Therapeutic Potential of Naringin and Naringenin in Long COVID: A Multifaceted Approach

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The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented unprecedented challenges to global health, economies, and scientific research communities. While much focus has been on acute infection management, the post-acute sequelae of SARS-CoV-2 infection, widely known as long COVID, have emerged as a multifaceted public health issue. Long COVID is characterized by a wide range of persistent symptoms that significantly impact individuals’ quality of life, healthcare systems, and workforces across the globe. This article delves into the pathogenesis of long COVID and explores the therapeutic potential of naringin and naringenin, two naturally occurring flavonoids, in mitigating its diverse symptoms.

Understanding Long COVID

Long COVID presents with a constellation of symptoms, including but not limited to fatigue, cognitive dysfunction, immune dysregulation, microbiota dysbiosis, and organ-specific pathologies such as myocarditis and pulmonary fibrosis. The underlying mechanisms are complex, involving persistent viral reservoirs, immune dysfunction, microthrombosis, and systemic inflammation. These mechanisms contribute to a wide spectrum of clinical manifestations, affecting nearly every organ system in the body. The persistence of symptoms like cognitive dysfunction, commonly referred to as “brain fog,” alongside physical disabilities such as dyspnea and fatigue, underscores the need for comprehensive therapeutic strategies.

Naringin and Naringenin: A Closer Look

Naringin and naringenin, predominantly found in citrus fruits, have been recognized for their broad spectrum of biological activities, including anti-inflammatory, antioxidant, anticancer, and antiviral effects. These compounds have garnered interest for their potential role in addressing the multifaceted symptoms of long COVID through various mechanisms. Their anti-inflammatory properties, for instance, could mitigate the cytokine storm associated with acute and long-term COVID-19 sequelae. Furthermore, their antioxidant capabilities may counteract oxidative stress, contributing to the alleviation of symptoms like fatigue and cognitive impairment.

Exploring the Impact of Naringin and Naringenin on Inflammation

Inflammation serves as a pivotal adaptive defense mechanism against infection or injury, playing a crucial role in maintaining our overall health. However, excessive or chronic inflammation can lead to various inflammatory diseases, including atherosclerosis, rheumatoid arthritis, asthma, pulmonary fibrosis, and septic shock. The production of cytokines like interleukin (IL), tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and inflammatory mediators such as nitric oxide (NO) and prostaglandins (PG) by macrophages during inflammation can exacerbate these conditions.

Macrophages are essential players in the body’s immune response, but their overactivity can contribute to harmful inflammation. Several external stimuli, including lipopolysaccharides and interferon (IFN-β), can trigger macrophages to release inflammatory mediators such as NO, prostaglandin E2 (PGE2), and reactive oxygen species (ROS), along with enzymes like inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Addressing these inflammatory mediators becomes crucial in treating various diseases with anti-inflammatory components.

Enter naringin and naringenin, two compounds with the potential to modulate macrophage activity, thereby reducing inflammation. These flavanones have garnered attention in the scientific community due to their anti-inflammatory properties, which are achieved through multiple mechanisms.

  • Modulation of Regulatory Enzymes: Studies have demonstrated that naringin and naringenin can inhibit regulatory enzymes involved in the inflammatory response, thereby curbing inflammation [58,61,62].
  • Arachidonic Acid Metabolism: These flavanones can influence arachidonic acid metabolism, a key pathway in inflammation control [61,62,63,64].
  • Gene Expression: Naringin and naringenin can modulate gene expression, which plays a pivotal role in regulating inflammatory mediators [65].
  • Effects on Transcription Factors: These compounds also affect transcription factors essential in controlling inflammation-related mediators [66].

Furthermore, naringin and naringenin exhibit potent antioxidant properties, capable of neutralizing harmful free radicals and reducing their formation. They also exert significant effects on immune cells and immune mechanisms involved in inflammatory processes.

In vitro experiments have demonstrated the effectiveness of naringenin in alleviating colitis in a murine colitis model. This effect appears to be associated with the inhibition of Toll-like receptor 4 (TLR4) protein and nuclear factor-kappa B (NF-kB) activity. Additionally, naringenin downregulates the expression of various inflammatory mediators and inhibits the production of inflammatory cytokines such as TNF-α and IL-6 [46].

Recent research has explored the anti-inflammatory effects of naringin and naringenin in diabetic rats. Both flavonoid compounds were found to decrease the levels of circulating proinflammatory cytokines and downregulate the expression of IL-6 in adipose tissue [68].

The anti-inflammatory potential of flavonoids extends to their ability to bind to cyclooxygenases (COXs), enzymes responsible for the synthesis of prostaglandins and thromboxanes. Flavanones, including naringin and naringenin, have demonstrated the ability to bind to COX-2, suggesting their potential in developing potent anti-inflammatory inhibitors [69].

In vivo studies have further reinforced the anti-inflammatory effects of naringin and naringenin. Naringin was shown to reduce airway inflammation and modulate pulmonary endothelial permeability in mouse models of lipopolysaccharide/cigarette smoke-induced inflammation [70]. These flavanones also displayed topical anti-inflammatory and anti-allergic activities in mouse models of ear edema induced by arachidonic acid (AA) and tetradecanoylphorbol-13-acetate (TPA) [64].

Moreover, in a rat model of cyclophosphamide-induced hepatotoxicity, naringin exhibited potential by reducing oxidative stress, fibrosis, and inflammation [71]. In another study involving Wistar rats with 1,2-dimethylhydrazine (DMH)-induced precancerous colon lesions, naringenin showed promise by reducing lipid peroxidation, ROS generation, lesion formation, and TNF-α levels [72].

These findings collectively highlight the potential of naringin and naringenin as potent anti-inflammatory agents in various in vitro and in vivo models of inflammation. As chronic low-grade inflammation underlies numerous chronic diseases, these flavanones offer promising avenues for safer, less toxic, and cost-effective treatment alternatives in the fight against inflammatory disorders and related chronic conditions.

Naringin and Naringenin: Unraveling Their Impact on Angiogenesis

Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a critical role in various physiological processes and is especially prominent in tumor development and progression. Tumors rely on the proliferation of blood vessels to ensure a steady supply of nutrients and oxygen, and angiogenic factors, particularly vascular endothelial growth factor (VEGF), are key drivers of this process.

Emerging research suggests that naringin and naringenin, two flavanones with well-documented anti-inflammatory properties, may also have a significant impact on angiogenesis, shedding light on their potential in cancer therapy.

  • Suppression of Endothelial Cell Activity: In a study involving mice with subcutaneous gliomas, naringin administration at a dosage of 120 mg/kg/day demonstrated remarkable effects on endothelial cells. It suppressed tube formation and reduced cell invasion, showcasing its potential to inhibit vascular proliferation and tumor angiogenesis [89].
  • Inhibition of VEGF Release: Naringin exhibited its anti-angiogenic properties by inhibiting the release of VEGF in various cancer cell lines, including MDA human breast cancer cells, U-343, and U-118 glioma cells. At a concentration of 0.1 µmol/L, naringin significantly curtailed the production of this pivotal angiogenic factor [88].
  • Targeting Malignant Melanoma: Malignant melanoma, a deadly form of skin cancer known for its aggressive behavior and metastasis, also faces the brunt of naringenin’s anti-angiogenic potential. In vitro and ex vivo angiogenesis assays involving B16F10 and SK-MEL-28 cells revealed that naringenin treatment effectively suppressed endothelial cell migration, tube formation, and microvessel sprouting in a dose-dependent manner [90].
  • Inhibition of In Vitro Angiogenesis: Naringenin’s impact on angiogenesis extends to in vitro models involving human endothelial cells. Studies demonstrated that naringenin treatment had multifaceted effects, including inhibiting proliferation, inducing apoptosis, reducing migration, and suppressing tube formation, collectively dampening the angiogenic process [91].
  • In Vivo Anti-Angiogenic Effects: The anti-angiogenic potential of naringenin wasn’t limited to in vitro settings. The chick chorioallantoic membrane (CAM) assay revealed its ability to inhibit physiological angiogenesis in vivo. Naringenin’s administration led to a reduction in CAM neovascularization, further underlining its anti-angiogenic prowess [91].

Understanding the impact of naringin and naringenin on angiogenesis opens up exciting possibilities for cancer therapy and anti-angiogenic strategies. Targeting the blood vessels that nourish tumors is a promising approach in curbing tumor growth and metastasis, and these flavanones appear to hold great potential in this endeavor.

While more research is needed to fully elucidate the mechanisms and assess their clinical applicability, these findings highlight the multifaceted nature of naringin and naringenin, offering new avenues in the quest to combat cancer and inhibit pathological angiogenesis. The potential synergy of their anti-inflammatory and anti-angiogenic properties may pave the way for innovative cancer treatments that target both tumor growth and the supporting vascular network.

Cognitive Dysfunction and Long COVID

Cognitive dysfunction in long COVID, manifesting as memory lapses, attention deficits, and executive functioning challenges, is a significant concern. The neuroprotective properties of naringin and naringenin, through the modulation of inflammatory pathways and protection against oxidative stress, offer a promising avenue for therapeutic intervention. By mitigating glial cell activation and promoting neuronal repair, these flavonoids could potentially improve cognitive outcomes in long COVID patients.

Immune Dysregulation: A Target for Naringin and Naringenin

The immune dysregulation observed in long COVID patients, characterized by altered immune cell profiles and persistent inflammation, could be modulated by the immunomodulatory effects of naringin and naringenin. These compounds may help rebalance the immune response, reducing the risk of autoimmune phenomena and facilitating recovery from persistent symptoms.

Addressing Microbiota Dysbiosis

The impact of SARS-CoV-2 on the gut microbiome, resulting in dysbiosis, has implications for long COVID pathophysiology. Naringin and naringenin’s ability to modulate gut flora and enhance barrier function presents a potential strategy to restore microbial balance, thus addressing gastrointestinal symptoms and possibly reducing systemic inflammation.

Mitigating Organ-specific Pathologies

The cardioprotective and antifibrotic effects of naringin and naringenin are particularly relevant to long COVID, where myocarditis and pulmonary fibrosis are prevalent complications. By inhibiting pro-fibrotic pathways and reducing inflammation, these flavonoids could play a role in preventing or ameliorating organ-specific damage.

Conclusion

As the scientific community continues to unravel the complexities of long COVID, the potential of natural compounds like naringin and naringenin offers a glimmer of hope. Their multifaceted biological activities align with the multisystemic nature of long COVID, providing a rationale for their inclusion in therapeutic regimens. While further clinical research is necessary to fully understand their efficacy and safety in this context, the existing evidence points to a promising role for these flavonoids in the holistic management of long COVID. The pursuit of comprehensive, evidence-based therapeutic strategies will be crucial in addressing the long-term impacts of the COVID-19 pandemic on individual and public health.


reference link : https://www.mdpi.com/2076-2607/12/2/332

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313440/

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