Current and further outlook on the protective potential of Antrodia camphorata against neurological disorders.

Prevalent neurological disorders such as Alzheimer's disease, Parkinson's disease, and stroke are increasingly becoming a global burden as society ages. It is well-known that degeneration and loss of neurons are the fundamental underlying processes, but there are still no effective therapies for these neurological diseases. In recent years, plenty of studies have focused on the pharmacology and feasibility of natural products as new strategies for the development of drugs that target neurological disorders. Antrodia camphorata has become one of the most promising candidates, and the crude extracts and some active metabolites of it have been reported to play various pharmacological activities to alleviate neurological symptoms at cellular and molecular levels. This review highlights the current evidence of Antrodia camphorata against neurological disorders, including safety evaluation, metabolism, blood-brain barrier penetration, neuroprotective activities, and the potential on regulating the gut-microbiome-brain axis. Furthermore, potential strategies to resolve problematic issues identified in previous studies are also discussed. We aim to provide an overview for the ongoing development and utilization of Antrodia camphorata in cerebral neuropathology.

GADD45B in the ventral hippocampal CA1 modulates aversive memory acquisition and spatial cognition.

AIMS: This study was designed to investigate the role of growth arrest and DNA damage-inducible ß (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. MAIN METHODS: Adeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. KEY FINDINGS: Knockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SIGNIFICANCE: These results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.

HFpEF as systemic disease, insight from a diagnostic prediction model reminiscent of systemic inflammation and organ interaction in HFpEF patients.

Systemic inflammation and reciprocal organ interactions are associated with the pathophysiology of heart failure with preserved ejection fraction (HFpEF). However, the clinical value, especially the diagnositc prediction power of inflammation and extra-cardiac organ dysfunction for HfpEF is not explored. In this cross-sectional study, 1808 hospitalized patients from January 2014 to June 2022 in ChiHFpEF cohort were totally enrolled according to inclusion and exclusion criteria. A diagnostic model with markers from routine blood test as well as liver and renal dysfunction for HFpEF was developed using data from ChiHFpEF-cohort by logistic regression and assessed by receiver operating characteristic curve (ROC) and Brier score. Then, the model was validated by the tenfold cross-validation and presented as nomogram and a web-based online risk calculator as well. Multivariate and LASSO regression analysis revealed that age, hemoglobin, neutrophil to lymphocyte ratio, AST/ALT ratio, creatinine, uric acid, atrial fibrillation, and pulmonary hypertension were associated with HFpEF. The predictive model exhibited reasonably accurate discrimination (ROC, 0.753, 95% CI 0.732-0.772) and calibration (Brier score was 0.200). Subsequent internal validation showed good discrimination and calibration (AUC = 0.750, Brier score was 0.202). In additoin to participating in pathophysiology of HFpEF, inflammation and multi-organ interactions have diagnostic prediction value for HFpEF. Screening and optimizing biomarkers of inflammation and multi-organ interactions stand for a new field to improve noninvasive diagnostic tool for HFpEF.

Discovery of sesquiterpene from Youngia japonica with antitumor effect.

Fourteen sesquiterpenes, including one undescribed sesquiterpene lactone, were isolated from Youngia japonica, and their structures were identified by NMR, HRESIMS, ECD and calculated ECD. Cytotoxic activities of all isolates against A549, HeLa, and 4 T1 cell lines were detected by CCK8 assay. Among them, 2 showed obvious cytotoxic activity against A549 cells. Subsequently, the production of ROS, and apoptosis of A549 cells treated with 2 were evaluated. The result showed that 2 distinctly increased the ROS level, and induced the apoptosis of A549 cells. Further anticancer mechanism studies showed that 2 increased the expression of cleaved caspase 3. Taken together, our results demonstrated that 2 might become potential leading compounds for the treatment of lung cancer.

Mediation of PM2.5-induced cytotoxicity: the role of P2X7 receptor in NR8383 cells.

Ambient fine particulate matter (PM2.5) is a threat to public health. The P2 X 7purinergic receptor (P2X7R) is a modulator that responds to inflammation. Yet the role of P2X7R in the mediation of PM2.5-induced pulmonary cytotoxicity is rarely investigated. In this study, the expression of P2X7R and its effect on cell viability, oxidative damage, apoptosis, mitochondrial dysfunction and underlying mechanism following PM2.5 treatment in rat alveolar macrophages (NR8383) were analyzed. The outcome indicated that PM2.5 exposure significantly increased the expression of P2X7R, while P2X7R antagonist oATP markedly alleviate the production of reactive oxygen species (ROS), Nitrite Oxidation (NO), mitochondrial membrane potential, apoptosis rate, and release of inflammatory cytokines. In contrast, P2X7 agonist BzATP showed opposite effect in PM2.5-treated NR8383 cells. Therefore, these results demonstrated that P2X7R participated in PM2.5-induced pulmonary toxicity, while the blockade of P2X7R is a promising therapeutic approach of treating PM2.5-induced lung diseases.

Protocol for screening α-synuclein PET tracer candidates in vitro and ex vivo.

Alpha-synuclein (α-Syn) positron emission tomography (PET) imaging is a valuable approach for diagnosing and monitoring synucleinopathies-related diseases, such as Parkinson disease. Here, we present a protocol for screening potential α-Syn PET tracers using in vitro and ex vivo approaches. We describe steps for employing recombinant pre-formed fibrils and conducting screening procedures on neuronal models, mouse models, and patients' brain tissue sections to assess the specificity and selectivity of the candidate compounds. For complete details on the use and execution of this protocol, please refer to Xiang et al. (2023).1.

FSH and ApoE4 contribute to Alzheimer's disease-like pathogenesis via C/EBPß/δ-secretase in female mice.

Alzheimer's disease (AD) is the most common dementia. It is known that women with one ApoE4 allele display greater risk and earlier onset of AD compared with men. In mice, we previously showed that follicle-stimulating hormone (FSH), a gonadotropin that rises in post-menopausal females, activates its receptor FSHR in the hippocampus, to drive AD-like pathology and cognitive impairment. Here we show in mice that ApoE4 and FSH jointly trigger AD-like pathogenesis by activating C/EBPß/δ-secretase signaling. ApoE4 and FSH additively activate C/EBPß/δ-secretase pathway that mediates APP and Tau proteolytic fragmentation, stimulating Aß and neurofibrillary tangles. Ovariectomy-provoked AD-like pathologies and cognitive defects in female ApoE4-TR mice are ameliorated by anti-FSH antibody treatment. FSH administration facilitates AD-like pathologies in both young male and female ApoE4-TR mice. Furthermore, FSH stimulates AD-like pathologies and cognitive defects in ApoE4-TR mice, but not ApoE3-TR mice. Our findings suggest that in mice, augmented FSH in females with ApoE4 but not ApoE3 genotype increases vulnerability to AD-like process by activating C/EBPß/δ-secretase signalling.

Bacteroides Fragilis in the gut microbiomes of Alzheimer's disease activates microglia and triggers pathogenesis in neuronal C/EBPß transgenic mice.

Gut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPß transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPß transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPß/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors' fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPß transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPß transgenic mice.

Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies.

Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.

Neuronal ApoE4 in Alzheimer's disease and potential therapeutic targets.

The most prevalent genetic risk factor for Alzheimer's disease (AD) is Apolipoprotein E (ApoE), a gene located on chromosome 19 that encodes three alleles (e2, e3, and e4) that give rise to the ApoE subtypes E2, E3, and E4, respectively. E2 and E4 have been linked to increased plasma triglyceride concentrations and are known to play a critical role in lipoprotein metabolism. The prominent pathological features of AD mainly include senile plaques formed by amyloid ß (Aß42) aggregation and neuronal fibrous tangles (NFTs), and the deposited plaques are mainly composed of Aß hyperphosphorylation and truncated head. In the central nervous system, the ApoE protein is primarily derived from astrocytes, but ApoE is also produced when neurons are stressed or affected by certain stress, injury, and aging conditions. ApoE4 in neurons induces Aß and tau protein pathologies, leading to neuroinflammation and neuronal damage, impairing learning and memory functions. However, how neuronal ApoE4 mediates AD pathology remains unclear. Recent studies have shown that neuronal ApoE4 may lead to greater neurotoxicity, which increases the risk of AD development. This review focuses on the pathophysiology of neuronal ApoE4 and explains how neuronal ApoE4 mediates Aß deposition, pathological mechanisms of tau protein hyperphosphorylation, and potential therapeutic targets.

Estimated pulse wave velocity is associated with all-cause mortality and cardiovascular mortality among adults with diabetes.

Aims: We aim to examine the association of estimated pulse wave velocity (ePWV) with all-cause and cardiovascular mortality in patients with diabetes. Methods: All of adult participants with diabetes from the National Health and Nutrition Examination Survey (NHANES) (1999-2018) were enrolled. ePWV was calculated according to the previously published equation based on age and mean blood pressure. The mortality information was obtained from the National Death Index database. Weighted Kaplan-Meier (KM) plot and weighted multivariable Cox regression was used to investigate the association of ePWV with all-cause and cardiovascular mortality risks. Restricted cubic spline was adopted to visualize the relationship between ePWV and mortality risks. Results: 8,916 participants with diabetes were included in this study and the median follow-up duration was ten years. The mean age of study population was 59.0 ± 11.6 years, 51.3% of the participants were male, representing 27.4 million patients with diabetes in weighted analysis. The increment of ePWV was closely associated with increased risks of all-cause mortality (HR: 1.46, 95% CI: 1.42-1.51) and cardiovascular mortality (HR: 1.59, 95% CI: 1.50-1.68). After adjusting for cofounding factors, for every 1 m/s increase in ePWV, there was a 43% increased risk of all-cause mortality (HR: 1.43, 95% CI: 1.38-1.47) and 58% increased of cardiovascular mortality (HR: 1.58, 95% CI: 1.50-1.68). ePWV had positive linear associations with all-cause and cardiovascular mortality. KM plots also showed that the risks of all-cause and cardiovascular mortality were significantly elevated in patients with higher ePWV. Conclusions: ePWV had a close association with all-cause and cardiovascular mortality risks in patients with diabetes.

Systemic Immune Inflammation Index (SII), System Inflammation Response Index (SIRI) and Risk of All-Cause Mortality and Cardiovascular Mortality: A 20-Year Follow-Up Cohort Study of 42,875 US Adults.

BACKGROUND AND AIM: Chronic low-grade inflammation is associated with various health outcomes, including cardiovascular diseases (CVDs) and cancers. Systemic immune inflammation index (SII) and system inflammation response index (SIRI) have lately been explored as novel prognostic markers for all-cause mortality and cardiovascular mortality. However, studies on prediction value in nationwide representative population are scarce, which limit their generalization. To bridge the knowledge gap, this study aims to prospectively assess the association of SII, SIRI with all-cause mortality and cardiovascular mortality in the National Health and Nutrition Examination Survey (NHANES). METHODS: From 1999 to 2018, 42,875 adults who were free of pregnancy, CVDs (stroke, acute coronary syndrome), cancers, and had follow-up records and participated in the NHANES were included in this study. SII and SIRI were quantified by calculating the composite inflammation indicators from the blood routine. To explore the characteristics of the population in different SII or SIRI levels, we divided them according to the quartile of SII or SIRI. The associations between SII, SIRI, and all-cause mortality and cardiovascular mortality events were examined using a Cox regression model. To investigate whether there was a reliable relationship between these two indices and mortalities, we performed subgroup analysis based on sex and age. RESULTS: A total of 42,875 eligible individuals were enrolled, with a mean age of 44 ± 18 years old. During the follow-up period of up to 20 years, 4250 deaths occurred, including 998 deaths from CVDs. Cox proportional hazards modeling showed that adults with SII levels of >655.56 had higher all-cause mortality (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.18-1.41) and cardiovascular mortality (HR, 1.33; 95% CI, 1.11-1.59) than those with SII levels of <335.36. Adults with SIRI levels of >1.43 had higher risk of all-cause (HR, 1.39; 95% CI, 1.26-1.52) and cardiovascular death (HR, 1.39; 95% CI, 1.14-1.68) than those with SIRI levels of <0.68. In general population older than 60 years, the elevation of SII or SIRI was associated with the risk of all-cause death. CONCLUSION: Two novel inflammatory composite indices, SII and SIRI, were closely associated with cardiovascular death and all-cause death, and more attention should be paid to systemic inflammation to provide better preventive strategies.

Disparate Clinical Characteristics and Prognosis of HFpEF versus HFrEF Phenotype of Diabetic Cardiomyopathy.

AIMS: Diabetic cardiomyopathy (DCM) is an ill-defined entity. This study aims to explore the clinical characteristics and prognosis of diabetic patients that disparately develop heart failure (HF) with preserved ejection fraction (HFpEF) other than HF with reduced ejection fraction (HFrEF). PATIENTS AND METHODS: A total of 911 patients diagnosed with diabetes mellitus were identified in the ChiHFpEF cohort (NCT05278026). DCM was defined as diabetic patients diagnosed with HF, absent from flow obstructive coronary artery disease (CAD), uncontrolled refractory hypertension and hemodynamics significant heart valvular diseases, arrhythmia and congenital heart diseases. The primary endpoint was a composite of all-cause death and rehospitalization due to HF. RESULTS: As compared to DCM-HFrEF patients, DCM-HFpEF patients had a longer duration of diabetes, were older and more noticeable in hypertension and non-obstructive CAD. After a median follow-up of 45.5 months, survival analysis showed that DCM-HFpEF patients had a better composite endpoint. Cox regression implicated that non-obstructive CAD was a negative (HR 0.101, 95% CI 0.028-0.373, p = 0.001) predictor for the composite endpoint of DCM-HFrEF patients. Age was a positive predictor for the composite endpoint of DCM-HFpEF patients (HR 1.044, 95% CI 1.007-1.082, p = 0.018). CONCLUSION: DCM-HFpEF is a disparate entity from DCM-HFrEF. Additional phenomic studies are needed to explore the molecular mechanisms and develop targeted therapies.

C/EBPß/AEP is age-dependently activated in Parkinson's disease and mediates α-synuclein in the gut and brain.

Parkinson's disease (PD) is the most common neurodegenerative motor disorder, and its pathologic hallmarks include extensive dopaminergic neuronal degeneration in the Substantia nigra associated with Lewy bodies, predominantly consisting of phosphorylated and truncated α-Synuclein (α-Syn). Asparagine endopeptidase (AEP) cleaves human α-Syn at N103 residue and promotes its aggregation, contributing to PD pathogenesis. However, how AEP mediates Lewy body pathologies during aging and elicits PD onset remains incompletely understood. Knockout of AEP or C/EBPß from α-SNCA mice, and their chronic rotenone exposure models were used, and the mechanism of α-Syn from the gut that spread to the brain was observed. Here we report that C/EBPß/AEP pathway, aggravated by oxidative stress, is age-dependently activated and cleaves α-Syn N103 and regulates Lewy body-like pathologies spreading from the gut into the brain in human α-SNCA transgenic mice. Deletion of C/EBPß or AEP substantially diminished the oxidative stress, neuro-inflammation, and PD pathologies, attenuating motor dysfunctions in aged α-SNCA mice. Noticeably, PD pathologies initiate in the gut and progressively spread into the brain. Chronic gastric exposure to a low dose of rotenone initiates Lewy body-like pathologies in the gut that propagate into the brain in a C/EBPß/AEP-dependent manner. Hence, our studies demonstrate that C/EBPß/AEP pathway is critical for mediating Lewy body pathology progression in PD.

Rictor maintains endothelial integrity under shear stress.

Background: Endothelial injury induced by low shear stress (LSS) is an initiating factor in the pathogenesis of various cardiovascular diseases, including atherosclerosis, hypertension, and thrombotic diseases. Low shear stress activates the mammalian target of rapamycin complex 2 (mTORC2) signaling pathway. Rictor, the main constituent protein of mTORC2, is involved in vascular development. However, the impact of conditional Rictor ablation on endothelial homeostasis, especially on endothelial-specific markers, such as vascular endothelial-cadherin (VE-cadherin) and von Willebrand factor (VWF), under blood flow stimulation is unclear. Objective: We aimed to investigate whether endothelial Rictor is involved in maintaining vascular endothelial integrity and the potential role of Rictor in atheroprone blood flow-mediated endothelial injury. Methods and results: Immunofluorescence staining showed that endothelial Rictor was successfully knocked out in a mouse model. Scanning electron microscopy (EM) detection revealed disruption of the endothelial monolayer in the thoracic aorta of Rictor-deficient mice. Furthermore, scanning electron microscopy and transmission electron microscopy showed that Rictor deletion disrupted endothelial integrity and expanded cell junctions in the left common carotid artery region. In vitro, low shear stress disrupted actin filament polarity and the promoted the translocation of vascular endothelial-cadherin, the key component of adherens junctions (AJs) in human umbilical vein endothelial cells. After Rictor downregulation by small interfering RNA, the translocation of vascular endothelial-cadherin and stress fibers increased. Rictor knockdown inhibited low shear stress-induced von Willebrand factor upregulation, and downregulation of vascular endothelial-cadherin decreased low shear stress-induced von Willebrand factor expression. These results suggest that vascular endothelial-cadherin/von Willebrand factor is a possible mechanism mediated by Rictor in the pathological process of low shear stress-induced endothelial injury. Conclusion: Rictor is a key protein that regulates endothelial integrity under vascular physiological homeostasis, and Rictor mediates low shear stress-induced endothelial injury by regulating adherens junctions and von Willebrand factor.

Involvement of pyroptosis pathway in epicardial adipose tissue - myocardium axis in experimental heart failure with preserved ejection fraction.

Epicardial adipose tissue (EAT) is a metabolically active organ which generates inflammatory cytokines. Thickness of EAT is associated with onset and development of heart failure with preserved ejection fraction (HFpEF). However, it is still unclear the specific mechanisms and pharmacological targets on EAT induced inflammation in HFpEF. A two-hit protocol with western diet and Nω-nitrol-arginine methyl ester (L-NAME) was used to establish HFpEF mouse model. In HFpEF mice, inflammatory biomarkers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and von willebrand factor (vWF) elevated in myocardium compared to control. Inflammatory cell infiltration in myocardium was increased. In HFpEF mice, inflammasome-mediated pyroptosis pathway was activated in the EAT. Suppression of pyroptosis-related protein gasdermin D (GSDMD) in cultured EAT could lower cardiomyocyte inflammation and autophagy. Furthermore, spironolactone and rosuvastatin, the two-hit anti-inflammatory agents, reduced NLR family pyrin domain containing 3 (NLRP3)/GSDMD pyroptosis in EAT and autophagy in myocardium of HFpEF mouse. The combination treatment also enhanced exercise tolerance and appeased inflammatory injuries in HFpEF mice. CONCLUSION: Pyroptosis signaling is involved in EAT-myocardium axis in mouse model of HFpEF. Targeting adipocyte-derived inflammation in EAT bears potential to treatment HFpEF.

High-fat diet-induced diabetes couples to Alzheimer's disease through inflammation-activated C/EBPß/AEP pathway.

Diabetes is a risk factor for Alzheimer's disease (AD), which is also called type 3 diabetes with insulin reduction and insulin resistance in AD patient brains. However, the molecular mechanism coupling diabetes to AD onset remains incompletely understood. Here we show that inflammation, associated with obesity and diabetes elicited by high-fat diet (HFD), activates neuronal C/EBPß/AEP signaling that drives AD pathologies and cognitive disorders. HFD stimulates diabetes and insulin resistance in neuronal Thy1-C/EBPß transgenic (Tg) mice, accompanied with prominent mouse Aß accumulation and hyperphosphorylated Tau aggregation in the brain, triggering cognitive deficits. These effects are profoundly diminished when AEP is deleted from C/EBPß Tg mice. Chronic treatment with inflammatory lipopolysaccharide (LPS) facilitates AD pathologies and cognitive disorders in C/EBPß Tg but not in wild-type mice, and these deleterious effects were substantially alleviated in C/EBPß Tg/AEP -/- mice. Remarkably, the anti-inflammatory drug aspirin strongly attenuates HFD-induced diabetes and AD pathologies in neuronal C/EBPß Tg mice. Therefore, our findings demonstrate that inflammation-activated neuronal C/EBPß/AEP signaling couples diabetes to AD.

Mimicking Metabolic Disturbance in Establishing Animal Models of Heart Failure With Preserved Ejection Fraction.

Heart failure (HF), the terminal state of different heart diseases, imposed a significant health care burden worldwide. It is the last battlefield in dealing with cardiovascular diseases. HF with preserved ejection fraction (HFpEF) is a type of HF in which the symptoms and signs of HF are mainly ascribed to diastolic dysfunction of left ventricle, whereas systolic function is normal or near-normal. Compared to HF with reduced ejection fraction (HFrEF), the diagnosis and treatment of HFpEF have made limited progress, partly due to the lack of suitable animal models for translational studies in the past. Given metabolic disturbance and inflammatory burden contribute to HFpEF pathogenesis, recent years have witnessed emerging studies focusing on construction of animal models with HFpEF phenotype by mimicking metabolic disorders. These models prefer to recapitulate the metabolic disorders and endothelial dysfunction, leading to the more detailed understanding of the entity. In this review, we summarize the currently available animal models of HFpEF with metabolic disorders, as well as their advantages and disadvantages as tools for translational studies.

Neuronal C/EBPß/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression.

The age-related cognitive decline of normal aging is exacerbated in neurodegenerative diseases including Alzheimer's disease (AD). However, it remains unclear whether age-related cognitive regulators in AD pathologies contribute to life span. Here, we show that C/EBPß, an Aß and inflammatory cytokine-activated transcription factor that promotes AD pathologies via activating asparagine endopeptidase (AEP), mediates longevity in a gene dose-dependent manner in neuronal C/EBPß transgenic mice. C/EBPß selectively triggers inhibitory GABAnergic neuronal degeneration by repressing FOXOs and up-regulating AEP, leading to aberrant neural excitation and cognitive dysfunction. Overexpression of CEBP-2 or LGMN-1 (AEP) in Caenorhabditis elegans neurons but not muscle stimulates neural excitation and shortens life span. CEBP-2 or LGMN-1 reduces daf-2 mutant-elongated life span and diminishes daf-16-induced longevity. C/EBPß and AEP are lower in humans with extended longevity and inversely correlated with REST/FOXO1. These findings demonstrate a conserved mechanism of aging that couples pathological cognitive decline to life span by the neuronal C/EBPß/AEP pathway.

Endothelial Mechanosensors for Atheroprone and Atheroprotective Shear Stress Signals.

Vascular endothelial cells (ECs), derived from the mesoderm, form a single layer of squamous cells that covers the inner surface of blood vessels. In addition to being regulated by chemical signals from the extracellular matrix (ECM) and blood, ECs are directly confronted to complex hemodynamic environment. These physical inputs are translated into biochemical signals, dictating multiple aspects of cell behaviour and destination, including growth, differentiation, migration, adhesion, death and survival. Mechanosensors are initial responders to changes in mechanical environments, and the overwhelming majority of them are located on the plasma membrane. Physical forces affect plasma membrane fluidity and change of protein complexes on plasma membrane, accompanied by altering intercellular connections, cell-ECM adhesion, deformation of the cytoskeleton, and consequently, transcriptional responses in shaping specific phenotypes. Among the diverse forces exerted on ECs, shear stress (SS), defined as tangential friction force exerted by blood flow, has been extensively studied, from mechanosensing to mechanotransduction, as well as corresponding phenotypes. However, the precise mechanosensors and signalling pathways that determine atheroprone and atheroprotective phenotypes of arteries remain unclear. Moreover, it is worth to mention that some established mechanosensors of atheroprotective SS, endothelial glycocalyx, for example, might be dismantled by atheroprone SS. Therefore, we provide an overview of the current knowledge on mechanosensors in ECs for SS signals. We emphasize how these ECs coordinate or differentially participate in phenotype regulation induced by atheroprone and atheroprotective SS.