BREAKING! Wuhan Study Shows That Glutamine And Pyruvate Supplementation, Also Rosiglitazone Can Reduce And Prevent Hyperinflammation In COVID-19!

COVID-19 Drugs: A new breakthrough study by researchers from the Zhongnan Hospital of Wuhan University-China and Southern University of Science and Technology, Shenzhen-China has found that glutamine and pyruvate supplementation, and also the drug diabetic drug Rosiglitazone can reduce and prevent cytokine upregulation hyperinflammation as result of inflammation in macrophages induced by the SARS-CoV-2 virus, hence preventing disease severity and risk of mortality.


 
These therapeutic protocols were based on the principle of rewiring dysfunctional cellular metabolism brought about by the SARS-CoV-2 infection.
 
According to the study team, SARS-CoV-2 infection induces imbalanced immune response such as hyperinflammation in patients with severe COVID-19.
 
The study team analyzed in detail the immunometabolic regulatory mechanisms for the pathogenesis of COVID-19.
 
The study finding depicted the metabolic landscape of immune cells, especially macrophages, from bronchoalveolar lavage fluid of COVID-19 patients at single-cell level.
 
The study findings show that most metabolic processes were upregulated in macrophages from lungs of mild COVID-19 patients compared to cells from heathy controls, whereas macrophages from severe COVID-19 showed downregulation of most of the core metabolic pathways including glutamate metabolism, fatty acid oxidation, citrate cycle and oxidative phosphorylation, and upregulation of a few pathways such as glycolysis.
 
Rewiring cellular metabolism by amino acid supplementation, glycolysis inhibition or PPARγ stimulation reduces inflammation in macrophages stimulated with SARS-CoV-2.
 
The COVID-19 Drugs study found that glutamine and pyruvate supplementation could be used to prevent hyperinflammation as a result of COVID-19 and that the PPARγ agonist rosiglitazone enhances fatty acid uptake and phagocytosis capacity of macrophages, and reduces hyperinflammation in macrophages.
 
The study also found that careful supplementation with the amino acid arginine might also help.
 
It also validated previous study findings that 2-Deoxy-D-glucose or 2 DG can be used to inhibit glycolysis and prevent hyperinflammation in COVID-19.
 
The study findings demonstrate that metabolic imbalance of bronchoalveolar macrophages may contribute to hyperinflammation in patients with severe COVID-19, and provides insights into treating COVID-19 by immunometabolic modulation.
 
The study findings were published in the peer reviewed journal: iScience.
https://www.cell.com/iscience/fulltext/S2589-0042(22)01591-7
 
The study findings were consistent with a recent report showing that blood nutrients including amino acid and lipid metabolites were significantly reduced in severe compared to mild COVID-19 patients.
https://pubmed.ncbi.nlm.nih.gov/33171100/
 
Cellular metabolism is intimately connected to the mechani sms of disease pathogenesis in various infectious diseases and also in the resulting pathology, as well as the host defense response.
 
The study findings depicted the immunometabolic landscape in lungs of COVID-19 patients.
 
The study findings revealed that improper metabolic reprograming of macrophages exacerbated the imbalanced immune response such as hyperinflammatory and reduced endocytosis function.
 
Importantly, the study findings found that modulating lipid metabolism by PPARγ agonist rosiglitazone reduced hyperinflammation in macrophages stimulated with SARS-CoV-2. These findings shed light on treating COVID-19 by immunometabolic modulation.
 
Corresponding author, Dr Zheng Zhang from the Institute for Hepatology at the Southern University of Science and Technology, Shenzhen told Thailand Medical News, “Metabolism is a key regulator of immune cell phenotype and function, but it remains difficult to investigate the metabolic status of individual cells in humans. Gene expression has been used as one of the indirect means to evaluate metabolic activity. Recent developed computational algorithms allow for detection of metabolic pathway activity and metabolic flux based on metabolic gene expression using single-cell transcriptomic approach. Our study team took advantage of the integrated single-cell metabolic profiling platforms and depicted a global picture of immunometabolic profile in lungs of COVID-19 patients with different disease severity.”
 
He further added, “Our study findings suggested that SARS-CoV-2 infection increased glycolysis but decreased most other core metabolic processes in BALF macrophages from severe COVID-19, which correlates with elevated inflammation and reduced antigen presentation and endocytosis functions. Our study thus established the foundation to study metabolic state and functional phenotype of individual immune cells in clinical samples from COVID-19 or other diseases.”
 
It should be noted that past studied have already reported that SARS-CoV-2 infection can induce glycolytic reprogramming of isolated monocytes in vitro.
https://pubmed.ncbi.nlm.nih.gov/35181310/
 
https://pubmed.ncbi.nlm.nih.gov/32697943/
 
https://pubmed.ncbi.nlm.nih.gov/34858397/
 
The study findings also uncovered dramatic metabolic shift in BALF macrophages from mild to severe COVID-19 patients. However, analysis using paired PBMCs indicated minor changes of metabolic activities of peripheral blood monocytes between mild and severe COVID-19 patients. This may be caused by the lack of direct exposure to SARS-CoV-2 virus of the circulating monocytes in vivo.
 
However, in lung tissue, where direct exposure of macrophages to SARS-CoV-2 occurs, the study findings indeed showed the increased level of glycolysis pathways from both mild and severe COVID-19 patients.
 
Importantly, the citrate cycle, oxidative phosphorylation and fatty acid degradation were inhibited in macrophages from severe COVID-19 patients compared to patients with mild diseases.
 
It was suggested that the much higher levels of SARS-CoV-2 particles in lungs of severe patients may lead to the glycolytic reprogramming but inhibition of mitochondrial oxidative metabolism of macrophages.
 
These findings were consistent with reports showing that SARS-CoV-2 infection suppresses OXPHOS and alters mitochondrial function in monocytes and cell lines in vitro.
https://pubmed.ncbi.nlm.nih.gov/33245857/
 
https://pubmed.ncbi.nlm.nih.gov/33293527/
 
The previous studies highlight the importance to study the metabolic and immunological events in SARS-CoV-2 infected lungs to further understand the mechanisms of immune dysfunction and immunopathogenesis.


                                                    Graphical Abstract    
 
The present study findings also validated in vitro that glutamine and pyruvate supplementation or glycolysis inhibition by 2-DG reduced the levels of proinflammatory cytokines and chemokines in human primary macrophages stimulated with SARS-CoV-2 or TLR7/8 agonist.
 
The study findings were consistent with the findings that pro-inflammatory macrophages undergo metabolic reprogramming toward aerobic glycolysis.
 
The study team utilized 2-DG as a model to inhibit glycolysis. High dose of 2-DG (10mM) was reported to suppress both glycolysis and mitochondrial metabolism, while low dose of 2-DG (< 1.25mM) slightly increased oxidative phosphorylation in bone marrow derived macrophages indicating the dose-dependent effect of 2-DG.
 
The study team found that low dose of 2-DG (1mM) can significantly suppress proinflammatory cytokines production by macrophages stimulated with either SARS-CoV-2 or R848. Consistently, 5mM of 2-DG treatment reduced SARS-CoV-2-induced proinflammatory cytokines by monocytes in vitro.
 
Interestingly, amino-acid starvation also resulted in defective anti-inflammatory polarization in macrophages.
 
Taking into consideration that hospitalized COVID-19 patients presented malnutrition and patients with severe COVID-19 exhibited a sharp drop in blood nutrients such as amino acid, the study team proposed that amino acid supplementation in patients with severe COVID-19 might alleviate inflammatory cytokines production by macrophages.
https://pubmed.ncbi.nlm.nih.gov/33171100/
 
Also, it is already known that Lipid metabolism plays a critical role in the differentiation and function of macrophage. Past research showed that anti-inflammatory macrophages trigger a metabolic program of increased oxidative phosphorylation and fatty acid oxidation.
 
The present study findings also showed that reduced lipid metabolism in macrophages from bronchoalveolar of severe COVID-19.
 
It is known that the nuclear receptor PPARγ is known to regulate lipid metabolism in many tissues and it’s the target of anti-diabetic thiazolidinedione drugs.
 
Numerous past studies have shown that in macrophages, PPARγ has been shown to play important roles in inflammation and metabolism.
 
Significantly, PPARγ signaling controls lipid uptake and intracellular metabolism.
 
Any impairment in PPARγ expression and lipid metabolism have been shown to be associated with blocked anti-inflammatory macrophage polarization.
 
The present study findings showed that expression of PPARγ was inhibited in macrophages from patients with severe COVID-19 as reported in another past study and also in human primary macrophages stimulated with SARS-CoV-2 in vitro.
https://pubmed.ncbi.nlm.nih.gov/33015591/
 
Importantly, the study team proved that activating of PPARγ signaling in vitro by rosiglitazone, an anti-diabetic drug, enhanced lipid metabolism and phagocytosis functions of macrophages, and reduced proinflammatory cytokines and chemokines production in human primary macrophages stimulated with SARS-CoV-2 or TLR7/8 agonist.
 
This study finding indicated that rosiglitazone may reduce hyperinflammation in macrophages by regulating lipid metabolism.
 
It is already known that PPARγ in alveolar macrophages limits inflammation and promotes tissue recovery after respiratory viral infection.
https://pubmed.ncbi.nlm.nih.gov/30787149/
 
Furthermore, depletion and altered antigen presentation of alveolar macrophages was also reported to correlate with the severe COVID-19.
https://pubmed.ncbi.nlm.nih.gov/36103512/
 
A past study suggested that targeting metabolism by arginine, epacadostat (a potent and selective indoleamine 2,3-dioxygenase inhibitor), mycophenolic acid (an inosine monophosphate dehydrogenase inhibitor) reduced cytokine release in PBMCs of infected monkeys in vitro.
https://www.nature.com/articles/s41467-021-21907-9
 
The study team concluded that their research findings past published data further support drug repurposing for targeting immunometabolism for COVID-19 treatment.
 
In summary, the study team characterized the immunometabolic landscape in lungs of COVID-19 patients and suggested that regulating metabolism by 2-DG and rosiglitazone might reduce cytokine release syndrome in patients with severe COVID-19.
 
The study findings have identified immunometabolism dysregulation as a mechanism for COVID-19 pathogenesis, and further facilitated the development of novel therapeutic for COVID-19.
 
For the latest on COVID-19 Drugs, keep on logging to Thailand Medical News.
 
Note: Do not attempt to self-treat for COVID-19 using any of the supplements or drugs mentioned here without consulting a licensed medical doctor first!