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Nature Communications Sep 2023Sleep and circadian rhythm disruptions are frequent comorbidities of Parkinson's disease (PD), a disorder characterized by the progressive loss of dopaminergic (DA)...
Sleep and circadian rhythm disruptions are frequent comorbidities of Parkinson's disease (PD), a disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, the causal role of circadian clocks in the degenerative process remains uncertain. We demonstrated here that circadian clocks regulate the rhythmicity and magnitude of the vulnerability of DA neurons to oxidative stress in male Drosophila. Circadian pacemaker neurons are presynaptic to a subset of DA neurons and rhythmically modulate their susceptibility to degeneration. The arrhythmic period (per) gene null mutation exacerbates the age-dependent loss of DA neurons and, in combination with brief oxidative stress, causes premature animal death. These findings suggest that circadian clock disruption promotes dopaminergic neurodegeneration.
Topics: Male; Animals; Circadian Clocks; Dopaminergic Neurons; Drosophila; Circadian Rhythm; Dopamine
PubMed: 37737209
DOI: 10.1038/s41467-023-41540-y -
Ageing Research Reviews Sep 2023Degenerative musculoskeletal diseases (Osteoporosis, Osteoarthritis, Degenerative Spinal Disease and Sarcopenia) are pathological conditions that affect the function and... (Review)
Review
Degenerative musculoskeletal diseases (Osteoporosis, Osteoarthritis, Degenerative Spinal Disease and Sarcopenia) are pathological conditions that affect the function and pain of tissues such as bone, cartilage, and muscles, and are closely associated with ageing and long-term degeneration. Enhancer of zeste homolog 2 (EZH2), an important epigenetic regulator, regulates gene expression mainly through the PRC2-dependent trimethylation of histone H3 at lysine 27 (H3K27me3). Increasing evidence suggests that EZH2 is involved in several biological processes closely related to degenerative musculoskeletal diseases, such as osteogenic-adipogenic differentiation of bone marrow mesenchymal stem cells, osteoclast activation, chondrocyte functional status, and satellite cell proliferation and differentiation, mainly through epigenetic regulation (H3K27me3). Therefore, the synthesis and elucidation of the role of EZH2 in degenerative musculoskeletal diseases have attracted increasing attention. In addition, although EZH2 inhibitors have been approved for clinical use, whether they can be repurposed for the treatment of degenerative musculoskeletal diseases needs to be considered. Here, we reviewed the role of EZH2 in the development of degenerative musculoskeletal diseases and brought forward prospects of its pharmacological inhibitors in the improvement of the treatment of the diseases.
Topics: Humans; Histones; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Aging; Osteoarthritis
PubMed: 37597667
DOI: 10.1016/j.arr.2023.102034 -
Journal of Internal Medicine Sep 2023The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population.... (Review)
Review
The prevalence of cognitive dysfunction, dementia, and neurodegenerative disorders such as Alzheimer's disease (AD) is increasing in parallel with an aging population. Distinct types of chronic stress are thought to be instrumental in the development of cognitive impairment in central nervous system (CNS) disorders where cognitive impairment is a major unmet medical need. Increased GABAergic tone is a mediator of stress effects but is also a result of other factors in CNS disorders. Positive GABA-A receptor modulating stress and sex steroids (steroid-PAMs) such as allopregnanolone (ALLO) and medroxyprogesterone acetate can provoke impaired cognition. As such, ALLO impairs memory and learning in both animals and humans. In transgenic AD animal studies, continuous exposure to ALLO at physiological levels impairs cognition and increases degenerative AD pathology, whereas intermittent ALLO injections enhance cognition, indicating pleiotropic functions of ALLO. We have shown that GABA-A receptor modulating steroid antagonists (GAMSAs) can block the acute negative cognitive impairment of ALLO on memory in animal studies and in patients with cognitive impairment due to hepatic encephalopathy. Here we describe disorders affected by steroid-PAMs and opportunities to treat these adverse effects of steroid-PAMs with novel GAMSAs.
Topics: Animals; Humans; Aged; Receptors, GABA-A; Neurosteroids; Cognitive Dysfunction; Pregnanolone; Alzheimer Disease; gamma-Aminobutyric Acid
PubMed: 37518841
DOI: 10.1111/joim.13705 -
Movement Disorders : Official Journal... Nov 2023Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder characterized by motor and nonmotor symptoms. Several features have prognostic importance and have...
BACKGROUND
Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder characterized by motor and nonmotor symptoms. Several features have prognostic importance and have been used as key indicators for identifying clinical subtypes. However, the symptom-based classification approach has limitations with respect to the stability of the obtained subtypes.
OBJECTIVES
The purpose of this study was to identify subtypes of PD using nuclear imaging biomarkers targeting the cardiac sympathetic nervous and nigro-striatal systems and to compare patterns of cortical morphological change among obtained subtypes.
METHODS
We performed unbiased hierarchical cluster analysis using I-metaiodobenzylguanidine cardiac scintigraphy and I-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane single photon emission computed tomography data for 56 patients with PD. We compared clinical characteristics and the patterns of cortical atrophy in the obtained clusters.
RESULTS
Three clusters were identified and showed distinct characteristics in onset ages and dopamine-replacement therapy and deep brain stimulation requirements. According to the characteristics, clusters were classified into two subtypes, namely, "cardio-cortical impairment (CC)" and "dopaminergic-dominant dysfunction (DD)" subtype. The three clusters were named according to subtype and time since onset in which 14 patients were classified as "early DD," 25 as "advanced DD," and 17 as "early CC." Compared with the early DD subtype, the early CC subtype showed parietal-dominant diffuse cortical atrophy and the advanced DD subtype showed left-side predominant mild cortical atrophy.
CONCLUSIONS
Nuclear imaging biomarker-based classification can be used to identify clinically and pathologically relevant PD subtypes with distinct disease trajectories. © 2023 International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Radionuclide Imaging; Tomography, Emission-Computed, Single-Photon; Corpus Striatum; Atrophy; Tropanes; Dopamine Plasma Membrane Transport Proteins
PubMed: 37638533
DOI: 10.1002/mds.29582 -
Stem Cell Reviews and Reports Nov 2023Maintenance of the visual function is the desired outcome of ophthalmologic therapies. The shortcomings of the current treatment options, like partial recovery,... (Review)
Review
Maintenance of the visual function is the desired outcome of ophthalmologic therapies. The shortcomings of the current treatment options, like partial recovery, post-operation failure, rigorous post-operative care, complications, etc., which are usually encountered with the conventional treatment options has warranted newer treatment options that may eliminate the root cause of diseases and minimize the side effects. Cell therapies, a class of regenerative medicines, have emerged as cutting-edge treatment option. The corneal and retinal dystrophies during the ocular disorders are the major cause of blindness, worldwide. Corneal disorders are mainly categorized mainly into corneal epithelial, stromal, and endothelial disorders. On the other hand, glaucoma, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, Stargardt Disease, choroideremia, Leber congenital amaurosis are then major retinal degenerative disorders. In this manuscript, we have presented a detailed overview of the development of cell-based therapies, using embryonic stem cells, bone marrow stem cells, mesenchymal stem cells, dental pulp stem cells, induced pluripotent stem cells, limbal stem cells, corneal epithelial, stromal and endothelial, embryonic stem cell-derived differentiated cells (like retinal pigment epithelium or RPE), neural progenitor cells, photoreceptor precursors, and bone marrow-derived hematopoietic stem/progenitor cells etc. The manuscript highlights their efficiency, drawbacks and the strategies that have been explored to regain visual function in the preclinical and clinical state associated with them which can be considered for their potential application in the development of treatment.
Topics: Humans; Cornea; Cell- and Tissue-Based Therapy; Retinal Degeneration; Retina; Corneal Diseases
PubMed: 37704835
DOI: 10.1007/s12015-023-10623-0 -
International Ophthalmology Oct 2023Age-related macular degeneration (AMD) is a retinal degenerative disorder prevalent in the elderly population, which leads to the loss of central vision. The disease... (Review)
Review
Age-related macular degeneration (AMD) is a retinal degenerative disorder prevalent in the elderly population, which leads to the loss of central vision. The disease progression can be managed, if not prevented, either by blocking neovascularization ("wet" form of AMD) or by preserving retinal pigment epithelium and photoreceptor cells ("dry" form of AMD). Although current therapeutic modalities are moderately successful in delaying the progression and management of the disease, advances over the past years in regenerative medicine using iPSC, embryonic stem cells, advanced materials (including nanomaterials) and organ bio-printing show great prospects in restoring vision and efficient management of either forms of AMD. This review focuses on the molecular mechanism of the disease, model systems (both cellular and animal) used in studying AMD, the list of various regenerative therapies and the current treatments available. The article also highlights on the recent clinical trials using regenerative therapies and management of the disease.
Topics: Aged; Animals; Humans; Macular Degeneration; Retina; Retinal Pigment Epithelium; Neovascularization, Pathologic
PubMed: 37347455
DOI: 10.1007/s10792-023-02767-2 -
The American Journal of Geriatric... Nov 2023A systematic review was conducted to answer whether adult-onset post-traumatic stress disorder (PTSD) is associated with increased risk of Parkinson's disease (PD) and...
OBJECTIVE
A systematic review was conducted to answer whether adult-onset post-traumatic stress disorder (PTSD) is associated with increased risk of Parkinson's disease (PD) and related synucleinopathies.
DESIGN
A systematic search of Medline (Ovid), Embase (Elsevier), PsycInfo (Ovid), Cochrane Library (Wiley), and Web of Science (Clarivate) was performed using MeSH headings and equivalent terms for PTSD, PD, DLB, and related disorders.
SETTING
No restrictions.
PARTICIPANTS
Eligible articles were published in peer-reviewed journals, sampled adult human populations, and treated PTSD and degenerative synucleinopathies as exposures and outcomes, respectively.
MEASUREMENTS
Extracted data included diagnostic methods, sample characteristics, matching procedures, covariates, and effect estimates. Bias assessment was performed with the Newcastle-Ottawa scale. Hazard ratios were pooled using the random effects model, and the Hartung-Knapp adjustment was applied due to the small number of studies.
RESULTS
A total of six articles comprising seven unique samples (total n = 1,747,378) met eligibility criteria. The risk of PD was reported in three retrospective cohort studies and one case-control study. Risk of DLB was reported in one retrospective cohort, one case-control, and one prospective cohort study. No studies addressed potential relationships with multiple system atrophy or pure autonomic failure. Meta-analysis of hazard ratios from four retrospective cohort studies supported the hypothesis that incident PTSD was associated with PD and DLB risk (pooled HR 1.88, 95% C.I. 1.08-3.24; p = 0.035).
CONCLUSIONS
The sparse literature to-date supports further investigations on the association of mid- to late-life PTSD with Parkinson's and related neurodegenerative disorders.
PubMed: 37236879
DOI: 10.1016/j.jagp.2023.04.016 -
Frontiers in Molecular Neuroscience 2023Alzheimer's disease (AD) is a central nervous system (CNS) degenerative disorder, is caused by various factors including β-amyloid toxicity, hyperphosphorylation of tau... (Review)
Review
Alzheimer's disease (AD) is a central nervous system (CNS) degenerative disorder, is caused by various factors including β-amyloid toxicity, hyperphosphorylation of tau protein, oxidative stress, and others. The dysfunction of microglia has been associated with the onset and advancement of different neurodevelopmental and neurodegenerative disorders, such as AD. The gut of mammals harbors a vast and complex population of microorganisms, commonly referred to as the microbiota. There's a growing recognition that these gut microbes are intrinsically intertwined with mammalian physiology. Through the circulation of metabolites, they establish metabolic symbiosis, enhance immune function, and establish communication with different remote cells, including those in the brain. The gut microbiome plays a crucial part in influencing the development and performance of microglia, as indicated by recent preclinical studies. Dysbiosis of the intestinal flora leads to alterations in the microglia transcriptome that regulate the interconversion of microglia subtypes. This conversation explores recent research that clarifies how gut bacteria, their byproducts, and harmful elements affect the activation and characteristics of microglia. This understanding opens doors to innovative microbial-based therapeutic strategies for early identification and treatment goals in AD.
PubMed: 38098943
DOI: 10.3389/fnmol.2023.1295916 -
The International Journal of... Nov 2023Respiratory diseases of infectious, allergic, neoplastic or degenerative origin are due to the interaction of environmental and occupational risk factors, individual...
Respiratory diseases of infectious, allergic, neoplastic or degenerative origin are due to the interaction of environmental and occupational risk factors, individual susceptibility and other co-factors and comorbidities. Asthma and other respiratory pathologies can be worsened by climate change and exposure to other agents in occupational environments. PubMed and Scopus, and several websites on public and occupational health were queried to find publications and documents on work-related respiratory diseases, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), pneumoconiosis and allergic alveolitis in association with climate change. Most of the retrieved articles concerned asthma (75 in Scopus), while the other topics were less frequently covered in the scientific literature, with a maximum of 29 papers for rhinitis and 23 for COPD. The most important terms highlighted by the word clouds were 'health', 'air', 'pollution', and, only for asthma and rhinitis, 'pollen' and 'allergic/allergy'. Website data on public and occupational health, and climate change were reported. Assessment and management of respiratory diseases that recognise occupational exposures should be improved, and more research into integrated approaches should be favoured. Health surveillance practices for workers exposed to agents that cause respiratory diseases should be implemented. The development of biomarkers of exposure, effect and susceptibility needs further study.
Topics: Humans; Rhinitis; Climate Change; Asthma; Hypersensitivity; Respiration Disorders; Occupational Diseases; Occupational Exposure; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Diseases
PubMed: 37880894
DOI: 10.5588/ijtld.23.0131 -
Molecular Nutrition & Food Research Sep 2023Ageing is inevitable and poses a universal challenge for all living organisms, including humans. The human body experiences rapid cell division and metabolism until... (Review)
Review
Ageing is inevitable and poses a universal challenge for all living organisms, including humans. The human body experiences rapid cell division and metabolism until approximately 25 years of age, after which the accumulation of metabolic by-products and cellular damage leads to age-related diseases. Neurodegenerative diseases are of concern due to their irreversible nature, lack of effective treatment, and impact on society and the economy. Researchers are interested in finding drugs that can effectively alleviate ageing and age-related diseases without side-effects. Psychobiotics are a novel class of probiotic organisms and prebiotic interventions that confer mental health benefits to the host when taken appropriately. Psychobiotic strains affect functions related to the central nervous system (CNS) and behaviors mediated by the Gut-Brain-Axis (GBA) through various pathways. There is an increasing interest in researchers of these microbial-based psychopharmaceuticals. Psychobiotics have been reported to reduce neuronal ageing, inflammation, oxidative stress, and cortisol levels; increase synaptic plasticity and levels of neurotransmitters and antioxidants. The present review focuses on the manifestation of elderly neurodegenerative and mental disorders, particularly Alzheimer's disease (AD), Parkinson's disease (PD), and depression, and the current status of their potential alleviation through psychobiotic interventions, highlighting their possible mechanisms of action.
PubMed: 37715243
DOI: 10.1002/mnfr.202300461