Computational exploration of the dual role of the phytochemical fortunellin: Antiviral activities against SARS-CoV-2 and immunomodulatory abilities against the host

Agrawal, Shivangi; Pathak, Ekta; Mishra, Rajeev; Mishra, Vijay Kumar; Parveen, Afifa; Mishra, S. K.; Byadgi, Parameswarappa S; Dubey, Shikha; Chaudhary, Ashvanee Kumar; Singh, Vakil; Chaurasia, Rameshwar Nath; Atri, Neelam

doi:10.1016/j.compbiomed.2022.106049

Cited by 4 publications

(7 citation statements)

References 134 publications

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“…Interestingly, the promoted cell apoptosis triggered by LPS was suppressed after fortunellin treatment. This finding was consistent with the reported studies 9,10 . Xiong et al revealed that fortunellin repressed epithelial cell apoptosis by controlling phosphatase and tensin homolog deleted on chromosome 10 expression in colitis 9 .…”

Section: Discussionsupporting

confidence: 92%

“… 1 , 2 An effective strategy for ALI therapy still needs to be developed due to the continuously increasing drug resistance and the emergence of new pathogens. 6 Fortunellin has anti‐inflammation properties, 7 , 9 , 10 while its role in ALI progression remains elusive. Hence, we investigated the function of fortunellin on ALI development and studied the potential mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Kumquat extracts usually possess anticancer, antioxidant, and anti‐inflammation properties 8 . Accumulating evidence reveals that fortunellin has similar functions to kumquat extracts and is regarded as a valuable anti‐inflammation agent 7,9,10 . For example, Zhao et al reported that fortunellin improved the histopathological alterations and heart function and suppressed inflammatory response in diabetic cardiomyopathy 7 .…”

Section: Introductionmentioning

confidence: 99%

“… 8 Accumulating evidence reveals that fortunellin has similar functions to kumquat extracts and is regarded as a valuable anti‐inflammation agent. 7 , 9 , 10 For example, Zhao et al reported that fortunellin improved the histopathological alterations and heart function and suppressed inflammatory response in diabetic cardiomyopathy. 7 Xiong et al found that fortunellin restrained the dysregulated inflammation and inhibited cell apoptosis in colitis.…”

Section: Introductionmentioning

confidence: 99%

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Fortunellin ameliorates LPS‐induced acute lung injury, inflammation, and collagen deposition by restraining the TLR4/NF‐κB/NLRP3 pathway

Liu,

Guo,

Shi

et al. 2024

Immunity Inflam & Disease

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ObjectiveAcute lung injury (ALI) is the prevalent respiratory disease of acute inflammation with high morbidity and mortality. Fortunellin has anti‐inflammation property, but its role in ALI remains elusive. Thus, this study clarified the function of fortunellin on ALI pathogenesis.MethodsThe ALI mouse model was established by lipopolysaccharide (LPS) induction, and lung tissue damage was evaluated utilizing hematoxylin–eosin (HE) staining. The edema of lung tissue was measured by the lung wet/dry (W/D) ratio. The lung capillary permeability was reflected by the protein content in bronchoalveolar lavage fluid (BALF). Inflammatory cell infiltration was measured by the evaluation of the content of myeloperoxidase (MPO), neutrophils, and leukocytes in BALF. Cell apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The secretions of inflammatory cytokines were quantified using enzyme‐linked immunosorbent assay (ELISA) assays. Lung tissue collagen deposition was evaluated by Masson staining.ResultsFortunellin attenuated LPS‐induced lung tissue damage and reduced the W/D ratio, the content of MPO in lung tissue, the total protein contents in BALF, and the neutrophils and leukocytes number. Besides, fortunellin alleviated LPS‐stimulated lung tissue apoptosis, inflammatory response, and collagen deposition. Furthermore, Fortunellin repressed the activity of the Toll‐like receptor 4 (TLR4)/nuclear factor kappa‐B (NF‐κB)/NLR Family Pyrin Domain Containing 3 (NLRP3) pathway in the LPS‐stimulated ALI model and LPS‐induced RAW264.7 cells. Moreover, fortunellin attenuated LPS‐stimulated tissue injury, apoptosis, inflammation, and collagen deposition of the lung via restraining the TLR4/NF‐κB/NLRP3 pathway.ConclusionFortunellin attenuated LPS‐stimulated ALI through repressing the TLR4/NF‐κB/NLRP3 pathway. Fortunellin may be a valuable drug for ALI therapy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fortunellin ameliorates LPS‐induced acute lung injury, inflammation, and collagen deposition by restraining the TLR4/NF‐κB/NLRP3 pathway

Liu,

Guo,

Shi

et al. 2024

Immunity Inflam & Disease

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“…The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has significantly impacted global health. Characterized by symptoms such as acute respiratory distress syndrome, it is often linked with host immunological dysfunction and lymphopenia [1][2][3][4]. This association leads to increased mortality and adverse outcomes in multiple organ systems among hospitalized patients.…”

Section: Introductionmentioning

confidence: 99%

Naringenin-7-O-glucoside: Targeting SERPINE1, MMP7, and MMP1 for COVID-19 Lung Pathology and Immune Modulation

Mishra,

Agrawal,

Malik

et al. 2023

Preprint

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The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been a defining global health crisis, marked by severe respiratory distress and high mortality rates. The search for effective treatments against this highly mutable virus has been a significant challenge. Here, we explored the therapeutic potential of Naringenin-7-O-glucoside (N7G), a bioactive flavone glycoside, in the context of COVID-19. Known for its wide-ranging pharmacological effects, including antiviral, antibacterial, antimalarial, and anticancer properties, Utilizing gene expression data from the EBI Expression Atlas, we analyzed lung samples from deceased COVID-19 patients and healthy individuals to understand N7G’s molecular mechanisms and potential therapeutic targets. Our enrichment analysis revealed a significant association of N7G targets with biological functions and pathways crucial in immune responses and cellular signaling. We highlighted the importance of pathways such as HIF-1, AGE-RAGE, and IL-17 in the pathogenesis of diseases like COVID-19. Suppressing the HIF-1 pathway could mitigate lung inflammation, while targeting the AGE-RAGE pathway, a key player in oxidative stress and inflammation, emerges as a promising strategy. Modulating the IL-17 pathway, implicated in cytokine storms during infection, could also be effective. Furthermore, the relaxin signaling pathway, known for its anti-inflammatory and anti-fibrotic properties, was identified as a potential target for post-COVID-19 syndrome or long-haul COVID. We prioritized SERPINE1, MMP7, and MMP1 as key therapeutic targets. Elevated SERPINE1 levels in COVID-19 patients have been linked to early mortality risk and are involved in processes like platelet degranulation and fibrinolysis impairment, contributing to thrombocytopenia. MMP1 and MMP7, part of the matrix metalloproteinases family, play crucial roles in tissue homeostasis and have been identified as biomarkers and potential therapeutic targets in COVID-19, linked to pulmonary edema and severe inflammatory responses. Our molecular docking and MD simulation studies, conducted over 200 ns in triplicates, demonstrated stable complex formation of N7G with MMP7 and SERPINE1. N7G consistently occupied the zinc binding catalytic site of MMP7, similar to other MMP7 inhibitors, and tightly bound to the inhibitor site of SERPINE1, indicating strong interactions. The MMGBSA analysis confirmed the stability of these complexes, suggesting the effective inhibitory potential of N7G against these targets. Although N7G showed transient complex formation with MMP1, its role in COVID-19 pathogenesis, particularly in inflammation, cannot be ignored. Elevated MMP1 levels have been associated with increased inflammatory responses in COVID-19 patients, underscoring its importance as a therapeutic target. In conclusion, our study identifies MMP7, MMP1, and SERPINE1 as critical immune-related targets of N7G in combating COVID-19. The results position N7G as a potential novel inhibitor for treating COVID-19-induced lung inflammation and long-haul COVID. However, these initial findings require further validation. This study contributes to the understanding of natural compounds in viral infection treatment, opening pathways for exploring flavonoids like N7G against SARS-CoV-2 and other viruses. It underscores the importance of diverse therapeutic strategies, including natural substances, in combating the global challenge of COVID-19.

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Herbal Formulations in Fighting Against the SARS-CoV-2 Infection

Abidharini,

Souparnika,

Elizabeth

et al. 2023

Ethnopharmacology and Drug Discovery for COVID-19: Anti-Sars-CoV-2 Agents From Herbal Medicines and Natural Products

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Computational exploration of the dual role of the phytochemical fortunellin: Antiviral activities against SARS-CoV-2 and immunomodulatory abilities against the host

Cited by 4 publications

References 134 publications

Fortunellin ameliorates LPS‐induced acute lung injury, inflammation, and collagen deposition by restraining the TLR4/NF‐κB/NLRP3 pathway

Fortunellin ameliorates LPS‐induced acute lung injury, inflammation, and collagen deposition by restraining the TLR4/NF‐κB/NLRP3 pathway

Naringenin-7-O-glucoside: Targeting SERPINE1, MMP7, and MMP1 for COVID-19 Lung Pathology and Immune Modulation

Herbal Formulations in Fighting Against the SARS-CoV-2 Infection

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