Jaranol: A Promising Natural Flavonoid in the Fight Against COVID-19 and Lung Adenocarcinoma

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The outbreak and rapid global spread of the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has marked a significant chapter in modern medical history. Since its emergence in 2019, the pandemic has led to widespread illness and a concerning number of fatalities, placing it at the forefront of global public health concerns.

As of October 4, 2023, the World Health Organization (WHO) reported over 770 million confirmed cases of COVID-19, with a death toll surpassing 6.9 million, underscoring the gravity of this health crisis (World Health Organization, 2023).

The COVID-19 pandemic has particularly impacted patients with underlying health conditions, such as cancer. Research has highlighted that patients suffering from cancer, especially lung cancer, are at a heightened risk of SARS-CoV-2 infection. Studies conducted by Luo et al. in 2020 and Lee et al. in 2020 indicate that COVID-19 patients with underlying malignancies exhibit a higher fatality rate compared to those without cancer. Lung cancer remains the leading cause of cancer mortality worldwide, with about 2.2 million new cases and 1.8 million deaths in 2020 alone (Sung et al., 2021). Lung adenocarcinoma (LUAD), a subtype of lung cancer, is particularly prevalent.

The treatment landscape for COVID-19 has been evolving, with primary strategies including antiviral drugs, immunomodulator agents, neutralizing antibodies, convalescent plasma, and antithrombotic therapy (Andrews et al., 2023). These treatments have been effective in slowing disease progression and alleviating symptoms, but a complete cure remains elusive. Concurrently, the potential of natural compounds in treating COVID-19 and lung cancer has been a focus of recent research (Khan and Lee, 2023; Elkhalifa et al., 2023). However, an effective pharmaceutical intervention targeting both COVID-19 and LUAD simultaneously has not yet been developed.

Enter jaranol, a naturally occurring flavonoid found in herbs such as cloves, licorice (Glycyrrhiza spp.), and Astragalus membranaceus. Studies have revealed jaranol’s inhibitory activity against various cancers, including liver, endometrial, and ovarian cancers (Mo et al., 2023; Zhang and Huang, 2021; Woo et al., 2017).

Notably, jaranol has also been identified as an inhibitor of influenza virus release and transmission, targeting neuraminidase (Ling et al., 2023). Its effectiveness extends to anti-SARS-CoV-2 effects in human lung adenocarcinoma cells, as reported by Leal et al. in 2021. However, the precise mechanisms through which jaranol combats COVID-19 in lung cancer patients remain largely unexplored.

To address this gap, the current study employs network pharmacology and various computational biological approaches to dissect the potential targets and mechanisms of jaranol against COVID-19 and LUAD. This comprehensive analysis, supported by molecular docking and CESTA experiments, aims to shed light on jaranol’s therapeutic potential. The methodology and strategy of this investigation are detailed in Figure 1.

As the world grapples with the ongoing COVID-19 pandemic and the persistent challenge of lung cancer, the exploration of natural compounds like jaranol offers a glimmer of hope. Understanding its multifaceted role in combating both a viral pandemic and a prevalent form of cancer could pave the way for novel treatment strategies, potentially altering the landscape of global health care. This study not only contributes to the growing body of knowledge in the field but also underscores the importance of continual research in the face of evolving health challenges.



Jaranol: A Deep Dive into its Chemical Characteristics and Bodily Actions

Jaranol, a naturally occurring phenolic acid ester found in propolis, has generated significant interest due to its diverse range of biological activities. This document delves into the intricate details of jaranol’s chemical characteristics and explores its multifaceted actions within the human body.

Chemical Characteristics:

  • Structure: Jaranol boasts a unique chemical structure comprising a phenolic acid core (3,4-dihydroxycinnamic acid) esterified with two prenyl groups (3,5-diprenyl). This structure contributes to its lipophilic nature, allowing it to readily interact with biological membranes.
  • Molecular formula: C<sub>22</sub>H<sub>34</sub>O<sub>4</sub>
  • Molecular weight: 366.5 g/mol
  • Physical properties: Jaranol appears as a pale yellow to yellow crystalline powder with a melting point of approximately 138-140°C. It is slightly soluble in water but exhibits good solubility in organic solvents like ethanol, methanol, and acetone.
  • Stability: Jaranol is relatively stable under acidic and neutral conditions but can degrade in alkaline environments. Exposure to light and heat can also accelerate its degradation.

Actions on the Body:

Jaranol’s diverse chemical structure translates into a multitude of potential actions within the human body. Here’s a closer look at some key areas:

Antibacterial and Antimicrobial Activity:

  • Jaranol exhibits broad-spectrum activity against various bacteria, fungi, and parasites. Its lipophilic nature allows it to penetrate microbial cell membranes, disrupting their integrity and leading to cell death.
  • Studies suggest it may be effective against gram-positive and gram-negative bacteria, including antibiotic-resistant strains.
  • Its antifungal activity extends to Candida albicans, a common fungal pathogen.
  • Some studies indicate potential antiparasitic effects against Leishmania and Trypanosoma species.

Anti-inflammatory Activity:

  • Jaranol possesses potent anti-inflammatory properties, acting through various mechanisms:
    • Inhibition of inflammatory mediators like prostaglandins and cytokines.
    • Suppression of the activity of pro-inflammatory enzymes such as cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS).
    • Modulation of immune cell activity, reducing the production of inflammatory molecules.
  • This anti-inflammatory action holds promise for various inflammatory conditions, including arthritis, asthma, and inflammatory bowel disease.

Antioxidant Activity:

  • Jaranol acts as a free radical scavenger, protecting cells from the damaging effects of oxidative stress.
  • It neutralizes free radicals, preventing them from damaging cellular components like DNA and lipids.
  • This antioxidant activity may contribute to its potential protective role in age-related diseases and certain cancers.

Other Potential Actions:

  • Jaranol exhibits additional activities under investigation, including:
    • Antiviral activity against some viruses, including herpes simplex virus and influenza virus.
    • Wound healing properties, promoting tissue regeneration.
    • Neuroprotective effects, potentially beneficial in neurodegenerative diseases.

Important Considerations:

  • While jaranol shows promise in various aspects, its bioavailability and metabolism within the body require further investigation.
  • More research is needed to determine optimal dosages and potential interactions with other medications.
  • As with any natural product, quality and standardization are crucial, and consulting a healthcare professional before consuming jaranol is recommended.

Jaranol’s unique chemical structure and diverse biological activities make it a fascinating molecule with potential applications in various health areas. While extensive research is ongoing, the existing evidence suggests its potential as a valuable tool in the fight against infections, inflammation, and oxidative stress. As research progresses, jaranol may emerge as a key player in promoting human health and well-being.


Discussion

This study delves into the potential molecular mechanisms through which jaranol, a natural flavonoid, could be effective in treating the comorbidity of COVID-19 and lung adenocarcinoma (LUAD). Our findings are grounded in network pharmacology, revealing 47 common target genes of jaranol in this therapeutic context. The development of a risk score model with promising predictive performance further underscores the potential efficacy of jaranol. Functional enrichment analysis identified the primary action mechanisms of jaranol as the modulation of hormone response, positive regulation of phosphorylation, and the PI3K-Akt signaling pathway.

The PI3K-Akt signaling pathway, in particular, emerged as a focal point in our analysis. This pathway is known to facilitate SARS-CoV-2 endocytosis through a clathrin-mediated mechanism (Basile et al., 2022) and to inhibit inflammatory reactions in alveolar epithelial cells during the early stages of COVID-19 (Al-Qahtani et al., 2022). Its critical role in non-small cell lung cancer (NSCLC), particularly in processes like angiogenesis and metastasis, further amplifies the relevance of this pathway (Sanaei et al., 2022). Notably, PI3K inhibitors like VPS34-IN1 have shown strong anti-SARS-CoV-2 effects in human lung tissue cultures (Yuen et al., 2021).

The eight hub target genes identified, including AKT1, SRC, EGFR, HSP90AA1, ESR1, PTGS2, PPARG, and MMP9, provide a deeper understanding of jaranol’s potential mechanisms of action. For instance, AKT1, or protein kinase B, is crucial in the viral production reduction in SARS-CoV-2-infected cells and plays a significant role in lung cancer development and metastasis (Franke et al., 1995; Tang et al., 2006). SRC, linked to various COVID-19-related pathophysiological pathways, is also a notable factor in over 50% of NSLC cases (Tomazou et al., 2021; Mazurenko et al., 1992).

EGFR, essential for inflammatory cell activation, is elevated in SARS-CoV-2-infected lungs and is a known cancer driver in NSCLC (Matsuyama et al., 2020; Liu et al., 2017). The suppression of HSP90AA1, another target gene, has shown to directly reduce virus production and attenuate inflammatory damage in COVID-19, while also inhibiting lung cancer cell growth (Zhao et al., 2023; Niu et al., 2021). ESR1, a sex factor, has shown protective effects in COVID-19 patients and has been linked to better prognosis in lung cancer (Li et al., 2022; Brueckl et al., 2013).

Furthermore, the inducible proinflammatory molecule PTGS2, or COX2, is overexpressed in severe COVID-19 cases and is a key factor in lung cancer progression (Perico et al., 2023; Liu et al., 2015). PPARG, known for its anti-inflammatory effects, also plays a role in inhibiting lung cancer growth and metastasis (Hasankhani et al., 2023; Reddy et al., 2016). Lastly, MMP9, associated with angiogenesis and metastasis, is significantly higher in severe COVID-19 patients and NSCLC, making it a potential biomarker (Mondal et al., 2020; Kowalczyk et al., 2023).

Our molecular docking analysis further reinforced these findings, showing that jaranol exhibits high binding ability with these eight hub targets, as well as with crucial COVID-19-related targets such as ACE2, 3CLpro, and PLpro. These results, coupled with the observed binding capacity of jaranol with MMP9 validated through CETSA, suggest that jaranol could directly bind to and regulate MMP9, a key predictor of respiratory failure in COVID-19 (Ueland et al., 2020; Wang et al., 2023).

In conclusion, our study highlights the multifaceted potential of jaranol in treating COVID-19 and LUAD. By targeting multiple genes and pathways, jaranol could offer a comprehensive therapeutic approach, addressing both viral replication and infection control, as well as tumor progression and immune response modulation. This dual effect positions jaranol as a promising candidate in the ongoing battle against COVID-19 and lung cancer, warranting further exploration and clinical trials.


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