The prenatal use of agmatine prevents social behavior deficits in VPA-exposed mice by activating the ERK/CREB/BDNF signaling pathway.

BACKGROUND: According to reports, prenatal exposure to valproic acid can induce autism spectrum disorder (ASD)-like symptoms in both humans and rodents. However, the exact cause and therapeutic method of ASD is not fully understood. Agmatine (AGM) is known for its neuroprotective effects, and this study aims to explore whether giving agmatine hydrochloride before birth can prevent autism-like behaviors in mouse offspring exposed prenatally to valproic acid. METHODS: In this study, we investigated the effects of AGM prenatally on valproate (VPA)-exposed mice. We established a mouse model of ASD by prenatally administering VPA. From birth to weaning, we evaluated mouse behavior using the marble burying test, open-field test, and three-chamber social interaction test on male offspring. RESULTS: The results showed prenatal use of AGM relieved anxiety and hyperactivity behaviors as well as ameliorated sociability of VPA-exposed mice in the marble burying test, open-field test, and three-chamber social interaction test, and this protective effect might be attributed to the activation of the ERK/CREB/BDNF signaling pathway. CONCLUSION: Therefore, AGM can effectively reduce the likelihood of offspring developing autism to a certain extent when exposed to VPA during pregnancy, serving as a potential therapeutic drug.

Identification of ferroptosis-related genes in acute phase of temporal lobe epilepsy based on bioinformatic analysis.

BACKGROUND: Epilepsy is a prevalent neurological disorder, and while its precise mechanism remains elusive, a connection to ferroptosis has been established. This study investigates the potential clinical diagnostic significance of ferroptosis-related genes (FRGs) during the acute phase of temporal lobe epilepsy. METHODS: To identify differentially expressed genes (DEGs), we accessed data from the GEO database and performed an intersection analysis with the FerrDB database to pinpoint FRGs. A protein-protein interaction (PPI) network was constructed. To assess the diagnostic utility of the discovered feature genes for the disease, ROC curve analysis was conducted. Subsequently, qRT-PCR was employed to validate the expression levels of these feature genes. RESULTS: This study identified a total of 25 FRGs. PPI network analysis revealed six feature genes: IL6, PTGS2, HMOX1, NFE2L2, TLR4, and JUN. ROC curve analysis demonstrated that the combination of these six feature genes exhibited the highest diagnostic potential. qRT-PCR validation confirmed the expression of these feature genes. CONCLUSION: We have identified six feature genes (IL6, PTGS2, HMOX1, NFE2L2, TLR4, and JUN) strongly associated with ferroptosis in epilepsy, suggesting their potential as biomarkers for the diagnosis of temporal lobe epilepsy.

Exploring the Causality Between Plasma Brain-Derived Neurotrophic Factor and Neurological Diseases: A Mendelian Randomization Study.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a protein synthesized in the brain and widely expressed in the nervous system. Previous studies have demonstrated a controversial role of BDNF in neurological diseases. OBJECTIVE: In this study, we aimed to assess the association between BDNF levels and the risk of neurological diseases by Mendelian randomization analysis. METHODS: From a genome-wide association analysis of plasma proteins comprising 3,301 European participants, we isolated 25 genetic variations as instrumental variables for BDNF levels. Summary statistics data on six common neurological diseases as outcome variables. Two-sample Mendelian randomization (MR) analysis was used to assess whether plasma BDNF is causally related to neurological diseases. We also performed sensitivity analysis to ensure the robustness of the results and reverse MR to exclude potential reverse causality. RESULTS: We confirmed the significant causal relationship between BDNF levels and the risk of Alzheimer's disease (AD) (OR, 0.92; 95% CI, 0.85, 0.98; p = 0.013). Other methods have also shown similar results. We infer that BDNF also reduces the risk of epilepsy (OR, 0.94; 95% CI, 0.90, 0.98; p = 0.004). In reverse MR analysis, we also found that AD can affect the level of BDNF. CONCLUSIONS: Our study suggests higher plasma BDNF was associated with the reduced risk of AD. Moreover, higher plasma BDNF is a protective factor on AD and focal epilepsy. The results provide credence to the idea that BDNF may play a significant role in the development of focal epilepsy and AD.

Fibroblast growth factor 10 ameliorates neurodegeneration in mouse and cellular models of Alzheimer's disease via reducing tau hyperphosphorylation and neuronal apoptosis.

Alzheimer's disease (AD) is characterized with senile plaques formed by Aß deposition, and neurofibrillary tangles composed of hyperphosphorylated tau protein, which ultimately lead to cognitive impairment. Despite the heavy economic and life burdens faced by the patients with AD, effective treatments are still lacking. Previous studies have reported the neuroprotective effects of FGF10 in CNS diseases, but its role in AD remains unclear. In this study, we demonstrated that FGF10 levels were reduced in the serum of AD patients, as well as in the brains of 3xTg-AD mice and APPswe-transfected HT22 cells, suggesting a close relationship between FGF10 and AD. Further investigations revealed that intranasal delivery of FGF10 improved cognitive functions in 3xTg-AD mice. Additionally, FGF10 treatment reduced tau hyperphosphorylation and neuronal apoptosis, thereby mitigating neuronal cell damage and synaptic deficits in the cortex and hippocampus of 3xTg-AD mice, as well as APPswe-transfected HT22 cells. Furthermore, we evaluated the therapeutic potential of FGF10 gene delivery for treating AD symptoms and pathologies. Tail vein delivery of the FGF10 gene using AAV9 improved cognitive and neuronal functions in 3xTg-AD mice. Similarly, endogenous FGF10 overexpression ameliorated tau hyperphosphorylation and neuronal apoptosis in the cortex and hippocampus of 3xTg-AD mice. Importantly, we confirmed that the FGFR2/PI3K/AKT signaling pathway was activated following intranasal FGF10 delivery and AAV9-mediated FGF10 gene delivery in 3xTg-AD mice and APPswe-transfected HT22 cells. Knockdown of FGFR2 attenuated the protective effect of FGF10. Collectively, these findings suggest that intranasal delivery of FGF10 and AAV9-mediated FGF10 gene delivery could be a promising disease-modifying therapy for AD.

11ß-HSD1 participates in epileptogenesis and the associated cognitive impairment by inhibiting apoptosis in mice.

BACKGROUND: Glucocorticoid signalling is closely related to both epilepsy and associated cognitive impairment, possibly through mechanisms involving neuronal apoptosis. As a critical enzyme for glucocorticoid action, the role of 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) in epileptogenesis and associated cognitive impairment has not previously been studied. METHODS: We first investigated the expression of 11ß-HSD1 in the pentylenetetrazole (PTZ) kindling mouse model of epilepsy. We then observed the effect of overexpressing 11ß-HSD1 on the excitability of primary cultured neurons in vitro using whole-cell patch clamp recordings. Further, we assessed the effects of adeno-associated virus (AAV)-induced hippocampal 11ß-HSD1 knockdown in the PTZ model, conducting behavioural observations of seizures, assessment of spatial learning and memory using the Morris water maze, and biochemical and histopathological analyses. RESULTS: We found that 11ß-HSD1 was primarily expressed in neurons but not astrocytes, and its expression was significantly (p < 0.05) increased in the hippocampus of PTZ epilepsy mice compared to sham controls. Whole-cell patch clamp recordings showed that overexpression of 11ß-HSD1 significantly decreased the threshold voltage while increasing the frequency of action potential firing in cultured hippocampal neurons. Hippocampal knockdown of 11ß-HSD1 significantly reduced the severity score of PTZ seizures and increased the latent period required to reach the fully kindled state compared to control knockdown. Knockdown of 11ß-HSD1 also significantly mitigated the impairment of spatial learning and memory, attenuated hippocampal neuronal damage and increased the ratio of Bcl-2/Bax, while decreasing the expression of cleaved caspase-3. CONCLUSIONS: 11ß-HSD1 participates in the pathogenesis of both epilepsy and the associated cognitive impairment by elevating neuronal excitability and contributing to apoptosis and subsequent hippocampal neuronal damage. Inhibition of 11ß-HSD1, therefore, represents a promising strategy to treat epilepsy and cognitive comorbidity.

Effect of Exercise Prescription Implementation Rate on Cardiovascular Events.

BACKGROUND: Exercise prescription of cardiac rehabilitation (CR) is vital in patients with cardiovascular diseases (CVDs) and those carrying high risk for CVDs. However, the relation between the implementation rate of exercise prescription and cardiovascular events (CVEs) is unclear. DESIGN AND METHODS: In this retrospective study, using the administration data from the Rehabilitation Center in a hospital, patients aged ≥18 years with CVDs were consecutively enrolled from November 2018 to May 2021. Patients were divided into the high execution group (HEG) and low execution group (LEG) depending on whether they completed more than half the time of the exercise prescriptions. Baseline characteristics, ultrasonic cardiogram, cardiopulmonary exercise test, follow-up data, and CVEs were collected. RESULTS: The mean age of the 197 CR patients was 61.8 ± 13.7 years and the mean follow-up duration was 10.9 ± 4.2 months. Among them, 15 patients suffered CVEs: 4 in the HEG and 11 in the LEG. The incidence of CVEs showed significant differences between HEG and LEG (chi-square test). Free-event survival analysis using Kaplan-Meier survival plots showed that patients in LEG had poor survival. Cox proportional hazards regression analysis revealed that the prescription implementation rate was an independent predictor of CVEs. CONCLUSIONS: Our study suggested a significant effect of exercise prescription execution rate on the occurrence of CVEs. Further, the HEG of exercise prescription was associated with lower CVDs.

Electroacupuncture stimulation at CV4 prevents ovariectomy-induced osteoporosis in rats via Wnt-ß-catenin signaling.

The present study aimed to investigate the effect of electroacupuncture stimulation at CV4 (also termed Guanyuan) on femoral osteocalcin also termed bone gla protein (BGP), alkaline phosphatase (ALP), bone mineral density (BMD) and biomechanics, as well as the Wnt­ß­catenin signaling pathway in rats with postmenopausal osteoporosis. Female Sprague­Dawley rats (4.5­months old) were randomly divided into sham, Ovx, CV4 and mock groups (n=10/group). With the exception of those in the sham group, the rats were ovariectomized to induce postmenopausal osteoporosis. The rats in the CV4 and mock groups were given electroacupuncture at CV4 and non­acupoint, respectively. The rats in the Ovx model and sham groups underwent identical fixing procedures, but did not undergo electroacupuncture. Following treatment, hematoxylin and eosin staining was used to observe morphological changes in the left femoral trabecular bone, and a three­point­bending test was used to analyze femur biomechanics and determine the BMD. In addition, an enzyme­linked immunosorbent assay was used to measure the serum levels of ALP/BGP and reverse transcription­quantitative polymerase chain reaction was used detect the expression levels of Wnt3a, ß­catenin and Runx2. In the present study, it was demonstrated that electroacupuncture at CV4 significantly improved the osteoporotic morphological changes that occurred in the ovariectomized rats, increased serum ALP and BGP levels, enhanced the maximum and fracture loads, increased BMD (P<0.01), and activated the Wnt­ß­catenin signaling pathway. These findings demonstrated that electroacupuncture stimulation at CV4 affected bone formation and promoted bone metabolism in rats with postmenopausal osteoporosis, possibly by activating the Wnt­ß­catenin signaling pathway.

[Effects of electroacupuncture stimulation at "Guanyuan" (CV 4) on serum insulin-like growth factor-1 content and bone biomechanics in ovariectomy-induced osteoporosis rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on serum insulin-like growth factor-1 (IGF-1) content and bone biomechanics in osteoporosis rats so as to explore its mechanism underlying improvement of postmenopausal osteoporosis (PMOP). METHODS: Forty female SD rats (4.5 months old) were randomly divided into sham-operation (sham), model, medication and EA groups (10 rats/group). The rat's bilateral ovaries were removed to establish the PMOP model. For rats in the sham group, similar procedures were conducted except removing comparable weight of fat tissues around the ovaries. For rats in the EA group, "Guanyuan" (CV 4) was punctured with filiform needles and stimulated electrically (1 mA, 2 Hz) for 20 min, once a day for 30 days. For rats in the medication group, pentanoic acid estradiol (50 microg/500 g) was administrated by gavage. The serum IGF-1 content was examined by ELISA and the bone biomechanics measured by three-point bending tests, respectively. RESULTS: Compared with the sham group, the serum IGF-1 level, femoral maximum load and fracture load were significantly reduced in the model group (P < 0.05, P < 0.01). In comparison with the model group, these indexes were significantly increased in rats of the EA and medication groups (P < 0.05, P < 0.01), but without significant difference between the EA and medication groups (P > 0.05). CONCLUSION: EA produces benefits on postmenopausal osteoporosis through increasing the serum IGF-1 contents and bone strength.

[Effect of electroacupuncture of "Mingmen" (GV 4) on bone morphogenetic protein-2 expression in osteoporosis rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Mingmen" (GV 4) on the bone morphogenetic protein-2 (BMP-2) content and biomechanics in osteoporosis rats so as to explore its mechanism underlying improvement of osteoporosis. METHODS: Fifty female SD rats were randomized into sham operation (sham), model, EA-GV 4, EA-non-acupoint (non-acupoint) and estrogen (medication) groups, with 10 rats in each group. Postmenopausal osteoporosis model was established by removing the rats' bilateral ovaries under anesthesia. EA (2 Hz/15 Hz, 1.0 mA) was applied to "Mingmen" (GV 4) or non-acupoint for 20 min, once daily for 30 times, with one day's interval between every two 10 times. Rats of the medication group were lavaged with Pentanoic Acid Estradiol (25 microg/mL, 2 mL/500 g), once every day (the dosage of estradiol was adjusted according to their body weight) continuously for 1 month. Rats of the model and sham groups experienced the fixing and fastening procedures as the other rats in the EA and medication groups. After intervention, the BMP-2 expression level of the femoral bone tissue, and bone biomechanical values were determined by immunohistochemistry and three-point bending tests, respectively. RESULTS: (1) In comparison with the sham operation group, the femoral biochemical maximum load and fracture load values were significantly decreased in the model group (P < 0.05). While compared with the model group, the biochemical maximum load and fracture load values were obviously increased in the EA-GV 4 and medication groups (P < 0.05), but not in the non-acupoint group (P > 0.05). (2) Compared with the sham group, the femoral BMP-2 expression of model group was significantly decreased (P < 0.05), compared with the model group, the expression of BMP-2 of GV 4 and medication groups significantly increased (P < 0.05). CONCLUSION: EA-GV 4 intervention can improve bone biomechanical changes in osteoporosis rats.

[Discussion on method for locating acupoint "Mingmen" (GV 4) in adult rats].

"Mingmen" (GV 4) is one of the most frequently used acupoints in acupuncture clinic. In recent years, more and more experimental researches have been focusing on GV 4 or acupoint recipe containing GV 4 in rats. Accurate location of GV 4 is probably not only related to fully display its therapeutic effect, but also to help study its underlying mechanisms. However, there has been no unified standard about the accurate location of GV 4 in the adult rat at present. In the present paper, the authors review related literature about GV 4 location in experimental studies in recent 10 years, and put forward a practical method for locating GV 4 in the rat by combining their own experience. That is, GV 4 is taken according to the relative relationship of ilium and spinous process of the lumbar vertebra. In addition, the authors also recommend some matters needing attention in locating GV 4 in rats.

Rainwater utilization and storm pollution control based on urban runoff characterization.

The characteristics of urban runoffs and their impact on rainwater utilization and storm pollution control were investigated in three different functional areas of Zhengzhou City, China. The results showed that in the same rain event the pollutant loads (chemical oxygen demand (COD) and total suspended solids (TSS)) in the sampling areas were in the order of industrial area > commercial area > residential area, and within the same area the COD and TSS concentrations of road runoffs were higher than those of roof runoffs. The first flush effects in roof and road runoffs were observed, hence the initial rainwater should be treated separately to reduce rainwater utilization cost and control storm pollution. The initial roof rainfall of 2 mm in residential area, 5 mm in commercial area and 10 mm in industrial area, and the initial road rainfall of 4 mm in residential area and all the road rainfall in commercial and industrial areas should be collected and treated accordingly before direct discharge or utilization. Based on the strong correlation between COD and TSS (R2, 0.87-0.95) and the low biodegradation capacity (biochemical oxygen demand BOD5/COD < 0.3), a sedimentation process and an effective filtration system composed of soil and slag were designed to treat the initial rainwater, which could remove over 90% of the pollutant loads. The above results may help to develop better rainwater utilization and pollution control strategies for cities with water shortages.

Microbial biodegradation of microcystin-RR by bacterium Sphingopyxis sp. USTB-05.

A strain, USTB-05, isolated from Lake Dianchi, China, degraded the cyanobacterial toxin microcystin-RR (MC-RR) at the rate of 16.7 mg/L per day. Analysis of 16S rDNA sequence showed that the strain was Sphingopyxis sp. Enzymatic degradation pathways for MC-RR by Sphingopyxis sp. USTB-05 were identified. Adda-Arg peptide bond of MC-RR was cleaved and then a hydrogen and a hydroxyl were combined onto the NH2 group of Adda and the carboxyl group of arginine to form a linear molecule as intermediate product within the first few hours. Then, through dehydration reaction, two hydrogen of amino group on arginine reacted with adjacent hydroxyl on carbon to form a linear MC-RR with two small peptide rings as the final product after 24 hr. These biodegradation pathways were different from those reported for other strains, implying that MC-RR may undergo different transformations and different products were formed due to various bacteria in natural lakes and reservoirs.