Overview
As we mentioned before, team iBowu-China mainly focused on Alzheimer's disease (AD) this year, which is a common neurodegenerative disease in the elderly. The pathological features of AD are extracellular plaques, neuronal fibrillary tangles, vacuolar degeneration of hippocampal pyramidal neurons, and neural loss. People with AD suffer from progressive nervous system degeneration, which is characterized by aphasia, apraxia, agnosia, visuospatial skills impairment, personality and behavior changes, and other comprehensive dementia symptoms. (Gauthier. S., 2022) In recent years, while gradually more people have been diagnosed with AD, more and more scientists are paying attention to AD. However, the causes are still unknown. Among all possible theories, the amyloid beta (Aβ) theory and the tau protein theory have been the most important and experimentally tested theories of the past few decades. 74% of drugs for AD treatment target the two components, but none of the drugs can radically cure AD. In our project this year, we try to improve the synthesis pathway of a small molecule named astragalin which could cross the blood-brain barrier and could alleviate the AD process. We constructed the astragalin production pathway in E.coli so that synthetic biology methods could be used to produce astragalin cheaply and environmentally friendly. We believe that astragalin will play an essential role in new generation AD drugs, but how can we achieve this goal? Here comes our implementation suppose.
Users
Alzheimer's disease (AD) patient Medical workers for Alzheimer's disease (AD) treatment
Envisioned usage: Product formats and methods of use
As for a drug, the form and method of administration are worthy of in-depth discussion. First, we conducted an HP survey to get the drug delivery form more in line with the demand. We investigated people's tendency to take medicine through a questionnaire. The results showed that sprays and oral medications were the best choices, followed by mainline (intravenous) and intramuscular injections. Indeed, spray and oral administration give the greatest freedom to patients to use drugs independently in different scenarios. At the same time, intravenous injection and intramuscular injection demand the help of doctors or nurses to complete and may even cause some pain. For our project, sprays can only act on the body surface and have a weak absorption capacity, which is unsuitable for carrying AD drugs. Additionally, Astragalin is a small molecule drug that has a molecular mass of 448 Da and is in the category of a natural flavonoid. Subsequently, it defines Astragalin as a drug more suitable for oral drugs absorbed through the GI tract and liver. Since our product can go through the blood-brain barrier, we find it best for Astragalin to be implemented as an oral drug.
In addition, considering the comprehensive dementia manifestations that AD patients often show, we preferred to use a capsule, which can cover the bitter taste and delay the release to help the elderly absorb it more easily. As for the drug delivery method, we mainly focused on using E.coli to produce astragalin in this year's project. However, the drug delivery method for human cells needs to be verified by more cellular biological experiments. Previous in vitro studies have shown that Astragalin (0-80 μg/mL; 24 h, 48 h, 72 h) inhibits cancer cell viability and migration at 20, 40, 80 μM and shows no cytotoxicity to regular human colon epithelial cell lines NCM460. In vivo work shows that astragalin (25, 50, and 75 mg/kg; p.o.; once every two days; 25 d) can reduce the tumor volumes, tumor weight, and tumor formation rates; it can decrease the expression of p-NFκB and p-iκκα in a nude mouse model with human colon cancer. However, the exact dose for human use still needs to be determined based on clinical trials.
Safety
Astragalin is a kind of natural flavonoid compound widely existing in medicinal plants. It has significant functions in anti-inflammatory, antioxidant, cardiotonic, analgesic, antibacterial, anti-allergic, and anti-hepatotoxic effects. It can repair damaged DNA and inhibit the generation of TNF-α, IL-1β, and IL-6. It has been reported that astragalin is edible and has oral activity, which protects the nerves and heart and protects against osteoporosis.
Challenge
We communicated in-depth with Prof. Hu, a Psychiatry teacher, during the project process. He led us to understand Alzheimer's disease (AD) from the perspectives of pathogenesis, symptoms, current diagnostic methods, treatment methods, and so on. Mr. Hu also provided us with much favorable support and help for our project of producing astragalin. However, according to Mr. Hu's latest study, astragalin is not the end product of the metabolism: although it can cross the blood-brain barrier into the brain, it may also continue to be metabolized into smaller molecules. Therefore, if we can further explore the downstream metabolites of astragalin, we may provide more ideas for treating AD.