Acoustic damage is a common cause of hearing loss, and excessive oxidative stress has been identified as a key pathology in noise-induced hearing loss (NIHL). Despite its widespread occurrence, there are currently no effective therapeutic drugs available for the treatment of NIHL. Therefore, antioxidant therapy is widely used for the treatment of NIHL. Compound Danshen Dripping Pills (CDDP) is a traditional medicine with antioxidant, anti-inflammatory and microcirculatory improvement properties. However, it remains unknown whether CDDP has a hearing-protective function. In this study, we demonstrated that CDDP has the ability to cross the blood-lymphatic circulation barrier to the inner ear and is effective in improving ABR thresholds in a noise-exposed mouse model. Additionally, RNA-seq and immunofluorescence analysis revealed that CDDP exerts its protective effects by modulating the respiratory chain and reducing levels of 4-HNE, a marker of oxidative stress, thereby highlighting its antioxidant mechanism. In conclusion, CDDP shows promise as a therapeutic agent for protecting against NIHL, with potential for development into a clinically viable treatment for human patients.

BackgroundAlzheimer's disease (AD) is commonly treated with memantine alone or in combination with cholinesterase inhibitors (ChEIs) or second-generation antipsychotics (SGAs), but the safety of these combinations remains unclear.ObjectiveTo characterize FDA Adverse Event Reporting System (FAERS)-based signals of disproportionate reporting associated with memantine-based combination therapies in patients with AD.MethodsA disproportionality analysis was conducted using data from FAERS from 2014Q1 to 2025Q2 via the MY FAERS platform. Reporting odds ratios (RORs) with 95% confidence intervals (CI) were calculated to identify safety signals. Sensitivity analyses were conducted using ChEIs or SGAs monotherapy as reference groups to assess the robustness.Results2531 patients prescribed memantine were identified, comprising memantine monotherapy (n = 1965), memantine-ChEIs combination (n = 482), and memantine-SGAs combination (n = 84). Compared to memantine monotherapy, the memantine- ChEIs combination showed disproportionate reporting signals for skin (ROR, 3.46; 95% CI, 2.05-5.85), gastrointestinal (ROR, 2.53; 95% CI, 1.92-3.33), musculoskeletal (ROR, 2.13; 95% CI, 1.29-3.50), psychiatric (ROR, 1.60; 95% CI, 1.27-2.00), general (ROR, 1.53; 95% CI, 1.18-1.97), and nervous system disorders (ROR, 1.48; 95% CI, 1.19-1.84). The memantine-SGAs combination was strongly associated with the signals of general (ROR, 3.97; 95% CI, 1.74-9.05), psychiatric (ROR, 2.14; 95% CI, 1.32-3.49), nervous system disorders (ROR, 2.03; 95% CI, 1.20-3.43), and hip fracture (ROR, 15.84; 95% CI, 3.72-67.41). Sensitivity analyses confirmed robustness across subgroups.ConclusionsMemantine-based combination therapies were associated with distinct safety signals of disproportionate reporting compared with monotherapies. These findings should be interpreted as pharmacovigilance signals that warrant cautious interpretation and further validation in well-designed observational or prospective studies.

BackgroundAlzheimer-associated neuronal thread protein (AD7c-NTP) has emerged as a potential diagnostic biomarker for Alzheimer's disease (AD) and mild cognitive impairment (MCI). Growing research indicates neuroinflammatory mechanisms contribute to AD pathogenesis.ObjectiveTo investigate the relationship between AD7c-NTP level and inflammatory biomarkers.MethodsThis cross-sectional study enrolled 112 participants comprising 72 cognitively impaired individuals (CI group) and 40 demographically matched controls with cognitively normal (CN group). Comprehensive physical evaluations and standardized neuropsychological assessments were administered. Urinary AD7c-NTP concentrations were quantified through enzyme-linked immunosorbent assay (ELISA), while plasma levels of twelve inflammatory markers-IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, TNF-α, IFN-α, and IFN-γ-were analyzed via flow cytometry-based immunofluorescence techniques.ResultsConcentrations of IL-2, IFN-α, and IFN-γ showed marked elevation in CI patients relative to CN controls (p = 0.005, 0.008, and 0.010, respectively). Strong positive associations emerged between AD7c-NTP concentrations and both IL-2 (r = 0.492, p < 0.001) and IFN-α (r = 0.492, p < 0.001). The four-marker panel (AD7c-NTP combined with IL-2, IFN-α, and IFN-γ) achieved optimal diagnostic accuracy for cognitive impairment, yielding an AUC value of 0.9774 with 94% sensitivity and 75% specificity.ConclusionsIntegrating IL-2, IFN-α, and IFN-γ measurements with AD7c-NTP detection could constitute a superior diagnostic framework for early-stage cognitive decline. The observed correlations between AD7c-NTP and these cytokine profiles may indicate previously unrecognized metabolic pathways relevant to AD pathology.

INTRODUCTION:To establish and verify reference intervals (RIs) for Alzheimer's disease (AD) plasma biomarkers amyloid beta (Aβ) 40, Aβ42, phosphorylated tau 181 (p-tau181), p-tau217, and total tau (t-tau) after defining optimal pre-analytical procedures. METHODS:Pre-analytical procedures were assessed, including storage of whole blood and plasma under different conditions and freeze-thaw times. RIs were established using 738 samples, with grouping by sex and age (≤ 44, 45 to 59, ≥60 years), and verified with 120 samples from four clinical centers. RESULTS:Samples stored at 2°C to 8°C for 22 to 28 h or -20°C to -80°C for 30 days were stable. Though sex/age differences in biomarker levels existed, they did not require partitioning. RIs of Aβ40, Aβ42, p-tau181, p-tau217, and t-tau were 12.71 to 283.6, 2.313 to 25.96, 0.8342 to 18.36, 0.3351 to 4.310, and 0.8096 to 18.65 pg/mL, respectively. The verification rates of RIs with the multicenter cohort (n = 120) were 93.33% to 99.14%. DISCUSSION:The established RIs for Chinese adults can potentially facilitate the early diagnosis of AD. Highlights:Optimized pre-analytical procedures: Plasma levels of Aβ40, Aβ42, p-tau181, p-tau217, and t-tau are unstable at room temperature (25 ± 3°C) but remain stable for 22 to 28 h at 2°C to 8°C (fluctuation ≤10%). For long-term storage, -20°C to -80°C is suitable, with stability maintained for 30 days; ≤5 freeze-thaw cycles have minimal impact on biomarker levels.Established reference intervals (RIs) for healthy Chinese adults: Using non-parametric 2.5th to 97.5th percentiles, RIs were determined as follows: Aβ40 (12.71 to 283.6 pg/mL), Aβ42 (2.313 to 25.96 pg/mL), p-tau181 (0.8342 to 18.36 pg/mL), p-tau217 (0.3351 to 4.310 pg/mL), and t-tau (0.8096 to 18.65 pg/mL).Validated multicenter applicability: Verification with 120 samples from four clinical centers showed that 93.33% to 99.14% of samples fell within the established RIs, confirming broad applicability.No need for stratification by sex or age: Despite significant differences in some biomarkers between sexes (e.g., higher p-tau181/217 in males) and age groups (e.g., age-related increase in Aβ40), Harris-Boyd tests indicated no requirement for stratification, supporting combined RIs.Clinical value: These RIs and pre-analytical guidelines facilitate standardized early diagnosis, risk assessment, and therapeutic monitoring of AD in the Chinese population.

Vascular cognitive impairment (VCI) is a syndrome characterized by cognitive decline resulting from insufficient perfusion to the entire brain or specific brain regions. The lack of a clear understanding of the mechanisms linking cerebrovascular disease to cognitive impairment has impeded the development of targeted treatments for VCI. Increasing evidence indicates that exercise may offer significant benefits for patients with VCI. This study explores how neuroinflammatory mechanisms mediate the effects of exercise on VCI, focusing on the broader biological processes involved. Exercise plays a crucial role in mitigating vascular risk factors, reducing oxidative stress, and promoting neurogenesis. Furthermore, exercise influences neuroinflammatory mediators and central immune cells via various signaling pathways. Different types and intensities of exercise, including resistance and endurance training, have been shown to differentially modulate neuroinflammation during the progression of VCI. This paper summarizes the current mechanisms of action and proposes exercise interventions targeting neuroinflammatory pathways, along with biomarker studies, to enhance our understanding of VCI pathogenesis and inform clinical practice. A more in-depth understanding of the inflammatory mechanisms underlying VCI may facilitate the development of targeted therapeutic interventions.

Background:Urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) is a biomarker for the early diagnosis of Alzheimer's disease (AD). It remains unclear whether hepatorenal function affects the urinary AD7c-NTP level. Objective:To evaluate the effects of hepatorenal function on urinary AD7c-NTP level. Methods:We enrolled 453 participants aged 60-100 years. An automated chemistry analyzer was used to determine the indicators of serum hepatorenal function. Enzyme-linked immunosorbent assay was used to measure the urinary AD7c-NTP level. Results:Spearman's correlation analysis showed a negative correlation between urinary AD7c-NTP levels and indicators of hepatorenal function, including albumin (r = -0.181, p < 0.001), albumin/globulin ratio (r = -0.224, p < 0.001), cholinesterase (r = -0.094, p = 0.046), total carbon dioxide (r = -0.102, p = 0.030), and glomerular filtration rate (r = -0.260, p < 0.001), as well as a positive correlation with globulin (r = 0.141, p = 0.003), aspartate transaminase (r = 0.186, p < 0.001), blood urine nitrogen (r = 0.210, p < 0.001), creatinine (r = 0.202, p < 0.001), uric acid (r = 0.229, p < 0.001), and cystatin C (r = 0.265, p < 0.001). The least absolute shrinkage and selection operator (LASSO) regression analysis and multiple linear regression model analyses showed that the statistically significant hepatorenal indicators for predicting AD7c-NTP were A/G (p = 0.007), AST (p = 0.002), BUN (p = 0.019), and UA (p = 0.003). Conclusions:The effects of hepatorenal indicators should be considered when using urinary AD7c-NTP levels in clinical settings.

Vascular cognitive impairment and dementia (VCID), resulting from chronic cerebral hypoperfusion, represent the second most prevalent form of dementia globally. Aerobic exercise is widely acknowledged as an effective intervention for various cognitive disorders. This study utilized a bilateral common carotid artery stenosis (BCAS) model to investigate whether aerobic exercise promotes cognitive recovery through the Annexin-A1 (ANXA1)/mitogen-activated protein kinase (MAPK) axis in BCAS mice. Our findings demonstrate that aerobic exercise improved spatial memory in BCAS mice by enhancing white matter (WM) integrity and hippocampal function. WM integrity was confirmed through Luxol Fast Blue (LFB) staining and protein assays. Additionally, aerobic exercise mitigated BCAS-induced long-term potentiation (LTP) decay and upregulated hippocampal expression of key synaptic proteins, including N-methyl-D-aspartate receptor subunits NR2B and NR1, vesicular glutamate transporter 1 (vGluT1), and the synaptic scaffolding protein postsynaptic density protein 95 (PSD95). Furthermore, aerobic exercise enhanced the expression of the antiinflammatory mediator ANXA1 through exosome secretion while simultaneously suppressing the MAPK signaling pathway. These molecular changes were associated with increased astrocyte proliferation and the polarization of astrocytes toward the A2 phenotype. These findings were further validated using an in vitro coculture model of astrocytes (U251) and neurons (HT22). In summary, our study demonstrates that aerobic exercise improves WM integrity and hippocampal function by modulating the ANXA1/MAPK axis following astrocyte polarization. Thus, aerobic exercise emerges as a promising intervention for promoting functional recovery in VCID.

The difficulty of increasing the Curie temperature TC of magnetic semiconductors such as (Ga,Mn)As above the room temperature is related to the p-type doping bottleneck in this system, which has hindered the further development of dilute magnetic semiconductors. To overcome the p-type doping bottleneck, we investigate the doping properties of Mn in GaAs with hybrid functional calculations and propose strategies that can improve the p-type dopability in (Ga,Mn)As. We find that tensile strain and high temperature quenching are effective approaches to enhance p-type doping in epitaxial (Ga,Mn)As. The tensile strain applied, e.g., by the substrate with a larger lattice constant can decrease the formation energy of the substitutional dopant MnGa−, which is an acceptor with large size, and increase that of interstitial Mni2+, which is a small size compensating donor, thus improving the p-type dopability. The high temperature quenching also can achieve higher hole density by limiting the formation of compensating interstitial Mn. We suggest that the combination of these two schemes would effectively enhance the p-type dopability and further raise the Curie temperature TC of (Ga,Mn)As.

Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a candidate biomarker of Alzheimer's disease (AD). First, we confirmed through methodological research that AD7c-NTP can be tested using random urine instead of the first morning urine. If the specimen cannot be tested in time, boric acid appears to be an acceptable preservative with storage at 4°C, freezing is not recommended.

Methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor and plays an important role in neuronal degradation of Alzheimer’s disease (AD). According to molecular modeling docking studies, we have designed the compound Arg-Glu-Arg-Met-Ser-(3,5)-dimethyladamantan-1-amine (RERMS-MEM), consisting of an AβPP 5-mer peptide (RERMS) and memantine (MEM). This compound could dock into the active sites of N-methyl-D-aspartate receptor type 2B (NMDAR2B) with a −64.14 kcal/mol CDOCKER interaction energy. The stability of RERMS-MEM was evaluated through a 50 ns molecular dynamics simulation. The results revealed that the docked ligand-receptor complex was stable. Furthermore, surface plasmon resonance (SPR) revealed that the RERMS-MEM binding affinity to the NMDAR2B fragment exhibited over 15-fold enhancement compared to MEM. The SH-SY5Y cell assays showed that RERMS-MEM or RERMS at concentrations of 0.1, 1, 10, or 50 μM could enhance the metabolic rate, and MEM showed no difference compared to the control and indicated cytotoxic effects at 50 μM. RERMS-MEM at concentrations of 0.01, 0.1, 1, 10, or 50 μM increased the number of viable cells and reduced the release of lactate dehydrogenase (LDH). RERMS at concentrations of 10 or 50 μM was similar to RERMS-MEM for increasing viable cells, and MEM showed no difference compared to the control and decreased the number of viable cells at 50 μM. RERMS-MEM or RERMS at concentrations of 10 or 50 μM could antagonize Aβ25-35-induced cytotoxicity, and MEM at 50 μM strengthened the cytotoxicity effects. The results revealed that RERMS-MEM showed a strong NMDAR-blocking activity as a potential NMDAR antagonist, enhancing the neurotrophic effect and cellular growth in SH-SY5Y cells.

Clinical studies have shown that asthma is a risk factor for dementia or Alzheimer's disease (AD). To investigate whether asthma aggravates AD in APP/PS1 mice and explore the potential mechanisms, an asthma model was established using six-month-old APP/PS1 mice, and montelukast was used as a therapeutic agent in APP/PS1 mice with asthma. The Morris water maze test showed that asthma aggravates spatial learning and memory abilities. Asthma also upregulates the NF-κB inflammatory pathway in APP/PS1 mice and promotes the expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid-β (Aβ) deposition, neuronal damage, synaptic plasticity deficiency, activation of microglia and astrocytes. The level of LTD4 and its receptor CysLT1R in the hippocampus of APP/PS1 mice after the asthma modeling was established was higher than that in APP/PS1 mice, suggesting that asthma may affect the pathology of AD through LTD4 and its receptor Cys-LT1R. Montelukast ameliorates these pathological changes and cognitive impairment. These results suggest that asthma aggravates AD pathology and cognitive impairment of APP/PS1 mice via upregulation of the NF-κB inflammatory pathway, and montelukast ameliorates these pathological changes.

衰老被定义为一个复杂的相互关联的网络,由渐进的功能有害表型偏差(相对于年轻人的表型)构成,这些偏差是生物衰老的基础,导致个体的适应性、生理和心理功能以及恢复力下降[1] .

目的 探讨不同处理时间及浓度下L-谷氨酸对HT22、SY5Y两种细胞活性和细胞形态的影响,为构建L-谷氨酸诱导细胞损伤模型提供参考.方法 以0、0.25、0.5、1、2、5、10、15、20、25 mmol/L的L-谷氨酸处理HT22、SY5Y两种细胞,24 h后采用MTT、CCK8法检测两种细胞活性,检测细胞培养液中乳酸脱氢酶漏出率来观察细胞死亡情况;选取10和5 mmol/L的L-谷氨酸处理SY5Y细胞和HT22细胞0、2、4、8、12、18、24、36、48 h,采用MTT、CCK8法观察不同时间下L-谷氨酸对两种细胞活性影响的差异,并用显微镜观察其对细胞形态的损伤.结果 L-谷氨酸浓度为1、2、5、10、15、20、25 mmol/L时的SY5Y、HT22细胞活性低于0 mmol/L,差异有统计学意义(P<0.05);使用10、5 mmol/L的L-谷氨酸分别处理SY5Y、HT22细胞,4、8、12、18、24、36、48 h两种细胞的活性低于0 h,差异有统计学意义(P<0.05).2、10、15、20、25 mmol/L的L-谷氨酸处理SY5Y细胞24 h,乳酸脱氢酶漏出率高于0 mmol/L,差异有统计学意义(P<0.05);1、2、5、20、25 mmol/L的L-谷氨酸处理HT22细胞24 h的乳酸脱氢酶漏出率高于0 mmol/L,差异有统计学意义(P<0.05).采用10 mmol/L的L-谷氨酸处理SY5Y细胞24 h后,MTT法检测细胞活性为(82.80±9.71)％,细胞形态表现为轻度损伤;采用5 mmol/L的L-谷氨酸处理HT22细胞24 h后,MTT法检测细胞活性为(72.01±5.33)％,细胞形态表现为轻度损伤.结论 采用5 mmol/L的L-谷氨酸处理HT22细胞24 h为HT22细胞理想的造模条件,采用10 mmol/L的L-谷氨酸处理SY5Y细胞24 h为SY5Y细胞的理想造模条件,为应用L-谷氨酸损伤细胞模型研究神经系统疾病的发病机制提供了实验条件参考.

This paper by Huang S., et al. has retrospectively described the recent progress in biomarkers based on the A-T-N-X framework, A-T-N respectively represents Amyloid-Tau-Neurodegeneration, X represents biomarkers from central or peripheral related to the whole pathological course of Alzheimer's disease (AD). The framework of A-T-N-X is of great significance for understanding the whole spectrum of AD, but we still want to stress the importance of urine biomarkers for the early identification and effective management of AD.

We demonstrate that nitrogen (N) dopants are prone to spontaneously decorate the most important dislocation of basal plane dislocation (BPD) during the N doping of 4H silicon carbide (4H-SiC). The N decoration shifts the acceptor-like states of BPDs to donor-like states, which results in the donor-like character of BPDs in N-doped 4H-SiC. Kinetically, N decoration enhances the slip and piling up of BPDs, reducing the hardness, elastic modulus and fracture toughness of 4H-SiC.

The p-type doping efficiency of 4H silicon carbide (4H-SiC) is rather low due to the large ionization energies of p-type dopants. Such an issue impedes the exploration of the full advantage of 4H-SiC for semiconductor devices. In this study, we show that co-doping group-IVB elements effectively decreases the ionization energy of the most widely used p-type dopant, i.e., aluminum (Al), through the defect-level repulsion between the energy levels of group-IVB elements and that of Al in 4H-SiC. Among group-IVB elements Ti has the most prominent effectiveness. Ti decreases the ionization energy of Al by nearly 50%, leading to a value as low as ∼ 0.13 eV. As a result, the ionization rate of Al with Ti co-doping is up to ∼ 5 times larger than that without co-doping at room temperature when the doping concentration is up to 1018 cm−3. This work may encourage the experimental co-doping of group-IVB elements such as Ti and Al to significantly improve the p-type doping efficiency of 4H-SiC.

目的 本研究通过检测小鼠皮肤光损伤后相关氧化应激产物,探讨P165对中波紫外线(UVB)损伤后小鼠皮肤的光保护作用.方法 建立小鼠急性光损伤模型.照光前分别用500、1 000、2 000μmol/L的P165湿敷小鼠皮肤,再予3倍最小红斑量(MED)进行UVB照射.苏木精-伊红(HE)染色观察小鼠皮肤组织病理变化,检测皮肤活性氧簇(ROS)水平、8-羟基-2-脱氧鸟苷(8-OHdG)含量、蛋白质羰基化(PC)含量以及丙二醛(MDA)含量.结果 500、1 000、2000μmol/LP165可显著降低UVB辐照后小鼠皮肤的ROS、8-OHdG、PC和MDA水平,且随着药物浓度升高,其保护作用增强.结论 P165对UVB造成的皮肤氧化应激损伤具有保护作用,其为预防及治疗氧化应激性光损伤提供了新的研究方向,具有潜在的临床应用价值.

In this work, we propose to reveal the subsurface damage (SSD) of 4H-SiC wafers by photo-chemical etching and identify the nature of SSD by molten-alkali etching. Under UV illumination, SSD acts as a photoluminescence-black defect. The selective photo-chemical etching reveals SSD as the ridge-like defect. It is found that the ridge-like SSD is still crystalline 4H-SiC with lattice distortion. The molten-KOH etching of the 4H-SiC wafer with ridge-like SSD transforms the ridge-like SSD into groove lines, which are typical features of scratches. This means that the underlying scratches under mechanical stress give rise to the formation of SSD in 4H-SiC wafers. SSD is incorporated into 4H-SiC wafers during the lapping, rather than the chemical mechanical polishing (CMP).

Objective To analyze the changes of neurotransmitter metabolites in the hippocampus and cortex of six-month-old APP/PS1 transgenic mice and wild-type mice of the same age. Methods A total of 8 healthy female 6-month-old wild-type mice and 8 APP/PS1 transgenic mice were selected. Congo red test was conducted in 3 mice, and ultrahigh performance liquid chromatography tandem mass spectrometry was used to analyze the content of neurotransmitter metabolites in hippocampus and cortex in 5 mice. The difference metabolites between groups were screened by independent sample t test P＜0.05 or the fold change（FC） ≥1.2or FC≤ 0.8, on the basis of variable influence on projection（VIP） ≥ 1 of the principal component of orthogonal partial least squares discriminant analysis（OPLS-DA） model. Results Amyloid-β protein deposition appears in hippocampus and cortex of 6-month-old APP/PS1 transgenic mice. The metabolic profiles of hippocampus and cortex of the two groups of mice showed a trend of separation. A total of 17 different metabolites were identified in the hippocampus of mice, including epinephrine, norepinephrine, levodopa, dopamine, 3,4-dihydroxyphenylacetate（DOPAC）, 3,4-dihydroxyphenyldiol, 3,4-dihydroxymandelic acid, methoxy norepinephrine（NMN）, 4-hydroxy-3-methoxyphenylene glycol（MHPG）, 4-hydroxy-3-methoxy-mandelic acid/homovanillic acid（HVA）, glutamine, glutamate γ-aminobutyric acid, 5-hydroxytryptamine（5-HT）, hydroxyindoleacetic acid（5-HIAA）, ornithine and tyramine. A total of 12 different metabolites were identified in the cortex of mice, including dopamine, DOPAC, NMN, 3-methoxy tyramine, MHPG, HVA, 5-HT, 5-HIAA, ethanolamine, L-tyrosine, L-phenylalanine and threonine. Conclusions The trend of neurotransmitter metabolism in hippocampus and cortex of APP/PS1 transgenic mice is different, which can be used as the target of early pathological changes in cognitive dysfunction of APP/PS1 transgenic mice.