SARS-CoV-2 cytokine storm inhibited by curcumin nanoparticles

In a recent study published in the journal ACS Applied Bio Materials, researchers demonstrated the inhibitory potential of curcumin-encapsulated polysaccharide nanoparticles (CUR−PS-NPs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (CoV2-SP)-stimulated cytokine storm in lung and liver epithelial cells.

The multi-organ failure, lung injury, and poor prognosis of severe disease in coronavirus disease 2019 (COVID-19) patients are directly associated with the interleukin (IL)-induced profound cytokine storm developed in response to SARS-CoV-2 infection in these patients. The interaction between SARS-CoV-2 and human angiotensin-converting enzyme 2 (hACE2) receptors triggers the cytokine storm followed by life-threatening systemic inflammatory responses. The fatal inflammatory syndrome is characterized by higher circulating cytokine levels and immune cell hyperactivation, leading to secondary organ dysfunction, especially hepatic, pulmonary, or renal.

A dietary polyphenolic antioxidant compound named CUR obtained from turmeric plant Curcuma longa L. is famous for its robust anti-inflammatory activity. However, in vivo efficacy of CUR is constrained because of its inadequate bioavailability.

Study: Nanocurcumin Potently Inhibits SARS-CoV-2 Spike Protein-Induced Cytokine Storm by Deactivation of MAPK/NF-κB Signaling in Epithelial Cells​​​​​​​. Image Credit: COLOA Studio / ShutterstockStudy: Nanocurcumin Potently Inhibits SARS-CoV-2 Spike Protein-Induced Cytokine Storm by Deactivation of MAPK/NF-κB Signaling in Epithelial Cells​​​​​​​. Image Credit: COLOA Studio / Shutterstock

About the study

In the present study, the authors compared the anti-inflammatory effect of CUR−PS-NPs directed towards CoV2-SP-stimulated cytokine storm with bulk-CUR (B-CUR) and PS-NPs in lung and liver epithelial cells. Further, the researchers interpreted the mechanism associated with the inhibition of nuclear factor κB (NF-κB) signaling and mitogen-activated protein kinase (MAPK) deactivation by CUR that inhibited the CoV2-SP-mediated cytokine storms. The team also evaluated the function of CUR in lowering CoV2-SP-induced phosphorylation of p42/44 MAPK, p65/NF-κB, p38 MAPK, and nuclear p65/NF-κB expression, and release of growth factors, chemokines, and cytokines associated with the lung and liver epithelial cell injury.

CUR (97% purity), purified biotinylated recombinant hACE2, and SARS-CoV-2 S recombinant glycoproteins were used in this study. Further, the liver Huh7.5 and lung A549 epithelial cells were procured from the American Type Culture Collection (ATCC)-recognized cell repository at National Centre for Cell Sciences, Pune, India.

The PS-rich fraction was isolated and characterized from the dried rhizomes of C. longa. An emulsion solvent evaporation technique with minor changes was used in the CUR−PS-NPs' preparation. The epithelial cells were seeded and incubated with CoV2-SP containing stock solution.

The total ribonucleic acid (RNA) was isolated from the CoV2-SP-exposed epithelial cell pallets using an RNeasy mini kit. Subsequently, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) experiments were conducted in the genes of CoV2-SP-exposed and unexposed epithelial cells. The interaction between CoV2-SP and hACE2 was assessed by enzyme-linked immunosorbent assay (ELISA). The cell viability was evaluated by the fluorescence-activated cell sorting (FACS) analysis, fluorescence microscopy, and Alamar blue assay using propidium iodide (PI) and Annexin V-FITC.

Study findings

The results indicated that the size of the CUR−PS-NPs was within the nanomaterial range, and there was a continuous CUR release from the CUR–PS-NPs. 

CUR–PS-NPs showed a high potential to inhibit the release of chemokines such as IP10, MCP-1, and CXCL8, growth factors such as vascular endothelial growth factor (VEGF) and C-C chemokine ligand 3 (CCL3), and cytokines such as IL-12, IL-6, and IL-1 associated with the impairment of CoV2-SP-triggered lung A549 and liver Huh7.5 epithelial cells.

The inhibition of chemokines, cytokines, and growth factors by CUR–PS-NPs in A549 and Huh7.5 cells was higher than PS-NPs and B-CUR-treated cells. However, the inhibition of VEGF-A, CCL10, and CCL5 in PS-NPs and B-CUR-treated A549 cells were higher than the CUR–PS-NPs-treated cells. No significant inhibitory effects on the release of IL-8 and IL-6 in CoV2-SPs-triggered Huh7.5 and A549 cells were demonstrated by the PS-NPs treatment alone.

Therapeutical strategies employing CUR–PS-NPs successfully diminished the interaction between CoV2-SP and host ACE2. CUR−PS-NPs’ potential to inhibit the interaction of CoV2-SP and human ACE2 was higher than that of PS-NPs and B-CUR.

At the 10 μM dose, both B-CUR and nano-CUR caused significant reductions in cell viability whereas, at the 5 μM dose, neither B-CUR nor nano-CUR caused any lethality to the cells. Additionally, nano-CUR had superior bioavailability than B-CUR.

CUR-PS-NPs act by lowering NF-κB/MAPK signaling, resulting in the reduction of CoV2-SP-induced phosphorylation of p65/NF-κB, p38 MAPK, p65/NF-κB, and p42/44 MAPK expression. The reduction of CoV2-SP-induced phosphorylation of protein kinases caused by CUR-PS-NPs was higher than B-CUR-induced reductions.

Conclusions

The study findings indicated that organic NPs of CUR obtained from a PS-affluent fraction of turmeric rhizome, CUR−PS-NPs, have a high inhibitory potential towards CoV2-SP-induced cytokine storm in human lung A549 and liver Huh7.5 epithelial cells. Furthermore, the treatment of CUR−PS-NPs in CoV2-SP-triggered epithelial cells prevented the epithelial cell damage by inhibiting the release of chemokines, growth factors, and cytokines through the deactivation of the NF-κB/MAPK signaling pathway.  

Overall, the study emphasized that the CUR−PS-NPs might have the potential to become a safe and effective drug for COVID-19 treatment. However, additional in vivo investigations are needed to validate the CoV2-SP-induced cytokine storm inhibitory potential of CUR-PS-NPs in lung and liver epithelial cells.

Journal reference:
  • Nanocurcumin Potently Inhibits SARS-CoV-2 Spike Protein-Induced Cytokine Storm by Deactivation of MAPK/NF-κB Signaling in Epithelial Cells, Vivek K. Sharma, Prateeksha, Shailendra P. Singh, Brahma N. Singh, Chandana V. Rao, and Saroj K. Barik, ACS Applied Bio Materials Article ASAP, DOI: 10.1021/acsabm.1c00874, https://pubs.acs.org/doi/10.1021/acsabm.1c00874
Shanet Susan Alex

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Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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