scholarly journals Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1548
Author(s):  
Mustafa N. Mithaiwala ◽  
Danielle Santana-Coelho ◽  
Grace A. Porter ◽  
Jason C. O’Connor
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Kynurenine Pathway ◽  
Economic Problem ◽  
Cns Disease ◽  
Therapeutic Implications ◽  
Efficacious Treatment ◽  
The Central Nervous System ◽  
Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

scholarly journals Myeloma Bone Disease: Update on Pathogenesis and Novel Treatment Strategies

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 202 ◽  
Author(s):  
Sonia Vallet ◽  
Julia-Marie Filzmoser ◽  
Martin Pecherstorfer ◽  
Klaus Podar
Keyword(s):  
Bone Disease ◽  
Molecular Mechanisms ◽  
Bone Fractures ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Nf Kappa B ◽  
Skeletal Involvement ◽  
Myeloma Bone Disease ◽  
Skeletal Related Events ◽  
Novel Treatment Strategies

Bone disease, including osteolytic lesions and/or osteoporosis, is a common feature of multiple myeloma (MM). The consequences of skeletal involvement are severe pain, spinal cord compressions, and bone fractures, which have a dramatic impact on patients’ quality of life and, ultimately, survival. During the past few years, several landmark studies significantly enhanced our insight into MM bone disease (MBD) by identifying molecular mechanisms leading to increased bone resorption due to osteoclast activation, and decreased bone formation by osteoblast inhibition. Bisphosphonates were the mainstay to prevent skeletal-related events in MM for almost two decades. Excitingly, the most recent approval of the receptor activator of NF-kappa B ligand (RANKL) inhibitor, denosumab, expanded treatment options for MBD, for patients with compromised renal function, in particular. In addition, several other bone-targeting agents, including bone anabolic drugs, are currently in preclinical and early clinical assessment. This review summarizes our up-to-date knowledge on the pathogenesis of MBD and discusses novel state-of-the-art treatment strategies that are likely to enter clinical practice in the near future.

scholarly journals Current Concepts of Hyperinflammation in Chronic Granulomatous Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Nikolaus Rieber ◽  
Andreas Hector ◽  
Taco Kuijpers ◽  
Dirk Roos ◽  
Dominik Hartl
Keyword(s):  
Chronic Granulomatous Disease ◽  
Fungal Infections ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Antimicrobial Treatment ◽  
Inflammasome Activation ◽  
Granulomatous Disease ◽  
Therapeutic Implications ◽  
Immunological Mechanisms ◽  
Surface Redox

Chronic granulomatous disease (CGD) is the most common inherited disorder of phagocytic functions, caused by genetic defects in the leukocyte nicotinamide dinucleotide phosphate (NADPH) oxidase. Consequently, CGD phagocytes are impaired in destroying phagocytosed microorganisms, rendering the patients susceptible to bacterial and fungal infections. Besides this immunodeficiency, CGD patients suffer from various autoinflammatory symptoms, such as granuloma formation in the skin or urinary tract and Crohn-like colitis. Owing to improved antimicrobial treatment strategies, the majority of CGD patients reaches adulthood, yet the autoinflammatory manifestations become more prominent by lack of causative treatment options. The underlying pathomechanisms driving hyperinflammatory reactions in CGD are poorly understood, but recent studies implicate reduced neutrophil apoptosis and efferocytosis, dysbalanced innate immune receptors, altered T-cell surface redox levels, induction of Th17 cells, the enzyme indolamine-2,3-dioxygenase (IDO), impaired Nrf2 activity, and inflammasome activation. Here we discuss immunological mechanisms of hyperinflammation and their potential therapeutic implications in CGD.

scholarly journals Caveolae-Mediated Endothelial Transcytosis across the Blood-Brain Barrier in Acute Ischemic Stroke

2021 ◽  
Vol 10 (17) ◽  
pp. 3795
Author(s):  
Min Zhou ◽  
Samuel X. Shi ◽  
Ning Liu ◽  
Yinghua Jiang ◽  
Mardeen S. Karim ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Hemorrhagic Transformation ◽  
Brain Barrier ◽  
Blood Brain ◽  
Entry Points

Blood-brain barrier (BBB) disruption following ischemic stroke (IS) contributes to hemorrhagic transformation, brain edema, increased neural dysfunction, secondary injury, and mortality. Brain endothelial cells form a para and transcellular barrier to most blood-borne solutes via tight junctions (TJs) and rare transcytotic vesicles. The prevailing view attributes the destruction of TJs to the resulting BBB damage following IS. Recent studies define a stepwise impairment of the transcellular barrier followed by the paracellular barrier which accounts for the BBB leakage in IS. The increased endothelial transcytosis that has been proven to be caveolae-mediated, precedes and is independent of TJs disintegration. Thus, our understanding of post stroke BBB deficits needs to be revised. These recent findings could provide a conceptual basis for the development of alternative treatment strategies. Presently, our concept of how BBB endothelial transcytosis develops is incomplete, and treatment options remain limited. This review summarizes the cellular structure and biological classification of endothelial transcytosis at the BBB and reviews related molecular mechanisms. Meanwhile, relevant transcytosis-targeted therapeutic strategies for IS and research entry points are prospected.

Anaplastic (undifferentiated) thyroid cancer: improved insight and therapeutic strategy into a highly aggressive disease

2005 ◽  
Vol 119 (8) ◽  
pp. 585-591 ◽  
Author(s):  
J P O’Neill ◽  
B O’Neill ◽  
C Condron ◽  
M Walsh ◽  
D Bouchier-Hayes
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
De Novo ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Anaplastic Thyroid Cancer ◽  
Anaplastic Thyroid Carcinoma ◽  
P53 Mutation ◽  
Therapeutic Implications ◽  
Undifferentiated Thyroid Cancer

Background: This review article discusses the clinical and diagnostic implications of anaplastic thyroid cancer, recognizing the aggressive nature of the disease and extensive disease progression upon diagnosis. Standard treatment strategies (surgical, chemotherapy, radiation) are discussed, comparing adjuvant and neo-adjuvant regimens and the emergence of tumour resistance with expression of multidrug resistance pumps. We question the pathological evolution of anaplasia as a ‘de novo’ disease or a post malignant transformation or dedifferentiation and the therapeutic implications of p53 mutation. Future treatment options are reviewed with an emphasis on specific molecular targets responsible for the neoplastic phenotype.Method: An electronic search on Medline and Pubmed was performed under ‘anaplastic thyroid carcinoma’, ‘anaplastic thyroid carcinogenesis’, ‘anaplastic thyroid carcinoma treatment reviews’. Relevant papers were systematically reviewed from 1965 to present.

scholarly journals The Validation Path of Hypoxia PET Imaging: Focus on Brain Tumours

2018 ◽  
Vol 25 (26) ◽  
pp. 3074-3095 ◽  
Author(s):  
Natale Quartuccio ◽  
Marie-Claude Asselin
Keyword(s):  
Brain Tumours ◽  
Imaging Techniques ◽  
Treatment Strategies ◽  
Imaging Method ◽  
Therapeutic Implications ◽  
Non Invasive ◽  
Positron Emission ◽  
Malignant Brain Tumours ◽  
The Central Nervous System ◽  
Different Levels

Background: Gliomas are brain tumours arising from the glia, the supportive tissue of the central nervous system (CNS), and constitute the commonest primary malignant brain tumours. Gliomas are graded from grade I to IV according to their appearance under the microscope. One of the most significant adverse features of high-grade gliomas is hypoxia, a biological phenomenon that develops when the oxygen concentration becomes insufficient to guarantee the normal tissue functions. Since tumour hypoxia influences negatively patient outcome and targeting hypoxia has potential therapeutic implications, there is currently great interest in imaging techniques measuring hypoxia. Objectives: The aim of this review is to provide up to date evidence on the radiotracers available for measuring hypoxia in brain tumours by means of positron emission tomography (PET), the most extensively investigated imaging approach to quantify hypoxia. Methods: The review is based on preclinical and clinical papers and describes the validation status of the different available radiotracers. Results: To date, [F-18] fluoromisonidazole ([18F]FMISO) remains the most widely used radiotracer for imaging hypoxia in patients with brain tumours, but experience with other radiotracers has expanded in the last two decades. Validation of hypoxia radiotracers is still on-going and essential before these radiopharmaceuticals can become widely used in the clinical setting. Conclusion: Availability of a non-invasive imaging method capable of reliably measuring and mapping different levels of oxygen in brain tumours would provide the critical means of selecting patients that may benefit from tailored treatment strategies targeting hypoxia.

scholarly journals Current perspectives on cardiac amyloidosis

2012 ◽  
Vol 302 (3) ◽  
pp. H544-H552 ◽  
Author(s):  
Jian Guan ◽  
Shikha Mishra ◽  
Rodney H. Falk ◽  
Ronglih Liao
Keyword(s):  
Light Chain ◽  
Cardiac Amyloidosis ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Clinical Syndrome ◽  
Precursor Protein ◽  
Immunoglobulin Light Chain ◽  
Infiltrative Cardiomyopathy ◽  
Almost All

Amyloidosis represents a group of diseases in which proteins undergo misfolding to form insoluble fibrils with subsequent tissue deposition. While almost all deposited amyloid fibers share a common nonbranched morphology, the affected end organs, clinical presentation, treatment strategies, and prognosis vary greatly among this group of diseases and are largely dependent on the specific amyloid precursor protein. To date, at least 27 precursor proteins have been identified to result in either local tissue or systemic amyloidosis, with nine of them manifesting in cardiac deposition and resulting in a syndrome termed “cardiac amyloidosis” or “amyloid cardiomyopathy.” Although cardiac amyloidosis has been traditionally considered to be a rare disorder, as clinical appreciation and understanding continues to grow, so too has the prevalence, suggesting that this disease may be greatly underdiagnosed. The most common form of cardiac amyloidosis is associated with circulating amyloidogenic monoclonal immunoglobulin light chain proteins. Other major cardiac amyloidoses result from a misfolding of products of mutated or wild-type transthyretin protein. While the various cardiac amyloidoses share a common functional consequence, namely, an infiltrative cardiomyopathy with restrictive pathophysiology leading to progressive heart failure, the underlying pathophysiology and clinical syndrome varies with each precursor protein. Herein, we aim to provide an up-to-date overview of cardiac amyloidosis from nomenclature to molecular mechanisms and treatment options, with a particular focus on amyloidogenic immunoglobulin light chain protein cardiac amyloidosis.

Chronic Nonbacterial Osteomyelitis: Pathophysiological Concepts and Current Treatment Strategies

2016 ◽  
Vol 43 (11) ◽  
pp. 1956-1964 ◽  
Author(s):  
Sigrun R. Hofmann ◽  
Anja Schnabel ◽  
Angela Rösen-Wolff ◽  
Henner Morbach ◽  
Hermann J. Girschick ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Chronic Recurrent Multifocal Osteomyelitis ◽  
Current Treatment ◽  
Multifocal Osteomyelitis ◽  
The One ◽  
Molecular Pathophysiology ◽  
Bone Inflammation ◽  
Chronic Nonbacterial Osteomyelitis

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder, covering a clinical spectrum with asymptomatic inflammation of single bones at the one end, and chronic recurrent multifocal osteomyelitis (CRMO) at the other end. The exact molecular pathophysiology of CNO remains largely unknown. Provided familial clusters and the association with inflammatory disorders of the skin and intestine suggest a genetic predisposition. Recently, profound dysregulation of cytokine responses was demonstrated in CRMO. Failure to produce antiinflammatory cytokines interleukin (IL)-10 and IL-19 contributes to activation of inflammasomes and subsequent IL-1β release. In IL-10–deficient and in CNO-prone chronic multifocal osteomyelitis mice, IL-1β was linked to bone inflammation. Further, alterations to the gut microbiome were suggested in contributing to IL-1β release from innate immune cells in mice, offering an interesting target in the search for molecular mechanisms in CNO. Here, we summarize clinical presentation and treatment options in CNO/CRMO, current pathophysiological concepts, available mouse models, and promising future scientific directions.

scholarly journals Tryptophan metabolism in the central nervous system: medical implications

2006 ◽  
Vol 8 (20) ◽  
pp. 1-27 ◽  
Author(s):  
Jon P. Ruddick ◽  
Andrew K. Evans ◽  
David J. Nutt ◽  
Stafford L. Lightman ◽  
Graham A.W. Rook ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Mechanisms ◽  
Kynurenine Pathway ◽  
Tryptophan Metabolism ◽  
Integral Role ◽  
The Central Nervous System ◽  
Acquired Immunodeficiency ◽  
Hydroxyanthranilic Acid ◽  
Immunodeficiency Syndrome

The metabolism of the amino acid l-tryptophan is a highly regulated physiological process leading to the generation of several neuroactive compounds within the central nervous system. These include the aminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), products of the kynurenine pathway of tryptophan metabolism (including 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic acid and kynurenic acid), the neurohormone melatonin, several neuroactive kynuramine metabolites of melatonin, and the trace amine tryptamine. The integral role of central serotonergic systems in the modulation of physiology and behaviour has been well documented since the first description of serotonergic neurons in the brain some 40 years ago. However, while the significance of the peripheral kynurenine pathway of tryptophan metabolism has also been recognised for several decades, it has only recently been appreciated that the synthesis of kynurenines within the central nervous system has important consequences for physiology and behaviour. Altered kynurenine metabolism has been implicated in the pathophysiology of conditions such as acquired immunodeficiency syndrome (AIDS)-related dementia, Huntington's disease and Alzheimer's disease. In this review we discuss the molecular mechanisms involved in regulating the metabolism of tryptophan and consider the medical implications associated with dysregulation of both serotonergic and kynurenine pathways of tryptophan metabolism.

scholarly journals Contemporary views of the mechanisms for development of myofascial pain syndrome and its treatment strategies

2020 ◽  
Vol 12 (6) ◽  
pp. 83-89
Author(s):  
G. R. Tabeeva ◽  
E. A. Kiryanova
Keyword(s):  
Molecular Mechanisms ◽  
Myofascial Pain ◽  
Trigger Point ◽  
Meta Analysis ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Pain Syndrome ◽  
Myofascial Pain Syndrome ◽  
Diagnostic Value ◽  
Pathological Process

Myofascial pain syndrome (MFPS) is a regional pain syndrome that can be diagnosed in any age group and is characterized by the presence of a trigger point in the muscle involved in the pathological process. Clarifying the molecular mechanisms of trigger point formation and dysregulation of specific skeletal muscle proteins is important to understand the causes of abnormal sarcomere contraction observed in myofascial pain. Wide variability in using the diagnostic criteria in some cases leads to the impossibility of performing a meta-analysis of the data; in this connection, the search for the gold standard for MFPS diagnosis is actively underway. At the moment, a special clinical examination is of paramount diagnostic value. The paper considers various treatment options for myofascial pain and discusses the priority importance of using nonsteroidal anti-inflammatory drugs and muscle relaxants, as well as non-drug therapies.

scholarly journals Pre-Clinical Research Advancements Relating to Improving the Diagnosis and Treatment of Malignant Pleural Mesothelioma: A Review

Onco ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 49-82
Author(s):  
Ben Johnson ◽  
Kenneth Lee ◽  
Yuen Yee Cheng
Keyword(s):  
Clinical Research ◽  
Malignant Pleural Mesothelioma ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Latency Period ◽  
Pleural Mesothelioma ◽  
Diagnostic Biomarkers ◽  
Disease Biology ◽  
Long Latency

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the lung lining that is predominantly associated with occupational exposure to asbestos. MPM is responsible for thousands of deaths worldwide every year, with the median survival of MPM of 8–14 months. There are limited biomarkers available in the clinic to effectively diagnose MPM, an invasive biopsy procedure is usually required to provide a definitive diagnosis. Due to the long latency period associated with MPM disease presentation, the cancer is usually at an advanced stage at the time of diagnosis where treatment options are largely ineffective at controlling disease progression. Previous MPM-based pre-clinical studies have made significant strides in determining the exact molecular mechanisms associated with asbestos carcinogenesis. Exploring less invasive blood-based biomarkers and treatment strategies involving targeted therapy, immunotherapy, and virotherapy is particularly important. Research in these areas is of crucial importance in relation to improving the rate of novel diagnostic biomarkers and treatment strategies progressing through to clinical trials and ultimately into the clinical setting. This review comprehensively summarises both previous and current pre-clinical research developments that have specifically contributed to an improved understanding of MPM disease biology, and the development of novel diagnostic biomarkers and treatment strategies.

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