OBJECTIVE: Cholangiocarcinoma (CCA) is a rare tumor with a poor prognosis and poses significant therapeutic challenges. Herein, we investigated the mechanism of efficacy of 125I seed implantation therapy in CCA, focusing on the induction of reactive oxygen species (ROS)-mediated apoptosis and the involvement of glutathione peroxidase 2 (GPX2).
METHODS: Human cholangiocarcinoma cell lines QBC939 and RBE were purchased for in vitro studies. In vivo studies were performed using a rabbit VX2 CCA model. Apoptosis and proliferation were detected by TUNEL staining and clone formation, respectively. ROS generation was detected by dihydroethidium staining. Histological evaluation was performed by hematoxylin and eosin staining. Protein expression was determined by Western blotting and immunohistochemistry.
RESULTS: Our results demonstrate that 125I seeds effectively inhibited tumor growth in the rabbit VX2 tumor model and promoted the apoptosis of CCA cells in vitro in a dose-dependent manner. Molecular analyses indicate a marked increase in reactive oxygen species (ROS) levels following treatment with 125I seeds, suggesting the involvement of ROS-mediated apoptosis in the therapeutic mechanism. Furthermore, the downregulation of glutathione peroxidase 2 (GPX2) was observed, indicating its potential role in modulating ROS-mediated apoptosis in CCA.
CONCLUSIONS: 125I seed implantation therapy exerts therapeutic effects on CCA by inducing ROS-mediated apoptosis. The downregulation of GPX2 may contribute to enhanced ROS accumulation and apoptotic cell death. These findings provide mechanistic insights into the therapeutic potential of 125I seed implantation for CCA and highlight ROS-mediated apoptosis and GPX2 regulation as promising targets for further investigation and therapeutic intervention in this malignancy.

Aims: Reactive oxygen species (ROS) play a vital role in conveying the cytotoxicity and resistance of most chemotherapy drugs. Therefore, gaining a comprehensive understanding of the intricate activities against oxidative stress in cancer cells may provide valuable insights into the discovery of common mechanisms underlying chemoresistance. Results: We identified a novel long noncoding RNA (lncRNA), designated fluorouracil-associated transcript-1 (FUAT1), as a key nongenetic player involved in ROS-mediated intrinsic chemoresistance by employing a unique screening strategy based on transcriptome sequencing (RNA-Seq) technology. To investigate the precise role of the FUAT1 regulatory axis in chemoresistance, we conducted a series of in vitro and in vivo assays including gain/loss-of-function and rescue experiments. Mechanistically, our findings revealed that FUAT1 upregulates Tensin 4 (TNS4) by sponging miR-140-5p, which allows gastric cancer cells to survive chemotherapy by inhibiting ROS-mediated apoptosis. Clinically, we observed that the FUAT1/TNS4 regulatory axis is negatively associated with overall survival and progression-free survival among gastric and colon cancer patients treated with 5-fluorouracil adjuvant chemotherapy. Innovation: We devised a novel screening strategy distinct from conventional approaches using drug-resistant strains. Through this approach, we identified the previously unrecognized lncRNA FUAT1/TNS4 axis that plays a critical role in ROS-mediated intrinsic chemoresistance. Conclusions: Our findings shed light on fundamental adaptive mechanisms employed by cancer cells to respond to chemotherapy and provide new insights into developing strategies aiming at overcoming chemoresistance.

In this paper, we report the synthesis of bioactive copper-gallic acid nanoscale metal-organic framework for the codelivery of anticancer agent (gallic acid) and photosensitizer (methylene blue) to cancer cells. A supramolecular coordination complex of copper-bioactive frameworks (bio MOFs) were employed as the carrier of two anticancer agents. The first one is the natural phenolic acid (gallic acid), which forms a part of the framework structure (building block). The other one is the photosensitizer methylene blue, loaded as a guest molecule within the amphiphilic pores of the framework. In vitro cytotoxicity and in vivo tumor regression assays revealed enhanced cytotoxicity of dual drug nanoframework when compared with the equivalent dosages of free drugs in the presence of light.

A wide variety of polyphenols are reported to have considerable antioxidant and skin photoprotective effects, although the mechanisms of action are not fully known. Environmentally friendly and inexpensive sources of natural bioactive compounds, such as olive mill wastewater (OMWW), the by-product of olive-oil processing, can be considered an economic source of bioactive polyphenols, with a range of biological activities, useful as chemotherapeutic or cosmeceutical agents. Green strategies, such as the process based on membrane technologies, allow to recover active polyphenols from this complex matrix. This study aims to evaluate the antioxidant, pro-oxidant, and photoprotective effects, including the underlying action mechanism(s), of the ultra-filtered (UF) OMWW fractions, in order to substantiate their use as natural cosmeceutical ingredient. Six chemically characterized UF-OMWW fractions, from Italian and Greek olive cultivar processing, were investigated for their antioxidant activities, measured by Trolox Equivalent Antioxidant Capacity (TEAC), LDL oxidation inhibition, and ROS-quenching ability in UVA-irradiated HEKa (Human Epidermal Keratinocytes adult) cultures. The photoprotective properties of UF-OMWW were assayed as a pro-oxidant-mediated pro-apoptotic effect on the UVA-damaged HEKa cells, which can be potentially involved in the carcinogenesis process. All the UF-OMWW fractions exerted an effective antioxidant activity in vitro and in cells when administered together with UV-radiation on HEKa. A pro-oxidative and pro-apoptotic effect on the UVA-damaged HEKa cells were observed, suggesting some protective actions of polyphenol fraction on keratinocyte cell cultures.

Ammonium assimilation is linked to fundamental cellular processes that include the synthesis of non-essential amino acids like glutamate and glutamine. In Saccharomyces cerevisiae glutamate can be synthesized from α-ketoglutarate and ammonium through the action of NADP-dependent glutamate dehydrogenases Gdh1 and Gdh3. Gdh1 and Gdh3 are evolutionarily adapted isoforms and cover the anabolic role of the GDH-pathway. Here, we review the role and function of the GDH pathway in glutamate metabolism and we discuss the additional contributions of the pathway in chromatin regulation, nitrogen catabolite repression, ROS-mediated apoptosis, iron deficiency and sphingolipid-dependent actin cytoskeleton modulation in S.cerevisiae. The pleiotropic effects of GDH pathway in yeast biology highlight the importance of glutamate homeostasis in vital cellular processes and reveal new features for conserved enzymes that were primarily characterized for their metabolic capacity. These newly described features constitute insights that can be utilized for challenges regarding genetic engineering of glutamate homeostasis and maintenance of redox balances, biosynthesis of important metabolites and production of organic substrates. We also conclude that the discussed  pleiotropic features intersect with basic metabolism and set a new background for further glutamate-dependent applied research of biotechnological interest.