TABLE 7.
CSFs.
| CSF | Description | Action potential of the biological influence of CO₂/Carbonic acid |
|---|---|---|
| Inwardly Rectifying Potassium Channels (Kir) (Putnam et al., 2004; Zhang et al. (2020a), Xia et al. (2023)) |
Kir channels stabilize resting membrane potential and cell volume by favoring K⁺ influx, aligning the membrane potential with potassium’s equilibrium | Changes in CO₂/carbonic acid levels modulate Kir channel activity, impacting action potentials and cellular functions like muscle and neuronal activities |
| Calcium/calmodulin-dependent protein kinases (Huang et al., 2021; Zhan et al., 2022) | An enzyme essential for intracellular signaling is activated by binding to calmodulin, a protein that attaches to calcium (Zhang et al., 2022) | Alterations in CO₂/carbonic acid levels influence calmodulin kinase signaling in the CNS and other pH-sensitive tissues, impacting biological action potentials |
| Carbonic Anhydrase IX (Angeli et al., 2020) | The emphasis is on how hypoxia aids tumor growth and the importance of amino acid and pH balance, underlining carbonic anhydrase’s role in managing O₂ and CO₂ levels in the tumor environment | Carbonic anhydrase activity in tumors regulates pH by converting CO₂, affecting cancer cell metabolism and pathophysiology beyond simple gas balance, indicating a significant influence on action potentials. (Venkateswaran and Dedhar, 2020) |
| Extracellular Acidic Environment (Boedtkjer and Pedersen, 2020) | The tumor microenvironment is complex due to increased lactic acid production and cancer cells’ active removal of protons, leading to extracellular acidification | Introducing carbonic acid into an acidic environment triggers a neutralization reaction, turning CO₂ into bicarbonate and protons, thus buffering extracellular acidity. This modification influences tumor progression and treatment response by affecting the action potential through altered pH dynamics |
| Mitochondrial Dysfunction (Wang et al., 2022) | This dysfunction is involved in numerous diseases, including cancer. It impacts cellular metabolism, potentially leading to a pro-inflammatory state and tissue damage. (Menchikov et al., 2023). | Mitochondrial dysfunction alters cancer metabolism (Warburg effect), and extracellular pH changes, driven by CO₂/carbonic acid levels, impact tumor cell invasion, migration, and therapy resistance, affecting biological action potentials |
| H⁺ ATPases (Liu et al., 2021; Qi et al., 2022), and Na⁺/H⁺ Exchangers Zhou et al. (2021), Liao et al. (2024) |
H⁺ ATPases and Na⁺/H⁺ exchangers have critical roles in the tumor microenvironment. They contribute to unique cancer characteristics, including invasion, metastasis, and therapy resistance | The coordinated activity of H⁺ ATPases and Na⁺/H⁺ exchangers, influenced by CO₂/carbonic acid levels, drives a cycle of extracellular acidification and intracellular pH stabilization, aiding tumor survival, invasion, metastasis, and therapy resistance. Understanding these dynamics is crucial for developing therapies targeting the tumor microenvironment’s pH to combat cancer |
| Cell Membrane Instability (Fan et al., 2021; Zhu et al., 2023) | Several factors impact the cell membrane’s stability. These include lipid composition, cholesterol presence, membrane proteins, and the cytoskeleton | Changes in CO₂/carbonic acid levels affect membrane fluidity, barrier selectivity, and molecule transport, impacting the biological action potential and cellular functions |
| Extracellular Vesicles (EV) Parayath et al. (2020), Gondaliya et al. (2023) |
EVs, encompassing exosomes and microvesicles, are deliberately released by cells, including cancer cells, for extracellular communication, carrying proteins, lipids, and nucleic acids from healthy and malignant origins | CO₂/carbonic acid levels influence cancer cells’ use of EVs to modify their environment, promoting angiogenesis, immune evasion, and metastasis. EVs facilitate genetic and protein exchanges that boost tumor survival and spread, including mechanisms for drug resistance, thus affecting the biological action potential and cancer therapy outcomes |
| Ionic or Gas Leaks (Bożyk et al., 2022) | Ion and gas leakage into the extracellular space affects pH, signaling, membrane potential, and immune reactions within the tumor environment, impacting cancer progression, angiogenesis, invasion, and metastasis | Balancing ion transporter activity, influenced by CO₂/carbonic acid levels, is essential to prevent ionic leakages that threaten cell integrity. This regulation ensures proper osmolarity and volume, affecting the cell’s action potential and stability |
| Reduction in CO₂ Production by Cancer Cells due to the Warburg effect (Bożyk et al., 2022) | The Warburg effect, a metabolic shift in cancer cells to aerobic glycolysis, produces lactate instead of CO₂, allowing adaptation to hypoxia and affecting CO₂ output | Cancer cells’ preference for aerobic glycolysis, leading to variable CO₂ production across tumors, reflects the impact of CO₂/carbonic acid levels on the tumor microenvironment. This metabolic shift to lactate production affects biological action potentials and cellular behavior differently than mitochondrial respiration |
| Cellular Zeta Pontential (Mendivil-Alvarado et al., 2023; Hughes, 2024) |
The zeta potential measures the electrical potential of particle surfaces in suspension, indicating the colloidal stability of these particles in a solution | The acidity influenced by CO₂/carbonic acid levels can modify the surface charge and zeta potential of EVs and target cells, altering their interactions, binding, and internalization capabilities. This regulation of EV effectiveness in transmitting biological information like microRNAs or proteins affects cell signaling and action potentials within the tumor microenvironment |
| Heme Oxygenase (Surh et al., 2020; Luu Hoang et al., 2021) | Heme catabolism, facilitated by heme oxygenase (HO), with HO-1 expression induced by stress like hypoxia, plays a role in cancer progression, impacting cell growth, apoptosis resistance, angiogenesis, and metastasis | HO-1 enzyme activity, producing CO from heme catabolism, impacts biological pathways and action potentials through signaling effects. While CO has anti-inflammatory and cytoprotective roles at normal levels, in cancer, it can enhance a tumor microenvironment conducive to cancer cell growth and survival, influenced by CO₂/carbonic acid dynamics |
| Autophagy (Chung et al., 2020; Kang et al., 2020; Zhan et al., 2022) | The autophagy process is intricate, involving numerous sequential steps that could intracellular pH impact | The influence of CO₂/carbonic acid on pH is pivotal for autophagy regulation, crucial for cellular health and implicated in diseases like cancer and neurodegeneration, thereby impacting biological action potentials |
| Gasotransmitters (Salihi et al., 2022). | The relationship between carbonic acid, nitric oxide (NO), hydrogen sulfide, CO, and the tumor microenvironment | Adjustments in CO₂/carbonic acid levels can influence blood flow and oxygenation, affecting NO generation and H₂S enzyme activity, including, including cystathionine gamma-lyase (CSE), cystathionine beta-synthase (CBS), and 3-mercaptosulfur transferase (3-MST), thereby altering their availability and effects, impacting biological action potentials and physiological responses |
| Intracellular Reactive Oxygen Species (ROS) (Scharping et al., 2021; Li et al., 2022) |
The intracellular ROS concentration significantly influences multiple cellular processes. ROS are highly reactive molecules capable of causing oxidative harm to proteins, lipids, and DNA. However, they also serve as secondary messengers in cellular signaling pathways | CO₂/carbonic acid levels affecting intracellular and extracellular acid-base balance can alter ROS production. Acidic conditions boost ROS-generating enzyme activities like NADPH oxidase and can reduce antioxidant defenses, raising ROS levels. Mitochondrial function and the electron transport chain are impacted by pH shifts, with increased acidity heightening oxidative stress through enhanced mitochondrial ROS, influencing biological action potentials and cellular health |
| Chronobiological Variations (Zhou et al., 2022) | The circadian rhythm is an evolutionarily preserved timing system that governs various processes such as sleep-wake, feeding-fasting, and activity-rest cycles. It coordinates all organs’ behavior and physiological functions to maintain the body’s overall homeostasis | The human body’s pH buffering system, influenced by CO₂/carbonic acid levels, maintains a tight acid-base balance, despite daily and circadian rhythm-induced variations that affect physiological behaviors. These pH fluctuations, driven by sleep, diet, and activity patterns, can impact cancer progression, suggesting that targeting circadian and behavioral influences on pH could offer new approaches to altering the tumor microenvironment and affecting biological action potentials |
| Sirtuins (Katsyuba et al., 2020; Wu et al., 2022; Xu et al., 2022) and Ampk (Keerthana et al., 2023) | Sirtuins and AMP-activated protein kinase (AMPK) are critical metabolic regulators. They react to changes in the cellular environment, including nutrient availability, energy levels, and cellular stress. These enzymes are essential in preserving energy stability, promoting longevity, and resisting stress | CO₂/carbonic acid-induced pH changes can affect energy metabolism and NAD + levels, thereby influencing sirtuin activity and cellular stress responses like hypoxia, leading to alterations in acid-base metabolism. These pH shifts can activate sirtuin-involved signaling pathways and indirectly modulate AMPK activation by impacting the cell’s energy state, highlighting the role of pH in cellular adaptive mechanisms and biological action potentials |
| Matrix Metalloproteinases (MMPs) (Gonzalez-Avila et al., 2020; Niland et al., 2021) |
Matrix metalloproteinases are proteolytic enzymes integral to the degradation of extracellular matrix components such as collagen, gelatins, elastin, fibronectin, and laminin | CO₂/carbonic acid levels influencing the tumor microenvironment’s pH can regulate MMP expression, crucial for tumor invasion and metastasis through the degradation of extracellular matrices. Understanding this pH-MMP relationship is key to developing therapies that either modify the microenvironment’s acidity or inhibit MMP activity directly, aiming to halt cancer spread by affecting biological action potentials and cellular interactions |