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The prevention and treatment of gastrointestinal mucosal injury caused by a plateau hypoxic environment is a clinical conundrum due to the unclear mechanism of this syndrome; however, oxidative stress and microbiota dysbiosis may be involved. The Robinia pseudoacacia L. flower, homologous to a functional food, exhibits various pharmacological effects, such as antioxidant, antibacterial, and hemostatic activities. An increasing number of studies have revealed that plant exosome-like nanoparticles (PELNs) can improve the intestinal microbiota and exert antioxidant effects. In this study, the oral administration of Robinia pseudoacacia L. flower exosome-like nanoparticles (RFELNs) significantly ameliorated hypoxia-induced gastric and small intestinal mucosal injury in mice by downregulating hypoxia-inducible factor-1α (HIF-1α) and HIF-2α expression and inhibiting hypoxia-mediated ferroptosis. In addition, oral RFELNs partially improved hypoxia-induced microbial and metabolic disorders of the stomach and small intestine. Notably, RFELNs displayed specific targeting to the gastrointestinal tract. In vitro experiments using gastric and small intestinal epithelial cell lines showed that cell death caused by elevated HIF-1α and HIF-2α under 1% O2 mainly occurred via ferroptosis. RFELNs obviously inhibited HIF-1α and HIF-2α expression and downregulated the expression of NOX4 and ALOX5, which drive reactive oxygen species production and lipid peroxidation, respectively, suppressing ferroptosis under hypoxia. In conclusion, our findings underscore the potential of oral RFELNs as novel, naturally derived agents targeting the gastrointestinal tract, providing a promising therapeutic approach for hypoxia-induced gastric and small intestinal mucosal ferroptosis.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Exosomas , Ferroptosis , Flores , Mucosa Gástrica , Subunidad alfa del Factor 1 Inducible por Hipoxia , Mucosa Intestinal , Intestino Delgado , Peroxidación de Lípido , Nanopartículas , Animales , Ferroptosis/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Exosomas/metabolismo , Exosomas/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patología , Administración Oral , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Flores/química , Nanopartículas/química , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Humanos , Ratones Endogámicos C57BLRESUMEN
Transcription factors are challenging to target with small-molecule inhibitors due to their structural plasticity and lack of catalytic sites. Notable exceptions include naturally ligand-regulated transcription factors, including our prior work with the hypoxia-inducible factor (HIF)-2 transcription factor, showing that small-molecule binding within an internal pocket of the HIF-2α Per-Aryl hydrocarbon Receptor Nuclear Translocator (ARNT)-Sim (PAS)-B domain can disrupt its interactions with its dimerization partner, ARNT. Here, we explore the feasibility of targeting small molecules to the analogous ARNT PAS-B domain itself, potentially opening a promising route to modulate several ARNT-mediated signaling pathways. Using solution NMR fragment screening, we previously identified several compounds that bind ARNT PAS-B and, in certain cases, antagonize ARNT association with the transforming acidic coiled-coil containing protein 3 transcriptional coactivator. However, these ligands have only modest binding affinities, complicating characterization of their binding sites. We address this challenge by combining NMR, molecular dynamics simulations, and ensemble docking to identify ligand-binding "hotspots" on and within the ARNT PAS-B domain. Our data indicate that the two ARNT/transforming acidic coiled-coil containing protein 3 inhibitors, KG-548 and KG-655, bind to a ß-sheet surface implicated in both HIF-2 dimerization and coactivator recruitment. Furthermore, while KG-548 binds exclusively to the ß-sheet surface, KG-655 can additionally bind within a water-accessible internal cavity in ARNT PAS-B. Finally, KG-279, while not a coactivator inhibitor, exemplifies ligands that preferentially bind only to the internal cavity. All three ligands promoted ARNT PAS-B homodimerization, albeit to varying degrees. Taken together, our findings provide a comprehensive overview of ARNT PAS-B ligand-binding sites and may guide the development of more potent coactivator inhibitors for cellular and functional studies.
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Cancer cells undergo metabolic reprogramming to survive in hypoxic conditions and meet the elevated energy demands of the cancer microenvironment. This metabolic alteration is orchestrated by hypoxia-inducible factor 1 (HIF-1), regulating various processes within cancer cells. The intricate metabolic modifications induced by hypoxia underscore the significance of HIF-1-induced metabolic reprogramming in promoting each aspect of cancer progression. The complex interactions between HIF-1 signalling and cellular metabolic processes in response to hypoxia are examined in this study, focusing on the metabolism of carbohydrates, nucleotides, lipids, and amino acids. Comprehending the various regulatory mechanisms controlled by HIF-1 in cellular metabolism sheds light on the intricate biology of cancer growth and offers useful insights for developing targeted treatments.
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Neoplasias , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Animales , Factor 1 Inducible por Hipoxia/metabolismo , Microambiente Tumoral , Transducción de Señal , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Reprogramación Celular , Reprogramación MetabólicaRESUMEN
The mammalian brain's complete dependence on oxygen for ATP production makes it highly susceptible to hypoxia, at high altitudes or in clinical scenarios including anemia or pulmonary disease. Hypoxia plays a crucial role in the development of various brain disorders, such as Alzheimer's, Parkinson's, and other age-related neurodegenerative diseases. On the other hand, a decrease in environmental oxygen levels, such as prolonged stays at high elevations, may have beneficial impacts on the process of ageing and the likelihood of death. Additionally, the utilization of controlled hypoxia exposure could potentially serve as a therapeutic approach for age-related brain diseases. Recent findings indicate that the involvement of HIF-1α and the NLRP3 inflammasome is of significant importance in the development of Alzheimer's disease. HIF-1α serves as a pivotal controller of various cellular reactions to oxygen deprivation, exerting influence on a multitude of physiological mechanisms such as energy metabolism and inflammatory responses. The NLRP3 plays a crucial role in the innate immune system by coordinating the initiation of inflammatory reactions through the assembly of the inflammasome complex. This review examines the information pertaining to the contrasting effects of hypoxia on the brain, highlighting both its positive and deleterious effects and molecular pathways that are involved in mediating these different effects. This study explores potential strategies for therapeutic intervention that focus on restoring cellular balance and reducing neuroinflammation, which are critical aspects in addressing this severe neurodegenerative condition and addresses crucial inquiries that warrant further future investigations.
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Hipoxia , Inflamación , Enfermedades Neurodegenerativas , Estrés Oxidativo , Humanos , Enfermedades Neurodegenerativas/metabolismo , Animales , Estrés Oxidativo/fisiología , Hipoxia/metabolismo , Inflamación/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Encéfalo/metabolismoRESUMEN
Hypoxia is a condition in which tissues of the body do not receive sufficient amounts of oxygen supply. Numerous studies have elucidated the intricate roles of hypoxia and its involvement in both physiological and pathological conditions. This study aimed to clarify the impact of a forced low-oxygen environment in early pregnancy by exposing mice to low-oxygen conditions for 24-72 h after fertilization. The treatment resulted in the complete failure of blastocyst implantation, accompanied by vascular hyperpermeability in the uterus. A transcriptome analysis of the uterus revealed remarkable alterations in gene expression between control normoxic- and hypoxic-treatment groups. These alterations were characterized by the differentially expressed genes categorized into the immune responses and iron coordination. Furthermore, exposure to a low-oxygen environment caused apoptosis in the corpus luteum within the ovary and a reduction in progesterone secretion. Consequently, diminished plasma progesterone levels were considered to contribute to implantation failure in combination with the activation of the hypoxic pathway in the uterus. Additionally, previous studies have demonstrated the impact of hypoxic reactions on blastocyst development and the pre-implantation process in the endometrium. Our findings suggest that the corpus luteum exhibits elevated susceptibility to hypoxia, thereby elucidating a critical aspect of its physiological response.
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Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.
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Anemia , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Macaca fascicularis , Inhibidores de Prolil-Hidroxilasa , Animales , Anemia/tratamiento farmacológico , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Administración Oral , Humanos , Inhibidores de Prolil-Hidroxilasa/farmacología , Inhibidores de Prolil-Hidroxilasa/química , Inhibidores de Prolil-Hidroxilasa/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Eritropoyetina , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis químicaRESUMEN
In hypoxic regions of malignant solid tumors, cancer cells acquire resistance to conventional therapies, such as chemotherapy and radiotherapy, causing poor prognosis in patients with cancer. It is widely recognized that some of the key genes behind this are hypoxia-inducible transcription factors, e.g., hypoxia-inducible factor 1 (HIF-1). Since HIF-1 activity is suppressed by two representative 2-oxoglutarate-dependent dioxygenases (2-OGDDs), PHDs (prolyl-4-hydroxylases), and FIH-1 (factor inhibiting hypoxia-inducible factor 1), the inactivation of 2-OGDD has been associated with cancer therapy resistance by the activation of HIF-1. Recent studies have also revealed the importance of hypoxia-responsive mechanisms independent of HIF-1 and its isoforms (collectively, HIFs). In this article, we collate the accumulated knowledge of HIF-1-dependent and independent mechanisms responsible for resistance of hypoxic cancer cells to anticancer drugs and briefly discuss the interplay between hypoxia responses, like EMT and UPR, and chemoresistance. In addition, we introduce a novel HIF-independent mechanism, which is epigenetically mediated by an acetylated histone reader protein, ATAD2, which we recently clarified.
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Drusen are one of the most characteristic pathologies of precursor lesion of age-related macular degeneration (AMD). Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid, crystallin, and others. In the past, many researchers have focused on drusen and tried to elucidate the pathophysiology of AMD because they believed that disease progression from early AMD to advanced AMD might be based on drusen or drusen might cause AMD. In fact, it is well established that drusen are the hallmark of precursor lesion of AMD and a major risk factor for AMD progression mainly based on their size and number. However, the existence of advanced AMD without drusen has long been recognized. For example, polypoidal choroidal vasculopathy (PCV), which comprises the majority of AMD cases in Asians, often lacks drusen. Thus, there is the possibility that drusen might be no more than a biomarker of AMD and not a cause of AMD. Now is the time to reconsider the relationship between AMD and drusen. In this review, we focus on early AMD pathogenesis based on basic research from the perspective of cholesterol metabolism and hypoxic response in the retina, and we discuss the role of drusen.
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Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvß3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.
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Reduced blood flow (hypoxia) to the brain is thought to be the main cause of strokes because it deprives the brain of oxygen and nutrients. An increasing amount of evidence indicates that the Centella-Asiatica (HA-CA) hydroalcoholic extract has a variety of pharmacological benefits, such as antioxidant activity, neuroprotection, anti-inflammatory qualities, and angiogenesis promotion. Intermittent fasting (IF) has neurological benefits such as anti-inflammatory properties, neuroprotective effects, and the ability to enhance neuroplasticity. The current study evaluates the combined effect of IF (for 1, 6, and 12 days) along with HA-CA (daily up to 12 days) in adult zebrafish subjected to hypoxia every 5 min for 12 days followed by behavioral (novel tank and open-field tank test), biochemical (SOD, GSH-Px, and LPO), inflammatory (IL-10, IL-1ß, and TNF-α), mitochondrial enzyme activities (Complex-I, II, and IV), signaling molecules (AMPK, MAPK, GSK-3ß, Nrf2), and imaging/staining (H&E, TTC, and TEM) analysis. Results show that sub-acute hypoxia promotes the behavioral alterations, and production of radical species and alters the oxidative stress status in brain tissues of zebrafish, along with mitochondrial dysfunction, neuroinflammation, and alteration of signaling molecules. Nevertheless, HA-CA along with IF significantly ameliorates these defects in adult zebrafish as compared to their effects alone. Further, imaging analysis significantly provided evidence of infarct damage along with neuronal and mitochondrial damage which was significantly ameliorated by IF and HA-CA. The use of IF and HA-CA has been proven to enhance the physiological effects of hypoxia in all dimensions.
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Centella , Accidente Cerebrovascular Isquémico , Triterpenos , Animales , Pez Cebra/metabolismo , Centella/química , Centella/metabolismo , Ayuno Intermitente , Glucógeno Sintasa Quinasa 3 beta/farmacología , Antioxidantes/metabolismo , Estrés Oxidativo , Extractos Vegetales/farmacología , Antiinflamatorios/farmacología , HipoxiaRESUMEN
Paragangliomas (PGLs) are rare neuroendocrine tumors. Sometimes, these tumors secrete excessive catecholamines, which results in the manifestations of various signs and symptoms, usually with a triad of hypertension, tachycardia, and headache. We report the case of a 42-year-old woman presenting with uncontrolled hypertension, right facial palsy, vomiting, and disturbed gait. Diagnosis for PGL was confirmed on postoperative histological examination of the excised mass and correlated with preoperative clinical and radiological findings. Tumor excision was done via a suboccipital craniotomy approach. Our case presents the typically severe features of a jugulotympanic PGL, but most importantly, it highlights the necessity of biochemical diagnosing, thorough probing of the causes of hypertension, and a multi-disciplinary approach in dealing with these tumors. Moreover, the case emphasizes necessitating the use of preoperative embolization in vascular tumors of the head and neck to avoid a hemorrhagic crisis during surgery. Unfortunately, due to a lack of adequate hospital funds, the surgeon had to proceed without preoperative embolization. Despite such a risk, the excision was a success.
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Patients with chronic kidney disease (CKD) often experience mild cognitive impairment and other neurocognitive disorders. Studies have shown that erythropoietin (EPO) and its receptor have neuroprotective effects in cell and animal models of nervous system disorders. Recombinant human EPO (rHuEPO), commonly used to treat anemia in CKD patients, could be a neuroprotective agent. In this systematic review, we aimed to assess the published studies investigating the cognitive benefits of rHuEPO treatment in individuals with reduced kidney function. We comprehensively searched Pubmed, Cochrane Library, Scopus, and Web of Science databases from 1990 to 2023. After selection, 24 studies were analyzed, considering study design, sample size, participant characteristics, intervention, and main findings. The collective results of these studies in CKD patients indicated that rHuEPO enhances brain function, improves performance on neuropsychological tests, and positively affects electroencephalography measurements. These findings suggest that rHuEPO could be a promising neuroprotective agent for managing CKD-related cognitive impairment.
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Disfunción Cognitiva , Eritropoyetina , Fármacos Neuroprotectores , Insuficiencia Renal Crónica , Humanos , Eritropoyetina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/psicología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Animales , Proteínas Recombinantes/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Cognición/efectos de los fármacosRESUMEN
Cataract, a leading cause of blindness, is characterised by lens opacification. Type 2 diabetes is associated with a two- to fivefold higher prevalence of cataracts. The risk of cataract formation increases with the duration of diabetes and the severity of hyperglycaemia. Hydroxyapatite deposition is present in cataractous lenses that could be the consequence of osteogenic differentiation and calcification of lens epithelial cells (LECs). We hypothesised that hyperglycaemia might promote the osteogenic differentiation of human LECs (HuLECs). Osteogenic medium (OM) containing excess phosphate and calcium with normal (1 g/L) or high (4.5 g/L) glucose was used to induce HuLEC calcification. High glucose accelerated and intensified OM-induced calcification of HuLECs, which was accompanied by hyperglycaemia-induced upregulation of the osteogenic markers Runx2, Sox9, alkaline phosphatase and osteocalcin, as well as nuclear translocation of Runx2. High glucose-induced calcification was abolished in Runx2-deficient HuLECs. Additionally, high glucose stabilised the regulatory alpha subunits of hypoxia-inducible factor 1 (HIF-1), triggered nuclear translocation of HIF-1α and increased the expression of HIF-1 target genes. Gene silencing of HIF-1α or HIF-2α attenuated hyperglycaemia-induced calcification of HuLECs, while hypoxia mimetics (desferrioxamine, CoCl2) enhanced calcification of HuLECs under normal glucose conditions. Overall, this study suggests that high glucose promotes HuLEC calcification via Runx2 and the activation of the HIF-1 signalling pathway. These findings may provide new insights into the pathogenesis of diabetic cataracts, shedding light on potential factors for intervention to treat this sight-threatening condition.
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Calcinosis , Catarata , Subunidad alfa 1 del Factor de Unión al Sitio Principal , Glucosa , Hiperglucemia , Factor 1 Inducible por Hipoxia , Cristalino , Humanos , Fosfatasa Alcalina/metabolismo , Fosfatasa Alcalina/genética , Calcinosis/etiología , Calcinosis/metabolismo , Calcinosis/patología , Catarata/etiología , Catarata/metabolismo , Catarata/patología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Glucosa/metabolismo , Hiperglucemia/complicaciones , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Cristalino/metabolismo , Cristalino/patología , Osteocalcina/metabolismo , Osteocalcina/genética , Transducción de Señal , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción SOX9/genética , Factor 1 Inducible por Hipoxia/genética , Factor 1 Inducible por Hipoxia/metabolismoRESUMEN
The hypoxia-inducible factors are α,ß-heterodimeric transcription factors that mediate the chronic response to hypoxia in humans and other animals. Protein hydroxylases belonging to two different structural subfamilies of the Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase superfamily modify HIFα. HIFα prolyl-hydroxylation, as catalysed by the PHDs, regulates HIFα levels and, consequently, α,ß-HIF levels. HIFα asparaginyl-hydroxylation, as catalysed by factor inhibiting HIF (FIH), regulates the transcriptional activity of α,ß-HIF. The activities of the PHDs and FIH are regulated by O2 availability, enabling them to act as hypoxia sensors. We provide an overview of the biochemistry of the HIF hydroxylases, discussing evidence that their kinetic and structural properties may be tuned to their roles in the HIF system. Avenues for future research and therapeutic modulation are discussed.
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Oxigenasas de Función Mixta , Factores de Transcripción , Animales , Humanos , Oxigenasas de Función Mixta/química , Oxigenasas de Función Mixta/metabolismo , Factores de Transcripción/metabolismo , Hipoxia/metabolismo , HidroxilaciónRESUMEN
Humans and other mammals inhabit hypoxic high-altitude locales. In many of these species, genes under positive selection include ones in the Hypoxia Inducible Factor (HIF) pathway. One is PHD2 (EGLN1), which encodes for a key oxygen sensor. Another is HIF2A (EPAS1), which encodes for a PHD2-regulated transcription factor. Recent studies have provided insights into mechanisms for these high-altitude alleles. These studies have (i) shown that selection can occur on nonconserved, unstructured regions of proteins, (ii) revealed that high altitude-associated amino acid substitutions can have differential effects on protein-protein interactions, (iii) provided evidence for convergent evolution by different molecular mechanisms, and (iv) suggested that mutations in different genes can complement one another to produce a set of adaptive phenotypes.
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Adaptación Fisiológica , Altitud , Humanos , Animales , Adaptación Fisiológica/genética , Hipoxia/genética , Fenotipo , Regulación de la Expresión Génica , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Mamíferos/genéticaRESUMEN
PURPOSE: Hypoxia-inducible factor (HIF) drives transcription of critical hypoxia response genes, increasing the production of red blood cells in low oxygen conditions. In the absence of hypoxia, HIF is degraded by prolyl hydroxylases (HIF-PHs). Pharmacological HIF-PH inhibition stabilizes HIF and is being studied as a treatment for anemia. However, like sustained hypoxia, HIF-PH inhibition may increase pulmonary arterial pressure leading to right ventricular hypertrophy. The aim of this study was to assess the cardiac effects of sustained pharmacological HIF-PH inhibition using multimodal imaging, blood analysis, and histology. METHODS: Rats were dosed daily with a pan HIF-PH inhibitor or vehicle for 4 weeks followed by a 2-week washout period and underwent longitudinal magnetic resonance imaging (MRI) and echocardiography to simultaneously assess RV and LV function. Blood samples from weeks four and six were analyzed to determine red blood cell composition. Histology was performed on the cardiac tissue from a subset of rats at weeks four and six to assess structural effects. RESULTS: Imaging revealed that RV ejection fraction was reduced in animals receiving HIF-PH inhibitor and resulted in RV hypertrophy. Interestingly, HIF-PH inhibition had the opposite effect on the left ventricle (LV), increasing contractility measured by LV ejection fraction. LV effects were reversed by week six, while RV effects (functional and structural) were sustained. CONCLUSION: These opposing cardiac effects of HIF-PH inhibition warrant further study to both understand the potential negative effects on RV structure and function and investigate the therapeutic potential of increased LV contractility for conditions like heart failure.
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Hipertensión Pulmonar , Función Ventricular Izquierda , Ratas , Animales , Prolil Hidroxilasas/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Hipoxia , Imagen MultimodalRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B -/- and Fmr1 -/y mice, we found that IHH training at an altitude of 5,000â m for 4â h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B -/- mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.
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Trastorno del Espectro Autista , Trastorno Autístico , Ratones , Masculino , Animales , Trastorno Autístico/genética , Trastorno Autístico/terapia , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/terapia , Núcleo Dorsal del Rafe , Neuronas Serotoninérgicas/fisiología , Hipoxia , Fenotipo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X FrágilRESUMEN
Hypoxia can lead to different responses from cancer cells, including cell death or survival, partially depending on how long it is exposed. Patients with cancer and under hypoxic tumour conditions have a poorer prognosis and are at greater risk of metastasis. Physiological response to low oxygen levels is controlled by hypoxia-inducible factor (HIF)-1. Curcumin, the major component of the rhizomes of Curcuma longa L., reduces HIF-1 levels and function, inhibiting the production of vascular endothelial growth factor (VEGF). In addition, curcumin efficiently inhibits the angiogenesis of vascular endothelial cells triggered by hypoxia. One of the most compelling features that drive continued interest in curcumin is the molecules' modulation of initiation, promotion, and progression stages of cancer while concomitantly acting as a radiosensitizer and chemosensitizer for tumours. In this review, we discuss the role of curcumin in modulating hypoxia and investigate the mechanisms and regulatory factors of hypoxia in tumour tissues.
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Transcription factors are generally challenging to target with small molecule inhibitors due to their structural plasticity and lack of catalytic sites. Notable exceptions to this include a number of transcription factors which are naturally ligand-regulated, a strategy we have successfully exploited with the heterodimeric HIF-2 transcription factor, showing that a ligand-binding internal pocket in the HIF-2α PAS-B domain could be utilized to disrupt its dimerization with its partner, ARNT. Here, we explore the feasibility of directly targeting small molecules to the structurally similar ARNT PAS-B domain, potentially opening a promising route to simultaneously modulate several ARNT-mediated signaling pathways. Using solution NMR screening of an in-house fragment library, we previously identified several compounds that bind ARNT PAS-B and, in certain cases, antagonize ARNT association with the TACC3 transcriptional coactivator. However, these ligands only have mid-micromolar binding affinities, complicating characterization of their binding sites. Here we combine NMR, MD simulations, and ensemble docking to identify ligand-binding 'hotspots' on and within the ARNT PAS-B domain. Our data indicate that the two ARNT/TACC3 inhibitors, KG-548 and KG-655, bind to a ß-sheet surface implicated in both HIF-2 dimerization and coactivator recruitment. Furthermore, KG-548 binds exclusively to the ß-sheet surface, while KG-655 binds to the same site but can also enter a water-accessible internal cavity in ARNT PAS-B. Finally, KG-279, while not a coactivator inhibitor, exemplifies ligands that preferentially bind only to the internal cavity. Taken together, our findings provide a comprehensive overview of ARNT PAS-B ligand-binding sites and may guide the development of more potent coactivator inhibitors for cellular and functional studies.
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Injured neurons sense environmental cues to balance neural protection and axon regeneration, but the mechanisms are unclear. Here, we unveil aryl hydrocarbon receptor (AhR), a ligand-activated bHLH-PAS transcription factor, as molecular sensor and key regulator of acute stress response at the expense of axon regeneration. We demonstrate responsiveness of DRG sensory neurons to ligand-mediated AhR signaling, which functions to inhibit axon regeneration. Ahr deletion mimics the conditioning lesion in priming DRG to initiate axonogenesis gene programs; upon peripheral axotomy, Ahr ablation suppresses inflammation and stress signaling while augmenting pro-growth pathways. Moreover, comparative transcriptomics revealed signaling interactions between AhR and HIF-1α, two structurally related bHLH-PAS α units that share the dimerization partner Arnt/HIF-1ß. Functional assays showed that the growth advantage of AhR-deficient DRG neurons requires HIF-1α; but in the absence of Arnt, DRG neurons can still mount a regenerative response. We further unveil a link between bHLH-PAS transcription factors and DNA hydroxymethylation in response to peripheral axotomy, while neuronal single cell RNA-seq analysis revealed a link of the AhR regulon to RNA polymerase III regulation and integrated stress response (ISR). Altogether, AhR activation favors stress coping and inflammation at the expense of axon regeneration; targeting AhR can enhance nerve repair.