Edaravone dexborneol regulates γ-aminobutyric acid transaminase in rats with acute intracerebral hemorrhage.

OBJECTIVES: Edaravone dexborneol is neuroprotective against ischemic stroke, with free radical-scavenging and anti-inflammatory effects, but its effects in hemorrhagic stroke remain unclear. We evaluated whether edaravone dexborneol has a neuroprotective effect in intracerebral hemorrhage, and its underlying mechanisms. MATERIALS AND METHODS: Bioinformatics were used to predict the pathway of action of edaravone dexborneol. An intracerebral hemorrhage model was established using type IV collagenase in edaravone dexborneol, intracerebral hemorrhage, Sham, adeno-associated virus + edaravone dexborneol, and adeno-associated virus + intracerebral hemorrhage groups. The modified Neurological Severity Score was used to evaluate neurological function in rats. Brain water content was measured using the dry-wet weight method. Tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and γ-aminobutyric acid levels were determined by enzyme-linked immunosorbent assay. The expression levels of neurofilament light chain and γ-aminobutyric acid transaminase were determined by western blot. Nissl staining was used to examine neuronal morphology. Cognitive behavior was evaluated using a small-animal treadmill. RESULTS: Edaravone dexborneol alleviated neurological defects, improved cognitive function, and reduced cerebral edema, neuronal degeneration, and necrosis in rats with cerebral hemorrhage. The expression levels of neurofilament light chain, tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and γ-aminobutyric acid were decreased, while γ-aminobutyric acid transaminase expression was up-regulated. CONCLUSIONS: Edaravone dexborneol regulates γ-aminobutyric acid content by acting on the γ-aminobutyric acid transaminase signaling pathway, thus alleviating oxidative stress, neuroinflammation, neuronal degeneration, and death caused by excitatory toxic injury of neurons after intracerebral hemorrhage.

Bioinformatics-based analysis of mechanistic differences in vascular endothelial injury ischemic stroke induced by atrial fibrillation and atherosclerosis.

Studies of the intracranial vasculature in patients with ischemic stroke caused by atherosclerosis (AS) and cardiac embolism have revealed significantly different degrees of AS, plaque, and vascular stenosis. And the endothelium has a great influence on the vasculature throughout the circulatory system, especially in the brain. This study aimed to investigate the mechanistic differences in endothelial injury between atrial fibrillation (AF)- and AS-induced ischemic stroke. All target genes of AF, AS, and the vascular endothelial cell (VC) were obtained from the GeneCards database; the differential genes of AF and AS separately associated with the VC were established by a Venn diagram. A protein-protein interaction network was created, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were used to perform genomic enrichment and functional enrichment analysis. Hub genes were selected by Maximal Clique Centrality algorithm ranking and correlation linkage in the STRING database, and then, clinical serum samples were used to verify the quantitative expressions in the AF, AF stroke, AS, and AS stroke groups. Fifty-five AF-VC-related genes and ninety-three AS-VC-related genes were screened, which differed in biological function, cellular composition, and molecular function. The genes correlation between AF and vascular endothelial cells (VCs) was KRAS and PTPN11, and those correlation between AS and VCs was IL-4, IFNG, IL-17A, and CSF-2. IL-4 and CSF-2 may be relevant proteins involved in the differences in stroke mechanisms between AF and AS, and they may act by further influencing the function of their downstream cells. This study provides a preliminary theoretical basis for investigating the differences in mechanisms of endothelial injury between AF- and AS-induced ischemic stroke.

Association between Sleep and Alzheimer's Disease: A Bibliometric Analysis from 2003 to 2022.

INTRODUCTION: Alzheimer's disease (AD) often presents with sleep disorders, which are also an important risk factor for AD, affecting cognitive function to a certain extent. This study aimed to reveal the current global status, present hotspots, and discuss emerging trends of sleep and AD using a bibliometric approach. METHODS: Research and review articles related to sleep and AD from 2003 to 2022 were extracted from the Web of Science Core Collection. VOSviewer 1.6.18.0, Scimago Graphica, and CiteSpace 6.2.R2 were used to map the productive and highly cited countries, institutions, journals, authors, references, and keywords in the field. RESULTS: Overall, 4,008 publications were included in this bibliometric analysis. The number of publications and citations showed an increasing trend over the past two decades. The USA and China had the largest and second largest, respectively, number of publications and citations and cooperated with other countries more closely. Ancoli-Israel Sonia published the most papers, and Holtzman David M was co-cited most frequently. The most productive journal was Journal of Alzheimer's Disease, and Neurology was the most frequently cited journal. The risk factors, ß-amyloid (Aß), tau, neuroinflammation, astrocytes, glymphatic system, orexin, functional connectivity, and management have been the main research directions of researchers over the past few years and may be the future trend of valuable research. CONCLUSION: We identified hotspots and emerging trends including risk factors, Aß, tau, neuroinflammation, the glymphatic system, orexin, and management, which may help identify new therapeutic targets and improve clinical efficacy of sleep and AD.

A bibliometric analysis of cerebral microbleeds and cognitive impairment.

BACKGROUND AND OBJECTIVES: Cerebral microbleeds (CMBs) are imaging markers for small cerebral vascular diseases, which can accumulate and impact the corresponding brain networks. CMBs can affect cognitive function, including executive function, information processing speed, and visuospatial memory. Bibliometrics is a scientific and innovative method that can analyze and visualize the scientific field quantitatively. In this study, we aimed to use bibliometric analysis to demonstrate the relationship and mechanisms between CMBs and cognitive impairment. Furthermore, we reviewed the relationship between CMBs and different cognitive disorders. The use of bibliometrics can help further clarify this relationship. METHODS: We retrieved articles on CMBs and cognitive impairment from the Web of Science Core Collection. The keywords (such as stroke, dementia, and cerebral amyloid angiopathy), authors, countries, institutions and journals, in the field were visually analyzed using VOSviewer software and bibliometric websites. RESULTS: This bibliometric analysis reveals the related trends of CMBs in the field of cognitive impairment. CMBs, along with other small vascular lesions, constitute the basis of cognitive impairment, and studying CMBs is essential to understand the mechanisms underlying cognitive impairment. CONCLUSION: This bibliometric analysis reveals a strong link between CMBs and cognitive impairment-related diseases and that specific brain networks were affected by CMBs. This provides further insights into the possible mechanisms and causes of CMBs and cognitive impairment. The direct and indirect damage (such as oxidative stress and neuroinflammation) to the brain caused by CMBs, destruction of the frontal-subcortical circuits, elevated Cystatin C levels, and iron deposition are involved in the occurrence and development of cognitive impairment. CMBs may be a potential marker for detecting, quantifying, and predicting cognitive impairment.

To betray or to fight? The dual identity of the mitochondria in cancer.

Mitochondria are highly dynamic organelles that provide energy for oxidative phosphorylation in cells. Equally, they are the major sites for the metabolism of amino acids, lipids and iron. When cells become cancerous, the morphology, cellular location and metabolic mode of the mitochondria change accordingly. These mitochondrial changes can have two opposing effects on cancer: procancer and anticancer effects. Specifically, mitochondria play roles in the fight against cancer by participating in processes such as ferroptosis, mitophagy and antitumor immunity. Contrastingly, cancer cells can also enslave mitochondria to give them the conditions necessary for growth and metastasis. Moreover, through mitochondria, cancer cells can escape from immune surveillance, resulting in their immune escape and enhanced malignant transformation ability. At present, cancer-related studies of mitochondria are one-sided; therefore, we aim to provide a comprehensive understanding by systematically reviewing the two-sided cancer-related properties of mitochondria. Mitochondrial-targeted drugs are gradually emerging and showing significant advantages in cancer treatment; thus, our in-depth exploration of mitochondria in cancer will help to provide theoretical support for the future provision of efficient and low-toxicity cancer treatments.

Piperine ameliorates insulin resistance via inhibiting metabolic inflammation in monosodium glutamate-treated obese mice.

BACKGROUND: Metabolic inflammation is an essential event in obesity-induced diabetes and insulin resistance. In obesity, an increasing number of macrophages recruited into visceral adipose tissues undergo significant M1-like polarization, secreting variable amounts of pro-inflammatory cytokines and causing insulin resistance. Piperine has excellent anti-inflammatory activities and may be used in the treatment of a variety of inflammatory diseases. In this study, we investigated the effect of piperine on adipose tissue inflammation and insulin resistance in obese mice. METHODS: Newborn mice were subcutaneously (s.c.) injected with monosodium glutamate (MSG) to establish a diabetes model. After 24 weeks, the MSG obese mice were divided into three groups and treated with piperine (40 mg/kg/day), metformin (150 mg/kg/day) and vehicle for 10 successive weeks, respectively. RESULTS: The obesity model was successfully established, as the body weight, insulin resistance, fasting blood glucose (FBG) and dyslipidemia were significantly increased. The 10-week administration of piperine to the obese mice not only significantly decreased the elevated FBG (Model: 6.45 ± 0.41 mM; Piperine: 4.72 ± 0.44 mM, p < 0.01), serum TC (Model: 5.66 ± 0.66 mM; Piperine: 3.55 ± 0.30 mM, p < 0.01) and TG (Model: 1.41 ± 0.08 mM; Piperine: 0.94 ± 0.05 mM, p < 0.001), but also enhanced the glucose infusion rate in the hyperglycemic clamp experiment. Meanwhile, piperine improved glucose intolerance and insulin resistance in MSG obese mice. Piperine markedly decreased the total and differential white blood cell (WBC) count, the serum levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines such as galectin-3 (Gal-3) and interleukin-1ß (IL-1ß). Furthermore, piperine clearly down-regulated the mRNA levels of pro-inflammatory cytokines and the protein levels of M1-like polarization marker CD11c and Gal-3 in adipose tissues. The in vitro study showed that piperine inhibited LPS-stimulated polarization of RAW 264.7 cells toward the M1 phenotype. CONCLUSIONS: Piperine served as an immunomodulator for the treatment of obesity-related diabetes through its anti-inflammatory effects, which might be achieved by inhibiting macrophages M1 polarization in adipose tissues.

A brief review: some compounds targeting YAP against malignancies.

YAP, acting as a crucial transcription factor in nucleus, regulates the organ size, tissue homeostasis and tumorigenesis. Dysregulation of Hippo-YAP pathway brings a significant impact on the occurrence and development of various tumor types. Moreover, regulation of YAP/TAZ far exceeds the core kinase of the Hippo pathway, and gradually opens up new therapeutic targets. For the moment, chemotherapy together with radiotherapy act as routine methods to prolong the lives of cancer patients. Seeking more effective anti-neoplastic agents seems to be the urgent problem. This brief review focuses on the research progress of YAP inhibitors as the antineoplastic targets. Small molecule inhibitors or drugs have been discovered including verteporfin, dasatinib, statins, A35, JQ1, norcantharidin, agave, MLN8237, dobutamine and peptide-based YAP inhibitors. We are trying to seek novel therapies from the relationship between known drugs and potential mechanisms.

Four-wave mixing in Ar-filled hollow core bandgap photonic crystal fiber.

To study the four-wave mixing (FWM) effect and wavelength conversion in a hollow core bandgap photonic crystal fiber filled with Ar, we conducted an experiment using a femtosecond laser with the pulse width of 120 fs, a repetition rate of 76 MHz, and tunable central wavelength from 760 to 980 nm. It is observed that new spectra are generated in both sides of the pump at a special wavelength, which can exactly satisfy the phase matching conditions of FWM. Combining experimental results with theoretical analysis, we find that the experimental phenomenon is mainly caused by FWM, and some other nonlinear phase effects, such as self-phase modulation, stimulated Raman scattering, and the soliton effect, have also occurred in this nonlinear process.

The effects of berberine on a murine model of multiple sclerosis and the SPHK1/S1P signaling pathway.

Berberine (BBR) has shown neuroprotective properties. The present study aims to investigate the effects of BBR on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), and SphK1/S1P signaling, which plays a key role in MS. EAE was induced in mice, followed by treatment with BBR at 50, 100, or 300 mg/kg/d. Neurophysiological function was evaluated daily; inflammation, cell infiltration, and the severity of demyelination were also examined. The SphK1, SphK2, and S1P levels in the animals and primary astrocyte culture were measured. We found that treatment with BBR reduced the loss of neurophysiological function and the degree of demyelination. Moreover, BBR was associated with a decrease in SphK1 and S1P levels both in the animals and in culture. These results indicated that BBR suppresses demyelination and loss of neurophysiological function by inhibiting the SphK1/S1P signaling pathway. The use of BBR as a treatment of MS warrant further exploration.

Effect of synaptic adhesion-like molecule 3 on epileptic seizures: Evidence from animal models.

Axonal sprouting and synaptic reorganization are the primary pathophysiological characteristics of epilepsy. Recent studies demonstrated that synaptic adhesion-like molecule 3 (SALM3) is highly expressed in the central nervous system and plays important roles in neurite outgrowth, branching, and axon guidance, mechanisms that are also observed in epilepsy. However, the expression of SALM3 in the epileptic brain and the effect of SALM3 in the pathogenesis of epilepsy remain unclear. The aims of this study were to investigate SALM3 expression in rat models of epilepsy and to explore the functional significance of SALM3 in epilepsy. We demonstrated that SALM3 was expressed at significantly higher levels in epileptic rats compared with controls. Inhibition of SALM3 by SALM3 shRNA inhibited status epilepticus in the acute stage of disease and decreased spontaneous recurrent seizures in the Lithium-pilocarpine model of chronic stages of epilepsy. Consistent with these findings, SALM3 shRNA significantly prolonged the latent period in the PTZ kindling model. Our study suggests that the overexpression of SALM3 might be associated with epileptogenesis and that selectively inhibiting SALM3 may have therapeutic potential in treating epilepsy.

The microRNA miR-124 suppresses seizure activity and regulates CREB1 activity.

miR-124, a brain-specific microRNA, was originally considered as a key regulator in neuronal differentiation and the development of the nervous system. Here we showed that miR-124 expression was suppressed in patients with epilepsy and rats after drug induced-seizures. Intrahippocampal administration of a miR-124 duplex led to alleviated seizure severity and prolonged onset latency in two rat models (pentylenetetrazole- and pilocarpine-induced seizures), while miR-124 inhibitor led to shortened onset latency in pilocarpine-induced seizure rat models. Moreover, the result of local field potentials (LFPs) records further demonstrated miR-124 may have anti-epilepsy function. Inhibition of neuronal firing by miR-124 was associated with the suppression of mEPSC, AMPAR- and NMDAR-mediated currents, which were accompanied by decreased surface expression of NMDAR. In addition, miR-124 injection resulted in decreased activity and expression of cAMP-response element-binding protein1 (CREB1). a key regulator in epileptogenesis. A dual-luciferase reporter assay was used to confirm that miR-124 targeted directly the 3'UTR of CREB1 gene and repressed the CREB1 expression in HEK293T cells. Immunoprecipitation studies confirmed that the CREB1 antibody effectively precipitated CREB1 and NMDAR1 but not GLUR1 from rat brain hippocampus. These results revealed a previously unknown function of miR-124 in neuronal excitability and provided a new insight into molecular mechanisms underlying epilepsy.

Increased Expression of Rac1 in Epilepsy Patients and Animal Models.

The mechanisms of epilepsy remain incompletely understood. Rac1 (ras-related C3 botulinum toxin substrate 1) belongs to the Rho family of small GTPases. Rac1 play important roles in cytoskeleton rearrangement and neuronal synaptic plasticity, which had also been implicated in epilepsy. However, little is known regarding the expression of Rac1 in the epileptic brain or whether Rac1-targeted interventions affect the progression of epilepsy. The aim of this study was to investigate the expression profile of Rac1 in brain tissues from patients suffering from temporal lobe epilepsy (TLE) and experimental epileptic rats and determine the possible role of Rac1 in epilepsy. We demonstrated that the expression of Rac1 is significantly increased in TLE patients and in lithium-pilocarpine epilepsy model animals compared to the corresponding controls. Rac1 inhibitor NSC23766 reduced the severity of status epilepticus during the acute stage in a lithium-pilocarpine animal model. Consistent with these results, the latent period of a PTZ kindling animal model also increased. Our results demonstrated that the increased expression of Rac1 may contribute to pathophysiology of epilepsy.

Prognostic value of electroencephalography (EEG) for brain injury after cardiopulmonary resuscitation.

Cardiac arrest (CA) patients can experience neurological sequelae or even death after successful cardiopulmonary resuscitation (CPR) due to cerebral hypoxia- and ischemia-reperfusion-mediated brain injury. Thus, it is important to perform early prognostic evaluations in CA patients. Electroencephalography (EEG) is an important tool for determining the prognosis of hypoxic-ischemic encephalopathy due to its real-time measurement of brain function. Based on EEG, burst suppression, a burst suppression ratio >0.239, periodic discharges, status epilepticus, stimulus-induced rhythmic, periodic or ictal discharges, non-reactive EEG, and the BIS value based on quantitative EEG may be associated with the prognosis of CA after successful CPR. As measures of neural network integrity, the values of small-world characteristics of the neural network derived from EEG patterns have potential applications.

Expression levels of microRNA-199 and hypoxia-inducible factor-1 alpha in brain tissue of patients with intractable epilepsy.

OBJECTIVES: During the last decade, experimental evidence has demonstrated an important role of hypoxia, which leads to neuronal cell death and angiogenesis, in the mechanisms of seizure precipitation and recurrence. MicroRNA-199 targets hypoxia-inducible factor-1alpha (HIF-1α), which has recently been implicated in the pathophysiology of the hypoxic state and brain injury. However, little is known about the roles of MicroRNA-199 and HIF-1α in the human epileptogenic process. DESIGN AND METHODS: In this study, we investigated the expression of miR-199a-5p, miR-199b-5p and HIF-1α using real-time PCR, immunohistochemistry and western blots in the temporal neocortex of twenty four patients with intractable epilepsy and twelve control subjects. RESULTS: Compared with the control group, the expression of miR-199a-5p and miR-199b-5p was significantly lower in epileptic brain tissues (p < 0.05). The levels of HIF-1α mRNA and protein were highly up-regulated in epileptic brain tissues compared with those of control subjects (p < 0.05). CONCLUSION: These data suggest that the abnormal expression of miR-199 and HIF-1α in epileptic brain tissue may be involved in the pathophysiology of human epilepsy and that the expression of HIF-1α may be regulated by miR-199. These findings may provide new insights into the treatment of epilepsy.

Insulin growth factor-1 (IGF-1) enhances hippocampal excitatory and seizure activity through IGF-1 receptor-mediated mechanisms in the epileptic brain.

Insulin-like growth factor-1 (IGF-1) is known to promote neurogenesis and survival. However, recent studies have suggested that IGF-1 regulates neuronal firing and excitatory neurotransmission. In the present study, focusing on temporal lobe epilepsy, we found that IGF-1 levels and IGF-1 receptor activation are increased in human epileptogenic tissues, and pilocarpine- and pentylenetetrazole-treated rat models. Using an acute model of seizures, we showed that lateral cerebroventricular infusion of IGF-1 elevates IGF-1 receptor (IGF-1R) signalling before pilocarpine application had proconvulsant effects. In vivo electroencephalogram recordings and power spectrogram analysis of local field potential revealed that IGF-1 promotes epileptiform activities. This effect is diminished by co-application of an IGF-1R inhibitor. In an in vitro electrophysiological study, we demonstrated that IGF-1 enhancement of excitatory neurotransmission and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor- and N-methyl-D-aspartate receptor-mediated currents is inhibited by IGF-1R inhibitor. Finally, activation of extracellular signal-related kinase (ERK)-1/2 and protein kinase B (Akt) in seizures in rats is increased by exogenous IGF-1 and diminished by picropodophyllin. A behavioural study reveals that the ERK1/2 or Akt inhibitor attenuates seizure activity. These results indicate that increased IGF-1 levels after recurrent hippocampal neuronal firings might, in turn, promote seizure activity via IGF-1R-dependent mechanisms. The present study presents a previously unappreciated role of IGF-1R in the development of seizure activity.

Altered expression of hypoxia-Inducible factor-1α participates in the epileptogenesis in animal models.

Although epilepsy is a common neurological disorder, its mechanism(s) are still not completely understood. Hypoxia can lead to neuronal cell death and angiogenesis, and the same mechanisms were also found in epilepsy. Hypoxia-inducible factor-1α (HIF-1α) is an important transcription protein that regulates gene expression in the brain and other tissues in response to decreases in oxygen availability. However, little is known regarding the expression of HIF-1α in the epileptic brain and whether HIF-1α interventions affect the epileptic process. The aims of this study are to investigate the expression profile of HIF-1α in rat models and to explore the role of HIF-1α in epilepsy. We performed Western blots and immunofluorescence in a lithium-pilocarpine rat epilepsy model. To determine the role of HIF-1α in epilepsy, we used the HIF-1α agonist DMOG and inhibitor KC7F2 to detect changes in the animal behavior in pentylenetetrazole (PTZ) and lithium-pilocarpine epilepsy models. The expression of HIF-1α was significantly increased after pilocarpine-induced status epilepticus. DMOG significantly prolonged the latent period in the PTZ kindling model and decreased the rate of spontaneous recurrent seizures during the chronic stage in the lithium-pilocarpine model. Conversely, the inhibitor KC7F2 produced an opposite behavioral change. Interestingly, both KC7F2 and DMOG had no effect on the acute stage of pilocarpine model and PTZ convulsive model. Our study suggests that upregulated HIF-1α may be involved in the process of epileptogenesis but not in the acute stage of epilepsy. The modulation of HIF-1α may offer a novel therapeutic target in epilepsy.

Melatonin as an add-on treatment for epilepsy: A systematic review and meta-analysis.

PURPOSE: Epilepsy, one severe prevalent brain disorder, primarily relies on drug treatment. However, approximately one-third of patients with epilepsy do not achieve effective control with current medications, underscoring the need for more innovative treatment approaches. Notably, melatonin has gained attention for its anti-seizure properties and favourable safety profile. This systematic review aimed to evaluate the efficacy and safety of melatonin as an add-on treatment for epilepsy. METHODS: We searched for articles published before June 2023 in Web of Science, Cochrane Library, and PubMed. We used RevMan 5.4 software to compute relative risks (RRs) and 95 % confidence intervals (CIs). Key outcomes included total sleep time, wakefulness after sleep onset, sleep latency, seizure frequency, seizure severity, and safety. The quality of randomised controlled studies (RCTs) was assessed using the Cochrane Risk of Bias tool. RESULTS: Of the 264 publications retrieved, 10 RCTs were included in the meta-analysis. Add-on melatonin treatment improved sleep latency (RR: 0.56; 95 %CI: 0.10-1.02; P = 0.02) and seizure severity (RR: 0.33; 95 %CI: 0.04-0.62; P = 0.03) compared with placebo treatment. Adverse events (increased headache severity in children with a history of migraines, bronchitis, ear infections, agitation, and urinary frequency) were reported in only one trial. CONCLUSION: This systematic review found that add-on melatonin therapy improved sleep latency and seizure severity in patients with epilepsy. However, several of the included studies did not systematically assess sleep quality, seizures, and safety and lacked long-term follow-up data. Further RCTs with extended follow-up periods are required to definitively determine the efficacy and safety of melatonin.

Bioinformatics analysis of the potential receptor and therapeutic drugs for Alzheimer's disease with comorbid Parkinson's disease.

Background: Now, there are no sensitive biomarkers for improving Alzheimer's disease (AD) and comorbid Parkinson's disease (PD). The aim of the present study was to analyze differentially expressed genes (DEGs) in brain tissue from AD and PD patients via bioinformatics analysis, as well as to explore precise diagnostic and therapeutic targets for AD and comorbid PD. Methods: GFE122063 and GSE7621 data sets from GEO in NCBI, were used to screen differentially expressed genes (DEGs) for AD and PD, and identify the intersected genes, respectively. Intersected genes were analyzed by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, STRING site and Cytoscape were used to construct a protein-protein interaction (PPI) network, CytoNCA algorithm to analyze and evaluate centrality, Mcode plug-in to analyze module, and Cytohubba to screen key genes. Combined GO-KEGG enrichment analysis with Cytoscape algorithm to screen the key gene in AD complicated with PD. Then, the DEGs for AD and PD were imported into the Association Map (CMap) online platform to screen out the top 10 small molecule drugs, and using molecular docking techniques to evaluate the interactions between small molecule drugs and key genes receptors. Results: In total, 231 upregulated genes and 300 downregulated genes were identified. GO analysis revealed that the DEGs were highly enriched in signal transduction, and KEGG analysis revealed that the DEGs were associated with the MAPK and PI3K-Akt signaling pathways. Epidermal growth factor receptor (EGFR) was identified as a potential receptor gene in AD and comorbid PD. EGFR was upregulated in both AD and PD, and the proteins that interact with EGFR were enriched in the Ras/Raf/MAPK and PI3K/Akt signaling pathways. Semagacestat was identified as a drug with therapeutic potential for treating AD complicated with PD. There was a high binding affinity between semagacestat and EGFRNTD, with seven hydrogen bonds and one hydrophobic bond. Discussion: Semagacestat may improve the health of patients with AD complicated with PD through the regulation of the Ras/Raf/MAPK and PI3K/Akt signaling pathways by EGFR, providing evidence supporting the structural modification of semagacestat to develop a more effective drug for treating AD complicated with PD.

Human gestational diabetes mellitus-derived exosomes impair glucose homeostasis in pregnant mice and stimulate functional maturation of offspring-islets.

AIMS: Pancreatic islets undergo critical development and functional maturation during the perinatal period when they are highly sensitive to microenvironment. We aim to determine the effects and mechanisms of gestational diabetes mellitus (GDM) hypermetabolic stress on glucose homeostasis in pregnant mice and functional maturation of the islets of their offspring. MAIN METHODS: Exosomes were extracted from the umbilical vein blood of individuals with or without GDM for administration to pregnant mice. The blood glucose, serum insulin, glycosylated hemoglobin, and lipopolysaccharide levels were measured in pregnant mice. The expression and localization of insulin, glucagon, PC1/3, PDX1, and p-S6 in the islets of neonatal rats were continuously monitored using immunofluorescence to evaluate their functional status. Primary islet cells were cultured and treated with GDM exosomes and exendin to determine the expression of GLP-1R, AKT, p-AKT, and p-S6 via western blotting. KEY FINDINGS: GDM exosomes induced remarkable oral glucose intolerance, hyperinsulinemia, and metabolic inflammation in pregnant mice. The islets of GDM offspring exhibited high insulin, glucagon, PC1/3, PDX1, and p-S6 expression at and after birth, and activation of the local GLP-1/GLP-1R axis. The functional maturation of normal-offspring islets did not commence until after birth, while it was activated prior to birth in GDM offspring, seriously disrupting the whole process. GDM exosomes activated the GLP-1/GLP-1R axis between α and ß cells, and stimulated functional maturation of ß cells via the Akt-mTORC1-pS6 pathway. SIGNIFICANCE: These findings provide preliminary insights into the mechanisms underlying the high incidence of diabetes in the offspring of mothers with GDM.