bims-oxygme 2024-11-10 papers

Issue of 2024–11–10
six papers selected by
Onurkan Karabulut, Berkeley City College

Medicine (Baltimore). 2024 Nov 01. 103(44): e40273

Central role of hypoxia-inducible factor-1α in metabolic reprogramming of cancer cells: A review.

Bing Zhu, Lichao Cheng, Baosu Huang, Runzhi Liu, Bin Ren.

Metabolic reprogramming is one of the characteristics of tumor cell metabolism. In tumor cells, there are multiple metabolic enzymes and membrane proteins to regulate metabolic reprogramming, and hypoxia inducible factor-1α (HIF-1α) can be regulated in transcription, translation, posttranslational modification and other aspects through multiple pathways, and HIF-1α affects multiple metabolic enzymes and membrane proteins during metabolic reprogramming, thus playing a central role in the metabolic reprogramming process, and thus has some implications for tumor therapy and understanding chemotherapy drug resistance. HIF-1α affects a number of metabolic enzymes and membrane proteins in the metabolic reprogramming process, thus playing a central role in the metabolic reprogramming process, which has certain significance for the treatment of tumors and the understanding of chemotherapeutic drug resistance. In this paper, we review the central role of HIF-1α in metabolic reprogramming, chemotherapeutic agents targeting HIF-1α, and chemotherapeutic drug resistance.

DOI: https://doi.org/10.1097/MD.0000000000040273

Methods Enzymol. 2024 ;pii: S0076-6879(24)00405-1. [Epub ahead of print]707 519-539

Analysis of mitochondrial biogenesis regulation by oxidative stress.

Dheeraj Pathak, Thanuja Krishnamoorthy, Naresh Babu V Sepuri.

Of all the causes of metabolic and neurological disorders, oxidative stress distinguishes itself by its sweeping effect on the dynamic cellular redox homeostasis and, in its wake, exposing the vulnerabilities of the protein machinery of the cell. High levels of Reactive Oxygen Species (ROS) that mitochondria produce during ATP synthesis can damage mtDNA, lipids, and essential mitochondrial proteins. ROS majorly oxidizes cysteine and methionine amino acids in peptides, which can lead to protein unfolding or misfolding of proteins, which ultimately can have a toll on their function. As mitochondrial biogenesis relies on the continuous import of nuclear-encoded proteins into mitochondria mediated by mitochondrial protein import complexes, oxidative stress triggered by mitochondria can rapidly and detrimentally affect mitochondrial biogenesis and homeostasis. Functional Mge1 is a homodimer and acts as a cochaperone and a nucleotide exchange factor of mitochondrial heat shock protein 70 (mHsp70), crucial for mitochondrial protein import. Oxidative stress like ROS, oxidizes Met 155 in Mge1, compromising its ability to dimerize and interact with mHsp70. The cell employs Methionine sulphoxide reductase 2 (Mxr2), a member of the methionine sulphoxide reductase family, to reduce oxidized Met 155 and thereby restore the essential function of Mge1. Oxidation of methionine as a regulated post-translational modification has been gaining traction. Future high throughput studies that can scan the entire mitochondrial proteome to interrogate methionine oxidation and reversal may increase the repertoire of mitochondrial proteins undergoing regulated oxidation and reduction. In this chapter, we describe the methods followed in our laboratory to study the oxidation of Mge1 and its reduction by Mxr2 in vitro.

Keywords: Cross linking; Methionine oxidation; Methionine sulfoixde reductase 2; Mge1; Mitochondria; Reactive Oxygen Species

DOI: https://doi.org/10.1016/bs.mie.2024.07.060

Front Physiol. 2024 ;15 1474933

Hyperbaric oxygen-induced acute lung injury: A mouse model study on pathogenic characteristics and recovery dynamics.

Shu Wang, Hong Chen, Zhi Li, Guangxu Xu, Xiaochen Bao.

Oxygen is an essential substance for the maintenance of human life. It is also widely used in clinical and diving medicine. Although oxygen is crucial for survival, too much oxygen can be harmful. Excessive oxygen inhalation in a short period of time can lead to injury, and the lung is one of the main target organs. Acute lung injury (ALI) induced by hyperbaric oxygen (HBO) is notably more severe than that caused by normobaric oxygen, yet systematic research on such injury and its regression is scarce. In this study, two independent experiments were designed. In the first experiment, mice were exposed to 2 atmospheres absolute (ATA), ≥95% oxygen for 2, 4, 6, and 8 h. Changes in lung histopathology, inflammation and expression of chemokines, alveolar-capillary barrier, and 8-OHdG were detected before and after the exposure. In the second experiment, these parameters were measured at 0 h, 12 h, and 24 h following 6 h of exposure to 2 ATA of ≥95% oxygen. Research indicates that ALI induced by HBO is characterized histologically by alveolar expansion, atelectasis, inflammatory cell infiltration, and hemorrhage. At 2 ATA, significant changes in the alveolar-capillary barrier were observed after more than 95% oxygen exposure for 4 h, as evidenced by increased Evans blue (EB) extravasation (p = 0.0200). After 6 h of HBO exposure, lung tissue pathology scores, 8-OHdG levels, and inflammatory and chemotactic factors (such as Il6, CCL2, CCL3, CXCL5, and CXCL10), intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1) were significantly elevated. Compared to lung injury caused by normobaric oxygen, the onset time of injury was significantly shortened. Additionally, it was observed that these markers continued to increase after leaving the HBO environment, peaking at 12 h and starting to recover at 24 h, indicating that the peak of inflammatory lung injury occurs within 12 h post-exposure, with recovery beginning at 24 h. This contradicts the common belief that lung injury is alleviated upon removal from a high-oxygen environment. However, EB levels, which reflect damage to the alveolar-capillary barrier, and VE-Cadherin (VE-Cad), tight junction protein 1 (ZO-1), ICAM1, and VCAM1 remained significantly altered 24 h after leaving the HBO environment. This suggests that the alveolar-capillary barrier is the most sensitive and slowest recovering part of the lung injury induced by HBO. These findings can provide insights into the pathogenesis and progression of lung injury caused by HBO and offer references for identifying corresponding intervention targets.

Keywords: acute lung injury (ALI); hyperbaric oxygen (HBO); hyperoxic acute lung injury (HALI); pulmonary oxygen toxicity (POT); reactive oxygen species (ROS)

DOI: https://doi.org/10.3389/fphys.2024.1474933

Spectrochim Acta A Mol Biomol Spectrosc. 2024 Oct 23. pii: S1386-1425(24)01493-8. [Epub ahead of print]327 125327

Simultaneous production of singlet oxygen and superoxide anion by thiocarbonyl coumarin for photodynamic therapy.

Zhijing Xu, Yingzhuang Song, Jinyu Sun.

Photodynamic therapy (PDT) is a medical treatment that kills target cells through reactive oxygen species (ROS) generated by photosensitizers (PS) and surrounding oxygen under the stimulus of light. Despite of its popularity in cancer treatment, PDT relys on oxygen and therefore suffers from long response time and low efficiency under low-oxygen situations such as tumor hypoxia. Herein, to improve the usage of oxygen and increase ROS yield, we synthesized six potential PSs termed DC-O, DC-S, DC-BrO, DC-BrS, DC-IO, and DC-IS, by modifying coumarins with thiocarbonyl and bromine/iodine. We found that the thiocarbonyl group induces a significant bathochromic shift of the absorption spectra. In addition, the ROS production was significantly improved, likely because these PSs can simultaneously generate singlet oxygen (1O2) and superoxide anions (O2•-) through different pathways. Among these compounds, DC-BrS produces largest amount of ROS and exhibits strongest cytotoxicity towards cells, the survival rate of B16-F10 cells incubated with DC-BrS was only 20.7 % after irradiation at 460 nm for 10 min, indicating DC-BrS as a strong candidate for photodynamic therapy. Most importantly, this work provides an important direction for the design of PSs in the future.

Keywords: Coumarin; Photodynamic therapy; Photosensitizer; Singlet oxygen; Superoxide anion

DOI: https://doi.org/10.1016/j.saa.2024.125327

Cancer Control. 2024 Jan-Dec;31:31 10732748241299072

A Review of Advances in Mitochondrial Research in Cancer.

Zhiru Li, Wu Zhang, Shaowei Guo, Guoyan Qi, Jiandi Huang, Jin Gao, Jing Zhao, Lin Kang, Qingxia Li.

BACKGROUND: Abnormalities in mitochondrial structure or function are closely related to the development of malignant tumors. Mitochondrial metabolic reprogramming provides precursor substances and energy for the vital activities of tumor cells, so that cancer cells can rapidly adapt to the unfavorable environment of hypoxia and nutrient deficiency. Mitochondria can enable tumor cells to gain the ability to proliferate, escape immune responses, and develop drug resistance by altering constitutive junctions, oxidative phosphorylation, oxidative stress, and mitochondrial subcellular relocalization. This greatly reduces the rate of effective clinical control of tumors.
PURPOSE: Explore the major role of mitochondria in cancer, as well as targeted mitochondrial therapies and mitochondria-associated markers.
CONCLUSIONS: This review provides a comprehensive analysis of the various aspects of mitochondrial aberrations and addresses drugs that target mitochondrial therapy, providing a basis for clinical mitochondria-targeted anti-tumor therapy.

Keywords: cancer; immune microenvironment; metabolic reprogramming; mitochondria-targeting; mitochondrial dysfunction

DOI: https://doi.org/10.1177/10732748241299072

Nephrol Dial Transplant. 2024 Nov 04. pii: gfae225. [Epub ahead of print]

Oxygen sensing in the kidney.

Lisa Geis, Armin Kurtz.

The kidneys fulfil several essential homeostatic functions for the body. One of them is the maintenance of sufficient oxygen supply to the organs. For this purpose, the kidneys control the formation of red blood cells by the production of the hormone erythropoietin. This control of red cell formation is not only relevant to prevent states of oxygen deficiency but also to prevent an unwanted increase of red cell numbers causing thromboembolic risks. The adequate production of erythropoietin requires a sensing of the arterial oxygen content and transduction to hormone production. This oxygen sensing is a two-step process which includes a translation of the arterial oxygen content to respective oxygen tension in the tubulointerstitium and a perception of the resulting local interstitial oxygen tension to translate them into specific cellular responses such as the production of erythropoietin. This contribution will describe these steps of oxygen sensing for the healthy kidney and for the changes occurring during states of chronic renal disease, which are commonly associated with anemia. In this context a special focus will also be set on intrarenal hypoxia and oxygen sensing in the diabetic kidney including the treatment with tubular glucose transport (SGLT-2) inhibitors which might influence the oxygen sensing in the kidney. Finally, we will consider the effects of prolylhydroxylase inhibitors (PHD-I), which fundamentally interfere with the cellular oxygen sensing and which are meanwhile treatment options in renal anemia.

Keywords: SGLT2 inhibitor; anemia; diabetes mellitus; erythropoietin; hypoxia inducible (transcription) factor (HIF); prolylhydroxylase inhibitor

DOI: https://doi.org/10.1093/ndt/gfae225