bims-oxygme 2024-11-17 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2024–11–17
thirteen papers selected by
Onurkan Karabulut, Berkeley City College

Hypoxia and TNF-alpha modulate extracellular vesicle release from human induced pluripotent stem cell-derived cardiomyocytes.
Hypoxia-Induced Mitochondrial ROS and Function in Pulmonary Arterial Endothelial Cells.
Creating Physiological Cell Environments In Vitro: Adjusting Cell Culture Media Composition and Oxygen Levels to Investigate Mitochondrial Function and Cancer Metabolism.
A mechanistic integration of hypoxia signaling with energy, redox and hormonal cues.
[Mitochondrial adaptations in acute respiratory distress syndrome].
Is there a rationale for hyperbaric oxygen therapy in the patients with Post COVID syndrome? : A critical review.
Singlet oxygen storage and controlled release for improving photodynamic therapy against hypoxic tumor.
Deciphering the inhibitory effects of trimetazidine on pulmonary hypertension development via decreasing fatty acid oxidation and promoting glucose oxidation.
Hypoxia-Induced Differences in the Expression of Pyruvate Dehydrogenase Kinase 1-Related Factors in the Renal Tissues and Renal Interstitial Fibroblast-like Cells of Yak (Bos Grunniens).
Ischemic Rescue Potential of Conditioned Medium Derived from Skeletal Muscle Cells-Seeded Electrospun Fiber-Coated Human Amniotic Membrane Scaffolds.
Iron-based MOF with Catalase-like activity improves the synergistic therapeutic effect of PDT/ferroptosis/starvation therapy by reversing the tumor hypoxic microenvironment.
[Activation of ALDH2 alleviates hypoxic pulmonary hypertension in mice by upregulating the SIRT1/PGC-1α signaling pathway].
The mouse gingiva and HIF-1α, a key gene of hypoxic environment, as tools for post-mortem time estimation.

J Extracell Vesicles. 2024 Nov;13(11): e70000

Hypoxia and TNF-alpha modulate extracellular vesicle release from human induced pluripotent stem cell-derived cardiomyocytes.

Margarida Viola, Maarten P Bebelman, Renee G C Maas, Willemijn S de Voogt, Frederik J Verweij, Cor S Seinen, Saskia C A de Jager, Pieter Vader, Dirk Michiel Pegtel, Joost Petrus Gerardus Sluijter.

  Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in the heart under homeostatic and pathological conditions, such as myocardial infarction (MI). However, the basic mechanisms driving cardiomyocyte-derived EV (CM-EV) production following stress are poorly understood. In this study, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that express NanoLuc-tetraspanin reporters. These modified hiPSC-CMs allow for quantification of tetraspanin-positive CM-EV secretion from small numbers of cells without the need for time-consuming EV isolation techniques. We subjected these cells to a panel of small molecules to study their effect on CM-EV biogenesis and secretion under basal and stress-associated conditions. We observed that EV biogenesis is context-dependent in hiPSC-CMs. Nutrient starvation decreases CM-EV secretion while hypoxia increases the production of CM-EVs in a nSmase2-dependent manner. Moreover, the inflammatory cytokine TNF-α increased CM-EV secretion through a process involving NLRP3 inflammasome activation and mTOR signalling. Here, we detailed for the first time the regulatory mechanisms of EV biogenesis in hiPSC-CMs upon MI-associated stressors.

Keywords:  EV biogenesis; NanoLuc; cardiomyocytes; extracellular vesicles; myocardial infarction

DOI:  https://doi.org/10.1002/jev2.70000
Cells. 2024 Nov 01. pii: 1807. [Epub ahead of print]13(21):

Hypoxia-Induced Mitochondrial ROS and Function in Pulmonary Arterial Endothelial Cells.

Harrison Wang, Teng-Yao Song, Jorge Reyes-García, Yong-Xiao Wang.

  Pulmonary artery endothelial cells (PAECs) are a major contributor to hypoxic pulmonary hypertension (PH) due to the possible roles of reactive oxygen species (ROS). However, the molecular mechanisms and functional roles of ROS in PAECs are not well established. In this study, we first used Amplex UltraRed reagent to assess hydrogen peroxide (H2O2) generation. The result indicated that hypoxic exposure resulted in a significant increase in Amplex UltraRed-derived fluorescence (i.e., H2O2 production) in human PAECs. To complement this result, we employed lucigenin as a probe to detect superoxide (O2-) production. Our assays showed that hypoxia largely increased O2- production. Hypoxia also enhanced H2O2 production in the mitochondria from PAECs. Using the genetically encoded H2O2 sensor HyPer, we further revealed the hypoxic ROS production in PAECs, which was fully blocked by the mitochondrial inhibitor rotenone or myxothiazol. Interestingly, hypoxia caused an increase in the migration of PAECs, determined by scratch wound assay. In contrast, nicotine, a major cigarette or e-cigarette component, had no effect. Moreover, hypoxia and nicotine co-exposure further increased migration. Transfection of lentiviral shRNAs specific for the mitochondrial Rieske iron-sulfur protein (RISP), which knocked down its expression and associated ROS generation, inhibited the hypoxic migration of PAECs. Hypoxia largely increased the proliferation of PAECs, determined using Ki67 staining and direct cell number accounting. Similarly, nicotine caused a large increase in proliferation. Moreover, hypoxia/nicotine co-exposure elicited a further increase in cell proliferation. RISP knockdown inhibited the proliferation of PAECs following hypoxia, nicotine exposure, and hypoxia/nicotine co-exposure. Taken together, our data demonstrate that hypoxia increases RISP-mediated mitochondrial ROS production, migration, and proliferation in human PAECs; nicotine has no effect on migration, increases proliferation, and promotes hypoxic proliferation; the effects of nicotine are largely mediated by RISP-dependent mitochondrial ROS signaling. Conceivably, PAECs may contribute to PH via the RISP-mediated mitochondrial ROS.

Keywords:  hypoxia; nicotine; pulmonary artery endothelial cells; pulmonary hypertension

DOI:  https://doi.org/10.3390/cells13211807
Methods Mol Biol. 2025 ;2878 163-199

Creating Physiological Cell Environments In Vitro: Adjusting Cell Culture Media Composition and Oxygen Levels to Investigate Mitochondrial Function and Cancer Metabolism.

Sónia A Pinho, Georgina L Gardner, Ricardo Alva, Jeff A Stuart, Teresa Cunha-Oliveira.

  In vitro and ex vivo studies are crucial for mitochondrial research, offering valuable insights into cellular mechanisms and aiding in diagnostic and therapeutic strategies. Accurate in vitro models rely on adequate cell culture conditions, such as the composition of culture media and oxygenation levels. These conditions can influence energy metabolism and mitochondrial activities, thus impacting studies involving mitochondrial components, such as the effectiveness of anticancer drugs. This chapter focuses on practical guidance for creating setups that replicate in vivo microenvironments, capturing the original metabolic context of cells. We explore protocols to better mimic the physiological cell environment, promote cellular reconfiguration, and prime cells according to the modeled context. The first part is dedicated to the use of human dermal fibroblasts, which are a promising model for pre-clinical mitochondrial research due to their adaptability and relevance to human mitochondrial physiology. We present an optimized protocol for gradually adjusting extracellular glucose levels, which demonstrated significant mitochondrial, metabolic, and redox remodeling in normal adult dermal fibroblasts. The second part is dedicated to replication of tumor microenvironments, which are relevant for studies targeting cellular energy metabolism to inhibit tumor growth. Currently available physiological media can mimic blood plasma metabolome but not the specific tumor microenvironment. To address this, we describe optimized media formulation and oxygenation protocols, which can simulate the tumor microenvironment in cell culture experiments. Replicating in vivo microenvironments in in vitro and ex vivo studies can enhance our understanding of cellular processes, facilitate drug development, and advance personalized therapeutics in mitochondrial medicine.

Keywords:  Cell culture media; Energy metabolism; Fibroblasts; Glucose; Hypoxia; Mitochondrial function; Mitochondrial medicine; Nutrient composition; Oxidative phosphorylation; Pericellular oxygen levels; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_9
Plant Physiol. 2024 Nov 12. pii: kiae596. [Epub ahead of print]

A mechanistic integration of hypoxia signaling with energy, redox and hormonal cues.

Tilo Renziehausen, Rim Chaudhury, Sjon Hartman, Angelika Mustroph, Romy R Schmidt-Schippers.

Oxygen deficiency (hypoxia) occurs naturally in many developing plant tissues but can become a major threat during acute flooding stress. Consequently, plants as aerobic organisms must rapidly acclimate to hypoxia and the associated energy crisis to ensure cellular and ultimately organismal survival. In plants, oxygen sensing is tightly linked with oxygen-controlled protein stability of group VII ETHYLENE-RESPONSE FACTORs (ERFVII) which, when stabilized under hypoxia, act as key transcriptional regulators of hypoxia-responsive genes (HRGs). Multiple signaling pathways feed into hypoxia signaling to fine-tune cellular decision making under stress. First, ATP shortage upon hypoxia directly affects the energy status and adjusts anaerobic metabolism. Secondly, altered redox homeostasis leads to reactive oxygen and nitrogen species (ROS and RNS) accumulation, evoking signaling and oxidative stress acclimation. Finally, the phytohormone ethylene promotes hypoxia signaling to improve acute stress acclimation, while hypoxia signaling in turn can alter ethylene, auxin, abscisic acid, salicylic acid and jasmonate signaling to guide development and stress responses. In this Update, we summarize the current knowledge on how energy, redox and hormone signaling pathways are induced under hypoxia and subsequently integrated at the molecular level to ensure stress-tailored cellular responses. We show that some HRGs are responsive to changes in redox, energy and ethylene independently of the oxygen status, and propose an updated HRG list that is more representative for hypoxia marker gene expression. We discuss the synergistic effects of hypoxia, energy, redox and hormone signaling and their phenotypic consequences in the context of both environmental and developmental hypoxia.

DOI: https://doi.org/10.1093/plphys/kiae596
Rev Med Inst Mex Seguro Soc. 2024 May 06. pii: E5450. [Epub ahead of print]62(3): 1-7

[Mitochondrial adaptations in acute respiratory distress syndrome].

Valeria Sanclemente-Cardoza, José Luis Estela-Zape.

  Mitochondria play an important role in cell energy metabolism due to the main function of producing biologically available energy in the form of adenosine triphosphate (ATP), through biochemical processes such as oxidative phosphorylation, beta oxidation of fatty acids and the Krebs cycle. Acute respiratory distress syndrome is a severe lung disease characterized by the appearance of diffuse alveolar infiltrates, dysregulated immune response and alveolocapillary injury that limits gas exchange. Alveolar cells maintain an oxygen tension of 5% and mitochondria consume oxygen through the cytochrome c oxidase enzyme in the electron transport chain, allowing ATP production. The reduction in oxygen consumption is crucial in mitochondrial damage, as mitochondria are sensitive to hypoxemia, affecting the transfer of molecules in the electron transport chain that disrupt the Krebs cycle. Hypoxia due to hypoxemia affects mitochondrial fusion and fission, while OXPHOS remodels, mainly in complex I, to maintain mitochondrial integrity. Lack of oxygen activates hypoxia-inducible factors, generating oxidative stress, acidosis and cell damage; therefore, this review aims to describe mitochondrial adaptations in acute respiratory distress syndrome.

Keywords:  Adenosine Triphosphate; Adult Respiratory Distress Syndrome; Cell Respiration; Immunity; Mitochondria

DOI:  https://doi.org/10.5281/zenodo.10998887
Eur Arch Psychiatry Clin Neurosci. 2024 Nov 15.

Is there a rationale for hyperbaric oxygen therapy in the patients with Post COVID syndrome? : A critical review.

M T Pawlik, G Rinneberg, A Koch, H Meyringer, T H Loew, A Kjellberg.

  The SARS-CoV-2 pandemic has resulted in 762 million infections worldwide from 2020 to date, of which approximately ten percent are suffering from the effects after infection in 2019 (COVID-19) [1, 40]. In Germany, it is now assumed that at least one million people suffer from post-COVID condition with long-term consequences. These have been previously reported in diseases like Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS). Symptoms show a changing variability and recent surveys in the COVID context indicate that 10-30 % of outpatients, 50 to 70% of hospitalised patients suffer from sequelae. Recent data suggest that only 13% of all ill people were completely free of symptoms after recovery [3, 9]. Current hypotheses consider chronic inflammation, mitochondrial dysfunction, latent viral persistence, autoimmunity, changes of the human microbiome or multilocular sequelae in various organ system after infection. Hyperbaric oxygen therapy (HBOT) is applied since 1957 for heart surgery, scuba dive accidents, CO intoxication, air embolisms and infections with anaerobic pathogens. Under hyperbaric pressure, oxygen is physically dissolved in the blood in higher concentrations and reaches levels four times higher than under normobaric oxygen application. Moreover, the alternation of hyperoxia and normoxia induces a variety of processes at the cellular level, which improves oxygen supply in areas of locoregional hypoxia. Numerous target gene effects on new vessel formation, anti-inflammatory and anti-oedematous effects have been demonstrated [74]. The provision of intermittently high, local oxygen concentrations increases repair and regeneration processes and normalises the predominance of hyperinflammation. At present time only one prospective, randomized and placebo-controlled study exists with positive effects on global cognitive function, attention and executive function, psychiatric symptoms and pain interference. In conclusion, up to this date HBO is the only scientifically proven treatment in a prospective randomized controlled trial to be effective for cognitive improvement, regeneration of brain network and improvement of cardiac function. HBOT may have not only theoretical but also potential impact on targets of current pathophysiology of Post COVID condition, which warrants further scientific studies in patients.

Keywords:  Brain fog; COVID-19; Chronic fatigue syndrome; Hyperbaric oxygen therapy (HBOT); Hypoxia-inducible-factor-1; Long COVID; Post COVID condition; SARS-CoV-2

DOI:  https://doi.org/10.1007/s00406-024-01911-y
Chem Commun (Camb). 2024 Nov 13.

Singlet oxygen storage and controlled release for improving photodynamic therapy against hypoxic tumor.

Long Yao, Shaoqi Xie, Yuqing Liu, Liu Mengqi, Jiachen Xia, Bing Lu.

Photodynamic therapy (PDT) is considered to be a promising tumor treatment method due to its non-invasiveness and low risk. However, there are two factors that affect the efficacy of this therapy. One is the light source and the other is the tumor hypoxia. An emerging PDT strategy has been developed to break these limits. This strategy is to adopt compounds, such as 2-pyridone, anthracene, and naphthalene derivatives, that have the ability to store and controlledly release the singlet oxygen (1O2) to achieve PDT in the dark. In this review, we focus on the construction strategies for integrated antitumor drugs containing these 1O2 storage/release units and photosensitizers and summarize their PDT performance in hypoxic tumors or in the dark. The methods to integrate these compounds with photosensitizers or nanocarriers are also discussed in detail to provide insightful design guidelines for the design of highly efficient antitumor systems based on 1O2 storage and controlled release.

DOI: https://doi.org/10.1039/d4cc04619f
Sci Rep. 2024 11 07. 14(1): 27069

Deciphering the inhibitory effects of trimetazidine on pulmonary hypertension development via decreasing fatty acid oxidation and promoting glucose oxidation.

Asako Yanagisawa, Jun-Dal Kim, Akira Naito, Takayuki Kobayashi, Tomoko Misawa, Seiichiro Sakao, Takayuki Jujo-Sanada, Takeshi Kawasaki, Shin-Ichi Muroi, So-Ichiro Sasaki, Takuji Suzuki, Yoshihiro Hayakawa, Yoshimi Nakagawa, Yoshitoshi Kasuya, Koichiro Tatsumi.

  Pulmonary hypertension (PH) is a devastating disease characterized by vascular remodeling, resulting in right ventricular failure and death. Dysregulation of energy metabolism is linked to PH pathogenesis. Trimetazidine (TMZ), a selective long-chain 3-ketoacyl coenzyme A thiolase inhibitor, is critical in maintaining energy metabolism. Despite the indicated TMZ's inhibitory effect on pulmonary vascular remodeling in PH development, the integrated evaluation of the changes in biomolecules, such as metabolites and transcripts, that TMZ induces in the lung and heart tissues is largely unknown in vivo. For an improved understanding of the molecular mechanism involving the effects of TMZ on PH development, we performed a comprehensive analysis of the changes in cardiac metabolites and pulmonary transcripts of SU5416-Hypoxia (Su/Hx) rats treated with TMZ. Metabolomic analysis of the Su/Hx-induced PH hearts demonstrated that TMZ reduced the long-chain fatty acid concentration. Additionally, TMZ alleviated PH degree and excessive strain on the right heart functions in rats with Su/Hx-induced PH. We identified the candidate target genes for TMZ treatment during PH development. Interestingly, the mRNA levels of the fatty acid transporters were substantially downregulated by TMZ administration in the lungs with Su/Hx-induced PH. Notably, TMZ suppressed excessive proliferation of human pulmonary artery smooth muscle cells under hypoxic conditions. Our study suggests that TMZ ameliorates PH development by involving energy metabolism in the lungs and heart.

Keywords:  Cardiac metabolome; Pulmonary hypertension; Pulmonary transcriptome; SU5416-hypoxia; Trimetazidine

DOI:  https://doi.org/10.1038/s41598-024-76100-x
Animals (Basel). 2024 Oct 29. pii: 3110. [Epub ahead of print]14(21):

Hypoxia-Induced Differences in the Expression of Pyruvate Dehydrogenase Kinase 1-Related Factors in the Renal Tissues and Renal Interstitial Fibroblast-like Cells of Yak (Bos Grunniens).

Manlin Zhou, Jun Wang, Ruirui Cao, Fan Zhang, Xuehui Luo, Yiyuan Liao, Weiji Chen, Haie Ding, Xiao Tan, Zilin Qiao, Kun Yang.

  Hypoxia is one of the factors severely affect renal function, and, in severe cases, it can lead to renal fibrosis. Although much progress has been made in identifying the molecular mediators of fibrosis, the mechanisms that govern renal fibrosis remain unclear, and there have been no effective therapeutic anti-fibrotic strategies to date. Mammals exposed to low oxygen in the plateau environment for a long time are prone to high-altitude disease, while yaks have been living in the plateau for generations do not develop kidney fibrosis caused by low oxygen. It has been suggested that metabolic reprogramming occurs in renal fibrosis and that pyruvate dehydrogenase kinase 1 (PDK1) plays a crucial role in metabolic reprogramming as an important node between glycolysis and the tricarboxylic acid cycle. The aim of this study was to investigate the effects of hypoxia on the renal tissues and renal interstitial fibroblasts of yaks. We found that, at the tissue level, HIF-1α, PDK1, TGF-β1, Smad2, Smad3, and α-SMA were mainly distributed and expressed in tubular epithelial cells but were barely present in the renal mesenchymal fibroblasts of healthy cattle and yak kidneys. Anoptical density analysis showed that in healthy cattle kidneys, TGF-β1, Smad2, and Smad3 expression was significantly higher than in yak kidneys (p < 0.05), and HIF-1α and PDK1 expression was significantly lower than in yak kidneys (p < 0.05). The results at the protein and gene levels showed the same trend. At the cellular level, prolonged hypoxia significantly elevated PDK1 expression in the renal mesangial fibroblasts of cattle and yak kidneys compared with normoxia (p < 0.05) and was proportional to the degree of cellular fibrosis. However, PDK1 expression remained stable in yaks compared with renal interstitial fibroblast-like cells in cattle during the same hypoxic time period. At the same time, prolonged hypoxia also promoted changes in cellular phenotype, promoting the proliferation, activation, glucose consumption, lactate production, and anti-apoptosis in the both of cattle and yaks renal interstitial fibroblasts The differences in kidney structure and expression of PDK1 and HIF-1α in kidney tissue and renal interstitial fibroblasts induced by different oxygen concentrations suggest that there may be a regulatory relationship between yak kidney adaptation and hypoxic environment at high altitude. This provides strong support for the elucidation of the regulatory relationship between PDK1 and HIF-1α, as well as a new direction for the treatment or delay of hypoxic renal fibrosis; additionally, these findings provide a basis for further analysis of the molecular mechanism of hypoxia adaptation-related factors and the adaptation of yaks to plateau hypoxia.

Keywords:  PDK1; TGF-β1/Smad signaling pathway; kidney; renal fibrosis; yak

DOI:  https://doi.org/10.3390/ani14213110
Int J Mol Sci. 2024 Oct 30. pii: 11697. [Epub ahead of print]25(21):

Ischemic Rescue Potential of Conditioned Medium Derived from Skeletal Muscle Cells-Seeded Electrospun Fiber-Coated Human Amniotic Membrane Scaffolds.

Hanis Nazihah Hasmad, Abid Nordin, Shiplu Roy Chowdhury, Nadiah Sulaiman, Yogeswaran Lokanathan.

  Revascularization procedures such as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are crucial to restore blood flow to the heart and are used in the treatment of myocardial infarction (MI). However, these techniques are known to cause myocardial reperfusion injury in the ischemic heart. The present study aims to mimic ischemia-reperfusion injury in vitro on primary human cardiomyocytes (HCMs) and use the established injury model to study the rescue mechanism of skeletal muscle cell (SkM)-seeded electrospun fiber-coated human amniotic membrane scaffold (EF-HAM) on injured cardiomyocytes through paracrine secretion. An in vitro ischemia-reperfusion injury model was established by exposing the HCM to 5 h of hypoxia, followed by a 6 h reoxygenation period. Six different conditioned media (CM) including three derived from SkM-seeded EF-HAMs were introduced to the injured cells to investigate the cardioprotective effect of the CM. Cell survival analysis, caspase-3 and XIAP expression profiling, mitochondrial membrane potential analysis, and measurement of reactive oxygen species (ROS) were conducted to evaluate the outcomes of the study. The results revealed a significant increase in the viability of HCM exposed to H/R injury by 77.2% (p < 0.01), 111.8% (p < 0.001), 68.7% (p < 0.05), and 69.5% (p < 0.05) when supplemented with HAM CM, EF-HAM 3 min CM, EF-HAM 5 min CM, and EF-HAM 7 min CM, respectively. Furthermore, CM derived from SkM-seeded EF-HAM scaffolds positively impacted hypoxia-/reoxygenation-induced changes in caspase-3 expression, mitochondrial membrane potential, and reactive oxygen species generation, but not in XIAP expression. These findings suggest that EF-HAM composite scaffolds can exert antiapoptotic and cardioregenerative effects on primary human cardiomyocytes through the paracrine mechanism.

Keywords:  amnion; electrospun fiber; ischemia; paracrine signaling; skeletal muscle cells

DOI:  https://doi.org/10.3390/ijms252111697
J Nanobiotechnology. 2024 Nov 14. 22(1): 705

Iron-based MOF with Catalase-like activity improves the synergistic therapeutic effect of PDT/ferroptosis/starvation therapy by reversing the tumor hypoxic microenvironment.

Yukun Chen, Yuanyuan Chen, Zhenzhi Wang, Lian Yang, Yu Zhang, Zhanxia Zhang, Lijun Jia.

  Reversing the hypoxic microenvironment of tumors is an important method to enhance the synergistic effect of tumor treatment. In this work, we developed the nanoparticles called Ce6@HGMOF, which consists of a photosensitizer (Ce6), glucose oxidase (GOX), chemotherapy drugs (HCPT) and an iron-based metal-organic framework (MOF). Ce6@HGMOF can consume glucose in tumor cells through "starvation therapy", cut off their nutrition source, and produce gluconic acid and hydrogen peroxide (H2O2). Utilizing this feature, Ce6@HGMOF can produce oxygen through catalase-like catalytic activity, thereby reversing the hypoxic microenvironment of tumors. This strategy of changing the hypoxic environment can help to slow down the growth of tumor blood vessels and improve the drug-resistant microenvironment to some extent. Meanwhile, increasing the supply of oxygen can enhance the effect of photodynamic therapy (PDT) and enhance the oxidative stress damage caused by reactive oxygen species (ROS) in tumor cells. On the other hand, cancer cells usually produce higher levels of glutathione (GSH) to adapt to high oxidative stress and protect themselves. The Ce6@HGMOF we designed can also consume GSH and induce ferroptosis of tumor cells through Fenton reaction with H2O2, while enhancing the effect of PDT. This innovative synergistic strategy, the combination of PDT/ferroptosis /starvation therapy, can complement each other and enhance each other. It has great potential as a powerful new anti-tumor paradigm in the future.

Keywords:  Antitumor; Nano-drug delivery systems; Synergistic treatment; Tumor hypoxia

DOI:  https://doi.org/10.1186/s12951-024-02921-7
Nan Fang Yi Ke Da Xue Xue Bao. 2024 Oct 20. 44(10): 1955-1964

[Activation of ALDH2 alleviates hypoxic pulmonary hypertension in mice by upregulating the SIRT1/PGC-1α signaling pathway].

L Wang, F Bian, F Ma, S Fang, Z Ling, M Liu, H Sun, C Fu, S Ni, X Zhao, X Feng, Z Sun, G Lu, P Kang, S Wu.

   OBJECTIVE: To investigate whether activation of mitochondrial acetal dehydrogenase 2 (ALDH2) alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.
METHODS: Thirty 8-week-old C57 BL/6 mice were randomized into control, hypoxia, and hypoxia +Alda-1 (an ALDH2 activator) group (n=10), and the mice in the latter two groups, along with 10 ALDH2 knockout (ALDH2-/-) mice, were exposed to hypoxia (10% O2, 90% N2) with or without daily intraperitoneal injection of Alda-1 for 4 weeks. The changes in right ventricular function and pressure (RVSP) of the mice were evaluated by echocardiography and right ventricular catheter test, and pulmonary artery pressure was estimated based on RVSP. Pulmonary vascular remodeling, right ventricular injury, myocardial α -SMA expression, distal pulmonary arteriole muscle normalization, right ventricular cross-sectional area, myocardial cell hypertrophy, and right cardiac hypertrophy index were assessed with HE staining, immunofluorescence staining and WGA staining, and the expressions of ALDH2, SIRT1, PGC-1α, P16INK4A and P21CIP1 were detected. In pulmonary artery smooth muscle cells with hypoxic exposure, the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.
RESULTS: The wild-type mice with hypoxic exposure showed significantly increased RVSP, right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1, which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/- mice. In cultured pulmonary artery smooth muscle cells, hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1, which were all lowered by treatment with Alda-1, but its effect was obviously attenuated by EX527 treatment.
CONCLUSION: ALDH2 alleviates hypoxiainduced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.

Keywords:  ALDH2; PGC-1α; SIRT1; pulmonary hypertension; smooth muscle cell senescence

DOI:  https://doi.org/10.12122/j.issn.1673-4254.2024.10.14
PLoS One. 2024 ;19(11): e0311050

The mouse gingiva and HIF-1α, a key gene of hypoxic environment, as tools for post-mortem time estimation.

Salomé Mascarell, Coralie Torrens, Caroline Andrique, Asmaa Foda, Tania Delabarde, Bertrand Ludes, Anne-Margaux Collignon, Anne Poliard.

The post-mortem interval (PMI) is the time elapsed between the death of an individual and its forensic examination. It is a crucial information for judicial authorities, but current techniques still cannot establish a precise time interval. Novel approaches are therefore required. Recently, gingival tissue has emerged as interesting for forensic analysis thanks to the protection offered by lips to this tissue, limiting the influence of environmental factors. It is also easily accessible, and its sampling is minimally invasive even in the presence of rigor mortis. Moreover, the expression of HIF-1α, a master mediator of the hypoxic environment, has been described in gingival samples at different post-mortem (PM) times. We have hypothesized that the time-dependent post-mortem expression of HIF-1α could serve as a biomarker to more accurately predict the PMI. Our analyses were performed in an animal model, the mouse, where environment can be precisely controlled. Therewith, gingival tissue morphology was evaluated through histochemical staining and HIF-1α expression was analyzed by qPCR, western blots and immunofluorescence at different post-mortem times (0h to 100h). Our results showed (a) a global post-mortem stability of gingival tissue (b) a rapid increase in HIF-1α mRNA expression in the short post-mortem times followed by a slow decrease in transcript expression until 100h PM (c) an expression of the HIF- 1α protein and its degradation products, that follows the mRNA pattern (d) the presence of HIF-1α protein in the epithelial and connective layers of the tissue, with signal accumulation in both gingival strata until at least 32h post-mortem. This pilot study thus validated the mouse and the gingival tissue as models for post-mortem analyses, as well as for studying the fate of proteins such as HIF-1α. Transferring these approaches to human subjects may provide a more accurate estimate of PMI.

DOI: https://doi.org/10.1371/journal.pone.0311050