti‐Doping Agency (WADA). British journal of pharmacology, 154(3), 606-622.PramiracetamFirst discovered in the late 1970’s, Pramiracetam is considered to be upwards of 30 times more potent than its predecessor, Piracetam [1]. Pramiracetam is fat-soluble, meaning it is absorbed most efficiently when consumed with a fatty food source [2]. Pramiracetam is believed to significantly increase acetylcholine uptake and activity within the hippocampus, two crucial mechanisms for memory, learning and cognition [3]. Pramiracetam is also asserted to play a neuroprotective role, increasing cerebral blood flow and promoting oxygen and nutrients delivery throughout the brain [4]. In the nootropic community, Pramiracetam is favorite among students and workaholics looking for a cognitive boost.REFERENCESPugsley, T. A., Shih, Y., Coughenour, L., & Stewart, S. F. (1983). Some neurochemical properties of pramiracetam (CI‐879), a new cognition‐enhancing agent. Drug development research, 3(5), 407-420.Dodd, J., Hershenson, F., Hicks, J., Butler, D., Lewis, E., & Huang, C. (1986). Synthesis of tritium labeled pramiracetam (CI‐879; N‐[2‐[bis (1‐methylethyl) amino] ethyl]‐2‐oxo‐1‐pyrrolidineacetamide). Journal of Labelled Compounds and Radiopharmaceuticals,23(4), 415-420.Ogiso, T., Iwaki, M., Tanino, T., Ikeda, K., Paku, T., Horibe, Y., et al. (1998).Pharmacokinetics of aniracetam and its metabolites in rats. Journal of pharmaceutical sciences,87(5), 594-598.Corasaniti, M., Paoletti, A., Palma, E., Granato, T., Navarra, M., & Nistico, G. (1994).Systemic administration of pramiracetam increases nitric oxide synthase activity in the cerebral cortex of the rat. Functional neurology, 10(3), 151-155.SulbutiamineSulbutiamine is a synthetic derivative of vitamin B1 and is comprised of the combination of two Thiamine (Vitamin B1) molecules [1]. It was first created in Japan by scientists working at the Taisho Pharmaceutical Co. in 1965, during a time that Japan’s population was dealing with prevalent thiamine deficiency [2].Due to its higher bioavailability than normal Thiamine supplements, Sulbutiamine is easily transported across the blood brain barrier [3]. Sulbutiamine is reported to enhance focus, mental energy, and memory by increasing the production of acetylcholine within the brain while, in the body, converting carbohydrates into glucose [4]. Today many nootropic users take Sulbutiamine on an as-needed basis for when their the day calls for an extra cognitive boost.REFERENCESVan Reeth, O. (1999). Pharmacologic and therapeutic features of sulbutiamine.Drugs Today (Barc), 35(3), 187-192.Kawai, C., Wakabayashi, A., Matsumura, T., & Yui, Y. (1980).Reappearance of beriberi heart disease in Japan: a study of 23 cases. The American journal of medicine,69(3), 383-386.Kwag, J., Majid, A. S. A., & Kang, K. D. (2011). Evidence for neuroprotective effect of sulbutiamine against oxygen-glucose deprivation in rat hippocampal CA1 pyramidal neurons. Biological and Pharmaceutical Bulletin, 34(11), 1759-1764.Ollat, H., Laurent, B., Bakchine, S., Michel, B., Touchon, J., & Dubois, B. (2006).[Effects of the association of sulbutiamine with an acetylcholinesterase inhibitor in early stage and moderate Alzheimer disease]. L'Encephale, 33(2), 211-215.Natural Nootropics crucial for your brain (and body)AshwagandhaAshwagandha-- also called Withania Somnifera, Indian Ginseng, and Winter Cherry-- is a popular herb used in traditional Ayurvedic medicine [1]. Considered one of the most powerful herbs in ancient Ayurvedic healing, Ashwagandha has been the subject of recent research assessing its protection over to cells in the central nervous system and upregulation of neuron regeneration, as well as its role as a free radical-seeking antioxidant [2].Within the brain, Ashwagandha is reported to boost cognitive processes by increasing the amount of available extracellular acetylcholine– a key neurotransmitter responsible for our learning and memory capacity [3]. On a holistic level, Ashwagandha has also been suggested reduces the stress hormone cortisol, lowers blood sugar levels, and improves lipid profiles.The name Ashwagandha translates to “Smell of the Horse”, referring both to its scent and its use as an ancient means to promote bodily strength and virility [4]. Although ingesting Ashwagandha extract appears to be the most popular means of supplementation, one can also apply the herb topically or brew it in a tea [5][6].REFERENCESPratte, M. A., Nanavati, K. B., Young, V., & Morley, C. P. (2014). An alternative treatment for anxiety: a systematic review of human trial results reported for the Ayurvedic herb ashwagandha (Withaniasomnifera).The Journal of Alternative and Complementary Medicine, 20(12), 901-908.Dhuley, J. N. (2001). Retracted: Nootropic‐like effect of ashwagandha (Withania somnifera L.) in mice.Phytotherapy Research, 15(6), 524-528.Choudhary, M. I., Yousuf, S., Nawaz, S. A., & Ahmed, S. (2004). Cholinesterase inhibiting withanolides from Withania somnifera. Chemical and pharmaceutical bulletin,52(11), 1358-1361.Uddin, Q., Samiulla, L., Singh, V., & Jamil, S. (2012).Phytochemical and pharmacological profile of WithaniasomniferaDunal: a review. Journal of Applied Pharmaceutical Science,2(01), 170-175.Mirjalili, M. H., Moyano, E., Bonfill, M., Cusido, R. M., & Palazón, J. (2009). Steroidal lactones from Withaniasomnifera,an ancient plant for novel medicine.Molecules 14(7), 2373-2393.Bhat, J., Damle, A., Vaishnav, P. P., Albers, R., Joshi, M., & Banerjee, G. (2010). In vivo enhancement of natural killer cell activity through tea fortified with Ayurvedic herbs.Phytotherapy Research, 24(1), 129-135.Rhodiola RoseaRhodiola Rosea is a flowering plant found in the Eastern European and Central Asian regions. The plant's root was originally used in Traditional Chinese Medicine for its adaptogenic properties [1]. Rhodiola Rosea is thought to both reduce stress and improve mood by simultaneously increasing serotonin and epinephrine levels in the brain while inhibiting corticosteroids [2]. Also studied for its benefits to brain health, Rhodiola Rosea is also suggested to encourage neural regeneration by upregulating the rate of ATP synthesis needed for neuronal repair and growth [3]. Rhodiola Rosea is commonly used to promote wakeful focus and it remains popular among seasoned nootropic users due to its cognition and mood enhancing potential.REFERENCESMannucci, C., Navarra, M., Calzavara, E., Caputi, A., & Calapai, G. (2012). Serotonin involvement in Rhodiola rosea attenuation of nicotine withdrawal signs in rats.Phytomedicine, 19(12), 1117-1124.Panossian, A., Wikman, G., & Sarris, J. (2010). Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy.Phytomedicine, 17(7), 481-493.Qin, Y., Zeng, Y., Zhou, C., Li, Y., & Zhong, Z. (2008). [Effects of Rhodiola rosea on level of 5-hydroxytryptamine, cell proliferation and differentiation, and number of neuron in cerebral hippocampus of rats with depression induced by chronic mild stress]. Zhongguo Zhong yao za zhi= Zhongguo zhongyao zazhi= China journal of Chinese materia medica, 33(23), 2842-2846.Milk ThistleMilk Thistle, also called Silybum Marianum, originates from the Mediterranean region where it has been in recorded use for its natural antioxidant properties dating as far as 2,000 years ago [1]. Milk Thistle has long been used in Traditional Medicine with the belief that it might detoxify the body [2].The active constituent in Milk Thistle, silybin, is thought to act as antioxidant– protective against cell damage by inhibiting lipid peroxidation and scavenging free radicals [3]. As a health supplement, Milk Thistle has been a research target for its promising potential as both an anti-diabetic and chemotherapeutic agent due to its protective influence over liver function [4]. Within the brain, studies have also reported Milk Thistle’s ameliorating effects on learning and memory impairment through the activation of neurotrophin protein synthesis in the hippocampus [5].Milk Thistle has been correctly considered a “liver elixir” for several millennia now [6], but efforts in modern science demonstrate that its health benefits are likely even greater in scope.RESEARCHKarkanis, A., Bilalis, D., & Efthimiadou, A. (2011). Cultivation of milk thistle (Silybum marianum L. Gaertn.), a medicinal weed. Industrial Crops and Products, 34(1), 825-830.Blumenthal, M., Goldberg, A., & Brinckmann, J. (2000).Herbal Medicine. Expanded Commission E monographs.Integrative Medicine Communications.Scarborough, J. (1977). Nicander's Toxicology I: Snakes.Pharmacy in History,19(1), 3-23.Ramasamy, K., & Agarwal, R. (2008). Multitargeted therapy of cancer by silymarin.Cancer letters, 269(2), 352-362.Song, X., Zhou, B., Zhang, P., Lei, D., Wang, Y., Yao, G., et al. (2016). Protective Effect of Silibinin on Learning and Memory Impairment in LPS-Treated Rats via ROS–BDNF–TrkB Pathway. Neurochemical research, 1-11.Brandon-Warner, E., Eheim, A. L., Foureau, D. M., Walling, T. L., Schrum, L. W., & McKillop, I. H. (2012). Silibinin (Milk Thistle) potentiates ethanol-dependent hepatocellular carcinoma progression in male mice. Cancer letters, 326(1), 88-95.Disclaimer: I work at Modern AlkaMe and am truly authentic in my opinions. If interested in giving nootropics a test run, you are able to procure them at the Modern AlkaMe Marketplace.