Reactive Oxygen Species in Cardiometabolic Syndrome, Neuronal Diseases and Cancer: From Bench to its Potential Therapeutics

1. Your book discusses the foundational aspects of reactive oxygen species (ROS). How do current understandings of ROS differ from traditional views that considered them merely as damaging by-products of metabolism?

For a long time, there was a strong belief in the academic community that ROS is toxic and, therefore, leads to oxidative stress. However, today's most recent results suggest that ROS has two functions. The first is related to its toxicity, but the second is an important signaling molecule. ROS is the major contributor to many cellular functions. In addition, ROS is involved in the gene's expression and the immune response and adaptation of an organism to stress.

2. Can you elaborate on the specific signaling pathways through which ROS modulate gene expression in cardio metabolic syndrome?

In cardiometabolic syndrome, oxidants such as hydrogen peroxide activate signaling pathways, including MAPKs and PI3K/Akt. In addition, ROS activates transcription factors such as Nrf2, HIF-1α, AP-1, and NF-κB, as well as ion channels: TRP channel family, RyR, and IP3R.

3. In your research, what are some of the most compelling insights into the dual role of ROS as both signaling molecules and pathological agents in neuronal diseases?

Neuronal cells, like other types of cells, are one area where the formation of new learning and memory experiences, neuroplasticity, are influenced by ROS. ROS serve both as potent sources of macromolecular damage, as well as essential signaling molecules, and so maintaining a balance between these negative and positive effects is fundamentally important for normal cellular physiology.

4. What emerging evidence suggests a causative rather than a correlative role of ROS in the development and progression of cancer?

While ROS was initially associated with tumor progression through oxidative DNA damage, emerging evidence suggests that they actively participate in oncogenesis by triggering epigenetic modifications, activating oncogenic pathways, and reprogramming the tumor microenvironment. The fact that ROS is involved in diverse processes makes it both a therapeutic target and a difficult target for treatment due to its varied effects.

5. How does ROS-induced epigenetic modulation contribute to the dysregulation of gene expression across cardio metabolic and neurodegenerative disorders?

These epigenetic ROS-induced changes often include DNA methylation, histone modifications, and Non-Coding RNAs. This could significantly contribute to the dysregulation of gene expression across cardiometabolic and neurodegenerative diseases.

6. Could you describe the interplay between mitochondrial dysfunction and ROS generation, particularly in the context of metabolic syndromes?

The electron transport chain within mitochondria is the main driver of ROS production. Disruption of the above pathway activates the mitochondrial permeability transition pore, leading to energy depletion and chronic oxidative damage. Metabolic disorders cause mitochondrial dysfunction, leading to insulin resistance and lipid deregulation.

7. Your book highlights the role of antioxidant supplementation. Based on current findings, what are the challenges in translating antioxidant therapies from bench to bedside?

Reduced bioavailability, restricted transport to target locations, and insufficient antioxidant defenses could all contribute to possible difficulties. Aggressive antioxidant therapy may have unforeseen repercussions because of its ability to disturb the body's normal balance of reactive oxygen species

8. What specific mechanisms underlie the selective vulnerability of neuronal cells to ROS damage compared to other cell types?

Because of their high oxygen consumption, lipid-rich membranes, and limited antioxidant defenses, neurons are especially vulnerable. This sensitivity underlies the selective neurodegeneration observed in conditions such as ALS and Huntington's disease.

9. How do ROS differentially affect signaling cascades in acute versus chronic phases of cardio metabolic and neurodegenerative diseases?

In acute phases, ROS production acts as a signaling trigger, while in chronic conditions, it contributes to persistent oxidative damage and inflammation. ROS can affect immune and adaptive responses as a signaling trigger, while chronic oxidative stress leads to sustained damage, inflammation, and metabolic dysregulation.

10. What are some of the most promising small-molecule modulators or therapeutic agents targeting intracellular ROS that are currently under investigation?

Small-molecule modulators currently under investigation, whose function is to restore oxidative balance without eliminating physiological ROS functions, are NADPH oxidase inhibitors, mitochondrial-directed antioxidants ( MitoQ), and selective ROS-scavenging nanoparticles ( catalase mimetics).

11. How does ROS contribute to the tumor microenvironment, and what implications does this have for resistance to conventional cancer therapies?

ROS plays a fundamental role in the tumor microenvironment, contributing to hypoxia, angiogenesis, promoting growth, and immune escape. ROS enhances therapy resistance by facilitating drug resistance, genomic instability, and immunosuppression.

12. Are there any specific biomarkers of ROS activity that hold potential for early diagnosis or prognosis in any of the three disease categories discussed?

Specific ROS biomarkers, a reliable indicator of oxidative stress in cardiometabolic diseases and for assessing atherosclerosis risk, include Isoprostanes and oxidized LDL. Biomarkers of neurodegeneration, signaling mitochondrial dysfunction and neuronal damage, are Malondialdehyde (MDA) and miRNAs. Distinct markers of cancer progression, reflecting chronic oxidative stress, genomic instability, and therapy resistance, are Advanced Oxidation Protein Products (AOPP) and Total Oxidant Status (TOS).

13. Given the complexity and context-dependent effects of ROS, how do you propose stratifying patient populations for potential ROS-targeted therapies?

Patient stratification for ROS-targeted therapies needs a multi-factor approach and could be based on: genetic profiling for predisposition, genetic variations in antioxidant defenses, oxidative stress markers, and disease–specific ROS profile assessment. In addition, AI-driven precision medicine can be used to integrate omics data for personalized treatment. Also, factors such as age, diet, and lifestyle will further refine stratification. Combining all these elements will ensure optimized therapy selection, improving patient outcomes in ROS-related diseases

14. In your opinion, what are the most urgent unanswered questions in ROS research that need addressing to move closer to effective therapeutics?

The most urgent unanswered question in ROS research is to find a way to precisely modulate ROS levels to achieve therapeutic benefits without inducing toxicity. Besides that, it is important to elucidate the mechanisms of ROS-driven epigenetic changes to find optimal therapeutic targets and strategies for balancing ROS homeostasis in disease treatment. Furthermore, understanding the dual role of antioxidants in disease progression and refining biomarker validation for early diagnosis is also very important in moving closer to effective therapies.