DigitalUM :: Browsing by Subject "Hypoxia"

Browsing by Subject "Hypoxia"

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Open Access
Anti-platelet agents reduce morphological changes of chronic hypoxic pulmonary hypertension
(Murcia : F. Hernández, 1987) Keith, lngegerd; Will, James A.; Huxtable, Ryan J.; Weir, Kenneth
The pathophysiologic mechanism by which chronic hypoxia causes pulmonary hypertension is unknown. If anti-platelet agents, or other pharmacologic interventions, altered the pulmonary vascular changes induced by hypoxia, information concerning the pathogenesis of the pulmonary hypertension or the potential therapeutic usefulness of the drugs might be obtained. In Study 1, rats exposed to chronic hypobaric hypoxia (P, = 520 mmHg) had a pulmonary arterial medial thickness of 6.7 * 0.6 p compared to 4.1 + 0.2 p * for control, normoxic rats (*p<0.05). Administration of dipyridamole (2mg/kg/day), or sulfinpyrazone (1 1 mg/ kglday) in the drinking water reduced the medial thickness to 5.0 2 0.3 p* and 5.4 2 0.5 p* respectively, thus suggesting the possible involvement of platelets in the response of the media to chronic hypoxia. In Study 2, hypoxic rats treated with the calcium blocker, flunarizine, were found to have less medial hypertrophy than a control group of hypoxic rats. This observation suggests that a decrease in transmembrane calcium flux may also reduce medial hypertrophy.
Open Access
Atrophic hepatocytes express keratin 7 in ischemia-associated liver lesions
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2016) Delladetsima, Ioanna; Sakellariou, Stratigoula; Kokkori, Aikaterini; Tiniakos, Dina
Aim: To investigate atrophic parenchymal changes in ischemic liver conditions. Design: We studied 18 cases of hepatic lesions with atrophic changes due to altered blood flow (hepatic venous congestion n=15 including 4 cases with additional nodular regenerative hyperplasia-NRH, NRH n=1, and antiphospholipid syndrome with patchy parenchymal atrophy n=2). Metaplastic hepatocellular changes, hepatocyte proliferation, hepatic stellate cell (HSC) activation, and sinusoidal capillarization were examined immunohistochemically with antibodies to keratins (K) 7 and 19, Ki67, αSMA and CD34, respectively. Results: K7 was positive and K19 was negative in zone 3 atrophic hepatocytes in venous congestion and in areas of plate atrophy, as well as in congested or compressed sites in NRH. Sinusoidal CD34-positivity indicating capillarization accompanied K7 immunoexpression. Masson trichrome revealed sinusoidal fibrosis to be restricted in atrophic areas, usually mild and in 7 cases focally dense. αSMA expression expanded beyond K7- positive areas. Ki67 was negative in K7-positive hepatocytes. Conclusion: Ischemic parenchymal changes are characterized by hepatocyte K7 immunoexpression, sinusoidal capillarization, HSC activation and lack of cellular proliferation, indicating an early reaction of the major liver parenchyma cellular components creating a more resistant microenvironment. These phenotypic alterations may prove valuable in the discrimination of ischemic liver lesions.
Open Access
Bone biology in postnatal Wistar rats following hypoxia-reoxygenation
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Hameister, Rita; Lohmann, Christoph H.; Dheen, Thameem; Singh, Gurpal; Kaur, Charanjit
Hypoxia response pathways have a central role in normal and abnormal bone biology but the effect of systemic hypoxia-reoxygenation on bone is not clear. Following hypoxic exposure, aberrant synthesis, folding and trafficking of proteins has been reported to occur, which can result in endoplasmic reticulum (ER) stress and may finally cause cell death. This study aimed to examine the effect of systemic hypoxia-reoxygenation injury on bone biology in postnatal rats. Immunoexpression of HIF-1α and VEGF was upregulated in femurs of newborn Wistar rats in response to systemic hypoxia-reoxygenation. Along with that, increased apoptosis of osteoblast precursors, osteoblasts, osteocytes and endothelial cells was observed in comparison to femurs of control animals by transmission electron microscopy, TUNEL staining and immunoexpression of cleaved caspase-3. The viability of osteoclasts was not affected. After hypoxia- reoxygenation, ER stress was observed in the osteoblasts and osteocytes as indicated by dilatation of the ER and enhanced immunoexpression of the ER stress marker GRP78. Localisation of collagen α1 immunoreaction was widespread in the bone matrix of control femurs but was confined to the osteoblasts and osteocytes in response to hypoxia-reoxygenation. In support of these findings, in vitro work showed reduced viability of osteoblast-like SaOs-2 cells and upregulation of GRP78 protein expression in them by western blotting following exposure to hypoxia. This suggests that systemic hypoxia-reoxygenation may disturb bone biology in postnatal Wistar rats by inducing ER stress and apoptosis in osteoblasts and osteocytes, without affecting the viability of osteoclasts. More in-depth research is needed to confirm causality between ER stress and apoptosis of osteoblasts and osteocytes
Open Access
Calbindin D-28k immunoreactive nerve fibers in the carotid body of normoxic and chronically hypoxic rats
(Murcia : F. Hernández, 2000) Kusakabe, T.; Matsuda, H.; Hirakawa, H.; Hayashida, Y.; Ichikawa, T.; Kawakami, T.; Takenaka, T.
The distribution and ultrastructural characteristics of calbindin D-28k immunoreactive nerve fibers were examined in the carotid body of the normoxic control rats by light and electron microscopy, and the abundance of calbindin D-28k fibers in the carotid body was compared in normoxic and chronically hypoxic rats (10% O2 and 3.0-4.0% CO2 for 3 months). Calbindin D-28k immunoreactivity was recognized in nerve fibers within the carotid body. Calbindin D-28k immunoreactive nerve fibers appeared as thin processes with many varicosities. They were distributed around clusters of glomus cells, and around blood vessels. Immunoelectron microscopy revealed that the calbindin D-28k immunoreactive nerve terminals are in close apposition with the glomus cells, and membrane specialization is visible in some terminals. Some densecored vesicles in the glomus cells were aggregated in this contact region. The chronically hypoxic carotid bodies were found to be enlarged several fold, and a relative abundance of calbindin D-28k fibers was lesser than in the normoxic carotid bodies. When expressed by the density of varicosities per unit area of the parenchyma, the density of calbindin D-28k fibers associated with the glomus cells in chronically hypoxic carotid bodies was decreased by 70%. These immunohistochemical findings indicate a morphological basis for involvement of calcium binding protein in the neural pathway that modulates carotid body chemoreception.
Open Access
Changes in the distribution of the substance P and calcitonin gene-related peptide immunoreactive nerve fibers in the laryngeal mucosa of chronically hypoxic rats
(Murcia : F. Hernández, 1999) Yoshida, T.; Matsuda, H.; Hayashida, Y.; Gono, Y.; Nagahara, T.; Kawakami, T.; Takenaka, T.; Tsukuda, M.; Kusakabe, T.
The distribution and abundance of substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactive nerve fibers in four different regions of the laryngeal mucosa were compared between normoxic and chronically hypoxic rats (10% O2 and 3.0-4.0% CO, for 3 months). In the chronically hypoxic laryngeal mucosa, the number of SP and CGRP fibers within and just beneath the epithelium, and around the laryngeal gland was increased in comparison with those in the normoxic controls. Especially in the epiglottic and arytenoid regions, the number of intraepithelial SP fibers was increased remarkably. Most intraepithelial SP and CGRP fibers penetrated into the epithelium to extend to the lumina1 surface. There was no distinct difference in the distribution and abundance of these peptidergic fibers in the mucosa of the normoxic and chronically hypoxic vocal cord regions. These results suggest that the increased density of SP and CGRP fibers within the epithelium of the upper laryngeal mucosa is a predominant feature of hypoxic adaptation, and this may be involved in airway protection, swallowing, and other functions in the chronically hypoxic environment. In addition, the increased SP and CGRP fibers around the laryngeal gland suggest an enhanced mucous secretion, and this may participate in the airway defense mechanism in low O2 conditions.
Open Access
Comprehensive insights into the understanding of hypoxia in ameloblastoma
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Bologna Molina, Ronell; Schuch, Lauren; Niklander, Sven Eric
Hypoxia is characterized by a disparity between supply and demand of oxygen. The association between hypoxia and head and neck tumors is a topic of significant interest. Tumors frequently encounter areas with inadequate oxygen supply, resulting in a hypoxic microenvironment. Ameloblastoma is one of the most common benign odontogenic tumors of the maxillofacial region. It is a slow-growing but locally invasive tumor with a high recurrence rate. The literature has demonstrated the correlation between hypoxia and ameloblastoma, revealing a discernible link between the heightened expression of hypoxic markers in low oxygen conditions. This association is intricately tied to the tumoral potential for invasion, progression, and malignant transformation. Hypoxia profoundly influences the molecular and cellular landscape within ameloblastic lesions. The present review sheds light on the mechanisms, implications, and emerging perspectives in understanding this intriguing association to clarify the dynamic relationship between hypoxia and ameloblastoma.
Open Access
De novo expression of the hemoglobin scavenger receptor CD163 by activated microglia is not associated with hemorrhages in human brain lesions
(Editores F. Hernandez y Juan F. Madrid. Murcia, Universidad de Murcia, Departamento de Biologia Celular e Histologia, 2011) Holfelder, K.; Schittenhelm, J.; Trautmann, K.; Haybaeck, J.; Meyermann, R.; Beschorner, R.
The main function of CD163 (hemoglobin scavenger receptor) is to bind the hemoglobinhaptoglobin complex, thereby mediating extravasal hemolysis. However, CD163 also has an antiinflammatory function. After CD163-mediated endocytosis, hemoglobin is catabolized further by hemeoxygenase 1 (HO-1). Previously, we found expression of HO-1 to be restricted to microglia/ macrophages at sites of hemorrhages in human traumatic and ischemic brain lesions. We now investigated if CD163 expression is also correlated with hemorrhages in brain lesions. Methods. Autopsy brain tissue from 44 cases with hemorrhagic brain lesions (32 traumatic brain injuries/TBI, 12 intracerebral bleedings/ICB), 56 nonhemorrhagic brain lesions (30 ischemias, 26 hypoxias) and 6 control brains were investigated. The post injury survival times ranged from a few minutes to 60 months. Results. In controls, single perivascular monocytes expressed CD163, but only single CD163+ microglia were found in 3/6 cases. CD163+ cells in the parenchyma (activated microglia/macrophages) increased significantly within 24 hours after trauma and ischemia and within 1-7 days following ICB or hypoxia. Overall, significantly lower and higher levels of parenchymal CD163+ cells occurred in hypoxia and ischemia, respectively. Perivascular CD163+ cells also increased significantly in all pathological conditions. In areas remote from circumscribed brain lesions (TBI, ICB, ischemia), significant changes were only found in ICB and ischemia. Conclusions. De novo expression of CD163 by activated microglia/macrophages and CD163+ infiltrating monocytes are neither restricted to nor predominant in hemorrhagic brain lesions. Thus, the antiinflammatory function of CD163 probably predominates, both in hemorrhagic and non-hemorrhagic brain lesions and points to possible immunomodulatory treatment strategies targeting CD163
Open Access
DEC1 expression in 1p-aberrant oligodendroglial neoplasms
(Murcia : F. Hernández, 2005) Preusser, Matthias; Birner, P.; Ambros, I.M.; Ambros, P.F.; Budka, H.; Harris, A.L.; Hainfellner, J.A.
Background. Expression of hypoxia-related tissue factors in 1p-aberrant oligodendroglial neoplasms diminishes patient outcome. Differentiated embryochondrocyte expressed gene 1 (DEC1) has been described as novel hypoxia-related tissue factor. In our study, we assessed the expression of DEC1 in 1p aberrant oligodendroglial neoplasms and its association with necrosis and expression of hypoxia-inducible factor 1a (HIF-1a), carbonic anhydrase-9 (CA9), and vascular endothelial growth factor-mRNA (VEGF). Materials and methods. 44 primary and 16 recurrent oligodendroglial neoplasms with 1p-aberrations were investigated immunohistochemically for the expression of DEC1, HIF-1a, and CA9. Expression of VEGF was investigated using in situ hybridization. DEC1 expression was correlated with necrosis and with expression of HIF-1a, CA9, and VEGF. Results. DEC1 was expressed in tumor cell nuclei, and occasionally in nuclei of endothelial cells, and glial and neuronal cells of surrounding brain tissue. High expression (>10% of tumor cells immunolabeled) of DEC1 was found in 56 cases, low expression (<10% of tumor cells immunolabeled) was found in 3 cases. In 1 case no expression of DEC1 was evident. DEC1 expression showed no topographical association with necrosis or expression of HIF-1a, CA9, or VEGF. Conclusion. DEC1 expression is found in the majority of 1p-aberrant oligodendroglial neoplasms and does not correlate with necrosis or expression of HIF-1a, CA9, VEGF. Thus, immunohistochemical analysis of DEC1 expression is in our hands not suitable for detection of tissue hypoxia in this type of primary brain tumor.
Open Access
Endothelial heat shock response in cerebral ischemia
(Murcia : F. Hernández, 2007) Scumpia, A.J.; Kafel, J.; Hallas, B.H.; Horowitz, J.M.; Torres, G.
Blood vessels and nerve fibers often course alongside one another in an orderly fashion throughout the brain. This clustering gives rise to a reciprocal signaling network between endothelial and nerve cells that follows highly stereotyped anatomical patterns. One such molecular signal that is produced by endothelial cells and acts on surrounding neurons is heat shock protein 70. Here we briefly review recent studies that have revealed a critical role of this signaling pathway during harmful insults to the brain, particularly during episodes of cerebral ischemia.
Open Access
Enhanced expression of endothelin-1 and endothelinconverting enzyme-1 in acute hypoxic rat aorta
(Murcia : F. Hernández, 2002) Doi, Y.; Kudo, H.; Nishino, T.; Yamamoto, O.; Nagata, T.; Nara, S.; Morita, M.; Fujimoto, S.
Deeply anesthetized male Wistar rats were perfused by Hanks’ balanced salt solution bubbled with either 95%air and 5%CO2 (normoxic group) or 95%N2 and 5%CO2 (hypoxic group) from the thoracic aorta for 30 min, and the isolated abdominal aortae from both groups were used for electron microscopy, immunocytochemistry of endothelin (ET)-1 and ETconverting enzyme (ECE)-1, and in situ hybridization of p r e p r o E T-1 mRNA. A remarkable increase in the number of Weibel-Palade (WP) bodies, storage sites of E T-1 and ECE-1, occurred in the hypoxic group when compared to the normoxic group. Immunoreactivities for E T-1 and ECE-1, and signals for preproET-1 mRNA were seen along the endothelia of both groups, but the intensities were significantly elevated in the hypoxic group. The increase in the number of ECE-1 immunoreactive gold particles was noticed especially in WP bodies in the hypoxic group. These findings indicate the enhancement of preproET-1 synthesis in the aortic endothelial cells as well as the acceleration of ET- 1 processing in increased WP bodies in such cells in an experimentally hypoxic condition of the rat aortae.
Open Access
Evaluation of C-reactive-like protein in Mytilus galloprovincialis
(Elsevier, 2019-07-05) Franco-Martínez, Lorena; Tvarijonaviciute, Asta; Mateo, Sandra V.; Cerón, José J.; Romero, Diego; Oliveira, Miguel; Teles, Mariana; Martínez-Subiela, Silvia; Ciencias Sociosanitarias
C-reactive protein (CRP) is an acute phase protein of the innate immune system with an important role as biomarker in many biological processes in mammals. However, there is a lack of information regarding CRP in molluscs and there is no data about the presence of CRP-like protein in mussels. In the present work, CPR-like protein was identified and purified from the digestive gland of the Mediterranean mussel Mytilus galloprovincialis In addition, it was demonstrated that CRP-like protein can be measured accurately and precisely by a high- throughput automated method. Finally, higher levels of CRP-like protein in mussels exposed to hypoxia and nanoplastics were detected when compared to controls. The results obtained indicate that CRP-like protein could be a suitable novel biomarker of inflammatory response in mussels for biomonitoring programs being economic, easy and rapid to determine.
Open Access
Expression of ADAMTS-5 in deformed human temporomandibular joint discs
(Murcia : F. Hernández, 2008) Matsumoto, Takashi; Tojyo, Itaru; Kiga, Norifumi; Hiraishi, Yukihiro; Fujita, Shigeyuki
Objective: To study the expression of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) in tissue samples of deformed human temporomandibular joint (TMJ) discs and cells obtained from the discs. Materials and methods: Eleven adult human TMJ discs (nine diseased discs and two normal discs) were used in this study. The nine diseased discs were obtained from nine patients with internal derangement (ID) and osteoarthritis (OA) in the TMJ. These patients all had anteriorly displaced discs and deformed mandibular condyles, making conservative therapy impossible. The tissues were immunohistochemically stained using ADAMTS-5 antibodies. In addition, an articular disc cell line from one case was established by collagenase treatment. The subcultured cells under both normal and hypoxic conditions (O2: 2%) were incubated for 3, 6, 12 and 24 h after addition of interleukin-1ß (IL-1ß) (1 ng/mL). Subsequently, the expression of ADAMTS-5 was examined using reverse transcription-polymerase chain reaction (RT-PCR). Results: The control group showed negative reactions on immunohistochemical staining. The discs extracted from cases with ID and OA presented positive reactions for ADAMTS-5. The expression of ADAMTS-5 mRNA increased under both normoxia and hypoxia with the addition of IL-1ß, and the peak was observed after 3 h. Conclusion: These results suggest that ADAMTS-5 is related to deformation and destruction of human TMJ discs affected by ID and OA.
Open Access
Expression of the HIF-1α/VEGF pathway is upregulated to protect alveolar bone density reduction in nasal-obstructed rats
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Liu, Zishan; Li, Yongming
Background. Hypoxia and mouth breathing are closely related to maxillofacial bone metabolism and are characteristic of obstructive sleep apnea-hypopnea syndrome (OSAHS). Being key factors in the hypoxia response, hypoxia-inducible factor 1α (HIF-1α) and HIF-responsive gene vascular endothelial growth factor (VEGF) are essential for bone remodeling. This study focuses on the role of the HIF-1α/VEGF pathway in alveolar bone metabolism during OSAHS. Materials and methods. 36 three-week-old male Wistar rats were divided into three groups: twelve control rats, twelve bilateral nasal obstructed (BNO) rats, twelve BNO rats treated with intraperitoneal injection of Dimethyloxalylglycine (DMOG). After two weeks, the microstructure and bone mineral density (BMD) of alveolar bone were evaluated using microcomputed tomography (micro-CT). The expressions of HIF-1α and VEGF in the alveolar bone were then assessed via immunohistochemistry staining, quantitative real-time polymerase chain reaction (qRTPCR) and Western blot. Alkaline phosphatase (ALP) staining and Alizarin red S staining were performed to evaluate osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). Results. Significant reductions in alveolar bone density were noted in BNO rats. Bilateral nasal obstruction increased the expressions of HIF-1α and VEGF in alveolar bone. With upregulation of HIF1α/VEGF via DMOG, alveolar bone density of BNO rats increased. Furthermore, DMOG promoted the osteogenic differentiation of BMSCs by stabilizing the HIF-1α protein and increasing the expression of VEGF. Conclusion. Bilateral nasal obstruction changes alveolar bone structure and leads to a reduction in alveolar bone density. Moreover, the expression of the HIF-1α/VEGF signaling pathway increases to protect alveolar bone density reduction in BNO rats.
Open Access
Glucose-mediated cytoprotection in the gut epithelium under ischemic and hypoxic stress
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Huang, Chung Yen; Pai, Yu Chen; Yu, Linda Chia Hui
Single-layered intestinal epithelia play key roles in the maintenance of gut homeostasis and barrier integrity. Various types of epithelial cell death, including apoptosis, necrosis, and necroptosis, have been detected in ischemic and hypoxic stress conditions, thus resulting in bacterial translocation and gut-derived septic complications. Cytoprotective strategies, such as enteral glucose uptake, rescue intestinal epithelium from cell death after ischemic and hypoxic injury. Although glucose metabolism and energy production are generally considered to be the key factors in cytoprotection, the precise modes and sites of action have not been clarified. Our recent studies have demonstrated that energy restoration promotes crypt hyperplasia but does not prevent epithelial cell death under ischemic stress. On the other hand, glycolytic pyruvate prevents epithelial cells from undergoing apoptosis and necroptosis by scavenging free radicals in an ATP-independent manner. Distinct gut protective mechanisms involving ATP, pyruvate, glucose metabolic enzymes, and sodiumdependent glucose transporter activation are discussed here. Overall, glucose-mediated cytoprotection may be a universal mechanism that has evolved in epithelial cells for the maintenance of intestinal homeostasis. Enteral glucose supplementation is beneficial as a perioperative supportive therapy for the protection of gut barrier integrity.
Open Access
Grow2: The HIF system, energy homeostasis and the cell cycle
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2014) Moniz, Sónia; Biddlestone, John; Rocha, Sónia
Cell cycle progression is an energy demanding process and requires fine-tuned metabolic regulation. Cells must overcome an energy restriction checkpoint before becoming committed to progress through the cell cycle. Aerobic organisms need oxygen for the metabolic conversion of nutrients into energy. As such, environmental oxygen is a critical signalling molecule regulating cell fate. The Hypoxia Inducible Factors (HIFs) are a family of transcription factors that respond to changes in environmental oxygen and cell energy and coordinate a transcriptional program which forms an important part of the cellular response to a hostile environment. A significant proportion of HIFdependent transcriptional target genes, code for proteins that are involved in energy homeostasis. In this review we discuss the role of the HIF system in the regulation of energy homeostasis in response to changes in environmental oxygen and the impact on cell cycle control, and address the implications of the deregulation of this effect in cancer.
Open Access
Hepatic response to chronic hypoxia in experimental rat model through HIF-1 alpha, activator protein-1 and NF-kappa B
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Lau, Thomas Y.H.; Xiao, Jia; Liong, Emily C.; Liao, Linchuan; Leung, Tung-Ming; Nanji, Amin A.; Fung, Man Lung; Tipoe, George L.
Chronic liver diseases are commonly associated with tissue hypoxia that may cause inflammation, oxidative stress, liver cell injury and increased nuclear transcriptional regulation. The hepatic response to chronic hypoxia at the molecular level has not yet been clearly understood until now. The aim of this study is to investigate whether nuclear transcription factors [hypoxia-inducible factor-1 (HIF-1α), activator protein-1 (AP-1), nuclear factor-kappa B (NF-κB)] exhibit activity changes during hepatic response to chronic hypoxia. Blood and liver samples were collected from adult Sprague-Dawley rats living in atmospheric air or 10% oxygen for four weeks. Levels of serum alanine aminotransferase (ALT), 8-isoprostane and nitrotyrosine were measured. The activities of nuclear transcription factors and the expression of downstream genes (iNOS, eNOS, ET-1 and VEGF) were measured using RT-PCR, Western blotting and Gel shift analysis. Results showed that serum ALT level, 8-isoprostane level and formation of nitrotyrosine were within normal range at all time-points. In the hypoxic liver, DNAbinding activities of HIF-1α, NF-κB and AP-1 increased significantly. Expression levels of iNOS, VEGF and ET1 progressively increased from day 7 to day 28. eNOS was also elevated in the hypoxic liver. In conclusion, our study suggests that increased activity of HIF-1α, AP-1 and NF-κB may partly play a significant role in the hepatic response to oxidative stress and liver injury under chronic hypoxia. The increased expression of VEGF, ET-1, iNOS and eNOS may be partly due to the compensatory mechanism in the vascular beds of the liver in response to chronic hypoxia.
Open Access
Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Cannito, Stefania; Paternostro, Claudia; Busletta, Chiara; Bocca, Claudia; Colombatto, Sebastiano; Miglietta, Antonella; Novo, Erica; Parola, Maurizio
Fibrogenic progression of chronic liver diseases (CLDs) towards the end-point of cirrhosis is currently regarded, whatever the aetiology, as a dynamic and highly integrated cellular response to chronic liver injury. Liver fibrogenesis (i.e., the process) is sustained by hepatic populations of highly proliferative, pro-fibrogenic and contractile myofibroblast-like cells (MFs) that mainly originate from hepatic stellate cells (HSC) or, to a less extent, from portal fibroblasts or bone marrow-derived cells. As is well known, liver fibrosis (i.e., the result) is accompanied by perpetuation of liver injury, chronic hepatitis and persisting activation of tissue repair mechanisms, leading eventually to excess deposition of extracellular matrix (ECM) components. In this scenario, hypoxic areas represent a very common and major feature of fibrotic and cirrhotic liver during the progression of CLDs. Cells exposed to hypoxia respond by means of heterodimeric hypoxia-inducible factors (HIFs) that translocate into the nucleus and binds to a specific core sequence defined hypoxia-responsive element (HRE), present in the promoter on several genes which are considered as hypoxia-regulated target genes. HIFs transcription factors can activate a complex genetic program designed to sustain several changes necessary to efficiently counteract the decrease in oxygen tension. Accordingly, hypoxia, through up-regulation of angiogenesis, is currently believed to significantly contribute to fibrogenic progression of CLDs, mostly by affecting the pro-fibrogenic and pro-angiogenic behaviour of hepatic MFs. In addition, experimental and clinical evidence generated in the last decade also indicates that angiogenesis and fibrogenesis in CLDs may also be sustained by HIF-dependent but hypoxia-independent mediators.
Open Access
Hypoxia-induced Factor-1α in endometrial carcinoma: a mini-review of current evidence
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2012) Dousias, Vassilis; Vrekoussis, Thomas; Navrozoglou, Iordanis; Paschopoulos, Minas; Stefos, Theodore; Makrigiannakis, Antonis; Jeschke, Udo
Despite the well-established role of hypoxia in cancer biology, the literature on its effects on endometrial cancer is scarce; it mainly refers to experimental settings rather than patient-derived results. Herein, an overview of the hypoxia inducible factor 1α (HIF-1α) biology, focusing on endometrial cancer, is presented. The molecular mechanisms possibly involved in endometrial cancer progression are presented, followed by a systematic approach to the current literature on immunohistochemistry evaluation of HIF-1α expression in endometrial carcinoma. Since no consensus has been made regarding HIF-1α evaluation, the evidence of possible involvement of HIF-1α in endometrial carcinoma prognosis is weak. After a consensus has been made, properly powered studies may be able to clarify whether HIF-1α can act as a prognosticator in endometrial carcinoma.
Open Access
Hypoxic adaptation of the rat carotid body
(Murcia : F. Hernández, 2005) Kusakabe, T.; Matsuda, H.; Hayashida, Y.
Three types of hypoxia with different levels of carbon dioxide (hypocapnic, isocapnic, and hypercapnic hypoxia) have been called systemic hypoxia. The systemic hypoxic carotid bodies were enlarged several fold, but the degree of enlargement was different for each. The mean short and long axes of hypocapnic and isocapnic hypoxic carotid bodies were 1.6 (short axis) and 1.8-1.9 (long axis) times larger than normoxic control carotid bodies, respectively. Those of hypercapnic hypoxic carotid bodies were 1.2 (short axis) and 1.5 (long axis) times larger than controls, respectively. The rate of enlargement in hypercapnic hypoxic carotid bodies was lower than in hypocapnic and isocapnic hypoxic carotid bodies. The rate of vascular enlargement in hypercapnic hypoxic carotid bodies was also smaller than in hypocapnic and isocapnic hypoxic carotid bodies. Thus, the enlargement of hypoxic carotid bodies is mainly due to vascular dilation. Different levels of arterial CO2 tension change the peptidergic innervation during chronically hypoxic exposure. The characteristic vascular arrangement was under the control of altered peptidergic innervation. During the course of hypoxic adaptation, the enlargement of the carotid bodies with vascular expansion began soon after the start of hypoxic exposure. During the course of recovery, the shrinking of the carotid bodies with vascular contraction also started at a relatively early period after the termination of chronic hypoxia. These processes during the course of hypoxic adaptation and during the course of recovery were under the control of peptidergic innervation. These findings may provide a standard for further studies of hypoxic carotid bodies.
Open Access
Induction of lncRNA MALAT1 by hypoxia promotes bone formation by regulating the miR-22-3p/CEBPD axis
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Huang, Jiang; Shen, Hui liang; Feng, Ming-li; Li, Zheng; An, Shuai; Cao, Guang-lei
Adaptation to hypoxia promotes fracture healing. However, the underlying molecular mechanism remains unknown. Increasing evidence has indicated that long non-coding RNAs (lncRNAs) play crucial roles in several diseases, including fracture healing. In the present study, lncRNA microarray analysis was performed to assess the expression levels of different lncRNAs in MC3T3-E1 cells cultured under hypoxic conditions. A total of 42 lncRNAs exhibited significant differences in their expression, including metastasis associated lung adenocarcinoma transcript 1 (MALAT1), maternally expressed 3, AK046686, AK033442, small nucleolar RNA host gene 2 and distal-less homeobox 1 splice variant 2. Furthermore, overexpression of MALAT1 promoted osteoblast differentiation, alkaline phosphatase (ALP) activity and matrix mineralization of MC3T3-E1 cells, whereas its knockdown diminished hypoxia-induced cell differentiation, ALP activity and matrix mineralization in these cells. Moreover, functional analysis indicated that MALAT1 regulated the mRNA and protein expression levels of CCAAT/ enhancer binding protein δ by competitively binding to microRNA-22-3p. Adenoviral-mediated MALAT1 knockdown inhibited fracture healing in a mouse model. Taken together, the results indicated that MALAT1 may serve a role in hypoxia-mediated osteogenesis and bone formation.