Interleukin‐6 inhibitory effect of natural product naringenin compared to a synthesised monoclonal antibody against life‐threatening COVID‐19

Abstract

Coronavirus Disease 2019 (COVID‐19) has become a global pandemic in 2020 with high patient mortality due to acute respiratory distress syndrome which is possibly induced by a Cytokine release syndrome and more specifically through an interleukin‐6 (IL‐6) booster. Currently, IL‐6/IL‐6R inhibitors indicated an effective function in reducing the inflammatory markers in severe COVID‐19 patients. In this comprehensively narrative review, we searched online academic databases including (Google Scholar, Web of Science, and Pub Med), the relevant literature was extracted from the databases by using search terms of COVID‐19, IL‐6, and IL6 inhibitor as free‐text words and also with the combination with OR/AND to summarise the latest discoveries on the inhibitors of IL‐6 and its receptor's especially focussing on the role of natural product, Naringin (NAR) as a flavonoid found in citrus fruits, with considerable anti‐inflammatory and antiviral properties in COVID‐19 treatments. Our data Therefore in comparison with other synthetic monoclonal antibodies NAR may provide a good qualification for the development of novel anti‐inflammatory agents, especially against Covid 19 based on recent studies.

Potential Beneficial Effects of Naringin and Naringenin on Long COVID—A Review of the Literature

“…Naringin has been shown to significantly reduce the infiltration of inflammatory cells induced by lipopolysaccharide and decrease the production of macrophage nitrogen monoxide (NO) and IL-6 [ 169 ]. In critically ill COVID-19 patients, naringenin also showed excellent IL-6 inhibition compared to synthetic monoclonal antibodies [ 46 ]. In a paraquat-induced acute lung injury model, naringin not only decreased the production of the inflammatory cytokines TNF-α and TNF-β1 but also inhibited oxidative stress by activating the expression of antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and heme oxygenase 1) and regulated collagen formation by modulating the ratio of tissue inhibitors of metalloproteinases-1 (TIMP-1) to MMP-9, thereby preventing lung fibrosis [ 170 ].…”

“…The efficacy of naringin and naringenin is due to anti-inflammatory [ 41 ], anticancer [ 42 ], antioxidant properties [ 43 , 44 ], treatment of cardiovascular disease [ 45 ], antiviral [ 36 ] and immune-modulation effects [ 41 ], which may play an effective role in treating long COVID. The anti-inflammatory and antioxidant effects of naringenin can effectively counteract the cytokine storm induced by SARS-CoV-2, especially targeting and inhibiting interleukin(IL)-6, the main pro-inflammatory factor of COVID-19 [ 46 ]. Moreover, numerous molecular docking studies reveal that naringenin binds to viral spiking proteins, viral major proteases, host receptors, and host viral transport channels and has multiple antiviral effects against SARS-CoV-2 [ 47 ].…”

Naringin’s Alleviation of the Inflammatory Response Caused by Actinobacillus pleuropneumoniae by Downregulating the NF-κB/NLRP3 Signalling Pathway

“…After NAR enters the body, its active metabolite naringenin protects endothelial cells from apoptosis and inflammation by regulating the Hippo-YAP pathway [12]. Most notably, NAR has shown effectiveness in repairing inflammatory damage in the respiratory tract, and reducing sputum secretion and inflammatory infiltration in lungs [13]. NAR can improve lung inflammation by inhibiting the release of interleukin (IL)-8, leukotriene B4, tumour necrosis factor (TNF)-α, and persistent neutrophilic infiltration due to infection [14].…”

“…Porcine alveolar macrophages (PAM) are widely distributed on the alveolar and bronchial surfaces, forming a vital defence barrier for innate lung immunity [16]. When APP invades, pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) in PAM are activated, causing it to release an excess of inflammatory cytokines [13,16]. When lung tissue is overloaded with inflammatory factors, it activates the NLRP3 inflammatory vesicle classical/non-classical pathway in turn, which mediates apoptosis as well as cellular pyroptosis via the caspase-1, caspase-8, and caspase-9 pathways, further exacerbating inflammation [17,18].…”