Translational evaluation of metabolic risk factors impacting DBS efficacy for PD-Related sleep and depressive disorders: preclinical, prospective and cohort studies.

BACKGROUND: Parkinson's disease (PD) is linked with metabolic risk factors including body mass index (BMI), fasting blood glucose (FBG), cholesterol levels, and triglycerides (TG). The extent to which these factors affect motor symptoms, depression, and sleep problems in PD, as well as their role in determining the success of deep brain stimulation (DBS) therapy, is yet to be fully understood. METHODS: This study delved into the effects of metabolic risk factors like BMI, FBG, cholesterol, and TG on the outcomes of DBS in treating PD-related depression and sleep disturbances, across both mouse models and human subjects. RESULTS: DBS showcased noticeable betterment in depression and sleep perturbations in both PD-afflicted mice and patients. High-sugar-high-fat diet aggravates MPTP-induced depression and sleep disorders in mice. PD-afflicted individuals presenting with depressive and sleep disorders demonstrated elevated metrics of BMI, FBG, blood cholesterol, and TG. Remarkably, these metrics bore considerable adverse influences on the efficiency of DBS in ameliorating depression and sleep issues, yet spared motor symptoms. The favorable impacts of DBS persisted for approximately 6 years, post which a significant decline was noted. Importantly, our translational evidence from both murine controls and patient cohorts indicated that antihyperglycemic and antihyperlipidemic therapies bolstered the efficacy of DBS in mitigating PD-related depression and sleep disturbances, without impinging upon motor functions in patients. CONCLUSION: In summary, this research emphasizes that DBS is a powerful treatment option for depression and sleep issues in PD, with its success influenced by metabolic risk factors. It further suggests that incorporating treatments for high blood sugar and cholesterol can enhance the efficacy of DBS in treating depression and sleep disturbances in PD, without impacting motor symptoms, highlighting the importance of metabolic risk management in PD patients receiving DBS.

Clinical, Demographic, and Radiological Characteristics of Patients Demonstrating Antibodies Against Myelin Oligodendrocyte Glycoprotein

Background: Optic neuritis, myelitis, and neuromyelitis optica spectrum disorder (NMOSD) have been associated with antibodies against myelin oligodendrocyte glycoprotein-immunoglobulin G (anti-MOG-IgG). Furthermore, patients with radiological and demographic features atypical for multiple sclerosis (MS) with optic neuritis and myelitis also demonstrate antibodies against aquaporin-4 and anti-MOG-IgG. However, data on the diagnosis, treatment, follow-up, and prognosis in patients with anti-MOG-IgG are limited. Aims: To evaluate the clinical, radiological, and demographic characteristics of patients with anti-MOG-IgG. Study Design: Multicenter, retrospective, observational study. Methods: Patients with blood samples demonstrating anti-MOG-IgG that had been evaluated at the Neuroimmunology laboratory at Ondokuz Mayis University's Faculty of Medicine were included in the study. Results: Of the 104 patients with anti-MOG-IgG, 56.7% were women and 43.3% were men. Approximately 2.4% of the patients were diagnosed with MS, 15.8% with acute disseminated encephalomyelitis (ADEM), 39.4% with NMOSD, 31.3% with isolated optic neuritis, and 11.1% with isolated myelitis. Approximately 53.1% of patients with spinal involvement at clinical onset demonstrated a clinical course of NMOSD. Thereafter, 8.8% of these patients demonstrated a clinical course similar to MS and ADEM, and 28.1% demonstrated a clinical course of isolated myelitis. The response to acute attack treatment was lower and the disability was higher in patients aged > 40 years than patients aged < 40 years at clinical onset. Oligoclonal band was detected in 15.5% of the patients. Conclusion: For patients with NMOSD and without anti-NMO antibodies, the diagnosis is supported by the presence of anti-MOG-IgG. Furthermore, advanced age at clinical onset, Expanded Disability Status Scale (EDSS) score at clinical onset, spinal cord involvement, and number of attacks may be negative prognostic factors in patients with anti-MOG-IgG.

Thymoquinone oxime synthesis and its effects on melanoma cells: cytotoxic, genotoxic, and apoptotic evaluation.

Strong evidence supports the anticancer properties of natural plant product isolates. The cytotoxic, genotoxic, and apoptotic properties of an oxime derivative of thymoquinone (TQ) in melanoma cancer cells were investigated. The structure of TQ-Oxime was elucidated through nuclear magnetic resonance, and its effect on B16F10 and L929 cell lines was assessed using a luminometric adenosine triphosphate assay. Intracellular reactive oxygen species (iROS) were quantified via fluorometry, mitochondrial membrane potential (MMP) was assessed using flow cytometry, glutathione (GSH) levels were measured using a luminometric GSH/oxidized glutathione assay, DNA damage via comet assay, and apoptosis was detected using acridine orange/ethidium bromide staining. Concentrations (0.5-20 µM) of TQ-Oxime significantly increased cytotoxicity, DNA damage, apoptosis, and iROS, in a concentration-dependent manner compared (p < 0.001). In addition, MMP and GSH levels decreased significantly with increasing concentrations compared with the control (p < 0.001). Overall, these findings contribute to our understanding of the therapeutic potential of TQ and its derivatives in cancer treatment.

LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF-ß1 in Parkinson's Disease.

The gene mutations of LRRK2, which encodes leucine-rich repeat kinase 2 (LRRK2), are associated with one of the most prevalent monogenic forms of Parkinson's disease (PD). However, the potential effectors of the Gly2019Ser (G2019S) mutation remain unknown. In this study, the authors investigate the effects of LRRK2 G2019S on endoplasmic reticulum (ER) stress in induced pluripotent stem cell (iPSC)-induced dopamine neurons and explore potential therapeutic targets in mice model. These findings demonstrate that LRRK2 G2019S significantly promotes ER stress in neurons and mice. Interestingly, inhibiting LRRK2 activity can ameliorate ER stress induced by the mutation. Moreover, LRRK2 mutation can induce ER stress by directly interacting with thrombospondin-1/transforming growth factor beta1 (THBS1/TGF-ß1). Inhibition of LRRK2 kinase activity can effectively suppress ER stress and the expression of THBS1/TGF-ß1. Knocking down THBS1 can rescue ER stress by interacting with TGF-ß1 and behavior burden caused by the LRRK2 mutation, while suppression of TGF-ß1 has a similar effect. Overall, it is demonstrated that the LRRK2 mutation promotes ER stress by directly interacting with THBS1/TGF-ß1, leading to neural death in PD. These findings provide valuable insights into the pathogenesis of PD, highlighting potential diagnostic markers and therapeutic targets.

Oxidative and Inflammatory Parameters in Children and Adolescents With ADHD.

OBJECTIVE: This study aims that oxidative stress and inflammation status in children and adolescents with attention deficit hyperactivity disorder (ADHD) compared to their healthy peers. METHOD: Thirty ADHD and healthy controls were included in this study. ADHD diagnosis according to the DSM-V and Conners' teacher and parent rating scale by a structured psychiatric interview. Total oxidant status (TOS), total antioxidant status (TAS), and total and native thiol levels were determined using photometric methods. Presepsin, Interleukin (IL) 1-ß, IL-6, and Tumor Necrosis Factor-alpha (TNF-α) levels were measured with commercial ELISA kits. RESULTS: We showed that TOS and oxidative stress index were significantly higher in the ADHD group, and TAS was lower than in the control group (p<.001). Similarly, IL1-ß, IL-6, and TNF-α levels were statistically higher in the ADHD group. Backward LR regression analysis reveals that TOS and IL-6 predicted ADHD. CONCLUSION: TOS and IL-6 levels may play a role in the pathogenesis of ADHD.

The Role of Non-Coding RNAs in the Pathogenesis of Parkinson's Disease: Recent Advancement.

Parkinson's disease (PD) is a prevalent neurodegenerative aging disorder that manifests as motor and non-motor symptoms, and its etiopathogenesis is influenced by non-coding RNAs (ncRNAs). Signal pathway and gene sequence studies have proposed that alteration of ncRNAs is relevant to the occurrence and development of PD. Furthermore, many studies on brain tissues and body fluids from patients with PD indicate that variations in ncRNAs and their target genes could trigger or exacerbate neurodegenerative pathogenesis and serve as potential non-invasive biomarkers of PD. Numerous ncRNAs have been considered regulators of apoptosis, α-syn misfolding and aggregation, mitochondrial dysfunction, autophagy, and neuroinflammation in PD etiology, and evidence is mounting for the determination of the role of competing endogenous RNA (ceRNA) mechanisms in disease development. In this review, we discuss the current knowledge regarding the regulation and function of ncRNAs as well as ceRNA networks in PD pathogenesis, focusing on microRNAs, long ncRNAs, and circular RNAs to increase the understanding of the disease and propose potential target identification and treatment in the early stages of PD.

Bioinformatic Analysis of Genetic Factors from Human Blood Samples and Postmortem Brains in Parkinson's Disease.

Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders characterized by motor and nonmotor symptoms due to the selective loss of midbrain dopaminergic neurons. Pharmacological and surgical interventions have not been possible to cure PD; however, the cause of neurodegeneration remains unclear. Here, we performed and tested a multitiered bioinformatic analysis using the GEO and Proteinexchange database to investigate the gene expression involved in the pathogenesis of PD. Then we further validated individual differences in gene expression in whole blood samples that we collected in the clinic. We also made an interaction analysis and prediction for these genetic factors. There were in all 1045 genes expressing differently in PD compared with the healthy control group. Protein-protein interaction (PPI) networks showed 10 top hub genes: ACO2, MDH2, SDHA, ATP5A1, UQCRC2, PDHB, SUCLG1, NDUFS3, UQCRC1, and ATP5C1. We validated the ten hub gene expression in clinical PD patients and showed the expression of MDH2 was significantly different compared with healthy control. Besides, we also identified the expression of G6PD, GRID2, RIPK2, CUL4B, BCL6, MRPS31, GPI, and MAP 2 K1 were all significantly increased, and levels of MAPK, ELAVL1, RAB14, KLF9, ARF1, ARFGAP1, ATG7, ABCA7, SFT2D2, E2F2, MAPK7, and UHRF1 were all significantly decreased in PD. Among them, to our knowledge, we presently have the most recent and conclusive evidence that GRID2, RIPK2, CUL4B, E2F2, and ABCA7 are possible PD indicators. We confirmed several genetic factors which may be involved in the pathogenesis of PD. They could be promising markers for discriminating the PD and potential factors that may affect PD development.

Genetic Imaging of Neuroinflammation in Parkinson's Disease: Recent Advancements.

Parkinson's disease (PD) is one of the most prevalent neurodegenerative aging disorders characterized by motor and non-motor symptoms due to the selective loss of midbrain dopaminergic (DA) neurons. The decreased viability of DA neurons slowly results in the appearance of motor symptoms such as rigidity, bradykinesia, resting tremor, and postural instability. These symptoms largely depend on DA nigrostriatal denervation. Pharmacological and surgical interventions are the main treatment for improving clinical symptoms, but it has not been possible to cure PD. Furthermore, the cause of neurodegeneration remains unclear. One of the possible neurodegeneration mechanisms is a chronic inflammation of the central nervous system, which is mediated by microglial cells. Impaired or dead DA neurons can directly lead to microglia activation, producing a large number of reactive oxygen species and pro-inflammatory cytokines. These cytotoxic factors contribute to the apoptosis and death of DA neurons, and the pathological process of neuroinflammation aggravates the primary morbid process and exacerbates ongoing neurodegeneration. Therefore, anti-inflammatory treatment exerts a robust neuroprotective effect in a mouse model of PD. Since discovering the first mutation in the α-synuclein gene (SNCA), which can cause disease-causing, PD has involved many genes and loci such as LRRK2, Parkin, SNCA, and PINK1. In this article, we summarize the critical descriptions of the genetic factors involved in PD's occurrence and development (such as LRRK2, SNCA, Parkin, PINK1, and inflammasome), and these factors play a crucial role in neuroinflammation. Regulation of these signaling pathways and molecular factors related to these genetic factors can vastly improve the neuroinflammation of PD.