The Lands cycle is a fundamental process for the continuous renewal of phospholipids in cell membranes, directly influencing their fluidity and functionality. This cycle is particularly active in tissues such as the nervous and immune systems and is crucial for cellular homeostasis. It is implicated in the development of inflammatory, neurodegenerative, and cancerous diseases. The present review discusses the biochemical regulation of the Lands cyclefocusing on phospholipase A2 (PLA₂) and lysophospholipid acyltransferase (LPCAT)and its impact on lipid metabolism, cell signaling, and disease. Dysregulation of this cycle has been linked to pathological conditions, including oncogenesis and hepatotoxicity. This suggests that modulation of the cycle may have an effect on inflammatory responses and tumor resistance. Advances in the fields of lipidomics and computational modeling have resulted in a more comprehensive understanding of the Lands cycle, thereby emphasizing its potential as a therapeutic target.

(1) Background: Gallic acid (GA) has been characterized as an effective anti-inflammatory, antivenom, and promising drug for therapeutic use. (2/3) Methods and Results: GA was identified from ethanolic extract of fresh pitanga (Eugenia uniflora) leaves, which was identified using commercial GA. Commercial GA neutralized the enzymatic activity of secretory PLA2 (sPLA2) by inhibiting the active site and inducing changes in the secondary structure of the enzyme. Pharmacological edema assays showed that GA strongly decreased edema when the compound was previously incubated with sPLA2. However, prior treatment of GA (30 min before) significantly increased the edema and myotoxicity induced by sPLA2. The molecular docking results of GA with platelet-acetylhydrolase (PAF-AH) and acetylcholinesterase reveal that this compound was able to interact with the active site of both molecules, inhibiting the hydrolysis of platelet-activating factor (PAF) and acetylcholine (ACh). (4) Conclusion: GA has a great potential application; however, our results show that this compound can also induce adverse effects in previously treated animals. Additionally, the increased edema and myotoxicity observed experimentally in GA-treated animals may be due to the inhibition of PAF-AH and Acetylcholinesterase.

Quercetin derivatives have already shown their anti-inflammatory potential, inhibiting essential enzymes involved in this process. Among diverse pro-inflammatory toxins from snake venoms, phospholipase A2 is one of the most abundant in some species, such as Crotalus durissus terrificus and Bothrops jararacussu from the Viperidae family. These enzymes can induce the inflammatory process through hydrolysis at the sn-2 position of glycerophospholipids. Hence, elucidating the main residues involved in the biological effects of these macromolecules can help to identify potential compounds with inhibitory activity. In silico tools were used in this study to evaluate the potential of quercetin methylated derivatives in the inhibition of bothropstoxin I (BthTX-I) and II (BthTX-II) from Bothrops jararacussu and phospholipase A2 from Crotalus durissus terrificus. The use of a transitional analogous and two classical inhibitors of phospholipase A2 guided this work to find the role of residues involved in the phospholipid anchoring and the subsequent development of the inflammatory process. First, main cavities were studied, revealing the best regions to be inhibited by a compound. Focusing on these regions, molecular docking assays were made to show main interactions between each compound. Results reveal that analogue and inhibitors, Varespladib (Var) and p-bromophenacyl bromide (BPB), guided quercetins derivatives analysis, revealing that Leu2, Phe5, Tyr28, glycine in the calcium-binding loop, His48, Asp49 of BthTX-II and Cdtspla2 were the main residues to be inhibited. 3MQ exhibited great interaction with the active site, similar to Var results, while Q anchored better in the BthTX-II active site. However, strong interactions in the C-terminal region, highlighting His120, seem to be crucial to decreasing contacts with phospholipid and BthTX-II. Hence, quercetin derivatives anchor differently with each toxin and further in vitro and in vivo studies are essential to elucidate these data.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for their cyclooxygenase (COX) inhibitory activity. However, mounting evidence suggests that their pharmacology extends beyond this canonical pathway. In this study, the potential of NSAIDs to modulate human acetylcholinesterase (AChE), a key enzyme linking neuroinflammation, metabolic dysfunction and degenerative diseases, was evaluated. An integrative strategy combining silicon and vitro approaches was employed. Structure-based molecular docking using GOLD, molecular dynamics simulations with AMBER21, and MM-GBSA free energy calculations were performed to assess binding stability and energetic favorability. Among the compounds that were tested, nimesulide displayed the highest binding affinity (ΔG = −24.2 kcal/mol), followed by dipyrone (−16.0 kcal/mol), ibuprofen (−11.0 kcal/mol), and paracetamol (−9.0 kcal/mol). The per-residue energy decomposition revealed the involvement of aromatic and polar residues in the catalytic gorge, displaying interaction patterns analogous to those of classical AChE inhibitors. Experimental enzymatic assays corroborated these predictions, demonstrating a dose-dependent inhibition of AChE activity by nimesulide at micromolar concentrations. These findings suggest that NSAIDs, particularly nimesulide, may act as dual modulators with both anti-inflammatory and cholinergic regulatory effects. This work underscores the translational potential of drug repurposing and highlights the importance of combining computational and biochemical methods to uncover novel therapeutic functions of established drugs.

Snake venom serine protease (SVSP) interferes with the regulation and control of important biological reactions in homeostasis and can be classified as an activator of the fibrinolytic system and platelet aggregation. Our group has recently isolated a new serine protease from Crotalus durissus terrificus total venom (Cdtsp-2). This protein exhibits edematogenic capacity and myotoxic activity. A Kunitz-like EcTI inhibitor protein with a molecular mass of 20 kDa was isolated from Enterolobium contortisiliquum and showed high trypsin inhibition. Thus, the objective of this work is to verify the possible inhibition of the pharmacological activities of Cdtsp-2 by the Kutinz-type inhibitor EcTI. To isolate Cdtsp-2 from total C. d. terrificus venom, we used three-step chromatographic HPLC. Using the mice paw edema model, we observed an edematogenic effect, myotoxicity and hepatotoxicity caused by Cdtsp-2. In vitro and in vivo experiments showed that the alterations in hemostasis caused by Cdtsp-2 are crucial for the development of marked hepatotoxicity and that EcTI significantly inhibits the enzymatic and pharmacological activities of Cdtsp-2. Kunitz-like inhibitor may be a viable alternative for the development of ancillary treatments against the biological activities of venoms.