bims-oxygme 2024-11-24 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2024–11–24
eleven papers selected by
Onurkan Karabulut, Berkeley City College

The role of hypoxic microenvironment in autoimmune diseases.
Cardioprotective Effect of Chronic Hypoxia Involves Inhibition of Mitochondrial Permeability Transition Pore Opening.
Deficiency of lysophosphatidic acid receptor 3 decreases erythropoietin production in hypoxic mouse kidneys.
A Hypoxia-Inflammation Cycle and Multiple Sclerosis: Mechanisms and Therapeutic Implications.
Investigating the effect of Quercetin in the presence of CoCl2 as an inducing hypoxia agent on the biological characteristics of human telomerase reverse transcription-immortalized adipose tissue-derived MSCs.
Alleviating hypoxia by integrating MnO2 with metal-organic frameworks coated upconversion nanocomposites for enhanced photodynamic therapy in vitro.
From Hypoxia to Oxidative Stress: Antioxidants' Role to Reduce Male Reproductive Damage.
Impairing Ferroptosis Through the PI3K/Akt/Nrf2 Pathway: The Way for Nerve Growth Factor to Mitigate Hypoxia-induced Cardiomyocyte Damage.
Auto-Deactivation of BODIPY-Derived Type I Photosensitizer Post Photodynamic Therapy under Hypoxia.
Exploring the effects of hypoxia and reoxygenation time on hepatocyte apoptosis and inflammation.
Oxygen control in cell culture - your cells may not be experiencing what you think!

Front Immunol. 2024 ;15 1435306

The role of hypoxic microenvironment in autoimmune diseases.

Xun Gong, Su-Yin Yang, Zhen-Yu Wang, Min Tang.

  The hypoxic microenvironment, characterized by significantly reduced oxygen levels within tissues, has emerged as a critical factor in the pathogenesis and progression of various autoimmune diseases (AIDs). Central to this process is the hypoxia-inducible factor-1 (HIF-1), which orchestrates a wide array of cellular responses under low oxygen conditions. This review delves into the multifaceted roles of the hypoxic microenvironment in modulating immune cell function, particularly highlighting its impact on immune activation, metabolic reprogramming, and angiogenesis. Specific focus is given to the mechanisms by which hypoxia contributes to the development and exacerbation of diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and dermatomyositis (DM). In these conditions, the hypoxic microenvironment not only disrupts immune tolerance but also enhances inflammatory responses and promotes tissue damage. The review also discusses emerging therapeutic strategies aimed at targeting the hypoxic pathways, including the application of HIF-1α inhibitors, mTOR inhibitors, and other modulators of the hypoxic response. By providing a comprehensive overview of the interplay between hypoxia and immune dysfunction in AIDs, this review offers new perspectives on the underlying mechanisms of these diseases and highlights potential avenues for therapeutic intervention.

Keywords:  autoimmune diseases; hypoxia-inducible factor-1; hypoxic microenvironment; immune cells; rheumatoid arthritis

DOI:  https://doi.org/10.3389/fimmu.2024.1435306
Physiol Res. 2024 Nov 19. 73(5): 881-884

Cardioprotective Effect of Chronic Hypoxia Involves Inhibition of Mitochondrial Permeability Transition Pore Opening.

P Alanova, L Alan, J Neckar, B Ostadal, F Kolar.

The aim of the study was to examine the potential role of mitochondrial permeability transition pore (mPTP) in the cardioprotective effect of chronic continuous hypoxia (CH) against acute myocardial ischemia/reperfusion (I/R) injury. Adult male Wistar rats were adapted to CH for 3 weeks, while their controls were kept under normoxic conditions. Subsequently, they were subjected to I/R insult while being administered with mPTP inhibitor, cyclosporin A (CsA). Infarct size and incidence of ischemic and reperfusion arrhythmias were determined. Our results showed that adaptation to CH as well as CsA administration reduced myocardial infarct size in comparison to the corresponding control groups. However, administration of CsA did not amplify the beneficial effect of CH, suggesting that inhibition of mPTP opening contributes to the protective character of CH.
Lipids Health Dis. 2024 Nov 18. 23(1): 381

Deficiency of lysophosphatidic acid receptor 3 decreases erythropoietin production in hypoxic mouse kidneys.

Nan Yin, Xuyuan Li, Di Zhang, Mengxia Qu, Shengqiang Pei, Xi Chen, Xiaotian Zhang, Junjie Zhang.

   BACKGROUND: Lysophosphatidic acid (LPA) is a lipid mediator with diverse biological functions through its receptors on the cell membrane. As one of the six LPA receptors, LPA receptor 3 (LPAR3) is highly expressed in mouse kidneys, but its physiological function in the kidney has been poorly explored.
METHODS: Wild-type (WT) and Lpar3-/- mice were used to investigate the renal physiological function of LPAR3 under hypoxia. The expression levels of LPA receptors in the kidneys of WT mice with or without exposure to hypoxia (8% O2) were detected by RT‒qPCR. RNA sequencing analysis was performed to identify differences in gene expression profiles between the hypoxic kidneys of WT and Lpar3-/- mice. The effects of LPAR3 deficiency and treatment with the LPAR1/3 inhibitor Ki16425 or the LPAR3 selective agonist 2S-OMPT on erythropoietin (EPO) production in the kidneys of hypoxic mice were determined by RT‒qPCR and ELISAs. The mechanism of LPAR3-mediated regulation of EPO expression was further studied in vivo with mouse models and in vitro with cultured human cells.
RESULTS: LPAR3 is the major LPA receptor in mouse kidneys, and its expression is significantly upregulated under hypoxic conditions. RNA sequencing analysis revealed that, compared with WT mice, Lpar3-/- mice presented a significant decrease in hypoxia-induced EPO expression in the kidney, together with reduced plasma EPO levels and lower hematocrit and hemoglobin levels. Hypoxic renal EPO expression in WT mice was diminished by the administration of the LPAR1/3 inhibitor Ki16425 and increased by 2S-OMPT, a selective agonist of LPAR3. Hypoxia-induced HIF-2α accumulation in mouse kidneys was impaired by LPAR3 deficiency. Further studies revealed that the PI3K/Akt pathway participated in the regulation of HIF-2α accumulation and EPO expression by LPAR3 under hypoxic conditions.
CONCLUSIONS: Our study revealed the role of LPAR3 in promoting the HIF-2α‒EPO axis in hypoxic mouse kidneys, suggesting that the LPA receptor may serve as a novel potential pharmaceutical target to regulate renal EPO production in hypoxia-related situations, such as chronic kidney disease and altitude disease.

Keywords:  Erythropoietin; HIF-2α; Hypoxia; Kidney; LPA receptor 3

DOI:  https://doi.org/10.1186/s12944-024-02367-8
Curr Treat Options Neurol. 2025 ;27(1): 6

A Hypoxia-Inflammation Cycle and Multiple Sclerosis: Mechanisms and Therapeutic Implications.

Ateyeh Soroush, Jeff F Dunn.

   Purpose of Review: Multiple sclerosis (MS) is a complex neurodegenerative disease characterized by inflammation, demyelination, and neurodegeneration. Significant hypoxia exists in brain of people with MS (pwMS), likely contributing to inflammatory, neurodegenerative, and vascular impairments. In this review, we explore the concept of a negative feedback loop between hypoxia and inflammation, discussing its potential role in disease progression based on evidence of hypoxia, and its implications for therapeutic targets.
Recent Findings: In the experimental autoimmune encephalomyelitis (EAE) model, hypoxia has been detected in gray matter (GM) using histological stains, susceptibility MRI and implanted oxygen sensitive probes. In pwMS, hypoxia has been quantified using near-infrared spectroscopy (NIRS) to measure cortical tissue oxygen saturation (StO2), as well as through blood-based biomarkers such as Glucose Transporter-1 (GLUT-1). We outline the potential for the hypoxia-inflammation cycle to drive tissue damage even in the absence of plaques. Inflammation can drive hypoxia through blood-brain barrier (BBB) disruption and edema, mitochondrial dysfunction, oxidative stress, vessel blockage and vascular abnormalities. The hypoxia can, in turn, drive more inflammation.
Summary: The hypoxia-inflammation cycle could exacerbate neuroinflammation and disease progression. We explore therapeutic approaches that target this cycle, providing information about potential treatments in MS. There are many therapeutic approaches that could block this cycle, including inhibiting hypoxia-inducible factor 1-α (HIF-1α), blocking cell adhesion or using vasodilators or oxygen, which could reduce either inflammation or hypoxia. This review highlights the potential significance of the hypoxia-inflammation pathway in MS and suggests strategies to break the cycle. Such treatments could improve quality of life or reduce rates of progression.

Keywords:  Hypoxia; Hypoxia-inducible factor; Inflammation; Multiple sclerosis; Treatment

DOI:  https://doi.org/10.1007/s11940-024-00816-4
Ecotoxicol Environ Saf. 2024 Nov 21. pii: S0147-6513(24)01465-9. [Epub ahead of print]288 117389

Investigating the effect of Quercetin in the presence of CoCl2 as an inducing hypoxia agent on the biological characteristics of human telomerase reverse transcription-immortalized adipose tissue-derived MSCs.

Maryam Aref, Sajjad Sisakhtnezhad, Hossein Fallahi.

  Studying the effect of small chemical molecules on stem cell characteristics under normoxia and hypoxia conditions is crucial to discovering the best conditions for effective biomedical applications. This study aimed to investigate the effect of Quercetin (QC; a flavonoid) in the presence of CoCl2 as a mimicking hypoxia chemical on the biological features of human telomerase reverse transcription-immortalized mesenchymal stem cell (hTERT-MSC) lines. The effect of CoCl2, QC, and their combination on the viability, proliferation, and migration of hTERT-MSCs were evaluated by MTT, Trypan-blue staining and cell counting by hemocytometer, and in vitro wound healing assays, respectively. Moreover, the effect of treatments on the reactive oxygen species (ROS) production, cell cycle, and HIF1a, c-MET, H19, and CASP3 gene expression was assessed by NBT, PI-staining and flow-cytometry, and real-time PCR assays, respectively. We found that CoCl2 and QC have different effects on the viability, proliferation, and migration of hTERT-MSCs in a dose-dependent manner. In addition, CoCl2 and QC affect ROS levels in cells in a dose- and time-dependent manner. While CoCl2 up-regulated HIF1a, QC and CoCl2 down-regulated CASP3 and c-MET in hTERT-MSCs. Moreover, QC reduced HIF1a and lncRNA-H19 expression in cells. Furthermore, in the presence of CoCl2, QC at low concentrations reduced hTERT-MSC survival, proliferation, and migration at 48 h; however, at high concentrations, it induced cell survival and proliferation. The combination treatment also up-regulated ROS levels and down-regulated the investigated genes in cells. Altogether, we conclude that QC at high concentrations under CoCl2-mediated hypoxia and short exposure time induces hTERT-MSCs survival and proliferation.

Keywords:  Cellular behaviors; CoCl(2); Gene expression; Hypoxia; Quercetin; hTERT-MSC

DOI:  https://doi.org/10.1016/j.ecoenv.2024.117389
Dalton Trans. 2024 Nov 22.

Alleviating hypoxia by integrating MnO2 with metal-organic frameworks coated upconversion nanocomposites for enhanced photodynamic therapy in vitro.

Junxun Zhou, Mengyue Jiang, Qiangqiang Zhang, Yuan Jiang, Haifang Wang, Lining Sun.

Photodynamic therapy (PDT) requires the participation of abundant oxygen while the hypoxic tumor microenvironment limits the efficacy of PDT. Here, upconversion luminescent nanocomposites coated with metal-organic frameworks (MOFs) were synthesized and modified with MnO2 (named UMMnP) to alleviate hypoxia of the tumor microenvironment. Under 980 nm light irradiation, the upconversion nanoparticles (UCNPs) achieve upconversion emission to excite porphyrin MOFs, which then transfer energy to oxygen to produce singlet oxygen for PDT. At the same time, the MnO2 in the UMMnP nanocomposites can catalyze the generation of O2 from H2O2, which could increase singlet oxygen production in a hypoxic environment, thus enhancing the PDT effect. The HeLa cell viability assay shows that the UMMnP nanocomposites possess good biocompatibility, while after irradiation with 980 nm light, the cell viability decreases dramatically, demonstrating efficient PDT. Furthermore, the nanocomposites can be successfully applied for upconversion luminescence imaging in vitro. Thus, this work provides a promising application of bioimaging and enhanced photodynamic therapy by alleviating hypoxia in tumor treatment.

DOI: https://doi.org/10.1039/d4dt02605e
Reprod Sci. 2024 Nov 18.

From Hypoxia to Oxidative Stress: Antioxidants' Role to Reduce Male Reproductive Damage.

Siyao Li, Wenjing Liu, Xin Chen, Zhaoyu Chen, Jingtian Shi, Juan Hua.

  Hypoxia is one of the main reasons causing male reproductive damage for people living in high altitude. Pathological evidences have been presented both in humans and animal models. Spermatogenesis disruption, worse sperm parameters, hormone disorder and erectile dysfunction are emblematic of male reproductive impairments brought by hypoxia. Among many mechanisms impairing male reproductive systems, oxidative stress is always a field of interest to explore. Although previous reviews have discussed about hypoxia or oxidative stress and antioxidants on male fertility respectively, no one has elucidated the concrete role of oxidative stress in hypoxia and correlating antioxidants that can ameliorate the negative effects. In this review, we firstly introduce hypoxia etiology and describe specific damage of hypoxia on male reproductive functions. Then, we emphasized interplays between hypoxia and oxidative stress as well as negative influences brought by oxidative stress. Finally, we listed antioxidants for oxidative stress and hypoxia-induced reproductive damage and discussed their controversial experimental effects for male infertility.

Keywords:  Antioxidants; Hypoxia; Male reproductive damage; Male reproductive health; Oxidative stress

DOI:  https://doi.org/10.1007/s43032-024-01746-x
Cell Biochem Biophys. 2024 Nov 16.

Impairing Ferroptosis Through the PI3K/Akt/Nrf2 Pathway: The Way for Nerve Growth Factor to Mitigate Hypoxia-induced Cardiomyocyte Damage.

Ling Wang, Wenming Yang, Yuan Song.

  Myocardial infarction (MI) is an acute cardiovascular diseases, distinguished primarily by cardiomyocyte damage due to ischemia and hypoxia. Nerve growth factor (NGF) is paramount in ischemic heart disease, it contributes to maintaining heart function and protecting the heart. Nonetheless, the effects of NGF on cardiomyocyte damage induced by hypoxia and the precise mechanisms involved are still to be elucidated. Utilizing western blot and immunofluorescence methods to quantify the NGF levels in cardiomyocytes (H9C2) of rats after hypoxia. Cell Counting Kit-8 (CCK-8) assay was employed to monitor the dynamic changes in cells vitality. The lactate dehydrogenase (LDH), Fe2+, malondialdehyde (MDA), superoxide dismutase (SOD) and reactive oxygen species (ROS) levels were evaluated by different kits. Moreover, the PI3K/Akt/Nrf2 pathway and ferroptosis-linked protein levels were analyzed using western blotting. In H9C2 cells, exposure to hypoxia for 24 h led to weakened NGF level, as well as lowered cell vitality and SOD activity, but elevated levels of LDH, Fe2+, MDA, and ROS, triggering ferroptosis. Overexpression NGF alleviated the ferroptosis in H9C2 cells caused by hypoxia, while NGF knockdown intensified this process. Additionally, overexpression NGF reinforced heme oxygenase-1 (HO-1) and Nrf2 levels, and Akt and PI3K phosphorylation, whereas NGF silencing produced contrary outcomes. Furthermore, the PI3K/Akt pathway inhibitor negated the elevation in HO-1 and Nrf2 levels mediated by NGF amplification. In contrast, the pathway activator reversed the lowering in Nrf2 and HO-1 levels caused by silencing NGF. This suggested that NGF mediates the activation of Nrf2 through the PI3K/Akt axis. Overall, by mediating the activation of Nrf2 through the PI3K/Akt axis, NGF reduced the damage to H9C2 cells caused by hypoxia and thus hindered ferroptosis.

Keywords:  Cardiomyocyte damage; Ferroptosis; NGF; Nrf2; PI3K/Akt pathway

DOI:  https://doi.org/10.1007/s12013-024-01613-1
Chembiochem. 2024 Nov 19. e202400767

Auto-Deactivation of BODIPY-Derived Type I Photosensitizer Post Photodynamic Therapy under Hypoxia.

Xia Wang, Zhaobin Wang, He Hang, Fude Feng.

  The long-lasting activity of photosensitizers during photodynamic therapy (PDT) causes excessive damage and arouses great concerns about biosafety. Herein, we synthesized a pyridinium-decorated diiodo-BODIPY compound (PyBDP) and investigated its photosensitizing activity under hypoxic condition in the presence of NADH that is abundant in the mitochondria of hypoxic tumors. The unique property of PyBDP lies in the redox environment-dependent photo-response. At green light exposure, PyBDP is converted into a colorless inactive form by interacting with NADH in a two-step one-electron transfer process. Interestingly, the NADH-dependent hydrogenation of PyBDP is affected by the presence of cytochrome c (Cyt cox) that is an important component of mitochondrial electron transport chain (Mito-ETC), unless Cyt cox is exhausted. Active radical species is produced during the photocatalytic reaction, which adds the understanding of PyBDP-induced photodamage. Therefore, we applied the strategy of auto-deactivation PDT using a BODIPY photosensitizer by tethering triphenylphosphonium to PyBDP. After PDT effect in a type I pathway, the photosensitizer underwent almost entire auto-deactivation in hypoxic HeLa cells. This work paves a way for the development of reductive PDT with enhanced safety and efficacy in fighting hypoxic tumors independent on reactive oxygen species (ROS).

Keywords:  BODIPY; NADH; auto-deactivation; hypoxia-tolerant photodynamic therapy; in-cell photoredox catalysis

DOI:  https://doi.org/10.1002/cbic.202400767
PLoS One. 2024 ;19(11): e0310535

Exploring the effects of hypoxia and reoxygenation time on hepatocyte apoptosis and inflammation.

Xinlu Xu, Tanfang Zhou, Alimu Tulahong, Rexiati Ruze, Yingmei Shao.

Hepatic Ischemia-Reperfusion Injury (HIRI) is an unavoidable pathological process during liver surgeries such as liver transplantation and hepatic resection, which involves a complex set of molecular and cellular mechanisms. The mechanisms of HIRI may involve a variety of biological processes in which inflammation and apoptosis play a central role. Therefore, it is crucial to deeply investigate the effects of different hypoxia and reoxygenation times on the construction of an in vitro model of hepatic ischemia-reperfusion injury. The human normal liver cell line HL-7702 IRI model was constructed by hypoxia chamber, and the inflammation and apoptosis focal levels of cells were detected by enzyme-linked immunosorbent assay, western blot and quantitative reverse transcription polymerase chain reaction. When 12-hour reoxygenation time was fixed, the inflammation and apoptosis indexes of HIRI model increased with the prolongation of hypoxia time (6, 12 and 24 hours). These indices reached highest level in the model group of 24-hour fixed hypoxia and 12-hour reoxygenation. Inflammation and apoptosis indices were significantly higher in the model group of 24-hours fixed hypoxia and 12-hours reoxygenation than in the group of 6 and 24 hours of reoxygenation. Taken together, the findings from this research demonstrated that during hypoxia phase, cells exhibited a clear time-dependent response of inflammation and cell death; on the contrary, during the reoxygenation phase, the cellular damage was not monotonically incremental, but showed an inverted U-shaped dynamic pattern. The present study reveals in depth the dynamic changes of cellular responses under hypoxia and reoxygenation conditions, providing us with an important theoretical basis to guide the selection and optimization of in vitro experimental models.

DOI: https://doi.org/10.1371/journal.pone.0310535
Free Radic Biol Med. 2024 Nov 20. pii: S0891-5849(24)01070-0. [Epub ahead of print]

Oxygen control in cell culture - your cells may not be experiencing what you think!

Zachary J Rogers, Darragh Flood, Cormac T Taylor.

  Oxygen (O2)-controlled cell culture has been pivotal in studying mammalian mechanisms of O2 sensing, regulation, and utilization. We posit, however, that O2-controlled cell culture is paradoxically not controlling O2. There is overwhelming evidence that the pericellular O2 is lower than the surrounding gas phase due to cellular O2 consumption. Standard hypoxic cell culture is at high risk of inducing pericellular anoxia. We discuss the implications of poor O2 control for cellular O2 regulation mechanisms, bioenergetics, and redox signaling. We also highlight the evidence of frequent under-oxygenation in standard (i.e., normoxic) cell culture. This issue has been largely overlooked because strategies to control pericellular O2 have been lacking. Here, we propose a framework to control pericellular O2 based on our recent investigation into the nature of the gas/pericellular O2 gradient. Implementing this framework into standard practice will unlock quantitative O2 control in vitro, improving our ability to understand the role of O2 in biology.

Keywords:  cell culture; hypoxia; hypoxia-inducible factors; oxygen; pericellular; physioxia

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.036