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Background: Photodynamic diagnosis-assisted transurethral resection of bladder tumors (PDD-TURBT) enhances detection of elusive lesions compared to standard white light-transurethral resection of bladder tumors (WL-TURBT). If minimal light exposure during PDD-TURBT induces the accumulation of reactive oxygen species (ROS), potentially resulting in phototoxicity in small lesions, apoptosis may be triggered in residual small tumors, allowing them to escape resection. We investigated the hypothesis of a potential photodynamic therapeutic effect during PDD-TURBT., Methods and Materials: Our study, conducted between January 2016 and December 2020 at Nara Medical University Hospital, focused on a specific emphasis on ROS production. Immunohistochemical analysis for thymidine glycol and N ε -hexanoyl-lysine was performed on 69 patients who underwent 5-aminolevulinic acid-mediated PDD-TURBT and 28 patients who underwent WL-TURBT. Additionally, we incrementally applied the minimal irradiation energy to T24 and UM-UC-3 cells treated with 5-aminolevulinic acid using instruments similar to those used in PDD-TURBT and evaluated intracellular ROS production and phototoxicity., Results: Immunohistochemical analysis revealed a significant increase in production of thymidine glycol and N ε -hexanoyl-lysine within the PDD-TURBT group. In T24 and UM-UC-3 cells treated with 5-aminolevulinic acid and light exposure, immunofluorescent staining demonstrated a dose-dependent increase in intracellular ROS production. In addition, higher irradiation energy levels were associated with a greater increase in ROS production and phototoxicity, as well as more significant decrease in mitochondrial membrane potential., Conclusion: Although the irradiation energy used in PDD-TURBT did not reach the levels commonly used in photodynamic therapy, our findings support the presence of a potential cytotoxic effect on bladder lesions during PDD-TURBT., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Nobutaka Nishimura et al.)

The major nitroimine insecticide imidacloprid (IMI) and the nicotinic analgesics epibatidine and ABT-594 contain the 6-chloro-3-pyridinyl moiety important for high activity and/or selectivity. ABT-594 has considerable nicotinic acetylcholine receptor (AChR) subtype specificity which might carry over to the chloropyridinyl insecticides. This study considers nine IMI analogues for selectivity in binding to immuno-isolated alpha1, alpha3 and alpha7 containing nicotinic AChRs and to purported alpha4beta2 nicotinic AChRs. Alpha1- and alpha3-containing nicotinic AChRs (both immuno-isolated by mAb 35, from Torpedo and human neuroblastoma SH-SY5Y cells, respectively) are between two and four times more sensitive to DN-IMI than to (-)-nicotine. With immuno-isolated alpha3 nicotinic AChRs, the tetrahydropyrimidine analogues of IMI with imine or nitromethylene substituents are 3-4 fold less active than (-)-nicotine. The structure-activity profile with alpha3 nicotinic AChRs from binding assays is faithfully reproduced in agonist potency as induction of 86rubidium ion efflux in intact cells. Alpha7-containing nicotinic AChRs of SH-SY5Y cells (immuno-isolated by mAb 306) and rat brain membranes show maximum sensitivity to the tetrahydropyrimidine analogue of IMI with the nitromethylene substituent. The purported alpha4beta2 nicotinic AChRs [mouse (Chao & Casida, 1997) and rat brain] are similar in sensitivity to DN-IMI, the tetrahydropyrimidine nitromethylene and nicotine. The commercial insecticides (IMI, acetamiprid and nitenpyram) have low to moderate potency at the alpha3 and purported alpha4beta2 nicotinic AChRs and are essentially inactive at alpha1 and alpha7 nicotinic AChRs. In conclusion, the toxicity of the analogues and metabolites of nicotinoid insecticides in mammals may involve action at multiple receptor subtypes with selectivity conferred by minor structural changes.

Nicotinoids and neonicotinoids are characterized by the presence of the 3-pyridylmethylamine moiety in their structure. In the former, the amino nitrogen atom is ionized, while in the latter the corresponding nitrogen atom is not ionized but bears a partial positive charge. Both types of insecticides interact with nicotinic acetylcholine receptor (nAChR) of insect origin. The poor interaction of neonicotinoids with vertebrate nAChR was shown by its poor binding affinity to the nAChR from Torpedo electric organ and rat brain and poor activation with nAChR expressed in Xenopus oocytes. The full positive charge was essential to interact with the vertebrate nAChR, while the 3-pyridylmethylamine moiety with a partial positive charge was enough to interact with the insect nAChR. For penetration into the insect central nervous system, hydrophobicity seemed to play an important role, as indicated by the binding of the injected compounds to the housefly head nAChR. The ionization reduced hydrophobicity and limited the penetration of nicotinoids, resulting in less insecticidal activity. Among neonicotinoids, nitromethylene type compounds, though far higher in binding affinity, were less hydrophobic than the corresponding nitroimine type, and the net result was better or inferior insecticidal activity. A chlorine atom at the 6 position of the 3-pyridyl group found in commercialized neonicotinoids contributes to increased binding affinity and more importantly hydrophobicity, thus increasing insecticidal activity. N-Me-imidacloprid was found to be a propesticide of imidacloprid.