Physiological ß-amyloid clearance by the liver and its therapeutic potential for Alzheimer's disease.

Cerebral amyloid-ß (Aß) accumulation due to impaired Aß clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aß is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aß and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aß42 and 8.9% of Aß40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aß receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aß levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aß clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aß burden and cognitive deficits, while enhancing hepatic Aß clearance via LRP-1 overexpression attenuated cerebral Aß deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aß and regulates brain Aß levels, suggesting that a decline of hepatic Aß clearance during aging could be involved in AD development, and hepatic Aß clearance is a novel therapeutic approach for AD.

Blood cell-produced amyloid-ß induces cerebral Alzheimer-type pathologies and behavioral deficits.

It is traditionally believed that cerebral amyloid-beta (Aß) deposits are derived from the brain itself in Alzheimer's disease (AD). Peripheral cells such as blood cells also produce Aß. The role of peripherally produced Aß in the pathogenesis of AD remains unknown. In this study, we established a bone marrow transplantation model to investigate the contribution of blood cell-produced Aß to AD pathogenesis. We found that bone marrow cells (BMCs) transplanted from APPswe/PS1dE9 transgenic mice into wild-type (Wt) mice at 3 months of age continuously expressed human Aß in the blood, and caused AD phenotypes including Aß plaques, cerebral amyloid angiopathy (CAA), tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits in the Wt recipient mice at 12 months after transplantation. Bone marrow reconstitution in APPswe/PS1dE9 mice with Wt-BMCs at 3 months of age reduced blood Aß levels, and alleviated brain Aß burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the AD model mice at 12 months after transplantation. Our study demonstrated that blood cell-produced Aß plays a significant role in AD pathogenesis, and the elimination of peripheral production of Aß can decrease brain Aß deposition and represents a novel therapeutic approach for AD.

Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer's disease.

Amyloid-ß (Aß) accumulation in the brain is a pivotal event in the pathogenesis of Alzheimer's disease (AD), and its clearance from the brain is impaired in sporadic AD. Previous studies suggest that approximately half of the Aß produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral Aß clearance remain largely unknown. The kidney is thought to be responsible for Aß clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in Aß in the blood and brain in both humans and animals and on behavioural deficits and AD pathologies in animals. Furthermore, the therapeutic effects of the diuretic furosemide on Aß clearance via the kidney were assessed. We detected Aß in the kidneys and urine of both humans and animals and found that the Aß level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain Aß deposition; aggravated AD pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, and neuronal loss; and aggravated cognitive deficits in APP/PS1 mice. In addition, chronic furosemide treatment reduced blood and brain Aß levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears Aß from the blood, suggesting that facilitation of Aß clearance via the kidney represents a novel potential therapeutic approach for AD.

Integrin ß3 Mediates the Endothelial-to-Mesenchymal Transition via the Notch Pathway.

BACKGROUND/AIMS: Neointimal hyperplasia is responsible for stenosis, which requires corrective vascular surgery, and is also a major morphological feature of many cardiovascular diseases. This hyperplasia involves the endothelial-to-mesenchymal transition (EndMT). We investigated whether integrin ß3 can modulate the EndMT, as well as its underlying mechanism. METHODS: Integrin ß3 was overexpressed or knocked down in human umbilical vein endothelial cells (HUVECs). The expression of endothelial markers and mesenchymal markers was determined by real-time reverse transcription PCR (RT-PCR), immunofluorescence staining, and western blot analysis. Notch signaling pathway components were detected by real-time RT-PCR and western blot analysis. Cell mobility was evaluated by wound-healing, Transwell, and spreading assays. Fibroblast-specific protein 1 (FSP-1) promoter activity was determined by luciferase assay. RESULTS: Transforming growth factor (TGF)-ß1 treatment or integrin ß3 overexpression significantly promoted the EndMT by downregulating VE-cadherin and CD31 and upregulating smooth muscle actin α and FSP-1 in HUVECs, and by enhancing cell migration. Knockdown of integrin ß3 reversed these effects. Notch signaling was activated after TGF-ß1 treatment of HUVECs. Knockdown of integrin ß3 suppressed TGF-ß1-induced Notch activation and expression of the Notch downstream target FSP-1. CONCLUSION: Integrin ß3 may promote the EndMT in HUVECs through activation of the Notch signaling pathway.

Notch Signaling in Endothelial Cells: Is It the Therapeutic Target for Vascular Neointimal Hyperplasia?

Blood vessels respond to injury through a healing process that includes neointimal hyperplasia. The vascular endothelium is a monolayer of cells that separates the outer vascular wall from the inner circulating blood. The disruption and exposure of endothelial cells (ECs) to subintimal components initiate the neointimal formation. ECs not only act as a highly selective barrier to prevent early pathological changes of neointimal hyperplasia, but also synthesize and release molecules to maintain vascular homeostasis. After vascular injury, ECs exhibit varied responses, including proliferation, regeneration, apoptosis, phenotypic switching, interacting with other cells by direct contact or secreted molecules and the change of barrier function. This brief review presents the functional role of the evolutionarily-conserved Notch pathway in neointimal hyperplasia, notably by regulating endothelial cell functions (proliferation, regeneration, apoptosis, differentiation, cell-cell interaction). Understanding endothelial cell biology should help us define methods to prompt cell proliferation, prevent cell apoptosis and dysfunction, block neointimal hyperplasia and vessel narrowing.

HDAC1 inhibits beige adipocyte-mediated thermogenesis through histone crotonylation of Pgc1a/Ucp1.

Obesity, one of the most serious public health issues, is caused by the imbalance of energy intake and energy expenditure. Increasing energy expenditure via induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Although histone modifications have been confirmed to regulate cellular energy metabolism, the involved biochemical mechanism of thermogenesis in adipose tissue is not completely understood. Herein, we report that class I histone deacetylases (HDAC) inhibitor MS275 increased PGC1α/UCP1 protein levels in inguinal white adipose tissue (iWAT) concomitant with elevated energy expenditure, reduced obesity and ameliorated glucose tolerance compared to control littermates. H3K18cr and H3K18ac levels were elevated after MS275 treatment. MS275 also promoted the transcription of Pgc1α and Ucp1 by enhancing the enrichment of H3K18cr and H3K18ac in the Pgc1α/Ucp1 enhancer and promoter, with a notable increase in H3K18cr. Mechanistically, the deletion of Hdac1 in beige adipocyte increases H3K18cr levels in enhancers and promoters of Pgc1α and Ucp1 genes, regulated the chromosomal state, thereby affecting the transcription of Pgc1α/Ucp1. Taken together, HDAC1 inhibits beige adipocyte-mediated thermogenesis through histone crotonylation of Pgc1a/Ucp1. This finding may provide a therapeutic strategy through increasing energy expenditure in obesity and related metabolic disorders.

Genome-wide identification and comprehensive analysis heat shock transcription factor (Hsf) members in asparagus (Asparagus officinalis) at the seeding stage under abiotic stresses.

Heat shock transcription factors (Hsf) are pivotal as essential transcription factors. They function as direct transcriptional activators of genes regulated by thermal stress and are closely associated with various abiotic stresses. Asparagus (Asparagus officinalis) is a vegetable of considerable economic and nutritional significance, abundant in essential vitamins, minerals, and dietary fiber. Nevertheless, asparagus is sensitive to environmental stresses, and specific abiotic stresses harm its yield and quality. In this context, Hsf members have been discerned through the reference genome, and a comprehensive analysis encompassing physical and chemical attributes, evolutionary aspects, motifs, gene structure, cis-acting elements, collinearity, and expression patterns under abiotic stresses has been conducted. The findings identified 18 members, categorized into five distinct subgroups. Members within each subgroup exhibited analogous motifs, gene structures, and cis-acting elements. Collinearity analysis unveiled a noteworthy pattern, revealing that Hsf members within asparagus shared one, two, and three pairs with counterparts in Arabidopsis, Oryza sativa, and Glycine max, respectively.Furthermore, members displayed tissue-specific expression during the seedling stage, with roots emerging as viable target tissue. Notably, the expression levels of certain members underwent modification under the influence of abiotic stresses. This study establishes a foundational framework for understanding Hsf members and offers valuable insights into the potential application of molecular breeding in the context of asparagus cultivation.

Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease.

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aß neurotoxicity and promotes Aß clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.

Aspirin mediates protection from diabetic kidney disease by inducing ferroptosis inhibition.

Diabetic kidney disease (DKD) progression can be predicted by abnormalities in the tubulointerstitial lining, and their treatment may be useful for preventing the disease. DKD is a progressive disease that contributes to renal tubular cell death, but its underlying mechanisms remain unclear. Ferroptosis is a novel term linked to lipid hydroperoxidation, and it plays an important role in the pathogenesis of DKD. Overexpression of cyclooxygenase-2 (COX2), an enzyme of the proximal tubule, causes cellular redox damage in DKD. It remains unknown whether COX2 exacerbates tubular damage by accelerating ferroptosis in the kidneys of diabetic mice. HK-2 cells cultured in high glucose exhibited ferroptosis, which was inhibited by ferroptosis inhibitors. Additionally, alterations in the sensors of ferroptosis metabolism, such as glutathione peroxidase 4 (GPX4) activity, lipid hydroperoxidation, reduced glutathione (GSH) levels and changes in mitochondrial morphology, were observed in high glucose-cultured HK-2 cells. Diabetic mice manifested tubular injury and deranged renal physiological indices, which were mitigated by ferrostatin-1 (Fer-1). Importantly, these perturbations were ameliorated by downregulating COX2. In addition, the increased COX2 was observed to be elevated in the daibetic kindney. To explore the relevance of COX2 to ferroptosis, HK-2 cells that knocked down from COX2 exhibited decreased ferroptosis sensitivity under high glucose conditions. In RSL-3-treated HK-2 cells, ferroptosis was improved by downregulating COX2 by treatment with aspirin, which was confirmed in high glucose-cultured HK-2 cells. Furthermore, the ferroptosis changes were also suppressed by decreasing COX2 in diabetic mice treated with aspirin, which retarded DKD progression. In conclusion, our results demonstrated that ferroptosis in renal tubular cells contributes to DKD development and that diabetes-related ferroptosis was inhibited through the downregulation of COX2 by aspirin, thus retarding the progression of DKD. Our findings support a renoprotective mechanism by which aspirin inhibits COX2 activation, identify COX2 as a potential target of ferroptosis, and establish that ferroptosis in renal tubular cells is an integral process in the pathogenesis of DKD regulated by COX2 expression profiles.

A cell membrane repair protein-based nanoformulation with multiple actuators for scarless wound healing.

Diabetic wounds remain a major contributor to disability worldwide due to their difficulty of healing, and their primary etiologic factor involves impaired cell membrane repair. Additionally, ideal wound repair should prevent excessive scar formation from affecting tissue function following reconstruction. Therefore, the development of a therapeutic strategy for promoting rapid wound healing and reduced scar formation is urgently needed. In this study, a remote light-controlled thermosensitive nanoformulation was developed, which integrated the photothermal conversion performance of a photosensitizer and cell membrane repair protein (rhMG53). The nanoformulation not only protected rhMG53 from being degraded by proteases at the lesion site but also efficiently released this protein through photothermal stimulation. The nanoformulation remained stable at physiological temperatures and released approximately 80% rhMG53 at 45 °C. More protein was effectively delivered to tissue cells, achieving synergistic therapy with photothermal and rhMG53. By utilizing this approach, increased wound closure rate, reduced extent of cell membrane damage and inflammation, and improved cell function were observed in diabetic wounds. More importantly, rhMG53@TSCL3 treatment inhibited excessive skin fibrosis and angiogenesis, indicating a reduction in scar formation. Collectively, this work reveals a promising strategy for high-quality wound repair and provides a new route for rapid scarless wound healing.

Polysaccharide Krestin Prevents Alzheimer's Disease-type Pathology and Cognitive Deficits by Enhancing Monocyte Amyloid-ß Processing.

Deficits in the clearance of amyloid ß protein (Aß) by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer's disease (AD). Impaired uptake of Aß by dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aß clearance in AD. In the current study, flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin (PSK) on AD-related pathology in vitro and in vivo. We found that PSK, widely used in therapy for various cancers, has the potential to enhance Aß uptake and intracellular processing by human monocytes in vitro. After administration of PSK by intraperitoneal injection, APP/PS1 mice performed better in behavioral tests, along with reduced Aß deposition, neuroinflammation, neuronal loss, and tau hyperphosphorylation. These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aß clearance by blood monocytes and alleviating AD-like pathology.

Naturally-Occurring Antibodies Against Bim are Decreased in Alzheimer's Disease and Attenuate AD-type Pathology in a Mouse Model.

Increased neuronal apoptosis is an important pathological feature of Alzheimer's disease (AD). The Bcl-2-interacting mediator of cell death (Bim) mediates amyloid-beta (Aß)-induced neuronal apoptosis. Naturally-occurring antibodies against Bim (NAbs-Bim) exist in human blood, with their levels and functions unknown in AD. In this study, we found that circulating NAbs-Bim were decreased in AD patients. Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions. Furthermore, NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aß deposition, tau hyperphosphorylation, microgliosis, and neuronal apoptosis in APP/PS1 mice. In vitro investigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein. These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.

Time-restricted feeding improves blood glucose and insulin sensitivity in overweight patients with type 2 diabetes: a randomised controlled trial.

BACKGROUND: Time-restricted feeding is an emerging dietary intervention that is becoming increasingly popular. There are, however, no randomised clinical trials of time-restricted feeding in overweight patients with type 2 diabetes. Here, we explored the effects of time-restricted feeding on glycaemic regulation and weight changes in overweight patients with type 2 diabetes over 12 weeks. METHODS: Overweight adults with type 2 diabetes (n = 120) were randomised 1:1 to two diet groups: time-restricted feeding (n = 60) or control (n = 60). Sixty patients participated in a 10-h restricted feeding treatment program (ad libitum feeding from 8:00 to 18:00 h; fasting between 18:00 and 8:00 h) for 12 weeks. RESULTS: Haemoglobin A1c and body weight decreased in the time-restricted feeding group (- 1.54% ± 0.19 and - 2.98 ± 0.43 kg, respectively) relative to the control group over 12 weeks (p < 0.001). Homeostatic model assessment of ß-cell function and insulin resistance changed in the time-restricted feeding group (0.73 ± 0.21, p = 0.005; - 0.51 ± 0.08, p = 0.02, respectively) compared with the control group. The medication effect score, SF-12 score, and the levels of triglycerides, total cholesterol and low-density lipoprotein cholesterol were improved in the time-restricted feeding group (- 0.66 ± 0.17, p = 0.006; 5.92 ± 1.38, p < 0.001; - 0.23 ± 0.08 mmol/L, p = 0.03; - 0.32 ± 0.07 mmol/L, p = 0.01; - 0.42 ± 0.13 mmol/L, p = 0.02, respectively) relative to the control group. High-density lipoprotein cholesterol was not significantly different between the two groups. CONCLUSION: These results suggest that 10-h restricted feeding improves blood glucose and insulin sensitivity, results in weight loss, reduces the necessary dosage of hypoglycaemic drugs and enhances quality of life. It can also offer cardiovascular benefits by reducing atherosclerotic lipid levels. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-15006371).

The Association Between Sleep and Metabolic Syndrome: A Systematic Review and Meta-Analysis.

Purpose: Sleep duration is thought to play a key role in the development of metabolic syndrome. However, the results have been inconsistent. Methods: We conducted a systematic review and meta-analysis of cohort studies and searched publications in PubMed, Embase, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov. The summary relative risks (RRs) were estimated using a random model. The sensitivity analysis was performed by sequentially excluding each study to test the robustness of the pooled estimates. Finding: We included 13 studies involving 300,202 patients in which short sleep and long sleep significantly increased the risk of metabolic syndrome 15% (RR = 1.15, 95%CI = 1.09-1.22, p < 0.001) and 19% (RR = 1.19, 95%CI = 1.05-1.35, p < 0.001). Moreover, the relationship between sleep duration and metabolic syndrome risk presented a U-shaped curve. Short and long sleep increased the risk of obesity by 14% (RR = 1.14, 95%CI = 1.07-1.22, p<0.001) and 15% (RR = 1.15, 95%CI = 1.00-1.30, p = 0.04), and high blood pressure 16% (RR = 1.16, 95%CI = 1.02-1.31, p = 0.03) and 13% (RR = 1.13, 95%CI = 1.04-1.24, p = 0.01), respectively. Short sleep can potentially increase the risk of high blood sugar by 12% (RR = 1.12, 95%CI = 1.00-1.15, P = 0.05). Implications: Based on our findings, sleep is a behavior that can be changed and is economical. Clinically doctors and health professionals should be encouraged to increase their efforts to promote healthy sleep for all people.

Circadian Clock-Controlled Checkpoints in the Pathogenesis of Complex Disease.

The circadian clock coordinates physiology, metabolism, and behavior with the 24-h cycles of environmental light. Fundamental mechanisms of how the circadian clock regulates organ physiology and metabolism have been elucidated at a rapid speed in the past two decades. Here we review circadian networks in more than six organ systems associated with complex disease, which cluster around metabolic disorders, and seek to propose critical regulatory molecules controlled by the circadian clock (named clock-controlled checkpoints) in the pathogenesis of complex disease. These include clock-controlled checkpoints such as circadian nuclear receptors in liver and muscle tissues, chemokines and adhesion molecules in the vasculature. Although the progress is encouraging, many gaps in the mechanisms remain unaddressed. Future studies should focus on devising time-dependent strategies for drug delivery and engagement in well-characterized organs such as the liver, and elucidating fundamental circadian biology in so far less characterized organ systems, including the heart, blood, peripheral neurons, and reproductive systems.

Peripheral clearance of brain-derived Aß in Alzheimer's disease: pathophysiology and therapeutic perspectives.

Alzheimer's disease (AD) is the most common type of dementia, and no disease-modifying treatments are available to halt or slow its progression. Amyloid-beta (Aß) is suggested to play a pivotal role in the pathogenesis of AD, and clearance of Aß from the brain becomes a main therapeutic strategy for AD. Recent studies found that Aß clearance in the periphery contributes substantially to reducing Aß accumulation in the brain. Therefore, understanding the mechanism of how Aß is cleared in the periphery is important for the development of effective therapies for AD. In this review, we summarized recent findings on the mechanisms of Aß efflux from the brain to the periphery and discuss where and how the brain-derived Aß is cleared in the periphery. Based on these findings, we propose future strategies to enhance peripheral Aß clearance for the prevention and treatment of AD. This review provides a novel perspective to understand the pathogenesis of AD and develop interventions for this disease from a systemic approach.

Spicy food consumption is associated with cognition and cerebrospinal fluid biomarkers of Alzheimer disease.

BACKGROUND: Recent studies suggest that a healthy diet helps to prevent the development of Alzheimer disease (AD). This study aimed to investigate whether spicy food consumption is associated with cognition and cerebrospinal fluid (CSF) biomarkers of AD in the Chinese population. METHODS: We enrolled 55 AD patients and 55 age- and gender-matched cognitively normal (CN) subjects in a case-control study, as well as a cohort of 131 participants without subjective cognitive decline (non-AD) in a cross-sectional study. Spicy food consumption was assessed using the Food Frequency Questionnaire (FFQ). Associations of FFQ scores with cognition and CSF biomarkers of AD were analyzed. RESULTS: In the case-control study, spicy food consumption was lower in AD patients than that in CNs (4.0 [4.0-8.0] vs. 8.0 [4.5-10.0], P < 0.001); FFQ scores were positively associated with Mini-Mental Status Examination scores in the total sample (r = 0.218, P = 0.014). In the cross-sectional study, the association between spicy food consumption and cognition levels was verified in non-AD subjects (r = 0.264, P = 0.0023). Moreover, higher FFQ scores were significantly associated with higher ß-Amyloid (1-42) (Aß42) levels and lower phospho-tau/Aß42 and total tau/Aß42 ratios in the CSF of non-AD subjects (P < 0.05). CONCLUSION: Spicy food consumption is closely related to higher cognition levels and reversed AD biomarkers in the CSF, suggesting that a capsaicin-rich diet might have the potential to modify the cognitive status and cerebral pathologies associated with AD.

Amyloid-beta uptake by blood monocytes is reduced with ageing and Alzheimer's disease.

Deficits in the clearance of amyloid ß-protein (Aß) play a pivotal role in the pathogenesis of sporadic Alzheimer's disease (AD). The roles of blood monocytes in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aß phagocytosis function of peripheral monocytes during ageing and in AD patients. A total of 104 cognitively normal participants aged 22-89 years, 24 AD patients, 25 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson's disease patients (PD), and 15 age- and sex-matched CN subjects were recruited. The Aß uptake by blood monocytes was measured and its alteration during ageing and in AD patients were investigated. Aß1-42 uptake by monocytes decreased during ageing and further decreased in AD but not in PD patients. Aß1-42 uptake by monocytes was associated with Aß1-42 levels in the blood. Among the Aß uptake-related receptors and enzymes, the expression of Toll-like receptor 2 (TLR2) was reduced in monocytes from AD patients. Our findings suggest that monocytes regulate the blood levels of Aß and might be involved in the development of AD. The recovery of the Aß uptake function by blood monocytes represents a potential therapeutic strategy for AD.

Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer's disease-type pathology and cognitive deficits in APP/PS1 mice.

Alzheimer's disease (AD) is the most common cause of age-related dementia and is currently incurable. The failures of current clinical trials and the establishment of modifiable risk factors have shifted the AD intervention from treatment to prevention in the at-risk population. Previous studies suggest that there is a geographic overlap between AD incidence and spicy food consumption. We previously reported that capsaicin-rich diet consumption was associated with better cognition and lower serum Amyloid-beta (Aß) levels in people aged 40 years and over. In the present study, we found that intake of capsaicin, the pungent ingredient in chili peppers, reduced brain Aß burden and rescued cognitive decline in APP/PS1 mice. Our in vivo and in vitro studies revealed that capsaicin shifted Amyloid precursor protein (APP) processing towards α-cleavage and precluded Aß generation by promoting the maturation of a disintegrin and metalloproteinase 10 (ADAM10). We also found that capsaicin alleviated other AD-type pathologies, such as tau hyperphosphorylation, neuroinflammation and neurodegeneration. The present study suggests that capsaicin is a potential therapeutic candidate for AD and warrants clinical trials on chili peppers or capsaicin as dietary supplementation for the prevention and treatment of AD.

Protective effect of rapamycin on endothelial-to-mesenchymal transition in HUVECs through the Notch signaling pathway.

Neointima hyperplasia is one of the predominant features of cardiovascular diseases such as atherosclerosis, and is also responsible for the restenosis of vascular surgery including arteriovenous fistula and stent implantation. Endothelial-to-mesenchymal transition (EndMT) contributes to neointima hyperplasia by activation of the Notch or TGF-ß signaling pathway. Rapamycin has been utilized as anti-restenosis drug due to its anti-proliferative activity. However, its effects on the EndMT have not been investigated yet. Thus, we examined the biological effects of rapamycin on the EndMT and its potential mechanisms. We showed that rapamycin significantly reversed TGF-ß1 stimulated EndMT by upregulating endothelial marker CD31 expression and downregulating mesenchymal marker SMA-α expression in human umbilical vein endothelial cells (HUVECs). Rapamycin also inhibited TGF-ß1 induced expression of the Notch signaling pathway components expression, such as Notch-1, Jagged-1, RBP-jκ and Hes-5. Among the different Notch receptors and ligands, Jagged-1/Notch-1 cascade was most remarkably blocked by rapamycin. Finally, consistently with the results from Notch inhibitor DAPT treatment, rapamycin suppressed the migration of HUVECs in vitro. Together, these findings indicate that rapamycin may function as an effective inhibitor of the EndMT in HUVECs by suppressing targeting the Notch signaling pathway.