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Introduction:
Drug discovery for amyotrophic lateral sclerosis (ALS) has experienced a surge in clinical studies and remarkable preclinical milestones utilizing a variety of mutant superoxide dismutase 1 model systems. Of the drugs that were tested and showed positive preclinical effects, none demonstrated therapeutic benefits to ALS patients in c...
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Dermal fibroblasts were donated by a 43 year old male patient with clinically diagnosed familial amyotrophic lateral sclerosis (ALS), carrying the SOD1E101G mutation. The induced pluripotent stem cell (iPSC) line UOWi007-A was generated using repeated mRNA transfections for pluripotency transcription factors Oct4, Klf4, Sox2, c-Myc, Lin28 and Nanog...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by death of motor neurons. To date, neither etiology nor pathogenesis of ALS are known, which leads to the absence of an effective treatment strategy. ALS patient-specific induced pluripotent stem cells (iPSCs) represent an excellent tool for the disease study. We obta...
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... Dysfunction of Fused in Sarcoma (FUS) gene expression is associated with frontotemporal lobar degeneration (FTLD) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS) Puppala et al., 2021). Both FTDL and ALS are devastating incurable disorders and thus, their prevention and treatment remain an important unmet need (DeLoach et al., 2015;Sivasathiaseelan et al., 2019). Various forms of the FUS mutation cause RNA dysfunction and pathological protein aggregation in neurons, leading to their degeneration and death . ...
CNS inflammation, including microglial activation, in response to peripheral infections are known to contribute to the pathology of both familial and sporadic neurodegenerative disease. The relationship between Fused-in-Sarcoma Protein (FUS)-mediated disease in the transgenic FUS[1–359] animals and the systemic inflammatory response have not been explored. Here, we investigated microglial activation, inflammatory gene expression and the behavioural responses to lipopolysaccharide-induced (LPS; 0.1 mg/kg) systemic inflammation in the FUS[1–359] transgenic mice. The pathology of these mice recapitulates the key features of mutant FUS-associated familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, pre-symptomatic 8-week-old mutant or wild type controls were challenged with LPS or with saline and sucrose intake, novel cage exploration, marble burying and swimming behaviours were analyzed. The level of pro-inflammatory gene expression was also determined, and microglial activation was evaluated. In chronic experiments, to discover whether the LPS challenge would affect the onset of ALS-like paralysis, animals were evaluated for clinical signs from 5 to 7 weeks post-injection. Compared to controls, acutely challenged FUS[1–359]-tg mice exhibited decreased sucrose intake and increased floating behaviours. The FUS[1–359]-tg mice exhibited an increase in immunoreactivity for Iba1-positive cells in the prefrontal cortex and ventral horn of the spinal cord, which was accompanied by increased expression of interleukin-1β, tumour necrosis factor, cyclooxygenase-(COX)-1 and COX-2. However, the single LPS challenge did not alter the time to development of paralysis in the FUS[1–359]-tg mice. Thus, while the acute inflammatory response was enhanced in the FUS mutant animals, it did not have a lasting impact on disease progression.
... Diabetes is one of the diseases most associated with the progression of COVID-19, and people with diabetes are highly susceptible to SARS-CoV-2 infection and progression to severe disease and have a high risk of death [45]. In diabetes, long-term hyperglycemia and the production and accumulation of advanced glycation end products may mediate endothelial cell damage through PEN-1 protein, causing exacerbation in patients with COVID-19 and diabetes mellitus [46]. ...
As COVID-19 develops, dynamic changes occur in the patient's immune system. Changes in molecular levels in different immune cells can reflect the course of COVID-19. This study aims to uncover the molecular characteristics of different immune cell subpopulations at different stages of COVID-19. We designed a machine learning workflow to analyze scRNA-seq data of three immune cell types (B, T, and myeloid cells) in four levels of COVID-19 severity/outcome. The datasets for three cell types included 403,700 B-cell, 634,595 T-cell, and 346,547 myeloid cell samples. Each cell subtype was divided into four groups, control, convalescence, progression mild/moderate, and progression severe/critical, and each immune cell contained 27,943 gene features. A feature analysis procedure was applied to the data of each cell type. Irrelevant features were first excluded according to their relevance to the target variable measured by mutual information. Then, four ranking algorithms (last absolute shrinkage and selection operator, light gradient boosting machine, Monte Carlo feature selection, and max-relevance and min-redundancy) were adopted to analyze the remaining features, resulting in four feature lists. These lists were fed into the incremental feature selection, incorporating three classification algorithms (decision tree, k-nearest neighbor, and random forest) to extract key gene features and construct classifiers with superior performance. The results confirmed that genes such as PFN1, RPS26, and FTH1 played important roles in SARS-CoV-2 infection. These findings provide a useful reference for the understanding of the ongoing effect of COVID-19 development on the immune system.
... 24 There have been over 60 molecules tested as potential treatment options for ALS, yet none have demonstrated efficacy in clinical trials. 59,60 It is demonstrated that systemic and local alterations of T cells exacerbate ALS through the release of TNF-α, IL-1β and IFN-γ, supporting the role of these mediators in disease progression. 61 In response, resident microglia and infiltrating macrophages become over-activated, leading to neuroinflammation, oxidative stress and degeneration. ...
Neurodegenerative disorders are characterized by the gradual decline and irreversible loss of cognitive functions and CNS structures. As therapeutic recourse stagnates, neurodegenerative diseases will cost over a trillion dollars by 2050. A dearth of preventive and regenerative measures to hinder regression and enhance recovery has forced patients to settle for traditional therapeutics designed to manage symptoms, leaving little hope for a cure. In the last decade, pre-clinical animal models and clinical investigations in humans have demonstrated the safety and promise of an emerging cellular product from subcutaneous fat. The adipose-derived stromal vascular fraction (SVF) is an early intervention and late-stage novel 'at point' of care cellular treatment, demonstrating improvements in clinical applications for Multiple Sclerosis, Alzheimer's disease, and Parkinson's disease. SVF is a heterogeneous fraction of cells forming a robust cellular ecosystem and serving as a novel and valuable source of point-of-care autologous cell therapy, providing an easy-to-access population that we hypothesize can mediate repair through 'bi-directional' communication in response to pathological cues. We provide the first comprehensive review of all pre-clinical and clinical findings available to date and highlight major challenges and future directions. There is a greater medical and economic urgency to innovate and develop novel cellular therapy solutions that enable the repair and regeneration of neuronal tissue that has undergone irreversible and permanent damage.
... Mouse models created with ALS-linked mutations (e.g. SOD1, TDP-43, FUS) have significantly expanded our knowledge of ALS over the last 20 years (DeLoach et al. 2015). Multiple cellular pathologies (e.g., aggregation of mutant SOD1, TDP43, FUS, Ubiqulin2, mitochondrial dysfunction, neuroinflammation, and oxidative damage) are found to be contributing factors in the progressive loss of motor neurons, resulting in the paralysis of voluntary muscle and subsequent death. ...
Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, leads to the loss of motor neurons. There are currently no effective therapies to treat this disease as the molecular mechanisms of motor neuron degeneration are largely unknown. The diagnosis of ALS, or motor neuron disease, is not a simple process that can be carried out with one doctor visit or a single simple test. This has created a major problem for patients with ALS and their physicians since they are often not diagnosed until about a year into the disease. In order to combat this issue, new techniques of detecting the clinical and pathological changes of the disease are critical. These techniques are currently being studied and developed which can revolutionize the diagnosis of ALS. Once this technology is established, it may have application to monitor the progression of the disease. RNA-Seq is a powerful tool that has potential to identify RNA as small molecules in patients’ biological samples (Plasma, Cerebral Spinal Fluid) which can be used to inform the system changes in patients with ALS. In this review, we will explore and discuss our current work on RNA-Seq and its development of biomarkers to diagnose and assess the rate of progression in the disease.
... It is found that diabetes is one of the diseases most associated with progression in patients infected with SARS-CoV-2; and diabetic patients are more susceptible to infection by SARS-CoV-2 and its variants, and are more likely to progress to severe condition and at higher risk of death, which is believed to be related to vascular endothelial dysfunction of diabetic patients to a certain extent [11,12]. It is well known that for diabetes, long-term hyperglycemia and oxidative stress can lead to the production and accumulation of advanced glycation end products (AGEs), which may induce endothelial cell damage through Profilin-1 (PFN1) protein, resulting in the recombination and redistribution of endothelial cytoskeleton actin to increase endothelial permeability and endothelial dysfunction [13]. ACE2, as a binding target for the virus to invade the human body, is widely found in vascular endothelial cells in the human body. ...
Diabetes is considered to be one of the diseases most associated with COVID-19. In this study, interfering effects and potential mechanisms of several compounds from Lianqiao (Forsythia suspensa (Thunb.) Vahl) leaves on the bioactivities of some key proteins of COVID-19 and its variants, as well as diabetic endothelial dysfunctions were illuminated through in vitro and in silico analyses. Results showed that, among the main ingredients in the leaves, forsythoside A showed the strongest docking affinities with the proteins SARS-CoV-2-RBD-hACE2 of COVID-19 and its variants (Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617)), as well as neuropilin-1 (NRP1), and SARS-CoV-2 main protease (MPro) to interfere coronavirus entering into the human body. Moreover, forsythoside A was the most stable in binding to receptors in Delta (B.1.617) system. It also has good antiviral activities and drug properties and has the strongest binding force to the RBD domain of COVID-19. In addition, forsythoside A reduced ROS production in AGEs-induced EA.hy926 cells, maintained endothelial integrity, and bound closely to protein profilin-1 (PFN1) receptor. This work may provide useful knowledge for further understanding the interfering effects and potential mechanisms of compounds, especially forsythoside A, from Lianqiao leaves on the bioactivities of key proteins of COVID-19/variants in diabetes.
... During T2DM, long-term hyperglycemia leads to the production and accumulation of advanced glycation end products (AGEs) in blood [4]. Studies have reported that AGEs are believed to be key factors that promote vascular damage and inflammation through receptor-independent and receptor-dependent mechanisms, leading to a series of vascular complications [5,6]. The combination of AGEs and their receptors (i.e., RAGE, receptor for AGEs) can activate macrophages and produce excessive pro-inflammatory cytokines through RAGE, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) [4]. ...
... The combination of AGEs and their receptors (i.e., RAGE, receptor for AGEs) can activate macrophages and produce excessive pro-inflammatory cytokines through RAGE, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) [4]. In addition, AGEs can also induce endothelial cell damage through profilin-1 (PFN1), causing the reorganization and redistribution of endothelial cytoskeleton actin and leading to endothelial cell dysfunction [6]. Moreover, the overproduction of reactive oxygen species (ROS) caused by AGEs is also considered a trigger for inflammation and vascular endothelial (VE)-cadherin endocytosis associated with the maintenance of the cytoskeleton [4,7]. ...
... In addition, AGEs can cause the reorganization and redistribution of endothelial cytoskeletal actin, leading to increased endothelial cell permeability. PFN1 is considered the target molecule of endothelial cell damage induced by AGEs [6]. Some dietary flavonoids have been proven to reduce vascular complications caused by AGEs by selectively binding RAGE and PFN1 [32,33]. ...
The aim of this study was to compare the protective effects of three dietary flavonoids
(apigenin-7-O-glucoside (A7G), isorhamnetin-3-O-rutinoside (I3R), and cyanidin-3-O-glucoside (C3G)) on advanced glycation end products (AGEs)-induced inflammation and vascular endothelial dysfunction. Furthermore, the potential mechanisms of varied effects of those three dietary flavonoids were analyzed by molecular docking analysis. Results showed that C3G (40 µM) achieved the best inhibition on inflammatory cytokines (TNF-α, IL-1β, and IL-6) in AGEs-induced RAW264.7 cells, followed by I3R, and A7G was the weakest. The molecular docking results also showed that C3G exhibited the closest binding with the receptor for AGE. However, I3R (40 µM) demonstrated the best effect in improving endothelial dysfunction in AGEs-induced EA.hy926 cells, followed by C3G, and A7G was the weakest, as evidenced by the molecular docking results of flavonoids with
profilin-1. This work may provide knowledge and helpful suggestions regarding the benefits of dietary flavonoids in diabetic vascular complications.
... L'aspect de non-autonomie cellulaire de la pathogénèse de la SLA et la présence de neuroinflammation mit beaucoup d'espoir dans l'utilisation de médicaments anti-inflammatoires pour le traitement de cette maladie. Malheureusement, à ce jour, tous les traitements anti-inflammatoires testés en phase cliniques ont échoué (Benatar 2007, DeLoach et al. 2015. ...
... En tenant compte du supposé phénotype pro-inflammatoire de la microglie durant la phase symptomatique de l'ALS, l'utilisation de drogues anti-inflammatoires pourrait protéger les motoneurones de la microglie. Malheureusement, les traitements anti-inflammatoires sont des échecs lors des essais cliniques (Benatar 2007, DeLoach et al. 2015. Par exemple, les médicaments anti-inflammatoires comme le celecoxib, la minocycline, la thalidomide ou le plioglitazone ont échoué en phase clinique (DeLoach et al. 2015). ...
... Malheureusement, les traitements anti-inflammatoires sont des échecs lors des essais cliniques (Benatar 2007, DeLoach et al. 2015. Par exemple, les médicaments anti-inflammatoires comme le celecoxib, la minocycline, la thalidomide ou le plioglitazone ont échoué en phase clinique (DeLoach et al. 2015). Ainsi, bien qu'il soit clair que la microglie soit neurotoxique au stade symptomatique, des recherches plus récentes démontrent que le phénotype microglial est plus complexe, ou du moins, diffère substantiellement du phénotype pro-inflammatoire. ...
... muscle metabolic dysregulation and atrophy before MN degeneration in ALS animal models 16,17 . In a study by Deloach et al., they reported that ALS skeletal muscle secreted axonal chemorepellent molecules such as Nogo-A, that stunt axonal growth 18 . Also, there are reports of altered morphology and regenerative capabilities of satellite cells derived from patient skeletal muscle biopsies 19,20 . ...
Recent findings suggest a pathologic role of skeletal muscle in amyotrophic lateral sclerosis (ALS) onset and progression. However, the exact mechanism by which this occurs remains elusive due to limited human-based studies. To this end, phenotypic ALS skeletal muscle models were developed from induced pluripotent stem cells (iPSCs) derived from healthy individuals (WT) and ALS patients harboring mutations in the superoxide dismutase 1 (SOD1) gene. Although proliferative, SOD1 myoblasts demonstrated delayed and reduced fusion efficiency compared to WT. Additionally, SOD1 myotubes exhibited significantly reduced length and cross-section. Also, SOD1 myotubes had loosely arranged myosin heavy chain and reduced acetylcholine receptor expression per immunocytochemical analysis. Functional analysis indicated considerably reduced contractile force and synchrony in SOD1 myotubes. Mitochondrial assessment indicated reduced inner mitochondrial membrane potential (ΔΨm) and metabolic plasticity in the SOD1-iPSC derived myotubes. This work presents the first well-characterized in vitro iPSC-derived muscle model that demonstrates SOD1 toxicity effects on human muscle regeneration, contractility and metabolic function in ALS. Current findings align with previous ALS patient biopsy studies and suggest an active contribution of skeletal muscle in NMJ dysfunction. Further, the results validate this model as a human-relevant platform for ALS research and drug discovery studies.
... Therefore, mice were killed and the hippocampus and the prefrontal cortex collected for RNA isolation/cDNA synthesis and RT-PCR assay of FTDL-related pro-inflammatory markers: tumour necrosis factor (TNF), cyclooxygenase-1 (COX-1), interleukin-1β (IL-1β) and cytokine expression regulatory molecules implicated in the ALS pathology, matrix-metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). 2 For experimental details, see Appendix S1 and Table S1). ...
Genetic mutations in FUS, a DNA/RNA‐binding protein, are associated with inherited forms of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A novel transgenic FUS[1‐359]‐tg mouse line recapitulates core hallmarks of human ALS in the spinal cord, including neuroinflammation and neurodegeneration, ensuing muscle atrophy and paralysis, as well as brain pathomorphological signs of FTLD. However, a question whether FUS[1‐359]‐tg mouse displays behavioural and brain pro‐inflammatory changes characteristic for the FTLD syndrome was not addressed. Here, we studied emotional, social and cognitive behaviours, brain markers of inflammation and plasticity of pre‐symptomatic FUS[1‐359]‐tg male mice, a potential FTLD model. These animals displayed aberrant behaviours and altered brain expression of inflammatory markers and related pathways that are reminiscent to the FTLD‐like syndrome. FTLD‐related behavioural and molecular Journal of Cellular and Molecular Medicine features were studied in the pre‐symptomatic FUS[1‐359]‐tg mice that received standard or new ALS treatments, which have been reported to counteract the ALS‐like syndrome in the mutants. We used anti‐ALS drug riluzole (8 mg/kg/d), or anti‐inflammatory drug, a selective blocker of cyclooxygenase‐2 (celecoxib, 30 mg/kg/d) for 3 weeks, or a single intracerebroventricular (i.c.v.) infusion of human stem cells (Neuro‐Cells, 500 000‐CD34⁺), which showed anti‐inflammatory properties. Signs of elevated anxiety, depressive‐like behaviour, cognitive deficits and abnormal social behaviour were less marked in FUS‐tg–treated animals. Applied treatments have normalized protein expression of interleukin‐1β (IL‐1β) in the prefrontal cortex and the hippocampus, and of Iba‐1 and GSK‐3β in the hippocampus. Thus, the pre‐symptomatic FUS[1‐359]‐tg mice demonstrate FTLD‐like abnormalities that are attenuated by standard and new ALS treatments, including Neuro‐Cell preparation.
... The etiology of ALS like other neurodegenerative diseases is multifactorial [2,11,12] and the pathogenesis is mediated by various cellular pathways including glutamate excitotoxicity, oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis, and proteasomal dysfunction [13][14][15][16]. Targeting these different pathophysiological abnormalities remains a challenge in the ALS [17][18][19][20][21]. ...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive motor neuron degeneration, muscle weakness, paralysis, and ultimately death within a short period after diagnosis. The pathogenesis of ALS is mediated by diverse cellular pathways such as oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. Advancement in genetic discoveries in ALS emphasizes that ALS is a syndrome rather than a single disorder. It is therefore utmost needed to better understand the underlying disease mechanism and etiology and search for neuroprotective agents that might delay disease onset and progression, extends survival, and ultimately reduces the burden of disease. In this chapter, we focus on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discuss their impact on disease progression. Furthermore, we also summarize the progress in the non-pharmacological therapy trials in ALS. Currently, no therapeutic effort seems to be successful, but recent findings in ALS will certainly help in the discovery of an effective treatment.
