Nobiletin Ameliorates Cellular Damage and Stress Response and Restores Neuronal Identity Altered by Sodium Arsenate Exposure in Human iPSCs-Derived hNPCs

Abstract

Environmental exposure to arsenic has been profoundly associated with chronic systemic disorders, such as neurodegeneration, in both experimental models and clinical studies. The neuronal cells of the brain and the nervous system have a limited regeneration capacity, thus making them more vulnerable to exposure to xenobiotics, leading to long-lasting disabilities. The functional and anatomical complexity of these cells hinders the complete understanding of the mechanisms of neurodegeneration and neuroprotection. The present investigations aimed to evaluate the neuroprotective efficacy of a herbal formulation of Nobiletin (NOB) against the toxic insult induced by sodium arsenate (NA) in human neural progenitor cells (hNPCs) derived from human induced pluripotent stem cells (hiPSCs). Prior to the neuroprotective experiments, biologically safe doses of both NOB and NA were ascertained using standard endpoints of cytotoxicity. Thereafter, the hNPCs were exposed to either NOB (50 μM) or NA (50 μM) and co-exposed to biologically safe concentrations of NA (50 μM) with NOB (50 μM) for a period of up to 48 h. NOB treatment restored the morphological damage (neurite damage), the levels of stress granule G3BP1 (Ras-GTPase-activating protein (SH3 domain)-binding protein) and TIA1 (T cell-restricted intracellular antigen), and the expression of neuronal markers (Tuj1, Nestin, MAP2, and PAX6) when compared to NA-exposed cells. A substantial restoration of reactive oxygen species and mitochondrial membrane potential was also witnessed in the co-exposure group (NA + NOB) in comparison to the NA-exposed group. The findings suggest that NOB possesses a significant restorative/protective potential against the NA challenge in hNPCs under experimental conditions and imply that nobiletin may impart a potential therapeutic impact if studied adequately using in vivo studies.

Evaluation of the Possible Protective Role of Nobiletin against Arsenic-Induced Liver Damage in Male Albino Rats

“…It may be due to the healing ability of the NOB, which decreased TOS and ultimately increased TAS in the liver tissues. Our results were in line with the study by Jahan et al who reported that NOB restored the oxidative stress altered by sodium arsenate exposure in human iPSCs-derived hNPCs [ 33 ].…”

Nobiletin as a Neuroprotectant against NMDA Receptors: An In Silico Approach

“…In the mammalian central nervous system, glutamatergic mechanisms are involved in learning, memory, and cellular plasticity; imbalances in this mechanism have been implicated in several neurodegenerative diseases, including schizophrenia, PD, and AD. Recent research has identified nobiletin as being a potential neuroprotectant [35]. This potential was explored through computational techniques such as docking and molecular dynam-ics simulation.…”

“…A compound's bioactivities are determined by its structure and metabolism. Because of its high lipophilic nature and permeability, nobiletin is efficiently absorbed, even without a glycoside moiety, and nobiletin has also been reported as an anti-stress agent [34,35]. Memory and learning are similarly dependent on the NMDA receptor.…”

Principles and functions of condensate modifying drugs

“…Another small molecule Nobiletin ( Table 1 and plotted in Figure 2A ) was shown to dissolve SGs and rescue neuronal health in human iPSC derived neuronal models of ALS. The exact mode of action for dissolution is not reported ( Jahan et al, 2022 ), but based on the optical phenotype, we argue it is a dissolver c-mod.…”