Search Results (4)

Reactive oxygen species (ROS) function as critical signaling molecules in cancer biology, promoting proliferation, angiogenesis, and metastasis at controlled levels while inducing lethal damage when exceeding the cell’s buffering capacity. To survive under this state of chronic oxidative stress, cancer cells become dependent on a hyperactive antioxidant shield, primarily orchestrated by the Nrf2, glutathione (GSH), and thioredoxin (Trx) systems. These defenses maintain redox homeostasis and sustain oncogenic signaling, notably through the oxidative inactivation of tumor-suppressor phosphatases, such as PTEN, which drives the PI3K/AKT/mTOR pathway. Targeting this addiction to a rewired redox state has emerged as a compelling therapeutic strategy. Pro-oxidant therapies aim to overwhelm cellular defenses, with agents like high-dose vitamin C and arsenic trioxide (ATO) showing significant tumor-selective toxicity. Inhibiting the master regulator Nrf2 with compounds such as Brusatol or ML385 disrupts the core antioxidant response. Disruption of the GSH system by inhibiting cysteine uptake with sulfasalazine or erastin potently induces ferroptosis, a non-apoptotic cell death driven by lipid peroxidation. Furthermore, the thioredoxin system is targeted by the repurposed drug auranofin, which irreversibly inhibits thioredoxin reductase (TrxR). Extensive preclinical data and ongoing clinical trials support the concept that this reliance on redox adaptation is a cancer-selective vulnerability. Moreover, novel therapeutic strategies, including the expanding field of redox-active metal complexes, such as manganese porphyrins, which strategically leverage the differential redox state of normal versus cancer cells through both pro-oxidant and indirect Nrf2-mediated antioxidative mechanisms (triggered by Keap1 oxidation), with several agents currently in advanced clinical trials, have also been discussed. Essentially, pharmacologically tipping the redox balance beyond the threshold of tolerance offers a rational and powerful approach to eliminate malignant cells, defining a novel frontier for targeted cancer therapy. Full article

Water temperature stands as a crucial environmental element, exerting an impact on the survival and growth of organisms in aquaculture. Heat stress poses a significant threat to the survival and aquaculture of the Hong Kong oyster Magallana hongkongensis (also known as Crassostrea hongkongensis), yet the underlying physiological and molecular mechanisms remain poorly understood. This study investigated the effects of elevated temperatures (35 °C and 37 °C) on survival, DNA damage, antioxidant enzyme activities, and gene expression related to apoptosis, inflammation, and heat shock proteins (HSPs) in M. hongkongensis. The median lethal temperature (LT50) of M. hongkongensis was determined to be 37.09 °C, with significant mortality observed at 35 °C compared with the control (29 °C). Antioxidant enzyme activities (SOD, CAT, and GPx) and T-AOC were up-regulated initially but exhibited divergent patterns under prolonged stress, indicating a temperature-dependent threshold for oxidative defense. Comet assay results also showed that heat stress induced severe DNA damage in hemocytes. Moreover, heat stress significantly up-regulated mRNA expression of apoptosis-related genes (Caspase-2, Caspase-8, Bax, and P53), inflammatory genes (TNF, p38-MAPK, and AP-1), and HSP family members (Hsp70, Hsp90, Hsp27, and Hsp68). The expression peaks of these genes were generally earlier and more pronounced at 37 °C, reflecting intensified cellular damage and protective responses. Collectively, this study demonstrates that M. hongkongensis employs integrated antioxidant, apoptotic, inflammatory, and HSP-mediated mechanisms to counteract heat stress, but temperatures exceeding 35 °C disrupt these defenses, leading to survival impairment. These findings provide critical insights into the heat adaptation strategies of M. hongkongensis and serve as a scientific foundation for developing sustainable aquaculture practices to mitigate summer heat stress. Full article

This study aims to identify the function of the cytochrome P450 2E1 (CYP2E1) gene in the kidneys of Lepus yarkandensis. CYP2E1 is a significant metabolic enzyme involved in the metabolism of various endogenous and exogenous compounds and is associated with the occurrence and progression of multiple diseases. Given L. yarkandensis’s ability to survive in the extremely arid L. yarkandensis, we hypothesize that CYP2E1 in its kidneys plays a crucial role in adaptability. Through molecular cloning and sequence analysis, we discovered that the CYP2E1 gene of Lepus yarkandensis encodes a protein of 493 amino acids. The 493-amino acid protein encoded by the Lepus yarkandensis CYP2E1 gene shows 13 amino acid variation sites compared to the homologous protein in Oryctolagus cuniculus. The protein is primarily localized to the endoplasmic reticulum membrane and lacks transmembrane structures. In the yeast expression system, the heterologous expression of the CYP2E1 gene enhanced the yeast’s tolerance to drought, salinity, and high temperatures, achieved by increasing antioxidant enzyme activity and reducing levels of oxidative stress markers. Additionally, this study identified a “Yeast Oxidative Stress Lethal Threshold (Yeast OSLT)” under specific stress conditions. Once this threshold is exceeded, the cell’s antioxidant defense system can no longer maintain cellular homeostasis, leading to massive cell death. Although CYP2E1 did not change this threshold, it contributed to cell survival to some extent. These findings not only reveal the function of L. yarkandensis CYP2E1 in stress adaptation but also provide valuable molecular insights into its survival strategy in extreme environments. Full article

The increasing use of nanocomposites has raised concerns about the potential environmental impacts, which are less understood than those observed with individual nanomaterials. The purpose of this study was to investigate the toxicity of nanosilver carbon-walled nanotube (AgNP–CWNT) composites in Hydra vulgaris. The lethal and sublethal toxicity was determined based on the characteristic morphological changes (retraction/loss of tentacles and body disintegration) for this organism. In addition, a gene expression array was optimized for gene expression analysis for oxidative stress (superoxide dismutase, catalase), regeneration and growth (serum response factor), protein synthesis, oxidized DNA repair, neural activity (dopamine decarboxylase), and the proteasome/autophagy pathways. The hydras were exposed for 96 h to increasing concentrations of single AgNPs, CWNTs, and to 10% AgNPs–90% CWNTs, and 50% AgNPs–50% CNWT composites. Transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDS) analysis revealed the presence of AgNPs attached to the carbon nanotubes and AgNP aggregates. The data revealed that the AgNP–CWNT composites were more toxic than their counterparts (AgNPs and CNWT). The sublethal morphological changes (EC50) were strongly associated with oxidative stress and protein synthesis while lethal morphological changes (LC50) encompassed changes in dopamine activity, regeneration, and proteasome/autophagic pathways. In conclusion, the toxicity of AgNP–CWNT composites presents a different pattern in gene expression, and at lower threshold concentrations than those obtained for AgNPs or CWNTs alone. Full article