Targeting epigenetic mechanisms in amyloid-ß-mediated Alzheimer's pathophysiology: unveiling therapeutic potential.

Alzheimer's disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia. Growing evidence suggests that Alzheimer's disease is associated with accumulating various amyloid-ß oligomers in the brain, influenced by complex genetic and environmental factors. The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer's disease are believed to primarily result from synaptic dysfunction. Throughout life, environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders. These changes, known as epigenetic modifications, also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity. In this context, we highlight recent advances in understanding the roles played by key components of the epigenetic machinery, specifically DNA methylation, histone modification, and microRNAs, in the development of Alzheimer's disease, synaptic function, and activity-dependent synaptic plasticity. Moreover, we explore various strategies, including enriched environments, exposure to non-invasive brain stimulation, and the use of pharmacological agents, aimed at improving synaptic function and enhancing long-term potentiation, a process integral to epigenetic mechanisms. Lastly, we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer's disease. We suggest that addressing Alzheimer's disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.

NDRG2 acts as a negative regulator of the progression of small-cell lung cancer through the modulation of the PTEN-AKT-mTOR signalling cascade.

N-myc downstream-regulated gene 2 (NDRG2) has been recognised as a negative regulator of the progression of numerous tumours, yet its specific role in small-cell lung carcinoma (SCLC) is not fully understood. The purpose of the current study was to investigate the biological role and mechanism of NDRG2 in SCLC. Initial investigation using the Gene Expression Omnibus (GEO) dataset revealed marked downregulation of NDRG2 transcripts in SCLC. The decreased abundance of NDRG2 in SCLC was verified by examining clinical specimens. Increasing NDRG2 expression in SCLC cell lines caused significant changes in cell proliferation, cell cycle progression, colony formation, and chemosensitivity. NDRG2 overexpression decreased the levels of phosphorylated PTEN, AKT and mTOR. In PTEN-depleted SCLC cells, the upregulation of NDRG2 did not result in any noticeable impact on AKT or mTOR activation. Additionally, the reactivation of AKT reversed the antitumour effects of NDRG2 in SCLC cells. Notably, increasing NDRG2 expression retarded the growth of SCLC cell-derived xenografts in vivo. In conclusion, NDRG2 serves as an inhibitor of SCLC, and its cancer-inhibiting effects are achieved through the suppression of AKT/mTOR via the activation of PTEN. This work suggests that NDRG2 is a potential druggable target for SCLC treatment.

Changing of mechanical property and bearing capacity of strongly chlorine saline soil under freeze-thaw cycles.

Freeze-thaw cycles and compactness are two critical factors that significantly affect the engineering properties and safety of building foundations, especially in seasonally frozen regions. This paper investigated the effects of freeze-thaw cycles on the shear strength of naturally strongly chlorine saline soil with the compactness of 85%, 90% and 95%. Three soil samples with different compactness were made. Size and mass changes were measured and recorded during freeze-thaw cycles. Shear strength under different vertical pressures was determined by direct shear tests, and the cohesion and friction angle were measured and discussed. Microstructure characteristic changes of saline soil samples were observed using scanning electron microscopy under different freeze-thaw cycles. Furthermore, numerical software was used to calculate the subsoil-bearing capacity and settlement of the electric tower foundation in the Qarhan Salt Lake region under different freeze-thaw cycles. Results show that the low-density soil shows thaw settlement deformation, but the high-density soil shows frost-heaving deformation with the increase in freeze-thaw cycles. The shear strength of the soil samples first increases and then decreases with the increase in freeze-thaw cycles. After 30 freeze-thaw cycles, the friction angle of soil samples is 28.3%, 29.2% and 29.6% lower than the soil samples without freeze-thaw cycle, the cohesion of soil samples is 71.4%, 60.1% and 54.4% lower than the samples without freeze-thaw cycle, and the cohesion and friction angle of soil samples with different compactness are close to each other. Microstructural changes indicate that the freeze-thaw cycle leads to the breakage of coarse particles and the aggregation of fine particles. Correspondingly, the structure type of soil changes from a granular stacked structure to a cemented-aggregated system. Besides, the quality loss of soil samples is at about 2% during the freeze-thaw cycles. Results suggest that there may be an optimal compactness between 90 and 95%, on the premise of meeting the design requirements and economic benefits. This study can provide theoretical guidance for foundation engineering constructions in seasonally frozen regions.

Multi-functional composite dressings with sustained release of MSC-SLP and anti-adhesion property for accelerating wound healing.

Exudate management is of significant clinical value for the treatment of acute wound. Various wound dressings have been developed to restore the function of injured tissues and promote wound healing, but proper exploiting the healing factors inside exudate and achieving anti-adhesion wound care remains a challenge. Herein, we present a novel multi-functional composite dressing (MCD) by coupling supernatant lyophilized powder of mesenchymal stem cells (MSC-SLP) with a sandwich-structured wound dressing (SWD). The developed MCDs demonstrated unique unidirectional drainage capability, stable anti-adhesion characteristics, and improved wound healing performance. The designed SWD with both superhydrophobic inner surface and liquid-absorption ability of mid layer enables the dressings exhibit desired anti-adhesion property to neoformative granulation tissues, favorable shielding effect to exogenous bacteria, as well as appropriate exudate-retaining capability and unidirectional exudate-absorption property. The introduction of MSC-SLP in SWD was demonstrated to further improve wound healing quality. Compared to medical gauze, the synergic effect of SWD and MSC-SLP significantly accelerates wound healing rate by over 30%, avoids tissue avulsion when changing dressings, and produces a flat-smooth closure surface. More importantly, the wound treated with MCDs presents more skin accessory organs and blood vessels in regenerated tissues than other groups. In vivo/vitro biocompatibility evaluations indicated little toxicity, demonstrating the biosecurity of the developed dressings. The proposed method offers great potential in clinical applications particularly for chronic wound treatments.

Outcomes following the excision of sarcoma and chest wall reconstruction using 3D printed implant.

The survival outcomes of patients with chest wall sarcomas (CWS) were evaluated after receiving wide excision and chest wall reconstruction by using three-dimensional printed (3DP) implants. The survival outcomes evaluating the effect of 3DP implants for chest wall reconstruction is lacking. Here, forty-nine patients with CWS underwent radical wide excision and chest wall reconstruction using 3DP implants. The surgical data and long-term survival outcomes were collected and analyzed. With a median follow-up of 36 months, the disease-free survival (DFS) and overall survival (OS) were 31.7% and 58.5%, respectively. In addition, the 3-year DFS and OS can be significantly differentiated using the classification criteria of tumor grade, tumor size tumor area. Hence, wide excision and chest wall reconstruction using three-dimensional printed implants are a safe and effective treatment for chest wall sarcoma. The novel classification criteria of tumor size and area have the potential to predict the prognosis of CWS.

Hypoxia-induced SHMT2 protein lactylation facilitates glycolysis and stemness of esophageal cancer cells.

Esophageal cancer (EC) is a familiar digestive tract tumor with highly lethal. The hypoxic environment has been demonstrated to be a significant factor in modulating malignant tumor progression and is strongly associated with the abnormal energy metabolism of tumor cells. Serine hydroxymethyl transferase 2 (SHMT2) is one of the most frequently expressed metabolic enzymes in human malignancies. The study was designed to investigate the biological functions and regulation mechanisms of SHMT2 in EC under hypoxia. We conducted RT-qPCR to assess SHMT2 levels in EC tissues and cells (TE-1 and EC109). EC cells were incubated under normoxia and hypoxia, respectively, and altered SHMT2 expression was evaluated through RT-qPCR, western blot, and immunofluorescence. The biological functions of SHMT2 on EC cells were monitored by performing CCK-8, EdU, transwell, sphere formation, glucose uptake, and lactate production assays. The SHMT2 protein lactylation was measured by immunoprecipitation and western blot. In addition, SHMT2-interacting proteins were analyzed by bioinformatics and validated by rescue experiments. SHMT2 was notably upregulated in EC tissues and cells. Hypoxia elevated SHMT2 protein expression, augmenting EC cell proliferation, migration, invasion, stemness, and glycolysis. In addition, hypoxia triggered lactylation of the SHMT2 protein and enhanced its stability. SHMT2 knockdown impeded the malignant phenotype of EC cells. Further mechanistic studies disclosed that SHMT2 is involved in EC progression by interacting with MTHFD1L. Hypoxia-induced SHMT2 protein lactylation and upregulated its protein level, which in turn enhanced MTHFD1L expression and accelerated the malignant progression of EC cells.

High-Performance Single-Crystal Lithium-Rich Layered Oxides Cathode Materials via Na2WO4-Assisted Sintering.

Single-crystal lithium-rich layered oxides (LLOs) with excellent mechanical properties can enhance their crystal structure stability. However, the conventional methods for preparing single-crystal LLOs, require large amounts of molten salt additives, involve complicated washing steps, and increase the difficulty of large-scale production. In this study, a sodium tungstate (Na2WO4)-assisted sintering method is proposed to fabricate high-performance single-crystal LLOs cathode materials without large amounts of additives and additional washing steps. During the sintering process, Na2WO4 promotes particle growth and forms a protective coating on the surface of LLOs particles, effectively suppressing the side reactions at the cathode/electrolyte interface. Additionally, trace amounts of Na and W atoms are doped into the LLOs lattice via gradient doping. Experimental results and theoretical calculations indicate that Na and W doping stabilizes the crystal structure and enhances the Li+ ions diffusion rate. The prepared single-crystal LLOs exhibit outstanding capacity retention of 82.7% (compared to 65.0%, after 200 cycles at 1 C) and a low voltage decay rate of 0.76 mV per cycle (compared to 1.80 mV per cycle). This strategy provides a novel pathway for designing the next-generation high-performance cathode materials for Lithium-ion batteries (LIBs).

Combinative predictive effect of left ventricular mass index, ratio of HDL and CRP for progression of chronic kidney disease in non-dialysis patient.

PURPOSE: This current study scrutinized the association among left ventricular mass index (LVMI), ratio of high-density lipoprotein (HDL) and C-reactive protein (CRP), and renal function. Furthermore, we examined the predictive effects of left ventricular mass index and HDL/CRP on progression of non-dialysis chronic kidney disease. METHODS: We enrolled adult patients with chronic kidney disease (CKD) who were not receiving dialysis and obtained follow-up data on them. We extracted and compared data between different groups. To investigate the relationship between left ventricular mass index (LVMI), high-density lipoprotein (HDL)/C-reactive protein (CRP) levels, and CKD, we employed linear regression analysis, Kaplan-Meier analysis, and Cox proportional hazards regression analysis. RESULTS: Our study enrolled a total of 2351 patients. Compared with those in the non-progression group, subjects in the CKD progression group had lower ln(HDL/CRP) levels (- 1.56 ± 1.78 vs. - 1.14 ± 1.77, P < 0.001) but higher left ventricular mass index (LVMI) values (115.45 ± 29.8 vs. 102.8 ± 26.31 g/m2, P < 0.001). Moreover, after adjusting for demographic factors, ln(HDL/CRP) was found to be positively associated with estimated glomerular filtration rate (eGFR) (B = 1.18, P < 0.001), while LVMI was negatively associated with eGFR (B = - 0.15, P < 0.001). In the end, we found that both LVH (HR = 1.53, 95% CI 1.15 to 2.05, P = 0.004) and lower ln(HDL/CRP) (HR = 1.46, 95% CI 1.08 to 1.96, P = 0.013) independently predicted CKD progression. Notably, the combined predictive power of these variables was stronger than either variable alone (HR = 1.98, 95% CI 1.5 to 2.62, P < 0.001). CONCLUSION: Our study findings indicate that in pre-dialysis patients, both HDL/CRP and LVMI are associated with basic renal function and are independently correlated with CKD progression. These variables may serve as predictors for CKD progression, and their combined predictive power is stronger than that of either variable alone.

Predictive Effect of System Inflammation Response Index for Progression of Chronic Kidney Disease in Non-Dialyzing Patient.

Purpose: Scant research has been conducted on the interplay between the systemic inflammation response index (SIRI) and chronic kidney disease (CKD). The present study endeavors to meticulously scrutinize the association between SIRI and renal function. Additionally, we aim to assess its efficacy in predicting the progression of CKD in non-dialysis patients. Patients and Methods: Adult patients with CKD who were not undergoing dialysis were enrolled, and follow-up data were obtained. Data from distinct groups were extracted and meticulously compared. A comprehensive analytical approach was adopted, including logistic regression analysis, Kaplan-Meier analysis, Cox proportional hazards regression analysis, and subgroup analysis. Results: Our study included 1420 patients, with a mean age of 61 ± 17 years, and 63% were male. 244 (17.2%) patients experienced the progression of CKD. As the level of ln(SIRI) increased, patients tended to be older, with a higher proportion of males, and increased prevalence rates of hypertension, stroke, heart failure, and progression of CKD. Additionally, the levels of baseline creatinine and C-reactive protein were elevated, while the levels of estimated glomerular filtration rate and hemoglobin decreased. Upon adjusting for demographic and biochemical variables, logistic regression analysis indicated that ln(SIRI) was independently associated with advanced CKD in pre-dialysis patients (OR=1.59, 95% CI: 1.29-1.95, P<0.001). Moreover, Cox proportional-hazard analysis revealed that ln(SIRI) independently predicted CKD progression (HR: 1.3, 95% CI: 1.07-1.59, P=0.009). Conducting a subgroup analysis, we observed significant interactions between ln(SIRI) levels and gender (p<0.001), age (p=0.046), and hypertension (p=0.028) in relation to the progression of CKD. Conclusion: Our study's findings demonstrate a significant association between SIRI and fundamental renal function, and independently establish a correlation between SIRI and the progression of CKD in pre-dialysis patients. These observations suggest that SIRI holds promise as a potential predictor for CKD progression.

Increased palmitoylation improves estrogen receptor alpha-dependent hippocampal synaptic deficits in a mouse model of synucleinopathy.

Parkinson's disease (PD) is characterized by conversion of soluble α-synuclein (αS) into intraneuronal aggregates and degeneration of neurons and neuronal processes. Indications that women with early-stage PD display milder neurodegenerative features suggest that female sex partially protects against αS pathology. We previously reported that female sex and estradiol improved αS homeostasis and PD-like phenotypes in E46K-amplified (3K) αS mice. Here, we aimed to further dissect mechanisms that drive this sex dimorphism early in disease. We observed that synaptic abnormalities were delayed in females and improved by estradiol, mediated by local estrogen receptor alpha (ERα). Aberrant ERα distribution in 3K compared to wild-type mice was paired with its decreased palmitoylation. Treatment with ML348, a de-palmitoylation inhibitor, increased ERα availability and soluble αS homeostasis, ameliorating synaptic plasticity and cognitive and motor phenotypes. Our finding that sex differences in early-disease αS-induced synaptic impairment in 3KL mice are in part mediated by palmitoylated ERα may have functional and pathogenic implications for clinical PD.

SHMT2 regulates esophageal cancer cell progression and immune Escape by mediating m6A modification of c-myc.

BACKGROUND: In recent years, the role of altered cellular metabolism in tumor progression has attracted widespread attention. Related metabolic enzymes have also been considered as potential cancer therapeutic targets. Serine hydroxymethyltransferase 2 (SHMT2) has been reported to be upregulated in several cancers and associated with poor prognosis. However, there are few studies of SHMT2 in esophageal cancer (EC), and the related functions and mechanisms also need to be further explored. METHODS: In this study, we first analyzed SHMT2 expression in EC by online database and clinical samples. Then, the biological functions of SHMT2 in EC were investigated by cell and animal experiments. The intracellular m6A methylation modification levels were also evaluated by MeRIP. Linked genes and mechanisms of SHMT2 were analyzed by bioinformatics and rescue experiments. RESULTS: We found that SHMT2 expression was abnormally upregulated in EC and associated with poor prognosis. Functionally, SHMT2 silencing suppressed c-myc expression in an m6A-dependent manner, thereby blocking the proliferation, migration, invasion and immune escape abilities of EC cells. Mechanistically, SHMT2 encouraged the accumulation of methyl donor SAM through a one-carbon metabolic network, thereby regulating the m6A modification and stability of c-myc mRNA in a METTL3/FTO/ALKBH5/IGF2BP2-dependent way. In vivo animal experiments also demonstrated that SHMT2 mediated MYC expression by m6A-methylation modification, thus boosting EC tumorigenesis. CONCLUSION: In conclusion, our data illustrated that SHMT2 regulated malignant progression and immune escape of EC cell through c-myc m6A modification. These revealed mechanisms related to SHMT2 in EC and maybe offer promise for the development of new therapeutic approaches.

The high-risk features and effect of postoperative radiotherapy on survival for patients with surgically treated stage IIIA-N2 non-small cell lung cancer.

OBJECTIVES: Although postoperative radiotherapy (PORT) could reduce the incidence of local recurrence in patients with IIIA-N2 non-small cell lung cancer (NSCLC), the role of PORT on survival in patients with surgically treated stage IIIA-N2 NSCLC remains controversial. Therefore, this study was designed to evaluate the effect of PORT on survival for patients with surgically treated stage IIIA-N2 NSCLC. MATERIALS AND METHODS: This study population was chosen from the Surveillance, Epidemiology, and End Results database. The Cox proportional hazards regression analysis was used to determine significant contributors to overall survival (OS) and cancer special survival (CSS) outcomes. To balance baseline characteristics between the non-PORT group and PORT group, propensity score matching (PSM) with 1:1 propensity nearest-neighbor match by 0.001 matching tolerance was conducted by R software. Furthermore, a Kaplan-Meier curve was used to visualize the OS and CSS between the PORT group and non-PORT group survival probability. RESULTS: Of all evaluated cases, 4511 with IIIA-N2 NSCLC were eligible for inclusion, of which 1920 were enrolled into the PORT group. On univariate analysis and multivariate analysis, sex, age, year of diagnosis, race, histologic type, T stage, PORT, use of chemotherapy, and positive regional nodes were significantly associated with OS and CSS in IIIA-N2 NSCLC (P < 0.05). However, PORT was not significantly associated with OS (univariate HR = 0.92, 95%CI 0.85-0.99, P = 0.02; multivariate HR = 1.01, 95%CI 0.93-1.08, P = 0.91) and CSS (univariate HR = 0.92, 95%CI 0.85-1.01, P = 0.06; multivariate HR = 1.103 95%CI 0.94-1.12, P = 0.56) in IIIA-N2 NSCLC. Meanwhile, after PSM, neither OS nor CSS did differ significantly between the non-PORT group and PORT group (OS HR = 1.08, 95%CI 0.98-1.19, P = 0.12; CSS HR = 1.10, 95%CI 0.99-1.23, P = 0.07). CONCLUSION: PORT did not contribute to a survival benefit in patients with surgically treated stage IIIA-N2 NSCLC.

Propensity score-matched analysis comparing hippocampus-avoidance whole-brain radiotherapy plus simultaneous integrated boost with hippocampus­avoidance whole-brain radiotherapy alone for multiple brain metastases-a retrospective study in multiple institutions.

BACKGROUND: The optimal treatment for multiple brain metastases has been recently controversially discussed.This study was aimed to explore the feasibility of Hippocampus-Avoidance Whole-Brain Radiotherapy plus a simultaneous integrated boost (HA-WBRT + SIB) in patients with multiple brain metastases and assess tumor control in comparison with Hippocampus-Avoidance Whole-Brain Radiotherapy (HA-WBRT) alone for brain metastases. METHODS: In this study, 63 patients with multiple brain metastases (≥ 4 metastases) had undergone HA-WBRT + SIB between January 2016 and December 2020 in the observation group:HA-WBRT (30 Gy in 12 fractions, the maximum dose of the hippocampus ≤ 14 Gy) plus a simultaneous integrated boost (48 Gy in 12 fractions) for brain metastases.Overall Survival (OS), Median survival,intracranial control (IC = control within the entire brain), intracranial progression-free survival (iPFS) and adverse events were compared with the control group (a HA-WBRT retrospective cohort) by propensity score matching analysis. RESULTS: After 1:1 propensity score matching,there were 56 patients in each group (the observation group, the control group). OS, median survival and iPFS were significantly longer in the observation group (18.4 vs. 10.9 months, P<0.001), (13.0 vs. 8.0 months, P<0.001), (13.9 vs.7.8 months, P<0.001). In comparison of 1-year-IC rates, the observation group also demonstrated higher than the control group (51.8% vs. 21.4%, P = 0.002), respectively. Seven hippocampal metastases were found in the control group (4/56,7.1%) and the observation group (3/56,5.4%) after HA-WBRT. The death rate of intracranial progression were 23.2% in the observation group and 37.5% in the control group.All adverse events were not significant difference between the two groups (P>0.05). CONCLUSIONS: HA-WBRT + SIB resulted in better OS,median survival, IC, iPFS, an acceptable risk of radiation response, and a potential way of declining neurocognitive adverse events, which may be a better treatment for patients with multiple brain metastases.

The correlation between the severity of cerebral microbleeds and serum HMGB1 levels and cognitive impairment in patients with cerebral small vessel disease.

Objective: The study investigated the correlation and predictive value between the severity of cerebral microbleeds (CMBs) and the level of serum High Mobility Group Protein B1 (HMGB1) and the occurrence of cognitive impairment in patients with cerebral small vessel disease (CSVD). Methods: A total of 139 patients with CSVD admitted to the Department of Neurology of the First Affiliated Hospital of Xinxiang Medical University from December 2020 to December 2022 were selected as study subjects. The Montreal Cognitive Assessment (MoCA) scale was used to assess the cognitive function and was divided into the cognitive impairment group and the cognitive normal group. Magnetic Resonance Imaging (MRI) and Susceptibility Weighted Imaging (SWI) were used to screen and assess the severity of CMBs. Serum HMGB1 levels of CSVD patients were measured by enzyme linked immunosorbent assay (ELISA). Multivariable logistic regression analysis was used to explore risk factors for cognitive impairment and CMBs. Pearson correlation analysis was used to investigate the correlation between HMGB1 and cognitive function. Receiver Operating Characteristics (ROC) curves were used to assess the predictive value of HMGB1 for the occurrence of cognitive impairment in patients with CMBs. Results: High Mobility Group Protein B1, uric acid (UA), glycosylated hemoglobin (HbA1c), CMBs, lacunar cerebral infarction (LI), years of education, and history of hypertension were risk factors for cognitive impairment (P < 0.05); HMGB1 was significantly and negatively associated with total MoCA score, visuospatial/executive ability, and delayed recall ability (P < 0.05). HMGB1 was significantly and positively correlated with the number of CMBs (P < 0.05). The area under the ROC curve for HMGB1 predicting cognitive impairment in patients with CMBs was 0.807 (P < 0.001). Conclusion: Serum HMGB1 levels are associated with the development of cognitive impairment in CSVD patients, and serum HMGB1 levels have a high predictive value for the development of cognitive impairment in CSVD patients with combined CMBs, which can be used for early clinical identification and intervention of vascular cognitive impairment.

Anion-Cation Dual-Ion Multisite Doping Stabilizes the Crystal Structure of Li-Rich Layered Oxides.

Li-rich layered oxide (LLOs) cathode materials are gaining increasing attention as lithium-ion batteries (LIBs) pursue greater energy density. However, LLOs still suffer from severe capacity fading and voltage decay due to their unstable crystal structure. Hence, the anion-cation dual-ion multisite doping strategy based on Mg and S atoms is used to stabilize the crystal structures of LLOs. Mg substitutes Li atoms in the Li and transition-metal (TM) layers, while S atoms occupy tetrahedral interstitial sites and lattice O sites, all of which contribute to the crystal structure stability of LLOs. Theoretical calculations show that Mg/S dual-ion multisite doping successfully reduces the energy levels of the TM 3d-O 2p and isolated O 2p orbitals, which effectively stabilizes the lattice oxygen. Therefore, multisite-doped samples exhibit promising electrochemical performance. This strategy provides a new approach to enhance the crystal structure stability of LLOs for the design of high-energy-density Li-ion batteries.

Complement C3a receptor antagonist alleviates tau pathology and ameliorates cognitive deficits in P301S mice.

Human tauopathies, including Alzheimer's disease (AD), are a major class of neurodegenerative diseases characterized by intracellular deposition of pathological hyperphosphorylated forms of Tau protein. Complement system is composed of many proteins, which form a complex regulatory network to modulate the immune activity in the brain. Emerging studies have demonstrated a critical role of complement C3a receptor (C3aR) in the development of tauopathy and AD. The underlying mechanisms by which C3aR activation mediates tau hyperphosphorylation in tauopathies, however, remains largely unknown. Here, we observed that the expression of C3aR is upregulated in the brains of P301S mice - a mouse model of tauopathy and AD. Pharmacologic blockade of C3aR ameliorates synaptic integrity and reduced tau hyperphosphorylation in P301S mice. Besides, the administration of C3aR antagonist (C3aRA: SB 290157) improved spatial memory as tested in the Morris water maze. Moreover, C3a receptor antagonist inhibited tau hyperphosphorylation by regulating p35/CDK5 signaling. In summary, results suggest that the C3aR plays an essential role in the accumulation of hyperphosphorylated Tau and behavioral deficits in P301S mice. C3aR could be a feasible therapeutic target for the treatment of tauopathy disorders, including AD.

Activation of ß2-adrenergic receptors prevents AD-type synaptotoxicity via epigenetic mechanisms.

We previously reported that prolonged exposure to an enriched environment (EE) enhances hippocampal synaptic plasticity, with one of the significant mechanistic pathways being activation of ß2-adrenergic receptor (ß2-AR) signaling, thereby mitigating the synaptotoxic effects of soluble oligomers of amyloid ß-protein (oAß). However, the detailed mechanism remained elusive. In this work, we recorded field excitatory postsynaptic potentials (fEPSP) in the CA1 region of mouse hippocampal slices treated with or without toxic Aß-species. We found that pharmacological activation of ß2-AR, but not ß1-AR, selectively mimicked the effects of EE in enhancing LTP and preventing oAß-induced synaptic dysfunction. Mechanistic analyses showed that certain histone deacetylase (HDAC) inhibitors mimicked the benefits of EE, but this was not seen in ß2-AR knockout mice, suggesting that activating ß2-AR prevents oAß-mediated synaptic dysfunction via changes in histone acetylation. EE or activation of ß-ARs each decreased HDAC2, whereas Aß oligomers increased HDAC2 levels in the hippocampus. Further, oAß-induced inflammatory effects and neurite degeneration were prevented by either ß2-AR agonists or certain specific HDAC inhibitors. These preclinical results suggest that activation of ß2-AR is a novel potential therapeutic strategy to mitigate oAß-mediated features of AD.

The Relevance of Serum Macrophage Migration Inhibitory Factor Level and Executive Function in Patients with White Matter Hyperintensity in Cerebral Small Vessel Disease.

(1) Objective: To investigate the relationship between serum macrophage migration inhibitory factor (MIF) level and white matter hyperintensity (WMH) and executive function (EF) in cerebral small vascular disease (CSVD), and assess the impact and predictive value of MIF level and Fazekas scores in CSVD-related cognitive impairment (CI) (CSVD-CI); (2) Methods: A total of 117 patients with WMH admitted to the First Affiliated Hospital of Xinxiang Medical College from January 2022 to August 2022 were enrolled. According to the Montreal cognitive assessment (MoCA) scale, subjects were divided into a normal cognitive group and an impaired group. All subjects required serum MIF level, 3.0 T MRI, and neuropsychological evaluation to investigate the risk factors for CDVD-CI, analyze the correlation between MIF level, WMH, and EF, and to analyze the diagnostic value of MIF and WMH degree in predicting CSVD-CI; (3) Results: 1. Fazekas score and MIF level were the risk factors of CSVD-CI. 2. The Fazekas score was negatively correlated with MoCA score, positively correlated with Stroop C-Time, Stroop C-Mistake, Stroop interference effects (SIE)-Time, SIE-Mistake, and color trails test (CTT) interference effects (CIE) (B-A). 3. The MIF level was positively correlated with Fazekas score, Stroop C-Time, SIE-Time, CTT B-Time, and CIE (B-A), and negatively correlated with MoCA score. 4. Fazekas score and MIF level were significant factors for diagnosing CSVD-CI; (4) Conclusion: The Fazekas score and MIF level may be the risk factors of CSVD-CI, and they are closely correlated to CI, especially the EF, and they have diagnostic value for CSVD-CI.