Perioperative neurocognitive disorder (PND), a major contributor to poor postoperative outcomes and excessive healthcare costs, has been associated with isoflurane inhalation, although the underlying mechanisms remain poorly defined. Voltage-gated sodium channels (VGSCs or Nav) have been implicated in mediating the anesthetic effects of isoflurane. We previously reported that the Nav1.6 subtype modulates neural network activity and cognitive function. Here we investigated whether Nav1.6-mediated network disturbances contribute to isoflurane-induced PND. In the present study, we observed an increase in hippocampal Nav1.6 expression, accompanied by abnormal neural network excitability characterized by decreased β- and γ-band power on electroencephalogram (EEG) recordings. This dysfunction led to excessive glutamate release and subsequent cognitive impairment. Correspondingly, downregulation of Nav1.6 by lidocaine abolished both the abnormal network excitability and excessive glutamate release in isoflurane-exposed mice. In parallel, changes in excitatory synaptic proteins and excitatory amino acid transporters contributed to improved cognitive performance in isoflurane-inhaled mice. Taken together, isoflurane-induced increase in Nav1.6 evokes the abnormal network excitability, leading to excessive glutamate release and eventually cognitive decline. Our study offers a novel potential mechanism linking Nav1.6 to isoflurane-induced PND and suggests lidocaine as a potential therapeutic candidate.

Diabetic foot ulcer (DFU) remains a major cause of morbidity and lower-limb amputation worldwide. Accurate risk assessment and timely intervention are critical for improving healing outcomes. A recent study identified the decapping scavenger enzyme (DCPS), an N7-methylguanosine (m7G)-related gene, as a potential diagnostic and therapeutic biomarker for DFU. Reduced DCPS expression was found to impair keratinocyte proliferation, migration, and cell-cycle progression, highlighting its possible role in m7G-mediated wound repair. Despite these promising insights, several challenges must be addressed before DCPS can be translated into clinical practice. First, DCPS expression may vary among patients with metabolic or inflammatory disorders, limiting its disease specificity. Second, standardized reference ranges for DCPS quantification have not yet been established. Moreover, whether DCPS modulation can directly enhance wound healing remains uncertain. Overall, DCPS provides a novel mechanistic link between RNA methylation and chronic wound pathology, but its clinical application as a biomarker or therapeutic target warrants careful validation.

BACKGROUND AND PURPOSE:Parkinson's disease (PD), characterized by motor dysfunction and dopaminergic neuron loss in the substantia nigra, is frequently complicated by depression (depression-associated PD, DPD), affecting 40-50% of patients and accelerating disease progression. This study investigated neuroprotective effects in a chronic MPTP-induced mouse model of DPD. EXPERIMENTAL APPROACH:We established a chronic PD model induced by MPTP, with motor deficits assessed via rotarod and gait analysis. Depressive phenotypes were confirmed by tail suspension, sucrose preference and forced swim tests. Mice were categorized into DPD and non-depressive groups, followed by 14-day treatment with SVHRSP or vehicle. KEY RESULTS:Post-treatment behavioural evaluations demonstrated that SVHRSP significantly ameliorated depressive symptoms, as evidenced by increased sucrose preference, reduced immobility in the forced swim test and restored cognitive performance in the Y-maze, passive-avoidance and novel-object-recognition tests. Molecular analyses demonstrated that SVHRSP enhanced neuroprotection by normalizing the phosphorylated Akt and CREB levels, reducing neuroinflammatory markers (IBA1, GFAP and cytokines) and modulating synaptic proteins (NR2B and PSD-95). Immunofluorescence further corroborated these findings, confirming reduced NR2B and NR1 expression and preserved neuronal integrity. SVHRSP downregulated Nav1.6 ion channel expression and restored 5-HT2C receptor levels and normalized stress-axis glucocorticoid receptor (GR) expression. Molecular docking simulations revealed strong binding affinities between SVHRSP and CREB/Akt. CONCLUSION AND IMPLICATIONS:The results indicate that SVHRSP mitigates motor deficits, depressive symptoms and cognitive impairments in MPTP-induced DPD mice by suppressing CREB-Akt-mediated neuroinflammation and modulating synaptic plasticity. The multitarget mechanism of SVHRSP underscores its potential as a novel therapeutic candidate for DPD.

Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide. Accurate prognostic assessment, which is essential for enhancing overall survival (OS), currently depends on pathologic and clinical staging. This underscores the urgent need for reliable and real-time prognostic biomarkers. The triglyceride-glucose (TyG) index, a readily available marker of insulin resistance, has recently emerged as a potential prognostic tool in GC. Numerous studies have consistently shown a significant association between elevated TyG levels and inferior OS as well as progression-free survival. Despite these promising findings, several challenges must be addressed before the TyG index can be widely adopted in clinical practice. Firstly, the TyG index lacks cancer-specificity, reflecting broader metabolic disturbances commonly observed in conditions such as obesity, diabetes, and cardiovascular disease. This lack of specificity complicates its interpretation in oncological settings. Additionally, the cutoff values for TyG index vary across studies, hindering the establishment of a standardized threshold for clinical application. While the TyG index provides valuable insights into a patient's metabolic health, its limited cancer specificity necessitates cautious use when evaluating the prognosis of GC treatment.

Introduction: Nav1.6 is closely related to the pathology of Alzheimer's Disease (AD), and astrocytes have recently been identified as a significant source of (3-amyloid (A(3). However, little is known about the connection between Nav1.6 and astrocyte-derived A(3. Objective: This study explored the crucial role of Nav1.6 in mediated astrocyte-derived A(3 in AD and knockdown astrocytic Nav1.6 alleviates AD progression by promoting autophagy and lysosome-APP fusion. Methods: A mouse model for astrocytic Nav1.6 knockdown was constructed to study the effects of astrocytic Nav1.6 on amyloidosis. The role of astrocytic Nav1.6 on autophagy and lysosome-APP(amyloid precursor protein) fusion was used by transmission electron microscope, immunostaining, western blot and patch clamp. Glial cell activation was detected using immunostaining. Neuroplasticity and neural network were assessed using patch-clamp, Golgi stain and EEG recording. Behavioral experiments were performed to evaluate cognitive defects. Results: Astrocytic Nav1.6 knockdown reduces amyloidosis, alleviates glial cell activation and morphological complexity, improves neuroplasticity and abnormal neural networks, as well as promotes learning and memory abilities in APP/PS1 mice. Astrocytic Nav1.6 knockdown reduces itself-derived A(3 by promoting lysosome-APP fusion, which is related to attenuating reverse Na'-Ca2' exchange current thus reducing intracellular Ca2' to facilitate autophagic through AKT/mTOR/ULK pathway. Conclusion: Our findings unveil the crucial role of astrocyte-specific Nav1.6 in reducing astrocyte-derived A(3, highlighting its potential as a cell-specific target for modulating AD progression. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Scorpion venom heat-resistant peptide (SVHRP) is a component purified from Buthus martensii Karsch scorpion venom. Our previous studies have shown that SVHRP is neuroprotective in models of Alzheimer's disease and Parkinson's disease. The present study aimed to explore the potential neuroprotective effects of SVHRP on cerebral ischemia/reperfusion (I/R) injury, using a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a cellular model of oxygen-glucose deprivation/reoxygenation (OGD/R). Our results showed that SVHRP treatment decreased the neurological deficit scores, edema formation, infarct volume and neuronal loss in the MCAO/R mice, and protected primary neurons against OGD/R insult. SVHRP pretreatment suppressed the alterations in protein levels of N-methyl-D-aspartate receptors (NMDARs) and phosphorylated p38 MAPK as well as some proinflammatory factors in both the animal and cellular models. These results suggest that SVHRP has neuroprotective effects against cerebral I/R injury, which might be associated with inhibition of the NMDA-MAPK-mediated excitotoxicity.

In the contemporary research landscape of mental illness treatment, fear-related disorders such as post-traumatic stress disorder continue to pose significant challenges. Although exposure therapy remains a fundamental component of treatment, its efficacy varies considerably among individuals. DNA methylation plays a pivotal role in the extinction of fear memories, providing a promising molecular mechanism that could enhance the success of exposure-based interventions. Extensive studies have consistently demonstrated a substantial association between DNA methylation and neuronal plasticity. While DNA methylation holds potential regulatory effects on the effectiveness of exposure therapy, the bidirectional regulatory relationship between it and neuronal activity necessitates addressing several challenges before its widespread clinical application for mental disorders. First, excessive DNA methylation may suppress neural function, and non-selective enhancement of methylation could be counterproductive. Furthermore, due to potential systemic side effects, the use of methylation-modulating agents might disrupt the physiological balance and functionality of other organs and systems. Despite the dynamic interplay between DNA methylation and neuronal activity offering novel insights into the treatment of mental disorders, the strict consideration of target specificity and an appropriate dosing window requires cautious implementation in clinical practice.

INTRODUCTION:Alzheimer's disease (AD) neuropathology exhibits early accumulation of amyloid beta (Aβ) plaques within the perforant pathway. This study explores how tenascin-R, a myelin-associated protein at nodes of Ranvier (NORs), modulates Aβ generation through Nav1.6 within this cortico-hippocampal circuit. METHODS:We integrated genetic, electrophysiological, and microdialysis techniques in APP/PS1 mice and constructed tenascin-R gene fragments and GEDC motif to identify potential therapeutic sequences for AD treatment. RESULTS:Stimulating the entorhinal cortex increased Aβ1-42 release along the perforant pathway through Nav-dependent mechanisms. Reducing tenascin-R decreased Aβ deposition and alleviated cognitive deficits. Overexpressing tenascin-R enhanced Nav1.6 currents and upregulated amyloid precursor protein and β-secretase. The GEDC motif within tenascin-R's epidermal growth factor-like domain controlled Nav1.6 activity. DISCUSSION:Our findings demonstrate that NORs signaling modulates Aβ processing independently of synaptic mechanisms. Tenascin-R regulates Aβ pathogenesis via Nav1.6 at NORs, underscoring myelin proteins and Nav1.6 as therapeutic targets. The GEDC motif represents a potential peptide-based compound for AD therapy. HIGHLIGHTS:Nodes of Ranvier-associated tenascin-R (Tn-R) regulate amyloid beta (Aβ) production in the perforant pathway of APP/PS1 mice. Tn-R enhances Nav1.6-mediated sodium currents, promoting amyloid precursor protein (APP) transcription and Aβ generation. Genetic downregulation of Tn-R mitigates Aβ deposition, restores synaptic integrity, and improves cognition. The conserved GEDC motif within Tn-R's epidermal growth factor-like domain is critical for modulating Nav1.6 activity and amyloidogenesis. The Tn-R/Nav1.6 axis represents a novel therapeutic target for Alzheimer's disease, with GEDC-derived peptides offering translational potential.

Clinical and preclinical studies increasingly support the antidepressant potential of several anesthetic agents, including ketamine, propofol, nitrous oxide (N2O), sevoflurane, and isoflurane. Their therapeutic effects appear to arise from the regulation of multiple interconnected systems: modulation of glutamatergic and GABAergic signaling, interaction with monoaminergic neurotransmitters (5-HT, DA, NE), activation of neuropeptide-related pathways such as BDNF and VGF, regulation of the hypothalamic-pituitary-adrenal (HPA) axis, and suppression of inflammatory responses. These pathways overlap with core pathophysiological changes in depression and thus represent promising targets for intervention. Given the limited efficacy and delayed onset of traditional antidepressants, anesthetics with rapid antidepressant properties have emerged as attractive alternatives. However, their precise mechanisms of action, as well as questions regarding long-term safety and optimal clinical application, remain to be fully clarified. This review summarizes recent advances in both experimental and clinical research on the antidepressant effects of anesthetics, highlighting their underlying molecular and neural mechanisms, therapeutic potential, and current limitations. By integrating mechanistic insights with translational evidence, this article provides new perspectives and serves as a reference for future research aimed at developing safe and effective anesthetic-based therapies for treatment-resistant depression.

BACKGROUND:Amyloid beta (Aβ) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to "spread" through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied.METHODS:To genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP).RESULTS:It is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, Aβ production in the perforant path and levels of soluble Aβ and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the α-secretase and β-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway.CONCLUSIONS:Our findings demonstrate that perforant path NgR plays an important role in regulating APP/Aβ level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression.

Introduction Nav1.6 is closely related to the pathology of Alzheimer’s Disease (AD), and astrocytes have recently been identified as a significant source of β-amyloid (Aβ). However, little is known about the connection between Nav1.6 and astrocyte-derived Aβ. Objective This study explored the crucial role of Nav1.6 in mediated astrocyte-derived Aβ in AD and knockdown astrocytic Nav1.6 alleviates AD progression by promoting autophagy and lysosome-APP fusion. Methods A mouse model for astrocytic Nav1.6 knockdown was constructed to study the effects of astrocytic Nav1.6 on amyloidosis. The role of astrocytic Nav1.6 on autophagy and lysosome-APP(amyloid precursor protein) fusion was used by transmission electron microscope, immunostaining, western blot and patch clamp. Glial cell activation was detected using immunostaining. Neuroplasticity and neural network were assessed using patch-clamp, Golgi stain and EEG recording. Behavioral experiments were performed to evaluate cognitive defects. Results Astrocytic Nav1.6 knockdown reduces amyloidosis, alleviates glial cell activation and morphological complexity, improves neuroplasticity and abnormal neural networks, as well as promotes learning and memory abilities in APP/PS1 mice. Astrocytic Nav1.6 knockdown reduces itself-derived Aβ by promoting lysosome- APP fusion, which is related to attenuating reverse Na+-Ca2+ exchange current thus reducing intracellular Ca2+ to facilitate autophagic through AKT/mTOR/ULK pathway. Conclusion Our findings unveil the crucial role of astrocyte-specific Nav1.6 in reducing astrocyte-derived Aβ, highlighting its potential as a cell-specific target for modulating AD progression.

Despite the increasing number of anti-hypertensive drugs have been developed and used in the clinical setting, persistent deficiencies persist, including issues such as lifelong dosage, combination therapy. Notwithstanding receiving the treatment under enduring these deficiencies, approximately 4 in 5 patients still fail to achieve reliable blood pressure (BP) control. The application of neuromodulation in the context of hypertension presents a pioneering strategy for addressing this condition, con-currently implying a potential central nervous mechanism underlying hypertension onset. We hypothesize that neurological networks, an essential component of maintaining appropriate neurological function, are involved in hypertension. Drawing on both peer-reviewed research and our laboratory investigations, we endeavor to investigate the underlying neural mechanisms involved in hypertension by identifying a close relationship between its onset of hypertension and an excitation and inhibition (E/I) imbalance. In addition to the involvement of excitatory glutamatergic and GABAergic inhibitory system, the pathogenesis of hypertension is also associated with Voltage-gated sodium channels (VGSCs, Nav)-mediated E/I balance. The overloading of glutamate or enhancement of glutamate receptors may be attributed to the E/I imbalance, ultimately triggering hypertension. GABA loss and GABA receptor dysfunction have also proven to be involved. Furthermore, we have identified that abnormalities in sodium channel expression and function alter neural excitability, thereby disturbing E/I balance and potentially serving as a mechanism underlying hypertension. These insights are expected to furnish potential strategies for the advancement of innovative anti-hypertensive therapies and a meaningful reference for the exploration of central nervous system (CNS) targets of anti-hypertensives.

Hypertension is well-known to be influenced by genetic and environmental factors. Managing stress is one of the non-pharmacologic approaches to treating hypertension. It is, therefore, imperative to unravel the molecular mechanism by which stress conditions influence hypertension. In this study, TIP60 expressions in human blood samples and cell lines, glutamatedmPFC-to-vCA1 release, and receptor expressions in the Stress-induced hypertension mice were determined using western blotting, CSF (obtained by microdialysis), and ELISA. The study reports increased protein expressions of TIP60 in the peripheral blood of hypertensive patients and in cell lines representing hypertension. In Chronic restraint stress (CRS) conditions TIP60 expression and vCA1 glutamate release were found to be up-regulated, with high SBP and DSP indicating hypertension was induced. After electrical stimulation at the dmPFC, release of glutamate in the vCA1 increased, indicating that activity within the dmPFC drives the release of glutamate in the vCA1, which was blocked by injecting MG149 (a TIP60 inhibitor) into dmPFC. To further determine whether TIP60 was involved in glutamate release and eventually results in hypertension, MG149 was also injected i.p. alongside CRS modeling. The increased glutamate release, NR2B, and IL-18 expressions as well as the CRS-induced hypertension was therefore reversed by chronic application with MG149. Altogether, these results suggest that TIP60 influences the glutamatedmPFC-to-vCA1 release and receptor expressions. This study, therefore, proposes that stressful condition induces increased expression of TIP60 which lead to the transcription of genes that result in conditions that favors glutamate release and receptor expressions hence triggering hypertension.

Neuronal loss is the central abnormality occurring in brains suffering from Alzheimer's disease (AD). The notion that AD causes the death of neurons point towards protection of neuronal morphology and function as important therapeutic strategies. The perforant path projections from the entorhinal cortex to the dentate gyrus is the most vulnerable circuit with respect to AD. It's known that the perforant path is a very important structure for synaptic plasticity and cognitive functions. NgR (Nogo receptor) is not only involved in limiting injury-induced axonal growth but also in pathological features of AD. So, the mechanism of how NgR affects the perforant path needs further investigation. In this study, the effect of NgR in the perforant path on the neuronal morphology and function in APP/PS1 transgenic mice was studied. The results showed that downregulation of NgR in perforant path ameliorate the damaged morphology and decreased number of neurons in APP/PS1 mice. Concurrently, NgR knockdown enhanced dendritic complexity and increased postsynaptic protein density in APP/PS1 mice. Furthermore, the RT-PCR results indicated that there is downregulation of M1 phenotypes of microglial gene expression in the hippocampus of TG-shNgR mice. Our study suggests that NgR plays a critical role in microglial phenotype polarization, which might account for the NgR knockdown in the perforant path initiated a decrease in neuronal death and improved synaptic function. Our study provided a better understanding of the perforant path and the role of NgR in AD pathogenesis, thus offering the potential application of hippocampal neurons in treatment of AD.

Aging is associated with physiological and pathological changes and presents health complications, such as dementia. Isolation has also been associated with the experience of growing old. Both have been linked individually to the incidence of cognitive decline. In this present study, the effects of these two phenomena have been looked at in animal models where aging was induced with D(+)Galactose in mice who underwent long-term post-weaned social isolation (L-PWSI). Assessing cognitive function using Y-maze, Morris water maze (MWM), and passive avoidance tests (PATs) confirmed that cognition is impaired in either of the treatments but worsened when the D(+)Galactose mice were subjected to L-PWSI. Moreover, a synaptic protein, PSD95, and dendritic spines density were significantly reduced in the L-PWSI and D(+)Galactose-treated mice. Our previous study revealed that autophagy deficit is involved in cognitive impairment in the L-PWSI model. Here, we first report the inhibited cell cycle in L-PWSI, combined with the decreased autophagy, aggravates cognitive impairment in D(+)Galactose-treated mice. Beyond these, the autophagy and cell cycle mechanisms that link isolation and aging have been explored. The close association between isolation and aging in humans is very real and needs much research attention going forward for possible therapeutic interventions.

Steroid receptor coactivator 1 (SRC-1) is one of the coactivators recruited by the nuclear receptors (NRs) when NRs are activated by steroid hormones, such as glucocorticoid. SRC-1 is abundant in hippocampus and hypothalamus and is also related to some major risk factors for depression, implicated by its reduced expression after stress and its effect on hypothalamus-pituitary-adrenal gland axis function. However, whether SRC-1 is involved in the formation of depression remains unclear. In this study, we firstly established chronic unpredictable stress (CUS) to induce depressive-like behaviors in mice and found that SRC-1 expression was reduced by CUS. A large number of studies have shown that neuroinflammation is associated with stress-induced depression and lipopolysaccharide (LPS) injection can lead to neuroinflammation and depressive-like behaviors in mice. Our result indicated that LPS treatment also decreased SRC-1 expression in mouse brain, implying the involvement of SRC-1 in the process of inflammation and depression. Next, we showed that the chronic unpredictable mild stress (CUMS) failed to elicit the depressive-like behaviors and dramatically promoted the expression of SRC-1 in brain of wild type mice. What's more, the SRC-1 knockout mice were more susceptible to CUMS to develop depressive-like behaviors and presented the changed expression of glucocorticoid receptor. However, SRC-1 deficiency did not affect the microglia activation induced by CUMS. Altogether, these results indicate a correlation between SRC-1 level and depressive-like behaviors, suggesting that SRC-1 might be involved in the development of depression induced by stress.