We aimed to explore the correlation of methionine (Met)/homocysteine (Hcy) ratio (MHR) with cerebral small vessel disease (CSVD)-related vascular cognitive impairment (VCI), and to assess its predictive value in B-complex vitamin intervention. This study enrolled 268 CSVD patients for cross-sectional analysis. Additionally, multivariate Logistic regression and receiver operating characteristic (ROC) curve analyses were implemented to investigate the prediction efficiency. Next, 12-week B-complex vitamin intervention (folic acid 5 mg/day, vitamin B6 50 mg/day, and vitamin B12 500 µg/day) was conducted on 86 patients to assess variations in MHR and cognitive function before and after intervention. Gradual increments in the Montreal Cognitive Assessment (MoCA) score (P < 0.001) and significant decrements in the white matter hyperintensity (WMH) and total CSVD score (P < 0.01) were observed with the elevation of MHR quartiles. MHR served as an independent protective factor against VCI [odds ratio (OR) = 0.44, P = 0.002]. After intervention, Hcy declined (P < 0.001), while MHR (P < 0.001) and MoCA score rose (P = 0.002). A positive association was observed between ΔMHR and ΔMoCA score (r = 0.46, P < 0.001), and the low baseline MHR group displayed more obvious improvements in cognitive function (P < 0.001). MHR has a close correlation with cognitive function and imaging impairment in CSVD patients. MHR acts as an independent protective factor against VCI and outperforms Hcy in prediction efficiency. The 12 weeks of B-complex vitamin intervention leads to significantly reduced Hcy, elevated MHR, and improved cognitive state.
This study aimed to figure out the correlation of stress hyperglycemia ratio (SHR) and serum interleukin-6 (IL-6) with elderly ICU patients’ occurrence, severity and duration of delirium, and to evaluate their predictive value for delirium. This research included 168 patients who were 60 years or older and admitted to our hospital’s ICU from August 2024 to August 2025. They were split into delirium group (n = 63) and Non-delirium group (n = 105) based on whether delirium happened during hospitalization. Delirium incidence was measured with the Confusion Assessment Method for ICU (CAM-ICU). CAM-ICU-7 was adopted to determined how severe delirium it was. Delirium/coma free days (DCFDs) were used as a negative proxy for how long delirium lasted. Patients’ baseline data and laboratory indicators within one day of being admitted were collected. SHR was calculated by detecting fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c), and serum IL-6 concentration was tested by enzyme-linked immunosorbent assay. The independent influencing factors of delirium were screened by uni-variate and multi-variate logistic regression. Kaplan–Meier curve was employed to analyze the first onset time of delirium. Correlation analysis helped determine the association of SHR and IL-6 with the severity of delirium and DCFDs. SHR and IL-6 predictive value was assessed through the ROC curve. SHR and IL-6 levels in delirium group were significantly higher when comparing to Non-delirium group (P < 0.01). According to multivariate Logistic regression, SHR and IL-6 were independent influencing factors of delirium in elderly ICU patients. Kaplan–Meier curve showed that the first delirium in patients with high-level SHR and IL-6 was earlier when comparing to individuals with low-to-medium-level SHR and IL-6 (Log-rank test < 0.05). Moreover, SHR and IL-6 were positively correlated with CAM-ICU-7 score and negatively correlated with DCFDs (P < 0.05). As shown by ROC curve, IL-6 and SHR had good predictive value for delirium. SHR and serum IL-6 have a close link to the occurrence, severity and first occurrence time of delirium in elderly ICU patients. The two are independent influencing factors of delirium and can be potential clinical biomarkers for evaluating delirium risk in elderly ICU patients.
Olfactory impairment is one of the earliest and most common non-motor symptoms of Parkinson’s disease (PD). According to Braak’s hypothesis on the staging of PD, the olfactory bulb (OB) is considered one of the potential regions where the pathological spread of alpha-synuclein aggregates originates. For these reasons, this region is of great interest for studying the development of neurodegenerative processes in the early stages of PD. In the present study, a whole-transcriptome analysis was performed in the OB of mice using an MPTP-induced model of the early symptomatic stage of PD. A total of 142 differentially expressed genes (DEGs) were identified. An enrichment analysis of these DEGs revealed the following processes: leukocyte adhesion to vascular endothelial cell, detection of chemical stimulus involved in sensory perception, and genitalia development. A total of 9 genes were associated with these processes: Ccl28, Fut4, Alox5, Olfr111, Olfr558, Gnat2, Tbx3, Trp63, and Foxf2. Further detailed analysis of gene functions has demonstrated their link to neuroinflammatory and neuroplasticity processes. Given the established link to processes affecting neuronal survival and function, these genes can be considered promising candidate genes for PD.
Memories play critical roles in our lives. Perhaps their importance is best appreciated when we start losing them. Making strong memories is beneficial for our day-to-day activities and for future planning. Most memories require repetitions or practice. Temporally spaced repetitions lead to better memory as compared to massed repetitions. This spacing effect is well established using several different learning tasks. This article discusses better memory formation by spaced training in several tasks at the behavioural level. Its potential neural mechanisms as revealed with brain imaging, and its beneficial effects in clinical conditions are also discussed. Further research needed to fully understand spacing effect is also discussed.
Oxidative stress has been implicated in the pathophysiology of schizophrenia; however, the role of key antioxidant regulators such as sestrin-2 (SESN2) and nuclear factor erythroid 2-related factor 2 (NRF2) remains unexplored. Furthermore, whether these alterations are present in unaffected first-degree relatives, suggesting a potential genetic vulnerability marker, has not been investigated. This study aimed to compare serum SESN2 and NRF2 levels among patients with schizophrenia, their healthy siblings, and healthy controls, hypothesizing that both patients and their siblings would exhibit lower levels compared to controls. The study population consisted of 25 patients diagnosed with schizophrenia according to DSM-5 criteria, 25 healthy siblings of these patients and 25 healthy controls. Scale for the Assessment of Negative Symptoms (SANS), Scale for the Assessment of Positive Symptoms (SAPS), Apathy Assessment Scale (AAS) and Short Form-36 (SF-36) Health Survey forms were administered to patients diagnosed with schizophrenia. Serum SESN2 and NRF2 levels of the participants were measured using ELISA method. When schizophrenia patients, their healthy siblings and control group were compared in terms of SESN2 and NRF2 levels, a statistically significant difference was found among groups (p < 0.001). SESN2 and NRF2 levels were significantly lower in schizophrenia patients compared to their healthy siblings and control group (p < 0.05). SESN2 and NRF2 levels were significantly lower in healthy siblings compared to the control group (p < 0.001 and p = 0.009, respectively). To our knowledge, this is the first study to demonstrate reduced serum SESN2 and NRF2 levels in both schizophrenia patients and their unaffected siblings compared with healthy controls.
Sinapic acid (SA) is a naturally occurring compound containing phenolic acids found in plants such as grapefruit, oranges, cranberries, canola, mustard seeds, and rapeseed, and is present in human diets. Recent experimental and clinical studies have demonstrated that SA possesses strong antioxidant, anti-inflammatory, anti-inflammatory, anticonvulsant, and neuroprotective effects. Furthermore, SA strengthens memory, improves cognitive function, and exhibits activity that reduces microglial activation. With the increasing elderly population in developed countries, there has been a significant increase in the number of neurodegenerative diseases, posing a serious threat to human health. In the vast majority of common neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, the causes are a variety of factors including oxidative stress, neuroinflammation, misfolded protein accumulation, ion channel disorders, and glutamate excitotoxicity. Alzheimer’s disease affects one in ten people aged 65 and older, and its incidence increases with age. These diseases manifest as structural deficiencies and neuronal loss in specific neurons, and are characterized by progressive functional impairment in organs. Particularly affecting the elderly population, these diseases urgently require the discovery of alternative medicines that are more effective and have fewer side effects, after thoroughly investigating the causes of each disease, in addition to current treatments. This review aimed to highlight the potential role of the natural compound SA in the treatment of various neurodegenerative brain disorders and to reveal its multifaceted neuroprotective effects.
Photoreceptor death is a major and common pathological hallmark of many human retinal diseases, for which effective curative treatments are lacking. Colony-stimulating factor 1 receptor (CSF1R) has been implicated in microglia-associated inflammatory responses, with its overexpression reported in retinal disorders. Therefore, exploring the role of CSF1R signaling in photoreceptor death and viability is essential. GW2580 is a selective CSF1R inhibitor. In this study, we first evaluated the therapeutic efficacy of GW2580 in vivo using a zebrafish model of intense light-induced retinal injury. Next, we investigated the effects of GW2580 on microglial inflammation, neurotoxicity, and polarization phenotypes. Finally, using a co-culture model of microglial cells and photoreceptor cells, we investigated the protective role of GW2580 against oxidative stress-induced photoreceptor cell death. The results showed that intraocular administration of GW2580 markedly promoted photoreceptor regeneration following retinal injury. GW2580 treatment also reduced the expression of pro-inflammatory cytokines and reactive oxygen species levels, as well as promoted microglial transition from M1 to M2. In addition, GW2580 modulated autophagy- and apoptosis-related genes expression and restored photoreceptor-associated gene expression. Collectively, these findings suggest that CSF1R inhibition alleviates microglia-mediated inflammation and oxidative stress, modulates apoptosis and autophagy-related pathways, thereby reducing photoreceptor damage. These results highlight GW2580 as a promising therapeutic strategy for retinal diseases.
In this study, the effects of sodium metabisulfite (Na2S2O5) on learning and memory as well as the relationship of these effects with arachidonic acid, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) signal pathway and PGE2 receptor subtypes were investigated. 3-months-old male Wistar rats were divided into 3 groups as control (C), S100 and S260. The C group were given tap water for 35 days via gastric gavage, while S100 and S260 groups were received sodium metabisulfite at doses of 100 mg/kg (S100) and 260 mg/kg (S260) for the same period. Morris water maze (MWM) and open field (OF) test were performed. After behavioral tests, blood samples were collected and their brain tissues were removed. In the hippocampus, arachidonic acid (AA), PGE2 levels and COX-2 activity were determined and mRNA levels of PGE2 receptor subtypes were analyzed with RT-PCR. In Na2S2O5 groups, the total distance and average velocity values in the MWM tests increased, while target quadrant entrance frequency decrease. Total distance and average velocity in the OF test, plasma S-sulfonate and AA levels in Na2S2O5 groups were significantly higher compared to control group. PGE2 level and COX-2 activity were found to be significantly higher only in S260 group. However, mRNA expressions of PGE2 receptor subtypes in the hippocampus increased significantly in the S100 group. In our study, Na2S2O5 intake above the safe dose impaired learning and spatial memory, and this deterioration may involve neurobiological mechanisms mediated through the AA, COX-2, PGE2 pathway and PGE2 receptor subtypes.
Long non-coding RNAs (lncRNAs) showed essential regulated function in mediating neuroinflammatory responses following ischemic stroke (IS). This study aims to elucidate the function and mechanism of lncRNA PRR34-AS1 in neuroinflammatory responses during IS. Serum levels of PRR34-AS1 were measured by quantitative real-time PCR (RT-qPCR) in 80 IS patients and 80 healthy controls. The oxygen-glucose deprivation/reperfusion (OGD/R) model of human microglial HMC3 cells was conducted to simulate ischemic conditions. The diagnosis of PRR34-AS1 in IS was evaluated using the ROC curve. The Pearson correlation coefficient was used to assess the relationship between PRR34-AS1 and NHISS scores. And the HMC3 cell inflammatory cytokine levels (TNF-α, IL-6, IL-1β), and miR-532-3p expression were measured by ELISA and RT-qPCR. PRR34-AS1 was upregulated in IS patients and OGD/R-induced HMC3 cells. Conversely, miR-532-3p levels were decreased in OGD/R-induced HMC3 cells. Additionally, both suppressing PRR34-AS1 and overexpressing miR-532-3p protected OGD/R-induced HMC3 cells from inflammation damage. Moreover, miR-532-3p was negatively regulated by PRR34-AS1, and its overexpression effectively reversed the inflammatory effects caused by PRR34-AS1 overexpression. PRR34-AS1 promoted neuroinflammation during IS by regulating miR-532-3p. Targeting this axis may present novel therapeutic strategies to mitigate neuronal damage following IS.
Neurofilament Light Chain (NfL), as a sensitive biomarker of neuronal axonal injury, holds significant value in the diagnosis, prognosis assessment, and treatment of Traumatic Brain Injury (TBI). This study integrates data from bioinformatics, basic experiments, and clinical research to systematically analyze the multi-dimensional role of NfL in TBI. NfL has important biological and clinical significance in TBI. As a sensitive biomarker of neural injury, it provides new research directions for the early diagnosis, prognosis assessment, and treatment of TBI.
Research findings provide compelling evidence that stress negatively impacts the course of many mental, somatic, and neurological conditions. The aim of this study was to evaluate the impact of prior psycho-emotional stress on neuroendocrine and autonomic regulation at rest and under mental stress in patients with nonpsychotic mental disorders (NPMD). The main group consisted of 53 patients with NPMD (39 women, 14 men) who had experienced significant stressful events in the year prior to hospitalization. The comparison group included 36 patients with NPMD without significant stressful events during the specified period (29 women and 7 men). The control group consisted of 27 healthy volunteers of similar age and gender. The results of a comparative analysis of the three groups: patients with NPMD, patients with NPMD who had experienced stressful events prior to hospitalization, and healthy subjects revealed different directions of neuroendocrine and autonomic adaptation mechanisms depending on the clinical status. According to the data obtained, episodic or chronic stress in people with NPMD leads to depletion of the neurohormonal and parasympathetic regulatory components, accompanied by increased sympathetic tone. This condition increases the risk of worsening the existing disease and developing vascular and other somatic pathologies, which should be taken into account when developing preventive and treatment strategies for this patient population.
This study investigates the anticonvulsant effects of Zingiber officinale on seizures, memory loss, depression, and hippocampal sclerosis in a temporal lobe epilepsy with hippocampus sclerosis (TLE-HS) model, a common form of drug-resistant epilepsy. A total of 21 Sprague-Dawley rats were divided into three groups: 1) Control (saline-treated), 2) Diseased (Lithium–Pilocarpine model + saline), and 3) Treated (Lithium–Pilocarpine model + Z. officinale). After TLE-HS induction, rats received oral treatments for 15 days. Seizures were monitored via Video/EEG for 15 days/24 h, behavioral tests assessed memory and depression (24 hours following the final monitoring session), and Nissl staining evaluated hippocampal neurons. The Z. officinale extract significantly reduced seizure frequency (p < 0.05), alleviated depressive symptoms (p < 0.05), and enhanced memory function (p < 0.05). Notably, treatment with Z. officinale provided significant neuroprotection in the Lithium–Pilocarpine-induced TLE-HS rat model. Z. officinale extract significantly reduced seizure frequency, alleviates depression, improves memory, and offers partial neuroprotection. Further studies are needed to elucidate its mechanism and potential for treating TLE-HS in humans.
Proteostasis is the process by which cells maintain proteome integrity through interconnected signalling networks that regulate protein synthesis, folding, assembly, transport and degradation. The subcellular organelle endoplasmic reticulum (ER), plays a central role in proteostasis, consisting of vital protein regulating components. ER function is altered as aging proceeds and challenged through many different internal or external signals; which might result in protein misfolding and aggregation of aberrant proteins in the ER lumen. This phenomenon is known as ER stress; stimulating the activation of a survival response called unfolded protein response (UPR). ER dysfunction and proteostasis impairment is implicated in neurodegeneration, developing the basis for various neurodegenerative diseases (NDs) including Alzheimer’ disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS) and more. In that aspect, targeting ER stress and UPR in translational studies is promising hope for the treatment of these diseases from a molecular perspective. Therefore, we aimed to provide a general understanding of proteostasis, ER stress, UPR signalling and how these cellular processes are related to neurodegeneration. We presented insights on the research regarding therapeutic approaches of NDs which intend to target molecular components.
Using mouse hippocampal cell cultures, the activation of the TrkA receptor, Akt 1/2/3, and Erk 1/2 kinases by GK-2 and GK-2(h)—dipeptide mimetics of the fourth loop of rat and human NGF, respectively—was examined in a comparative study. The findings suggest that both of these mimetics, like NGF, activate a specific neurotrophic TrkA receptor. However, the pattern of receptor activation in HT-22 cells under the action of GK-2 and GK-2(h) was different. GK-2 induced a more pronounced and prolonged activation of the receptor than GK-2(h). Both mimetics did not activate Erk 1/2. In studying the activation of Akt 1/2/3 kinases, we identified differences in the effects of these peptides. GK-2 induces longer-lasting phosphorylation of Akt 1/2/3 kinases in NT-22 mouse hippocampal cell cultures compared to GK-2(h).
In the early postnatal period, the striatum undergoes significant changes. As intense locomotion emerges in pups, the predominantly excitable state of medium spiny neurons (MSNs) shifts towards hyperpolarization, concurrent with increased arborization and elongation of neuronal processes. In this work, we show that the expression of Junb, a subunit of the AP1 complex, significantly decreases from the 3rd to the 8th day of life in pups. At the same time, the expression of another AP1 subunit, the immediate early gene c-Fos, did not change during this period, both at the mRNA level and at the level of the protein detected by immunohistochemistry. Half of the cells expressing Junb in the striatum on the third day of life also expressed the interneuron marker GAD1. Our findings demonstrate a downregulation of Junb expression and suggest a concomitant reduction in JunB transcriptional activity in striatal MSNs, indicating its regulatory role in the maturation of striatal neurons.
Piezo1 is a nonselective cationic mechanosensitive channel, the overactivation of which is closely associated with the pathogenesis of various neurological disorders. Our previous study has demonstrated that the protein expression of Piezo1 was upregulated after chronic cerebral hypoperfusion (CCH) injury. Inhibiting Piezo1 could ameliorate CCH-induced cognitive dysfunction and blood–brain barrier (BBB) damage. Pericytes plays a crucial role in maintaining the structural and functional integrity of BBB, yet whether inhibition of Piezo1 has a direct protective effect on pericytes remains uncertain. To mimic ischemic and hypoxic conditions, primary pericytes were exposed to oxygen glucose deprivation/reoxygenation (OGD/R). In the present study, we aimed to investigate the effects of inhibiting Piezo1 on OGD/R-induced pericytes injury and its potential mechanisms. Our results demonstrated that OGD/R-induced injury of pericytes was significantly reversed by the selective Piezo1 inhibitor GsMTx4. Additionally, GsMTx4 treatment increased the expression of N-cadherin protein in pericytes and decreased the levels of inflammatory cytokines IL-1β, TNF-α, and IL-18. Furthermore, GsMTx4 reversed OGD/R-induced ultrastructural changes of cell morphology, and reduced the expression levels of pyroptosis-associated proteins, including NLRP3, GSDMD-N, cleaved-caspase1 and ASC. Notably, Nigericin, an NLRP3 inflammasome agonist, attenuated the aforementioned effects of GsMTx4 on pericytes. In conclusion, inhibiting Piezo1 effectively ameliorated OGD/R-induced pericytes injury, mitigated inflammatory responses and pyroptosis. Moreover, these cytoprotective effects were related to inhibition of the NLRP3 inflammasome activity. The present study provided a potential theoretical basis and therapeutic target for the treatment of CCH and other related cerebrovascular diseases.
Alzheimer’s disease (AD) is a brain disorder accompanied by memory impairment. In this study, we investigated the neuroprotective effects of Berberine in a rat model of AD. Adult male Wistar rats were randomly divided into a control and 2 experimental groups. The control group received normal saline via intraperitoneal injection (i.p) for 21 days. The experimental groups were induced AD by using Scopolamine hydrobromide (3 mg/kg, i.p.) for 7 days, after which they were treated with either Berberine (50 mg/kg, i.p.) or normal saline for an additional 14 days. The Morris water maze test was used to assess spatial learning and memory. Also, histological analysis of the hippocampal CA1 region was conducted using Cresyl fast violet and H E staining, and cell apoptosis was evaluated using the TUNEL assay. The results indicated that Scopolamine administration impaired spatial memory, reduced the number of normal pyramidal cells, and increased the number of apoptotic cells in the CA1 region of the hippocampus. In contrast, treatment with Berberine improved spatial memory, preserved the integrity of pyramidal neurons, and significantly reduced apoptosis in the CA1 region of the hippocampus. These findings suggest that Berberine may be a potential therapeutic agent for AD.
Antipsychotic-induced weight gain (AIWG) is a significant clinical challenge. Leptin (LEP) and Leptin receptor (LEPR) play crucial roles in appetite and energy homeostasis, making them plausible candidates for influencing AIWG. This study investigated the associations of LEP and LEPR gene polymorphisms with AIWG in a Sri Lankan population. Five single nucleotide polymorphisms (SNPs), rs1137101 and rs1327118 (LEPR), and rs10954173, rs3828942, and rs2167270 (LEP), were genotyped via competitive amplification of differentially melting amplicons (CADMA) with high-resolution melt analysis (HRMA) and validated via the MassARRAY System. Statistical analyses, including association, interaction, and haplotype analyses, were performed using the SNPstats online tool. While initial analyses revealed only an association between rs1327118 and AIWG (odds ratio (OR): 1.80, 95
Aggressive behavior has a detrimental impact on public well-being and is characterized by significant socio-economic consequences, which underlines the relevance of a detailed study of the neurobiological mechanisms of this phenomenon. Research conducted across various fields of neuroscience demonstrates that alterations in the functional activity of the serotonin and dopamine neurotransmitter systems may underlie aggressive behavior. This review provides a comprehensive analysis of the relationship between structural and functional changes in the central nervous system, impairments in serotonin and dopamine activity, and the genetic architecture of the corresponding genes in the context of aggression. It substantiates the potential use of biomarkers characterizing the serotonergic and dopaminergic systems in personalized psychiatry. According to literature data, among other markers linked with serotonin- and dopaminergic systems, monoamine oxidase A (variable number tandem repeat polymorphism), the serotonin transporter (5-HTTLPR), the serotonin receptor HTR1A (rs6295), and catechol-O-methyltransferase (rs4680) polymorphisms may be associated with aggressive behavior.
Recently, the effects of social isolation have been actively studied due to its negative impact on the mental and cognitive processes of higher nervous activity in humans and animals. At the cellular level, the damaging effects of social isolation to brain structures remain poorly studied. Here, we examined the expression of heat shock protein Hsp40 in the neocortex and hippocampus of normotensive rats of Wistar (NWR) and Wistar-Kyoto (WKY) genotypes and spontaneously hypertensive rats (SHR) following 14-week isolation. Hsp40 expression of in the brain was evaluated using immunohistochemical labeling followed by quantitative microscopic analysis. The mRNA expression of the Dnajc6 gene, one of the neuron-specific genes of the family, was accessed using quantitative PCR in the frontal cortex and hippocampus. We found that Hsp40 expression was higher in WKY and SHR rats compared to NWRs in neocortical layers II, III, and IV. Isolation increased Hsp40 expression in neocortical layer V. Same differences in Hsp40 expression were revealed in the hippocampus. Specifically, the higher expression was observed in the CA1, CA3 fields and the dentate gyrus of WKY and SHR rats compared to NWR rats, and in the dentate gyrus, the differences were observed between WKY and SHR rats. Isolation increased Hsp40 expression in all the groups studied, but this effect was more pronounced in SHRs. Thus, social isolation damaged cells in the neocortex and hippocampus stimulating the expression of Hsp40.
