Characterisation of Nox4 inhibitors from edible plants
Philipp A Kofler1, Haymo Pircher, Susanne von Grafenstein
1Institute for Biomedical Aging Research (IBA), Austrian Academy of Sciences, Innsbruck, Austria.
Abstract:
NADPH oxidases transport electrons from cytosolic NADPH through biological membranes to generate reactive oxygen species. NADPH oxidase 4, broadly expressed in humans, is an interesting pharmacological target, since its activity is deregulated in several diseases, including pulmonary fibrosis, diabetic nephropathy, and cardiac hypertrophy. Whereas several candidate NADPH oxidase 4 inhibitors were recently described, most of these compounds are either unspecific or toxic. Here we set out to identify new NADPH oxidase 4 inhibitors from edible plants, in an attempt to decrease the number of hits with toxic side effects. We screened a compound library prepared from edible plants for new bioactives with the ability to inhibit the activity of NADPH oxidase 4. Using both cell-based and cell-free assays, we identified several compounds with significant inhibitory activity towards NADPH oxidase 4. For selected compounds, the activity profile towards NADPH oxidase 2 and NADPH oxidase 5 was established, and controls were carried out to exclude general reactive oxygen species scavengers. A number of promising NADPH oxidase 4 inhibitors from edible plants was identified and characterised. Several new chemical entities are disclosed which act as NADPH oxidase 4 inhibitors, and the efficacies of our best hits, in particular several diarylheptanoids and lignans, are comparable to the best available pharmacological NADPH oxidase 4 inhibitors. These findings will provide valuable tools to study mechanisms of NADPH oxidase inhibition.
Insights
Researchers identified novel NADPH oxidase 4 inhibitors from edible plants. These compounds show efficacy comparable to existing drugs, offering a safer alternative for treating diseases linked to NADPH oxidase 4 deregulation.
Area of Science:
- Biochemistry
- Pharmacology
- Natural Products Chemistry
Background:
- NADPH oxidases (NOX) generate reactive oxygen species (ROS) and are implicated in diseases like pulmonary fibrosis and cardiac hypertrophy.
- NOX4 is a key target, but existing inhibitors often lack specificity or are toxic.
- Edible plants represent a potential source for novel, safer bioactive compounds.
Purpose of the Study:
- To discover new, specific, and non-toxic inhibitors of NADPH oxidase 4 (NOX4) from edible plant sources.
- To characterize the inhibitory activity and specificity of identified plant-derived compounds against NOX4.
- To explore natural products as a viable alternative to synthetic compounds for NOX4 inhibition.
Main Methods:
- Screening of a compound library derived from edible plants for NOX4 inhibitory activity.
- Utilizing both cell-based and cell-free assays to measure NOX4 inhibition.
- Assessing specificity against NOX2 and NOX5, and excluding general ROS scavengers.
Main Results:
- Several compounds from edible plants demonstrated significant NOX4 inhibitory activity.
- Diarylheptanoids and lignans were identified as particularly effective NOX4 inhibitors.
- The efficacy of the best plant-derived inhibitors was comparable to established pharmacological agents.
Conclusions:
- Edible plants yield promising, specific, and potentially safer NOX4 inhibitors.
- Diarylheptanoids and lignans represent a valuable class of natural NOX4 inhibitors.
- These findings offer new tools for studying NOX4 inhibition and developing therapeutic strategies.
