Melatonin is a hormone produced by the pineal gland of the brain. People can also use it as a natural or synthetic supplement to promote sleep. Melatonin plays many roles in the body, but the main role is to maintain the circadian rhythm. For humans, the central biological clock is located in the suprachiasmatic nucleus (SCN) area of the brain. Using the daily day and night pattern, SCN creates and maintains a regular cycle of sleep and wakefulness. The light level signal reaches the SCN and is then transmitted to the pineal gland deep in the center of the brain. The pineal gland releases melatonin at night and prevents its release during the day. Some foods contain melatonin, which is also degradable or supplements in the form of gummies.
As COVID-19 continues to spread around the world, reusing drugs that have been approved by the FDA is still the most effective and lowest cost effective way to treat or prevent diseases. According to the research results published in “PLOS Biology” recently, a new artificial intelligence platform developed by researchers at the Cleveland Clinic Lerner Institute is used to identify possible drugs for COVID-19 reuse.
The platform quantifies the association of COVID-19 with 6 other diseases, including autoimmune, malignant tumor, cardiovascular, metabolic, neurological and lung diseases. First, perform network analysis and then perform single-cell RNA metabolism data analysis to identify the potential pathobiological relationship between COVID -19 and related symptoms. , Researchers used online medical survey results and patient data in a large COVID-19 patient registration database to identify existing FDA-approved drugs and prioritize them as potential COVID-19 alternative drugs. Melanin is a promising alternative medicine.
The “savior of sleep” melatonin has now become the “savior” of COVID-19 patients!
Network-based measurement of COVID-19 related disease performance
Researchers systematically assessed the network-based relationship between multiple diseases and COVID-19. Using the most advanced network proximity evaluation method to consider the topology of the human interaction genome network to evaluate disease proteins and SARS-CoV-2. Researchers found that there is a clear network-based definition between each disease and disease. If the footprint between the COVID-19 module and another disease module is very close (Z and low and P <0.05), then the degree of proximity indicates their biological relationship: a closer network proximity indicates that COVID-19 is associated with a specific disease Shows a higher potential in between. First, note that immunology, neurology, cancer and cardiovascular diseases have obvious similarities with certain SARS-CoV-2 data sets, indicating that there is a correlation at some level.
Network visualization can further show the connection between SARS-CoV-2 and other diseases. Respiratory distress syndrome and sepsis are the two main causes of death in patients with severe COVID-19. The protein is directly linked to disease-related proteins. ABCA3 is a transcriptional transporter located in the outer lamellar membrane of AT2 cells. Mutations in the ABCA3 gene can destroy the surfactants in the lungs and cause hereditary lung diseases. Membrane surface protein, the lung-related surfactant protein encoded by SFTPC, can cause lung damage if folded incorrectly. It has been shown that the overproduction of certain cytokines (such as IL-6) caused by the dysregulation of the innate immune response to SARS-CoV-2 infection. The analysis of 5 COVID-19 clinical studies showed that the ratio of patients with non-severe COVID-19 and the level of IL-6 in patients with severe COVID-19. These results indicate that IL-6 plays a key role in the respiratory hypertension syndrome and sepsis associated with COVID-19.
Web-based drug reuse for COVID-19
The understanding of the complex interaction between the SARS-CoV-2 target and human diseases suggests that drugs may be repurposed because drugs for other diseases may potentially be implanted into SARS-CoV through a shared functional PPI network. 2. Completely, reusing the drug may also reveal an unrecognizable biological link between the originally approved indication or disease and COVID-19.
Therefore, the next step is to use the drug target network established in this study and the SARS-CoV-2 interaction group map to conduct network-based drug reuse modeling. For drugs with multiple targets to be effective against diseases, the target protein should be in or near the corresponding disease network in the human interactome. Using the latest network proximity framework, the “closest” proximity of nearly 3,000 drugs and 4 SARS-CoV-2 host gene/protein profiles were measured. ,, used 5 gene/protein expression data sets for gene set enrichment analysis (GSEA): 1 SARS-CoV-2 transcriptomics data set, 1 SARS-CoV-2 proteomics data set, 1 MERS-CoV data set and 2 SARS-CoV-1 transcriptomics data sets. GSEA is evaluated to evaluate the potential of drugs to reverse expression at the transcriptome or proteome level of the viral alteration.
Network-based prediction of COVID-19 drug use
Network-based prediction of COVID-19 drug use (Source: PLOS Biology)
The researchers calculated a total of 34 drugs related to the SARS-CoV-2 data set, which are significantly close to 2 or more SARS-CoV-2 host protein sets. The most common categories of these drugs are antibiotics and β2 agonists. Among these 34 drugs, 3 drugs have significant network proximity to all 4 SARS-CoV-2 data sets studied here. These drugs are respectively, and the next most common disease category is cardiovascular disease. (1) The antibiotic cefdinir, which is a cephalosporin, used to treat bacterial infections; (2) the anti-tumor drug toremifene, a selective estrogen receptor modulator, at a low micromolar level Shows significant activity to destroy a variety of viral infections, including Ebola virus; (3) Antihypertensive drug Irbesartan, an angiotensin II receptor blocker (ARB), which can inhibit sodium or Bile acid cotransporter to inhibit virus entry.
Supporting predictive drug reuse strategies from COVID-19 registry data
Next, the researchers used a large patient data set from the Cleveland Clinic’s COVID-19 Patient Registry to evaluate the relationship between medications and outcomes. After repositioning these 34 drugs, melatonin and carvedilol were discovered. Hormones are physiological hormones common to many living organisms, and carvedilol is approved for hypertension and heart failure. A retrospective COVID-19 genetic analysis was performed to verify the potential preventive effects of melatonin and carvedilol.
A total of 26,779 patients were tested for COVID-19 in the Cleveland Clinic medical system in cardiovascular disease and other states. It was found that the use of melatonin reduced the possibility of a positive SARS-CoV-2 laboratory test result by 28%. Angiotensin-converting enzyme inhibitors (ACEIs) and ARBs are two common drugs for the treatment of high blood pressure. A recent study showed that the proportion of COVID-19 hypertensive patients who use ACEI or ARB and not use it. The predictions and various observational analyses show that the use of melatonin provides potential prevention and treatment strategies for COVID-19; however, randomized controlled clinical trials are urgently needed to test the effect of melatonin on COVID-19. .
Results and discussion
Researchers calculated the potential anti-SARS-CoV-2 effects of nearly 3,000 FDA-approved or investigational drugs through network proximity measurement and GSEA analysis. It highlights 34 reusable drugs and their reported antiviral spectrum. Among them, 8 drugs currently have COVID-19 clinical trials, among which melatonin is the main one. Researchers used a large-scale COVID-19 patient registration database to further explore the relationship between melatonin and drug-disease. Among individuals tested for SARS-CoV-2, the use of melatonin reduced the probability of a positive SARS-CoV-2 test result by 28% and 52%, respectively. Thus, melatonin inhibits the activation of NLRP3 inflammasomes caused by smoking and eliminates lung lesions, which can be achieved by reducing the expression of NF-κBp65 and tumor necrosis factor-α, and by increasing anti-inflammatory cytokines, which can also With anti-inflammatory effects, large-scale observational studies and randomized controlled trials are needed to verify the clinical symptoms of melatonin in patients with COVID-19. However, it is important to understand the mechanism of action of drugs to be reused when designing trials. For example, drugs that reduce virus entry may be very beneficial in preventing infection in the early stages of the COVID-19 course, but may not be effective in severe or mid- to late-stage infections. significance.
The researchers said that the study has certain limitations and integrated data from multiple sources to establish a human interaction genome and drug implantation network, but they are still incomplete. Recent studies have shown that COVID-19 is a systemic disease that affects multiple cell types, tissues and organs. Therefore, understanding the complex interactions between viruses and other diseases is to understand COVID-19-related complications and determine repeatable The key to using drugs. In conclusion, its research provides a powerful and comprehensive network medical strategy for enhancing the understanding of COVID-19-related comorbidities and promoting the identification of COVID-19 standard drugs. Dr. Feixiong Zheng, assistant assistant at the Cleveland Clinic Institute of Genomic Medicine, said: “It is important to note that these findings do not mean that people can start taking melatonin without consulting a physician.”