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Cellular Immunology 2023Rheumatoid arthritis (RA) is considered to be a degenerative and progressive autoimmune disorder. Although several medicinal regimens are used to treat RA, potential... (Review)
Review
Rheumatoid arthritis (RA) is considered to be a degenerative and progressive autoimmune disorder. Although several medicinal regimens are used to treat RA, potential adverse events such as metabolic disorders and increased risk of infection, as well as drug resistance in some patients, make it essential to find an effective and safe therapeutic approach. Mesenchymal stromal/stem cells (MSCs) are a group of non-hematopoietic stromal cells with immunomodulatory and inhibitory potential. These cells exert their regulatory properties through direct cell-to-cell interactions and paracrine effects on various immune and non-immune cells. As conventional therapeutic approaches for RA are limited due to their side effects, and some patients became refractory to the treatment, MSCs are considered as a promising alternative treatment for RA. In this review, we introduced various experimental and clinical studies conducted to evaluate the therapeutic effects of MSCs on animal models of arthritis and RA patients. Then, possible modulatory and suppressive effects of MSCs on different innate and adaptive immune cells, including dendritic cells, neutrophils, macrophages, natural killer cells, B lymphocytes, and various subtypes of T cells, were categorized and summarized. Finally, limitations and future considerations for the efficient application of MSCs as a therapeutic approach in RA patients were presented.
Topics: Animals; Humans; Arthritis, Rheumatoid; Mesenchymal Stem Cells; T-Lymphocytes; Macrophages; Killer Cells, Natural; Mesenchymal Stem Cell Transplantation
PubMed: 37783061
DOI: 10.1016/j.cellimm.2023.104771 -
Metabolic Brain Disease Jun 2024Neurodegeneration, known as the progressive loss of neurons in terms of their structure and function, is the principal pathophysiological change found in the majority of... (Review)
Review
Neurodegeneration, known as the progressive loss of neurons in terms of their structure and function, is the principal pathophysiological change found in the majority of brain-related disorders. Ageing has been considered the most well-established risk factor in most common neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). There is currently no effective treatment or cure for these diseases; the approved therapeutic options to date are only for palliative care. Ageing and neurodegenerative diseases are closely intertwined; reversing the aspects of brain ageing could theoretically mitigate age-related neurodegeneration. Ever since the regenerative properties of young blood on aged tissues came to light, substantial efforts have been focused on identifying and characterizing the circulating factors in the young and old systemic milieu that may attenuate or accentuate brain ageing and neurodegeneration. Later studies discovered the superiority of old plasma dilution in tissue rejuvenation, which is achieved through a molecular reset of the systemic proteome. These findings supported the use of therapeutic blood exchange for the treatment of degenerative diseases in older individuals. The first objective of this article is to explore the rejuvenating properties of blood-based therapies in the ageing brains and their therapeutic effects on AD. Then, we also look into the clinical applications, various limitations, and challenges associated with blood-based therapies for AD patients.
PubMed: 38842660
DOI: 10.1007/s11011-024-01368-x -
EMBO Molecular Medicine Oct 2023Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked...
Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndp ), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno-associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease.
PubMed: 37642150
DOI: 10.15252/emmm.202317393 -
Journal of Advanced Research Nov 2023The gut microbiota (GM) and brain are strongly associated, which significantly affects neuronal development and disorders. GM-derived metabolites modulate neuronal... (Review)
Review
BACKGROUND
The gut microbiota (GM) and brain are strongly associated, which significantly affects neuronal development and disorders. GM-derived metabolites modulate neuronal function and influence many cascades in age-related neurodegenerative disorders (NDDs). Because of the dual role of GM in neuroprotection and neurodegeneration, understanding the balance between beneficial and harmful bacteria is crucial for applying this approach to clinical therapies.
AIM OF THE REVIEW
This review briefly discusses the role of the gut-brain relationship in promoting brain and cognitive function. Although a healthy gut environment is helpful for brain function, gut dysbiosis can disrupt the brain's environment and create a vicious cycle of degenerative cascades. The ways in which the GM population can affect brain function and the development of neurodegeneration are also discussed. In the treatment and management of NDDs, the beneficial effects of methods targeting GM populations and their derivatives, including probiotics, prebiotics, and fecal microbial transplantation (FMT) are also highlighted.
KEY SCIENTIFIC CONCEPT OF THE REVIEW
In this review, we aimed to provide a deeper understanding of the mechanisms of the gut microbe-brain relationship and their twin roles in neurodegeneration progression and therapeutic applications. Here, we attempted to highlight the different pathways connecting the brain and gut, together with the role of GM in neuroprotection and neuronal development. Furthermore, potential roles of GM metabolites in the pathogenesis of brain disorders and in strategies for its treatment are also investigated. By analyzing existing in vitro, in vivo and clinical studies, this review attempts to identify new and promising therapeutic strategies for central nervous system (CNS) disorders. As the connection between the gut microbe-brain relationship and responses to NDD treatments is less studied, this review will provide new insights into the global mechanisms of GM modulation in disease progression, and identify potential future perspectives for developing new therapies to treat NDDs.
Topics: Humans; Gastrointestinal Microbiome; Probiotics; Prebiotics; Brain; Brain Diseases; Neurodegenerative Diseases
PubMed: 36496175
DOI: 10.1016/j.jare.2022.12.001 -
Cells Sep 2023Alzheimer's disease (AD), an age-related degenerative disorder, is characterized by β-amyloid deposition, abnormal phosphorylation of tau proteins, synaptic...
Alzheimer's disease (AD), an age-related degenerative disorder, is characterized by β-amyloid deposition, abnormal phosphorylation of tau proteins, synaptic dysfunction, neuroinflammation, and oxidative stress. Despite extensive research, there are no medications or therapeutic interventions to completely treat and reverse AD. Herein, we explore the potential of hydrocortisone (HC), a natural and endogenous glucocorticoid known to have potent anti-inflammatory properties, in an Aβ-induced AD mouse model. Our investigation highlights the beneficial effects of HC administration on cognitive impairment, synaptic function enhancement, and neuronal protection in Aβ-induced AD mice. Notably, HC treatment effectively suppresses the hyperactivation of microglia and astrocytes, leading to a reduction in proinflammatory factors and alleviation of neuroinflammation. Furthermore, HC intervention demonstrates the capacity to mitigate the generation of ROS and oxidative stress. These compelling findings underscore the potential therapeutic application of HC in AD and present promising opportunities for its utilization in AD prevention and treatment. The implications drawn from our findings indicate that hydrocortisone holds promise as a viable candidate for adjunctive use with other anti-AD drugs for the clinical management of patients presenting with moderate to severe AD.
Topics: Humans; Mice; Animals; Alzheimer Disease; Amyloid beta-Peptides; Hydrocortisone; Neuroinflammatory Diseases; Cognitive Dysfunction; Oxidative Stress
PubMed: 37830561
DOI: 10.3390/cells12192348 -
Frontiers in Cardiovascular Medicine 2023Rheumatic heart disease [RHD] is the most prevalent cause of valvular heart disease in the world, outstripping degenerative aortic stenosis numbers fourfold. Despite... (Review)
Review
Rheumatic heart disease [RHD] is the most prevalent cause of valvular heart disease in the world, outstripping degenerative aortic stenosis numbers fourfold. Despite this, global resources are firmly aimed at improving the management of degenerative disease. Reasons remain complex and include lack of resources, expertise, and overall access to valve interventions in developing nations, where RHD is most prevalent. Is it time to consider less invasive alternatives to conventional valve surgery? Several anatomical and pathological differences exist between degenerative and rheumatic valves, including percutaneous valve landing zones. These are poorly documented and may require dedicated solutions when considering percutaneous intervention. Percutaneous balloon mitral valvuloplasty (PBMV) is the treatment of choice for severe mitral stenosis (MS) but is reserved for patients with suitable valve anatomy without significant mitral regurgitation (MR), the commonest lesion in RHD. Valvuloplasty also rarely offers a durable solution for patients with rheumatic aortic stenosis (AS) or aortic regurgitation (AR). MR and AR pose unique challenges to successful transcatheter valve implantation as landing zone calcification, so central in docking transcatheter aortic valves in degenerative AS, is often lacking. Surgery in young RHD patients requires mechanical prostheses for durability but morbidity and mortality from both thrombotic complications and bleeding on Warfarin remains excessively high. Also, redo surgery rates are high for progression of aortic valve disease in patients with prior mitral valve replacement (MVR). Transcatheter treatments may offer a solution to anticoagulation problems and address reoperation in patients with prior MVR or failing ventricles, but would have to be tailored to the rheumatic environment. The high prevalence of MR and AR, lack of calcification and other unique anatomical challenges remain. Improvements in tissue durability, the development of novel synthetic valve leaflet materials, dedicated delivery systems and docking stations or anchoring systems to securely land the transcatheter devices, would all require attention. We review the epidemiology of RHD and discuss anatomical differences between rheumatic valves and other pathologies with a view to transcatheter solutions. The shortcomings of current RHD management, including current transcatheter treatments, will be discussed and finally we look at future developments in the field.
PubMed: 37771665
DOI: 10.3389/fcvm.2023.1234165 -
European Neuropsychopharmacology : the... Nov 2023Alzheimer's Disease (AD) is a currently incurable but increasingly prevalent fatal and progressive neurodegenerative disease, demanding consideration of therapeutically... (Review)
Review
Alzheimer's Disease (AD) is a currently incurable but increasingly prevalent fatal and progressive neurodegenerative disease, demanding consideration of therapeutically relevant natural products and their synthetic analogues. This paper reviews evidence for effectiveness of natural and synthetic psychedelics in the treatment of AD causes and symptoms. The plastogenic effects of serotonergic psychedelics illustrate that they have efficacy for addressing multiple facets of AD pathology. We review findings illustrating neuroplasticity mechanisms of classic (serotonergic) and non-classic psychedelics that indicate their potential as treatments for AD and related dementias. Classic psychedelics modulate glutamatergic neurotransmission and stimulate synaptic and network remodeling that facilitates synaptic, structural and behavioral plasticity. Up-regulation of neurotrophic factors enable psychedelics to promote neuronal survival and glutamate-driven neuroplasticity. Muscimol modulation of GABAR reduces Aβ-induced neurotoxicity and psychedelic Sig-1R agonists provide protective roles in Aβ toxicity. Classic psychedelics also activate mTOR intracellular effector pathways in brain regions that show atrophy in AD. The potential of psychedelics to treat AD involves their ability to induce structural and functional neural plasticity in brain circuits and slow or reverse brain atrophy. Psychedelics stimulate neurotrophic pathways, increase neurogenesis and produce long-lasting neural changes through rewiring pathological neurocircuitry. Psychedelic effects on 5-HT receptor target genes and induction of synaptic, structural, and functional changes in neurons and networks enable them to promote and enhance brain functional connectivity and address diverse mechanisms underlying degenerative neurological disorders. These findings provide a rationale for immediate investigation of psychedelics as treatments for AD patients.
Topics: Humans; Alzheimer Disease; Hallucinogens; Neurodegenerative Diseases; Brain; Atrophy
PubMed: 37451163
DOI: 10.1016/j.euroneuro.2023.07.003 -
Dysphagia Oct 2023Parkinson's disease (PD) is a degenerative disorder that can cause dysphagia and dysphonia. We studied upper esophageal sphincter (UES) function and vocal tests using...
Parkinson's disease (PD) is a degenerative disorder that can cause dysphagia and dysphonia. We studied upper esophageal sphincter (UES) function and vocal tests using high-resolution videomanometry (HRVM) in PD. Ten healthy volunteers and 20 patients with PD performed swallowings (5 ml and 10 ml) and vocal tests using HRVM synchronized to the vocal acoustic recording. Mean age of the Parkinson group was 68.7 ± 9.7 years and mean disease stage of 2.7 ± 1.1 (Hoehn & Yahr scale). In videofluoroscopy swallow study (VFSS) for 5 ml, laryngeal elevation was significantly reduced (p = 0.01) in PD and for 10 ml, anteriorization (p = 0.03), elevation (p = 0.03) and total displacement (p = 0.05) were reduced in PD. In high-resolution manometry (HRM) for both volumes, intrabolus pressure was significantly higher in PD (p = 0.0004 and p = 0.001) and a higher NADIR UES relaxation pressure and NADIR UES relaxation at pharyngeal peak contraction in PD (p = 0.00007 and p = 0.0003, p = 0.01 and p = 0.04), respectively. Vocal tests results showed differences between the groups, especially for larynx anteriorization with high pitch /a/ emission (p = 0.06) in VFSS and for UES length with high pitch /i/ with tongue protrusion (p = 0.07) in HRM. Our results demonstrated a reduced compliance and subtle changes in UES function in early and moderate PD stage. We also demonstrated using HRVM that vocal tests can affect UES function. The use of HRVM proved to be an important tool in the description of events related to phonation and swallowing, which can affect the rehabilitation of patients with PD.
Topics: Humans; Middle Aged; Aged; Parkinson Disease; Deglutition Disorders; Deglutition; Manometry; Esophageal Sphincter, Upper
PubMed: 36884091
DOI: 10.1007/s00455-023-10566-1 -
Frontiers in Medicine 2023Retinal degenerative diseases, including glaucoma, age-related macular degeneration, diabetic retinopathy, and a broad range of inherited retinal diseases, are leading... (Review)
Review
Retinal degenerative diseases, including glaucoma, age-related macular degeneration, diabetic retinopathy, and a broad range of inherited retinal diseases, are leading causes of irreversible vision loss and blindness. Gene therapy is a promising and fast-growing strategy to treat both monogenic and multifactorial retinal disorders. Vectors for gene delivery are crucial for efficient and specific transfer of therapeutic gene(s) into target cells. AAV vectors are ideal for retinal gene therapy due to their inherent advantages in safety, gene expression stability, and amenability for directional engineering. The eye is a highly compartmentalized organ composed of multiple disease-related cell types. To determine a suitable AAV vector for a specific cell type, the route of administration and choice of AAV variant must be considered together. Here, we provide a brief overview of AAV vectors for gene transfer into important ocular cell types, including retinal pigment epithelium cells, photoreceptors, retinal ganglion cells, Müller glial cells, ciliary epithelial cells, trabecular meshwork cells, vascular endothelial cells, and pericytes, via distinct injection methods. By listing suitable AAV vectors in basic research and (pre)clinical studies, we aim to highlight the progress and unmet needs of AAV vectors in retinal gene therapy.
PubMed: 38105897
DOI: 10.3389/fmed.2023.1310050