Hypoxia is relevant to several physiological and pathological processes and this also applies for the tooth. The adaptive response to lowering oxygen concentration is mediated by hypoxia-inducible factors (HIFs). Since HIFs were shown to participate in the promotion of angiogenesis, stem cell survival, odontoblast differentiation and dentin formation, they may play a beneficial role in the tooth reparative processes. Although some data were generated in vitro, little is known about the in vivo context of HIFs in tooth development. In order to contribute to this field, the mouse mandibular first molar was used as a model.The expression and in situ localisation of HIFs were examined at postnatal (P) days P0, P7, P14, using RT-PCR and immunostaining. The expression pattern of a broad spectrum of hypoxia-related genes was monitored by customised PCR Arrays. Metabolic aspects were evaluated by determination of the lactate level and mRNA expression of the mitochondrial marker Nd1.The results show constant high mRNA expression of Hif1a, increasing expression of Hif2a, and very low expression of Hif3a during early postnatal molar development. In the examined period the localisation of HIFs in the nuclei of odontoblasts and the subodontoblastic layer identified their presence during odontoblastic differentiation. Additionally, the lower lactate level and higher expression of mitochondrial Nd1 in advanced development points to decreasing glycolysis during differentiation. Postnatal nuclear localisation of HIFs indicates a hypoxic state in specific areas of dental pulp as oxygen demands depend on physiological events such as crown and root dentin mineralization.

• Klíčová slova
• Dental pulp, Development, Hypoxia-inducible factors, In vivo,
• MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa * metabolismus   genetika   MeSH
• metabolické sítě a dráhy MeSH
• moláry * metabolismus   růst a vývoj   MeSH
• myši MeSH
• odontoblasty metabolismus   MeSH
• proteiny regulující apoptózu MeSH
• represorové proteiny MeSH
• transkripční faktory bHLH * metabolismus   genetika   MeSH
• vývojová regulace genové exprese MeSH
• zubní dřeň * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• endothelial PAS domain-containing protein 1 MeSH Prohlížeč
• faktor 1 indukovatelný hypoxií - podjednotka alfa * MeSH
• Hif1a protein, mouse MeSH Prohlížeč
• Hif3a protein, mouse MeSH Prohlížeč
• proteiny regulující apoptózu MeSH
• represorové proteiny MeSH
• transkripční faktory bHLH * MeSH

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.

• Klíčová slova
• Cellular senescence, Circadian rhythm, Hypoxia, Potential therapy, Relationships,
• MeSH
• cílená molekulární terapie MeSH
• cirkadiánní rytmus * fyziologie   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• hypoxie buňky MeSH
• hypoxie metabolismus   patofyziologie   MeSH
• lidé MeSH
• signální transdukce MeSH
• stárnutí buněk * MeSH
• transkripční faktory ARNTL metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• transkripční faktory ARNTL MeSH

Changes in endocrine function of adipose tissue during surgery, such as excessive production of proinflammatory cytokines, can significantly alter metabolic response to surgery and worsen its outcomes and prognosis of patients. Therapeutic hypothermia has been used to prevent damage connected with perioperative ischemia and hypoperfusion. The aim of our study was to explore the influence of deep hypothermia on systemic and local inflammation, adipose tissue hypoxia and adipocytokine production. We compared serum concentrations of proinflammatory markers (CRP, IL-6, IL-8, sIL-2R, sTNFRI, PCT) and mRNA expression of selected genes involved in inflammatory reactions (IL-6, TNF-α, MCP-1, MIF) and adaptation to hypoxia and oxidative stress (HIF1-α, MT3, GLUT1, IRS1, GPX1, BCL-2) in subcutaneous and visceral adipose tissue and in isolated adipocytes of patients undergoing cardiosurgical operation with hypothermic period. Deep hypothermia significantly delayed the onset of surgery-related systemic inflammatory response. The relative gene expression of the studied genes was not altered during the hypothermic period, but was significantly changed in six out of ten studied genes (IL-6, MCP-1, TNF-α, HIF1-α, GLUT1, GPX1) at the end of surgery. Our results show that deep hypothermia suppresses the development of systemic inflammatory response, delays the onset of local adipose tissue inflammation and thus may protect against excessive expression of proinflammatory and hypoxia-related factors in patients undergoing elective cardiac surgery procedure.

• Klíčová slova
• Adipocytokines, Adipose tissue, Deep hypothermia, Hypoxia, Inflammation, Isolated adipocytes,
• MeSH
• cytokiny metabolismus   MeSH
• endarterektomie metody   MeSH
• hypoxie buňky fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• terapeutická hypotermie * MeSH
• transkriptom MeSH
• tuková tkáň metabolismus   patofyziologie   MeSH
• zánět metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH

High temperature can change the effects of intra- and intercellular regulators and therefore modify the cellular response to hypoxia. We investigated H(2)O(2) production by alveolar macrophages, isolated from adult male rats, which were incubated under conditions of oxygen deficiency and high temperature (experiment in vitro). The incubation of these cells for 2 hours at 10 % or 5 % oxygen led only to slight fluctuations in the H(2)O(2) level, while the rise of temperature from 37 degrees C up to 42 degrees C significantly increased its generation. Level of thiobarbituric acid-reactive substances (TBARS) underwent similar changes. Under these conditions the accumulation of H(2)O(2) was found to be caused mainly by its decreased cleavage rather than its enhanced production. This is indicated by decreased catalase and glutathione peroxidase activity together with a parallel absence of significant changes in superoxide dismutase (SOD) activity. Slight fluctuation of reduced glutathione level and the pronounced increase of glucose-6-phosphate dehydrogenase (G6PD) activity were detected. Strong (5 %) but not moderate (10 %) lack of oxygen led to a sharp increase in formation of cellular nitrite ions by alveolar macrophages. In general, our data showed that high temperature did not lead to any qualitative shifts of defined hypoxia-derived changes in oxidant/antioxidant balance in alveolar macrophages, but promoted sensitivity of cells to oxygen shortage.

• MeSH
• alveolární makrofágy cytologie   enzymologie   metabolismus   MeSH
• dusitany metabolismus   MeSH
• glukosa-6-fosfátdehydrogenasa metabolismus   MeSH
• glutathion metabolismus   MeSH
• glutathionperoxidasa metabolismus   MeSH
• hypoxie buňky fyziologie   MeSH
• katalasa metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• peroxid vodíku metabolismus   MeSH
• potkani Wistar MeSH
• superoxiddismutasa metabolismus   MeSH
• vysoká teplota * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dusitany MeSH
• glukosa-6-fosfátdehydrogenasa MeSH
• glutathion MeSH
• glutathionperoxidasa MeSH
• katalasa MeSH
• látky reagující s kyselinou thiobarbiturovou MeSH
• peroxid vodíku MeSH
• superoxiddismutasa MeSH

Obesity is associated with white adipose tissue (WAT) hypoxia and inflammation. We aimed to test whether mild environmental oxygen restriction (OxR, 13% O2), imposing tissue hypoxia, triggers WAT inflammation in obese mice. Thirteen weeks diet-induced obese male adult C57BL/6JOlaHsd mice housed at thermoneutrality were exposed for five days to OxR versus normoxia. WAT and blood were isolated and used for analysis of metabolites and adipokines, WAT histology and macrophage staining, and WAT transcriptomics. OxR increased circulating levels of haemoglobin and haematocrit as well as hypoxia responsive transcripts in WAT and decreased blood glucose, indicating systemic and tissue hypoxia. WAT aconitase activity was inhibited. Macrophage infiltration as marker for WAT inflammation tended to be decreased, which was supported by down regulation of inflammatory genes S100a8, Ccl8, Clec9a, Saa3, Mgst2, and Saa1. Other down regulated processes include cytoskeleton remodelling and metabolism, while response to hypoxia appeared most prominently up regulated. The adipokines coiled-coil domain containing 3 (CCDC3) and adiponectin, as well as the putative WAT hormone cholecystokinin (CCK), were reduced by OxR on transcript (Cck, Ccdc3) and/or serum protein level (adiponectin, CCDC3). Conclusively, our data demonstrate that also in obese mice OxR does not trigger WAT inflammation. However, OxR does evoke a metabolic response in WAT, with CCDC3 and adiponectin as potential markers for systemic or WAT hypoxia.

• Klíčová slova
• adipokine, cholecystokinin, hypoxia, inflammation, white adipose tissue, whole genome microarray gene expression,
• MeSH
• adipokiny genetika   metabolismus   MeSH
• bílá tuková tkáň metabolismus   patologie   MeSH
• biologické markery metabolismus   MeSH
• dieta s vysokým obsahem tuků MeSH
• hypoxie genetika   metabolismus   MeSH
• kyselina mléčná metabolismus   MeSH
• myši inbrední C57BL MeSH
• obezita genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• teplota MeSH
• zánět genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adipokiny MeSH
• biologické markery MeSH
• kyselina mléčná MeSH

BACKGROUND: Hypoxia is a common feature of many solid tumors and causes radiotherapy and immunotherapy resistance. Pharmacological inhibition of oxidative phosphorylation (OXPHOS) has emerged as a therapeutic strategy to reduce hypoxia. However, the OXPHOS inhibitors tested in clinical trials caused only moderate responses in hypoxia alleviation or trials were terminated due to dose-limiting toxicities. To improve the therapeutic benefit, FDA approved OXPHOS inhibitors (e.g. atovaquone) were conjugated to triphenylphosphonium (TPP+) to preferentially target cancer cell's mitochondria. In this study, we evaluated the hypoxia reducing effects of several mitochondria-targeted OXPHOS inhibitors and compared them to non-mitochondria-targeted OXPHOS inhibitors using newly developed spheroid models for diffusion-limited hypoxia. METHODS: B16OVA murine melanoma cells and MC38 murine colon cancer cells expressing a HIF-Responsive Element (HRE)-induced Green Fluorescent Protein (GFP) with an oxygen-dependent degradation domain (HRE-eGFP-ODD) were generated to assess diffusion-limited hypoxia dynamics in spheroids. Spheroids were treated with IACS-010759, atovaquone, metformin, tamoxifen or with mitochondria-targeted atovaquone (Mito-ATO), PEGylated mitochondria-targeted atovaquone (Mito-PEG-ATO) or mitochondria-targeted tamoxifen (MitoTam). Hypoxia dynamics were followed and quantified over time using the IncuCyte Zoom Live Cell-Imaging system. RESULTS: Hypoxic cores developed in B16OVA.HRE and MC38.HRE spheroids within 24 h hours after seeding. Treatment with IACS-010759, metformin, atovaquone, Mito-PEG-ATO and MitoTam showed a dose-dependent reduction of hypoxia in both B16OVA.HRE and MC38.HRE spheroids. Mito-ATO only alleviated hypoxia in MC38.HRE spheroids while tamoxifen was not able to reduce hypoxia in any of the spheroid models. The mitochondria-targeted OXPHOS inhibitors demonstrated stronger anti-hypoxic effects compared to the non-mito-targeted OXPHOS inhibitors. CONCLUSIONS: We successfully developed a high-throughput spheroid model in which hypoxia dynamics can be quantified over time. Using this model, we showed that the mitochondria-targeted OXPHOS inhibitors Mito-ATO, Mito-PEG-ATO and MitoTam reduce hypoxia in tumor cells in a dose-dependent manner, potentially sensitizing hypoxic tumor cells for radiotherapy.

• Klíčová slova
• Hypoxia, Live cell imaging, Metabolic reprogramming, Mitochondria-targeting, OXPHOS inhibitors, Spheroids,
• Publikační typ
• časopisecké články MeSH

Skeletal muscle relies on mitochondria for sustainable ATP production, which may be impacted by reduced oxygen availability (hypoxia). Compared with long-term hypoxia, the mechanistic in vivo response to acute hypoxia remains elusive. Therefore, we aimed to provide an integrated description of the Musculus gastrocnemius response to acute hypoxia. Fasted male C57BL/6JOlaHsd mice, fed a 40en% fat diet for six weeks, were exposed to 12% O2 normobaric hypoxia or normoxia (20.9% O2) for six hours (n = 12 per group). Whole-body energy metabolism and the transcriptome response of the M. gastrocnemius were analyzed and confirmed by acylcarnitine determination and Q-PCR. At the whole-body level, six hours of hypoxia reduced energy expenditure, increased blood glucose and tended to decreased the respiratory exchange ratio (RER). Whole-genome transcriptome analysis revealed upregulation of forkhead box-O (FOXO) signalling, including an increased expression of tribbles pseudokinase 3 (Trib3). Trib3 positively correlated with blood glucose levels. Upregulated carnitine palmitoyltransferase 1A negatively correlated with the RER, but the significantly increased in tissue C14-1, C16-0 and C18-1 acylcarnitines supported that β-oxidation was not regulated. The hypoxia-induced FOXO activation could also be connected to altered gene expression related to fiber-type switching, extracellular matrix remodeling, muscle differentiation and neuromuscular junction denervation. Our results suggest that a six-hour exposure of obese mice to 12% O2 normobaric hypoxia impacts M. gastrocnemius via FOXO1, initiating alterations that may contribute to muscle remodeling of which denervation is novel and warrants further investigation. The findings support an early role of hypoxia in tissue alterations in hypoxia-associated conditions such as aging and obesity.

• Klíčová slova
• FOXO, Hypoxia, Metabolism, Mitochondria, Neuromuscular junction, Skeletal muscle,
• Publikační typ
• časopisecké články MeSH

Abnormal rates of growth together with metastatic potential and lack of susceptibility to cellular signals leading to apoptosis are widely investigated characteristics of tumors that develop via genetic or epigenetic mechanisms. Moreover, in the growing tumor, cells are exposed to insufficient nutrient supply, low oxygen availability (hypoxia) and/or reactive oxygen species. These physiological stresses force them to switch into more adaptable and aggressive phenotypes. This paper summarizes the role of two key mediators of cellular stress responses, namely p53 and HIF, which significantly affect cancer progression and compromise treatment outcomes. Furthermore, it describes cross-talk between these factors.

• MeSH
• faktor 1 indukovatelný hypoxií metabolismus   MeSH
• fyziologický stres MeSH
• hypoxie buňky MeSH
• karcinogeneze genetika   metabolismus   MeSH
• lidé MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory genetika   metabolismus   MeSH
• poškození DNA * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií MeSH
• nádorový supresorový protein p53 MeSH
• TP53 protein, human MeSH Prohlížeč

This study investigated the effects of riboflavin on energy metabolism in hypoxic mice. Kunming mice were fed diets containing riboflavin at doses of 6, 12, 24 and 48 mg/kg, respectively for 2 weeks before exposure to a simulated altitude of 6000 m for 8 h. Changes of riboflavin status and energy metabolism were assessed biochemically. Simultaneously, a (1)H nuclear magnetic resonance (NMR) based metabolomic technique was used to track the changes of plasma metabolic profiling. It was found that the content of hepatic riboflavin was decreased and erythrocyte glutathione activation coefficient was elevated significantly under hypoxic condition. Meanwhile, increased plasma pyruvate, lactate, beta-hydroxybutyrate and urea, as well as decreased plasma carnitine were observed. Riboflavin supplementation improved riboflavin status remarkably in hypoxic mice and decreased plasma levels of pyruvate, free fatty acids and beta-hydroxybutyrate significantly. Plasma carnitine was increased in response to riboflavin supplementation. Results obtained from (1)H NMR analysis were basically in line with the data from biochemical assays and remarkable changes in plasma taurine, choline and some other metabolites were also indicated. It was concluded that riboflavin requirement was increased under acute hypoxic condition and riboflavin supplementation was effective in improving energy metabolism in hypoxic mice.

• MeSH
• energetický metabolismus účinky léků   MeSH
• hypoxie krev   farmakoterapie   MeSH
• karnitin krev   MeSH
• krevní glukóza účinky léků   MeSH
• kyselina 3-hydroxymáselná krev   MeSH
• kyselina mléčná krev   MeSH
• kyselina pyrohroznová krev   MeSH
• kyseliny mastné neesterifikované krev   MeSH
• magnetická rezonanční spektroskopie MeSH
• močovina krev   MeSH
• myši MeSH
• náhodné rozdělení MeSH
• potravní doplňky MeSH
• preklinické hodnocení léčiv MeSH
• riboflavin farmakologie   terapeutické užití   MeSH
• vitamin B komplex farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• karnitin MeSH
• krevní glukóza MeSH
• kyselina 3-hydroxymáselná MeSH
• kyselina mléčná MeSH
• kyselina pyrohroznová MeSH
• kyseliny mastné neesterifikované MeSH
• močovina MeSH
• riboflavin MeSH
• vitamin B komplex MeSH

The tumor microenvironment includes a complicated network of physiological gradients contributing to plasticity of tumor cells and heterogeneity of tumor tissue. Hypoxia is a key component generating intratumoral oxygen gradients, which affect the cellular expression program and lead to therapy resistance and increased metastatic propensity of weakly oxygenated cell subpopulations. One of the adaptive responses of tumor cells to hypoxia involves the increased expression and functional activation of carbonic anhydrase IX (CA IX), a cancer-related cell surface enzyme catalyzing the reversible conversion of carbon dioxide to bicarbonate ion and proton. Via its catalytic activity, CA IX participates in regulation of intracellular and extracellular pH perturbations that result from hypoxia-induced changes in cellular metabolism producing excess of acid. Through the ability to regulate pH, CA IX also facilitates cell migration and invasion. In addition, CA IX has non-catalytic function in cell adhesion and spreading. Thus, CA IX endows tumor cells with survival advantages in hypoxia/acidosis and confers an increased ability to migrate, invade and metastasize. Accordingly, CA IX is expressed in a broad range of tumors, where it is associated with prognosis and therapy outcome. Its expression pattern and functional implications in tumor biology make CA IX a promising therapeutic target, which can be hit either by immunotherapy with monoclonal antibodies or with compounds inhibiting its enzyme activity. The first strategy has already reached the clinical trials, whereas the second one is still in preclinical testing. Both strategies indicate that CA IX can become a clinically useful anticancer target, but urge further efforts toward better selection of patients for immunotherapy and deeper understanding of tumor types, clinical situations and synthetic lethality interactions with other treatment approaches.

• Klíčová slova
• Carbonic anhydrase IX, Hypoxia, Immunotherapy, Migration–invasion, pH regulation,
• MeSH
• antigeny nádorové imunologie   metabolismus   MeSH
• biokatalýza účinky léků   MeSH
• cílená molekulární terapie metody   MeSH
• hypoxie enzymologie   MeSH
• inhibitory enzymů terapeutické užití   MeSH
• karboanhydrasa IX MeSH
• karboanhydrasy imunologie   metabolismus   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• monoklonální protilátky imunologie   terapeutické užití   MeSH
• nádory farmakoterapie   enzymologie   patologie   MeSH
• pohyb buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antigeny nádorové MeSH
• CA9 protein, human MeSH Prohlížeč
• inhibitory enzymů MeSH
• karboanhydrasa IX MeSH
• karboanhydrasy MeSH
• monoklonální protilátky MeSH