HMOX1 x Nrf2 x SOD

Cadmium (Cd), a prevalent ecological and occupational pollutant from industrial discharge that poses serious health hazards, is known to be harmful to the kidneys. L-citrulline (L-Cit), a non-essential amino acid that has shown potential in lowering oxidative stress and improving organ function, is a good candidate for achieving renal protection against Cd-induced impaired antioxidant defenses in albino rats. Four groups of thirty-two adult male albino rats each were randomly assigned: control, L-Cit, CdCl₂, and L-Cit + CdCl₂. The L-Cit + CdCl₂ group received 900 mg/kg L-Cit 120 min before Cd exposure, while the CdCl₂ group received 5 mg/kg Cd for 30 days. Biochemical assays evaluated kidney functions, oxidative stress markers, and quantitative RT-PCR gene expression analysis for nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Tissue damage and apoptosis were assessed using histopathological analyses and immunohistochemistry labeling for Nrf2, HO-1, and caspase-3. Exposure to Cd significantly increased blood creatinine, urea, and uric acid levels, suggesting impaired renal function. Concurrent delivery of L-Cit significantly ameliorated these changes, further improving markers of kidney function beyond those of the control groups. Furthermore, elevated MDA levels, decreased GSH content, reduced SOD and CAT activities, and decreased serum nitric oxide (NO) indicated oxidative stress due to Cd exposure. L-Cit treatment successfully lowered MDA levels and restored antioxidant enzyme abilities. Histopathological studies found that L-Cit administration significantly reduced the Cd-induced renal damage in rats. L-Cit also upregulates the HO-1 and Nrf2 expression, which report its protective antioxidant properties. The current study shows that L-Cit showed protective effects against Cd-induced nephrotoxicity by modulating the NO and Nrf2/HO-1 signaling pathways, offering promising therapeutic insights for managing heavy metal-induced renal damage. Its mechanics and therapeutic applications merit further investigation.

Malathion (Mal), a commonly used organophosphate insecticide, causes significant lung damage through oxidative stress, inflammation, and stimulation of pulmonary fibrosis. Curcumin (Cur), a natural polyphenolic molecule, possesses strong antioxidant, anti-inflammatory, and antifibrotic functions.

This work aimed to evaluate the protective effects of Cur against Mal-induced lung injury in rats by modulating the Nrf2/HO-1, NF-κB/TNF-α, and COX-2 signaling pathways.

Twenty-four adult male Sprague Dawley rats were randomly divided into four equal groups: control, Cur-treated (150 mg/kg/day), Mal-treated (100 mg/kg/day), and Mal+Cur (received Cur followed by Mal after 3 h) groups. Both Mal and Cur were administered orally via gavage for four weeks. Oxidative stress markers, inflammatory mediators, and fibrotic alterations were assessed in lung tissues using biochemical and histological methods. The expression of key signaling molecules, including Nrf2/HO-1 (antioxidant response), NF-κB/TNF-α (inflammatory response), and COX-2 (pro-inflammatory enzyme), was measured via immunohistochemistry and quantitative PCR.

Compared to the control group, Mal exposure led to marked oxidative damage, evidenced by elevated Malondialdehyde (MDA) levels (p < 0.0001) and decreased superoxide dismutase (SOD) and acetylcholinesterase (AChE) levels (p < 0.0001). This was accompanied by increased expression of pro-inflammatory (TNF-α, IL-1β, IL-6, and PGE2 (p < 0.0001)) and pro-fibrotic (hydroxyproline) markers, and significant histopathological alterations. Co-administration of curcumin significantly attenuated these effects, restoring AChE activity, enhancing Nrf2/HO-1/ antioxidant signaling, and suppressing NF-κB/TNF-α and COX-2 inflammatory pathways.

These data demonstrate that curcumin protects against malathion-induced lung injury by modulating oxidative stress, inflammation, and fibrosis-related pathways, highlighting its therapeutic potential for mitigating organophosphate-induced respiratory damage.

Employing antioxidant nanozymes to eliminate reactive oxygen species (ROS) is a promising strategy for alleviating oxidative stress. However, most current nanozymes struggle to balance catalytic efficacy with biosafety, limiting their clinical applicability. In this study, we introduce a novel platform: DNA nanoribbon-templated copper nanoclusters (DNR/Cu NCs), which harness dual antioxidative mechanisms (direct ROS scavenging and activation of nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway) to synergistically mitigate oxidative stress. Unlike conventional nanozymes that rely on a single mechanism, DNR/Cu NCs exhibit combined superoxide dismutase (SOD)/catalase (CAT)/glutathione peroxidase (GPx), thereby enhancing overall ROS elimination. The biocompatible DNR scaffold facilitates the formation of ultrasmall Cu NCs with high catalytic activity and promotes NRF2 nuclear translocation to transcriptionally upregulate HO-1, amplifying endogenous antioxidant defenses. In both hepatocyte and zebrafish models of oxidative injury, the DNR/Cu NCs effectively suppressed ROS accumulation, suppressed apoptosis, and restored redox balance while mitigating tissue damage in vivo. This study highlights a paradigm-shifting approach in nanozyme design, offering a promising therapeutic avenue for oxidative stress-related diseases.