NAD(H)-loaded Nanoparticles for Efficient Sepsis Therapy
Sepsis, marked by dysregulated infection response, lacks effective treatment. NAD+'s role in inflammation remains unclear. NAD+ transport challenges limit its therapeutic impact. Novel NAD+-loaded nanoparticles (NPs) directly deliver NAD+ into cells, revealing its potent immune-modulating effects. These NPs curb inflammation, prevent cell damage, and show promise in treating severe sepsis by maintaining immune and vascular balance.
1. NAD+ and NADH: Vital Players in Cellular Energy Metabolism
NAD+ and NADH, two forms of nicotinamide adenine dinucleotide, play pivotal roles in cellular energy processes. These molecules act as cofactors in various metabolic reactions, shuttling electrons and facilitating energy conversion. In the context of glycolysis, the breakdown of glucose in the cytoplasm, NAD+ serves as a coenzyme, accepting electrons and hydrogen ions to form NADH. This step is critical in generating energy in the form of ATP while producing pyruvate.
In the subsequent stages of cellular respiration, such as the citric acid cycle and oxidative phosphorylation in the mitochondria, NADH participates in transfix erring electrons to the electron transport chain (ETC), where energy is harnessed to synthesize ATP. Concurrently, NAD+ is regenerated to continue the glycolytic cycle, completing the energetic cascade.
Figure 1 illustrates these metabolic pathways showcasing the sequential enzymatic reactions involving NAD+ and NADH. They depict the conversions between these molecules, elucidating their pivotal roles in energy production and the interplay within cellular metabolism.
2. Redox Functions of NAD+ and NADH: Orchestrating Cellular Oxidation-Reduction Reactions
Beyond their energy-related roles, NAD+ and NADH function as coenzymes in redox reactions, crucial for maintaining cellular homeostasis. In these processes, NAD+ acts as an oxidizing agent, accepting electrons and hydrogen ions to become reduced to NADH. Conversely, NADH, carrying high-energy electrons, serves as a reducing agent by donating these electrons to other molecules, regenerating NAD+.
This redox interconversion is instrumental in various cellular processes, including the biosynthesis of macromolecules like fatty acids and nucleotides(shown as Figure 2). Additionally, it facilitates the detoxification of reactive oxygen species (ROS) that can otherwise cause cellular damage. Researchers figured out that redox reactions involving NAD+ and NADH illustrate the transfer of electrons and the maintenance of cellular redox balance.
3. Enzymatic Regulation and NAD+/NADH Ratio: Impact on Cellular Function
The ratio of NAD+ to NADH serves as a critical indicator influencing cellular functions. Enzymes involved in metabolic pathways are often sensitive to this ratio, regulating their activity accordingly. A higher NAD+/NADH ratio typically indicates a cell's capacity for energy production and anabolic processes.
For instance, a higher ratio promotes the activity of enzymes involved in oxidative phosphorylation, driving ATP synthesis. Conversely, a lower ratio often corresponds to catabolic processes, such as glycolysis. Visual representations, like graphs or charts, depicting the relationship between the NAD+/NADH ratio and enzymatic activity offer insights into how cellular functions are modulated by these coenzymes.
Ye M., Zhao Y., et. NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis, Nature, 2023.
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