Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy.

Background: Exploiting synthetic lethality (SL) relationships between protein pairs has emerged as an important avenue for the development of anti-cancer drugs. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of the NAD+ salvage pathway, having an SL relationship with nicotinic acid phosphoribosyltransferase (NAPRT), the key enzyme in the NAD+ Preiss-Handler pathway. NAMPT inhibitor holds clinical potential not only as a promising cancer treatment but also as a means of protection against chemotherapy-induced-peripheral-neuropathy (CIPN). However, as NAD+ is essential for normal cells, the clinical use of NAMPT inhibitors is challenging. This study aimed to identify a novel NAMPT inhibitor with enhanced selective cytotoxicity against NAPRT-deficient cancer cells as well as prominent efficacy in alleviating CIPN. Methods: We began by conducting drug derivatives screening in a panel of lung cancer cell lines to select an agent with the broadest therapeutic window between the NAPRT-negative and-positive cancer cell lines. Both in vitro and In vivo comparative analyses were conducted between A4276 and other NAMPT inhibitors to evaluate the NAPRT-negative cancer cell selectivity and the underlying distinct NAMPT inhibition mechanism of A4276. Patient-derived tumor transcriptomic data and protein levels in various cancer cell lines were analyzed to confirm the correlation between NAPRT depletion and epithelial-to-mesenchymal transition (EMT)-like features in various cancer types. Finally, the efficacy of A4276 for axonal protection and CIPN remedy was examined in vitro and in vivo. Results: The biomarker-driven phenotypic screening led to a discovery of A4276 with prominent selectivity against NAPRT-negative cancer cells compared with NAPRT-positive cancer cells and normal cells. The cytotoxic effect of A4276 on NAPRT-negative cells is achieved through its direct binding to NAMPT, inhibiting its enzymatic function at an optimal and balanced level allowing NAPRT-positive cells to survive through NAPRT-dependent NAD+ synthesis. NAPRT deficiency serves as a biomarker for the response to A4276 as well as an indicator of EMT-subtype cancer in various tumor types. Notably, A4276 protects axons from Wallerian degeneration more effectively than other NAMPT inhibitors by decreasing NMN-to-NAD+ ratio. Conclusion: This study demonstrates that A4276 selectively targets NAPRT-deficient EMT-subtype cancer cells and prevents chemotherapy-induced peripheral neuropathy, highlighting its potential as a promising anti-cancer agent for use in cancer monotherapy or combination therapy with conventional chemotherapeutics.

Acute Toxicity Evaluation of the Disinfectant Containing Percarbonate and Tetraacetylethylenediamine by Measuring Behavioral Responses of Small Fish Using Image Analysis.

Disinfectants containing percarbonate and tetraacetylethylenediamine (TAED) has been developed as an effective and relatively safe disinfectant to destroy viruses and bacteria in animals and humans, however it is known that most disinfectants can cause danger to living organisms including humans. In the current study, acute toxicity of the disinfectant composed of percarbonate and TAED was assessed by measuring behavioral responses as well as lethal concentrations of aquatic organisms such as medaka and zebrafish when they were exposed to it. First, the breeding water properties were determined by measuring dissolved oxygen (DO) and pH changes over time up to 96 h in acute toxicity tests using the medaka, and the lethal concentration 50% (LC50, 88.39 ppm) was calculated using the lethality rate of the fish. This experiment was conducted in compliance with traditional OECD guidelines. Second, the assessment of behavioral responses (locomotive activity and swimming speed) with the zebrafish were assessed by the image analysis to capture the images per second for three hours, and the collected data were processed using image analysis to calculate the locomotive activity and swimming speed. Finally, the LC50 (135.76 ppm) of the disinfectant to the fish was also measured after three hours. Overall, the data revealed that LC50 of the disinfectant may be affected by the pH of the water exposed to the disinfectant, not by the DO in the water. In addition, the results from the image analysis indicated that the behavioral responses of the fish can further assess the acute toxicity of the disinfectant at concentrations below the LC50 and there was a relationship (R2 = 0.85) between the behavioral responses and the survival rate of the fish. Electronic Supplementary Material ESM: The online version of this article (doi: 10.1007/s12257-021-0419-0) contains supplementary material, which is available to authorized users.

A facile synthesis of metal ferrites and their catalytic removal of toxic nitro-organic pollutants.

Nitrocompounds are the major prime water contaminants. In this investigative study, toxic nitrocompounds (4-nitrophenol, 2,4-dinitrophenol, 2,4,6-trinitrophenol) were removed by using magnetic CuFe2O4, CoFe2O4, and NiFe2O4 material systems. The metal ferrites were synthesized through hydrothermal method and also followed with calcination process. The properties of metal ferrites were confirmed through using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and field emission scanning electron microscopy (FE-SEM) studies and results there on were presented. For the first time, the synthesized CuFe2O4, CoFe2O4, and NiFe2O4 material systems were used for the reduction of 4-nitrophenol (NP), 2,4-dinitrophenol (DNP), and 2,4,6-trinitrophenol (TNP) in aqueous medium. The UV-visible spectrometry was employed to monitor the removal of nitro compounds and formation of aminophenol. Among, the three catalysts, the CuFe2O4 displayed excellent removal activity for nitrocompounds. The CuFe2O4 nanoparticles completely removed the NP, DNP and TNP within 2, 5, 10 min, respectively. The NP reduction reaction follows the pseudo-first-order kinetics. Further, the investigated and proposed CuFe2O4, catalyst has given and demonstrated excellent kinetic rate constants 0.990, 0.317, 0.184 min-1 for 4-NP, DNP and TNP respectively, which was very fast kinetic than the already published reports. Also, the aminophenol formation was confirmed for the above mentioned and select nitrocompounds. The obtained results confirm suggest that CuFe2O4 nanoparticles based material system could be one of the promising catalysts for nitro compounds removal process.