inzicht - Pharmacology - # Capsaicin as a novel NRF2 agonist for oxidative stress-related diseases

Capsaicin, a Natural Compound, Alleviates Ethanol-Induced Gastric Mucosal Oxidative Damage by Disrupting the KEAP1-NRF2 Interaction

Q: How could the unique allosteric binding mode of capsaicin to KEAP1 be leveraged to develop more potent and selective NRF2 activators

The unique allosteric binding mode of capsaicin to KEAP1 presents an exciting opportunity for the development of more potent and selective NRF2 activators. By targeting specific allosteric sites on KEAP1, researchers can design molecules that interact with KEAP1 in a non-covalent manner, avoiding the potential off-target effects associated with covalent modifications. This approach allows for the creation of compounds that can modulate the KEAP1-NRF2 interaction with high specificity, enhancing the therapeutic efficacy of NRF2 activation. Leveraging the allosteric binding mode of capsaicin can lead to the development of novel lead compounds with improved pharmacokinetic properties and reduced side effects, paving the way for the discovery of more effective NRF2 agonists.

Q: What are the potential limitations or side effects associated with long-term, high-dose administration of capsaicin, and how can they be addressed

Long-term, high-dose administration of capsaicin may be associated with potential limitations and side effects that need to be carefully considered. Some of the possible drawbacks include gastrointestinal irritation, mucosal damage, and increased sensitivity in individuals with pre-existing gastric conditions. To address these concerns, dosage optimization and personalized treatment plans can be implemented to minimize adverse effects. Additionally, the use of targeted drug delivery systems, such as nanoparticles, can help enhance the bioavailability of capsaicin while reducing its systemic exposure, thereby mitigating the risk of side effects. Regular monitoring of patients and close observation for any signs of intolerance or adverse reactions are essential to ensure the safe and effective use of capsaicin in clinical settings.

Q: Given the multifaceted pharmacological effects of capsaicin, how might its antioxidant and anti-inflammatory properties be harnessed for the treatment of other oxidative stress-related diseases beyond gastric mucosal injury

The multifaceted pharmacological effects of capsaicin, including its antioxidant and anti-inflammatory properties, hold great potential for the treatment of various oxidative stress-related diseases beyond gastric mucosal injury. Capsaicin's ability to activate the NRF2-ARE signaling pathway and modulate oxidative stress makes it a promising candidate for conditions such as neurodegenerative diseases, cardiovascular disorders, and cancer. By harnessing its antioxidant properties, capsaicin can help combat free radical damage, reduce inflammation, and promote cellular health in diverse disease states. Future research can explore the therapeutic potential of capsaicin in these areas, focusing on targeted delivery systems and personalized treatment approaches to maximize its benefits while minimizing side effects.

Belangrijkste concepten

Capsaicin, a natural compound derived from chili peppers, can effectively mitigate oxidative stress by directly disrupting the KEAP1-NRF2 interaction and activating the NRF2-ARE signaling pathway.

Samenvatting

The study investigated the protective effects of capsaicin (CAP) against ethanol-induced oxidative damage in gastric mucosal cells and tissues. Key findings:

CAP pretreatment significantly enhanced cell viability, reduced ROS levels, and modulated redox balance in gastric epithelial cells exposed to ethanol.
CAP promoted the nuclear translocation of NRF2 and upregulated the expression of downstream antioxidant genes like HO-1, Trx, and NQO1.
CAP directly bound to the Kelch domain of KEAP1 and disrupted the KEAP1-NRF2 interaction, leading to NRF2 stabilization and activation.
In a rat model of ethanol-induced acute gastric mucosal injury, CAP and CAP-loaded nanoparticles (IR-HSA@CAP) effectively alleviated oxidative damage, inflammation, and histopathological changes.
Mechanistically, IR-HSA@CAP nanoparticles activated the NRF2/ARE signaling pathway and suppressed the production of pro-inflammatory cytokines in the gastric tissues.
The study provides evidence that CAP is a safe and novel NRF2 agonist that acts by allosterically regulating KEAP1, offering a promising therapeutic approach for oxidative stress-related diseases.

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biorxiv.org

Statistieken

Exposure to 5% ethanol for 1.5 hours decreased cell viability to approximately 50% in GES-1 cells.
Pretreatment with 8 μM CAP significantly enhanced cell viability to 93.84% in GES-1 cells exposed to ethanol.
CAP pretreatment reduced the percentage of apoptotic GES-1 cells from 28.85% to 13.95% in the ethanol-exposed group.
CAP pretreatment decreased intracellular ROS levels in GES-1 cells from 83.1% to 48.9%.
CAP treatment increased SOD activity and decreased MDA levels in GES-1 cells exposed to ethanol.
The ulcer injury (UI) index in the ethanol-exposed rat group was 36.0, which was significantly reduced to 7.0 and 5.3 in the CAP and IR-HSA@CAP pretreatment groups, respectively.
IR-HSA@CAP pretreatment reduced the pathological damage index in the rat gastric tissues from 6.3 in the ethanol group to 1.7.
IR-HSA@CAP pretreatment decreased ROS levels by 36.99% and lipid peroxidation (MDA) by 72.82% in the rat gastric tissues compared to the ethanol group.

Citaten

"CAP ameliorated mitochondrial damage, facilitated the nuclear translocation of NRF2, thereby promoting the expression of downstream antioxidant response elements, HO-1, Trx, GSS and NQO1 in GES1 cells."
"CAP non-covalently bound to Kelch domain and allosterically regulated three regions of KEAP1: L342-L355, D394-G423 and N482-N495."
"Our work provided new insights that CAP is a safe and novel NRF2 agonist by allosterically regulating KEAP1, which may contribute to the development of lead drugs for oxidative stress-related illness, e.g. aging, cancer, neurodegenerative and cardiovascular diseases."

Belangrijkste Inzichten Gedestilleerd Uit

Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction

by Gao,X., Zhan... om www.biorxiv.org 01-07-2024

https://www.biorxiv.org/content/10.1101/2024.01.06.574490v4

Diepere vragen

How could the unique allosteric binding mode of capsaicin to KEAP1 be leveraged to develop more potent and selective NRF2 activators

The unique allosteric binding mode of capsaicin to KEAP1 presents an exciting opportunity for the development of more potent and selective NRF2 activators. By targeting specific allosteric sites on KEAP1, researchers can design molecules that interact with KEAP1 in a non-covalent manner, avoiding the potential off-target effects associated with covalent modifications. This approach allows for the creation of compounds that can modulate the KEAP1-NRF2 interaction with high specificity, enhancing the therapeutic efficacy of NRF2 activation. Leveraging the allosteric binding mode of capsaicin can lead to the development of novel lead compounds with improved pharmacokinetic properties and reduced side effects, paving the way for the discovery of more effective NRF2 agonists.

What are the potential limitations or side effects associated with long-term, high-dose administration of capsaicin, and how can they be addressed

Long-term, high-dose administration of capsaicin may be associated with potential limitations and side effects that need to be carefully considered. Some of the possible drawbacks include gastrointestinal irritation, mucosal damage, and increased sensitivity in individuals with pre-existing gastric conditions. To address these concerns, dosage optimization and personalized treatment plans can be implemented to minimize adverse effects. Additionally, the use of targeted drug delivery systems, such as nanoparticles, can help enhance the bioavailability of capsaicin while reducing its systemic exposure, thereby mitigating the risk of side effects. Regular monitoring of patients and close observation for any signs of intolerance or adverse reactions are essential to ensure the safe and effective use of capsaicin in clinical settings.

Given the multifaceted pharmacological effects of capsaicin, how might its antioxidant and anti-inflammatory properties be harnessed for the treatment of other oxidative stress-related diseases beyond gastric mucosal injury

The multifaceted pharmacological effects of capsaicin, including its antioxidant and anti-inflammatory properties, hold great potential for the treatment of various oxidative stress-related diseases beyond gastric mucosal injury. Capsaicin's ability to activate the NRF2-ARE signaling pathway and modulate oxidative stress makes it a promising candidate for conditions such as neurodegenerative diseases, cardiovascular disorders, and cancer. By harnessing its antioxidant properties, capsaicin can help combat free radical damage, reduce inflammation, and promote cellular health in diverse disease states. Future research can explore the therapeutic potential of capsaicin in these areas, focusing on targeted delivery systems and personalized treatment approaches to maximize its benefits while minimizing side effects.