Spermidine is a naturally occurring polyamine involved in multiple cellular processes, including growth regulation, protein translation, and autophagy. Increasing attention has been devoted to its potential neuroprotective effects, particularly in Alzheimer's disease (AD), a neurodegenerative disorder characterized by β-amyloid and phosphorylated tau accumulation, synaptic dysfunction, and progressive neuronal loss. In this narrative review, we examine potential mechanisms through which spermidine may influence AD pathophysiology and summarize available preclinical and clinical evidence. Preclinical studies indicate that spermidine induces autophagy, a key cellular clearance pathway responsible for removing damaged organelles and aggregated proteins. Because impaired neuronal autophagy contributes to the accumulation of β-amyloid and tau in AD, increasing intracellular spermidine levels may enhance the degradation of these toxic species. In addition, spermidine exhibits anti-inflammatory and antioxidant properties, attenuates microglial activation, and supports mitochondrial function. In animal models of AD and brain aging, spermidine administration has been associated with improvements in cognitive performance and synaptic function. However, human clinical evidence remains limited and largely inconclusive. Observational studies suggest associations between higher dietary spermidine intake and better cognitive outcomes, but do not establish causality. Randomized clinical trials to date are few, include small and heterogeneous populations, and have not demonstrated consistent effects on primary cognitive endpoints. Overall, spermidine represents a biologically plausible modulator of pathways relevant to neurodegeneration, but translation of preclinical findings into clinical benefit remains uncertain. Current evidence is insufficient to support its use as a therapeutic or preventive intervention in AD, and further well-designed clinical studies are required to clarify its efficacy and mechanisms of action.
Parkinson's disease (PD) is the fastest growing progressive neurological disorder globally, characterized by motor symptoms such as bradykinesia, rigidity, resting tremor as well as a wide range of non-motor manifestations. Here, we report the case of a patient with advanced Parkinson's disease diagnosed for PD more than 12 years ago; clinical symptoms included a coarse resting tremor with a focus on the right arm and leg, gait and postural disturbances, sleep disorders and autonomic disfunctions. The patient received several medications for correction of dopamine deficiency, but clinical symptoms progressed over the years. We applied a series of double-filtration apheresis treatments and experienced marked symptomatic improvement, with near-complete resolution of motor deficits and strong decrease of MDS-UPDRS part III score. This case suggests a potential role of extracorporeal blood purification in the management of PD.
Duchenne muscular dystrophy (DMD) is a fatal X-linked neuromuscular disorder caused by mutations in the dystrophin gene, leading to sarcolemmal instability, chronic calcium overload, mitochondrial dysfunction, inflammation, and fibrosis. These effects manifest clinically as muscle atrophy, loss of mobility, and respiratory and cardiac insufficiencies. Although gene-targeted approaches such as exon skipping and microdystrophin delivery have advanced, their applicability is restricted by genotype and adverse effects. Thus, reasonably safe, effective therapies remain a critical unmet need. (Z)-endoxifen, the (Z)-isomer of endoxifen, is the principal active metabolite of tamoxifen, exhibiting higher potency in protein kinase C (PKC) inhibition than tamoxifen and regulating various protein activities differently than tamoxifen. This pharmacologic profile positions endoxifen to address multiple DMD pathological mechanisms simultaneously. Recent literature supports the prior hypothesis that endoxifen exerts pleiotropic benefits in DMD. Transcriptomic and preclinical evidence shows that endoxifen may have superior effects to tamoxifen in reversing DMD signatures given available dosing regimens. Additionally, pathway-level insights support endoxifen activation of myogenesis, oxidative phosphorylation, estrogen receptor beta (ERβ) activation, and inhibition of pro-inflammatory and epithelial-to-mesenchymal transition (EMT) pathways in DMD. These findings suggest (Z)-endoxifen may act on utrophin-linked regulatory axes, thereby potentially contributing to functional compensation for dystrophin deficiency. This provides justification for endoxifen's development as a mutation-agnostic DMD therapeutic approach.
Background:Dementia diagnosis in sub-Saharan Africa is constrained by limited access to specialist neuroimaging interpretation and reduced specificity of brief cognitive tools in low-literacy populations. We evaluated the agreement, incremental value, and comparative performance of Mini Mental State Exam (MMSE), visual MRI medial temporal atrophy (MTA), and automated brain morphometry in older Ugandan adults with suspected dementia. Methods:In this cross-sectional study, adults aged ≥50 years with suspected dementia were recruited from neurology and psychiatry clinics at two hospitals and from a community cohort. Participants underwent MMSE and standardized 1.5T brain MRI. Visual MRI ratings were performed by radiologists blinded to clinical data, and automated morphometry was generated using NeuroQuant® normative percentiles. Hippocampal occupancy (HOC <5th percentile) was used as a reference MRI biomarker for comparative classification. Agreement between visual and automated measures was assessed using Spearman correlation and intraclass correlation. Incremental value was assessed using regression models, and comparative performance using area under the curve (AUC). Results:Sixty-three participants were included (mean age 75.6 ± 8.7 years; 49 female). Agreement between visual ratings and automated morphometry was poor. MMSE correlated inversely with MTA (ρ = -0.47; p = 0.049) and correlated positively with hippocampal volume percentile (ρ = 0.46; p = 0.056). Adding hippocampal volume to MTA did not improve model fit for MMSE (ΔR2 = 0.028; p = 0.18). For comparative classification, MMSE alone was sensitive but poorly specific, while the combined MMSE-MTA model improved specificity and discrimination (AUC 0.70 vs 0.62 for either measure alone). Conclusion:Visual and automated MRI measures were not interchangeable in this heterogeneous cohort. Automated hippocampal volumetry added limited value beyond visual MTA for global cognition, while combining MMSE with visual MTA showed modest improvement in comparative classification and warrants further validation.
Objective:This study aimed to identify novel therapeutic targets for Alzheimer's disease (AD) by investigating the role of the intestinal flora (IF) via the gut-brain axis, and to predict a potential natural compound for AD treatment and elucidate its underlying mechanism. Methods:Following a primary analytical axis, we first employed Mendelian randomization (MR) to infer causal relationships between gut microbiota and AD. To pinpoint molecular targets, we integrated Summary-data-based MR (SMR) with single-cell and spatial transcriptomics. Subsequently, network pharmacology and molecular docking were used to identify stigmasterol as a candidate compound targeting the causal pathway. Finally, the neuroprotective effects and the STIM1/Orai1-mediated mechanism were experimentally validated in vitro using Aβ1-42 exposed SH-SY5Y cells. Results:MR-based causal inference identified Desulfovibrio as a risk factor for AD, while Slackia and the Lachnospiraceae NK4A136 group were protective factors. Seven key AD-related genes were identified by combining MR results with databases, which were highly druggable. SMR analysis and multi-omics integration pinpointed STIM1-mediated calcium signaling as the core causal pathway. Following the identification of stigmasterol via network pharmacology and molecular docking, in vitro experimental validation confirmed that stigmasterol significantly inhibited Aβ1-42 induced neuronal apoptosis and calcium overload by specifically modulating the STIM1/Orai1 pathway and the Bcl-2/Bax ratio. Conclusion:This study decodes the gut-brain axis by establishing the specific causal pathway. We demonstrate that Stigmasterol exerts neuroprotective effects by inhibiting apoptosis through a IF-associated mechanism involving the STIM1/Orai1 pathway, provideing novel insights into AD pathogenesis and offering a promising therapeutic strategy based on natural compounds.
Background:Limited real-world data exist on the effectiveness of siponimod in people living with secondary progressive multiple sclerosis (plwSPMS). Objective:To analyze the real-world data of patients receiving siponimod under a managed access program (MAP). Methods:The MAP was implemented in countries where siponimod was not approved and provision via MAP was permitted under local regulations. Data on the demographic/clinical characteristics and clinical outcomes of the cohort included in this MAP between February 2019 and April 2022, were collected from physicians using a Novartis database. Results:Among patients with evidence of starting siponimod treatment in the MAP (n=516), the mean EDSS at baseline was 5.2. Among those with post-baseline data available (n=423), the mean change from baseline in EDSS score at month 6 was -0.04 (95% confidence interval [CI]: -0.10, 0.01) and 0.03 (95% CI: -0.03, 0.10) at month 24), and the annual relapse rate was 0.023. Cognition was stable or improved in patients for whom data was available. Among patients with ≥1 MRI assessment (n=165), 154 (93.3%) had no findings of disease activity. Conclusion:This real-world data set analysis provides data on the demographic/clinical characteristics of plwSPMS taking siponimod in clinical practice under MAP criteria and on the effectiveness that can be attained.
Background:Conventional therapeutic interventions for Alzheimer's disease (AD) are limited by multiple drawbacks, including anticholinesterase inhibitors, glutamate receptor antagonists, intestinal flora regulators and Aβ-targeting monoclonal antibodies, which only achieve modest symptomatic relief, are accompanied by notable adverse events (e.g., intracerebral hemorrhage, cerebral edema) and have suboptimal clinical efficacy. In recent years, the cerebral lymphatic system, consisting of the glial lymphatic system (GLS) and meningeal lymphatic vessels (MLVs), has been identified as a key mediator of amyloid β-protein (Aβ) clearance and a critical driver of AD pathogenesis. Lymphatic dysfunction in this system precedes and exacerbates Aβ deposition and cognitive decline in AD patients, revealing the close association between cerebral lymphatic system impairment and AD progression. Purpose:This study aims to focus on the emerging therapeutic advancements for AD targeting the cerebral lymphatic system, moving beyond the conventional symptomatic treatments and Aβ-centric interventions. It also intends to systematically summarize the relevant mechanisms of the cerebral lymphatic system in AD and the diverse therapeutic strategies targeting this system, thus providing a framework for developing innovative clinical interventions for AD. Methods:This study adopted a review approach, systematically collating and analyzing existing research on the cerebral lymphatic system and AD, including the cerebral lymphatic pathway of Aβ clearance, the pathological consequences of lymphatic impairment in AD, and various therapeutic strategies targeting the cerebral lymphatic system that have been reported in current studies. Results:The review identified and summarized multiple categories of effective therapeutic strategies targeting the cerebral lymphatic system for AD, covering pharmacological agents (VEGF-C, traditional Chinese medicines, oxytocin), photobiotherapies (808 nm near-infrared light, 40 Hz multisensory stimulation), physiotherapies (aerobic exercise, rTMS), gene therapy (DSCR1 upregulation), and surgical interventions (lymphatic-venous anastomosis). All these strategies are designed to optimize cerebral lymphatic function and thereby enhance Aβ drainage in the brain. Conclusion:Optimizing cerebral lymphatic function to enhance Aβ drainage is a viable, disease-modifying therapeutic direction for AD. This therapeutic approach targeting the cerebral lymphatic system can serve as a complementary or alternative method to current symptomatic or Aβ-targeted treatments for AD, and also provides a theoretical and practical framework for the development of innovative clinical interventions for the disease.
Background:Aging is associated with increased oxidative stress, which leads to synaptic vulnerability and psychiatric and cognitive deficits. Maintaining redox homeostasis is crucial for synaptic health. However, age-related alterations in synapse-specific antioxidant capacity remain poorly understood. Moreover, effective therapeutic strategies to counteract these changes are lacking. This study aimed to assess redox parameters in ex vivo synaptic terminals from young and old rat brains and evaluate the modulatory effects of the phytotherapeutic compound emodin. Methods:Brain synaptosomes were isolated from young and old male Wistar rats. The antioxidant capacities were determined using 2,2'-azinobis-[3-ethylbenzothiazoline-6-sulfonic acid] (ABTS) and ferric-reducing antioxidant power (FRAP) assays. Oxidative stress and damage were assessed by quantifying reactive oxygen species (ROS) and nitrogen species (RNS) and examining oxidative modifications of proteins and lipids. The antioxidant effects of emodin were investigated in mitigating synaptic oxidative stress and damage. Results:A significant decline in antioxidant capacity and increase in ROS levels were observed in the synaptosomes of aged animals. Oxidative damage was also evident as increased protein carbonylation, thiol oxidation, and lipid peroxidation. Emodin treatment improved redox balance by reducing ROS levels, decreasing oxidative damage markers, and enhancing antioxidant defenses, particularly in older animals. Conclusion:Aging disrupts synaptic redox homeostasis and increases the susceptibility to oxidative damage. Emodin exerts protective antioxidant effects by mitigating oxidative stress and enhancing the redox capacity of the synaptosomes. These findings suggest that emodin may have therapeutic potential in preserving synaptic function under conditions of age-related oxidative stress, although further functional and molecular studies are warranted to validate its neuroprotective efficacy.
Objective:Multisystem proteinopathy (MSP) is a pleiotropic group of disorders initially presenting as inclusion body myopathy (IBM), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and/or Paget disease of bone (PDB). Additional genes including MATR3, OPTN, and ANXA11, have recently been implicated in MSP-like disorders, further expanding the genetic spectrum. This research aims to study the genetic and clinical characteristics of MSP and related disorders in a large Chinese cohort. Methods:Twenty-nine patients were identified in 953 patients diagnosed with ALS, IBM, or dementia at Huashan Hospital between 2000 and 2024. Variants in MSP-related genes were detected using next-generation sequencing and confirmed by Sanger sequencing. Clinical, pathological, imaging, and electromyography data were collected and analyzed. Results:A total of 29 patients (3.0%) were identified as carrying MSP-related gene variants. Most patients were male (72.4%), with disease onset predominantly in the third to fifth decades of life. The majority of patients (21/29) presented with a single clinical phenotype. ALS was the most common phenotype (20/29), followed by IBM (10/29), FTD (7/29), and PDB (1/29). The most frequent variants were in ANXA11 (34.5%) and VCP (20.7%), followed by OPTN (17.2%), SQSTM1 (10.3%), MATR3 (10.3%), and HNRNPA1 (6.9%). All patients with VCP variants presented with initial lower limb involvement, whereas those carrying ANXA11 or OPTN variants predominantly showed upper limb or bulbar onset. Patients harboring OPTN variants had a later age at onset compared with those carrying VCP or MATR3 variants. Patients with ALS-onset exhibited faster progression compared with those with myopathy-onset, even when harboring identical variants. Conclusion:This study broadens the clinical and genetic landscape of MSP and related disorders in a Chinese cohort. These results emphasize the clinical utility of next-generation sequencing for improving diagnostic accuracy in patients with unexplained neuromuscular or cognitive presentations, especially in the presence of multisystem involvement.
Objective:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons, and its pathogenesis has not been fully elucidated. TAR DNA-binding protein 43 (TDP-43), as one of the key pathogenic genes in ALS, participates in the disease process through interactions with various proteins. This study aims to investigate the interaction mechanism between TDP-43 and aldolase A (ALDOA) in ALS. Methods:HEK293T cell models transfected with wild-type and mutant TDP-43 (TDP-43M337V) plasmids were constructed. The interaction between TDP-43 and ALDOA was analyzed through proteomic screening of specific peptides and co-immunoprecipitation, and the co-localization of the two in cells was detected by immunofluorescence. Changes in ALDOA expression levels after intervention with mutant TDP-43 were detected by Western blot and quantitative real-time PCR. Results:Proteomic analysis identified ALDOA as a potential interacting protein of TDP-43. Protein-protein interaction (PPI) analysis, co-immunoprecipitation, and immunofluorescence experiments further confirmed that both wild-type and mutant TDP-43 interact with ALDOA. Western blot and quantitative real-time PCR results showed that, compared with the wild-type TDP-43 group, the ALDOA expression was significantly increased in the TDP-43M337V mutant group. Conclusion:TDP-43 interacts with ALDOA in ALS, and the TDP-43M337V mutation significantly promotes ALDOA expression, suggesting that ALDOA may be involved in the pathogenesis of TDP-43-mediated ALS. These findings provide new insights into the pathogenesis of ALS and highlight a potential therapeutic target.
Objective:To report the clinical and genetic characteristics of a rare Charcot-Marie-Tooth disease type 2F (CMT2F) pedigree, and to explore the phenotypic diversity and diagnostic essentials of the mutation in combination with literature review. Methods:The clinical data, electrophysiological findings, and genetic testing results of the proband and pedigree members were retrospectively analyzed, and relevant literatures were reviewed for comparative analysis. Results:Both patients had an onset in middle and old age (50/66 years), presenting with distal lower limb muscle weakness (Grade III), muscle atrophy, absent tendon reflexes, pes cavus, and sensory abnormalities. Serum creatine kinase (CK) was elevated (474 U/L), and electromyography indicated axonal peripheral nerve damage. Genetic testing revealed a heterozygous mutation of HSPB1 gene c.418C>G [p.Arg140Gly], which was verified by co-segregation in the pedigree. Literature review showed that this mutation causes axonal transport dysfunction by impairing the chaperone function of HSP27. Conclusion:This study expands the phenotypic spectrum of late-onset CMT2F, with some patients showing mild elevation of serum CK. It provides new clinical evidence for the pathogenicity of this mutation.
Purpose:The symptoms of patients with early to mid-stage Parkinson's disease (PD) are closely associated with their quality of life. However, few studies have explored the relationship between symptoms and quality of life. This study aims to investigate the symptom profiles of patients with early to mid-stage PD, construct a symptom network to identify core symptoms, and examine their associations with quality of life. Patients and Methods:This cross-sectional study was conducted from November 2024 to February 2025 among 954 patients with early to mid-stage PD in China, with stages 1-2 classified as early stage and stage 3 as mid stage. All participants completed the PD Symptom Experience Scale. Network models were constructed using R version 4.4.3 to identify core symptoms, describe inter-symptom relationships, and calculate centrality indices. Results:The top three symptoms in terms of prevalence were bradykinesia (77.46%), resting tremor (75.05%), and rigidity (59.01%). The most severe symptom was resting tremor. In the symptom network analysis, the top three symptoms with the highest node centrality were bradykinesia (re=1.27), postural instability (re=1.16), and limb stiffness (re=1.96). In the quality of life network, the dimensions with the highest node centrality were "mobility" (rbe=0.52), "emotional well-being" (rbe=0.50), and "cognitions" (rbe=0.49). "Mobility" was positively correlated with difficulty turning over in bed (r=0.19), freezing of gait (r=0.09), and difficulty standing up or sitting down (r=0.08). Conclusion:Multiple symptoms were simultaneously experienced by patients with early to mid-stage PD, and interrelationships among symptoms were observed. Bradykinesia was identified as the core symptom, and the "mobility" dimension was recognized as the central node in the quality of life network. Healthcare providers are advised to comprehensively consider patients' overall symptom profiles and their relationships with quality of life, and to implement targeted, integrated interventions.
Introduction:Amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA) are both neurodegenerative disorders. While ALS may present with clinical features resembling Parkinsonism, there have been no definitive reports of ALS mimicking MSA, only cases of Primary lateral sclerosis (PLS) mimicking Parkinsonism. Methods:This article reports a case of ALS presenting with Parkinsonism and anxiety as the initial symptoms. Five years after the initial diagnosis of MSA, the patient developed signs of lower motor neuron involvement, including fasciculations and muscle atrophy, ultimately leading to a revised diagnosis of ALS. This study combines literature analysis to explore the reasons for misdiagnosis and identifies key differentiating features. Results:Specifically, muscle rigidity in ALS is characterized by a velocity-dependent increase in muscle tone caused by damage to the upper motor neurons. This symptom tends to be more pronounced in the lower limbs than in the upper limbs and is often accompanied by spastic gait. Objective examinations may reveal early atrophy of the frontal and temporal lobes of the cerebrum on head magnetic resonance (MR) imaging, whereas 18F-FDG brain positron emission tomography (PET) may reveal reduced metabolism in the frontal and parietal lobes of the cerebrum with normal basal ganglial function, distinguishing ALS from basal ganglial metabolic decline in MSA. Discussion:To our knowledge, this is the first case of ALS misdiagnosed as MSA. Clinically, patients with parkinsonism who do not respond to dopaminergic drugs should be cautious about atypical ALS. Muscle rigidity manifesting as upper motor neuron damage, and MR and 18F-FDG brain PET imaging can provide early differential diagnosis indicators.
Background:The aim was to investigate the potential role of TP73-AS1 in the pathogenesis of Parkinson's disease. Methods:Peripheral blood samples were obtained from three patients with early-onset Parkinson's disease (PD), three patients with late-onset PD, and three healthy controls for the extraction of total RNA. Genomic long non-coding RNA (lncRNA) expression levels were analyzed using the Illumina HiSeq2500 sequencing platform. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to study the expression of TP73-AS1. Flow cytometry and Western blot analyses were conducted to assess the functional role of TP73-AS1 in SH-SY5Y cells in vitro. Moreover, the expression of inflammatory cytokines, such as IL-16, IL-6, and α-synuclein (SYN), was examined using cellular immunofluorescence techniques. Results:Among early-onset PD patients, 59 lncRNAs were significantly upregulated, and 57 lncRNAs were significantly downregulated compared to the control group. Similarly, late-onset PD patients showed 70 upregulated lncRNAs and 77 downregulated lncRNAs with statistical significance compared to the control group. In vitro studies indicated a significant increase in lncRNA TP73-AS1 expression in the MPP+-treated group in contrast with the control group (P < 0.001). Furthermore, the MPP+-treated group displayed elevated levels of Cleaved caspase-3, IL-16, as well as IL-6 (P < 0.001). Conversely, Bcl-2 expression decreased, Bax expression increased, and the Bax/Bcl-2 expression ratio demonstrated an increase (P < 0.001). Reducing lncRNA TP73-AS1 resulted in decreased apoptosis and inflammation, along with a decrease in α-SYN expression (P < 0.001). Notably, the absence of TP73-AS1 showed a protective effect against PD, suggesting it to be a potential target for the treatment of PD. These findings suggest that TP73-AS1 may serve as a potential molecular marker for the early diagnosis of PD, providing a new perspective for understanding the regulatory mechanisms of inflammation and apoptosis in PD.
Parkinson's disease is a neurodegenerative disorder that leads to neuronal loss. Though a variety of genetic and environmental factors may be involved in the etiology, the presentation of the disorder is very similar. Trace minerals such as manganese are essential for brain development and function though effective concentrations are paramount. Exposure to high concentrations of manganese is known to cause neurotoxicity and has been recently associated with manganese-induced parkinsonism, which will be explored in this review. This review synthesizes findings from peer-reviewed clinical, epidemiological, and experimental studies to explore the underlying mechanisms and contributing factors of manganese-induced parkinsonism. Specifically, it examines alterations in lipidomic and oxidative profiles, enhancement of redox cycling, transporter dysfunction and deficiency, ion homeostasis, dysregulation of signaling pathways and autophagy, mRNA disruption, dopamine toxicity, manganese contamination, and neuroprotective mechanisms. Preventative and therapeutic interventions-including chelation therapy with ethylene-diamine-tetra-acetic acid (CaNa2EDTA), with or without plasma exchange and para-aminosalicylic acid (PAS), as well as natural compounds such as vinpocetine (VIN), punicalagin (PUN), niacin, vitamin E, DNLA, curcumin, and sesame oil-are also reviewed. Given manganese's role as an oxidant in the synthesis of neurotoxic compounds, therapeutic strategies targeting both manganese, its associated molecular pathways, and its downstream neurotoxic effects may represent the most promising direction for future research.
Background:Apoptosis and immune inflammation play important roles in the pathological process of Alzheimer's disease (AD), but their specific pathogenesis is still unclear. Therefore, this article focuses on exploring the effects of Danzhi Xiaoyao Powder (DXP) on the learning and memory ability of AD model rats from the dual mechanisms of apoptosis and immune inflammation. Methods:The AD model was replicated by injecting Okadaic acid (100 ng) into the bilateral hippocampus of rats. Successful rats were selected and orally administered with donepezil hydrochloride and DXP decoction for 42 days. Their learning and memory abilities, hippocampal morphology, Aβ expression, inflammatory factors, apoptotic factors, anti apoptotic factors, as well as the expression of pathway proteins and mRNA were detected. Results:After DXP intervention, the learning and memory abilities of rats improved, the neuronal cell arrangement was more complete, the expression of Aβ decreased, the expression of pro-inflammatory cytokine and apoptotic factors decreased, the expression of anti apoptotic factors increased, Protein Kinase B (Akt) expression and activity significant up-regulation, and nuclear factor kappa-B (NF-κB), p38 MAPK (p38), MAPKAPK-2 (MK2), Cyclooxygenase-2 (COX-2) protein and mRNA expression were significantly down-regulated. Conclusion:DXP can improve the learning and cognitive abilities of AD model rats, and its mechanism of action may be related to the regulation of the Akt/NF-κB apoptosis pathway mediated by NF-κB interaction and the p38MAPK/MK2/COX-2 immune inflammatory dual pathway.
The CRISPR system has emerged as a ground-breaking gene-editing tool, offering promising therapeutic potential for Duchenne muscular dystrophy (DMD), a severe genetic disorder affecting approximately 1 in 5000 male births globally. DMD is caused by mutations in the dystrophin gene, which encodes a critical membrane-associated protein essential for maintaining muscle structure, function and repair. Patients with DMD experience progressive muscle degeneration, loss of ambulation, respiratory insufficiency, and cardiac failure, with most succumbing to the disease by their third decade of life. Despite the well-characterized genetic basis of DMD, curative treatments- such as exon skipping therapies, micro-dystrophin, and steroids- remain elusive. Recent preclinical studies have demonstrated the promise of CRISPR-based approaches in restoring dystrophin expression across various models, including human cells, murine systems, and large animal models. These advancements highlight the potential of gene editing to fundamentally alter the trajectory of the disease. However, significant challenges persist, including immunogenicity, off-target effects, and limited editing efficiency, which hinder clinical translation. This review provides a comprehensive analysis of the latest developments in CRISPR-based therapeutic strategies for DMD. It emphasizes the need for further innovation in gene-editing technologies, delivery systems, and rigorous safety evaluations to overcome current barriers and harness the full potential of CRISPR/Cas as a durable and effective treatment for DMD.
Duchenne Muscular Dystrophy (DMD) is an inherited, X-linked disorder that is progressive, debilitating, and ultimately fatal. The current therapeutic landscape offers no cures, but does include palliative treatments that delay disease progression, and there is progress on genetic therapies that have the promise to be curative. There is much room for new therapies, and foundational work with the estrogen receptor modulator tamoxifen suggests the potential of a unique spectrum of therapeutic benefit from endoxifen, a metabolite of tamoxifen. Here we describe the potential for this new DMD therapy in the context of the overall DMD therapeutic landscape.
Background: Cold inducible RNA-binding protein (CIRP) is an important danger-associated molecular pattern involved in tissue- specific and systemic inflammation related to inflammation and Alzheimer's disease (AD). However, the precise roles and mechanism of CIRP in the functional changes in astrocytes during the development of AD are still unknown. This study aimed to assess gene expression alterations in astrocytes after they overexpress CIRP (oe-CIRP) and to explore the relationship between abnormal CIRP expression and AD. Methods: We created astrocyte cell lines with a CIRP or control vector expression using three human glioma cell lines U87, U251 and H4, and analyzed the mRNA expression profiles of 3 pairs of cells via microarray. Bioinformatics identified differentially expressed mRNAs between CIRP-overexpressing (ov-CIRP) and control groups, validated by q-PCR and Western blotting (WB). Finally, the effect of CIRP overexpression in astrocytes on neurons was observed in a coculture system. Results: We identified 119 mRNAs with obvious fold changes between the ov-CIRP and control groups for all 3 pairs of human glioma cell lines. The biological functional analysis indicated that urokinase plasminogen activator (uPA), a gene whose expression significantly decreased after CIRP overexpression, was closely associated with AD. WB and q-PCR confirmed that CIRP over- expression significantly inhibited uPA at both mRNA and protein levels in U87, U251 and H4 cells. Moreover, compared with those cocultured with control astrocytes, SH-SY5Y cells cocultured with CIRP-overexpressing astrocytes exhibited a significant increase in the expression of amyloid-13 (A13)1-42 and the hyperphosphorylated microtubule-associated protein tau (Tau). Conclusion: CIRP overexpression in astrocytes inhibits uPA expression, promoting A131-42 production and tau phosphorylation in neurons, thereby increasing AD risk. These results suggest that the overexpression of CIRP in astrocytes contributes to the development of AD.
Purpose: Multiple sclerosis (MS) is a neurological disorder affecting almost 2.8 million people globally, approximately 80-85% of whom have the relapsing-remitting form of the disease (RRMS). There are several autoinjectors available for the administration of injectable disease- modifying therapies for the treatment of MS. The objective of the current study was to gain an understanding of factors related to patients' and nurses' autoinjector preferences, and to evaluate two autoinjectors for glatiramer acetate (MyJECTTM and CSYNCTM) against those preferences. Patients and Methods: Patients with RRMS and nurses experienced in training patients with an autoinjector were recruited from 12 health centers in Germany. Surveys were administered to patients and nurses and their answers to 13 questions over five categories (participants' characteristics, important autoinjector attributes, autoinjector performance, satisfaction with the autoinjector devices and demographics) were scored, where appropriate, using a 5-point Likert scale. Results: A total of 15 patients and 15 nurses were included in the study. Overall, the top four most important attributes, for both nurses and patients, were ease of handling, ability to use independently, ease of gripping the autoinjector and ease of self-injection. MyJECTTM received a mean score of at least 4.5 (out of 5) on more attributes than CSYNCTM and satisfaction with both autoinjectors was high. Conclusion: Nurses and patients with RRMS were highly satisfied with both the MyJECTTM and CSYNCTM autoinjectors, with scores suggesting that MyJECTTM performs better on the attributes they identified as most important. All patients currently using the MyJECTTM were likely or highly likely to recommend it to another patient with RRMS.
