The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in millions of infections and fatalities worldwide. Extensive research has highlighted the crucial role of immune system dysregulation in the pathogenesis of COVID-19.
Abnormalities in various immune cells, dysregulated cytokine production, and the development of cytokine storms have been identified as essential factors in severe forms of the disease and extensive lung damage leading to death.
Therefore, therapeutic approaches that modulate the immune response and reduce inflammation hold great promise in combating COVID-19.
Immune System Dysregulation in COVID-19
During SARS-CoV-2 infection, the virus interferes with the immune system’s normal responses, leading to several immune system abnormalities. Lymphopenia, characterized by a decrease in the frequency of T CD4+ and CD8+ cells, contributes to an imbalanced immune system and hyperinflammation due to elevated levels of inflammatory cytokines.
The dysregulation of immune cell subsets, such as granulocytes, monocytes, and regulatory T (Treg) cells, along with the excessive production of pro-inflammatory cytokines, including interleukin (IL)-1, 2, 6, 8, 17, and tumor necrosis factor-alpha (TNF-alpha), further exacerbate the inflammatory response.
Importance of Treg and Th17 Cells
Treg cells play a vital role in maintaining immune system homeostasis by generating anti-inflammatory cytokines such as IL-10 and TGF-beta. The transcription factor FoxP3 influences the differentiation and development of Treg cells. However, COVID-19 patients often exhibit a deficiency in Treg and Th2 cells, leading to an imbalance in the Th17/Treg cell ratio and a shift towards an inflammatory phenotype.
This dysregulated immune response contributes to disease progression. Therefore, therapeutic approaches that enhance the regulatory actions mediated by Treg and Th17 cells and related elements can potentially benefit COVID-19 patients.
Decreased frequency of Th17 cell following treatment with nano-curcumin+catechin
Compared to pre-treatment conditions, we discovered that the frequency of Th17 cells was significantly reduced in patients who received nano-curcumin and nano-curcumin+catechin (p=0.0020 and <0.0001, respectively). On the other hand, the degree of reduction in the group receiving nano-curcumin+catechin was more notable (Fig. 3 and Table 3).
Figure 3. Decreased frequency of Th17 cells in COVID‐19 patients after different treatments compared to the baseline. A. Gating strategy: The representative dot plot figure shows that at first cells were gated based on forward and side scatter for gating live lymphocytes. Then, CD4+ T lymphocytes were gated based on CD4 expression and finally CD4+ T lymphocytes were evaluated for IL-17 expression. B. Representative dot plot scatters of the studied population for Th17 cells frequency after treatment. C. The frequency of the Th17 cells was done according to the representative dot plots, indicating the percentage of Th17 cells (CD4+ IL-17+). According to the flow cytometric results, the frequency of Th17 cells was considerably downregulated in patients who received nano-curcumin and nano-curcumin+catechin compared to pre-treatment circumstances (p=0.0020 and <0.0001, respectively). Results were presented as mean ± SD; patients receiving placebo, n=24; nano-curcumin, n = 27; catechin, n=26; nano-curcumin+catechin, n = 33; ** P < 0.01, **** P < 0.0001.
Immunomodulatory effect of nano-curcumin+catechin on mRNA expression levels of the RORɣt, STAT3, and FoxP3 as Th17 and Treg cells transcription factor
Patients receiving nano-curcumin and nano-curcumin+catechin had significantly higher levels of FoxP3 expression (P=0.0397 and <0.0001, respectively). Besides, compared to groups who received a placebo, the level of FoxP3 gene expression was significantly higher after treatment with nano-curcumin+catechin (P=0.0001). Additionally, it was discovered that RORt was lower after receiving nano-curcumin (p=0.0082) and nano-curcumin+catechin (p<0.0001), more so than it was before therapy. Furthermore, compared to the placebo-receiving group, the outcomes for those who received nano-curcumin+catechin were significant (p<0.0001). Regarding STAT3 expression, after therapy, STAT3 expression levels were considerably downregulated in patients receiving nano-curcumin and nano-curcumin+catechin (P=0.0341 and 0.0003, respectively) (Fig. 5 and Table 3).
Figure 5. Immunomodulatory effect of nano-curcumin, catechin, and nano-curcumin+catechin on mRNA levels of Th17 and Treg cell transcription factors in comparison with placebo-treated group in COVID-19 patients. The results showed that in patients receiving nano-curcumin and nano-curcumin+catechin, the mRNA expression levels of FoxP3 were significantly upregulated after treatment (P=0.0397 and <0.0001, respectively). Also, after treatment with nano-curcumin+catechin, a substantially higher level of FoxP3 gene expression was seen compared to placebo-treated group (P=<0.0001). This figure also reveals the decreased gene expression levels of RORɣt in nano-curcumin (p=0.0082) and nano-curcumin+catechin (p=<0.0001) received patients compared to before treatment. Besides, the results were significant for those who received nano-curcumin+catechin compared to the placebo-received group (p=<0.0001). Regarding the STAT3 expression, in patients receiving nano-curcumin and nano-curcumin+catechin, the expression levels of STAT3 were significantly downregulated after treatment (P=0.0341 and 0.0003, respectively). Results were presented as mean ± SD; patients receiving placebo, n=24; nano-curcumin, n = 27; catechin, n=26; nano-curcumin+catechin, n = 33; * P < 0.05, ** P < 0.01, *** P < 0.001 and **** P < 0.0001.
Catechins have many benefits including preventing or reducing skin damage. Catechins are important ingredients from tea leaves and have intensive anti-oxidant and representative physiological activities. They are members of the group of polyphenol compounds found in many medicinal plants.
The major sources of catechins are Camellia sinensis (C. sinensis) and C. assumica. Green tea contains 75–80% water and polyphenol compounds (flavanols, flavandiols, flavonoid, and phenolic acid) (Zillich et al. 2015), and catechins account for more than 75% of the polyphenol compounds in tea leaves.
They are condensation-type tannins with a ring and the basic structure of flavan-3-ol. They have many chemical structural features, such as hydroxyl groups (−OH), that combine easily with other materials (Singh et al. 2011). There are eight catechins (Fig. 1): C ((-)-catechin), EC ((-)-epicatechin), ECG ((-)-epicatechingallate), EGC ((-)-epigallocatechin), EGCG ((-)-epigallocatechin gallate), GC ((-)-gallocatechin), CG ((-)-catechingallate), and GCG ((-)-gallocatechingallate).
The principle types are EC, ECG, EGC, and EGCG (Jin et al. 2006), which are prominently present in green tea (Fung et al. 2012). Catechins provide several health advantages by scavenging free radicals and retarding extracellular matrix degradation induced by ultraviolet (UV) radiation and pollution (Shi et al. 2016).
Catechins also directly affect the skin by activating collagen synthesis and inhibiting the production of matrix metalloproteinase enzymes (Arct et al. 2003). Because of the hydroxyl in the gallate group, EGCG and ECG are highly effective free-radical scavengers compared with many other standard anti-oxidants, such as ascorbic acid, tocopherol, and trolox (Gulati et al. 2009; Matsubara et al. 2013; Kim et al. 2018). Because of these useful actions, tea catechins are increasingly used in medical, pharmaceutical, and cosmetic products and are being actively studied in a variety of approaches.
Catechins are well-studied substances with proven anti-oxidant effects. Studies have been conducted to boost the stability of catechins and increase their rate of absorption into the human body. Recent studies have focused on maximising the efficacy of anti-oxidants. Gallic acid and catechins show stable anti-oxidant activity by synthesis of galactan, and catechin anti-oxidants covalently bind to chains of proteins (Spizzirri et al. 2009).
Caesalpinia decapetala (C. decapetala) is effective in the oxidation stability of an oil-in-water emulsion (Gallego et al. 2017). Analysis using LC-ESI/LTQ Orbitrap/MS of autochthonous germplasm of the Campania region showed a higher level of anti-oxidant activity compared with the non-autochthonous germplasm (D’Urso et al. 2018).
Enzymatic glucosylation of caffeic acid and EGCG leads to improved anti-oxidant ability in a cellular model of UV-induced skin ageing (Nadim et al. 2014). The flamboyant tree (Delonix regia) has potent anti-oxidant and anti-microbial activities (Feng et al. 2014). EGCG anti-oxidant capacity is effective against H2O2-induced human dermal fibroblast injury (Feng et al. 2013). Lipophilized EGCG derivatives show increased anti-oxidant activity (Zhong and Shahidi 2011).
Flavonoids and triterpenoids from the fruit of Alphitonia neocaledonica have cytotoxicity, anti-oxidant, and anti-tyrosinase activities and are useful cosmetic ingredients (Muhammad et al. 2014). Approximately 106 phenolic compounds have been found using liquid chromatography assays coupled with electrospray ionisation for rapid profiling of phenolic compounds from red maple (Acer rubrum) leaves (Li and Seeram 2018). Bamboo stem extracts have demonstrated anti-melanogenic and anti-oxidative activities in a cell-free system and B16F10 melanoma cells (Choi et al. 2018).
The ethanol extract of the marula tree is very effective in boosting activities in vitro. ECG and EGCG in marula tree extract contribute to anti-ageing activities (Shoko et al. 2018). Cocos nucifera bark showed anti-oxidant and anti-depressant activities through oxidative alterations in the prefrontal cortex (Lima et al. 2016).
Catechins and Curcumin: Potential Therapeutic Agents
In the fight against the SARS-CoV-2 pandemic, various diagnostic and therapeutic approaches have been developed. One promising avenue is the utilization of plant-derived compounds with antiviral properties. Catechins and Curcumin are two such compounds that have shown potential in combating RNA viruses, including coronaviruses.
Curcumin, derived from the Curcuma longa L. plant, possesses anti-inflammatory, antimicrobial, and antioxidant activities. It down-regulates pro-inflammatory cytokines and inhibits transcription factors involved in inflammation. Recent studies have demonstrated the preventive and therapeutic effects of Curcumin in various diseases.
To overcome the limitations of free Curcumin use, a nanocurcumin product has been developed, which exhibits improved biological and pharmacological properties. Additionally, computer simulations have shown that Curcumin can prevent viral growth and inhibit the entry of SARS-CoV-2 into cells.
Catechins are phytochemicals found in various organic foods and medicinal plants. They possess a wide range of pharmacological effects, including antiviral, antibacterial, anti-inflammatory, and anticarcinogenic activities. Studies have shown that Catechins bind to the S protein of SARS-CoV-2, preventing its attachment to the ACE2 receptor.
Evaluation of Nano-Curcumin and Catechin Combination
The current study aims to evaluate the therapeutic potential of a combination of nano-curcumin and catechins as novel therapeutic agents for COVID-19. By comparing the frequency of immune cell subsets and their mediating factors in COVID-19 patients treated with the nano-curcumin and catechin combination versus a placebo group in the intensive care unit (ICU), the study seeks to shed light on the effectiveness of this approach.
The study is the first of its kind to examine how nano-curcumin and catechin combination therapy affects the frequency of CD4+ and CD8+ T cells, as well as inflammation reduction in COVID-19 patients. The findings from this study have the potential to provide valuable insights into the immunomodulatory effects of these compounds and their therapeutic benefits in the context of COVID-19.
The dysregulation of the immune system and the establishment of cytokine storms play a critical role in the severity and progression of COVID-19. Therapeutic approaches that modulate the immune response and reduce inflammation hold significant promise in combating this disease. Nano-curcumin and catechins, with their antiviral properties and ability to regulate immune cell subsets, offer a novel therapeutic avenue for COVID-19 patients.
Further research and clinical trials are needed to validate the findings of the current study and explore the optimal dosages and treatment regimens for nano-curcumin and catechin combination therapy. With ongoing efforts in understanding the immune response in COVID-19 and identifying effective therapeutic strategies, we can hope for improved outcomes and a step closer to controlling the SARS-CoV-2 pandemic.
reference link :https://www.sciencedirect.com/science/article/pii/S0198885923000824