INTRODUCTION: Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence the offspring's cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affects the development of the cardiac sympathetic system and, consequently, heightens health risks and predisposes to cardiovascular disease remain poorly understood. METHODS AND RESULTS: In the mouse model, we performed a comprehensive analysis of the combined impact of a Hif1a-deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and Hif1a deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of the adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, and dilated subepicardial veins and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA sequencing (RNA-seq) revealed significant transcriptome changes in Hif1a-deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population. DISCUSSION: Our data demonstrate that a failure to adequately activate the HIF-1α regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus increasing the risk of neonatal death.
- MeSH
- dítě MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus MeSH
- gestační diabetes * metabolismus MeSH
- kardiovaskulární nemoci * metabolismus MeSH
- lidé MeSH
- myokard metabolismus MeSH
- myši MeSH
- novorozenec MeSH
- srdce MeSH
- srdeční selhání * MeSH
- těhotenství MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- myši MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Trichothecene mycotoxin deoxynivalenol (DON) negatively regulates immune response by damaging host immune system and harming the organism's health. We hypothesized that DON can initiate an active immunosuppressive mechanism similar to "immune evasion" to alter the cellular microenvironment and evade immune surveillance. We tested this hypothesis using the RAW264.7 macrophage model. DON rapidly increased the expression of immune checkpoints PD-1 and PD-L1, inflammatory cytokine TGF-β, and key immune evasion factors STAT3, VEGF, and TLR-4, and caused cellular hypoxia. Importantly, hypoxia-inducible factor-1α (HIF-1α) acts as a key regulator of DON-induced immunosuppression. HIF-1α accumulated in the cytoplasm and was gradually transferred to the nucleus following DON treatment. Moreover, DON activated HIF-1α through STAT3 signaling to upregulate downstream signaling, including PD-1/PD-L1. Under DON treatment, immunosuppressive miR-210-3p, lncRNA PVT1, lncRNA H19, and lncRNA HOTAIR were upregulated by the STAT3/HIF-1α axis. Moreover, DON damaged mitochondrial function, causing mitophagy, and suppressed immune defenses. Collectively, DON triggered RAW264.7 intracellular hypoxia and rapidly activated HIF-1α via STAT3 signaling, activating immune evasion signals, miRNAs, and lncRNAs, thereby initiating the key link of immune evasion. This study offers further clues for accurate prevention and treatment of immune diseases caused by mycotoxins.
The presence of key hypoxia regulators, namely, hypoxia-inducible factor (HIF)-1α or HIF-2α, in tumors is associated with poor patient prognosis. Hypoxia massively activates several genes, including the one encoding the BCRP transporter that proffers multidrug resistance to cancer cells through the xenobiotic efflux and is a determinant of the side population (SP) associated with cancer stem-like phenotypes. As natural medicine comes to the fore, it is instinctive to look for natural agents possessing powerful features against cancer resistance. Hypericin, a pleiotropic agent found in Hypericum plants, is a good example as it is a BCRP substrate and potential inhibitor, and an SP and HIF modulator. Here, we showed that hypericin efficiently accumulated in hypoxic cancer cells, degraded HIF-1/2α, and decreased BCRP efflux together with hypoxia, thus diminishing the SP population. On the contrary, this seemingly favorable result was accompanied by the stimulated migration of this minor population that preserved the SP phenotype. Because hypoxia unexpectedly decreased the BCRP level and SP fraction, we compared the SP and non-SP proteomes and their changes under hypoxia in the A549 cell line. We identified differences among protein groups connected to the epithelial-mesenchymal transition, although major changes were related to hypoxia, as the upregulation of many proteins, including serpin E1, PLOD2 and LOXL2, that ultimately contribute to the initiation of the metastatic cascade was detected. Altogether, this study helps in clarifying the innate and hypoxia-triggered resistance of cancer cells and highlights the ambivalent role of natural agents in the biology of these cells.
- MeSH
- ABC transportér z rodiny G, člen 2 genetika metabolismus MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus MeSH
- hypoxie buňky MeSH
- hypoxie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny genetika metabolismus MeSH
- nádory * metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- transkripční faktory bHLH genetika metabolismus MeSH
- vedlejší populace buněk * patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Trichothecene mycotoxins have a strong immunosuppressive effect, which may even escape host immune surveillance and damage the immune repair to show an "immune evasion" effect. Increasing lines of evidence have shown that hypoxia and hypoxia-inducible factors (HIFs) are key mediators of trichothecenes, and these toxins appear to be closely related to the "immune evasion" mechanisms. Therefore, we used RAW264.7 cell model to explore the association of T-2 toxins with "immune evasion" process and hypoxia, as well as their cross-linking effects induced by T-2 toxin. Our results showed that HIF-1α is an important toxicity target of T-2 toxin, which could induce intracellular hypoxia. T-2 toxin induced an "immune evasion" process by activating the PD-1/PD-L1 signaling pathway. Interestingly, when HIF-1α activation was blocked, the "immune evasion" process regulated by PD-1/PD-L1 signaling was activated, resulting in the cells damage, suggesting that hypoxia induced by T-2 toxin plays a protective role for RAW264.7 cell damage. Thus, our work shows that HIF-1α inhibits T-2 toxin-mediated "immune evasion" process by negatively regulating PD-1/PD-L1signaling. This study contributes to a better understanding of the immunotoxicity mechanism of trichothecenes.
- MeSH
- antigeny CD274 metabolismus MeSH
- antigeny CD279 metabolismus MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa farmakologie MeSH
- hypoxie MeSH
- lidé MeSH
- T-2 toxin * toxicita MeSH
- trichotheceny * toxicita MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cíl: Cílem studie bylo zhodnotit úlohu genu pro hypoxií indukovatelný faktor 1alfa (hypoxia-inducible factor 1alpha, HIF1A; gen 1772C>T, rs11549465) v antracyklinem vyvolaném srdečním selhání (anthracycline-induced heart failure, AIHF) u žen bez kardiovaskulárního onemocnění (KVO) v předchozí 24 měsících. Metody: Do studie bylo zařazeno celkem 114 žen s mediánem věku 47,0 (44,0; 52,0) roku s AIHF stupně I-III NYHA, jimž byl podáván doxorubicin pro karcinom prsu. Při vstupu do studie u nich bylo s použitím polymerázové řetězové reakce provedeno vyšetření na genový polymorfismus. Výsledky: Po 24měsíčním sledování vykázaly všechny pacientky remisi karcinomu prsu; byly rozděleny do dvou skupin: skupinu 1 tvořily ženy s nepříznivým průběhem AIHF (n = 36), skupinu 2 tvořily ženy bez AIHF (n = 75). Přítomnost C/T genotypu s genem pro HIF1A (1772C>T, rs11549465) (OR = 3,65; p = 0,009) souvisela s nepříznivým průběhem AIHF. U žen s C/T genotypem s genem pro HIF1A (1772C>T, rs11549465) byla zjištěna další progrese AIHF: ejekční frakce levé komory se statisticky významně (p < 0,001) snížila o 11,8 % z 51 (47; 53) na 45 (43; 46) %, její end-systolický průměr se zvětšil o 7,8 % (p < 0,001) a end-diastolický průměr o 5,2 % (p < 0,001). Závěr: Polymorfismus C/T hypoxií indukovatelného faktoru pro gen 1alfa (1772C>T, rs11549465) u žen bez předchozího KVO byl spojen s nepříznivým průběhem AIHF za období 24 měsíců
Objective: The objective of the study was to evaluate the role of hypoxia-inducible factor 1alpha (HIF1A) gene (1772C>T, rs11549465) in the course of anthracycline-induced heart failure (AIHF) in women without previous cardiovascular diseases (CVD) during 24 months. Methods: A total of 114 women, median age of 47.0 (44.0; 52.0) years with AIHF of NYHA class I-III who received doxorubicin for breast cancer were enrolled. Evaluation of gene polymorphisms was carried out by polymerase chain reaction at baseline. Results: After 24 months of follow-up all patients had breast cancer remission and were divided into 2 groups: group 1 comprised women with adverse course of AIHF (n = 36), group 2 comprised those without it (n = 75). The presence of C/T genotype of HIF1A gene (1772C>T, rs11549465) (OR = 3.65; p = 0.009) was related with adverse course of AIHF. Women with C/T genotype of HIF1A gene (1772C>T, rs11549465) had further progression of AIHF: left ventricle ejection fraction significantly (p <0.001) decreased by 11.8% from 51 (47; 53) to 45 (43; 46)%, end-systolic dimension increased by 7.8% (p <0.001), and end-diastolic dimension by 5.2% (p <0.001). Conclusion: Polymorphism of C/T of hypoxia-inducible factor 1alpha gene (1772C>T, rs11549465) in women without previous CVD was associated with adverse course of AIHF during 24 months.
- MeSH
- antracykliny MeSH
- dospělí MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa * genetika MeSH
- genotyp MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu farmakoterapie komplikace MeSH
- polymorfismus genetický MeSH
- srdeční selhání * chemicky indukované farmakoterapie genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- hodnotící studie MeSH
Hypoxia, a common feature of the tumor microenvironment in various types of cancers, weakens cytotoxic T cell function and causes recruitment of regulatory T cells, thereby reducing tumoral immunogenicity. Studies have demonstrated that hypoxia and hypoxia-inducible factors (HIFs) 1 and 2 alpha (HIF1A and HIF2A) are involved in tumor immune escape. Under hypoxia, activation of HIF1A induces a series of signaling events, including through programmed death receptor-1/programmed death ligand-1. Moreover, hypoxia triggers shedding of complex class I chain-associated molecules through nitric oxide signaling impairment to disrupt immune surveillance by natural killer cells. The HIF-1-galactose-3-O-sulfotransferase 1-sulfatide axis enhances tumor immune escape via increased tumor cell-platelet binding. HIF2A upregulates stem cell factor expression to recruit tumor-infiltrating mast cells and increase levels of cytokines interleukin-10 and transforming growth factor-β, resulting in an immunosuppressive tumor microenvironment. Additionally, HIF1A upregulates expression of tumor-associated long noncoding RNAs and suppresses immune cell function, enabling tumor immune escape. Overall, elucidating the underlying mechanisms by which HIFs promote evasion of tumor immune surveillance will allow for targeting HIF in tumor treatment. This review discusses the current knowledge of how hypoxia and HIFs facilitate tumor immune escape, with evidence to date implicating HIF1A as a molecular target in such immune escape. This review provides further insight into the mechanism of tumor immune escape, and strategies for tumor immunotherapy are suggested.
Hypoxia leads to post-treatment metastasis and recurrences of cancer via the epithelial-mesenchymal transition (EMT). Radiotherapy itself may also contribute to the acquisition of EMT phenotypes. Despite extensive studies on the EMT driven by either hypoxia or radiation stimuli, the molecular mechanisms characterizing these EMT events remain unclear. Thus, we aimed to evaluate the differences in the molecular pathways between hypoxia-induced EMT (Hypo-EMT) and radiation-induced EMT (R-EMT). Further, we investigated the therapeutic effects of HIF-1α inhibitor (LW6) on Hypo-EMT and R-EMT cells. A549 cells, lung adenocarcinoma cell line, acquired enhanced wound-healing activity under both hypoxia and irradiation. Localization of E-cadherin was altered from the cell membrane to the cytoplasm in both hypoxia and irradiated conditions. Of note, the expression levels of vimentin, one of the major EMT markers, was enhanced in irradiated cells, while it decreased under hypoxia condition. Importantly, LW6 significantly blocked EMT-related malignant phenotypes in both Hypo-EMT cells and R-EMT cells with concomitant re-location of E-cadherin onto the cell membrane. Moreover, LW6 deflected stress responsive signalling, JNK, activated sustainably under hypoxic condition, and the blockage of JNK impaired EMT phenotypes. Together, this work demonstrated the molecular events underlying Hypo-EMT and R-EMT, and highlighted HIF-1α as a therapeutic target not only in Hypo- EMT, but also in R-EMT.
- MeSH
- buňky A549 MeSH
- CD antigeny MeSH
- epitelo-mezenchymální tranzice * účinky záření MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
- faktor 1 indukovatelný hypoxií metabolismus MeSH
- hypoxie buňky * MeSH
- kadheriny MeSH
- lidé MeSH
- nádory plic * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Gastric cancer is characterized by the presence of high invasion ability, hypoxia and chemoresistance. Previous studies reported that liver X receptor α (LXRα) was involved in epithelial-mesenchymal transition (EMT) of gastric cancer cells. However, hypoxia-mediated EMT and the role of LXRα in gastric cancer remained elusive. In this study, we demonstrated that LXRa mRNA and protein levels were up-regulated by hypoxia treatment and LXRα played an important role in HIF-1 dimer induced-EMT. The putative HIF-1α binding site was identified in the LXRa promoter. Expression of LXRα and HIF-1α was significantly up-regulated in gastric cancer tissues compared to that in normal tissues. More importantly, we noticed that the expression of LXRα and HIF-1α was significantly correlated. Taken together, these data suggested that LXRα is regulated by the activity and accumulation of HIF-1α and contributes to EMT of gastric cancer cells. This suggests that targeting LXRα might be a potential approach for improving survival of gastric cancer patients.
- MeSH
- epitelo-mezenchymální tranzice MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa genetika MeSH
- hypoxie buňky MeSH
- jaterní receptor X * genetika MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory žaludku * genetika MeSH
- pohyb buněk MeSH
- regulace genové exprese u nádorů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
This October, the Nobel Prize in Physiology or Medicine 2019 was jointly awarded to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza for their discoveries of "how cells sense and adapt to oxygen availability." Importantly, the protein named hypoxia-inducible factors (HIF) were revealed in the molecular machinery that how cells regulate the activity of genes in response to hypoxia. Hypoxia has a close relationship with oxidative stress and its related diseases including cancer. Actually, accumulating evidence and recent advances show that mycotoxins, including ochratoxin A, trichothecene mycotoxins T-2 toxin, deoxynivalenol, and diacetoxyscirpenol have the potential of triggering hypoxia in cells. Moreover, HIF-1α activation is involved in the mycotoxin-induced oxidative stress response. As is known, oxidative stress is considered to be a common mechanism of various toxicities of mycotoxins; however, an in-depth molecular mechanism, especially the molecular target in this context is not fully understood. Therefore, in this work, we have discussed the underlying mechanism(s) of hypoxia and HIF-1α in the mycotoxin-induced oxidative stress effect. We believe that the explanation of hypoxia and HIF-1α would open up new avenues for early diagnosis and treatment of mycotoxicosis. More importantly, under these circumstances, we compile a special issue, "Mycotoxins in Food: New Determination Methods, Toxic Mechanisms, and Control Strategies" for Food and Chemical Toxicology. Researchers are encouraged to submit their newest research articles and excellent work within this topic for the readers of Food and Chemical Toxicology.
The knowledge of mechanisms of regulation of IL-10 production by B cells remains still very limited. We show here that highly purified mouse B cells stimulated with LPS produce significant levels of IL-10, but Bregs in our model do not express detectable level of either Foxp3 or GATA-3. Nevertheless, IL-10 production by B cells is regulated by cytokines. In activated B cells, IL-10 production was significantly enhanced by IFN-γ and decreased in the presence of IL-4 or TGF-β. These findings are in sharp contrast with the observations in T cells, where IL-10 production correlates with GATA-3 or FoxP3 expression, and the cytokines regulate IL-10 production in a reverse manner than in activated B cells. These results thus show that the production of IL-10 by Bregs is regulated by cytokines independently of the expression of GATA-3 and FoxP3, which is clearly different from GATA-3-dependent IL-10 production by activated Th2 cells and FoxP3 expression in IL-10-producing Tregs.
- MeSH
- aktivace lymfocytů imunologie MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa imunologie MeSH
- forkhead transkripční faktory metabolismus MeSH
- interferon gama imunologie MeSH
- interleukin-10 biosyntéza MeSH
- interleukin-4 imunologie MeSH
- kultivované buňky MeSH
- lipopolysacharidy imunologie MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- regulační B-lymfocyty imunologie MeSH
- regulační T-lymfocyty imunologie MeSH
- Th2 buňky imunologie MeSH
- transformující růstový faktor beta imunologie MeSH
- transkripční faktor GATA3 metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
