Search Results (2,534)

Aizoon africanum (L.) Klak (Synonym Galenia africana L.) is traditionally used for a variety of medicinal purposes; however, it has been reported to cause liver damage and severe ascites, particularly in sheep and Angora goats in the arid regions of the Western Cape. This study explores its cytotoxic properties to identify potential cytotoxic compound(s) in the plant. The methanolic extract of A. africanum was re-investigated and subjected to various chromatographic techniques, including preparative HPLC, resulting in the isolation of eight compounds (1–8). Structural elucidation was primarily based on NMR data. Among the isolated compounds, four were flavanones, one was a flavonone, and three were chalcones. Notably, compound 8 was identified as a new chalcone, while compounds 2 and 3 were reported for the first time from this plant. The toxicity of these isolated compounds was evaluated against the HepG2 and SH-SY5Y cancer cell lines using the MTT assay. We further investigated markers of cell death using spectrophotometric and luminometric methods. Among the isolated compounds, 7 and 8 exhibited cytotoxic activities within the range of 3.0–20.0 µg/mL. Notably, the compounds demonstrated greater cytotoxicity towards liver-derived HepG2 cells compared to the neuronal SH-SY5Y cell line. Compound 7 (2′,4′-dihydroxychalcone) was identified as inducing apoptosis through the intrinsic pathway without causing overt necrosis. The findings indicate that the phytochemicals derived from A. africanum exhibit differential cytotoxic effects based on cell type, suggesting potential for developing novel anticancer agents, particularly compound 7. Additionally, the identification of compound 8 provides insight into the liver toxicity of this plant observed in sheep in South Africa. Full article

DNA connects the domains of genetic regulation and environmental interactions and plays a crucial role in neural development and cognitive function. The complex roles of genetic and epigenetic processes in brain development, synaptic plasticity, and higher-order cognitive abilities were reviewed in this study. Neural progenitors are formed and differentiated according to genetic instructions, whereas epigenetic changes, such as DNA methylation, dynamically control gene expression in response to external stimuli. These processes shape behavior and cognitive resilience by influencing neural identity, synaptic efficiency, and adaptation. This review also examines how DNA damage and repair mechanisms affect the integrity of neurons, which are essential for memory and learning. It also emphasizes how genetic predispositions and environmental factors interact to determine a person’s susceptibility to neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. Developments in gene-editing technologies, such as CRISPR, and non-viral delivery techniques provide encouraging treatment avenues for neurodegenerative disorders. This review highlights the fundamental role of DNA in coordinating the intricate interactions between molecular and environmental factors that underlie brain function and diseases. Full article

Hydrogen-rich water (HRW) has shown neuroprotective effects in acute brain injury, but its role in chronic radiation-induced brain injury (RIBI) remains unclear. This study investigated the long-term efficacy of HRW in mitigating cognitive impairment and neuronal damage caused by chronic RIBI. Fifty male Sprague Dawley rats were randomly divided into five groups: control, irradiation (IR), IR with memantine, IR with HRW, and IR with combined treatment. All but the control group received 20 Gy whole-brain X-ray irradiation, followed by daily interventions for 60 days. Behavioral assessments, histopathological analyses, oxidative stress measurements, ¹⁸F-FDG PET/CT imaging, transcriptomic sequencing, RT-qPCR, Western blot, and serum ELISA were performed. HRW significantly improved anxiety-like behavior, memory, and learning performance compared to the IR group. Histological results revealed that HRW reduced neuronal swelling, degeneration, and loss and enhanced dendritic spine density and neurogenesis. PET/CT imaging showed increased hippocampal glucose uptake in the IR group, which was alleviated by HRW treatment. Transcriptomic and molecular analyses indicated that HRW modulated key genes and proteins, including CD44, CD74, SPP1, and Wnt1, potentially through the MIF, Wnt, and SPP1 signaling pathways. Serum CD44 levels were also lower in treated rats, suggesting its potential as a biomarker for chronic RIBI. These findings demonstrate that HRW can alleviate chronic RIBI by preserving neuronal structure, reducing inflammation, and enhancing neuroplasticity, supporting its potential as a therapeutic strategy for radiation-induced cognitive impairment. Full article

The focal “hot spot” neuropathologies in COVID-19 infection are revealing footprints of a hidden underlying collapse of a novel ultrafast ultradian Piezo2 signaling system within the nervous system. Paradoxically, the same initiating pathophysiology may underpin the systemic findings in COVID-19 infection, namely the multiorgan SARS-CoV-2 infection-induced vascular pathologies and brain–body-wide systemic pro-inflammatory signaling, depending on the concentration and exposure to infecting SARS-CoV-2 viruses. This common initiating microdamage is suggested to be the primary damage or the acquired channelopathy of the Piezo2 ion channel, leading to a principal gateway to pathophysiology. This Piezo2 channelopathy-induced neural switch could not only explain the initiation of disrupted cell–cell interactions, metabolic failure, microglial dysfunction, mitochondrial injury, glutamatergic synapse loss, inflammation and neurological states with the central involvement of the hippocampus and the medulla, but also the initiating pathophysiology without SARS-CoV-2 viral intracellular entry into neurons as well. Therefore, the impairment of the proposed Piezo2-induced quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling seems to be the principal and critical underlying COVID-19 infection-induced primary damage along the brain axes, depending on the loci of SARS-CoV-2 viral infection and intracellular entry. Moreover, this initiating Piezo2 channelopathy may also explain resultant autonomic dysregulation involving the medulla, hippocampus and heart rate regulation, not to mention sleep disturbance with altered rapid eye movement sleep and cognitive deficit in the short term, and even as a consequence of long COVID. The current opinion piece aims to promote future angles of science and research in order to further elucidate the not entirely known initiating pathophysiology of SARS-CoV-2 infection. Full article

Background and Objectives: Anesthetic agents may influence brain function, and emerging evidence suggests possible neurotoxicity under certain conditions. S100β is a well-established biomarker of brain injury and blood–brain barrier disruption, and its prolonged elevation beyond 6–12 h, despite a short half-life, may indicate ongoing neuronal injury. Its use in cesarean section (C-section) remains limited, despite the potential neurological implications of both surgical stress and anesthetic technique. This study evaluates potential brain injury during caesarean section by comparing maternal and neonatal S100β levels under general and spinal anesthesia. Materials and Methods: This observational prospective study compared changes in the S100β brain damage biomarker in maternal (pre- and post-surgery) and umbilical artery blood during elective c-sections under general or spinal anesthesia. The 60 parturient women who underwent a C-section from 1 July 2021 to 30 December 2023 were evenly distributed into 2 groups: General anesthesia (GA) (n = 30) and Spinal anesthesia (SA) group (n = 30). It included healthy term pregnant women aged 18–40, ASA I–II and excluded those with major comorbidities or emergency conditions. Results: S100β concentrations slightly increased once the C-section was over in both the SA and GA groups, but without notable differences. In the SA and GA groups, preoperative S100β concentration in maternal blood was 195.1 ± 36.2 ng/L, 193.0 ± 54.3 ng/L, then increased to 200.9 ± 42.9 ng/L, 197.0 ± 42.7 at the end of operation. There was no statistically significant difference in S100β concentrations between the spinal and general anesthesia groups (p = 0.86). Conclusions: S100β concentrations slightly increased after C-section in both groups. The form of anesthesia seems to be irrelevant for the S100β level. However, further research is needed to confirm these findings and fully evaluate any potential long-term effects. Full article

Cerebral ischemic-reperfusion injury (CIRI) involves mitochondrial dysfunction, with mitophagy playing a key role. Astragaloside IV (AS-IV) shows neuroprotective potential; however, its mechanisms related to mitochondrial function and apoptosis remain unclear. Methods: Using a rat MCAO/R model, we evaluated the AS-IV’s effects via neurological scores, TTC staining, and histopathology. Molecular assays and docking were used to analyze mitophagy (PINK1, Parkin, p62, ROS, Bcl-2, and BAX) and apoptosis markers. Results: AS-IV improved neurological function, reduced infarct volume, and alleviated neuronal/mitochondrial damage. It upregulated PINK1/Parkin, decreased p62, and modulated Bcl-2/Bax. Docking confirmed AS-IV binds PINK1/Parkin with high affinity. Conclusions: AS-IV protects against CIRI by regulating the PINK1/Parkin pathway, improving mitochondrial function, and inhibiting neuronal apoptosis, providing an experimental basis for the clinical use Full article

Spinal cord injury (SCI) is a debilitating condition that results from a culmination of acute and chronic damage to neural tissue, specifically the myelin sheath, thus impacting neurons’ abilities to synergistically perform their physiological roles. This review explores the molecular underpinnings of myelination, demyelination, and remyelination, emphasizing the role of oligodendrocyte progenitor cells (OPCs), astrocytes, and microglia in physiological, and pathophysiological, healing. Furthermore, we link these processes with emerging therapeutic strategies currently under investigation in animal and human models, underscoring areas of translational medicine that remain underutilized. The goal of this review is to provide a framework for developing more advanced interventions to restore function and improve outcomes for individuals with SCI. Full article

Background: Parkinson’s disease (PD) involves progressive dopaminergic neuron degeneration and motor deficits. Oligodendrocyte dysfunction contributes to PD pathogenesis through impaired myelination. Methods: Single-nucleus RNA sequencing (snRNA-seq) of PD mice revealed compromised oligodendrocyte differentiation and STAT5B downregulation. Pseudotemporal trajectory analysis via Monocle2 demonstrated impaired oligodendrocyte maturation in PD oligodendrocytes, correlating with reduced myelin-related gene expression (Sox10, Plp1, Mbp, Mog, Mag, Mobp). DoRothEA-predicted regulon activity identified STAT5B as a key transcriptional regulator. Results: Oligodendrocyte-specific STAT5B activation improved myelin integrity, as validated by Luxol Fast Blue staining and transmission electron microscopy; attenuated dopaminergic neuron loss; and improved motor function. Mechanistically, STAT5B binds the MBP promoter to drive transcription, a finding confirmed by the luciferase assay, while the DNMT3A-mediated hypermethylation of the STAT5B promoter epigenetically silences its expression, as verified by MethylTarget sequencing and methylation-specific PCR. Conclusions: DNMT3A inhibited the expression of STAT5B by affecting its methylation, which reduced the transcription of MBP, caused oligodendrocyte myelin damage, and eventually led to dopamine neuron damage and motor dysfunction in an MPTP-induced mouse model. This DNMT3A-STAT5B-MBP axis underlies PD-associated myelin damage, connecting epigenetic dysregulation with oligodendrocyte dysfunction and subsequent PD pathogenesis. Full article

In familial Alzheimer’s disease (FAD), presenilin 1 (PSEN1) E280A cholinergic-like neurons (ChLNs) induce aberrant secretion of extracellular amyloid beta (eAβ). How PSEN1 E280A ChLNs-eAβ affects microglial activity is still unknown. We obtained induced microglia-like cells (iMG) from human peripheral blood cells (hPBCs) in a 15-day differentiation process to investigate the effect of bolus addition of Aβ42, PSEN1 E280A cholinergic-like neuron (ChLN)-derived culture supernatants, and PSEN1 E280A ChLNs on wild type (WT) iMG, PSEN1 E280A iMG, and sporadic Alzheimer’s disease (SAD) iMG. We found that WT iMG cells, when challenged with non-cellular (e.g., lipopolysaccharide, LPS) or cellular (e.g., Aβ42, PSEN1 E280A ChLN-derived culture supernatants) microenvironments, closely resemble primary human microglia in terms of morphology (resembling an “amoeboid-like phenotype”), expression of surface markers (Ionized calcium-binding adapter molecule 1, IBA-1; transmembrane protein 119, TMEM119), phagocytic ability (high pHrodo™ Red E. coli BioParticles™ phagocytic activity), immune metabolism (i.e., high generation of reactive oxygen species, ROS), increase in mitochondrial membrane potential (ΔΨm), response to ATP-induced transient intracellular Ca²⁺ influx, cell polarization (cluster of differentiation 68 (CD68)/CD206 ratio: M1 phenotype), cell migration activity according to the scratch wound assay, and especially in their inflammatory response (secretion of cytokine interleukin-6, IL-6; Tumor necrosis factor alpha, TNF-α). We also found that PSEN1 E280A and SAD iMG are physiologically unresponsive to ATP-induced Ca²⁺ influx, have reduced phagocytic activity, and diminished expression of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) protein, but when co-cultured with PSEN1 E280A ChLNs, iMG shows an increase in pro-inflammatory phenotype (M1) and secretes high levels of cytokines IL-6 and TNF-α. As a result, PSEN1 E280A and SAD iMG induce apoptosis in PSEN1 E280A ChLNs as evidenced by abnormal phosphorylation of protein TAU at residue T205 and cleaved caspase 3 (CC3). Taken together, these results suggest that PSEN1 E280A ChLNs initiate a vicious cycle between damaged neurons and M1 phenotype microglia, resulting in excessive ChLN death. Our findings provide a suitable platform for the exploration of novel therapeutic approaches for the fight against FAD. Full article

Bruton Tyrosine Kinase (BTK) has emerged as a critical mediator in the pathophysiology of neuroinflammation associated with neurodegenerative diseases. BTK, a non-receptor tyrosine kinase predominantly expressed in cells of the hematopoietic lineage, modulates B-cell receptor signaling and innate immune responses, including microglial activation. Recent evidence implicates aberrant BTK signaling in the exacerbation of neuroinflammatory cascades contributing to neuronal damage in disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ischemic stroke, and Huntington’s disease. Pharmacological inhibition of BTK has shown promise in attenuating microglial-mediated neurotoxicity, reducing pro-inflammatory cytokine release, and promoting neuroprotection in preclinical models. BTK inhibitors, originally developed for hematological malignancies, demonstrate favorable blood–brain barrier penetration and immunomodulatory effects relevant to central nervous system pathology. This therapeutic approach may counteract detrimental neuroimmune interactions without broadly suppressing systemic immunity, thus preserving host defense. Ongoing clinical trials are evaluating the safety and efficacy of BTK inhibitors in patients with neurodegenerative conditions, with preliminary results indicating potential benefits in slowing disease progression and improving neurological outcomes. This review consolidates current knowledge on BTK signaling in neurodegeneration and highlights the rationale for BTK inhibition as a novel, targeted therapeutic strategy to modulate neuroinflammation and mitigate neurodegenerative processes. Full article

Background/Objectives: Niemann-Pick disease Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 100,000 live births that belongs to the lysosomal storage diseases (LSDs). NPC is characterized by the abnormal accumulation of unesterified cholesterol, in addition to being an autosomal recessive inherited pathology, which belongs to LSDs. It occurs in 95% of cases due to mutations in the NPC1 gene, while 5% of cases are due to mutations in the NPC2 gene. In the cerebral cortex (CC), the disease shows lipid inclusions, increased cholesterol and multiple sphingolipids in neuronal membranes, and protein aggregates such as hyperphosphorylated tau, α-Synuclein, TDP-43, and β-amyloid peptide. Mitochondrial damage and oxidative stress are some alterations at the cellular level in NPC. Therefore, the aim of this work was to determine the gene expression profile in the CC of NPC1 mice in order to identify altered molecular pathways that may be related to the pathophysiology of the disease. Methods: In this study, we performed a microarray analysis of a 22,000-gene chip from the cerebral cortex of an NPC mutant mouse compared to a WT mouse. Subsequently, we performed a bioinformatic analysis in which we found groups of dysregulated genes, and their expression was corroborated by qPCR. Finally, we performed Western blotting to determine the expression of proteins probably dysregulated. Results: We found groups of dysregulated genes in the cerebral cortex of the NPC mouse involved in the ubiquitination, fatty acid metabolism, differentiation and development, and underexpression in genes with mitochondrial functions, which could be involved in intrinsic apoptosis reported in NPC, in addition, we found a generalized deregulation in the cortical circadian rhythm pathway, which could be related to the depressive behavior that has even been reported in NPC patients. Conclusions: Recognizing that there are changes in the expression of genes related to ubiquitination, mitochondrial functions, and cortical circadian rhythm in the NPC mutant mouse lays the basis for targeting treatments to new potential therapeutic targets. Full article

Neurological diseases encompass a variety of conditions that vary in terms of when they first manifest, who is affected, what area of the nervous system is impacted, what type of neurons are damaged, whether they are genetically or spontaneously inherited, and whether they are curable [...] Full article

Modified oligonucleotides (oligos) are widely used as convenient tools in many scientific fields, including biomedical applications and therapies. In particular, oligos with lipophilic groups attached to the backbone ensure penetration of the cell membrane without the need for transfection. This study examines the interaction between amphiphilic DNA duplexes, in which one of the chains contains a lipophilic substituent, and several DNA repair proteins, particularly DNA-damage-dependent PARPs, using various biochemical approaches. DNA with a lipophilic substituent (LS-DNA) demonstrates more efficient binding with DNA damage activated poly(AD-ribose) polymerases 1-3 (PARP1, PARP2, PARP3) and DNA polymerase β. Chemically reactive LS-DNA derivatives containing a photoactivatable nucleotide (photo-LS-DNAs) or a 5′ deoxyribose phosphate (dRP) group in the vicinity of double-strand breaks (DSBs) are used for the affinity labelling of PARPs and other proteins in several whole-cell extracts of human cells. In particular, photo-LS-DNAs are used to track the level of Ku antigen in the extracts of neuron-like differentiated SH-SY5Y, undifferentiated SH-SY5Y, and olfactory epithelial cells. In vitro, PARP1–PARP3 are shown to be able to slowly excise the 5′ dRP group at DSBs. LS-DNAs can activate PARP1 and PARP2 for autoPARylation, albeit less effectively than regular DNA duplexes. Full article

Background: Spinal muscular atrophy (SMA) is a treatable motor neuron disease. Biomarkers for skeletal muscle atrophy are extremely important for measuring the effects of treatment and monitoring the natural course of the disease. The urinary titin N fragment (UNT) has recently been proven to be related to muscle damage. Methods: The UNT was measured in 41 patients with SMA and 41 healthy controls. Clinical data, functional tests, and laboratory findings were also recorded. Results: We found significantly higher UNT levels in the patient samples than in the healthy subjects. The UNT was not related to disease type, functional test results, or serum creatine kinase levels. Conclusions: This cross-sectional study highlights the importance of the UNT as a potential noninvasive biomarker for spinal muscular atrophy. Its role can potentially be verified through longitudinal studies. Full article

Background/Objectives: Oxidative stress constitutes a principal pathophysiological mechanism driving neurodegeneration and brain aging. α-Ketoglutarate (AKG), a key intermediate of the tricarboxylic acid (TCA) cycle, has shown potential in longevity and oxidative stress resistance. However, the role of AKG in oxidative stress-induced neuronal senescence and its interaction with the mTOR signaling pathway during neuronal aging remain poorly understood, posing a key challenge for developing senescence-targeted therapies. Methods: We investigated the neuroprotective effects of AKG using H₂O₂-induced senescence in HT22 cells and a D-galactose-induced brain aging mouse model. Assessments encompassed SA-β-gal staining, EdU incorporation, mitochondrial membrane potential (JC-1), and ROS measurement. Antioxidant markers, ATP levels, and the NAD⁺/NADH ratio were also analyzed. Proteomic profiling (DIA-MS) and KEGG/GSEA enrichment analyses were employed to identify AKG-responsive signaling pathways, and Western blotting validated changes in mTOR signaling and downstream effectors. Results: AKG significantly alleviated H₂O₂-induced senescence in HT22 cells, evidenced by enhanced cell viability, reduced ROS level, restored mitochondrial function, and downregulated p53/p21 expression. In vivo, AKG administration improved cognitive deficits and vestibulomotor dysfunction while ameliorating brain oxidative damage in aging mice. Proteomics revealed mTOR signaling pathways as key targets for AKG’s anti-aging activity. Mechanistically, AKG suppressed mTOR phosphorylation and activated ULK1, suggesting modulation of autophagy and metabolic homeostasis. These effects were accompanied by enhanced antioxidant enzyme activities and improved redox homeostasis. Conclusions: Our study demonstrates that AKG mitigates oxidative stress-induced neuronal senescence through suppression of the mTOR pathway and enhancement of mitochondrial and antioxidant function. These findings highlight AKG as a metabolic intervention candidate for age-related neurodegenerative diseases. Full article