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Although Otto Warburg may be right about the role of glycolysis versus OXPHOS in cancer metabolism, it remains unclear whether an altered metabolism is causative or correlative and is the main driver or a mere passenger in the pathogenesis of cancer. Currently, most of our successful treatments are designed to eliminate non-cancer stem cells (non-CSCs) such as differentiated cancer cells. When the treatments also happen to control CSCs or the stem-ness niche, it is often unintended, unexpected, or undetected for lack of a pertinent theory about the origin of cancer that clarifies whether cancer is a metabolic, genetic, or stem cell disease. Perhaps cellular context matters. After all, metabolic activity may be different in different cell types and their respective microenvironments-whether it is in a normal progenitor stem cell vs. progeny differentiated cell and whether it is in a malignant CSC vs. non-CSC. In this perspective, we re-examine different types of cellular metabolism, e.g., glycolytic vs. mitochondrial, of glucose, glutamine, arginine, and fatty acids in CSCs and non-CSCs. We revisit the Warburg effect, an obesity epidemic, the aspartame story, and a ketogenic diet. We propose that a pertinent scientific theory about the origin of cancer and of cancer metabolism influences the direction of cancer research as well as the design of drug versus therapy development in cancer care.
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Microglia cells are activated in response to different stress signals. Several metabolic adaptations underlie microglia activation in the brain. Among these, in conditions like ischemic stroke and, hypoxic stress stimuli activate microglia cells. Hypoxic stress is mediated by HIF-1α. Although HIF-1α has been implicated in the alteration of metabolic pathways, changes in microglia lipid metabolism during M1 activation of microglia induced by elevated HIF-1α levels are yet to be understood. This can also merit interest in the development of novel targets to mitigate chronic inflammation. Our study aims to elucidate the transcriptional regulation of metabolic pathways in microglia cells during HIF-1α mediated activation. To study the adaptations in the metabolic pathways we induced microglia activation, by activating HIF-1α. Here, we show that microglia cells activated in response to elevated HIF-1α require ongoing lipogenesis and fatty acid breakdown. Notably, autophagy is activated during the initial stages of microglia activation. Inhibition of autophagy in activated microglia affects their viability and phagocytic activity. Collectively, our study expands the understanding of the molecular link between autophagy, lipid metabolism, and inflammation during HIF-1α mediated microglial activation that can lead to the development of promising strategies for controlling maladaptive activation states of microglia responsible for neuroinflammation. Together, our findings suggest that the role of HIF-1α in regulating metabolic pathways during hypoxia in microglia is beyond optimization of glucose utilization and distinctly regulates lipid metabolism during pro-inflammatory activation.
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Macrófagos , Microglía , Animales , Humanos , Ratones , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación , Microglía/metabolismoRESUMEN
Introduction: Interferon-gamma (IFN-γ), the sole member of the type-II interferon family, is well known to protect the host from infectious diseases as well as mount anti-tumor responses. The amounts of IFN-γ in the tumor microenvironment determine the host responses against tumors; however, several tumors employ evasive strategies by responding to low IFN-γ signaling. Methods: In this study, the response of various tumor cell lines to IFN-γ was studied in vitro. Results: IFN-γ-activation increases glycolytic flux and reduces mitochondrial function in a nitric oxide (NO)- and reactive oxygen species (ROS)-dependent manner in the H6 hepatoma tumor cell line. The higher glycolysis further fueled NO and ROS production, indicating a reciprocal regulation. These processes are accompanied by Hypoxia inducing factor (HIF)-1α stabilization and HIF-1α-dependent augmentation of the glycolytic flux. The IFN-γ enhancement of lactate production also occurred in other NO-producing cell lines: RAW 264.7 monocyte/macrophage and Renca renal adenocarcinoma. However, two other tumor cell lines, CT26 colon carcinoma and B16F10 melanoma, did not produce NO and lactate upon IFN-γ-activation. HIF-1α stabilization upon IFN-γ-activation led to lower cell growth of B16F10 but not CT26 cells. Importantly, the IFN-γ-activation of both CT26 and B16F10 cells demonstrated significant cellular growth reduction upon metabolic rewiring by exogenous administration of potassium lactate. Discussion: Clinical studies have shown the crucial roles of IFN-γ for successful cancer immunotherapies involving checkpoint inhibitors and chimeric antigen receptor T cells. The positive implications of this study on the metabolic modulation of IFN-γ activation on heterogeneous tumor cells are discussed.
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Interferón gamma , Neoplasias , Humanos , Interferón gamma/metabolismo , Óxido Nítrico/metabolismo , Ácido Láctico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Glucólisis , Línea Celular Tumoral , Hipoxia/metabolismo , Neoplasias/terapiaRESUMEN
OBJECTIVE: To observe the effects of Xingnao Kaiqiao (regaining consciousness and opening orifices) acupuncture therapy on the expression of hypoxia-inducible factor 1α (HIF-1α) and Nod-like receptor protein 3 (NLRP3) in cerebral ischemia-reperfusion rats, and to explore the mechanism of acupuncture against cerebral ischemia-reperfusion injury. METHODS: Seventy-two male SD rats were randomly divided into a sham-operation group, a model group, an acupuncture group and a non-point acupuncture group, with 18 rats in each one. Using modified Longa thread embolization method, the rat model of acute focal cerebral ischemia was prepared; and after 2 h ischemia, the reperfusion was performed to prepared the model of cerebral ischemia-reperfusion. Immediately after reperfusion, Xingnao Kaiqiao acupuncture method was applied to bilateral "Neiguan" (PC 6) and "Shuigou" (GV 26) in the acupuncture group, while in the non-point acupuncture group, acupuncture was delivered at non-points and all of the needles were retained for 30 min in these two groups. The samples were collected 24 h after reperfusion in the rats of each group. Zea-Longa neurological deficit score was used to evaluate the degree of cerebral neurological impairment, TTC staining was adopted to observe the volume percentage of cerebral infarction, HE staining was provided to observe the morphological changes of brain, and Western blot was applied for detecting the expression of HIF-1α and NLRP3 proteins in the cerebral cortex on the right side. RESULTS: Compared with the sham-operation group, neurological deficit score and volume percentage of cerebral infarction were increased in the model group (P<0.01), and HIF-1α and NLRP3 protein expression was elevated (P<0.01). Compared with the model group, neurological deficit score and volume percentage of cerebral infarction were decreased (P<0.01), and HIF-1α and NLRP3 protein expression was lower (P<0.01) in the acupuncture group. There was no significant difference in above indexes in the non-point acupuncture group compared with the model group (P>0.05). Compared with the sham-operation group, the brain tissue of the rats in the model group and the non-point acupuncture group was loose and edema, and the nuclei were shriveled. The brain tissue morphology in the acupuncture group was similar to that of the sham-operation group. CONCLUSION: Acupuncture can alleviate cerebral ischemia-reperfusion injury, and its mechanism may be related to the regulation of HIF-1α/NLRP3 signaling pathway to attenuate inflammatory response.
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Terapia por Acupuntura , Isquemia Encefálica , Daño por Reperfusión , Masculino , Animales , Ratas , Ratas Sprague-Dawley , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Daño por Reperfusión/terapia , Isquemia Encefálica/genética , Isquemia Encefálica/terapia , Infarto Cerebral/genética , Infarto Cerebral/terapia , Proteínas NLRRESUMEN
The study presents antioxidant, phytochemical, anti-proliferative, and gene repression activities against Hypoxia-inducible factor (HIF-1) alpha and Vascular endothelial growth factor (VEGF) of Elaeocarpus sphaericus extract. Elaeocarpus sphaericus dried and crushed plant leaves were extracted using water and methanol by ASE (Accelerated Solvent Extraction) method. Total phenolic content (TPC) and total flavonoid content (TFC) were used to measure the extracts' phytochemical activity (TFC). Antioxidant potential of the extracts was measured through DPPH, ABTS, FRAP, and TRP. Methanolic extract of the leaves of E.â sphaericus has shown a higher amount of TPC (94.666±4.040â mg/gm GAE) and TFC value (172.33±3.21â mg/gm RE). The antioxidant properties of extracts in the yeast model (Drug Rescue assay) showed promising results. Ascorbic acid, gallic acid, hesperidin, and quercetin were found in the aqueous and methanolic extracts of E.â sphaericus at varying amounts, according to a densiometric chromatogram generated by HPTLC analysis. Methanolic extract of E.â sphaericus (10â mg/ml) has shown good antimicrobial potential against all bacterial strains used in the study except E.â coli. The anticancer activity of the extract in HeLa cell lines ranged from 77.94±1.03 % to 66.85±1.95 %, while it ranged from 52.83±2.57 % to 5.44 % in Vero cell lines at varying concentration (1000â µg/ml-31.2â µg/ml). A promising effect of extract was observed on the expression activity of HIF-1 and VEGF gene through RT-PCR assay.
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Antioxidantes , Elaeocarpaceae , Humanos , Antioxidantes/química , Factor A de Crecimiento Endotelial Vascular/genética , Extractos Vegetales/farmacología , Extractos Vegetales/química , Células HeLa , Escherichia coli , Flavonoides/análisis , Metanol , Fenoles/farmacología , Fenoles/análisis , FitoquímicosRESUMEN
Hypoxia-inducible factors (HIFs) are a family of nuclear transcription factors that serve as the master regulator of the adaptive response to hypoxia. In the lung, HIFs orchestrate multiple inflammatory pathways and signaling. They have been reported to have a major role in the initiation and progression of acute lung injury, chronic obstructive pulmonary disease, pulmonary fibrosis, and pulmonary hypertension. Although there seems to be a clear mechanistic role for both HIF 1α and 2α in pulmonary vascular diseases including PH, a successful translation into a definitive therapeutic modality has not been accomplished to date.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Hipertensión Pulmonar , Humanos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Pulmón/metabolismo , HipoxiaRESUMEN
BACKGROUND: Preclinical models suggest synergy between anti-angiogenesis therapy, mammalian target of rapamycin (mTOR), and histone deacetylase inhibitors to promote anticancer activity. METHODS: This phase I study enrolled 47 patients between April 2012 and 2018 and determined safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) when combining bevacizumab, temsirolimus, and valproic acid in patients with advanced cancer. RESULTS: Median age of enrolled patients was 56 years. Patients were heavily pretreated with a median of 4 lines of prior therapy. Forty-five patients (95.7%) experienced one or more treatment-related adverse events (TRAEs). Grade 3 TRAEs were lymphopenia (14.9%), thrombocytopenia (8.5%), and mucositis (6.4%). Grade 4 TRAEs included lymphopenia (2.1%) and CNS cerebrovascular ischemia (2.1%). Six patients developed DLTs across 10 dose levels with grade 3 infection, rash, mucositis, bowel perforation, elevated lipase, and grade 4 cerebrovascular ischemia. The MTD was dose level 9 (bevacizumab 5 mg/kg days 1 and 15 intravenously (IV) plus temsirolimus 25 mg days 1, 8, 15, and 22 IV and valproic acid 5 mg/kg on days 1-7 and 15-21 per orally (PO)). Objective response rate (ORR) was 7.9% with confirmed partial response (PRs) in 3 patients (one each in parotid gland, ovarian, and vaginal cancers). Stable disease (SD) ≥+6 months was seen in 5 patients (13.1%). Clinical benefit state (CBR: PR + SD ≥+6 months) was 21%. CONCLUSION: Combination therapy with bevacizumab, temsirolimus, and valproic acid was feasible, but there were numerous toxicities, which will require careful management for future clinical development (ClinicalTrials.gov Identifier: NCT01552434).
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Linfopenia , Mucositis , Neoplasias , Trombocitopenia , Femenino , Humanos , Persona de Mediana Edad , Bevacizumab/efectos adversos , Ácido Valproico/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Trombocitopenia/tratamiento farmacológico , Isquemia/tratamiento farmacológico , Isquemia/etiología , Dosis Máxima ToleradaRESUMEN
Background and Objectives: Impaired wound healing represents an unsolved medical issue with a high impact on patients' quality of life and global health care. Even though hypoxia is a significant limiting factor for wound healing, it reveals stimulating effects in gene and protein expression at cellular levels. In particular, hypoxically treated human adipose tissue-derived stem cells (ASCs) have previously been used to stimulate tissue regeneration. Therefore, we hypothesized that they could promote lymphangiogenesis or angiogenesis. Materials and Methods: Dermal regeneration matrices were seeded with human umbilical vein endothelial cells (HUVECs) or human dermal lymphatic endothelial cells (LECs) that were merged with ASCs. Cultures were maintained for 24 h and 7 days under normoxic or hypoxic conditions. Finally, gene and protein expression were measured regarding subtypes of VEGF, corresponding receptors, and intracellular signaling pathways, especially hypoxia-inducible factor-mediated pathways using multiplex-RT-qPCR and ELISA assays. Results: All cell types reacted to hypoxia with an alteration of gene expression. In particular, vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor B (VEGFB), vascular endothelial growth factor C (VEGFC), vascular endothelial growth factor receptor 1 (VEGFR1/FLT1), vascular endothelial growth factor receptor 2 (VEGFR2/KDR), vascular endothelial growth factor receptor 3 (VEGFR3/FLT4), and prospero homeobox 1 (PROX1) were overexpressed significantly depending on upregulation of hypoxia-inducible factor 1 alpha (HIF-1a). Moreover, co-cultures with ASCs showed a more intense change in gene and protein expression profiles and gained enhanced angiogenic and lymphangiogenic potential. In particular, long-term hypoxia led to continuous stimulation of HUVECs by ASCs. Conclusions: Our findings demonstrated the benefit of hypoxic conditioned ASCs in dermal regeneration concerning angiogenesis and lymphangiogenesis. Even a short hypoxic treatment of 24 h led to the stimulation of LECs and HUVECs in an ASC-co-culture. Long-term hypoxia showed a continuous influence on gene expressions. Therefore, this work emphasizes the supporting effects of hypoxia-conditioned-ASC-loaded collagen scaffolds on wound healing in dermal regeneration.
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Factor A de Crecimiento Endotelial Vascular , Factor B de Crecimiento Endotelial Vascular , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor B de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/metabolismo , Linfangiogénesis , Células Endoteliales/metabolismo , Calidad de Vida , Hipoxia de la Célula/genética , Hipoxia , Células MadreRESUMEN
SUMMARY: Liver transplantation is the only available method to treat liver failure induced by chronic liver injury. We sought to determine whether the angiotensin-converting enzyme inhibitor, captopril, can inhibit the development of chronic liver injury induced by the hepatotoxic agent thioacetamide (TAA) in association with the suppression of inflammation (hsCRP, TNF-α, and IL-6) / hypoxia- inducible factor 1-alpha (HIF-1α) / profibrosis (TIMP-1, MMP-9, and α-SMA) axis that mediates liver injury. Therefore, the model group of rats was injected for eight weeks with 200 mg/kg TAA starting at week two. The protective group was pretreated with 150 mg/ kg captopril daily for two weeks prior to TAA injections and continued receiving both capropril and TAA agents until being humanely scrificed at week 10. We observed a substantial damage to liver tissue in the model group as demonstrated by a significant (p<0.0001) increase in blood and hepatic tissue levels of high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-a (TNF-α), interleukin- 6 (L-6), HIF-1α, tissue inhibitor of metalloproteinases-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), alpha-smooth muscle actin (α-SMA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). All these parameters were significantly (p<0.0244) protected by captopril. Also, a significant (p<0.0001) positive correlation was observed between a-SMA (profibrosis) and the serum and tissue levels of hsCRP, TNF-α, HIF-1α, TIMP-1, MMP-9, and ALT. Thus, these findings suggest that the induction of chronic liver injury by the hepatotoxic compound, TAA is associated with the upregulation of inflammation/HIF-1α/profibrosis, with captopril exhibiting beneficial hepatic pleotropic effects.
El trasplante de hígado es el único método disponible para tratar la insuficiencia hepática inducida por una lesión hepática crónica. Buscamos determinar si el inhibidor de la enzima convertidora de angiotensina, captopril, puede inhibir el desarrollo de lesión hepática crónica inducida por el agente hepatotóxico tioacetamida (TAA) en asociación con la supresión de la inflamación (hsCRP, TNF-α e IL-6) / factor inducible por hipoxia 1-alfa (HIF-1α) / profibrosis (TIMP-1, MMP-9 y α- SMA) eje que media la lesión hepática. Por lo tanto, al grupo modelo de ratas se le inyectó durante ocho semanas 200 mg/kg de TAA a partir de la semana dos. El grupo protector fue pretratado con 150 mg/kg de captopril al día durante dos semanas antes de las inyecciones de TAA y continuó recibiendo capropril y agentes TAA hasta que fue sacrificado en la semana 10. Observamos un daño sustancial en el tejido hepático en el grupo modelo, como lo demuestra un aumento significativo (p<0,0001) de los niveles en sangre y tejido hepático de proteína C reactiva de alta sensibilidad (hsCRP), factor de necrosis tumoral-α (TNF-a), interleucina-6 (L-6), HIF-1α, inhibidor tisular de metaloproteinasas-1 (TIMP-1), metaloproteinasa de matriz-9 (MMP-9), actina de músculo liso alfa (α-SMA), alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). Todos estos parámetros estaban significativamente (p<0,0244) protegidos por captopril. Además, se observó una correlación positiva significativa (p<0,0001) entre α-SMA (profibrosis) y los niveles séricos y tisulares de hsCRP, TNF-α, HIF-1α, TIMP- 1, MMP-9 y ALT. Por lo tanto, estos hallazgos sugieren que la inducción de daño hepático crónico por el compuesto hepatotóxico, TAA, está asociada con la regulación al alza de la inflamación/HIF-1α/profibrosis, con captopril exhibiendo efectos pleotrópicos hepáticos beneficiosos.
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Animales , Masculino , Ratas , Tioacetamida/toxicidad , Captopril/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Fibrosis , Inmunohistoquímica , Western Blotting , Actinas , Factor de Necrosis Tumoral alfa , Inhibidor Tisular de Metaloproteinasa-1 , Metaloproteinasa 9 de la Matriz , Modelos Animales de Enfermedad , Factor Nuclear 1-alfa del Hepatocito , Reacción en Cadena en Tiempo Real de la Polimerasa , Inhibidores de la Metaloproteinasa de la Matriz , Inflamación , Hígado/efectos de los fármacosRESUMEN
Hypoxia, or low oxygen tension, is frequently found in highly proliferative solid tumors such as anaplastic thyroid carcinoma (ATC) and is believed to promote resistance to chemotherapy and radiation. Identifying hypoxic cells for targeted therapy may thus be an effective approach to treating aggressive cancers. Here, we explore the potential of the well-known hypoxia-responsive microRNA (miRNA) miR-210-3p as a cellular and extracellular biological marker of hypoxia. We compare miRNA expression across several ATC and papillary thyroid cancer (PTC) cell lines. In the ATC cell line SW1736, miR-210-3p expression levels indicate hypoxia during exposure to low oxygen conditions (2% O2). Furthermore, when released by SW1736 cells into the extracellular space, miR-210-3p is associated with RNA carriers such as extracellular vesicles (EVs) and Argonaute-2 (AGO2), making it a potential extracellular marker for hypoxia.
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Proteínas Argonautas , Vesículas Extracelulares , MicroARNs , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Línea Celular Tumoral , Vesículas Extracelulares/metabolismo , Regulación Neoplásica de la Expresión Génica , Hipoxia/genética , MicroARNs/genética , Oxígeno/metabolismo , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/metabolismoRESUMEN
O2 is essential for the life of eukaryotic cells. The ability to sense oxygen availability and initiate a response to adapt the cell to changes in O2 levels is a fundamental achievement of evolution. The key switch for adaptation consists of the transcription factors HIF1A, HIF2A and HIF3A. Their levels are tightly controlled by O2 through the involvement of the oxygen-dependent prolyl hydroxylase domain-containing enzymes (PHDs/EGNLs), the von Hippel-Lindau tumour suppressor protein (pVHL) and the ubiquitin-proteasome system. Furthermore, HIF1A and HIF2A are also under the control of additional post-translational modifications (PTMs) that positively or negatively regulate the activities of these transcription factors. This review focuses mainly on two PTMs of HIF1A and HIF2A: phosphorylation and acetylation.
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Thoracic aortic aneurysm (TAA), in which arteries enlarge asymptomatically over time until dissection or rupture occurs, is a serious health risk. The mainstay of TAA treatment remains surgical repair due to the lack of effective drugs. The complex etiology and pathogenesis of TAA, including hemodynamic alterations and genetic factors, lead to inaccuracies in preclinical models for drug screening. Previously, our group designed an aorta smooth muscle-on-a-chip to emulate human aorta physiology and pathophysiology and screened three promising therapeutic drugs targeting mitochondrial dynamics in TAA. On this foundation, we updated the one-channel chip to an eighteen-well chip platform with four polydimethylsiloxane layers. Benefiting from this high-throughput chip, we rapidly screened multiple drugs simultaneously using distinct cell lines in vitro. In addition, we observed the abnormal activation of hypoxia-inducible factor 1-alpha (HIF-1alpha) in aortas from TAA patients by Western blot and bioinformatics analyses. Intriguingly, this phenomenon was replicated only when smooth muscle cells (SMCs) were strained on the chip. We then screened seven specific HIF-1alpha inhibitors and selected the two most effective drugs (2-methoxyestradiol and digoxin) by quantitative PCR and colorimetric methods. The results demonstrated that these two drugs can improve respiratory chain function and rescue the SMC contractile phenotype, showing applicability for the clinical treatment of TAA. This high-throughput aorta smooth muscle-on-a-chip will become a potential preclinical model for TAA drug screening.
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Aneurisma de la Aorta Torácica , Técnicas Biosensibles , Humanos , Aneurisma de la Aorta Torácica/tratamiento farmacológico , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/metabolismo , 2-Metoxiestradiol/metabolismo , Evaluación Preclínica de Medicamentos , Dispositivos Laboratorio en un Chip , Aorta/metabolismo , Aorta/patología , Digoxina , Dimetilpolisiloxanos , Factor 1 Inducible por Hipoxia/metabolismo , Músculo Liso/metabolismo , Músculo Liso/patologíaRESUMEN
Altered microenvironmental stiffness is a hallmark of inflammation. It is sensed by the mechanically activated cation channel Piezo1 in macrophages to induce subsequent immune responses. However, the mechanism by which the mechanosensitive signals shape the metabolic status of macrophages and tune immune responses remains unclear. We revealed that Piezo1-deficient macrophages exhibit reduced aerobic glycolysis in resting or liposaccharide (LPS)-stimulated macrophages with impaired LPS-induced secretion of inflammatory cytokines in vitro. Additionally, pretreatment with the Piezo1 agonist, Yoda1, or cyclical hydrostatic pressure (CHP) upregulated glycolytic activity and enhanced LPS-induced secretion of inflammatory cytokines. Piezo1-deficient mice were less susceptible to dextran sulfate sodium (DSS)-induced colitis, whereas Yoda1 treatment aggravated colitis. Mechanistically, we found that Piezo1 activation promotes aerobic glycolysis through the Ca2+-induced CaMKII-HIF1α axis. Therefore, our study revealed that Piezo1-mediated mechanosensitive signals Piezo1 can enhance aerobic glycolysis and promote the LPS-induced immune response in macrophages.
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Canales Iónicos/metabolismo , Mecanotransducción Celular , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Colitis/inducido químicamente , Citocinas/metabolismo , Sulfato de Dextran , Glucólisis , Canales Iónicos/genética , Lipopolisacáridos/metabolismo , Macrófagos/metabolismo , RatonesRESUMEN
OBJECTIVE: The study aimed to establish whether HIF1α entrains the core clock in chondrocytes and how the HIF1α affects the circadian rhythm. METHODS: We subjected primary chondrocytes to chronic circadian desynchrony (CCD) and subsequently treated with oxygen rhythm and dimethyloxalylglycine (DMOG). Circadian oscillations were analyzed with a real-time monitoring system of Per2 promoter activity and qPCR. Chondrocytes were assayed core clock genes expression patterns and extracellular matrix metabolism. HIF1α siRNA was used to knock down HIF1α. ChIP-qPCR and dual-luciferase reporter assay were used to validate that Per2 was the target gene of HIF1α. The surgical model of osteoarthritis was induced by destabilization of the medial meniscus (DMM). The chronic jet lag model was established light/dark cycle advance shift. Joint degeneration was measured using histological staining, immunological assays, and micro-CT scanning. RESULTS: We report that different patterns of clock genes expression between healthy and osteoarthritic cartilage tissues and oxygen rhythms and DMOG reset the molecular clockwork which was dampened after CCD culture in a HIF1α-dependent manner. HIF1α increased the amplitude of oscillation by directly binding to the HRE-like and E-box-like elements located on the Per2 promoter. The rhythmic circadian clock significantly enhanced extracellular matrix production. Our study also demonstrates that DMOG ameliorated the increased OA severity caused by jet lag in the DMM model. CONCLUSIONS: This study shows that circadian clock resetting caused by DMOG is at least partially mediated by the HIF1α through interaction with the Per2 promoter and proposes DMOG as supportive therapy for OA.
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Relojes Circadianos , Osteoartritis , Humanos , Relojes Circadianos/genética , Síndrome Jet Lag , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Osteoartritis/genética , Osteoartritis/metabolismo , Oxígeno/metabolismo , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismoRESUMEN
The Moroccan Glioma Dataset contains the clinical data of 32 patients with glioma. The clinical data including demographic data (age, sex), tumor characteristics (tumor location, Glioma type, Karnofsky performance score, mitotic activity, cell density, necrosis, endotheliocapillary vascular proliferation, MRI contrast pick-up, corpus collosum infiltration and Oedema), treatment strategy (subtotal resection, gross resection, biopsy, radiotherapy, chemotherapy), expression pattern of tumor biomarkers (IDH1, HIF-1alpha, P53, Ki-67), and survival data (Kaplan-Meier curves for disease progression). The dataset can be used to relate tumor characteristics to tumor biomarkers and to predict disease progression for a better treatment management. The data were presented, analyzed, and described in the article "Immunohistochemical expression of HIF-1α, IDH1 and TP53: prognostic profile of Moroccan patients with diffuse glioma" published in Journal of Chemical Neuroanatomy [1].
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Current studies have proven that the decreased expression of the core circadian clock gene Period 1 (PER1) is closely related to the occurrence and progression of multiple malignant tumors, including oral squamous cell carcinoma (OSCC). But the mechanism involved is largely unknown. In this study, we found that PER1 was negatively correlated with the expression of the key ferroptosis-regulated proteins glutathione peroxidase (GPX4) and hypoxia inducible factor-1alpha (HIF-1α) in OSCC tissues. The expression of the ferroptosis related proteins GPX4, solute carrier family 7 member 11 (SLC7A11) and transferrin receptor (TFRC) and the levels of glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS) and Fe2+ were detected in OSCC cells with overexpression or silencing of PER1. Mitochondrial morphology changes were observed. We found that PER1 promotes ferroptosis depending on HIF-1α in OSCC cells. In vivo tumorigenicity assays proved that PER1 overexpression inhibits HIF-1α, promotes ferroptosis and suppresses OSCC growth. Mechanistically, coimmunoprecipitation and cycloheximide tracking assays proved that PER1 binds to HIF-1α to promote HIF-1α protein degradation. ChIP and dual luciferase reporter assays proved that HIF-1α binds to the PER1 promoter leading to feedback inhibition of PER1 transcription. Our findings suggest that targeting the PER1/HIF-1α negative feedback loop may provide a new strategy for OSCC treatment.
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Metabolic reprogramming mediated by hypoxia-inducible factors and its downstream targets plays a crucial role in many human malignancies. Excessive proliferation of tumor cells under hypoxic conditions leads to metabolic reprogramming and altered gene expression enabling tumors to adapt to their hypoxic environment. Here we analyzed the metabolic signatures of primary cutaneous melanomas with positive and negative sentinel node status in order to evaluate potential differences in their metabolic signature. We found a positive correlation of the expression of glucose transporter 1 (GLUT-1) with tumor thickness and ulceration in all melanomas with subgroup analyses as well as in the subgroup with a negative sentinel node. Furthermore, the expression of vascular endothelial growth factor (VEGF) was positively correlated with the presence of ulceration in melanomas with positive sentinel node.
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Melanoma , Ganglio Linfático Centinela , Neoplasias Cutáneas , Hipoxia de la Célula , Humanos , Ganglios Linfáticos/patología , Melanoma/genética , Melanoma/patología , Ganglio Linfático Centinela/metabolismo , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/patología , Factor A de Crecimiento Endotelial VascularRESUMEN
Diffuse gliomas are growing brain tumors that occur in adult life. This study was designed to determine whether the immunohistochemical analysis of IDH1, HIF-1alpha, or TP53 can provide useful biomarkers of clinical severity and progression of diffuse gliomas. Also, it is hypothesized that the expression of IDH1 mutant induces HIF-1alpha. Immunohistochemical staining for HIF-1alpha, IDH1, and TP 53 was performed in biopsy or resection (sub-total or gross-total) tissue from diffuse gliomas in a clinical series of 32 patients. Associations of the HIF-1alpha, IDH1, and TP53 with clinical characteristics were evaluated and the co-expression of two biomarkers (HIF-1alpha and IDH1) was tested. Our data revealed that each biomarker is expressed in a subset of gliomas (IDH1 was positive in 56% cases, HIF-1alpha was positive in 50% cases and TP53 was positive in 44% cases). While no associations were found between clinical characteristics and the expression of HIF-1alpha, and TP53, IDH1 expression was associated with less severe clinical presentation (Karnofsky Performance Status) and disease progression and was more often expressed in females than males. In addition, there was no clear association between IDH1 and HIF-1alpha expression (21.9% of patients co-expressed IDH1 and HIF-1alpha). The current series provides clinical and immunohistochemical findings that can be useful for the clinical management of patients with diffused gliomas.
Asunto(s)
Neoplasias Encefálicas , Glioma , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Femenino , Glioma/diagnóstico , Glioma/metabolismo , Glioma/patología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Masculino , Marruecos , Pronóstico , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Hypoxia is a common characteristic in solid cancers. Hypoxia-inducible factors (HIFs) are involved in various aspects of cancer, such as angiogenesis, metastasis and therapy resistance. Targeting the HIF pathway has been regarded as a challenging but promising strategy in cancer treatment with recent FDA approval of a HIF2α-inhibitor. During the past several decades, numerous efforts have been made to understand how HIFs participate in cancer development and progression along with how HIF signaling can be modulated to achieve anti-cancer effect. In this chapter, we will provide an overview of the role of hypoxia and HIFs in cancer, summarize the oxygen-dependent and independent mechanisms of HIF-1α regulation, and discuss emerging approaches targeting hypoxia and HIF signaling which possess therapeutic potential in cancer. We will emphasize on two signaling pathways, involving cyclin-dependent kinases (CDKs) and heat shock protein 90 (HSP90), which contribute to HIF-1α (and HIF-2α) stabilization in an oxygen-independent manner. Through reviewing their participation in malignant progression and the potential targeting strategies, we discuss the non-canonical approaches to target HIF signaling in cancer therapy.
RESUMEN
Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease, which warrants the critical need to identify new therapeutic targets. We show that Zinc Fingers and Homeoboxes 2 (ZHX2) is amplified or overexpressed in TNBC cell lines and patients. Functionally, depletion of ZHX2 inhibited TNBC cell growth and invasion in vitro, orthotopic tumor growth, and spontaneous lung metastasis in vivo. Mechanistically, ZHX2 bound with hypoxia-inducible factor (HIF) family members and positively regulated HIF1α activity in TNBC. Integrated ChIP-seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1α on transcriptionally active promoters marked by H3K4me3 and H3K27ac, thereby promoting gene expression. Among the identified ZHX2 and HIF1α coregulated genes, overexpression of AP2B1, COX20, KDM3A, or PTGES3L could partially rescue TNBC cell growth defect by ZHX2 depletion, suggested that these downstream targets contribute to the oncogenic role of ZHX2 in an accumulative fashion. Furthermore, multiple residues (R491, R581, and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling ZHX2 transcriptional activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1α signaling, therefore serving as a potential therapeutic target for TNBC.