scholarly journals Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 979 ◽  
Author(s):  
Valeria De Pasquale ◽  
Anna Moles ◽  
Luigi Michele Pavone
Keyword(s):  
Molecular Mechanisms ◽  
Protein Processing ◽  
Lysosomal Storage ◽  
Therapeutic Approaches ◽  
Kidney Dysfunction ◽  
Nuclear Membranes ◽  
Intracellular Organelles ◽  
Primary Focus ◽  
Storage Disorders

Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

scholarly journals Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 332
Author(s):  
Valentina Brillo ◽  
Leonardo Chieregato ◽  
Luigi Leanza ◽  
Silvia Muccioli ◽  
Roberto Costa
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Eukaryotic Cells ◽  
Therapeutic Approaches ◽  
Cellular Functions ◽  
Lipid Trafficking ◽  
Mitochondrial Ros ◽  
Intracellular Organelles ◽  
Proliferation Regulation ◽  
Dynamic Plasticity

Mitochondria are key intracellular organelles involved not only in the metabolic state of the cell, but also in several cellular functions, such as proliferation, Calcium signaling, and lipid trafficking. Indeed, these organelles are characterized by continuous events of fission and fusion which contribute to the dynamic plasticity of their network, also strongly influenced by mitochondrial contacts with other subcellular organelles. Nevertheless, mitochondria release a major amount of reactive oxygen species (ROS) inside eukaryotic cells, which are reported to mediate a plethora of both physiological and pathological cellular functions, such as growth and proliferation, regulation of autophagy, apoptosis, and metastasis. Therefore, targeting mitochondrial ROS could be a promising strategy to overcome and hinder the development of diseases such as cancer, where malignant cells, possessing a higher amount of ROS with respect to healthy ones, could be specifically targeted by therapeutic treatments. In this review, we collected the ultimate findings on the blended interplay among mitochondrial shaping, mitochondrial ROS, and several signaling pathways, in order to contribute to the dissection of intracellular molecular mechanisms involved in the pathophysiology of eukaryotic cells, possibly improving future therapeutic approaches.

The role of current biomarkers in the management of lysosomal storage disorders

2008 ◽  
Vol 30 ◽  
pp. S90-S91 ◽  
Author(s):  
I MAIRE ◽  
N GUFFON ◽  
M PIRAUD ◽  
R FROISSART
Keyword(s):  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Storage Disorders

scholarly journals Insight into Salivary Gland Aquaporins

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1547 ◽  
Author(s):  
Claudia D’Agostino ◽  
Osama A. Elkashty ◽  
Clara Chivasso ◽  
Jason Perret ◽  
Simon D. Tran ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Physiological Role ◽  
Main Role ◽  
Osmotic Gradient ◽  
Therapeutic Approaches ◽  
Potential Therapeutic Target ◽  
Transmembrane Channel ◽  
Saliva Secretion ◽  
Insight Into

The main role of salivary glands (SG) is the production and secretion of saliva, in which aquaporins (AQPs) play a key role by ensuring water flow. The AQPs are transmembrane channel proteins permeable to water to allow water transport across cell membranes according to osmotic gradient. This review gives an insight into SG AQPs. Indeed, it gives a summary of the expression and localization of AQPs in adult human, rat and mouse SG, as well as of their physiological role in SG function. Furthermore, the review provides a comprehensive view of the involvement of AQPs in pathological conditions affecting SG, including Sjögren’s syndrome, diabetes, agedness, head and neck cancer radiotherapy and SG cancer. These conditions are characterized by salivary hypofunction resulting in xerostomia. A specific focus is given on current and future therapeutic strategies aiming at AQPs to treat xerostomia. A deeper understanding of the AQPs involvement in molecular mechanisms of saliva secretion and diseases offered new avenues for therapeutic approaches, including drugs, gene therapy and tissue engineering. As such, AQP5 represents a potential therapeutic target in different strategies for the treatment of xerostomia.

scholarly journals Insight into the Role of Extracellular Vesicles in Lysosomal Storage Disorders

Genes ◽  
2019 ◽  
Vol 10 (7) ◽  
pp. 510 ◽  
Author(s):  
Brunella Tancini ◽  
Sandra Buratta ◽  
Krizia Sagini ◽  
Eva Costanzi ◽  
Federica Delo ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Lysosomal Storage Disorders ◽  
Stress Conditions ◽  
Lysosomal Storage ◽  
Pharmacological Agents ◽  
Lysosomal System ◽  
Protein Nucleic Acid ◽  
Intracellular Storage ◽  
Storage Disorders

Extracellular vesicles (EVs) have received increasing attention over the last two decades. Initially, they were considered as just a garbage disposal tool; however, it has progressively become clear that their protein, nucleic acid (namely miRNA and mRNA), and lipid contents have signaling functions. Besides, it has been established that cells release different types of vesicular structures for which characterization is still in its infancy. Many stress conditions, such as hypoxia, senescence, and oncogene activation have been associated with the release of higher levels of EVs. Further, evidence has shown that autophagic–lysosomal pathway abnormalities also affect EV release. In fact, in neurodegenerative diseases characterized by the accumulation of toxic proteins, although it has not become clear to what extent the intracellular storage of undigested materials itself has beneficial/adverse effects, these proteins have also been shown to be released extracellularly via EVs. Lysosomal storage disorders (LSDs) are characterized by accumulation of undigested substrates within the endosomal–lysosomal system, due either to genetic mutations in lysosomal proteins or to treatment with pharmacological agents. Here, we review studies investigating the role of lysosomal and autophagic dysfunction on the release of EVs, with a focus on studies exploring the release of EVs in LSD models of both genetic and pharmacological origin. A better knowledge of EV-releasing pathways activated in lysosomal stress conditions will provide information on the role of EVs in both alleviating intracellular storage of undigested materials and spreading the pathology to the neighboring tissue.

scholarly journals The Role of Histone Acetylation-/Methylation-Mediated Apoptotic Gene Regulation in Hepatocellular Carcinoma

2020 ◽  
Vol 21 (23) ◽  
pp. 8894
Author(s):  
Pradeep Kumar Rajan ◽  
Utibe-Abasi Udoh ◽  
Juan D. Sanabria ◽  
Moumita Banerjee ◽  
Gary Smith ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Histone Modification ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Nuclear Changes ◽  
New Perspective ◽  
Effective Diagnosis

Epigenetics, an inheritable phenomenon, which influences the expression of gene without altering the DNA sequence, offers a new perspective on the pathogenesis of hepatocellular carcinoma (HCC). Nonalcoholic steatohepatitis (NASH) is projected to account for a significant share of HCC incidence due to the growing prevalence of various metabolic disorders. One of the major molecular mechanisms involved in epigenetic regulation, post-translational histone modification seems to coordinate various aspects of NASH which will further progress to HCC. Mounting evidence suggests that the orchestrated events of cellular and nuclear changes during apoptosis can be regulated by histone modifications. This review focuses on the current advances in the study of acetylation-/methylation-mediated histone modification in apoptosis and the implication of these epigenetic regulations in HCC. The reversibility of epigenetic alterations and the agents that can target these alterations offers novel therapeutic approaches and strategies for drug development. Further molecular mechanistic studies are required to enhance information governing these epigenetic modulators, which will facilitate the design of more effective diagnosis and treatment options.

scholarly journals The Role of Androgen Receptor Signaling in Ovarian Cancer

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 176 ◽  
Author(s):  
Taichi Mizushima ◽  
Hiroshi Miyamoto
Keyword(s):  
Ovarian Cancer ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Receptor Signaling ◽  
Therapeutic Approaches ◽  
Androgen Receptor Signaling ◽  
Ovarian Carcinogenesis ◽  
Androgen Receptor Activity

Emerging evidence has suggested that androgen receptor signaling plays an important role in ovarian cancer outgrowth. Specifically, androgen receptor activation appears to be associated with increased risks of developing ovarian cancer and inducing tumor progression. However, conflicting findings have also been reported. This review summarizes and discusses the available data indicating the involvement of androgens as well as androgen receptor and related signals in ovarian carcinogenesis and cancer growth. Although the underlying molecular mechanisms for androgen receptor functions in ovarian cancer remain far from being fully understood, current observations may offer effective chemopreventive and therapeutic approaches, via modulation of androgen receptor activity, against ovarian cancer. Indeed, several clinical trials have been conducted to determine the efficacy of androgen deprivation therapy in patients with ovarian cancer.

scholarly journals Fronto-temporal dementia risk gene TMEM106B has opposing effects in different lysosomal storage disorders

2020 ◽  
Author(s):  
Azucena Perez-Canamas ◽  
Hideyuki Takahashi ◽  
Jane A Lindborg ◽  
Stephen M Strittmatter
Keyword(s):  
Gaucher Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Vacuolar Atpase ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Lysosomal Compartment ◽  
Lysosomal Ph ◽  
Ceroid Lipofuscinosis ◽  
Storage Disorders

Abstract TMEM106B is a transmembrane protein localized to the endo-lysosomal compartment. Genome-wide association studies have identified TMEM106B as a risk modifier of Alzheimer’s disease and frontotemporal lobar degeneration, especially with progranulin haploinsufficiency. We recently demonstrated that TMEM106B loss rescues progranulin null mouse phenotypes including lysosomal enzyme dysregulation, neurodegeneration and behavioural alterations. However, the reason whether TMEM106B is involved in other neurodegenerative lysosomal diseases is unknown. Here, we evaluate the potential role of TMEM106B in modifying the progression of lysosomal storage disorders using progranulin-independent models of Gaucher disease and neuronal ceroid lipofuscinosis. To study Gaucher disease, we employ a pharmacological approach using the inhibitor conduritol B epoxide in wild-type and hypomorphic Tmem106b−/− mice. TMEM106B depletion ameliorates neuronal degeneration and some behavioural abnormalities in the pharmacological model of Gaucher disease, similar to its effect on certain progranulin null phenotypes. In order to examine the role of TMEM106B in neuronal ceroid lipofuscinosis, we crossbred Tmem106b−/− mice with Ppt1−/−, a genetic model of the disease. In contrast to its conduritol B epoxide-rescuing effect, TMEM106B loss exacerbates Purkinje cell degeneration and motor deficits in Ppt1−/− mice. Mechanistically, TMEM106B is known to interact with subunits of the vacuolar ATPase and influence lysosomal acidification. In the pharmacological Gaucher disease model, the acidified lysosomal compartment is enhanced and TMEM106B loss rescues in vivo phenotypes. In contrast, gene-edited neuronal loss of Ppt1 causes a reduction in vacuolar ATPase levels and impairment of the acidified lysosomal compartment, and TMEM106B deletion exacerbates the mouse Ppt1−/− phenotype. Our findings indicate that TMEM106B differentially modulates the progression of the lysosomal storage disorders Gaucher disease and neuronal ceroid lipofuscinosis. The effect of TMEM106B in neurodegeneration varies depending on vacuolar ATPase state and modulation of lysosomal pH. These data suggest TMEM106B as a target for correcting lysosomal pH alterations, and in particular for therapeutic intervention in Gaucher disease and neuronal ceroid lipofuscinosis.

scholarly journals Nitric Oxide: Exploring the Contextual Link with Alzheimer’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Nicholas Asiimwe ◽  
Seung Geun Yeo ◽  
Min-Sik Kim ◽  
Junyang Jung ◽  
Na Young Jeong
Keyword(s):  
Nitric Oxide ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
The Body ◽  
Bioactive Molecules ◽  
Therapeutic Approaches ◽  
Cellular Debris ◽  
And Oxidative Stress ◽  
Proinflammatory Factors

Neuronal inflammation is a systematically organized physiological step often triggered to counteract an invading pathogen or to rid the body of damaged and/or dead cellular debris. At the crux of this inflammatory response is the deployment of nonneuronal cells: microglia, astrocytes, and blood-derived macrophages. Glial cells secrete a host of bioactive molecules, which include proinflammatory factors and nitric oxide (NO). From immunomodulation to neuromodulation, NO is a renowned modulator of vast physiological systems. It essentially mediates these physiological effects by interacting with cyclic GMP (cGMP) leading to the regulation of intracellular calcium ions. NO regulates the release of proinflammatory molecules, interacts with ROS leading to the formation of reactive nitrogen species (RNS), and targets vital organelles such as mitochondria, ultimately causing cellular death, a hallmark of many neurodegenerative diseases. AD is an enervating neurodegenerative disorder with an obscure etiology. Because of accumulating experimental data continually highlighting the role of NO in neuroinflammation and AD progression, we explore the most recent data to highlight in detail newly investigated molecular mechanisms in which NO becomes relevant in neuronal inflammation and oxidative stress-associated neurodegeneration in the CNS as well as lay down up-to-date knowledge regarding therapeutic approaches targeting NO.

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