Complement Involvement in Periodontitis: Molecular Mechanisms and Rational Therapeutic Approaches

AbstractOn 12 March 2020, the outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization. As of 4 August 2020, more than 18 million confirmed infections had been reported globally. Most patients have mild symptoms, but some patients develop respiratory failure which is the leading cause of death among COVID-19 patients. Endothelial cells with high levels of angiotensin-converting enzyme 2 expression are major participants and regulators of inflammatory reactions and coagulation. Accumulating evidence suggests that endothelial activation and dysfunction participate in COVID-19 pathogenesis by altering the integrity of vessel barrier, promoting pro-coagulative state, inducing endothelial inflammation, and even mediating leukocyte infiltration. This review describes the proposed cellular and molecular mechanisms of endothelial activation and dysfunction during COVID-19 emphasizing the principal mediators and therapeutic implications.

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

Life ◽

10.3390/life11040332 ◽

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.

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Epigenetics

Oxford Textbook of Cancer Biology ◽

10.1093/med/9780198779452.003.0005 ◽

2019 ◽

pp. 56-70

Author(s):

Edward Hookway ◽

Nicholas Athanasou ◽

Udo Oppermann

Keyword(s):

Gene Expression ◽

Histone Deacetylases ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Tumour Suppressor Genes ◽

Epigenetic Mechanisms ◽

Therapeutic Approaches ◽

Control Of Gene Expression ◽

Non Coding Rnas ◽

Epigenetic Processes

Epigenetics is a term that refers to a collection of diverse mechanisms that are important in both the control of gene expression and the transmission of this information during cell division. Epigenetic processes are deranged in many cancers, leading to a combination of inappropriate silencing of tumour suppressor genes and overexpression of oncogenes. In this chapter, the molecular mechanisms that underpin the major epigenetic processes of DNA methylation, histone modification, and non-coding RNAs will be described in both their normal physiological roles and in the context of cancer. The challenge of understanding the complexity of the interactions between different epigenetic mechanisms and the limitations of our current knowledge will be highlighted. Therapeutic approaches towards targeting deranged epigenetic processes will also be described, such as the use of small molecule inhibitors of histone deacetylases.

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Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Cells ◽

10.3390/cells9040979 ◽

2020 ◽

Vol 9 (4) ◽

pp. 979 ◽

Cited By ~ 5

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.

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Molecular Mechanisms of Heat Shock Factors in Cancer

Cells ◽

10.3390/cells9051202 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1202

Author(s):

Mikael Christer Puustinen ◽

Lea Sistonen

Keyword(s):

Heat Shock ◽

Molecular Mechanisms ◽

Expression Patterns ◽

Heat Shock Factors ◽

Therapeutic Approaches ◽

The Past ◽

Cancer Types ◽

Cellular Pathways ◽

As Stress ◽

Regulatory Functions

Malignant transformation is accompanied by alterations in the key cellular pathways that regulate development, metabolism, proliferation and motility as well as stress resilience. The members of the transcription factor family, called heat shock factors (HSFs), have been shown to play important roles in all of these biological processes, and in the past decade it has become evident that their activities are rewired during tumorigenesis. This review focuses on the expression patterns and functions of HSF1, HSF2, and HSF4 in specific cancer types, highlighting the mechanisms by which the regulatory functions of these transcription factors are modulated. Recently developed therapeutic approaches that target HSFs are also discussed.

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A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21124277 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4277 ◽

Cited By ~ 1

Author(s):

Weronika Rzepnikowska ◽

Joanna Kaminska ◽

Dagmara Kabzińska ◽

Katarzyna Binięda ◽

Andrzej Kochański

Keyword(s):

Molecular Mechanisms ◽

Genetic Diagnosis ◽

Clinical Manifestations ◽

Model System ◽

Research Field ◽

Therapeutic Approaches ◽

Rare Disorders ◽

Advantages And Disadvantages ◽

Pathogenic Variants ◽

Disease Subtypes

Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of yeast as a model system in which to study CMT diseases. We show how this single-cell organism may be used to discriminate between pathogenic variants, to uncover the mechanism of pathogenesis, and to discover new therapies for CMT disease.

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Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities

Cells ◽

10.3390/cells9092033 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2033

Author(s):

Antonio Musarò

Keyword(s):

Molecular Mechanisms ◽

Regenerative Process ◽

Muscle Disease ◽

Original Research ◽

Therapeutic Approaches ◽

Environmental Signals ◽

Homeostatic Process ◽

Muscle Compartment ◽

Muscle Homeostasis ◽

Stem Cell Populations

The capacity of adult muscle to regenerate in response to injury stimuli represents an important homeostatic process. Regeneration is a highly coordinated program that partially recapitulates the embryonic developmental program and involves the activation of the muscle compartment of stem cells, namely satellite cells, as well as other precursor cells, whose activity is strictly dependent on environmental signals. However, muscle regeneration is severely compromised in several pathological conditions due to either the progressive loss of stem cell populations or to missing signals that limit the damaged tissues from efficiently activating a regenerative program. It is, therefore, plausible that the loss of control over these cells’ fate might lead to pathological cell differentiation, limiting the ability of a pathological muscle to sustain an efficient regenerative process. This Special Issue aims to bring together a collection of original research and review articles addressing the intriguing field of the cellular and molecular players involved in muscle homeostasis and regeneration and to suggest potential therapeutic approaches for degenerating muscle disease.

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Neuroinflammatory Nexus of Pediatric Epilepsy

Journal of Pediatric Epilepsy ◽

10.1055/s-0038-1668601 ◽

2018 ◽

Vol 07 (02) ◽

pp. 032-039

Author(s):

Shruti Bagla ◽

Alan Dombkowski

Keyword(s):

Inflammatory Mediators ◽

Molecular Mechanisms ◽

Potential Role ◽

Recent Literature ◽

Refractory Epilepsy ◽

Genetic Mutation ◽

Pediatric Epilepsy ◽

Therapeutic Approaches ◽

New Therapeutic Approaches

AbstractA rapidly growing body of evidence supports the premise that neuroinflammation plays an important role in initiating and sustaining seizures in a range of pediatric epilepsies. Clinical and experimental evidence indicates that neuroinflammation is both an outcome and a contributor to seizures. In this manner, seizures that arise from an initial insult (e.g., infection, trauma, and genetic mutation) contribute to an inflammatory response that subsequently promotes recurrent seizures. This cyclic relationship between seizures and neuroinflammation has been described as a “vicious cycle.” Studies of human tissue resected for surgical treatment of refractory epilepsy have reported activated inflammatory and immune signaling pathways, while animal models have been used to demonstrate that key inflammatory mediators lead to increased seizure susceptibility. Further characterization of the molecular mechanisms involved in this cycle may ultimately enable the development of new therapeutic approaches for the treatment of epilepsy. In this brief review, we focus on key inflammatory mediators that have become prominent in recent literature of epilepsy, including newly characterized microRNAs and their potential role in neuroinflammatory signaling.

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Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients

Nature Communications ◽

10.1038/s41467-019-13751-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 24

Author(s):

David Michalovich ◽

Noelia Rodriguez-Perez ◽

Sylwia Smolinska ◽

Michal Pirozynski ◽

David Mayhew ◽

...

Keyword(s):

Disease Severity ◽

Molecular Mechanisms ◽

Murine Models ◽

Therapeutic Approaches ◽

Asthma Phenotype ◽

Disease Phenotypes ◽

Disease States ◽

Asthma Patients ◽

Induced Changes ◽

Redundant Role

AbstractIn order to improve targeted therapeutic approaches for asthma patients, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as obese asthmatics or severe asthmatics, are required. Here we report immunological and microbiome alterations in obese asthmatics (n = 50, mean age = 45), non-obese asthmatics (n = 53, mean age = 40), obese non-asthmatics (n = 51, mean age = 44) and their healthy counterparts (n = 48, mean age = 39). Obesity is associated with elevated proinflammatory signatures, which are enhanced in the presence of asthma. Similarly, obesity or asthma induced changes in the composition of the microbiota, while an additive effect is observed in obese asthma patients. Asthma disease severity is negatively correlated with fecal Akkermansia muciniphila levels. Administration of A. muciniphila to murine models significantly reduces airway hyper-reactivity and airway inflammation. Changes in immunological processes and microbiota composition are accentuated in obese asthma patients due to the additive effects of both disease states, while A. muciniphila may play a non-redundant role in patients with a severe asthma phenotype.

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Molecular Mechanisms Related to Hormone Inhibition Resistance in Prostate Cancer

Cells ◽

10.3390/cells8010043 ◽

2019 ◽

Vol 8 (1) ◽

pp. 43 ◽

Cited By ~ 10

Author(s):

Veronica Mollica ◽

Vincenzo Di Nunno ◽

Alessia Cimadamore ◽

Antonio Lopez-Beltran ◽

Liang Cheng ◽

...

Keyword(s):

Prostate Cancer ◽

Advanced Prostate Cancer ◽

Molecular Mechanisms ◽

High Sensitivity ◽

New Drugs ◽

Prostate Cancer Cells ◽

Therapeutic Approaches ◽

Hormone Production ◽

Development Of Resistance ◽

History Of

Management of metastatic or advanced prostate cancer has acquired several therapeutic approaches that have drastically changed the course of the disease. In particular due to the high sensitivity of prostate cancer cells to hormone depletion, several agents able to inhibit hormone production or binding to nuclear receptor have been evaluated and adopted in clinical practice. However, despite several hormonal treatments being available nowadays for the management of advanced or metastatic prostate cancer, the natural history of the disease leads inexorably to the development of resistance to hormone inhibition. Findings regarding the mechanisms that drive this process are of particular and increasing interest as these are potentially related to the identification of new targetable pathways and to the development of new drugs able to improve our patients’ clinical outcomes.

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