Non-coding RNAs affecting NLRP3 inflammasome pathway in diabetic cardiomyopathy: a comprehensive review of potential therapeutic options

Figures

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  Fig. 1. Structure of the NLRP3 inflammasome. The receptor protein NLRP3 belongs to the NLR family, a group of pattern recognition receptors (PRRs) that function as cytoplasmic receptors. The common structure of NLR proteins is as follows: [1] a C-terminal leucine-rich repeats (LRR) domain that recognizes and binds PAMP or DAMP stimuli [2], a central nucleotide binding and oligomerization domain (NOD, also known as NACHT) that upon ligand binding, undergoes conformational changes, triggering oligomerization and activating adenosine triphosphate (ATP)ase activity through its ATP-binding site. This process is essential for NLRP3 self-association and activation [3]. and an N-terminal effector domain, which is pyrin (PYD) in the NLRP3 inflammasome. The adaptor apoptosis-associated speck-like protein containing a CARD (ASC) connects NLRP3 and pro-caspase-1. Its N-terminal PYD interacts with the PYD of the NLRP3, providing a tight connection, and its C-terminal CARD domain subsequently connects with pro-caspase-1 via the homotypic CARD–CARD reaction. The oligomerization of pro-caspase-1 on ASC filaments facilitates its proximity-driven autocatalytic cleavage into mature caspase-1, which then…

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  Fig. 2. Ionic flux. (A) K+ efflux: Detection of the elevated levels of ATP in the extracellular medium by P2 × 7R and activation of this receptor by caspase-4/5/11 results in the opening of the channel which induces K+ efflux. The decrease in intracellular potassium concentration activates the NLRP3 inflammasome. The binding of never-in-mitosis A-related kinase 7 (NEK7, a well‑conserved serine/threonine kinase also known as NIMA‑related kinase 7), to NLRP3 downstream to K+ efflux plays a key role in this process resulting in the molecular complex formation and further activating the NLRP3 inflammasome. Cell membrane destruction, some microbial toxins, and the non-canonical pathway also contribute to the NLRP3 inflammasome activation via K+ efflux. (B) Ca2+ mobilization: Calcium ion mobilization from the ER through Ca2+ channels or extracellular Ca2+ influx through the P2 × 7 receptor triggered by ATP results in increased intracellular Ca2+ levels. Ca2+ overload prompts the assembly of the NLRP3 inflammasome complex and plays an important role in the activation of the NLRP3 inflammasome. Ca2+ may facilitate the interaction between NLRP3 and ASC by inducing conformational changes

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  Fig. 3. Various stimuli, including PAMPs, DAMPs, LPS, ATP, Hyperglycemia, and asbestos, inhibit the respiratory chain reaction in mitochondria, leading to oxygen accumulation in the form of mtROS. Detection of increased ROS concentrations by thioredoxin interacting protein (TXNIP) results in its dissociation from thioredoxin (TRX). TXNIP then binds to NLRP3, activating the NLRP3 inflammasome complex. ROS can also promote the interaction between Nek7 and NLRP3, which recruits the ASC domain subsequently, inducing NLRP3 assembly and oligomerization