共找到 20 条结果
Aim: The aim of this review is to assess the role of neuromolecular biomarkers in post-traumatic stress disorder (PTSD) and their usefulness in improving diagnostic accuracy and supporting personalized treatment strategies. Materials and Methods: A narrative review of studies published between 2015 and 2025 was performed using databases such as PubMed, Scopus, and Web of Science. The analysis included clinical and experimental studies focusing on neuroinflammation, oxidative stress, endoplasmic reticulum stress, and markers of neuronal damage in PTSD. Special attention was given to associations between biomarkers and symptom severity, duration of illness, and treatment outcomes. Results: PTSD is associated with disturbances in neuroimmune and neuroendocrine pathways. Increased levels of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-18 (IL-18), are frequently observed. Activation of the NLR family pyrin domain containing 3 inflammasome (NLRP3 inflammasome) and elevated oxidative stress markers, such as malondialdehyde (MDA), indicate ongoing inflammatory and oxidative processes. Changes in neuronal injury markers, including ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), suggest neurodegenerative mechanisms. Altered chemokine signaling, particularly fractalkine (chemokine C-X3-C motif ligand 1, CX3CL1), and activation of endoplasmic reticulum stress pathways, such as inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6), are linked to impaired neuronal function and reduced synaptic plasticity. These findings indicate biological heterogeneity within PTSD. Conclusions: Neuromolecular biomarkers may improve the current symptom-based diagnostic model of PTSD. Their integration with clinical assessment tools may support identification of biologically defined subgroups and enable more targeted treatment.
Late-life depression (LLD) with high prevalence accelerates cognitive impairment and becomes a risk factor for dementia, yet the pathogenesis of LLD is still largely unclear. Delineating the neuromolecular mechanism of LLD is of great significance to its etiology, early diagnosis, and precision treatment. This study included 35 patients with LLD and 41 age-matched healthy controls (HCs). Brain entropy (BEN) and functional connectivity (FC) were used to assess the abnormalities in brain functional system irregularity and couplings in LLD, using resting-state functional magnetic resonance imaging. Additionally, transcriptome and neurotransmitter data were employed to investigate the neuromolecular mechanisms underlying these changes. Compared with HCs, patients with LLD exhibited significantly reduced BEN in the temporoparietal junction (TPJ) and decreased FC between TPJ and the middle frontal gyrus (MFG). Moreover, the changes of BEN were closely associated with the genes' expression profiles, which were involved in endocannabinoid, adrenergic, oxytocin, and cGMP-PKG signaling, glutamatergic, GABAergic, dopaminergic, cholinergic, serotonergic synapses, long-term potentiation, and long-term depression. We also found that the changes of BEN and FC were correlated with neurotransmitterreceptor distribution patterns of serotonin, histamine, acetylcholine, and dopamine. Reduced BEN of TPJ in LLD indicates impaired regional information-processing complexity, potentially driving persistent cognitive deficits and abnormal negative-emotion handling, even in early LLD without overt clinical symptoms. Decreased TPJ-MFG FC disrupts brain network synchronization, weakening MFG-mediated emotion regulation and cognition, and possibly elevating the risk of suicidal ideation. Some genes, such as PRKACA/PRKACB, GNAI1, MAPK-ERK, PLA2G4A, and LXN, along with neurotransmitter receptors, contribute to a more comprehensive understanding of LLD. Altered brain entropy and connectivity in the TPJ-MFG circuit and related neurobiomolecules may underlie the pathogenesis of LLD and provide predictive value for its diagnosis and treatment. Our study highlights the important role of the TPJ-MFG circuit in the neuropathology of LLD and links the macroscopic functional abnormalities with transcriptome and neurotransmitter to establish the molecular basis. Our findings contribute to understanding the neurobiological basis of LLD and may facilitate future precision therapy.
The opioid crisis has resulted in escalating rates of opioid use disorder in women of reproductive age and increased prevalence of fetal drug exposure. While medication for opioid use disorder (MOUD) - e.g., buprenorphine or methadone - improves maternal health outcomes, infants exposed to MOUD show a variety of physical and behavioral consequences. There are, however, few clinical or preclinical studies investigating long-term effects of MOUD exposure. The current work investigates the long-term effects of prenatal MOUD exposure on effort-based responding to a palatable food reward and gene expression in regions of the brain related to reward and feeding, including the nucleus accumbens and hypothalamus. Female Sprague Dawley rats were implanted with osmotic minipumps filled with methadone (10 mg/kg/day) or buprenorphine (1 mg/kg/day) or saline control (2.5 μL/hour for 28 days) and mated four days later. In adulthood, male and female offspring began sucrose pellet self-administration to assess the motivational strength of a food reward in MOUD-exposed animals compared to saline controls, followed by analysis of gene expression via RNAscope in situ hybridization. We observed long-term changes in reward motivation, where adults gestationally exposed to methadone - but not buprenorphine - demonstrated increased motivated responding for sucrose. We observed modest sex-dependent effects of MOUD on gene expression in the nucleus accumbens and arcuate nucleus of the hypothalamus following sucrose self-administration. These data suggest differential effects of methadone and buprenorphine on the brain and behavior, providing insight into the potential neuromolecular underpinnings of MOUD-induced changes in neural modulation of reward-motivated behavior.
Ischemic stroke (IS) induces profound dysregulation of the neuro-molecular innate immune-vascular network, yet the molecular immune states and regulatory mechanisms of key cellular subpopulations remain insufficiently defined. Although traditional Chinese medicine (TCM) exhibits multi-target immunomodulatory potential, its cell-type and cell-state-specific actions within the ischemic brain microenvironment at single-cell resolution remain unclear. Single-cell RNA sequencing was used to construct a cellular atlas of the ischemic mouse brain, followed by integrative bioinformatic analyses to characterize innate immune-related neural cell subpopulations and their regulatory networks. Network pharmacology and molecular docking were applied to identify salidroside (SAL), a major active compound of Rhodiola, and predict its potential molecular targets. In vivo experiments were performed to validate cellular and molecular changes associated with SAL treatment. In a mouse model of IS, ischemic injury induced pronounced imbalances across multiple immune and glial cell subpopulations. A transcriptionally defined Notch1+ Hes5+ astrocyte (ASC), enriched for progenitor-like and reparative gene signatures, was markedly reduced after ischemic injury, whereas reactive SerpinA3N+ ASC and pro-inflammatory Sell+ microglia (MG) were expanded. Additionally, alterations were observed in immune-regulatory cell populations, including Cxcl12+ endothelial cells (ECs) and Gpr34+ Ptgs1+ MG. In vivo validation showed that SAL treatment was associated with modulation of Notch1/Hes5 signaling in ASC, reduced reactive ASC features, and partial normalization of ECs alterations, accompanied by changes consistent with attenuated neuroimmune activation. These effects coincided with altered intercellular communication, particularly involving NOTCH signaling. This study provides single-cell-level insights into innate immune microenvironment remodeling following IS and identifies a Notch1+ Hes5+ ASC subpopulation with transcriptional features associated with reparative-related programs and responsiveness to SAL. The findings suggest that SAL-associated neuroprotection was accompanied by modulation of ASC states and immune-glial communication, highlighting the potential of SAL-associated immunoregulatory effects at the single-cell level in IS.
Hyperthyroidism is associated with cognitive impairment and neuropsychiatric symptoms, yet its effects on white matter architecture and neuromolecular organization remain poorly understood. We examined how hyperthyroidism alters white matter wiring architecture and the neuromodulatory systems underlying these disturbances. Diffusion MRI-derived structural connectomes were analyzed in 30 patients with hyperthyroidism (HT) and 28 matched healthy controls (HC). Structural connections were classified into short-, medium-, and long-range pathways, and global and nodal network topology was quantified using graph theoretical analysis. Molecular associations were examined using nine PET-derived neurotransmitter receptor density maps through spatial correlation, multiple regression, and dominance analysis. Associations with thyroid hormone levels, clinical measures, and cognitive scores were evaluated using permutation-based statistical testing. Neurotransmitter-weighted network measures were computed by linking normative neurotransmitter density with graph theoretical metrics. Spatial autocorrelation was controlled using spin permutation testing, with results additionally corrected for multiple comparisons using false discovery rate (FDR) correction. Hyperthyroid patients exhibited significantly increased medium-range (p = .002) and long-range connectivity (p = .02), reduced modularity (p = .009), and increased characteristic path length (p = .032) as compared to controls, indicating disrupted segregation and efficiency. Nodal alterations were predominantly right-lateralized, involving cortical, subcortical, and cerebellar regions. Clinically, BMI predicted modularity (p = .01), while free thyroxine levels predicted characteristic path length (p = .04) and long-range connectivity strength (p = .03). The Nahor-Benson score was associated with increased medium-range connectivity (p = .02) and nodal degree (p = .03) in right cerebellar lobule IV-V. Neurotransmitter receptor distributions explained substantial variance in network topology (adjusted R2 = 0.45 in controls; 0.38 in hyperthyroidism), with dominant contributions from 5-HT1A (33%) and dopamine transporter (17%). Furthermore, 5-HTT-weighted within module degree z-score predicted thyroid-stimulating hormone (TSH) levels in hyperthyroidism (p = .03), linking hormonal dysregulation to molecular connectomic reorganization. Our findings suggest that excess thyroid hormone drives right-lateralized connectomic reorganization and increased metabolic demand, mediated by serotonergic and dopaminergic receptor architecture, linking endocrine dysfunction to large-scale brain network vulnerability. These insights inform mechanistic models and biomarkers for clinical translation.
CBD is widely studied for its stress-reduction and cognitive-enhancing properties, but its effects on hippocampal molecular organisation under physiological settings are unknown. Acute and long-term intraperitoneal CBD treatment at different doses was tested on hippocampus gene expression, circulating corticosterone, and behavioural performance in C57BL/6J mice. Short-term administration did not induce detectable transcriptional changes. In contrast, long-term treatment with 10 mg/kg CBD, but not lower or higher doses, resulted in significant hippocampal transcriptional remodelling. Overrepresentation analysis showed coordinated control of mitochondrial oxidative phosphorylation genes, particularly numerous respiratory chain complex I components, and purine and nucleotide metabolic pathways. Shared mitochondrial respiratory genes, not classical disease-associated effectors, enriched KEGG categories for neurodegeneration and retrograde endocannabinoid signalling. The endocrine profile showed a temporary increase in circulating corticosterone after short-term exposure, but long-term dosing decreased it. Behavioural effects were modest and limited across paradigms. These results show that long-term administration of an intermediate CBD dose alters subsets of genes related to coordinated bioenergetic and nucleotide-related transcriptional adaptation in the hippocampus, which modulates endocrine stress markers but does not disrupt behaviour. The data suggest that chronic CBD exposure may cause metabolic recalibration in stress-sensitive brain circuits rather than acute neuromolecular reprogramming.
Dementia with Lewy bodies (DLB) is a common yet underdiagnosed neurodegenerative dementia, characterised neuropathologically by nigrostriatal dopaminergic degeneration and widespread α-synuclein aggregation. Clinical diagnosis remains challenging due to marked heterogeneity in presentation and substantial overlap with Alzheimer's disease (AD), resulting in diagnostic delays and frequent misdiagnosis. The ability to identify underlying pathological processes ante-mortem is essential to improve diagnostic accuracy, refine prognosis, stratify patients for clinical trials, and ultimately enable personalised therapeutic approaches. Over recent decades, major advances have been made in the development of neuroimaging biomarkers that reflect key features in Lewy body disease pathology, many of which have informed diagnostic criteria. In addition to dopaminergic dysfunction and α-synuclein pathology, co-existing neuropathologies including amyloid-β, tau, neuroinflammation, and vascular changes are increasingly recognised as important modifiers of clinical phenotype and disease trajectory in DLB. This review summarises the current landscape of neuroimaging modalities in DLB and critically examines their relationships with confirmed neuropathological correlates. We discuss indicative biomarkers such as striatal dopamine imaging and 123I-metaiodobenzylguanidine myocardial scintigraphy, alongside supportive imaging markers derived from structural magnetic resonance imaging and Fluorodeoxyglucose Positron Emission Tomography (FDG-PET). Emerging PET approaches targeting α-synuclein, as well as established amyloid and tau-PET techniques for assessing co-pathologies, are reviewed in the context of post-mortem validation studies. Finally, we consider Translocator protein PET imaging as a marker of neuroinflammation and highlight key methodological limitations and knowledge gaps. Together, these neuroimaging-pathological correlations provide critical insights into disease mechanisms and outline future directions toward earlier, biologically informed diagnosis and precision medicine in DLB.
Curculigoside (CUR), a flavonoid derived from traditional Chinese medicine, has shown potential in alleviating depressive symptoms. However, the mechanisms underlying its antidepressant effects remain unclear. The aim of this study was to investigate the effect of CUR on depressive-like behavior in the chronic social defeat stress (CSDS) model and its potential mechanism of action on pyramidal neuronal excitability and synaptic transmission. We injected 20 mg/kg of CUR intraperitoneally for seven days and found that CUR significantly alleviated emotional deficits in mice subjected to CSDS. CUR restored the activity of pyramidal neurons in the medial prefrontal cortex (mPFC) and ventral CA1 (vCA1) regions, which were suppressed by CSDS during depression-like behaviors. Through network pharmacology and molecular docking, we identified CUR's pharmacological targets and found that its antidepressant effects are partly mediated by modulating the cAMP-PKA signaling pathway. CUR treatment ameliorated synaptic transmission dysfunction in both the mPFC and vCA1. CUR regulated the cAMP-PKA signaling pathway and GluA1 subunit trafficking, thereby contributing to the restoration of synaptic function. CUR alleviated depression-like behaviors induced by CSDS by modulating the excitability and synaptic transmission of pyramidal neurons in the mPFC and vCA1 through activation of the cAMP-PKA-GluA1 signaling pathway. These findings provide new insights into CUR's antidepressant mechanisms and highlight its potential as a therapeutic agent for depression.
Chronic subdural hematoma (cSDH) is now better understood as a biologically active inflammatory disorder rather than purely a consequence of trauma. With recurrence occurring in up to 30% of cases after treatment, this pathology remains a major source of morbidity and cause for concern. A growing body of literature suggests that there is a complex interplay between inflammation, angiogenesis, fibrinolytic dysregulation, and structural membrane remodeling in driving cSDH persistence and recurrence. We performed a comprehensive narrative review to identify molecular, histopathological, biochemical, and radiographic correlates of cSDH activity and recurrence. Emphasis was placed on inflammatory mediators, immune cell dynamics, angiogenic signaling pathways, fibrinolytic imbalance, systemic modifiers, and their interaction with contemporary management techniques. Recurrent cSDH is characterized by a persistent pro-inflammatory and pro-angiogenic microenvironment within the neomembrane. Factors include elevated interleukins (particularly IL-6 and IL-8), macrophage polarization imbalance (M1/M2 ratio), VEGF/HIF-1α-driven immature angiogenesis, and excessive fibrinolytic activity mediated by tPA, uPA, and reduced endogenous inhibitors. Structural membrane phenotypes, metabolic and systemic inflammatory states, imaging biomarkers, and cerebrospinal fluid dynamics further affect and characterize recurrence risk. Emerging therapies, including middle meningeal artery embolization, statins, tranexamic acid, and targeted anti-angiogenic agents appear to act by interrupting key elements of this pathological loop. cSDH recurrence reflects failure of inflammatory resolution and vascular maturation rather than incomplete evacuation alone. Integrating molecular biomarkers, imaging surrogates of membrane biology, and patient-specific systemic modifiers may enable biologically informed risk stratification and guide personalized therapeutic strategies aimed at preventing recurrence.
Diabetic ischemic stroke leads to more severe brain damage. While the urokinase-type plasminogen activator receptor (PLAUR) is implicated in inflammation and cell migration, its precise role in diabetic stroke remains unclear. A streptozotocin-induced diabetic tMCAO mouse model was employed to simulate diabetic ischemic stroke. PLAUR expressions in mouse brain tissues were analyzed using microarray, Western blot, and immunofluorescence. PLAUR mRNA expression in endothelial cells (bEnd.3) was analyzed by RT-qPCR. We assessed cerebral infarct volume, brain water content, neurological deficits, and BBB integrity. Neutrophil infiltration (flow cytometry), inflammatory mediators, microglial polarization, and metabolic reprogramming (glycolytic proteins, ECAR/OCR) were investigated in vivo and in vitro. To test whether neutrophils are essential for PLAUR-mediated injury, we performed neutrophil depletion experiments using anti-Ly6G antibody, alone or combined with PLAUR knockdown. Neutrophil extracellular trap (NET) formation (CitH3 expression) and its impact on endothelial permeability and microglial polarization were also examined. PLAUR was significantly upregulated in the brains of diabetic stroke mice, particularly in microglia. PLAUR knockdown resulted in smaller infarct volumes, improved functional recovery, and maintained BBB integrity by restoring tight junction proteins. PLAUR knockdown was associated with reduced neutrophil infiltration, decreased pro-inflammatory mediator (MPO, MMP3) and attenuated pro-inflammatory M1 microglial polarization. PLAUR silencing also reduced NETosis in vivo and in isolated neutrophils. Neutrophil depletion alone significantly reduced infarct volume, improved neurological outcomes, and restored tight junction proteins; notably, PLAUR knockdown provided no additional benefit when neutrophils were already depleted, indicating that neutrophils are essential downstream effectors of PLAUR-mediated injury. Furthermore, PLAUR knockdown reversed the glycolytic shift in microglia. PLAUR is upregulated in diabetic ischemic stroke and its knockdown is associated with reduced neuroinflammation, preserved BBB integrity, decreased neutrophil infiltration, attenuated NETosis, and shifts in microglial polarization and metabolism. Therefore, targeting PLAUR represents a promising therapeutic strategy for attenuating brain injury in diabetic stroke.
Intracellular glucocorticoid metabolism plays a critical role in shaping glucocorticoid receptor signaling in the brain. 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) catalyzes the NAD+-dependent oxidation of active glucocorticoids to inactive 11-keto forms, yet its expression and functional capacity in the adult brain are generally considered negligible, except for discrete brainstem nuclei. Here, we examined HSD11B2 expression in the adult rat brain at the mRNA and protein levels using quantitative real-time PCR, Western blotting, and immunohistochemistry. To assess catalytic function, HSD11B2 was immunoprecipitated from hippocampal lysates and assayed in vitro in the presence of NAD+, using cortisol as a substrate. Hsd11b2 mRNA and HSD11B2 protein were detected across all brain regions examined. Immunohistochemistry indicated predominant HSD11B2 immunoreactivity in hippocampal neurons. Both hippocampal homogenates and HSD11B2 immunoprecipitates displayed NAD+-dependent glucocorticoid dehydrogenase activity, consistent with enzymatic functionality. Collectively, these findings provide molecular and functional evidence for HSD11B2 expression and activity in the adult rat brain and motivate further studies to define its cellular localization and to clarify how local glucocorticoid inactivation influences hippocampal signaling and physiology.
Modern IV iron formulations allow treatment of iron deficiency anemia (IDA) with 1 or 2 infusions. Ferric carboxymaltose (FCM) is a widely used IV iron, which causes hypophosphatemia in most of the patients. Osteomalacia and fractures are increasingly recognized after repeated infusions of FCM. It is unknown why ferric derisomaltose (FDI) rarely causes hypophosphatemia. In this study, we compare the effects of FCM and FDI on fracture risk and investigate potential underlying mechanisms explaining the different effects on bone and mineral metabolism. For this aim, fracture rate and osteomalacia were assessed in a cohort of 357 patients treated with either drug, who reported a significantly higher rate of incident osteomalacia or fracture after FCM. These findings were validated in >20 000 patients from the TriNetX database, where FCM treatment was independently associated with a higher fracture risk compared with FDI. The underlying mechanisms were investigated in a mouse model of IDA treated with FCM or FDI, an osteocyte model, and biochemically. FCM caused lower expression of collagen and ossification genes, associated with significantly higher bone iron concentrations than FDI. Electron microscopy showed iron-loaded vesicles in osteoblasts and early osteocytes. FCM but not FDI inhibited the binding of dentin matrix protein 1 to αVβ3-integrin on osteocytes. This is a potential mechanism for reduced bone formation and higher levels of intact fibroblast growth factor 23 after FCM. Our data report that IDA and FCM treatment can directly impair bone formation and increase fracture risk.
Vascular dementia (VaD), a major contributor to cognitive decline, arises primarily from impaired regulation of cerebral circulation. Pterostilbene (PTE), a natural stilbene, exhibits potent neuroprotective properties, including antioxidative, anti-apoptotic, and cognition-enhancing effects; however, the molecular basis of its protective action in VaD remains poorly defined. Here, we integrated network pharmacology with in-vitro and in-vivo validation to delineate the mechanistic underpinnings of PTE. An ischemic injury model was established in SH-SY5Y cells using oxygen-glucose deprivation/reoxygenation (OGD/R), while VaD was induced in rats by bilateral common carotid artery occlusion. Cognitive function was assessed by behavioural paradigms, and neuronal integrity, vascular architecture, mitochondrial function, respiratory complex activities, and synaptic plasticity via the cAMP/PKA/CREB signalling cascade were evaluated using histological, biochemical, and molecular assays. Network pharmacology identified the cAMP pathway as a principal mediator of PTE activity. In ischemia injured SH-SY5Y cells, PTE improved viability, reduced oxidative stress, stabilized mitochondrial membrane potential, and elevated ATP production. In VaD rats, PTE enhanced spatial learning and memory, preserved cortical and hippocampal structures, and promoted mitochondrial health, evidenced by upregulation of PGC-1α and TFAM, restoration of respiratory complex activities, and preservation of mitochondrial ultrastructure. PTE also increased expression of synaptic proteins (PSD95, Synaptophysin). Consistently across both models, PTE activated the cAMP/PKA/CREB signalling axis. Collectively, these findings demonstrate that PTE mitigates ischemia-induced cognitive impairment by reversing mitochondrial dysfunction while sustaining synaptic plasticity through cAMP/PKA/CREB activation, highlighting its translational potential as a therapeutic candidate for VaD.
Parkinson’s disease (PD) is a progressive neurodegenerative disease, which can’t be cured at present. Bone marrow mesenchymal stem cells (BMSCs)-derived exosomal microRNAs are involved in various neurodegenerative diseases. While BMSC-derived exosomes show therapeutic potential in PD, their specific mechanisms remain elusive. This research aims to elucidate the functional mechanism of exosomal miR-1278 from BMSCs in PD. The motor deficits and cognitive function of mice were assessed by Pole test, Rotarod test, Open field test, and Morris water maze. Western blotting assay and qRT-PCR were carried out to evaluate gene and miRNA expressions. Neuronal apoptosis was elevated by TUNEL assay. Immunofluorescence staining assessed microglial activation. Flow cytometry assay was conducted to detect microglia apoptosis and polarization. Inflammatory cytokines levels were measured by ELISA. Metabolic assays included Seahorse ECAR/OCR, FAO, and lactic acid quantification. BMSCs can improve the motor and cognitive deficits of PD mice by relieving neuronal damage and microglia-induced neuroinflammation. As for the molecular mechanism, downregulation of miR-1278 was identified in plasma exosomes and BMSCs from PD patients. And exosomes can transfer miR-1278 from BMSCs to microglia. Exosomal miR-1278 alleviated apoptosis and M1 polarization of microglia. Further, miR-1278 targets LDHA and downregulates its expression microglia. LDHA knockdown promoted M2 polarization and prevented apoptosis of microglia by impairing glycolysis and enhancing fatty acid oxidation (FAO). In vivo assay also demonstrated that BMSCs-derived miR-1278 relieved motor and cognitive deficits in PD mice through regulating LDHA-mediated polarization of microglia. Exosomal miR-1278 from BMSCs promotes M2 polarization of microglia by regulating LDHA-mediated metabolism reprogramming, thereby relieving neuronal damage and neuroinflammation in PD. This study elucidates a novel mechanistic pathway involving miR-1278/LDHA, offering a precise target for future PD therapies.
Background: Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration associated with oxidative stress, dysregulated endoplasmic reticulum (ER) stress, impaired mitophagy, and neuroinflammation. Although rotenone (ROT) reliably induces these pathological features, there remains a lack of effective pharmacological agents capable of simultaneously modulating ER-stress and PINK1/Parkin-dependent mitophagy representing an important gap in current PD research. Objective: This study aimed to investigate whether naftidrofuryl (NFD), a vasoactive and cytoprotective agent, can attenuate ROT-induced neurobehavioral, biochemical, and molecular alterations through modulation of ER-stress signaling and PINK1/Parkin-mediated mitophagy. Methods: Forty male Wistar rats were assigned to four groups (Control, NFD, ROT, ROT + NFD combination). Behavioral assessments (Y-maze, rotarod, tail suspension), oxidative/antioxidant biomarkers, inflammatory cytokines, dopamine levels, ER-stress markers (BIP, ATF6, eIF2α/CHOP), mitophagy mediators (PINK1, Parkin), SNCA expression, miR-124 expression, histopathology, and caspase-1 immunoreactivity were evaluated. Results: ROT administration induced marked cognitive and motor impairment, elevated oxidative and nitrosative stress, increased pro-inflammatory cytokines, reduced antioxidant capacity, and upregulated ER-stress mediators. ROT also downregulated PINK1/Parkin expression suppressed miR-124, elevated SNCA, and produced significant neuronal degeneration with increased caspase-1 activation. NFD treatment significantly ameliorated these alterations by reducing oxidative stress and inflammatory cytokines, restoring antioxidant markers, attenuating ER-stress activation, enhancing PINK1/Parkin-dependent mitophagy, normalizing miR-124 expression, reducing SNCA expression, and improving histopathological and behavioral outcomes. Conclusion: NFD demonstrated robust neuroprotective effects against ROT-induced neurotoxicity, likely through coordinated modulation of ER-stress pathways, restoration of PINK1/Parkin signaling, reduction of oxidative and inflammatory responses, and preservation of neuronal integrity. These findings suggest a potential mechanistic role for NFD in mitigating early PD-related neurodegenerative changes, warranting further preclinical investigation.
The inflammatory response is essential for host defense, but its persistence can lead to chronic systemic inflammation (CSI). Soluble urokinase-type plasminogen activator receptor (suPAR) has emerged as a reliable biomarker of CSI because elevated levels consistently indicate the presence and progression of chronic disease as well as increased mortality risk. There is growing evidence that CSI influences neurovascular regulation, including changes in blood-brain barrier (BBB) integrity, which suggests that suPAR may also be relevant to central nervous system (CNS) processes. This narrative review summarizes current findings on suPAR in CSI and examines its emerging implications for CNS. Higher suPAR concentrations have been linked to working memory impairment, executive dysfunction and worse clinical outcomes after brain injury. Evidence also indicates that suPAR reflects neuroinflammatory activity and BBB disruption, especially in conditions marked by heightened immune activation. However, available studies differ widely in design, sample type, follow-up duration and population characteristics, which limits mechanistic interpretation. Although suPAR appears to be a promising biomarker connecting systemic inflammation to CNS dysfunction, its role within the brain remains unclear. Future studies should determine its cellular origin, clarify its involvement in inflammatory signaling pathways and establish its predictive and prognostic value.
Brain cancers hijack biological systems involved in neural development and synaptic plasticity. Medulloblastoma (MB), the most common malignant brain tumor in children, is thought to arise from disruptions in neurodevelopmental programs. Glutamatergic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) has been implicated in synaptic communication between adult brain tumors and surrounding neurons; however, the possible role of AMPARs in MB remains largely unexplored. Here, we analyzed the expression of genes encoding AMPAR subunits, GRIA1-4, in datasets of MB tumors and cell lines, revealing distinct expression patterns and associations with overall survival (OS) across molecular subgroups and histological variants. Expression levels differed among MB molecular subgroups. Analysis using single-cell RNA sequencing (scRNA-seq) was consistent with enrichment of GRIA1 in Group 3 and GRIA4 in sonic hedgehog (SHH) MB. Higher GRIA1, GRIA2, and GRIA4 transcription was associated with more favorable patient outcomes in specific MB subgroups. In contrast, high expression of GRIA3 in SHH, or of either GRIA3 or GRIA4 in Group 3 MB, was associated with worse prognosis. Particularly robust but opposing associations with patient survival were found for GRIA3 and GRIA4 in SHH MB. Analysis of GRIA mRNA levels in MB cell lines using both quantitative reverse transcription polymerase chain reaction (qRT-PCR) and data from The Human Protein Atlas, supported some of the gene expression patterns observed in tumors. Together, these findings suggest that GRIA genes and their corresponding AMPAR subunits may have subgroup-specific prognostic relevance in MB.
High-grade gliomas (HGGs) are the most aggressive adult brain tumors, with a dismal median survival of approximately 15 months, highlighting the need for novel therapeutic strategies. In a prior immunotherapy trial using dendritic cells against glioblastoma, miR-216b emerged as a potential predictive biomarker. Thus, we hypothesize that miR-216b impacts glioma aggressiveness and thereby therapeutic success. Here, we demonstrate that miR-216b is significantly downregulated in the majority of Isocitrate dehydrogenase 1/2 (IDH) wild-type HGG tissue samples (n = 42) and cell models (n = 18). Functional assays revealed that miR-216b overexpression impairs glioma cell proliferation, migration, and stemness characteristics. Transcriptomic and target prediction analyses identified CDK4, a key cell cycle regulator, as a direct target of miR-216b, confirmed via luciferase reporter assays. Correspondingly, upregulating miR-216b (mimic) via transfection decreased CDK4 mRNA and protein levels accompanied by a p21-dependent increase of cells in G0/G1 phase. In addition, miR-216b expression correlated with increased sensitivity to the CDK4/6 inhibitor Abemaciclib. Notably, miR-216b levels were significantly higher in less aggressive IDH-mutant gliomas (n = 21), linking its downregulation to malignancy grade. Collectively, our findings discovered miR-216b as a tumor suppressor in HGGs, modulating CDK4 expression and affecting the responsiveness to CDK4/6 inhibitors. The observed results support the potential of miR-216b as both a prognostic and predictive indicator in HGGs.
Parkinson's disease (PD), is slowly advancing disease condition of the nervous system, which leads to interruption of normal motor function, resulting in symptoms such as tremor, muscle rigidity, bradykinesia, and postural instability. PD is commonly also accompanied by motor impairment, associated with broad non-motor symptoms, of which sensory prob 21qwlems are including behavioural and sleeping disorders and autonomic dysfunctions. The disease is characterised by slow degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc), and pathological misfolded α-synuclein (α-syn) deposition protein. Mitochondrial Rho GTPase (Miro1) is one of the major regulators of neuronal energy transport, mitochondrial motility, and communication in the central nervous system (CNS). It also regulates the quality of mitochondria in their interaction with regulatory proteins, PTEN-induced kinase 1 (PINK1), Parkin, and Leucine-rich repeat kinase2 (LRRK2). Studies stated that there are a few PD-related genes that are correlated with Miro1, which influences its activity. The dysregulation or genetic mutations of Miro1 disrupt the mitochondrial activities, including the transport, mitophagy, and calcium (Ca2+) homeostasis, particularly among dopaminergic neurons. These imbalances augment oxidative stress, mitochondrial dysfunction, and α-syn aggregation, which eventually regulate neuron exposure and are a risk factor in the development of PD. This review highlights the role of Miro1 in the development and pathophysiology of PD, with particular emphasis on recent experimental and clinical findings. It also focuses on the therapeutic prospect of Miro1-targeted approaches as new emerging interventions to reduce the development of the disease.