The liver is the center for uptake, synthesis, packaging, and secretion of lipids and lipoproteins. The research on lipid metabolism in pigs is limited. The objective of the present study is to identi Show more
The liver is the center for uptake, synthesis, packaging, and secretion of lipids and lipoproteins. The research on lipid metabolism in pigs is limited. The objective of the present study is to identify the genes related to lipid metabolism and oxidative stress in pigs by using transcriptomic analysis. Liver segments were collected from 60 Jinhua pigs for the determination of liver lipid content. The 7 pigs with the highest and lowest liver lipid content were set as group H and group L, respectively. Liver segments and serum samples were collected from each pig of the H and L groups for RNA sequencing and the determination of triglycerides (TG) content and high-density lipoprotein cholesterol (HDL) content, respectively. The HDL content in the serum of pigs in the H group was significantly higher than the L group ( Show less
Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune and demyelinating disease of the peripheral nervous system. Currently, valid biomarkers are unavailable for the diagnosis of GBS. A co Show more
Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune and demyelinating disease of the peripheral nervous system. Currently, valid biomarkers are unavailable for the diagnosis of GBS. A comparative proteomics analysis was performed on the cerebrospinal fluid (CSF) from 10 patients with GBS and 10 patients with noninflammatory neurological disease (NND) using the tandem mass tags technique. The differentially expressed proteins were analyzed by bioinformatics, and then the candidate proteins were validated by the enzyme-linked immunosorbent assay method in another cohort containing 160 samples (paired CSF and plasma of 40 patients with GBS, CSF of 40 NND patients and plasma of 40 healthy individuals). In all, 298 proteins were successfully identified in the CSF samples, of which 97 differentially expressed proteins were identified in the GBS and NND groups. Three key molecules were identified as candidate molecules for further validation. The CSF levels of TGOLN2 and NCAM1 decreased in GBS patients compared with NND patients, whereas the CSF levels of APOC3 increased. The enzyme-linked immunosorbent assay results were consistent with our proteomics analysis. Interestingly, in the validation cohort, serum APOC3 levels in the GBS group were consistent with those in the CSF samples and significantly higher than those in the healthy control group. Our preliminary data suggest that the CSF protein expression profile of patients with GBS is different from that of patients with NND. Moreover, alterations of TGOLN2, NCAM1and APOC3 may be used as novel biomarkers for identifying patients with GBS. Show less
The amplitude of Wnt/β-catenin signaling is precisely controlled by the assembly of the cell surface-localized Wnt receptor signalosome and the cytosolic β-catenin destruction complex. How these two d Show more
The amplitude of Wnt/β-catenin signaling is precisely controlled by the assembly of the cell surface-localized Wnt receptor signalosome and the cytosolic β-catenin destruction complex. How these two distinct complexes are coordinately controlled remains largely unknown. Here, we demonstrated that the signalosome scaffold protein Dishevelled 2 (Dvl2) undergoes liquid-liquid phase separation (LLPS). Dvl2 LLPS is mediated by an intrinsically disordered region and facilitated by components of the signalosome, such as the receptor Fzd5. Assembly of the signalosome is initiated by rapid recruitment of Dvl2 to the membrane, followed by slow and dynamic recruitment of Axin1. Axin LLPS mediates assembly of the β-catenin destruction complex, and Dvl2 attenuates LLPS of Axin. Compared with the destruction complex, Axin partitions into the signalosome at a lower concentration and exhibits a higher mobility. Together, our results revealed that Dvl2 LLPS is crucial for controlling the assembly of the Wnt receptor signalosome and disruption of the phase-separated β-catenin destruction complex. Show less
Pancreatic cancer (PC) is a lethal type of cancer for which effective therapies are limited. Long non‑coding RNAs (lncRNAs) represent a critical type of regulator category, mediating the tumorigenesis Show more
Pancreatic cancer (PC) is a lethal type of cancer for which effective therapies are limited. Long non‑coding RNAs (lncRNAs) represent a critical type of regulator category, mediating the tumorigenesis and development of various tumor types, including PC. However, the expression patterns and functions of numerous lncRNAs in PC remain poorly understood. In the present study, linc01614 was identified as a PC‑related lncRNA. linc01614 was notably upregulated in PC tissues and cell lines and was associated with the poor disease‑free survival of patients with PC according to the analysis of The Cancer Genome Atlas‑derived datasets. Functionally, linc01614 knockdown suppressed PC cell proliferation, migration and invasion Show less
Liver hepatocellular carcinoma (LIHC) is the major form of liver cancer that is the fourth most common cause of cancer death worldwide. It has been reported that the multifunctional protein p62 (also Show more
Liver hepatocellular carcinoma (LIHC) is the major form of liver cancer that is the fourth most common cause of cancer death worldwide. It has been reported that the multifunctional protein p62 (also known as SQSTM1) plays a cancer-promoting role in LIHC, but the detailed mechanisms underlying p62 interaction with LIHC remains unclear. To gain a comprehensive understanding of p62 interaction with LIHC in clinical settings, we performed bioinformatic analyses using various online algorithms derived from high throughput profiling. Our results indicate that p62 expression is significantly upregulated, partially due to its promoter demethylation, rather than p62 gene mutation, in LIHC. Mutation of TP53, CTNNB1, or ALB significantly correlates with, and mutation of AXIN1 reversely correlates with, the p62 expression level. Its upregulation occurs as early as liver cirrhosis, and go through all stages of the carcinogenesis. HCV infection makes a significant contribution to p62 upregulation in LIHC. We further identified p62-associated molecular signatures in LIHC, including many genes that are involved in antioxidant stress and metabolism, such as SRX1 and TXNRD1. Regarding to the clinical outcome, p62 expression level reversely correlates with the survival of LIHC patients (p<0.01). Importantly, we experimentally validated that p62 depletion in liver cancer cell lines downregulates the expression of SRX1 and TXNRD1 at both transcriptional and translational levels, and reduces cell proliferation. As the potential mechanisms underlying the tumor-promoting role of p62, we show that p62 upregulation is remarkably associated with reprogramming of pathways mediated by p53, Wnt/β-catenin, and Keap1-NRF2, which are crucial for oncogenesis in many contexts. Our findings provide a comprehensive insight into the interaction between p62 and LIHC, offering valuable information for understanding of LIHC pathogenesis. Show less
Axin1 is a fundamental scaffolding protein of the destruction complex in the canonical Wnt signaling pathway, which plays a critical role in various biological processes. However, how Axin1 is regulat Show more
Axin1 is a fundamental scaffolding protein of the destruction complex in the canonical Wnt signaling pathway, which plays a critical role in various biological processes. However, how Axin1 is regulated in the activation of the canonical Wnt signaling pathway remains elusive. Here, we report that Axin1 is constitutively acetylated in resting cells. Upon stimulation with Wnt, SIRT4 translocates from mitochondria to the cytoplasm and catalyzes Axin1 deacetylation, thus turning off the destruction complex. In this process, Lys147, a residue in the RGS domain of Axin1, plays a key role. We proved that the Axin1-K147R mutant impairs the assembly of β-TrCP to the destruction complex, which leads to β-catenin accumulation even without Wnt stimulation. In summary, our work proposes a new model for better understanding the initial stage of the canonical Wnt signaling pathway in which SIRT4 translocates from mitochondria into the cytoplasm to deacetylate Axin1-K147 after Wnt stimulation, which results in reduced assembly of β-TrCP to the destruction complex. Show less
Aberrant expression of tripartite motif 11 (TRIM11) and the Wnt/ To investigate the molecular changes linking the dysregulation of TRIM11 and Wnt/ The expression levels of TRIM11 were detected in GC t Show more
Aberrant expression of tripartite motif 11 (TRIM11) and the Wnt/ To investigate the molecular changes linking the dysregulation of TRIM11 and Wnt/ The expression levels of TRIM11 were detected in GC tissues and cells by immunohistochemistry and western blotting. The role of TRIM11 in the growth, proliferation, and invasion of gastric cancer cells was observed by a series of cell functional experiments and further verified in vivo. Co-immunoprecipitation (Co-IP), immunofluorescence, cycloheximide, and western blotting assays and other experiments were conducted to explore the mechanisms of TRIM11 underlying the regulation of the Wnt/ Using Co-IP assays, we identified TRIM11 as a potent binding partner of Axin1 in GC cells. Elevated TRIM11 levels were significantly correlated with unfavorable clinical outcomes and poor survival in patients with GC. In addition, TRIM11 promoted the cell proliferation and invasion capacities of GC cells in vitro and tumor growth in vivo. Mechanistic investigations revealed that TRIM11 destabilized Axin1 protein by interacting with Axin1, thus inducing the activation of the Wnt/ Collectively, our findings not only establish a pivotal TRIM11-Axin1- Show less
Recent studies have revealed the close correlation between microRNAs (miRs) and Parkinson's disease (PD). Here, we aimed to investigate the neuroprotective effect of miR-124 in a PD mouse model. MiR-1 Show more
Recent studies have revealed the close correlation between microRNAs (miRs) and Parkinson's disease (PD). Here, we aimed to investigate the neuroprotective effect of miR-124 in a PD mouse model. MiR-124 expression in human plasma was detected by qRT-PCR. PD mouse model was established by stereotactic injection of 6-hydroxydopmine. Lentivirus were used to deliver and overexpress miR-124 and Axin1 into the substantia nigra. Multiple behavioral tests and oxidative stress assays were carried out to access the protective effect of miR-124 against PD. Western blot and luciferase assay were conducted to dissect the underlying molecular mechanisms. MiR-124 expression was decreased in PD patients. Overexpression of miR-124 in PD mice could improve motor defects, ameliorate dopaminergic neurons loss, and reduce oxidative stress. Mechanistically, miR-124 targeted Axin1 directly, and then attenuated PD progression via suppressing Axin1 and activating the Wnt/β-catenin pathways in PD mice. MiR-124 is an important neuroprotective factor, which suppresses Axin1 and activates Wnt/β-catenin signaling pathways in PD mice. Show less
A meta-analysis of locus-based genome-wide association studies recently identified a relationship between AXIN1 and Parkinson's disease (PD). Few studies of Asian populations, however, have reported s Show more
A meta-analysis of locus-based genome-wide association studies recently identified a relationship between AXIN1 and Parkinson's disease (PD). Few studies of Asian populations, however, have reported such a genetic association. The influences of rs13337493, rs758033, and rs2361988, three PD-associated genetic variants of AXIN1, were investigated in the present study because AXIN1 is related to Wnt/β-catenin signaling. A total of 2,418 individuals were enrolled in our Taiwanese cohort for analysis of the genotypic and allelic frequency. Polymerase chain reaction-restriction fragment length polymorphism analysis was employed for rs13337493 genotyping, and the Agena MassARRAY platform (Agena Bioscience, San Diego, CA, USA) was used for rs758033 and rs2361988 genotyping in 672 patients with PD and 392 controls. Taiwan Biobank data of another 1,354 healthy controls were subjected to whole-genome sequencing performed using Illumina platforms at approximately 30× average depth. Our results revealed that rs758033 {odds ratios [OR] (95% confidence interval [CI]) = 0.267 [0.064, 0.795], p = 0.014} was associated with the risk of PD, and there was a trend toward a protective effect of rs2361988 (OR [95% CI] = 0.296 [0.071, 0.884], p = 0.026) under the recessive model. The TT genotype of rs758033 (OR [95% CI] = 0.271 [0.065, 0.805], p = 0.015) and the CC genotype of rs2361988 (OR [95% CI] = 0.305 [0.073, 0.913], p = 0.031) were less common in the PD group than in the non-PD group. Our findings indicate that the rs758033 and rs2361988 polymorphisms of AXIN1 may affect the risk of PD in the Taiwanese population. Show less
Genetic factors play a critical role in the pathogenesis of osteoporosis. The imbalance of WNT/β-catenin will cause the occurrence of osteoporosis. LRP5 and AXIN1 play an important role in the classic Show more
Genetic factors play a critical role in the pathogenesis of osteoporosis. The imbalance of WNT/β-catenin will cause the occurrence of osteoporosis. LRP5 and AXIN1 play an important role in the classical Wnt/β-catenin signaling pathway. Our study was aimed to determine the association between five candidate single nucleotide polymorphisms (SNPs) of LRP5 or AXIN1 and osteoporosis susceptibility in Chinese Han population. A total of 599 osteoporosis patients and 599 healthy individuals were recruited for this case-control study. Agena MassARRAY was used to genotype SNPs. The association between SNPs and osteoporosis susceptibility in different genetic models was analyzed by PLINK software. We used false-positive report probability (FPRP) analysis to detect whether the positive results were just chance or noteworthy observations. Multifactor dimension reduction (MDR) was used to analyze the interaction of SNP-SNP in the osteoporosis risk. Finally, haplotype analysis was performed by plink1.07 and Haploview software. We found that LRP5 rs11228240, AXIN1 rs2301522, and rs9921222 were significantly associated with the osteoporosis susceptibility. The results of subgroup analysis showed that LRP5 rs11228240 (protective factor) and AXIN1 rs2301522 (risk factor) were associated with the susceptibility of osteoporosis among participants who were age >60 years, female or BMI ≤ 24; AXIN1 rs9921222 significantly increased the risk of osteoporosis among participants with BMI ≤ 24. The genotype A The LRP5-rs11228240, AXIN1-rs2301522, and AXIN1- rs9921222 were associated with osteoporosis susceptibility in Chinese Han population. Show less
Neuritic plaques are one of the major pathological hallmarks of Alzheimer's disease. They are formed by the aggregation of extracellular amyloid-β protein (Aβ), which is derived from the sequential cl Show more
Neuritic plaques are one of the major pathological hallmarks of Alzheimer's disease. They are formed by the aggregation of extracellular amyloid-β protein (Aβ), which is derived from the sequential cleavage of amyloid-β precursor protein (APP) by β- and γ-secretase. BACE1 is the main β-secretase in the pathogenic process of Alzheimer's disease, which is believed to be a rate-limiting step of Aβ production. Presenilin 1 (PS1) is the active center of the γ-secretase that participates in the APP hydrolysis process. Mutations in the PS1 gene ( Show less
The interrelationships between neuronal viability, synaptic integrity, and microglial responses remain in infancy. In dealing with the question, we induced a stretch injury to evaluate the mechanical Show more
The interrelationships between neuronal viability, synaptic integrity, and microglial responses remain in infancy. In dealing with the question, we induced a stretch injury to evaluate the mechanical effects of trauma on rat primary cortical neurons and BV2 microglial cells in a transwell culture system. The viability of primary neurons and BV2 cells was determined by MTT. Synaptic integrity was evaluated by determining the expression of beta-secretase 1 (BACE1), amyloid-beta (Aβ), microtubule-associated protein 2 (MAP2), and synaptophysin (vehicle protein). Both CD16/32-positive (CD16/32 Show less
Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are prevalent diseases with similar pathophysiological characteristics and genetic predispositions. Polyunsaturated fatty acids (PUFAs) are Show more
Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are prevalent diseases with similar pathophysiological characteristics and genetic predispositions. Polyunsaturated fatty acids (PUFAs) are essential in maintaining normal brain function. However, little is known about the effect of dietary n-6/n-3 PUFA ratio on AD-like pathology, particularly in high-fat diet (HFD)-fed AD model mice. In the present study, the APP/PS1 mice were fed with 60 % HFD for 3.5 months to induce insulin resistance. After that, 45 % HFD with various n-6/n-3 PUFA ratios (n-6/n-3 = 1:1, 5:1 or 16:1) was applied for an additional 3.5 months of treatment. The behavior of mice was observed using the water maze after dietary intervention. The animals were euthanized after behavioral testing, and serum and tissue samples were collected for biochemical, histological, and pathological tests and evaluation. HFD caused insulin resistance, increased serum IL-6 and TNF-α levels, cortical soluble Aβ Show less
Being the most common form of dementia, Alzheimer's disease (AD) has a series of modifiable risk factors, including metal ions represented by aluminium. Aluminium (Al) exhibits its neurotoxic effects, Show more
Being the most common form of dementia, Alzheimer's disease (AD) has a series of modifiable risk factors, including metal ions represented by aluminium. Aluminium (Al) exhibits its neurotoxic effects, especially mainly by affecting amyloid-β protein (Aβ) aggregation and Tau hyperphosphorylation. As reported in our previous study, the combination of Alpinia Oxyphylla Fructus and Schisandra Chinensis Fructus (AS) had a neuroprotective effect. This study aimed to evaluate the anti-AD effect of AS and the mechanism by which AS reduces the neurotoxic effect of Al. Firstly, we used aluminium-maltol (Al(mal) Show less
Alzheimer's disease is a global public health problem and the most common form of dementia. Due to the failure of many single therapies targeting the two hallmarks, Aβ and Tau, and the multifactorial Show more
Alzheimer's disease is a global public health problem and the most common form of dementia. Due to the failure of many single therapies targeting the two hallmarks, Aβ and Tau, and the multifactorial etiology of AD, there is now more and more interest in nutraceutical agents with multiple effects such as Show less
Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular Show more
Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular compound 2JY-OBZ4 is one of structural analogue of Huperzine A (Hup-A), an anti-AD drug in China. In our previous work, 2JY-OBZ4 exhibited potent effects on tau hyperphosphorylation, Aβ production and acetylcholinesterase (AChE) activity. However, 2JY-OBZ4's anti-AD effects and the underlying molecular mechanisms remain unclear. We here reported that 2JY-OBZ4 resisted tau hyperphosphorylation at Thr181 and Ser396 sites in HEK293-hTau cells transfected with GSK-3β, decreased tau phosphorylation via upregulating the activity of PP2A in HEK293-hTau cells and reduced Aβ production through regulating protein levels of APP cleavage enzymes in N2a-hAPP cells. Meanwhile, we found that 2JY-OBZ4 had no adverse effects on cell viability of mice primary neuron even at high concentration, and ameliorated synaptic loss induced by human oligomeric Aβ42. 2JY-OBZ4 had moderate AChE inhibitory activity with the half maximal inhibitory concentration (IC50) to be 39.48 μg/ml Show less
Moderate physical exercise is conducive to the brains of healthy humans and AD patients. Previous reports have suggested that treadmill exercise plays an anti-AD role and improves cognitive ability by Show more
Moderate physical exercise is conducive to the brains of healthy humans and AD patients. Previous reports have suggested that treadmill exercise plays an anti-AD role and improves cognitive ability by promoting amyloid clearance, inhibiting neuronal apoptosis, reducing oxidative stress level, alleviating brain inflammation, and promoting autophagy-lysosome pathway in AD mice. However, few studies have explored the relationships between the ubiquitin-proteasome system and proper exercise in AD. The current study was intended to investigate the mechanism by which the exercise-regulated E3 ubiquitin ligase improves AD. Both wild type and APP/PS1 transgenic mice were divided into sedentary (WTC and ADC) and exercise (WTE and ADE) groups (n = 12 for each group). WTE and ADE mice were subjected to treadmill exercise of 12 weeks in order to assess the effect of treadmill running on learning and memory ability, Aβ plaque burden, hyperphosphorylated Tau protein and E3 ubiquitin ligase. The results indicated that exercise restored learning and memory ability, reduced Aβ plaque areas, inhibited the hyperphosphorylation of Tau protein activated PI3K/Akt/Hsp70 signaling pathway, and improved the function of the ubiquitin-proteasome system (increased UCHL-1 and CHIP levels, decreased BACE1 levels) in APP/PS1 transgenic mice. These findings suggest that exercise may promote the E3 ubiquitin ligase to clear β-amyloid and hyperphosphorylated Tau by activating the PI3K/Akt signaling pathway in the hippocampus of AD mice, which is efficient in ameliorating pathological phenotypes and improving learning and memory ability. Show less
As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer's disease (AD) for decades in China. However, Hup-A causes some side effects. Show more
As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer's disease (AD) for decades in China. However, Hup-A causes some side effects. To search for new analogs or derivatives of Hup-A, we produced five Lycopodium alkaloids and two analogues by chemical synthesis: Lyconadins A-E, H-R-NOB, and 2JY-OBZ4. To systematically evaluate the therapeutic effects of the seven compounds on AD cell models. We assessed the effects of the seven compounds on cell viability via CCK-8 kit and used HEK293-hTau cells and N2a-hAPP cells as AD cell models to evaluate their potential therapeutic effects. We examined their effects on cholinesterase activity by employing the mice primary neuron. All compounds did not affect cell viability; in addition, Lyconadin A and 2JY-OBZ4 particularly increased cell viability. Lyconadin D and Lyconadin E restored tau phosphorylation at Thr231, and H-R-NOB and 2JY-OBZ4 restored tau phosphorylation at Thr231 and Ser396 in GSK-3β-transfected HEK293-hTau cells. 2JY-OBZ4 decreased the level of PP2Ac-pY307 and increased the level of PP2Ac-mL309, supporting that 2JY-OBZ4 may activate PP2A. Lyconadin B, Lyconadin D, Lyconadin E, H-R-NOB, and 2JY-OBZ4 increased sAβPPα level in N2a-hAPP cells. 2JY-OBZ4 decreased the levels of BACE1 and sAβPPβ, thereby reduced Aβ production. Seven compounds exhibited weaker AChE activity inhibition efficiency than Hup-A. Among them, 2JY-OBZ4 showed the strongest AChE inhibition activity with an inhibition rate of 17% at 10μM. Among the seven Lycopodium compounds, 2JY-OBZ4 showed the most expected effects on promoting cell viability, downregulating tau hyperphosphorylation, and Aβ production and inhibiting AChE in AD. Show less
Alzheimer's disease is a neurodegenerative disease caused by excessive amyloid β protein-induced neurotoxicity. However, drugs targeting amyloid β protein production face many problems, such as the lo Show more
Alzheimer's disease is a neurodegenerative disease caused by excessive amyloid β protein-induced neurotoxicity. However, drugs targeting amyloid β protein production face many problems, such as the low utilization rate of drugs by cells and the difficulty of drugs in penetrating the blood-brain barrier. A tetrahedral framework nucleic acid is a new type of nanonucleic acid structure that functions as a therapy and drug carrier. Here, we synthesized a BACE1 aptamer-modified tetrahedral framework nucleic acid and tested its therapeutic effect on Alzheimer's disease Show less
The pathogenesis of Alzheimer's disease (AD) is very complex, and there are many hypotheses. Therefore, the development of a multi-target-directed-ligand may be an effective therapeutic strategy. Our Show more
The pathogenesis of Alzheimer's disease (AD) is very complex, and there are many hypotheses. Therefore, the development of a multi-target-directed-ligand may be an effective therapeutic strategy. Our previous study showed that notopterol (a natural product from Show less
Yuan-Zhi Decoction (YZD) is a traditional Chinese medical formulation with demonstrated clinical benefits in Alzheimer's disease (AD). We used liquid chromatography coupled with mass spectrometry to i Show more
Yuan-Zhi Decoction (YZD) is a traditional Chinese medical formulation with demonstrated clinical benefits in Alzheimer's disease (AD). We used liquid chromatography coupled with mass spectrometry to identify 27 unique chemical components of YZD. Analyzing these using network pharmacology and molecular docking models identified 34 potential interacting molecular targets involved in 26 biochemical pathways. When tested in an animal model of AD, the APP/PS1 transgenic mice showed measurable improvements in spatial orientation and memory after the administration of YZD. These improvements coincided with significantly reduced deposition of Aβ plaques and tau protein in the hippocampi in the treated animals. In addition, a decreased BACE1 and beta-amyloid levels, a downregulation of the p-GSK-3β/GSK-3β, and an upregulation of the PI3K and p-AKT/AKT pathway was seen in YZD treated animals. These Show less
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder for which there is no effective therapeutic strategy. PcActx peptide from the transcriptome of zoantharian
Triple ionic and electronic conductivity (TIEC) in cathode materials for protonic ceramic fuel cells (PCFCs) is a desirable feature that enhances the spatial expansion of active reaction sites for ele Show more
Triple ionic and electronic conductivity (TIEC) in cathode materials for protonic ceramic fuel cells (PCFCs) is a desirable feature that enhances the spatial expansion of active reaction sites for electrochemical oxygen reduction reaction. The realization of optimal TIEC in single-phase materials, however, is challenging. A facile route that facilitates the optimization of TIEC in PCFC cathodes is the strategic development of multiphase cathode materials. In this study, a cubic-rhombohedral TIEC nanocomposite material with the composition Ba(CeCo) Show less
Silver nanoparticles (AgNPs) are widely used in a variety of consumer products because of their antibacterial and antifungal characteristics, but little is known about their toxicity to the brain. In Show more
Silver nanoparticles (AgNPs) are widely used in a variety of consumer products because of their antibacterial and antifungal characteristics, but little is known about their toxicity to the brain. In this study, we investigated AgNP-induced neurotoxicity using the human neuroblastoma cancer (SH-SY5Y) cell line. After a 24 h treatment of AgNPs with two primary sizes (5 and 50 nm labeled as Ag-5 and Ag-50, respectively), a series of toxicological endpoints including cell viability, expression of proteins and genes in amyloid precursor protein (APP) amyloid hydrolysis process and ferritinophagy signaling pathways, oxidative stress, intracellular iron levels, and molecular regulators of iron metabolism were evaluated. Our results showed that both Ag-5 and Ag-50 induced notable neurotoxic effects on SH-SY5Y cells indicated by cell proliferation inhibition, increased BACE1 protein expression, and decreased APP and ADAM10 gene expression. Activation of nuclear receptor coactivator 4-mediated ferritinophagy and blockade of autophagic flux were induced by AgNPs, accompanied by intracellular iron accumulation and overexpression of divalent metal-ion transporter-1 and ferroportin1 in SH-SY5Y cells. In addition, AgNPs significantly decreased glutathione peroxidase 4 protein expression but increased malondialdehyde concentration, suggesting that AgNP-induced iron accumulation may trigger oxidative stress by disruption of the intracellular oxidant and antioxidant systems. In addition, compared with Ag-50, Ag-5 with higher cellular uptake efficiency caused more detrimental effects on SH-SY5Y cells. In conclusion, our findings demonstrated a size-dependent neurotoxicity in SH-SY5Y cells by AgNPs via ferritinophagy-mediated oxidative stress. Show less
Multi-targeted directed ligands (MTDLs) are emerging as promising Alzheimer's disease (AD) therapeutic possibilities. Coumarin is a multifunctional backbone with extensive bioactivity that has been ut Show more
Multi-targeted directed ligands (MTDLs) are emerging as promising Alzheimer's disease (AD) therapeutic possibilities. Coumarin is a multifunctional backbone with extensive bioactivity that has been utilized to develop innovative anti-neurodegenerative properties and is a desirable starting point for the construction of MTDLs. Herein, we explored and synthesized a series of novel coumarin derivatives and assessed their inhibitory effects on cholinesterase (AChE, BuChE), GSK-3β, and BACE1. Among these compounds, compound 30 displayed the multifunctional profile of targeting the AChE (IC Show less
The deposition of β-amyloid (Aβ) in the brain plays a major role in the pathogenesis of Alzheimer's disease (AD). Aβ is generated via amyloid precursor protein (APP) cleavage through the amyloidogenic Show more
The deposition of β-amyloid (Aβ) in the brain plays a major role in the pathogenesis of Alzheimer's disease (AD). Aβ is generated via amyloid precursor protein (APP) cleavage through the amyloidogenic pathway. In this pathway, β-secretase (BACE1) is the first and rate-limiting enzyme. Its expression increases through an unknown mechanism in patients with AD. Thus, the key regulatory mechanism of BACE1 in the AD process should be revealed to understand the pathogenesis of AD and explore the key treatment targets of AD. Here, APPswe/PS1dE9 (APP/PS1) mice were employed to observe the Krüppel-like factor 5 (KLF5) and BACE1 levels in the serum and brain tissues. HT22 cells were used to explore the relationship between KLF5 and BACE1. In this study, KLF5 was found to be a novel transcription factor that positively regulated BACE1 by binding to the BACE1 promoter. The KLF5 levels significantly increased not only in the CSF and serum of patients with AD but also in the brain tissue of APP/PS1 mice. They were closely related to cognitive capacity. KLF5 accelerated APP amyloidogenic metabolism and promoted Aβ synthesis through BACE1. Silencing BACE1 could block the KLF5-induced amyloidogenic process of APP. ML264 ameliorated the cognitive deficits and slowed down APP amyloidogenic cleavage in APP/PS1 mice. The findings above suggest that upregulation of KLF5 might be a critical element in AD progression by accelerating BACE1-mediated APP amyloidogenic cleavage. The inhibition of KLF5 or the combined inhibitory effect of KLF5 and the BACE1 promoter might be a potential strategy to prevent AD pathogenesis. Show less