Authors: Russel J. Reiter | Alexandre Tavartkiladze
Source: Journal of Cancer Research (article, 2025-06-30)
Field: Chemistry — Organic Chemistry

Antioxidant Activity of AminoTriComplex (AminoSineTriComplex) and Reduction of Oxidative Stress During Induced Stress Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and the body’s inherent antioxidant defense mechanisms, is increasingly recognized as a pivotal contributor to the pathogenesis of numerous chronic diseases, including type 2 diabetes, cancer, essential hypertension, neurodegenerative disorders, and chronic fatigue syndrome [1-3]. Mitochondrial dysfunction, frequently observed under conditions of heightened oxidative stress, is a critical factor that exacerbates cellular damage through impaired energy production and escalated ROS generation [4,5]. Consequently, developing interventions aimed at preserving mitochondrial function and bolstering antioxidant capacities remains a primary focus in mitigating oxidative stress-related pathophysiological processes. Natural compounds derived from medicinal plants have garnered extensive attention as therapeutic agents for oxidative stress-mediated conditions, largely due to their potent antioxidant effects and favorable safety profiles [6]. AminoTriComplex (AminoSineTriComplex) is a novel, multi-targeted formulation composed of bioactive compounds—such as epigallocatechin gallate (EGCG), resveratrol, and berberine—that exhibit free radical scavenging properties and modulate critical intracellular signaling cascades [7,13-15]. Prior investigations have suggested the efficacy of AminoTriComplex in multimodal tumor management, wherein it concurrently targeted inflammatory pathways and cancer-related signaling mechanisms [7]. However, its capacity to alleviate oxidative damage and preserve mitochondrial function has not been thoroughly explored, prompting the present study’s focus on evaluating AminoTriComplex in an established model of induced oxidative stress in Wistar rats. To investigate the antioxidant and mitochondrial-protective activities of AminoTriComplex, we employed a classic carbon tetrachloride (CCl_4) model of oxidative stress [8]. Male Wistar rats were randomly allocated into four groups: control, oxidative stress (OS), OS + AminoTriComplex (AT), and AT alone. Oxidative stress was initiated by a single intraperitoneal injection of CCl_4, whereas the control and AT-alone groups received vehicle treatments. AminoTriComplex (75 mg/kg) was administered orally for 14 days in both the OS+AT and AT-alone groups, with vehicle serving as a control. Following the treatment period, liver samples were harvested and assayed for well-established oxidative stress markers, including malondialdehyde (MDA) levels (measured via the thiobarbituric acid reactive substances assay [9]), reduced glutathione (GSH) content (determined with Ellman’s reagent [10]), and the activities of two principal antioxidant enzymes: superoxide dismutase (SOD) and catalase (CAT) [6]. Mitochondrial function was evaluated through the measurement of state 3 and state 4 respiration rates in isolated liver mitochondria using a Clark-type oxygen electrode, thus enabling calculation of the respiratory control ratio (RCR) [11,12]. Our findings revealed that CCl_4 administration caused a significant rise in MDA levels, indicative of heightened lipid peroxidation, and a concomitant reduction in GSH content, SOD activity, and CAT activity in the OS group relative to controls. These alterations underscored a pronounced oxidative challenge, as previously reported in other CCl_4-induced models [8]. Notably, treatment with AminoTriComplex markedly attenuated these disturbances. Specifically, MDA levels were substantially lowered, and the antioxidative milieu—evidenced by elevated GSH content alongside increased SOD and CAT activities—was effectively restored to near-control levels in the OS+AT group. Furthermore, mitochondria isolated from rats receiving AminoTriComplex exhibited improved oxidative phosphorylation, as signified by higher state 3 respiration rates and RCR values. These results highlight AminoTriComplex’s critical role in preserving mitochondrial integrity and reducing ROS-mediated damage, supporting previous observations that implicate coordinated pathways (e.g., PI3K/AKT/mTOR and AMPK) in sustaining mitochondrial biogenesis and function [16]. Taken together, our data illustrate that AminoTriComplex offers significant protection against CCl_4-induced oxidative stress and mitochondrial dysfunction in Wistar rats. By effectively normalizing lipid peroxidation markers, bolstering antioxidant defenses, and enhancing mitochondrial respiration, AminoTriComplex underscores a potentially broad therapeutic scope in addressing oxidative stress-mediated diseases. Given the multifactorial nature of conditions such as cancer, metabolic disorders, and neurodegenerative diseases [2,3,5], a multi-targeted intervention like AminoTriComplex could provide synergistic benefits in preventing or attenuating the debilitating effects of prolonged oxidative insult. Future work should seek to delineate the precise molecular mechanisms by which AminoTriComplex modulates mitochondrial biogenesis, antioxidant enzyme expression, and signaling networks integral to cellular homeostasis. In addition, clinical investigations are warranted to optimize dosing regimens, ascertain long-term safety profiles, and confirm the translational potential of this promising natural compound for human applications in mitigating oxidative damage and preserving mitochondrial health. Oxidative stress ; Antioxidant ; Reactive oxygen species ; Mitochondrion ; Oxidative phosphorylation ; Mitochondrial ROS ; Pathogenesis Synthesis of Tetrazole Derivatives ; Synthesis and Characterization of Heterocyclic Compounds ; Inorganic and Organometallic Chemistry