scholarly journals Hypoxia and Hypoxia-Inducible Factor Signaling in Muscular Dystrophies: Cause and Consequences

2021 ◽  
Vol 22 (13) ◽  
pp. 7220
Author(s):  
Thuy-Hang Nguyen ◽  
Stephanie Conotte ◽  
Alexandra Belayew ◽  
Anne-Emilie Declèves ◽  
Alexandre Legrand ◽  
...  
Keyword(s):  
Cell Function ◽  
Current Knowledge ◽  
Genetic Defect ◽  
Hypoxia Inducible Factor ◽  
Muscular Dystrophies ◽  
Compensatory Mechanisms ◽  
Hypoxia Response ◽  
Muscle Disorders ◽  
Almost All ◽  
The Impact

Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology.

Gastrointestinal defects and immunodeficiency syndrome with normal in vitro IgG production

2018 ◽  
Vol 5 (3) ◽  
pp. 91-99
Author(s):  
Alexandra Langlois ◽  
Bahar Torabi ◽  
Marieme Dembele ◽  
Marylin Desjardins ◽  
Reza Alizadehfar ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Current Knowledge ◽  
Genetic Defect ◽  
Peripheral Blood Mononuclear ◽  
Cardiac Malformations ◽  
Immunodeficiency Syndrome

Background: Gastrointestinal defects and immunodeficiency syndrome (GIDID) is a severe neonatal disorder usually fatal within the first months of life. We report a case presenting with intestinal atresia, combined immunodeficiency, and a novel association with hypothyroidism and cardiac malformations. The immune phenotype was remarkable for agammaglobulinemia, lymphopenia, and mildly decreased lymphocyte proliferation. We present here the unique phenotype as well as studies to determine if the agammaglobulinemia was due to an intrinsic B lymphocyte defect. Methods: Peripheral blood mononuclear cells from the patient and a healthy control were isolated by Ficoll-Hypaque centrifugation and stimulated with anti-CD40, IL-4 and IL-21 for 7 days. Total IgG production was measured by ELISA in the supernatant of the stimulated sample on day 7. Cells were stained for CD19, CD27, IgM, CD11b, CD11c, and CD14. Results: At day 7, supernatant from the patient stimulated cells contained levels of total IgG comparable to the control (755 ng/mL vs. 658 ng/mL, respectively). B cell maturation appeared impaired, as morphologically the patient sample demonstrated fewer B cell clones and cells with dendritic projections. Conclusions: Despite this typical severe clinical picture of GIDID with agammaglobulinemia, IgG production was detected under optimal stimulation for induction of plasma cells. This suggests that there may not be an inherent defect in class switching and antibody production in B cells in this disorder. It is possible that the in vivo physical or cytokine milieu may be defective for optimal B cell function. Further studies assessing the function of the immune cells as well as possible gastrointestinal loss of immunoglobulins are needed in this disease. Statement of novelty: Despite much improvement in understanding the effects of TTC7A mutations in GIDID, the root cause of hypogammaglobulinemia in these patients is still unclear. The work portrayed in this study furthers the current knowledge. It suggests that when appropriately stimulated in vitro, this patient’s B cells were capable of adequate immunoglobulin production. Moreover, to the best of our knowledge, this patient is the first with this genetic defect to be reported with hypothyroidism and cardiac malformations.

scholarly journals Targeting Cytoprotective Autophagy to Enhance Anticancer Therapies

2021 ◽  
Vol 11 ◽  
Author(s):  
Malina Xiao ◽  
Alice Benoit ◽  
Meriem Hasmim ◽  
Caroline Duhem ◽  
Guillaume Vogin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Current Knowledge ◽  
Therapeutic Benefit ◽  
Cancer Therapies ◽  
Cancer Resistance ◽  
Tumor Resistance ◽  
Anti Cancer ◽  
Almost All ◽  
The Impact

Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.

scholarly journals Hypoxia Pathway Proteins in Normal and Malignant Hematopoiesis

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 155 ◽  
Author(s):  
Ben Wielockx ◽  
Tatyana Grinenko ◽  
Peter Mirtschink ◽  
Triantafyllos Chavakis
Keyword(s):  
Cell Fate ◽  
Current Knowledge ◽  
Hypoxia Inducible Factor ◽  
Adult Life ◽  
Low Oxygen ◽  
Hematopoietic Stem ◽  
Metabolism Regulation ◽  
Hsc Niche ◽  
Hif Pathway ◽  
The Impact

The regulation of oxygen (O2) levels is crucial in embryogenesis and adult life, as O2 controls a multitude of key cellular functions. Low oxygen levels (hypoxia) are relevant for tissue physiology as they are integral to adequate metabolism regulation and cell fate. Hence, the hypoxia response is of utmost importance for cell, organ and organism function and is dependent on the hypoxia-inducible factor (HIF) pathway. HIF pathway activity is strictly regulated by the family of oxygen-sensitive HIF prolyl hydroxylase domain (PHD) proteins. Physiologic hypoxia is a hallmark of the hematopoietic stem cell (HSC) niche in the bone marrow. This niche facilitates HSC quiescence and survival. The present review focuses on current knowledge and the many open questions regarding the impact of PHDs/HIFs and other proteins of the hypoxia pathway on the HSC niche and on normal and malignant hematopoiesis.

scholarly journals How does chemotherapy treatment damage the prepubertal testis?

Reproduction ◽  
2018 ◽  
Vol 156 (6) ◽  
pp. R209-R233 ◽  
Author(s):  
Caroline M Allen ◽  
Federica Lopes ◽  
Rod T Mitchell ◽  
Norah Spears
Keyword(s):  
Cancer Survival ◽  
Cell Function ◽  
Current Knowledge ◽  
Survival Rates ◽  
Chemotherapy Treatment ◽  
Therapy Targets ◽  
Chemotherapy Agents ◽  
The Impact

Chemotherapy treatment is a mainstay of anticancer regimens, significantly contributing to the recent increase in childhood cancer survival rates. Conventional cancer therapy targets not only malignant but also healthy cells resulting in side effects including infertility. For prepubertal boys, there are currently no fertility preservation strategies in use, although several potential methods are under investigation. Most of the current knowledge in relation to prepubertal gonadotoxicity has been deduced from adult studies; however, the prepubertal testis is relatively quiescent in comparison to the adult. This review provides an overview of research to date in humans and animals describing chemotherapy-induced prepubertal gonadotoxicity, focusing on direct gonadal damage. Testicular damage is dependent upon the agent, dosage, administration schedule and age/pubertal status at time of treatment. The chemotherapy agents investigated so far target the germ cell population activating apoptotic pathways and may also impair Sertoli cell function. Due to use of combined chemotherapy agents for patients, the impact of individual drugs is hard to define, however, use of in vivo and in vitro animal models can overcome this problem. Furthering our understanding of how chemotherapy agents target the prepubertal testis will provide clarity to patients on the gonadotoxicity of different drugs and aid in the development of cytoprotective agents.

scholarly journals Involvement of E3 Ligases and Deubiquitinases in the Control of HIF-α Subunit Abundance

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 598 ◽  
Author(s):  
Kateryna Kubaichuk ◽  
Thomas Kietzmann
Keyword(s):  
Cancer Progression ◽  
Current Knowledge ◽  
Hypoxia Inducible Factor ◽  
Specific Treatment ◽  
Stress Factors ◽  
Cellular Functions ◽  
Α Subunit ◽  
E3 Ligases ◽  
Cellular Processes ◽  
The Impact

The ubiquitin and hypoxia-inducible factor (HIF) pathways are cellular processes involved in the regulation of a variety of cellular functions. Enzymes called ubiquitin E3 ligases perform protein ubiquitylation. The action of these enzymes can be counteracted by another group of enzymes called deubiquitinases (DUBs), which remove ubiquitin from target proteins. The balanced action of these enzymes allows cells to adapt their protein content to a variety of cellular and environmental stress factors, including hypoxia. While hypoxia appears to be a powerful regulator of the ubiquitylation process, much less is known about the impact of DUBs on the HIF system and hypoxia-regulated DUBs. Moreover, hypoxia and DUBs play crucial roles in many diseases, such as cancer. Hence, DUBs are considered to be promising targets for cancer cell-specific treatment. Here, we review the current knowledge about the role DUBs play in the control of HIFs, the regulation of DUBs by hypoxia, and their implication in cancer progression.

scholarly journals Role of hyperoxic treatment in cancer

2020 ◽  
Vol 245 (10) ◽  
pp. 851-860
Author(s):  
Sei W Kim ◽  
In K Kim ◽  
Sang H Lee
Keyword(s):  
Cancer Treatment ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Current Knowledge ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Multiple Tumor ◽  
Hypoxic State

The occurrence of hypoxia is common in many solid tumors, and it enhances aggressive features of cancer such as cell survival, angiogenesis, and metastasis while minimizing the efficacies of chemotherapy and radiotherapy. Hypoxia also plays a pivotal role in regulating immune cell function which is important for immunotherapy. Hypoxia-inducible factor has been suggested as a master regulator of tumor cell adaptation to the hypoxic microenvironment. Currently, several approaches have been proposed to eliminate the hypoxic state in tumors for delaying cancer progression and improving therapeutic efficacy. In this review, we summarize current findings on the relevance of hyperoxia-based therapeutics for cancer treatment. Accumulating evidence indicates that hyperoxic therapy inhibits tumor growth and increases treatment efficacy. Primary antitumor effect of hyperoxic therapy may be due to the reversal of tumor hypoxia and the generation of reactive oxygen species. Restoring immune function is also suggested as a potential mechanism. Hyperoxic therapy can also cause cellular injury and organ dysfunction. In conclusion, overcoming tumor hypoxia is a major problem that needs to be solved. Further studies to standardize and personalize hyperoxia therapy according to the type of cancer, stage, and comorbidities are needed. Impact statement Tumor hypoxia promotes cancer cell aggressiveness, and is strongly associated with poor prognosis across multiple tumor types. The hypoxic microenvironments inside tumors also limit the effectiveness of radiotherapy, chemotherapy, and immunotherapy. Several approaches to eliminate hypoxic state in tumors have been proposed to delay cancer progression and improve therapeutic efficacies. This review will summarize current knowledge on hyperoxia, used alone or in combination with other therapeutic modalities, in cancer treatment. Molecular mechanisms and undesired side effects of hyperoxia will also be discussed.

scholarly journals Role of Protein Kinase A-Mediated Phosphorylation in CFTR Channel Activity Regulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Angela Della Sala ◽  
Giulia Prono ◽  
Emilio Hirsch ◽  
Alessandra Ghigo
Keyword(s):  
Cystic Fibrosis ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Chloride Transport ◽  
Current Knowledge ◽  
Genetic Defect ◽  
Channel Activity ◽  
The Impact ◽  
Kinase A ◽  
R Domain

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel expressed on the apical membrane of epithelial cells, where it plays a pivotal role in chloride transport and overall tissue homeostasis. CFTR constitutes a unique member of the ATP-binding cassette transporter superfamily, due to its distinctive cytosolic regulatory (R) domain carrying multiple phosphorylation sites that allow the tight regulation of channel activity and gating. Mutations in the CFTR gene cause cystic fibrosis, the most common lethal autosomal genetic disease in the Caucasian population. In recent years, major efforts have led to the development of CFTR modulators, small molecules targeting the underlying genetic defect of CF and ultimately rescuing the function of the mutant channel. Recent evidence has highlighted that this class of drugs could also impact on the phosphorylation of the R domain of the channel by protein kinase A (PKA), a key regulatory mechanism that is altered in various CFTR mutants. Therefore, the aim of this review is to summarize the current knowledge on the regulation of the CFTR by PKA-mediated phosphorylation and to provide insights into the different factors that modulate this essential CFTR modification. Finally, the discussion will focus on the impact of CF mutations on PKA-mediated CFTR regulation, as well as on how small molecule CFTR regulators and PKA interact to rescue dysfunctional channels.

scholarly journals Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure

2008 ◽  
Vol 2008 ◽  
pp. 1-8 ◽  
Author(s):  
Arne Andersson ◽  
Sara Bohman ◽  
L. A. Håkan Borg ◽  
Johan F. Paulsson ◽  
Sebastian W. Schultz ◽  
...  
Keyword(s):  
Cell Function ◽  
Human Islets ◽  
Long Term Results ◽  
Amyloid Formation ◽  
Potential Candidate ◽  
Amyloid Deposits ◽  
Mouse Islets ◽  
Almost All ◽  
The Impact

Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of theβ-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.

Contemporary Qur'anic Studies in Iran and its Relationship with Qur'anic Studies in the West

2012 ◽  
Vol 14 (1) ◽  
pp. 45-72
Author(s):  
Morteza Karimi-Nia
Keyword(s):  
Islamic Law ◽  
Human Sciences ◽  
The West ◽  
Communications Technologies ◽  
Religious Learning ◽  
The Status ◽  
Islamic Republic Of Iran ◽  
Almost All ◽  
The Impact ◽  
The Relationship

The status of tafsīr and Qur'anic studies in the Islamic Republic of Iran has changed significantly during recent decades. The essay provides an overview of the state of Qur'anic studies in Iran today, aiming to examine the extent of the impact of studies by Western scholars on Iranian academic circles during the last three decades and the relationship between them. As in most Islamic countries, the major bulk of academic activity in Iran in this field used to be undertaken by the traditional ʿulamāʾ; however, since the beginning of the twentieth century and the establishment of universities and other academic institutions in the Islamic world, there has been increasing diversity and development. After the Islamic Revolution, many gradual changes in the structure and approach of centres of religious learning and universities have occurred. Contemporary advancements in modern sciences and communications technologies have gradually brought the institutions engaged in the study of human sciences to confront the new context. As a result, the traditional Shīʿī centres of learning, which until 50 years ago devoted themselves exclusively to the study of Islamic law and jurisprudence, today pay attention to the teaching of foreign languages, Qur'anic sciences and exegesis, including Western studies about the Qur'an, to a certain extent, and recognise the importance of almost all of the human sciences of the West.

IFRS IMPLEMENTATION AS ONE OF THE FACTORS FOR IMPROVING THE INVESTMENT CLIMATE IN UKRAINE

2017 ◽  
Author(s):  
Kateryna Sova ◽  
◽  
Natalia Yatsenko ◽  
Denys Zagirniak ◽  
◽  
...  
Keyword(s):  
Financial Reporting ◽  
Direct Investment ◽  
Financial Statements ◽  
International Standards ◽  
Investment Climate ◽  
The European Union ◽  
Economic Activities ◽  
Financial Reporting Standards ◽  
Almost All ◽  
The Impact

The article is devoted to the study of the impact of the introduction of International Financial Reporting Standards (IFRS) on changes in the investment climate in Ukraine. The relevance of the topic is that improving the practice of applying IFRS as a tool for exchanging financial information is one of the key conditions for improving the investment climate in Ukraine. The authors have created the generalized scheme that illustrates the chronological list of enterprises that are required by law to prepare financial statements in accordance with IFRS. It was noted that in 2018, in accordance with Part 2 of Article 12 of the law on accounting and financial reporting in Ukraine and resolution of the Cabinet of Ministers of Ukraine No. 547 from 11.07.2018, the criteria of enterprises that are required to prepare financial statements in accordance with IFRS were updated. This step significantly increased the level of application of international standards due to the adoption of such a decision at the legislative level. The dynamics of the number of IFRS enterprises in Ukraine was analyzed. The analysis showed that over the past three years, the number of almost all enterprises that must apply international standards has been growing. The advantages of using IFRS for different users of financial statements were determined. It was determined that the priority users of IFRS financial statements are investors. At the same time, it was noted that the main advantage for other users of financial statements prepared in accordance with international standards is the improvement of the investment climate. The dynamics of the Investment Attractiveness Index of Ukraine based on the Likert scale in the period from 2016 to 2020 was analyzed. The direct investment receipts to Ukraine from the European Union countries were studied. The dynamics of direct investment in the Ukrainian economy was analyzed for two types of economic activities that should form financial statements in accordance with IFRS, namely, the extractive industry and quarrying, as well as financial and insurance activities.

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