bims-oxygme 2025-01-05 papers

Issue of 2025–01–05
five papers selected by
Onurkan Karabulut, Berkeley City College

Oncol Rep. 2025 Feb;pii: 29. [Epub ahead of print]53(2):

Hypoxia studies in non‑small cell lung cancer: Pathogenesis and clinical implications (Review).

Sirui Zhou, Jiazheng Sun, Weijian Zhu, Zhiying Yang, Ping Wang, Yulan Zeng.

Non‑small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia‑inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient‑deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor‑associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC.

Keywords: detection; hypoxia; non‑small cell lung cancer; pathogenesis; treatment

DOI: https://doi.org/10.3892/or.2024.8862

Int J Med Sci. 2025 ;22(1): 188-196

Exploiting Mitochondria by Triggering a Faulty Unfolded Protein Response Leads to Effective Cardioprotection.

Yang Shen, Xin Gao, Ying Xiang, Hao Zhou, Hang Zhu, Qiang Wu, Jinfeng Liu.

This study investigates the role of Fundc1 in cardiac protection under high-altitude hypoxic conditions and elucidates its underlying molecular mechanisms. Using cardiomyocyte-specific Fundc1 knockout (Fundc1CKO ) mice, we demonstrated that Fundc1 deficiency exacerbates cardiac dysfunction under simulated high-altitude hypoxia, manifesting as impaired systolic and diastolic function. Mechanistically, we identified that Fundc1 regulates cardiac function through the mitochondrial unfolded protein response (mito-UPR) pathway. Fundc1 deficiency led to significant downregulation of multiple mito-UPR-related factors, including ATF5, Chop, and PITRM1. Further investigation revealed that Fundc1 deficiency results in increased cardiomyocyte apoptosis, calcium dysregulation, reduced cell viability, and impaired mitochondrial function, characterized by decreased ATP production, reduced membrane potential, and increased ROS production. Notably, activation of mito-UPR with oligomycin significantly ameliorated these cardiac abnormalities in Fundc1-deficient mice. We identified ATF5 as a key downstream effector of Fundc1, as ATF5 overexpression effectively reversed cardiac dysfunction and restored mito-UPR-related gene expression in Fundc1-deficient hearts. Additionally, we discovered that Fundc1-mediated cardioprotection involves regulation of mitophagy, where its activation improved cardiac function and mitochondrial homeostasis in Fundc1-deficient mice. Our findings reveal a novel Fundc1-ATF5-mito-UPR axis in cardioprotection against high-altitude hypoxia and highlight the crucial role of mitophagy in this protective mechanism, providing new insights into potential therapeutic strategies for high-altitude heart disease.

Keywords: ATF5; FUNDC1; mito-UPR; mitochondria.

DOI: https://doi.org/10.7150/ijms.100523

Int J Biol Sci. 2025 ;21(1): 175-188

Heat acclimation mediates cellular protection via HSP70 stabilization of HIF-1α protein in extreme environments.

Can Li, Jirui Wen, Ling Wang, Jun Lei, Zhengdong Lin, Yuhao Zou, Juan Cheng, Xuehong Wan, Jifeng Liu, Jiang Wu.

Heat acclimation (HA) is an evolutionarily conserved trait that enhances tolerance to novel stressors by inducing heat shock proteins (HSPs). However, the molecular mechanisms underlying this phenomenon remain elusive. In this study, we established a HA mouse model through intermittent heat stimulation. Subsequently, this model was evaluated using an array of physiological and histological assessments. In vitro, HA cell model with mouse brain microvascular endothelial cells (bEnd.3) was established and analyzed for cell viability and apoptosis markers. We investigated HA-mediated heat and hypoxia tolerance mechanisms using HIF-1α and HSP70 inhibitors and siRNA. Our results demonstrated that HA enhances the tolerance of bEnd.3 cells and mice to both heat and hypoxia, Mechanistically, HA upregulated the expression of HIF-1α and HSP70. However, inhibition of HIF-1α or HSP70 partially attenuated HA-induced tolerance to heat and hypoxia. Additionally, HA significantly decreased the ubiquitination levels of HIF-1α, whereas inhibition of HSP70 increased its ubiquitination. HA also substantially enhanced the interaction between HIF-1α and HSP70. In conclusion, our findings indicate that HA enhances tolerance to heat and hypoxia by stabilizing HIF-1α through increased interaction with HSP70. This discovery elucidates a novel mechanism of cellular protection conferred by HA and provides new strategies and potential targets for human adaptation to extreme environments.

Keywords: Heat acclimation; Heat shock protein 70; Heat stress; Hypoxia; Hypoxia-inducible factor 1-alpha; Ubiquitination

DOI: https://doi.org/10.7150/ijbs.103122

Mol Med. 2024 Dec 28. 30(1): 281

HIF-1α mediates hypertension and vascular remodeling in sleep apnea via hippo-YAP pathway activation.

Shoude Zhang, Yuan Zhao, Zhanwei Dong, Mao Jin, Ying Lu, Mina Xu, Hong Pan, Guojin Zhou, Mang Xiao.

BACKGROUND: Sleep apnea syndrome (SAS) is associated with hypertension and vascular remodeling. Hypoxia-inducible factor-1α (HIF-1α) and the Hippo-YAP pathway are implicated in these processes, but their specific roles remain unclear. This study investigated the HIF-1α/Hippo-YAP pathway in SAS-related hypertension.
METHODS: We established a rat model of SAS-induced hypertension via chronic intermittent hypoxia (CIH). Rats were treated with siRNA targeting HIF-1α. Blood pressure, inflammation, oxidative stress, vascular remodeling, and VSMC function were assessed. In vitro experiments with A7r5 cells and human aortic smooth muscle cells (HAoSMCs) explored the effects of HIF-1α silencing and YAP1 overexpression.
RESULTS: Compared with the control group, the CIH group presented significant increases in both HIF-1α and YAP1 expression, which correlated with increased blood pressure and vascular changes. HIF-1α silencing reduced hypertension, oxidative stress, inflammation, and the severity of vascular remodeling. Specifically, siRNA treatment for HIF-1α normalized blood pressure, decreased the levels of oxidative damage markers (increased SOD and decreased MDA), and reversed the changes in the levels of inflammatory markers (decreased high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and soluble E-selectin (sE-s)). Structural analyses revealed reduced vascular smooth muscle cell proliferation and collagen deposition, along with normalization of cellular markers, such as α-SMA and TGF-β1. Furthermore, the Hippo-YAP pathway appeared to mediate these effects, as evidenced by altered YAP1 expression and activity upon HIF-1α modulation.
CONCLUSIONS: Our findings demonstrate the significance of the HIF-1α/Hippo-YAP pathway in CIH-induced hypertension and vascular remodeling. HIF-1α contributes to these pathophysiological processes by promoting oxidative stress, inflammation, and aberrant VSMC behavior. Targeting this pathway could offer new therapeutic strategies for CIH-related cardiovascular complications in SAS patients.

Keywords: HIF-1α, Hippo; Inflammation; Sleep apnea syndrome; Vascular remodeling; YAP

DOI: https://doi.org/10.1186/s10020-024-00987-5

Trends Genet. 2024 Dec 27. pii: S0168-9525(24)00260-9. [Epub ahead of print]

Cell-autonomous adaptation: an overlooked avenue of adaptation in human evolution.

Ruthie Golomb, Orna Dahan, Dvir Dahary, Yitzhak Pilpel.

Adaptation to environmental conditions occurs over diverse evolutionary timescales. In multi-cellular organisms, adaptive traits are often studied in tissues/organs relevant to the environmental challenge. We argue for the importance of an underappreciated layer of evolutionary adaptation manifesting at the cellular level. Cell-autonomous adaptations (CAAs) are inherited traits that boost organismal fitness by enhancing individual cell function. For instance, the cell-autonomous enhancement of mitochondrial oxygen utilization in hypoxic environments differs from an optimized erythropoiesis response, which involves multiple tissues. We explore the breadth of CAAs across challenges and highlight their counterparts in unicellular organisms. Applying these insights, we mine selection signals in Andean highlanders, revealing novel candidate CAAs. The conservation of CAAs across species may reveal valuable insights into multi-cellular evolution.

Keywords: adaptation; cell-autonomous; high altitudes; human evolution

DOI: https://doi.org/10.1016/j.tig.2024.10.009