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Trends in Cell Biology Jun 2020Cell death is an essential feature of development in multicellular organisms, a critical driver of degenerative diseases, and can be harnessed for treating some cancers.... (Review)
Review
Cell death is an essential feature of development in multicellular organisms, a critical driver of degenerative diseases, and can be harnessed for treating some cancers. Understanding the mechanisms governing cell death is critical for addressing its role in disease. Similarly, metabolism is essential for normal energy and biomolecule production, and goes awry in many diseases. Metabolism and cell death are tightly linked in the phenomenon of ferroptosis, a form of regulated cell death driven by peroxidation of phospholipids. Glutathione peroxidase 4 (GPX4) uses glutathione to protect cells from ferroptosis by eliminating phospholipid peroxides. Recent data have revealed glutathione/GPX4-independent axes for suppressing ferroptosis, and insight into the regulation of iron and mitochondria in ferroptosis. Ferroptosis has recently been implicated in multiple diseases, and functions as a tumor suppression mechanism. Ferroptosis induction is a promising approach in treating several conditions, including neoplastic diseases. Here, we summarize these recent advances.
Topics: Animals; Disease; Ferroptosis; Humans; Iron; Lipid Peroxides; Metabolic Networks and Pathways; Neoplasms
PubMed: 32413317
DOI: 10.1016/j.tcb.2020.02.009 -
Continuum (Minneapolis, Minn.) Feb 2019This article reviews two of the primary progressive aphasias (PPAs), disorders characterized by the early and predominant impairment of language, and primary progressive... (Review)
Review
PURPOSE OF REVIEW
This article reviews two of the primary progressive aphasias (PPAs), disorders characterized by the early and predominant impairment of language, and primary progressive apraxia of speech, a degenerative motor speech disorder that is closely related to PPA. An outline of the history and controversy surrounding how these disorders are classified is provided before the article focuses on each disorder's clinical and imaging features.
RECENT FINDINGS
Over the past decade, the classification of degenerative speech and language disorders has been refined. Clinical, imaging, and pathologic evidence suggests that primary progressive apraxia of speech is a distinct degenerative disorder. Furthermore, multiple lines of evidence have highlighted issues with nonfluent/agrammatic variant PPA, which complicates the diagnosis, prognosis, and study of this disorder. Semantic variant PPA, while not without controversy, remains one of the most well-defined disorders, with good clinicopathologic correlation.
SUMMARY
Accurate classification and diagnosis of these degenerative speech and language disorders is crucial in clinical practice and ongoing research efforts. For nonfluent/agrammatic variant PPA, the authors suggest emphasizing agrammatism as the core inclusion criterion and taking care not to include patients with isolated or predominant apraxia of speech. Isolated apraxia of speech can be the manifestation of a degenerative disease and, based on the different prognosis, should be recognized as distinct from PPA. Finally, it is important to recognize that some patients with semantic dementia, despite sharing the same pathologic associations, may not meet criteria for PPA.
Topics: Aged; Aphasia, Primary Progressive; Apraxias; Brain; Female; Fluorodeoxyglucose F18; Frontotemporal Dementia; Humans; Magnetic Resonance Imaging; Neurologic Examination; Neuropsychological Tests; Positron-Emission Tomography; Speech
PubMed: 30707189
DOI: 10.1212/CON.0000000000000699 -
Mitochondrion May 2014The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical,... (Review)
Review
The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis.
Topics: Brain; Disease; Energy Metabolism; Health; Homeostasis; Humans; Metabolic Networks and Pathways; Mitochondria; Stress, Physiological
PubMed: 23981537
DOI: 10.1016/j.mito.2013.08.006 -
Nature Jan 2016In eukaryotic cells, the endoplasmic reticulum is essential for the folding and trafficking of proteins that enter the secretory pathway. Environmental insults or... (Review)
Review
In eukaryotic cells, the endoplasmic reticulum is essential for the folding and trafficking of proteins that enter the secretory pathway. Environmental insults or increased protein synthesis often lead to protein misfolding in the organelle, the accumulation of misfolded or unfolded proteins - known as endoplasmic reticulum stress - and the activation of the adaptive unfolded protein response to restore homeostasis. If protein misfolding is not resolved, cells die. Endoplasmic reticulum stress and activation of the unfolded protein response help to determine cell fate and function. Furthermore, endoplasmic reticulum stress contributes to the aetiology of many human diseases.
Topics: Animals; Disease; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Molecular Targeted Therapy; Protein Folding; Proteins; Unfolded Protein Response
PubMed: 26791723
DOI: 10.1038/nature17041 -
Orphanet Journal of Rare Diseases Oct 2006Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and characterized by retinal pigment deposits visible on fundus... (Review)
Review
Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and characterized by retinal pigment deposits visible on fundus examination. Prevalence of non syndromic RP is approximately 1/4,000. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. Some extreme cases may have a rapid evolution over two decades or a slow progression that never leads to blindness. In some cases, the clinical presentation is a cone-rod dystrophy, in which the decrease in visual acuity predominates over the visual field loss. RP is usually non syndromic but there are also many syndromic forms, the most frequent being Usher syndrome. To date, 45 causative genes/loci have been identified in non syndromic RP (for the autosomal dominant, autosomal recessive, X-linked, and digenic forms). Clinical diagnosis is based on the presence of night blindness and peripheral visual field defects, lesions in the fundus, hypovolted electroretinogram traces, and progressive worsening of these signs. Molecular diagnosis can be made for some genes, but is not usually performed due to the tremendous genetic heterogeneity of the disease. Genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, so the visual prognosis is poor. The therapeutic approach is restricted to slowing down the degenerative process by sunlight protection and vitaminotherapy, treating the complications (cataract and macular edema), and helping patients to cope with the social and psychological impact of blindness. However, new therapeutic strategies are emerging from intensive research (gene therapy, neuroprotection, retinal prosthesis).
Topics: Adolescent; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Infant; Metabolic Diseases; Nervous System Diseases; Night Blindness; Pregnancy; Prenatal Diagnosis; Prognosis; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Rhodopsin; Sensation Disorders; Syndrome
PubMed: 17032466
DOI: 10.1186/1750-1172-1-40 -
Annual Review of Cell and Developmental... 2004Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during... (Review)
Review
Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.
Topics: Animals; Cell Nucleus; Cytoplasm; Disease; Embryonic Development; Gene Expression Regulation; Glycoproteins; Humans; Intercellular Signaling Peptides and Proteins; Neoplasms; Protein Transport; Proto-Oncogene Proteins; Signal Transduction; Wnt Proteins
PubMed: 15473860
DOI: 10.1146/annurev.cellbio.20.010403.113126 -
Theranostics 2021Aging frailty is a complex geriatric syndrome that becomes more prevalent with advancing age. It constitutes a major health problem due to frequent adverse outcomes.... (Review)
Review
Aging frailty is a complex geriatric syndrome that becomes more prevalent with advancing age. It constitutes a major health problem due to frequent adverse outcomes. Frailty is characterized by disruption of physiological homeostasis and progressive decline of health status. Multiple factors contribute to development of frailty with advancing age, including genome instability, DNA damage, epigenetic alternations, stem cell exhaustion, among others. These interrelated factors comprehensively result in loss of tissue homeostasis and diminished reserve capacity in frailty. Therefore, the aged organism gradually represents symptoms of frailty with decline in physiological functions of organs. Notably, the brain, cardiovascular system, skeletal muscle, and endocrine system are intrinsically interrelated to frailty. The patients with frailty may display the diminished reserves capacity of organ systems. Due to the complex pathophysiology, no specific treatments have been approved for prevention of this syndrome. At such, effective strategies for intervening in pathogenic process to improve health status of frail patients are highly needed. Recent progress in cell-based therapy has greatly contributed to the amelioration of degenerative diseases related to age. Mesenchymal stem cells (MSCs) can exert regenerative effects and possess anti-inflammatory properties. Transplantation of MSCs represents as a promising therapeutic strategy to address the pathophysiologic problems of frail syndrome. Currently, MSC therapy have undergone the phase I and II trials in human subjects that have endorsed the safety and efficacy of MSCs for aging frailty. However, despite these positive results, caution is still needed with regard to potential to form tumors, and further large-scale studies are warranted to confirm the therapeutic efficacy of MSC therapy.
Topics: Aged; Aging; Animals; Frail Elderly; Frailty; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Regenerative Medicine; Syndrome
PubMed: 33897874
DOI: 10.7150/thno.46436 -
International Journal of Molecular... Jan 2017
Topics: Animals; DNA Damage; DNA Repair; Diet; Disease; Epigenesis, Genetic; Humans; Oxidative Stress
PubMed: 28275213
DOI: 10.3390/ijms18010166 -
Neurologia 2022Neurologists refer to numerous "syndromes," consisting of specific combinations of clinical manifestations, following a specific progression pattern, and with the... (Review)
Review
BACKGROUND
Neurologists refer to numerous "syndromes," consisting of specific combinations of clinical manifestations, following a specific progression pattern, and with the support of blood analysis (without genomic-proteomic parameters) and neuroimaging findings (MRI, CT, perfusion SPECT, or F-FDG-PET scans). Neurodegenerative "diseases," on the other hand, are defined by specific combinations of clinical signs and histopathological findings; these must be confirmed by a clinical examination and a histology study or evidence of markers of a specific disorder for the diagnosis to be made. However, we currently know that most genetic and histopathological alterations can result in diverse syndromes. The genetic or histopathological aetiology of each syndrome is also heterogeneous, and we may encounter situations with pathophysiological alterations characterising more than one neurodegenerative disease. Sometimes, specific biomarkers are detected in the preclinical stage.
DEVELOPMENT
We performed a literature review to identify patients whose histopathological or genetic disorder was discordant with that expected for the clinical syndrome observed, as well as patients presenting multiple neurodegenerative diseases, confirming the heterogeneity and overlap between syndromes and diseases. We also observed that the treatments currently prescribed to patients with neurodegenerative diseases are symptomatic.
CONCLUSIONS
Our findings show that the search for disease biomarkers should be restricted to research centres, given the lack of disease-modifying drugs or treatments improving survival. Moreover, syndromes and specific molecular or histopathological alterations should be managed independently of one another, and new "diseases" should be defined and adapted to current knowledge and practice.
Topics: Dementia; Humans; Neurodegenerative Diseases; Neuroimaging; Proteomics; Syndrome
PubMed: 35779868
DOI: 10.1016/j.nrleng.2019.03.027 -
Indian Journal of Ophthalmology Jan 2020
Topics: Aphakia, Postcataract; Cataract Extraction; Corneal Edema; Eyeglasses; Humans; Male; Middle Aged; Myopia, Degenerative; Slit Lamp Microscopy; Syndrome; Tomography, Optical Coherence; Visual Acuity
PubMed: 31856505
DOI: 10.4103/ijo.IJO_1124_19