Journal of Biochemical and Molecular Toxicology最新文献

For a very long time, Schiff base polymers (SBP) derived from p-phenylenediamine and salicylaldehyde have attracted considerable interest due to their bioactive and coordination properties. Here, we report the synthesis, characterization, computational, and antioxidant activities of Schiff base polymer-Ag-nanocomposites (SBP-AgNC) by combining p-phenylenediamine and salicylaldehyde Schiff bases with silver nanocomposites (AgNC). The reaction of Ag nanoparticles with SBP results in synergistic enhancement of antioxidant activity. The docking results with three different proteins, primarily dihydrofolate reductase of Staphylococcus aureus (3FRB), Sortase C of Streptococcus pneumoniae (3G69), and Glutaredoxin 2 of Escherichia coli (7DKP), shows a binding affinity of -11.6 Kcal/mol toward the dihydrofolate reductase (PDB: 3FRB), -9.0 Kcal/mol with Sortase C (PDB:3G69), and -8.6 Kcal/mol Glutaredoxin 2 (PDB:7DKP). Moreover, hydrogen bonding and π-π stacking interactions play a significant role in the antibacterial activity of SBP; thus, SBP-AgNC1 shows excellent antioxidant activity (IC₅₀ mM [DPPH] = 0.0719 ± 0.04) and good thermal stability up to 350°C. Lastly, this study explored innovative antioxidant materials that are suitable for applications in packaging, food preservation, and biomedicine.

Myocardial ischemia-reperfusion injury (MIRI) is featured by post-ischemic cardiomyocyte death and reperfusion myocardial damage, which is an unresolved fatal complication in acute myocardial infarction (AMI) treatment. Recent literature has indicated that glutaminase 2 (GLS2) is involved in promoting the ferroptosis of cardiomyocytes, but whether it plays a role in MIRI is still unknown. This research aims to explore the role and mechanism of GLS2 in the development of MIRI. Cell viability and apoptosis were analyzed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and flow cytometry. Bcl-2 related X protein (Bax), Cleaved-caspase-3, Specificity protein 1 (SP1), Glutathione Peroxidase 4 (GPX4), GLS2, p-AMPK, AMPK, p-mTOR, and mTOR protein abundances were determined using Western blot. Interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels were analyzed using ELISA. The Fe²⁺ level in AC16 cells was assessed using the Iron assay kit. Glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) products were examined using special assay kits. After JASPAR prediction, the binding between SP1 and GLS2 promoter was verified using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The effect of GLS2 on myocardial injury was detected using a mouse MI model. Ischemia/Reperfusion treatment repressed AC16 cell proliferation and induced cell apoptosis, inflammatory response, and ferroptosis. Moreover, GLS2 knockdown relieved hypoxia/reoxygenation (H/R)-triggered AC16 cell injury and ferroptosis. In the mechanism, SP1 was a transcription factor of GLS2 and upregulated the transcription of GLS2 via binding to its promoter region. Silencing of SP1 activated the AMPK/mTOR pathway by inhibiting GLS2. Meanwhile, AMPK inhibitor Dorsomorphin overturned the protective effect of GLS2 downregulation on myocardial cells. GLS2 silencing repressed myocardial damage in vivo. SP1-activated GLS2 could aggravate H/R-induced cardiomyocyte injury and ferroptosis by inactivating the AMPK/mTOR pathway, providing a promising therapeutic target for MIRI treatment in the future.

Geraniin, a complex tannin compound, was first extracted from Geranium thunbergii. Since its isolation, it has attracted significant scholarly interest due to its diverse biological activities. To facilitate the development of geraniin as a therapeutic agent, this review summarizes current pharmacological research on the compound. The findings indicate that geraniin exhibits a wide range of pharmacological effects, including immunomodulatory, antioxidant, antitumor, antiosteoporosis, anti-inflammatory, neuroprotective, antibacterial, antiviral, and antimetabolic syndrome effects. Further investigations have shown that these pharmacological actions are mediated through multiple mechanisms, such as upregulating the expression of endogenous antioxidant enzymes, inhibiting pro-inflammatory factors, inducing apoptosis in cancer cells, suppressing cancer cell migration and invasion, promoting osteoblast proliferation, inhibiting osteoclast proliferation, and reducing blood glucose and lipid levels. In conclusion, geraniin demonstrates considerable potential for the treatment or amelioration of various diseases, meriting further in-depth research.

Spinal cord injury (SCI) is a serious disease of the nervous system. Acetyl-l-carnitine-carnitine (ALC) is an acetylated product of l-carnitine, and exerts neuroprotection. The aim of this study was to investigate the effects of acetyl-l-carnitineALC) on mitophagy in rats with SCI and in PC12 cells injured by H₂O₂. By establishing SCI in vivo and in vitro, the levels of oxidative stress and mitophagy related factors were detected after ALC treatment. Cell viability was detected by CCK-8 assay, apoptosis was detected by TUNEL and flow cytometry. The mitochondria of PC12 cells after injury were observed by transmission electron microscopy (TEM). The activation of mitophagy related pathway PINK1/Parkin in ALC treated cells was detected. The results showed that ALC can protect neuronal cells in vivo and in vitro by promoting the normal growth of neuronal cells while inhibiting oxidative stress and promoting mitophagy. In addition, ALC can promote mitophagy by activating the PINK1/Parkin pathway and play a neuroprotective role. This study preliminarily demonstrated that the mechanism of action of ALC against SCI may be related to promotion of mitophagy.

Letrozole, a widely used aromatase inhibitor for hormone receptor-positive breast cancer, has been suggested to be associated with potential neurotoxic effects; however, the underlying mechanisms remain unclear. This study aimed to investigate the neurotoxic effects of letrozole and evaluate the neuroprotective potential of hesperidin, a natural flavonoid with antioxidant and anti-inflammatory properties. Adult female rats received letrozole alone or in combination with hesperidin for 4 weeks. Biochemical analyses showed that letrozole significantly increased total oxidant status (TOS) and decreased total antioxidant status (TAS), indicating oxidative stress. Gene expression results revealed upregulation of pro-apoptotic Bax and downregulation of anti-apoptotic Bcl2 in letrozole-treated rats, reflecting apoptotic activation. Additionally, inflammatory cytokine measurements demonstrated elevated pro-inflammatory markers (IL-1, IL-6, TNF-α) and reduced anti-inflammatory IL-10 following letrozole administration. Histopathological examination revealed cortical microhemorrhages, edema, and hyperemia. Importantly, co-treatment with hesperidin attenuated oxidative imbalance, normalized apoptotic gene expression, modulated inflammatory cytokine levels towards an anti-inflammatory profile, and ameliorated histological damage. These findings indicate that hesperidin confers neuroprotection by restoring redox balance, regulating apoptosis, and suppressing inflammation in letrozole-induced neurotoxicity. Further studies are warranted to elucidate the precise molecular mechanisms and potential therapeutic applications of hesperidin in letrozole-induced neurotoxicity.

Cadmium (Cd) exposure in occupational settings poses significant nephrotoxic risks, yet effective preventive strategies remain limited. This study investigated the protective effects of Naringenin (Nar) against Cd-induced nephrotoxicity. Twenty-four male SD rats (4 weeks old) were randomly assigned to control group, Cd group, Nar group, and Cd+ group for 14 days. Histopathological damage characterized by tubular necrosis and inflammatory infiltration. Cd exposure significantly impaired renal function, as evidenced by elevated serum uric acid and creatinine levels, increased oxidative stress markers (renal glutathione and malondialdehyde accumulation). Molecular analysis confirmed Cd-induced apoptosis through dysregulation of key apoptotic markers: downregulation of anti-apoptotic Bcl-2 and upregulation of pro-apoptotic Bax at both mRNA and protein levels, accompanied by increased cytochrome c release and activation of Caspase-9 and Caspase-3. These findings were further supported by TUNEL staining, which showed increased apoptosis in renal tubular cells. This study supports the potential application of naringin in alleviating cadmium-induced nephrotoxicity.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disorder. N5-methylcytosine (m5C) RNA modification, catalyzed by methyltransferases such as NOP2, plays a crucial role in regulating RNA stability and gene expression. This study aims to investigate the role of NOP2 in COPD and elucidate the underlying mechanism by which NOP2 modulates COPD progression through m5C modification. Sprague-Dawley (SD) rats subjected to cigarette smoke exposure and human bronchial epithelial (HBE) cells treated with lipopolysaccharide (LPS)+cigarette smoke extract were used as in vivo and in vitro COPD models. Differentially expressed m5C regulators between COPD patients and healthy controls and targets of NOP2 were screened from GSE106986 dataset. The role of NOP2 in inflammation and apoptosis was evaluated by flow cytometry, measuring IL-6, IL-1β and TNF-α in vivo and in vitro, hematoxylin-eosin and TUNEL staining. NOP2 expression was increased in LPS-induced HBE cells and COPD rat model. NOP2 knockdown inhibited inflammation and apoptosis in LPS-induced HBE cells, reduced IL-6, IL-1β and TNF-α contents in bronchoalveolar lavage fluid and serums, and inhibited inflammatory infiltration and apoptosis in lung tissues of COPD rats. NFKB1 was positive correlated with NOP2 expression. NFKB1 overexpression restored inflammation and apoptosis inhibited by NOP2 knockdown in LPS-induced HBE cells. Mechanistically, NOP2 knockdown inhibited NFKB1 transcription by decreasing m5C modification on NFKB1. NOP2 stabilized NFKB1 expression through m5C modification, thereby participating in inflammation and apoptosis in COPD. These findings revealed a new regulatory mechanism in COPD and highlight NOP2 as a potential therapeutic target.

Sepsis-associated acute lung injury (SALI) is a severe complication of sepsis, characterized by excessive inflammation and high mortality. Ferroptosis, an iron-dependent form of cell death, has been implicated in the pathogenesis of SALI. This study investigates the role of lncRNA KCNJ2-AS1 in SALI, focusing on its regulation of ferroptosis and inflammatory responses. Differential expression analysis identified KCNJ2-AS1 as upregulated in sepsis patients. KCNJ2-AS1 expression was measured by RT-qPCR in 115 SALI patients and controls. Its association with inflammatory markers and prognostic value for 28-day prognosis were further evaluated. The effects of KCNJ2-AS1 on ferroptosis markers and ROS levels were examined in HPAEpiC cells using in vitro experiments. The involvement of the KCNJ2-AS1/miR-212-3p/EGR1 axis was explored using dual-luciferase assays and functional studies. KCNJ2-AS1 was overexpressed in SALI patients, correlating with increased inflammatory cytokines and reduced survival. In vitro, KCNJ2-AS1 induced ferroptosis, increasing ROS and Fe²⁺ levels while downregulating GPX4 and upregulating ACSL4. Ferroptosis inhibition Fer-1 reversed these effects. Additionally, KCNJ2-AS1 regulated the miR-212-3p/EGR1 axis, modulating inflammation and ferroptosis in the LPS-induced SALI model. KCNJ2-AS1 may promote SALI pathogenesis by regulating ferroptosis and inflammation via the miR-212-3p/EGR1 axis, emerging as a potential biomarker and therapeutic target.

Occupational medicament-like dermatitis induced by trichloroethylene (TCE) is often linked to considerable renal impairment. However, the mechanisms underlying the renal damage remain poorly understood. The present study sought to elucidate the role of GSK3β in enhancing mitochondrial endoplasmic reticulum (ER) membrane tethering and calcium (Ca²⁺) exchange in the context of TCE sensitization-induced renal injury. Our results showed that GSK3β was localized within renal tubular epithelial cells and interacted with the IP3R1 calcium (Ca²⁺) channel complex at mitochondria-associated membranes (MAMs). TCE sensitization upregulated GSK3β activity and the expression of IP3R1 Ca²⁺ channel complex and its interactions, increased Ca²⁺ transfer from ER to mitochondria, Ca²⁺ overload, and apoptosis. The pharmacological inhibition of GSK3β disrupted the protein interaction between IP3R and the Ca²⁺ channel complex, leading to a decrease in Ca²⁺ exchange between the ER and mitochondria. This reduction resulted in a decrease in the mitochondrial Ca²⁺ concentration and an increase in the antiapoptotic ability of the cell. Coherent changes to renal function variables were also observed, demonstrating the functional relevance of the GSK3β pathway. Our results suggest that TCE sensitization damages renal tubular epithelial cells by promoting GSK3β-mediated crosstalk between the ER and mitochondria, identifying a key mechanism for TCE-induced renal injury. The findings from this study offer novel insights into the mechanisms of renal damage associated with TCE sensitization and lay down a foundation for the development of targeted preventive and therapeutic interventions.

Osteoarthritis (OA), marked by articular cartilage degeneration, severely impairs joint function. Ubiquitin-specific peptidase 16 (USP16) is crucial for regulating cellular protein stability and signaling pathways. This study seeks to elucidate USP16's impact and mechanism on chondrocyte injury in OA. The expression of USP16 in OA was analyzed using the Gene Expression Omnibus (GEO) database. An in vitro model using IL-1β to induce OA-like conditions. Real-time quantitative PCR (RT-qPCR) and western blot were used to detect gene expression in tissues and cells. The cellular oxidative stress levels were assessed using cell metabolism kits specifically targeted at reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Enzyme-linked immunosorbent (ELISA) assays were conducted to detect the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in cell culture supernatants and serum, thereby evaluating the inflammatory response state. The apoptotic status of the cells was detected by flow cytometry. The Ubibrowser website was used to predict proteins that interact with USP16. Co-immunoprecipitation (CoIP) and GST pull-down experiments were conducted to validate the interaction between USP16 and POU class 2 homeobox 1 (POU2F1). The cycloheximide (CHX) chase assay was utilized to determine the half-life of proteins. Mouse models of OA were established for in vivo validation, and the degree of cartilage degeneration was assessed through hematoxylin-eosin (HE) staining. USP16 expression was found to be reduced in OA patients and in HACCs induced by IL-1β. The induction of IL-1β led to an increase in oxidative stress levels in human articular chondrocyte cells (HACCs), accelerated the inflammatory response and the rate of apoptosis within HACCs, and inhibited the normal expression of chondrogenesis-related proteins in HACCs. However, overexpressing USP16 was able to alleviate these adverse effects. Furthermore, USP16 interacted with POU2F1 and stabilized its expression by means of deubiquitination. Notably, when POU2F1 was knocked down, the protective effect of overexpressing USP16 on IL-1β-induced HACCs was significantly weakened. In vivo experiments demonstrated that overexpressing USP16 effectively inhibited the degenerative process of mouse cartilage, significantly lowered the Osteoarthritis Research Society International (OARSI) and Mankin scores in mice, decreased oxidative stress levels, and suppressed inflammatory responses. USP16 regulates chondrocyte damage in OA by exerting its deubiquitination role to stabilize the POU2F1 protein, providing a potential target and theoretical foundation for OA treatment.