bims-oxygme 2025-02-02 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–02–02
ten papers selected by
Onurkan Karabulut, Berkeley City College

Metabolomic Profiles of Siberian Wood Frog Rana amurensis in Hypoxia and Upon Reoxygenation.
hUC-MSCs Prevent Acute High-Altitude Injury through Apoe/Pdgf-b/p-Erk1/2 Axis in Mice.
Hypoxia-Induced Reactive Oxygen Species: Their Role in Cancer Resistance and Emerging Therapies to Overcome It.
Adaptation mechanisms in cancer: Lipid metabolism under hypoxia and nutrient deprivation as a target for novel therapeutic strategies (Review).
Circadian rhythm, hypoxia, and cellular senescence: From molecular mechanisms to targeted strategies.
Catecholamine synthesis and secretion by adrenal chromaffin cells is reduced in deer mice native to high altitude.
Regulation of pathologic fibroblast functions in digestive diseases: a role for hypoxia?
Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity.
Alteration of Lipid Metabolism in Hypoxic Cancer Cells.
Quinoa Ethanol Extract Ameliorates Cognitive Impairments Induced by Hypoxia in Mice: Insights into Antioxidant Defense and Gut Microbiome Modulation.

Biochemistry (Mosc). 2024 Dec;89(12): 2133-2142

Metabolomic Profiles of Siberian Wood Frog Rana amurensis in Hypoxia and Upon Reoxygenation.

Sergei V Shekhovtsov, Nina A Bulakhova, Yuri P Tsentalovich, Nataliya A Osik, Ekaterina N Meshcheryakova, Tatiana V Poluboyarova, Daniil I Berman.

  Hypoxia poses a serious challenge for all animals; however, certain animals exhibit a remarkable resilience in the case of prolonged and severe hypoxia. The Siberian wood frog Rana amurensis is a unique amphibian capable of surviving for up to several months at almost complete anoxia. We investigated changes in the metabolome of R. amurensis at the onset of hypoxia (day 1) and within 1 h of reoxygenation after a long-term hypoxia using 1H NMR. We compared our results to the data obtained for animals exposed to 17 days of hypoxia and controls. Despite the differences between the samples analyzed in three different experimental series, we were able to obtain some interesting insights. In most studied vertebrates, succinate accumulates under hypoxic conditions and undergoes rapid conversion upon reoxygenation. We found that reoxygenation caused a decrease in the succinate content in the brain, but not in the liver, where it remained unchanged, suggesting an existence of a mechanism that inhibits succinate conversion. Furthermore, we observed intriguing differences in the behavior of two substances with unknown functions: glycerol and 2,3-butanediol. Glycerol exhibited rapid accumulation during hypoxia and equally rapid processing during reoxygenation. In contrast, 2,3-butanediol required an extended period of time to accumulate, yet persisted after reoxygenation. Overall, our data demonstrate rapid accumulation of most substances during exposure to hypoxia followed by their slower processing upon reoxygenation.

Keywords:  1H-NMR; 2,3-butanediol; glycerol; hypoxia; reoxygenation; succinate

DOI:  https://doi.org/10.1134/S0006297924120034
Stem Cell Rev Rep. 2025 Jan 28.

hUC-MSCs Prevent Acute High-Altitude Injury through Apoe/Pdgf-b/p-Erk1/2 Axis in Mice.

Siyu Yan, Youkun Bi, Qun Liu, Shaole Song, Lihong Ma, Guangju Ji.

   BACKGROUND: The hypobaric hypoxic atmosphere can cause adverse reactions or sickness. The purpose of this study was to explore the preventive effect and mechanism of human umbilical cord mesenchymal stem cells (hUC-MSCs) on acute pathological injury in mice exposed to high-altitude.
METHODS: We pretreated C57BL/6 mice with hUC-MSCs via the tail vein injection, and then the mice were subjected to hypobaric hypoxic conditions for five days. The effects of hUC-MSCs on the pathological injury of lung, heart, brain were assessed by biochemical analysis, histopathological testing, quantitative real-time polymerase chain reaction (qPCR), and western blot (WB). Further, transcriptome sequencing was used to screen for the potential therapeutic targets of hUC-MSCs in acute pathological injury, the identified signaling axis was characterized using Apoe-/- mice, qPCR and WB.
RESULTS: hUC-MSCs administration notably prevented and relieved gastrointestinal symptoms and inflammation of lung and heart, increased blood oxygen saturation and serum superoxide dismutase (SOD) level, decreased serum malondialdehyde (MDA) level, rescued lung tissue injury and myocardial mitochondrial disorder, elevated nissl bodies number in brain tissue and reduced the degree of pulmonary and cerebral edema. Furthermore, hUC-MSCs pretreatment reversed the down-regulated Apoe and up-regulated Pdgf-b and p-Erk1/2 in the lung of hypobaric hypoxic mice. Thus, hUC-MSCs protected against acute pathological injury caused by hypobaric hypoxic condition via the Apoe/Pdgf-b/p-Erk1/2 axis, and the identified pathway was confirmed by the negative results of Apoe-/- mice.
CONCLUSION: hUC-MSCs possess the preventive effect on acute pathological injury caused by hypobaric hypoxia environment at high-altitude.

Keywords:  Acute mountain sickness; Apoe; HUC-MSCs; Hypobaric hypoxia

DOI:  https://doi.org/10.1007/s12015-024-10840-1
Antioxidants (Basel). 2025 Jan 15. pii: 94. [Epub ahead of print]14(1):

Hypoxia-Induced Reactive Oxygen Species: Their Role in Cancer Resistance and Emerging Therapies to Overcome It.

Eleicy Nathaly Mendoza, Maria Rosa Ciriolo, Fabio Ciccarone.

  Normal tissues typically maintain partial oxygen pressure within a range of 3-10% oxygen, ensuring homeostasis through a well-regulated oxygen supply and responsive vascular network. However, in solid tumors, rapid growth often outpaces angiogenesis, creating a hypoxic microenvironment that fosters tumor progression, altered metabolism and resistance to therapy. Hypoxic tumor regions experience uneven oxygen distribution with severe hypoxia in the core due to poor vascularization and high metabolic oxygen consumption. Cancer cells adapt to these conditions through metabolic shifts, predominantly relying on glycolysis, and by upregulating antioxidant defenses to mitigate reactive oxygen species (ROS)-induced oxidative damage. Hypoxia-induced ROS, resulting from mitochondrial dysfunction and enzyme activation, exacerbates genomic instability, tumor aggressiveness, and therapy resistance. Overcoming hypoxia-induced ROS cancer resistance requires a multifaceted approach that targets various aspects of tumor biology. Emerging therapeutic strategies target hypoxia-induced resistance, focusing on hypoxia-inducible factors, ROS levels, and tumor microenvironment subpopulations. Combining innovative therapies with existing treatments holds promise for improving cancer outcomes and overcoming resistance mechanisms.

Keywords:  HIF; ROS; antioxidants; cancer resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/antiox14010094
Mol Med Rep. 2025 Apr;pii: 83. [Epub ahead of print]31(4):

Adaptation mechanisms in cancer: Lipid metabolism under hypoxia and nutrient deprivation as a target for novel therapeutic strategies (Review).

Shiro Koizume, Yohei Miyagi.

  Tumor tissues generally exist in a relatively hypovascular state, and cancer cells must adapt to severe tissue conditions with a limited molecular oxygen and nutrient supply for their survival. Lipid metabolism serves a role in this adaptation. Lipids are supplied not only through the bloodstream but also through autonomous synthesis by cancer cells, and they function as sources of adenosine triphosphate and cell components. Although cancer‑associated lipid metabolism has been widely reviewed, how this metabolism responds to the tumor environment with poor molecular oxygen and nutrient supply remains to be fully discussed. The main aim of the present review was to summarize the findings on this issue and to provide insights into how cancer cells adapt to better cope with metabolic stresses within tumors. It may be suggested that diverse types of lipid metabolism have a role in enabling cancer cells to adapt to both hypoxia and nutrient‑poor conditions. Gaining a deeper understanding of these molecular mechanisms may reveal novel possibilities of exploration for cancer treatment.

Keywords:  amino acid deprivation; cancer; glucose deprivation; hypoxia; lipid metabolism

DOI:  https://doi.org/10.3892/mmr.2025.13448
Eur J Pharmacol. 2025 Jan 23. pii: S0014-2999(25)00043-3. [Epub ahead of print]990 177290

Circadian rhythm, hypoxia, and cellular senescence: From molecular mechanisms to targeted strategies.

Tong Nie, Eugenie Nepovimova, Qinghua Wu.

  Cellular senescence precipitates a decline in physiological activities and metabolic functions, often accompanied by heightened inflammatory responses, diminished immune function, and impaired tissue and organ performance. Despite extensive research, the mechanisms underpinning cellular senescence remain incompletely elucidated. Emerging evidence implicates circadian rhythm and hypoxia as pivotal factors in cellular senescence. Circadian proteins are central to the molecular mechanism governing circadian rhythm, which regulates homeostasis throughout the body. These proteins mediate responses to hypoxic stress and influence the progression of cellular senescence, with protein Brain and muscle arnt-like 1 (BMAL1 or Arntl) playing a prominent role. Hypoxia-inducible factor-1α (HIF-1α), a key regulator of oxygen homeostasis within the cellular microenvironment, orchestrates the transcription of genes involved in various physiological processes. HIF-1α not only impacts normal circadian rhythm functions but also can induce or inhibit cellular senescence. Notably, HIF-1α may aberrantly interact with BMAL1, forming the HIF-1α-BMAL1 heterodimer, which can instigate multiple physiological dysfunctions. This heterodimer is hypothesized to modulate cellular senescence by affecting the molecular mechanism of circadian rhythm and hypoxia signaling pathways. In this review, we elucidate the intricate relationships among circadian rhythm, hypoxia, and cellular senescence. We synthesize diverse evidence to discuss their underlying mechanisms and identify novel therapeutic targets to address cellular senescence. Additionally, we discuss current challenges and suggest potential directions for future research. This work aims to deepen our understanding of the interplay between circadian rhythm, hypoxia, and cellular senescence, ultimately facilitating the development of therapeutic strategies for aging and related diseases.

Keywords:  Cellular senescence; Circadian rhythm; Hypoxia; Potential therapy; Relationships

DOI:  https://doi.org/10.1016/j.ejphar.2025.177290
Am J Physiol Regul Integr Comp Physiol. 2025 Jan 30.

Catecholamine synthesis and secretion by adrenal chromaffin cells is reduced in deer mice native to high altitude.

Nicole A Pranckevicius, Angela L Scott, Aedan J Rourke, Ranim Saleem, Oliver H Wearing, Graham R Scott.

  Hypoxia at high altitude can constrain aerobic metabolism and elicit physiological responses that are detrimental to health and fitness. Responses of the sympathoadrenal system are vital for coping with acute hypoxia, but can become maladaptive with prolonged activation in chronic hypoxia. We examined how adrenal function is altered in high-altitude populations of deer mice (Peromyscus maniculatus), which have evolved to overcome chronic hypoxia in their native environment. High- and low-altitude populations were each born and raised in common lab conditions, and then acclimated to normoxia or chronic hypoxia during adulthood. High-altitude mice exhibited lower plasma epinephrine concentrations than low-altitude mice in both normoxia and hypoxia. Primary cultures of chromaffin cells were used to examine the cellular mechanisms underlying differences in epinephrine secretion from the adrenal medulla. Chromaffin cells from high-altitude mice did not mount a diminished Ca2+ response to nicotinic stimulation, but cellular catecholamine stores were much lower in high-altitude mice than in low-altitude mice. Histological analyses of the adrenal gland showed that high-altitude mice did not have smaller adrenal medullae. Therefore, reductions in chromaffin cell catecholamine stores were the primary mechanism for lower secretion rates and circulating concentrations of catecholamines in high-altitude mice, which may help avoid sympathoadrenal over-activity in chronic hypoxia. Further exploratory analysis found that high-altitude mice have a larger adrenal cortex and higher plasma concentrations of corticosterone, which could reflect changes in stress responsiveness or metabolic regulation. Therefore, multiple evolved changes in the physiology of the adrenal gland may contribute to high-altitude adaptation in deer mice.

Keywords:  cardiovascular control; evolutionary physiology; high elevation; sympathetic nervous system

DOI:  https://doi.org/10.1152/ajpregu.00194.2024
Am J Physiol Gastrointest Liver Physiol. 2025 Jan 28.

Regulation of pathologic fibroblast functions in digestive diseases: a role for hypoxia?

Cian M Ohlendieck, Carlos Matellan, Mario C Manresa.

  The recent uncovering of fibroblast heterogeneity has given great insight into the versatility of the stroma. Among other cellular processes, fibroblasts are now thought to contribute to the coordination of immune responses in a range of chronic inflammatory diseases and cancer. While the pathologic roles of myofibroblasts, inflammatory fibroblasts and cancer associated fibroblasts in disease are reasonably well understood, the mechanisms behind their activation remain to be uncovered. In the gastrointestinal (GI) tract, several interleukins and tumour necrosis factor superfamily members have been identified as possible mediators driving the acquisition of inflammatory as well as fibrotic properties in fibroblasts. In addition to cytokines, other microenvironmental factors such as nutrient and oxygen availability are likely contributors to this process. In this respect, the phenomenon of low cellular oxygen levels known as hypoxia is common in a plethora of GI diseases. Indeed, the crosstalk between hypoxia and inflammation is well-documented, with an abundance of studies suggesting that oxygen-sensing enzymes may have regulatory effects on inflammatory signalling pathways such as NF-κB. However, the impact that this has in GI fibroblasts in the context of chronic diseases has not been fully uncovered. Here we discuss the role of fibroblasts in GI diseases, the mediators that have emerged as regulators of their functions and the potential impact of hypoxia in this process, highlighting areas that require further investigation.

Keywords:  cancer; fibroblast; fibrosis; gastrointestinal disease; hypoxia; hypoxic regulation; inflammation; inflammatory fibroblast

DOI:  https://doi.org/10.1152/ajpgi.00277.2024
BMJ Oncol. 2024 ;3(1): e000154

Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity.

Brian M Ortmann.

  Cancer remains one of the most formidable challenges in modern medicine, due to its complex and dynamic nature, which demands innovative therapeutic approaches. One major challenge to cancer treatment is the tumour microenvironment and in particular tumour hypoxia (low oxygen levels), which contributes to tumour progression and immune evasion. At the cellular level, this is primarily governed by hypoxia-inducible factor (HIF). HIF is a transcription factor that orchestrates cellular responses to low oxygen levels, driving angiogenesis, metabolic adaptation and immune regulation. HIF's dysregulation is frequently observed in various cancer types and correlates with increased aggressiveness, metastasis, resistance to therapy and poor patient prognosis. Consequently, understanding the cellular mechanisms underlying HIF activation and its downstream effects has become crucial to developing targeted cancer therapies for improving cancer patient outcomes and represents a key step towards precision medicine. Recent advancements in drug development have led to the emergence of HIF inhibitors, which aim to disrupt HIF-driven processes in cancer providing therapeutic benefit. Here, we provide a review of the molecular mechanisms through which HIF promotes tumour growth and resistance, emphasising the potential clinical benefits of HIF-targeted therapies. This review will discuss the challenges and opportunities associated with translating HIF inhibition into clinical practice, including ongoing clinical trials and future directions in the development of HIF-based cancer treatments.

Keywords:  Gene expression

DOI:  https://doi.org/10.1136/bmjonc-2023-000154
Chem Biomed Imaging. 2025 Jan 27. 3(1): 25-34

Alteration of Lipid Metabolism in Hypoxic Cancer Cells.

Gil A Gonzalez, Ezinne U Osuji, Natalie C Fiur, Matthew G Clark, Seohee Ma, Laura L Lukov, Chi Zhang.

Due to uncontrolled cell proliferation and disrupted vascularization, many cancer cells in solid tumors have limited oxygen supply. The hypoxic microenvironments of tumors lead to metabolic reprogramming of cancer cells, contributing to therapy resistance and metastasis. To identify better targets for the effective removal of hypoxia-adaptive cancer cells, it is crucial to understand how cancer cells alter their metabolism in hypoxic conditions. Here, we studied lipid metabolic changes in cancer cells under hypoxia using coherent Raman scattering (CRS) microscopy. We discovered the accumulation of lipid droplets (LDs) in the endoplasmic reticulum (ER) in hypoxia. Time-lapse CRS microscopy revealed the release of old LDs and the reaccumulated LDs in the ER during hypoxia exposure. Additionally, we explored the impact of carbon sources on LD formation and found that MIA PaCa2 cells preferred fatty acid uptake for LD formation, while glucose was essential to alleviate lipotoxicity. Hyperspectral-stimulated Raman scattering (SRS) microscopy revealed a reduction in cholesteryl ester content and a decrease in lipid saturation levels of LDs in hypoxic MIA PaCa2 cancer cells. This alteration in LD content is linked to reduced efficacy of treatments targeting cholesteryl ester formation. This study unveils important lipid metabolic changes in hypoxic cancer cells, providing insights that could lead to better treatment strategies for hypoxia-resistant cancer cells.

DOI: https://doi.org/10.1021/cbmi.4c00050
J Agric Food Chem. 2025 Jan 28.

Quinoa Ethanol Extract Ameliorates Cognitive Impairments Induced by Hypoxia in Mice: Insights into Antioxidant Defense and Gut Microbiome Modulation.

Yongli Lan, Yujie Song, Wengang Zhang, Shiyang Zhao, Xinze Wang, Lei Wang, Yutang Wang, Xijuan Yang, Hao Wu, Xuebo Liu.

  Quinoa, rich in pharmacologically active ingredients, possesses the potential benefit in preventing cognitive impairments induced by hypoxia. In this study, the efficacy of quinoa ethanol extracts (QEE) consumption (200 and 500 mg/kg/d, respectively) against hypobaric hypoxia (HH)-induced cognitive deficits in mice was investigated. QEE significantly ameliorated hypoxic stress induced by HH, as evidenced by improvements in baseline indices and reductions in hypoxia-inducible factor 1α levels. Furthermore, QEE enhanced antioxidant defense mechanisms, alleviated neuroinflammation in brain regions associated with memory, and improved HH-induced cognitive impairments by modulating the cyclic adenosine monophosphate response element-binding protein/brain-derived neurotrophic factor signaling pathway. Higher doses generally yielded more effective outcomes than lower doses. QEE also significantly reshaped the gut microbiome structure of HH mice, inhibited gut barrier damage, and reduced lipopolysaccharide migration, thereby increasing short-chain fatty acids (SCFAs) levels. Our findings suggest that QEE may be a promising strategy for preventing hypoxia-induced cognitive impairments by maintaining gut microbiome stability and increasing SCFAs levels.

Keywords:  cognitive function; gut–brain axis; hypoxia; microbiome; neuroinflammation; quinoa ethanol extract

DOI:  https://doi.org/10.1021/acs.jafc.4c07530