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Zoledronic acid, a nitrogen-containing bisphosphonate drug, is used for the treatment of osteoporosis, Paget's disease of bone, and tumor-induced osteolysis. Zoledronic acid has also gained a place in cancer treatment due to its cytotoxic and antiproliferative effects in many cancer cells. Although zoledronic acid is considered safe, kidney damage is still one of the concerns in therapeutic doses. In the study, the aim was to assess the nephrotoxic profiles of zoledronic acid in the human embryonic kidney (HEK-293) cells. Cytotoxicity evaluation was performed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and neutral red uptake tests, while oxidative stress was performed by reactive oxygen species (ROS) production via flow cytometry, and the incomprehensible evaluation of ROS-related genes by RT-PCR and apoptosis was performed with Annexin-PI analysis in flow cytometry. The obtained result showed that zoledronic acid inhibited cell viability (IC 50 values were determined as 273.16  by MTT) and cell proliferation in a concentration-dependent manner, induced ROS production, caused glutathione depletion, and increased oxidative stress index and endoplasmic reticulum (ER) stress, indicating severe cellular stress. The expression levels of oxidative damage (L-fabp, α-GST, Nrf2, and HMOX1), ER stress (CASP4, IRE1-α, GADD153, and GRP78), and apoptosis (Bcl-2, Bax, Cyt-c, p53, CASP9, CASP3, NF-κB, TNF-α, and JNK) related genes were altered as well as IRE1-α protein levels. Herein, we were the first to show that increased oxidative stress and ER stress resulting in apoptosis are the key molecular pathways in zoledronic acid-induced nephrotoxicity equivalent to clinically administered concentrations., (© 2022 Wiley Periodicals LLC.)

Simple Summary: Neonicotinoids constitute more than one-quarter of the insecticides on the market. Acetamiprid, a widely used neonicotinoid, has been found to be linked with neurological symptoms and there is an urge to understand its molecular mechanisms. It decreased cellular viability in millimole concentrations after 24 h in SH-SY5Y neural cells. Additionally, it increased reactive oxygen species, intracellular calcium and endoplasmic reticulum stress. Since overwhelmed cellular stress can destroy cellular structures and cause cell death, we also evaluated cellular death mechanisms. Acetamiprid induced apoptosis rather than necrosis indicating that cells undergo suicide initiated by self-generated death signals. Even though acetamiprid is considered to be a safe option in the struggle against harmful agricultural insects, these results suggest that the widespread use should be taken under strict control in order not to cause damage to the mammals. Acetamiprid (ACE), a commonly used neonicotinoid insecticide, is correlated with neurological symptoms, immunotoxicity and hepatotoxicity. Cellular stress and damage could play an important role in ACE-induced neurotoxicity; however, its mechanism has not been fully understood. We evaluated the effects of ACE on oxidative stress, endoplasmic reticulum (ER) stress, cellular death, mRNA expression levels of related genes and protein expressions of related molecular mechanisms in SH-SY5Y human neuroblastoma cells. The half maximal inhibition of enzyme activity (IC50) value of ACE was determined as 4.26 mM after 24 h of treatment by MTT assay. We revealed an increase in reactive oxygen species (ROS) production and calcium release. Significant increases were measured in inositol-requiring enzyme 1-alpha (IRE1-α) and binding immunoglobulin protein 90 (GRP90) levels as well as mRNA expression levels of caspase 3, 4 and 9 genes indicating enhanced ER stress. Apoptosis and ER stress-related genes were significantly upregulated at ≥2 mM. Indeed, ACE caused apoptosis and necroptosis while necrosis was not observed. There was a significant increase in the protein level of mitogen-activated protein kinase-8 (MAPK8) at 4 mM of ACE while no change was seen for nuclear factor kappa-B (NF-κB) and tumor necrosis factor-alpha (TNF-α). In conclusion, increased cellular stress markers could be proposed as an underlying mechanism of ACE-induced cell death in neural cells. [ABSTRACT FROM AUTHOR]