Neuronal Damage Research Articles

High Mobility Group Box Protein (HMGB1): A Potential Therapeutic Target for Diabetic Encephalopathy.

HMGB (high mobility group B) is one of the ubiquitous non-histone nuclear protein superfamilies that make up the HMG (high mobility group) protein group. HMGB1 is involved in a variety of physiological and pathological processes in the human body, including a structural role in the cell nucleus as well as replication, repair, DNA transcription, and assembly of nuclear proteins. It functions as a signaling regulator in the cytoplasm and a pro-inflammatory cytokine in the extracellular environment. Among several studies, HMGB1 protein is also emerging as a crucial factor involved in the development and progression of diabetic encephalopathy (DE) along with other factors such as hyperglycaemia-induced oxidative and nitrosative stress. Diabetes' chronic side effect is DE, which manifests as cognitive and psychoneurological dysfunction. The HMGB1 is released outside to the extracellular medium in diabetes condition through active or passive routes, where it functions as a damage-associated molecular pattern (DAMP) molecule to activate several signaling pathways by interacting with receptors for advanced glycosylation end-products (RAGE)/toll like receptors (TLR). HMGB1 reportedly activates inflammatory pathways, disrupts the blood-brain barrier, causes glutamate toxicity and oxidative stress, and promotes neuroinflammation, contributing to the development of cognitive impairment and neuronal damage which is suggestive of the involvement of HMGB1 in the enhancement of the diabetes-induced encephalopathic condition. Additionally, HMGB1 is reported to induce insulin resistance, further exacerbating the metabolic dysfunction associated with diabetes mellitus (DM). Thus, the present review explores the possible pathways associated with DM-induced hyperactivation of HMGB1 ultimately leading to DE.

Medicinal herbal remedies in neurodegenerative diseases: an update on antioxidant potential.

It has been widely documented that medicinal herbal remedies are effective, have fewer side effects than conventional medicine, and have a synergistic effect on health collaborations in the fight against complicated diseases. Traditional treatments for neurological problems in ancient times sometimes involved the use of herbal remedies and conventional methods from East Asian countries including India, Japan, China, and Korea. We collected and reviewed studies on plant-derived neuroprotective drugs and tested them in neurotoxic models. Basic research, preclinical and clinical transgene research can benefit from in silico, in vitro, and in vivo investigations. Research, summaries of the extracts, fractions, and herbal ingredients were compiled from popular scientific databases, which were then examined according to origin and bioactivity. Given the complex and varied causes of neurodegeneration, it may be beneficial to focus on multiple mechanisms of action and a neuroprotection approach. This approach aims to prevent cell death and restore function to damaged neurons, offering promising strategies for preventing and treating neurodegenerative diseases. Neurodegenerative illnesses can potentially be treated with natural compounds that have been identified as neuroprotective agents. To gain deeper insights into the neuropharmacological mechanisms underlying the neuroprotective and therapeutic properties of naturally occurring antioxidant phytochemical compounds in diverse neurodegenerative diseases, this study aims to comprehensively review such compounds, focusing on their modulation of apoptotic markers such as caspase, Bax, Bcl-2, and proinflammatory markers. In addition, we delve into a range of efficacies of antioxidant phytochemical compounds as neuroprotective agents in animal models. They reduce the oxidative stress of the brain and have been shown to have anti-apoptotic effects. Many researches have demonstrated that plant extracts or bioactive compounds can fight neurodegenerative disorders. Herbal medications may offer neurodegenerative disease patients' new treatments. This may be a cheaper and more culturally appropriate alternative to standard drugs for millions of people with age-related NDDs.

Longitudinal analysis of serum neurofilament light chain levels as marker for neuronal damage in hereditary transthyretin amyloidosis

Objective To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis patients and TTR variant (TTRv) carriers. Methods sNfL levels were assessed longitudinally in persistently asymptomatic TTRv carriers (N = 12), persistently asymptomatic ATTRv amyloidosis patients (defined as asymptomatic patients but with amyloid detectable in subcutaneous abdominal fat tissue) (N = 8), in TTRv carriers who developed polyneuropathy (N = 7) and in ATTRv amyloidosis patients with polyneuropathy on treatment (TTR-stabiliser (N = 20) or TTR-silencer (N = 18)). Polyneuropathy was confirmed by nerve conduction studies or quantitative sensory testing. sNfL was analysed using a single-molecule array assay. Results sNfL increased over 2 years in persistently asymptomatic ATTRv amyloidosis patients, but did not change in persistently asymptomatic TTRv carriers. In all TTRv carriers who developed polyneuropathy, sNfL increased from 8.4 to 49.8 pg/mL before the onset of symptoms and before polyneuropathy could be confirmed neurophysiologically. In symptomatic ATTRv amyloidosis patients on a TTR-stabiliser, sNfL remained stable over 2 years. In patients on a TTR-silencer, sNfL decreased after 1 year of treatment. Conclusion sNfL is a biomarker of early neuronal damage in ATTRv amyloidosis already before the onset of polyneuropathy. Current data support the use of sNfL in screening asymptomatic TTRv carriers and in monitoring of disease progression and treatment effect.

Inhibition of EHMT1/2 rescues synaptic damage and motor impairment in a PD mouse model

Epigenetic dysregulation that leads to alterations in gene expression and is suggested to be one of the key pathophysiological factors of Parkinson’s disease (PD). Here, we found that α-synuclein preformed fibrils (PFFs) induced histone H3 dimethylation at lysine 9 (H3K9me2) and increased the euchromatic histone methyltransferases EHMT1 and EHMT2, which were accompanied by neuronal synaptic damage, including loss of synapses and diminished expression levels of synaptic-related proteins. Furthermore, the levels of H3K9me2 at promoters in genes that encode the synaptic-related proteins SNAP25, PSD95, Synapsin 1 and vGLUT1 were increased in primary neurons after PFF treatment, which suggests a linkage between H3K9 dimethylation and synaptic dysfunction. Inhibition of EHMT1/2 with the specific inhibitor A-366 or shRNA suppressed histone methylation and alleviated synaptic damage in primary neurons that were treated with PFFs. In addition, the synaptic damage and motor impairment in mice that were injected with PFFs were repressed by treatment with the EHMT1/2 inhibitor A-366. Thus, our findings reveal the role of histone H3 modification by EHMT1/2 in synaptic damage and motor impairment in a PFF animal model, suggesting the involvement of epigenetic dysregulation in PD pathogenesis.

Homotherapy-for-heteropathy of Bupleurum Chinense DC.-Scutellaria baicalensis Georgi in treating depression and colorectal cancer: A network pharmacology and animal model approach

Ethnopharmacological relevanceBupleurum chinense DC.-Scutellaria baicalensis Georgi (BS) is a classic drug pair that has good clinical effects on depression and many tumors. However, the concurrent targeting mechanism of how the aforementioned drug pair is valid in the two distinct diseases, has not been clarified yet. Aim of the studyThe components of BS were detected by LC-MS, combined with network pharmacology to explore the active ingredients and common targeting mechanism of its multi-pathway regulation of BS in treating depression and CRC, and to validate the dual effects of BS using the CUMS mice model and orthotopic transplantation tumor mice model of CRC. ResultsTwenty-nine components were screened, 84 common gene targets were obteined, and the top 5 key targets including STAT3, PIK3R1, PIK3CA, AKT1, IL-6 were identified by PPI network. GO and KEGG analyses revealed that PI3K/AKT and JAK/STAT signaling pathways might play a crucial role of BS in regulating depression and CRC. BS significantly modulated CUMS-induced depressive-like behavior, attenuated neuronal damage, and reduced serum EPI and NE levels in CUMS model mice. BS improved the pathological histological changes of solid tumors and liver tissues and inhibited solid tumors and liver metastases in tumor-bearing mice. BS significantly decreased the proteins' expression of IL-6, p-JAK2, p-STAT3, p-PI3K, p-AKT1 in hippocampal tissues and solid tumors, and regulated the levels of IL-2, IL-6 and IL-10 in serum of two models of mice. ConclusionBS can exert dual antidepressant and anti-CRC effects by inhibiting the expression of IL-6/JAK2/STAT3 and PI3K/AKT pathway proteins and regulating the release of inflammatory cytokines.

Phyto-pharmacological Potential of Aegle marmelos (L.) for Neurological Disorders: Progress and Prospects.

Aegle marmelos, an Indian plant, has been extensively utilized by the people of the Indian subcontinent over about 5000 years. The leaves, bark, roots, and fruits, including seeds, are widely used to cure a variety of diseases in the Indian traditional system of medicine, Ayurveda, along with numerous folk medicines. By revealing the existence of significant bioactive chemicals, modern research has effectively substantiated the therapeutic effects of bael. The objective of this study was to review the literature regarding A. marmelos geographical distribution, morphology, therapeutic benefits, and phytochemicals found in the bael leaves, fruits, and other parts of the plant that offer a wide range of pharmacological applications in neurological disorders. A thorough literature search was conducted using five computerized databases, such as PubMed, Google Scholar, ScienceDirect, Elsevier, and Wiley Online Library (WOL), by using standard keywords "A. marmelos," "Geographical distribution," "Morphological description," "Ethnobotanical Uses," "Phytoconstituents" and "Neuroprotective activities" for review papers published between 1975 and 2023. A small number of earlier review articles focused on phyto-pharmacological potential of Aegle marmelos (L.) for neurological disorders. According to some research, Aegle marmelos extracts potentially have neuroprotective benefits. This is due to its capacity to alter cellular mechanisms that cause neuronal damage. Neurodegenerative illnesses usually induce permanent neuronal network loss overall the brain along with the spinal cord (CNS), resulting in chronic functional impairments. The review summarizes the multiple aspects and processes of A. marmelos extract and its components in several models of neurodegenerative diseases such as anxiety, epilepsy, depression, Parkinson's disease, Alzheimer's disease, and others. MDA, nitrite, TNF-, and IL-6 levels were dramatically elevated, whereas glutathione levels were significantly lowered in the hippocampus of STZ-treated rats. Furthermore, STZ-treated rats showed a substantial drop in catalase activity and an increase in AChE activity, indicating cholinergic hypofunction and neuronal injury. The neuroprotective ability of A. marmelos against STZ-induced oxidative stress and cognitive loss in rats suggests that it has therapeutic relevance in Alzheimer's disease (AD).

Hydrogen Sulfide Protects against Rat Ischemic Brain Injury by Promoting RhoA Phosphorylation at Serine 188.

The protective role of hydrogen sulfide against cerebral ischemia-reperfusion injury involves the inhibition of the RhoA-/Rho-associated coiled-coil kinase (ROCK) pathway. However, the specific mechanism remains elusive. This study investigates the impact of hydrogen sulfide on RhoA phosphorylation at serine 188 (Ser188) in vivo, aiming to test the hypothesis that hydrogen sulfide exerts neuroprotection by enhancing RhoA phosphorylation at Ser188, subsequently inhibiting the RhoA/ROCK pathway. Recombinant RhoAwild-pEGFP-N1 and RhoAS188A-pEGFP-N1 plasmids were constructed and administered via stereotaxic injection into the rat hippocampus. A rat global cerebral ischemia-reperfusion model was induced by bilateral carotid artery ligation to elucidate the neuroprotective mechanisms of hydrogen sulfide. Both RhoAwild-pEGFP-N1 and RhoAS188A-pEGFP-N1 plasmids expressed RhoAwild and RhoAS188A proteins, respectively, in rat hippocampal tissues, alongside the intrinsic RhoA protein. Systemic administration of the exogenous hydrogen sulfide donor sodium hydrosulfide led to an increase in Ser188 phosphorylation of transfected RhoAwild and intrinsic RhoA protein within the hippocampus. However, this effect was not observed in tissues transfected with RhoAS188A. Sodium hydrosulfide-mediated RhoA phosphorylation correlated with decreased RhoA and ROCK2 activity in rat hippocampal tissues. Furthermore, sodium hydrosulfide administration reduced cerebral ischemia-reperfusion-induced neuronal damage and apoptosis in rat hippocampal tissues transfected with RhoAwild. However, this neuroprotective effect was attenuated in rats transfected with RhoAS188A. These findings suggest that the neuroprotective mechanism of hydrogen sulfide against cerebral ischemia/reperfusion injury involves increased RhoA phosphorylation at Ser188. Promoting this phosphorylation may represent a potential intrinsic therapeutic target for ischemic stroke.

Diosmetin Ameliorates HFD-induced Cognitive Impairments via Inhibiting Metabolic Disorders, Mitochondrial Dysfunction and Neuroinflammation in Male SD Rats.

Currently, accumulating evidence has indicated that overnutrition-associated obesity may result in not only metabolic dysregulations, but also cognitive impairments. This study aimed to investigate the protective effects of Diosmetin, a bioflavonoid compound with multiple biological functions, on cognitive deficits induced by a high fat diet (HFD) and the potential mechanisms. In the present study, oral administration of Diosmetin (25, 50 and 100mg/kg) for 12 weeks significantly reduced the body weight, restored glucose tolerance and normalized lipid profiles in the serum and liver in HFD-induced obese rats. Diosmetin also significantly ameliorated depression-like behaviors and impaired spatial memory in multiple behavioral tests, including the open field test, elevated plus-maze and Morris water maze, which was in accordance with the decreased pathological changes and neuronal damage in different regions of hippocampus as suggested by H&E and Nissl staining. Notably, our results also indicated that Diosmetin could significantly improve mitochondrial dysfunction induced by HFD through upregulating genes involved in mitochondrial biogenesis and dynamics, increasing mitochondrial ATP levels and inhibiting oxidative stress. Moreover, the levels of key enzymes involved in the TCA cycle were also significantly increased upon Diosmetin treatment. Meanwhile, Diosmetin inhibited HFD-induced microglial overactivation and down-regulated inflammatory cytokines both in the serum and hippocampus. In conclusion, these results indicated that Diosmetin might be a novel nutritional intervention to prevent the occurrence and development of obesity-associated cognitive dysfunction via metabolic regulation and anti-inflammation.

BIN1K358R suppresses glial response to plaques in mouse model of Alzheimer's disease.

The BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing. To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology. The presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant. The BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities. BIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

Novel insights into RAGE signaling pathways during the progression of amyotrophic lateral sclerosis in RAGE-deficient SOD1 G93A mice.

Amyotrophic lateral sclerosis (ALS) is neurodegenerative disease characterized by a progressive loss of motor neurons resulting in paralysis and muscle atrophy. One of the most prospective hypothesis on the ALS pathogenesis suggests that excessive inflammation and advanced glycation end-products (AGEs) accumulation play a crucial role in the development of ALS in patients and SOD1 G93A mice. Hence, we may speculate that RAGE, receptor for advanced glycation end-products and its proinflammatory ligands such as: HMGB1, S100B and CML contribute to ALS pathogenesis. The aim of our studies was to decipher the role of RAGE as well as provide insight into RAGE signaling pathways during the progression of ALS in SOD1 G93A and RAGE-deficient SOD1 G93A mice. In our study, we observed alternations in molecular pattern of proinflammatory RAGE ligands during progression of disease in RAGE KO SOD1 G93A mice compared to SOD1 G93A mice. Moreover, we observed that the amount of beta actin (ACTB) as well as Glial fibrillary acidic protein (GFAP) was elevated in SOD1 G93A mice when compared to mice with deletion of RAGE. These data contributes to our understanding of implications of RAGE and its ligands in pathogenesis of ALS and highlight potential targeted therapeutic interventions at the early stage of this devastating disease. Moreover, inhibition of the molecular cross-talk between RAGE and its proinflammatory ligands may abolish neuroinflammation, gliosis and motor neuron damage in SOD1 G93A mice. Hence, we hypothesize that attenuated interaction of RAGE with its proinflammatory ligands may improve well-being and health status during ALS in SOD1 G93A mice. Therefore, we emphasize that the inhibition of RAGE signaling pathway may be a therapeutic target for neurodegenerative diseases.

Disrupting PIAS3-mediated SUMOylation of MLK3 ameliorates poststroke neuronal damage and deficits in cognitive and sensorimotor behaviors

Activated small ubiquitin-like modifiers (SUMOs) have been implicated in neuropathological processes following ischemic stroke. However, the target proteins of SUMOylation and their contribution to neuronal injury remain to be elucidated. MLK3 (mixed-lineage kinase 3), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, is a critical regulator of neuronal lesions following cerebral ischemia. Here, we found that SUMOylation of MLK3 increases in both global and focal ischemic rodent models and primary neuronal models of oxygen and glucose deprivation (OGD). SUMO1 conjugation at the Lys401 site of MLK3 promoted its activation, stimulated its downstream p38/c-Jun N-terminal kinase (JNK) cascades, and led to cell apoptosis. The interaction of MLK3 with PIAS3, a SUMO ligase, was elevated following ischemia and reperfusion. The PINIT domain of PIAS3 was involved in direct interactions with MLK3. Overexpression of the PINIT domain of PIAS3 disrupted the MLK3-PIAS3 interaction, inhibited SUMOylation of MLK3, suppressed downstream signaling, and reduced cell apoptosis and neurite damage. In rodent ischemic models, the overexpression of the PINIT domain reduced brain lesions and alleviated deficits in learning, memory, and sensorimotor functions. Our findings demonstrate that brain ischemia-induced MLK3 SUMOylation by PIAS3 is a potential target against poststroke neuronal lesions and behavioral impairments.

Total paeony glycoside relieves neuroinflammation to exert antidepressant effect via the interplay between NLRP3 inflammasome, pyroptosis and autophagy

BackgroundDepression is a common mental illness characterised by abnormal and depressed emotions. Total paeony glycoside (TPG) is a naturally active saponin extracted from the traditional Chinese medicine Radix Paeoniae rubra. However, the antidepressant and neuroinflammatory effects of TPG have not been thoroughly studied. PurposeTo study the therapeutic potential of TGP in depression caused by neuronal injury and neuroinflammation and to explore the mechanism of TGP and the relationship between the NLRP3 inflammasome, pyroptosis, and autophagy. Study designA chronic unpredictable mild stress (CUMS)-induced depression model and a cell model of corticosterone (CORT)-induced hippocampal neuron injury were established to evaluate the therapeutic effects of TPG. MethodsThe composition of TPG was analysed using high-performance liquid chromatography and mass spectrometry. The effects of TPG and fluoxetine on depression-like behaviour, neuronal injury, neuroinflammation, pyroptosis, and mitochondrial autophagy in the mice models were evaluated. ResultsTGP alleviated depression-like behaviours in mice and inhibited hippocampal neuronal apoptosis. The secretion of inflammatory cytokines was significantly reduced in CORT-induced hippocampal neuron cells and in the serum of a mouse model of CUMS-induced depression. In addition, TGP treatment reduced the levels of NLRP3 family pyrin structural domains, including NLRP3, pro-caspase-1, caspase-1, and IL-1β, and the pyroptosis related proteins such as GSDMD-N. Importantly, TPG attenuated mitochondrial dysfunction, promoted the clearance of damaged mitochondria, and the activation of mitochondrial autophagy, which reduced ROS accumulation and NLRP3 inflammasome activation. An in-depth study observed that the regulatory effect of TPG on autophagy was attenuated by the autophagy inhibitor 3-methyladenine (3-MA) in vitro and in vivo. However, administration of the caspase-1 inhibitor Belnacasan (VX-765) successfully inhibited pyroptosis and showed a synergistic therapeutic effect with TPG. ConclusionThese results indicate that TPG can repair neuronal damage by activating autophagy, restoring mitochondrial function, and reducing inflammation-mediated pyroptosis, thereby playing an important role in the alleviation of neuroinflammation and depression. This study suggests new potential drugs and treatment strategies for neuroinflammation-related diseases and depression.

The Effects of the S1P Receptor Agonist Fingolimod (FTY720) on Central and Peripheral Myelin in Twitcher Mice.

Krabbe's disease (KD) is caused by mutations in the lysosomal enzyme galactocerebrosidase and is associated with psychosine toxicity. The sphingosine 1-phosphate receptor (S1PR) agonist fingolimod (FTY720) attenuates psychosine-induced cell death of human astrocytes, demyelination in cerebellar slices, as well as demyelination in the central nervous system of twitcher mice. Psychosine also accumulates in the peripheral nervous system in twitcher mice; however, effects of fingolimod on this peripheral myelin have not been examined. The aim of this study was to investigate the effects of fingolimod administration on peripheral and central markers of myelination. Here, we report that fingolimod administration (1 mg/kg/day) from postnatal day 5 (PND) onwards did not alter peripheral demyelination in the sciatic nerve of twitcher mice, despite significantly reducing myelin debris, glial reactivity, and neuronal damage in the cerebellum. We also find fingolimod administration improves twitching and mobility scores in twitcher mice. Importantly, we find that fingolimod significantly increases the lifespan of twitcher mice by approximately 5 days. These findings suggest differential effects of fingolimod on peripheral and central neuropathy in twitcher mice, which may explain its modest efficacy on behavior and lifespan.

Silver nanoparticles induced synaptic degeneration via Ca2+/CaMKII signal and Drp1-dependent mitochondrial disorder in HT22 cells

Silver nanoparticles (AgNPs) have been widely used in biomedicine and cosmetics, increasing their potential risks in neurotoxicity. But the involved molecular mechanism remains unclear. This study aims to explore molecular events related to AgNPs-induced neuronal damage by RNA-seq, and elucidate the role of Ca2+/CaMKII signal and Drp1-dependent mitochondrial disorder in HT22cells synaptic degeneration induced by AgNPs. This study found that cell viabilities were decreased by AgNPs in a dose/time-dependent manner. AgNPs also increased protein expression of PINK1, Parkin, synaptophysin, and inhibited PGC-1α, MAP2 and APP protein expression, indicating AgNPs-induced synaptic degeneration involved in disturbance of mitophagy and mitochondrial biogenesis in HT22cells. Moreover, inhibition of AgNPs-induced Ca2+/CaMKII activation and Drp1/ROS rescued mitophagy disturbance and synaptic degeneration in HT22cells by reserving aforementioned protein express changes except for PGC-1α and APP protein. Thus, AgNPs-induced synaptic degeneration was mediated by Ca2+/CaMKII signal and Drp1-dependent mitochondrial disorder in HT22cells, and mitophagy is the sensitive to the mechanism. Our study will provide in-depth molecular mechanism data for neurotoxic evaluation and biomedical application of AgNPs.

Chronic exposure to PM10 induces anxiety-like behavior via exacerbating hippocampal oxidative stress

As one of the most environmental concerns, inhaled particulate matter (PM10) causes numerous health problems. However, the associations between anxiety behavior and toxicity caused by PM10 have rarely been reported so far. To investigate the changes of behavior after PM10 exposure and to identify the potential mechanisms of toxicity, PM10 samples (with doses of 15 mg/kg and 30 mg/kg) were intratracheally instilled into rats to simulate inhalation of polluted air by the lungs. After instillation for eight weeks, anxiety-like behavior was evaluated, levels of oxidative stress and morphological changes of hippocampus were measured. The behavioral results indicated that PM10 exposure induced obvious anxiety-like behavior in the open field and elevated plus maze tests. Both PM10 concentrations tested could increase whole blood viscosity and trigger hippocampal neuronal damage and oxidative stress by increasing superoxide dismutase (SOD) activities and malondialdehyde levels, and decreasing the expressions of antioxidant-related proteins (e.g., nuclear factor erythroid 2-related factor 2 (Nrf2), SOD1 and heme oxygenase 1). Furthermore, through collecting and analyzing questionnaires, the data showed that the participants experienced obvious anxiety-related emotions and negative somatic responses under heavily polluted environments, especially PM10 being the main pollutant. These results show that PM10 exposure induces anxiety-like behavior, which may be related to suppressing the Nrf2/Keap1-SOD1 pathway.

MicroRNA expression profiling of urine exosomes in children with congenital cytomegalovirus infection

Congenital cytomegalovirus (cCMV) infection can damage the central nervous system in infants; however, its prognosis cannot be predicted from clinical evaluations at the time of birth. Urinary exosomes can be used to analyze neuronal damage in neuronal diseases. To investigate the extent of neuronal damage in patients with cCMV, exosomal miRNA expression in the urine was investigated in cCMV-infected infants and controls. Microarray analysis of miRNA was performed in a cohort of 30 infants, including 11 symptomatic cCMV (ScCMV), 7 asymptomatic cCMV (AScCMV), and one late-onset ScCMV cases, and 11 healthy controls (HC). Hierarchical clustering analysis revealed the distinct expression profile of ScCMV. The patient with late-onset ScCMV was grouped into the ScCMV cluster. Pathway enrichment analysis of the target mRNAs differed significantly between the ScCMV and HC groups; this analysis also revealed that pathways related to brain development were linked to upregulated pathways. Six miRNAs that significantly different between groups (ScCMV vs. HC and ScCMV vs. AScCMV) were selected for digital PCR in another cohort for further validation. Although these six miRNAs seemed insufficient for predicting ScCMV, expression profiles of urine exosomal miRNAs can reveal neurological damage in patients with ScCMV compared to those with AcCMV or healthy infants.

Trichosanthis Semen Exerts Neuroprotective Effects in Alzheimer's Disease Models by Inhibiting Amyloid-β Accumulation and Regulating the Akt and ERK Signaling Pathways.

Alzheimer's disease (AD), the most common form of dementia, is characterized by memory loss and the abnormal accumulation of senile plaques composed of amyloid-β (Aβ) protein. Trichosanthis Semen (TS) is a traditional herbal medicine used to treat phlegm-related conditions. While TS is recognized for various bioactivities, including anti-neuroinflammatory effects, its ability to attenuate AD remains unknown. To evaluate the effects of TS extract (TSE) on neuronal damage, Aβ accumulation, and neuroinflammation in AD models. Thioflavin T and western blot assays were used to assess effects on Aβ aggregation in vitro. TS was treated to PC12 cells with Aβ to assess the neuroprotective effects. Memory functions and histological brain features were investigated in TSE-treated 5×FAD transgenic mice and mice with intracerebroventricularly injected Aβ. TSE disrupted Aβ aggregation and increased the viability of cells and phosphorylation of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) in vitro. TSE treatment also suppressed the accumulation of Aβ plaques in the brain of 5×FAD mice, protected neuronal cells in both the subiculum and medial septum, and upregulated Akt/ERK phosphorylation in the hippocampus. Moreover, TSE ameliorated the memory decline and glial overactivation observed in 5×FAD mice. As assessing whether TS affect Aβ-induced neurotoxicity in the Aβ-injected mice, the effects of TS on memory improvement and neuroinflammatory inhibition were confirmed. TSE disrupted Aβ aggregation, protected neurons against Aβ-induced toxicity, and suppressed neuroinflammation, suggesting that it can suppress the development of AD.

Alpha-, Beta-, and Gamma-Secretase, Amyloid Precursor Protein, and Tau Protein Genes in the Hippocampal CA3 Subfield in an Ischemic Model of Alzheimer's Disease with Survival up to 2 Years.

Understanding the phenomena underlying the non-selective susceptibility to ischemia of pyramidal neurons in the CA3 is important from the point of view of elucidating the mechanisms of memory loss and the development of dementia. The aim of the study was to investigate changes in genes expression of amyloid precursor protein, its cleaving enzymes and tau protein in CA3 post-ischemia with survival of 12-24 months. We used an ischemic model of Alzheimer's disease to study the above genes using an RT-PCR protocol. The expression of the amyloid precursor protein gene was above the control values at all times post-ischemia. The expression of the α-secretase gene also exceeded the control values post-ischemia. The expression of the β-secretase gene increased 12 and 24 months post-ischemia, and 18 months was below control values. Presenilin 1 and 2 genes expression was significantly elevated at all times post-ischemia. Also, tau protein gene expression was significantly elevated throughout the observation period, and peak gene expression was present 12 months post-ischemia. The study suggests that the genes studied are involved in the non-amyloidogenic processing of amyloid precursor protein. Additionally data indicate that brain ischemia with long-term survival causes damage and death of pyramidal neurons in the CA3 area of the hippocampus in a modified tau protein-dependent manner. Thus defining a new and important mechanism of pyramidal neuronal death in the CA3 area post-ischemia. In addition expression of tau protein gene modification after brain ischemia is useful in identifying ischemic mechanisms occurring in Alzheimer's disease.

Untargeted and Oxylipin-Targeted Metabolomics Study on the Plasma Samples of Primary Open-Angle Glaucoma Patients.

Purpose: to determine the metabolomics profiles in the plasma samples of primary open-angle glaucoma (POAG) patients. Methods: The plasma samples from 20 POAG patients under intraocular pressure (IOP)-lowering medication treatment and 20 control subjects were subjected to the untargeted metabolomics analysis, among which 10 POAG patients and 10 control subjects were further subjected to the oxylipin-targeted metabolomics analysis by liquid chromatography-mass spectrometry analysis. The prediction accuracy of the differentially abundant metabolites was assessed by the receiver operating characteristic curves. Pathway analysis and correlation analysis on the differentially abundant metabolites and clinical and biochemical parameters were also conducted. Results: Untargeted metabolomics profiling identified 33 differentially abundant metabolites in the POAG patients, in which the metabolism of linoleic acid, α-linolenic acid, phenylalanine, and tricarboxylic acid cycle were enriched. The correlation analysis indicated that the differentially abundant metabolites were associated with central corneal thickness, peripapillary retinal nerve fiber layer thickness, visual field defects, and lymphocytes. The oxylipin-targeted metabolomics analysis identified 15-keto-Prostaglandin F2 alpha, 13,14-Dihydro-15-keto-prostaglandin D2, 11-Dehydro-thromboxane B2, 8,9-Epoxyeicosatrienoic acid, and arachidonic acid to be significantly decreased in the POAG patients and enriched in the arachidonic acid (AA) pathway. Conclusions: This study revealed that the metabolites in the arachidonic acid metabolism pathway are differentially abundant, suggesting high IOP may not be the only detrimental factor for optic nerve cell damage in this group of POAG patients. Lipid metabolism instability-mediated alterations in oxylipins and AA pathways may be important in POAG, suggesting that oxidative stress and immune-related inflammation could be valuable directions for future therapeutic strategies.

Curculigoside, a traditional Chinese medicine monomer, ameliorates oxidative stress in Alzheimer's disease mouse model via suppressing ferroptosis.

Alzheimer's disease (AD) is a neurodegenerative disorder where oxidative stress, induced by ferroptosis, has been linked to neuronal damage and cognitive deficits. The objective of this study is to investigate if the potential therapeutic agent, Curculigoside (CUR), could ameliorate AD by inhibiting ferroptosis. The potential therapeutic targets, such as GPX4 and SLC7A11, were identified using weighted gene co-expression network analysis (WGCNA). Concurrently, CUR was also screened against these potential targets using various analytical methods. For the in vivo studies, intragastric administration of CUR significantly ameliorated cognitive impairment in AD model mice induced by scopolamine and okadaic acid (OA). In vitro, CUR protected neuronal cells by altering the levels of ferroptosis-related specific markers in OA and scopolamine-induced neurotoxicity. The administration of CUR through intragastric route significantly reduced the levels of AD-promoting factors (such as Aβ1-42 , p-tau) and ferroptosis-promoting factors in the hippocampus and cortex of AD mice. Furthermore, CUR up-regulated the expression of GPX4 and decreased the expression of SLC7A11 in the ferroptosis signaling pathway, thereby increasing the ratio of glutathione (GSH)/oxidized glutathione (GSSG) in vivo and vitro. In conclusion, the cumulative results suggest that the natural compound CUR may serve as a promising therapeutic agent to ameliorate AD by inhibiting ferroptosis.