Rapamycin has a lot of functions. What exactly?

November 30, 2019 / Bio Valley BIOON / - - rapamycin (rapa), also known as "sirolimus", was originally discovered due to its strong antifungal properties It is a secondary metabolite secreted by soil streptomyces, which was first discovered by scientists from the soil of Easter Island in Chile in 1975 Rapamycin is a macrolide antibiotic, which has similar structure with FK506, but has very different immunosuppressive mechanism FK506 inhibited the proliferation of T-lymphocytes from G0 to G1, while Rapa blocked the signal transduction through different cytokine receptors and blocked the process of T-lymphocytes and other cells from G1 to S compared with FK506, Rapa blocked the calcium dependent and calcium independent signal transduction pathways of T-lymphocytes and B-lymphocytes In view of the strong immunosuppressive effect of rapamycin in clinical trials, it can replace cyclosporine, which has a clinical history of more than 30 years Compared with cyclosporine, rapamycin oral liquid has smaller dose (only 2-3mg per time), stronger anti rejection effect and fewer side effects Therefore, rapamycin, as an immunosuppressant, has rapidly become a commonly used oral immunosuppressant for organ transplant recipients all over the world since it was listed on the market Now, scientists have recently discovered another use: it can be used to treat Alzheimer's disease Other experiments showed that rapamycin can restore the ability of memory defect in the experimental mouse model All in all, rapamycin has attracted great attention of scientists in the past 30 years due to its potential in anti-cancer, neuroprotection and anti-aging therapy Based on this, the editor reviewed the new progress made by scientists on rapamycin research in recent years, combed it and shared it with you 1 Geroscience: rapamycin may delay skin aging! Doi: 10.1007/s11357-019-00113-y is always obsessed with latex, supplements, serums and diets in pursuit of eternal youth, but a new discovery may provide us with new choices Rapamycin, an FDA approved drug commonly used to prevent organ rejection after transplantation, may also slow down the aging of human skin, according to a study published in geroscience by researchers at Drexel University School of medicine Rapamycin chemical structure, picture from Wikipedia In the study, 13 participants over 40 years of age used rapamycin cream once in each hand every 1-2 days and placebo in the other hand for 8 months The researchers examined the subjects after two, four, six and eight months, including blood tests and biopsies at six or eight months Eight months later, most of the collagen in the hands treated with rapamycin was increased, and the level of p16 protein was significantly reduced (p16 protein is a key marker of skin cell aging) Previous studies have shown that skin aging cells with low p16 content are less In addition to cosmetic effects, higher levels of p16 can also cause skin atrophy in the elderly, which is related to the vulnerability of the skin to tear, slow wound healing, and increased risk of infection or complications after injury So how does rapamycin work? In the mechanism, rapamycin can block the appropriately named "rapamycin target" (TOR), which plays a role of signaling in the metabolism, growth and aging of human cells When studying p16 protein further, the authors found that rapamycin's ability to improve human health is not only to keep young: when cells have mutations that would otherwise cause tumors, specific reactions can help prevent tumors by slowing down cell cycle processes 2 Prion: a new method against prion disease doi: 10.1080/19336896.2019.1670928 many potential therapeutic compounds target the misfolded protein with replication ability: prion In a new study, Abdulrahman and his colleagues speculated that combination therapy could be used to target different aspects of prion disease synergistically Their goal is to target the prion itself with cellulose ethers, and to target the autophagy pathway that degrades the prion with the PDK1 inhibitor ar12 or rapamycin, which activates autophagy When administered alone, both types of compounds showed promise for prolonging the life of mice However, the combination therapy did not bring any additional advantages Mice treated with both types of compounds died at the same time as those treated with a single compound In further studies, they found that cellulose ethers inhibited the autophagy of ar12 and rapamycin As a result, it seems that only the benefits of cellulose ethers are apparent in mice Although it is disappointing that this combination of therapies does not work together, this study highlights some important aspects of treatment protocol design that must be considered in future success Since there are few drugs for neurodegenerative diseases showing the hope of prolonging life span, the interaction between drugs is almost completely unknown, but Abdulrahman et al have confirmed the necessity of studying these phenomena Through the correct combination therapy, their method still provides an effective complementary therapy for prolonging the life span of prion patients 3 Aging cell: rapamycin can effectively inhibit age-related brain function degradation doi: 10.1111/acel.13057 recently, an international journal aging In the Research Report on cell, scientists from San Antonio health center and other institutions found that rapamycin could improve the reduction of brain blood flow (to the brain) and memory loss caused by age-related factors; the relevant research results are crucial for the development of new effective therapies to inhibit or treat Alzheimer's disease In this paper, the researchers began to add low-dose rapamycin to the diet of rats at 19 months old, and rapamycin therapy continued in the daily food until the rats were 34 months old (almost twice the age when they started treatment) The researchers found that even though the rats were very old, the blood circulation in their brain was exactly the same as that at the beginning of treatment (young) 。 In this study, untreated old rats were able to reflect the loss of blood flow to the brain and memory observed by the researchers in the elderly In contrast, the old rats treated with rapamycin looked like middle-aged rats Source: Wikipedia Tor, the target of rapamycin, is the main controller of cell growth and aging The researchers found that tor can drive the loss of synapses and the decrease of blood flow in the brain during the aging process Synapses can connect different neurons, while the brain relies on neurons to send and receive signals The brain consumes a lot of energy, but there is no substitute resource, the researchers said Neurons need glucose and oxygen to maintain their function, while blood vessels can provide nutrients for them In the end, the researchers said that they will continue to study further to clarify the molecular mechanism of rapamycin inhibiting age-related cerebrovascular deterioration 4 Science Journal: to reveal the therapeutic effect of rapamycin on β - thalassemia and its mechanism doi: 10.1126/scitraslmed.aav4881 in a new study, researchers from the United States and Italy found that ulk1 plays a key role in clearing accumulated α - globin in the mouse model of β - thalassemia and cells from β - thalassemia They also found that ulk1 deficiency reduced autophagy clearance of α - globin in erythroid precursor cells and increased the phenotype of the disease, whereas inactivation of classical autophagy related gene 5 (ATG5) had only a relatively small effect Relevant research results were published in the Journal of Science Translational Medicine on August 21, 2019 The title of the paper is "the autophagy activating kinase ulk1 mediates clearance of free α - globin in β - thalassemia" Systemic therapy with rapamycin, an inhibitor of mTORC1, can promote the elimination of accumulated α - globin by activating ulk1 dependent autophagy pathway and alleviate the symptoms of β - thalassemia in mice Similarly, rapamycin reduced the accumulation of free α - globin in erythroblasts derived from CD34 + cells of patients with β - thalassemia 5 Aging: rapamycin can delay epigenetic aging doi: 10.18632/aging.101976 in 2018, Steve Horvath of UCLA and Ken Raj of the British public health department developed an improved algorithm, called skin and blood clock, which is suitable for both in vitro cultured cells and in vivo cultured cells Using this epigenetic clock, Raj and Horvath have now demonstrated that rapamycin can delay aging, not only in many animal species, but also in human cells Photo source: aging Rapamycin may be the result of its multiple effects, including but not necessarily limited to inhibition of cell aging and epigenetic aging, and may enhance cell proliferation potential 6 PLoS Biol: scientists reveal the new mechanism of rapamycin, the "God drug" Doi: 10.1371/journal.pbio.300052 recently, a research report published in the international journal PLoS Biology, scientists from the University of Michigan revealed a new pathway of anti-aging drugs through research Zhang said that the main function of lysosomes is to maintain the healthy state of cells, because it can degrade harmful substances in cells During pressure, autophagy can maintain cell survival by degrading the components of abnormal functions in cells without cells providing basic elements For a long time, researchers believe that rapamycin can target at least one cell pathway Now researchers have found one of these pathways, namely the calcium channel named trpml1 on lysosomal membrane Relevant research findings may also expand the use of rapamycin Autophagy is very important for cell health It can be used as a waste recycling pathway to maintain the quality of proteins and organelles in cells In the process of natural aging, cells will be in a medium full of abnormal proteins and organelles, especially in the process of neurodegeneration such as Alzheimer's disease and Parkinson's disease Autophagy depends on lysosomal activity, t Rpml1, as the main calcium channel in lysosome, plays a key role in regulating lysosomal function Researcher Haoxing Xu pointed out that if there is no such channel, you will have neurodegeneration, if you stimulate the calcium channel, then there will be anti neurodegenerative effect; in this paper, researchers used a technology called lysosomal patch clamp to analyze trpml1 channel, when researchers applied rapamycin to lysosomes, the channel will be opened, whether mTOR is in active state or not, which is It is suggested that rapamycin can activate trpml1 channel independent of mTOR 7 PNAs: the new drug delivery system can inhibit tumor by 87%! Doi: 10.1073/pnas.1817251116 as cancer treatment becomes more and more complex, we need a more sophisticated drug delivery system that can deliver a variety of drugs with different chemical components at the same time Now, John A Paulson from Harvard University