Genistein alleviates pulmonary fibrosis by inactivating lung fibroblasts.

Pulmonary fibrosis is a serious lung disease that occurs predominantly in men. Genistein is an important natural soybeanderived phytoestrogen that affects various biological functions, such as cell migration and fibrosis. However, the antifibrotic effects of genistein on pulmonary fibrosis are largely unknown. The antifibrotic effects of genistein were evaluated using in vitro and in vivo models of lung fibrosis. Proteomic data were analyzed using nano-LC-ESI-MS/MS. Genistein significantly reduced transforming growth factor (TGF)-ß1-induced expression of collagen type I and α-smooth muscle actin (SMA) in MRC-5 cells and primary fibroblasts from patients with idiopathic pulmonary fibrosis (IPF). Genistein also reduced TGF-ß1-induced expression of p-Smad2/3 and p-p38 MAPK in fibroblast models. Comprehensive protein analysis confirmed that genistein exerted an anti-fibrotic effect by regulating various molecular mechanisms, such as unfolded protein response, epithelial mesenchymal transition (EMT), mammalian target of rapamycin complex 1 (mTORC1) signaling, cell death, and several metabolic pathways. Genistein was also found to decrease hydroxyproline levels in the lungs of BLM-treated mice. Genistein exerted an anti-fibrotic effect by preventing fibroblast activation, suggesting that genistein could be developed as a pharmacological agent for the prevention and treatment of pulmonary fibrosis. [BMB Reports 2024; 57(3): 143-148].

Possibility of decryption speed-up by parallel processing in CCA secure hashed ElGamal.

In order to prove the ElGamal CCA(Chosen Ciphertext Attack) security in the random oracle model, it is necessary to use the group where ICDH(Interactive Computational Diffie Hellman) assumption holds. Until now, only bilinear group with complex algebraic structure has been known as the ICDH group. In this paper, we introduce the ICDH group with simple algebraic structure. In other words, we prove that ICDH assumption holds in the integer group with composite modulus. On the basis of this, we propose the CCA secure hashed ElGamal and its fast variant to speed up decryption by parallel processing. Our parallel scheme has the fastest decryption among all CCA secure PKE(Public Key Encryption) schemes implemented in integer group and gives the possibility that ElGamal protocol could be practical when the big modulus numbers are used to resist the quantum attack.

Microbiota influences host exercise capacity via modulation of skeletal muscle glucose metabolism in mice.

The microbiota enhances exercise performance and regulates host physiology and energy metabolism by producing beneficial metabolites via bacterial fermentation. In this study, we discovered that germ-free (GF) mice had a reduced capacity for aerobic exercise as well as low oxygen consumption rates and glucose availability. Surprisingly, GF mice showed lower body weight gain and lower fat mass than specific pathogen-free (SPF) mice. Therefore, we hypothesized that these paradoxical phenotypes could be mediated by a compensatory increase in lipolysis in adipose tissues owing to impaired glucose utilization in skeletal muscle. Our data revealed that gut microbiota depletion impairs host aerobic exercise capacity via the deterioration of glucose storage and utilization. The improved browning ability of GF mice may have contributed to the lean phenotype and negatively affected energy generation. These adaptations limit obesity in GF mice but impede their immediate fuel supply during exercise, resulting in decreased exercise performance.

The Relationship Between Retinal and Choroidal Thickness and Adiponectin Concentrations in Patients With Type 2 Diabetes Mellitus.

Purpose: To evaluate the association between retinal and choroidal thickness and serum and aqueous humor (AH) adiponectin concentrations in patients with diabetic retinopathy (DR). Methods: This prospective study enrolled diabetic patients without DR (group 1, n = 46) and with DR (n = 130). Central foveal thickness (CFT), subfoveal choroidal thickness (SCT), and adiponectin in serum and AH concentrations were compared. For subgroup analysis, the DR group was divided into four subgroups: mild (group 2), moderate (group 3), severe nonproliferative DR (group 4), and panretinal photocoagulation (group 5). Results: The log-transformed serum and AH adiponectin concentrations in patients with DR (groups 2-5) were higher than in patients without DR (all Ps < 0.001). In addition, serum and AH adiponectin concentrations showed a positive linear correlation with DR severity (P < 0.001 and P = 0.001, respectively). In univariate analysis between serum or AH adiponectin concentrations and CFT or SCT, AH adiponectin significantly correlated with CFT and SCT (all Ps < 0.001). However, serum adiponectin concentration significantly correlated with SCT (P = 0.041) but not with CFT (P = 0.337). In multivariate analysis, AH adiponectin concentration significantly correlated with CFT, but serum adiponectin concentration did not (P = 0.002 and 0.309, respectively). In contrast, serum and AH adiponectin concentrations significantly correlated with SCT (P = 0.048 and 0.041, respectively). Conclusions: Serum and AH adiponectin concentrations are positively associated with DR development and progression. Additionally, SCT looks related to the serum and AH adiponectin concentrations, whereas CFT looks related to AH adiponectin concentrations.

Proteomic analysis for the effects of non-saponin fraction with rich polysaccharide from Korean Red Ginseng on Alzheimer's disease in a mouse model.

Background: The most common type of dementia, Alzheimer's disease (AD), is marked by the formation of extracellular amyloid beta (Aß) plaques. The impairments of axons and synapses appear in the process of Aß plaques formation, and this damage could cause neurodegeneration. We previously reported that non-saponin fraction with rich polysaccharide (NFP) from Korean Red Ginseng (KRG) showed neuroprotective effects in AD. However, precise molecular mechanism of the therapeutic effects of NFP from KRG in AD still remains elusive. Methods: To investigate the therapeutic mechanisms of NFP from KRG on AD, we conducted proteomic analysis for frontal cortex from vehicle-treated wild-type, vehicle-treated 5XFAD mice, and NFP-treated 5XFAD mice by using nano-LC-ESI-MS/MS. Metabolic network analysis was additionally performed as the effects of NFP appeared to be associated with metabolism according to the proteome analysis. Results: Starting from 5,470 proteins, 2,636 proteins were selected for hierarchical clustering analysis, and finally 111 proteins were further selected for protein-protein interaction network analysis. A series of these analyses revealed that proteins associated with synapse and mitochondria might be linked to the therapeutic mechanism of NFP. Subsequent metabolic network analysis via genome-scale metabolic models that represent the three mouse groups showed that there were significant changes in metabolic fluxes of mitochondrial carnitine shuttle pathway and mitochondrial beta-oxidation of polyunsaturated fatty acids. Conclusion: Our results suggested that the therapeutic effects of NFP on AD were associated with synaptic- and mitochondrial-related pathways, and they provided targets for further rigorous studies on precise understanding of the molecular mechanism of NFP.

Bifidobacterial carbohydrate/nucleoside metabolism enhances oxidative phosphorylation in white adipose tissue to protect against diet-induced obesity.

BACKGROUND: Comparisons of the gut microbiome of lean and obese humans have revealed that obesity is associated with the gut microbiome plus changes in numerous environmental factors, including high-fat diet (HFD). Here, we report that two species of Bifidobacterium are crucial to controlling metabolic parameters in the Korean population. RESULTS: Based on gut microbial analysis from 99 Korean individuals, we observed the abundance of Bifidobacterium longum and Bifidobacterium bifidum was markedly reduced in individuals with increased visceral adipose tissue (VAT), body mass index (BMI), blood triglyceride (TG), and fatty liver. Bacterial transcriptomic analysis revealed that carbohydrate/nucleoside metabolic processes of Bifidobacterium longum and Bifidobacterium bifidum were associated with protecting against diet-induced obesity. Oral treatment of specific commercial Bifidobacterium longum and Bifidobacterium bifidum enhanced bile acid signaling contributing to potentiate oxidative phosphorylation (OXPHOS) in adipose tissues, leading to reduction of body weight gain and improvement in hepatic steatosis and glucose homeostasis. Bifidobacterium longum or Bifidobacterium bifidum manipulated intestinal sterol biosynthetic processes to protect against diet-induced obesity in germ-free mice. CONCLUSIONS: Our findings support the notion that treatment of carbohydrate/nucleoside metabolic processes-enriched Bifidobacterium longum and Bifidobacterium bifidum would be a novel therapeutic strategy for reprograming the host metabolic homeostasis to protect against metabolic syndromes, including diet-induced obesity. Video Abstract.

The role of retinoid-related orphan receptor-α in cigarette smoke-induced autophagic response.

BACKGROUND: Retinoid-related orphan receptor-α (RORα) and autophagy dysregulation are involved in the pathophysiology of chronic obstructive pulmonary disease (COPD), but little is known regarding their association. We investigated the role of RORα in COPD-related autophagy. METHODS: The lung tissues and cells from a mouse model were analyzed for autophagy markers by using western blot analysis and transmission electron microscopy. RESULTS: Cigarette smoke increased the LC3-II level and decreased the p62 level in whole lung homogenates of a chronic cigarette smoking mouse model. Although cigarette smoke did not affect the levels of p62 in Staggerer mutant mice (RORαsg/sg), the baseline expression levels of p62 were significantly higher than those in wild type (WT) mice. Autophagy was induced by cigarette smoke extract (CSE) in Beas-2B cells and in primary fibroblasts from WT mice. In contrast, fibroblasts from RORαsg/sg mice failed to show CSE-induced autophagy and exhibited fewer autophagosomes, lower LC3-II levels, and higher p62 levels than fibroblasts from WT mice. Damage-regulated autophagy modulator (DRAM), a p53-induced modulator of autophagy, was expressed at significantly lower levels in the fibroblasts from RORαsg/sg mice than in those from WT mice. DRAM knockdown using siRNA in Beas-2B cells inhibited CSE-induced autophagy and cell death. Furthermore, RORα co-immunoprecipitated with p53 and the interaction increased p53 reporter gene activity. CONCLUSIONS: Our findings suggest that RORα promotes autophagy and contributes to COPD pathogenesis via regulation of the RORα-p53-DRAM pathway.

Serum and aqueous humor adiponectin levels correlate with diabetic retinopathy development and progression.

PURPOSE: To compare adiponectin (APN) levels in the serum and aqueous humor (AH) and evaluate their association with the development/progression of diabetic retinopathy (DR). METHODS: Diabetic patients with (group 3; n = 59) and without (group 2; n = 39) DR and age- and sex-matched normal subjects (group 1; n = 35) were compared. Duration of diabetes, body mass index, serum HbA1c, vascular endothelial growth factor (VEGF), APN, pentraxin 3 (PTX3), platelet derived growth factor (PDGF), intercellular adhesion molecule-1 (ICAM-1), and APN were measured and analyzed. RESULTS: One hundred and thirty-three participants were included. Compared to patients without diabetes, diabetic patients with DR had significantly elevated average serum APN levels (5.99±3.89 µg/ml versus 3.51±1.44 µg/ml, P = 0.002) and average AH APN levels (10.94±11.74 ng/ml versus 3.65±3.33 ng/ml, P<0.001). Serum APN was significantly correlated with AH APN (R = 0.512, P<0.001) and AH VEGF (R = 0.202, P = 0.020). The log serum APN was significantly correlated with intraocular cytokines, including log APN, log VEGF, log ICAM, log leptin, log PTX3, log PDGF, angiopoietin, C-reactive protein, and interleukins (IL)-5 and IL-10 (P<0.001, P = 0.020, P<0.001, P<0.001, P = 0.001, P<0.001, P = 0.008, P = 0.009, P<0.001, and P = 0.046, respectively). Log serum VEGF showed a significant correlation only with log AH VEGF (P = 0.001). Multivariate logistic analysis was performed to evaluate the association of DR progression and cytokine concentrations; log Serum APN and log AH APN showed good correlation with the DR progression in each model. CONCLUSIONS: AH APN levels correlated well with DR development and progression. Serum APN could be a better marker for estimating intraocular cytokines, including both intraocular APN and VEGF concentrations in clinical field, than serum VEGF in DR patients.

The arachidonic acid metabolite 11,12-epoxyeicosatrienoic acid alleviates pulmonary fibrosis.

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that are rapidly metabolized into diols by soluble epoxide hydrolase (sEH). sEH inhibition has been shown to increase the biological activity of EETs, which are known to have anti-inflammatory properties. However, the role of EETs in pulmonary fibrosis remains unexplored. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to analyze EETs in the lung tissues of patients with idiopathic pulmonary fibrosis (IPF, n = 29) and controls (n = 15), and the function of 11,12-EET was evaluated in in vitro and in vivo in pulmonary fibrosis models. EET levels in IPF lung tissues, including those of 8,9-EET, 11,12-EET, and 14,15-EET, were significantly lower than those in control tissues. The 11,12-EET/11,12-DHET ratio in human lung tissues also differentiated IPF from control tissues. 11,12-EET significantly decreased transforming growth factor (TGF)-ß1-induced expression of α-smooth muscle actin (SMA) and collagen type-I in MRC-5 cells and primary fibroblasts from IPF patients. sEH-specific siRNA and 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU; sEH inhibitor) also decreased TGF-ß1-induced expression of α-SMA and collagen type-I in fibroblasts. Moreover, 11,12-EET and TPPU decreased TGF-ß1-induced p-Smad2/3 and extracellular-signal-regulated kinase (ERK) expression in primary fibroblasts from patients with IPF and fibronectin expression in Beas-2B cells. TPPU decreased the levels of hydroxyproline in the lungs of bleomycin-induced mice. 11,12-EET or sEH inhibitors could inhibit pulmonary fibrosis by regulating TGF-ß1-induced profibrotic signaling, suggesting that 11,12-EET and the regulation of EETs could serve as potential therapeutic targets for IPF treatment.

Stearic acid attenuates profibrotic signalling in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Lipid metabolism dysregulation has been implicated in the pathogenesis of IPF; however, the roles of most lipid metabolites in lung fibrosis remain unexplored. Therefore, we aimed to identify changes in lipid metabolites in the lung tissues of IPF patients and determine their roles in pulmonary fibrosis. METHODS: Free fatty acids in the lung tissues of IPF patients and controls were quantified using a metabolomic approach. The roles of free fatty acids in fibroblasts or epithelial cells treated with TGF-ß1 were evaluated using fibrotic markers. The antifibrotic role of stearic acid was also assessed in a bleomycin-induced lung fibrosis mouse model. Protein levels in cell lysates or tissues were measured by western blotting. RESULTS: The levels of stearic acid were lower in IPF lung tissues than in control lung tissues. Stearic acid significantly reduced TGF-ß1-induced α-SMA and collagen type 1 expression in MRC-5 cells. Furthermore, stearic acid decreased the levels of p-Smad2/3 and ROS in MRC-5 cells treated with TGF-ß1 and disrupted TGF-ß1-induced EMT in Beas-2B cells. Stearic acid reduced the levels of bleomycin-induced hydroxyproline in a mouse model. CONCLUSION: Changes in the free fatty acid profile, including low levels of stearic acid, were observed in IPF patients. Stearic acid may exert antifibrotic activity by regulating profibrotic signalling.

Two-Stage Peroral Endoscopic Myotomy for Sigmoid-Type Achalasia.

Peroral endoscopic myotomy (POEM) has been recently considered as the first treatment option for achalasia. The standard POEM procedures are often successful in most patients, but sometimes technical challenges are encountered. We report a new technique that is divided between two tunneling sites in the esophagus for sigmoid-type achalasia. A 40-year-old male patient with dysphagia for 10 years was diagnosed with a sigmoid-shaped esophagus at our hospital. We devised a two-stage myotomy technique to treat sigmoidtype achalasia. The myotomy was first performed in the upper part of the greater flexion area and then in the lower part of the flexion. We termed this method "two-stage POEM", which was successfully performed without any complications. This new POEM method can also be used to improve symptoms in patients with achalasia who have a structural deformity that may result in a high change of treatment failure.

Anti-reflux mucosectomy using a cap-assisted endoscopic mucosal resection method for refractory gastroesophageal disease: a prospective feasibility study.

BACKGROUND AND AIMS: Endoscopic therapy of gastroesophageal reflux disease (GERD) overcomes the "treatment gap" for patients with refractory GERD, who are not willing to go into surgery. We propose an easy and efficient technique that is referred to as anti-reflux mucosectomy (ARMS) using cap-assisted endoscopic mucosal resection (EMR-C) which could be called ARMS-C. This study aimed to investigate the short-term outcomes of ARMS-C in GERD patients. METHODS: From December 2016 to February 2018, we performed ARMS-C in 33 patients with pathologic reflux disease and esophageal hypersensitivity. ARMS-C involved endoscopic mucosal resection at the circumference of the esophagogastric junction (EGJ), resulting in narrowing of the hiatal opening after healing. The GERD symptoms, 24-h pH monitoring results, manometry, endoscopy, and EGJ distensibility were compared before and after the procedure. RESULTS: Six months after ARMS-C, 63% of patients discontinued the use of pump inhibitors (PPIs), while 30% patients reduced their PPI dose. The GERD questionnaire scores significantly decreased after ARMS-C, from 11.0 to 6.0 (P < 0.001). The median DeMeester score and acid exposure time based on pH monitoring also improved after ARMS-C. Furthermore, the median flap valve grade and EGJ distensibility decreased from 3.0 to 1.0 (P < 0.001) and from 19.0 to 13.9 (P < 0.001), respectively. Two patients were treated with balloon dilation due to stricture, but no other serious adverse events were encountered. CONCLUSION: ARMS-C may be an effective and safe treatment method for GERD in terms of short-term outcomes.

Endoscopic Submucosal Dissection Followed by Concurrent Chemoradiotherapy in Patients with Early Esophageal Cancer with a High Risk of Lymph Node Metastasis.

Endoscopic submucosal dissection is recommended as an alternative therapy for early esophageal cancer. However, achieving curative resection in this procedure remains controversial since precise prediction of lymph node metastasis can be difficult. Here, we present the preliminary results of endoscopic submucosal dissection followed by concurrent chemoradiotherapy for early esophageal cancer with a high risk of lymph node metastasis. From May 2006 to January 2014, six patients underwent concurrent chemoradiotherapy after endoscopic submucosal dissection with a median follow-up period of 63 months. No complications were encountered during concurrent chemoradiotherapy. Although local recurrence did not occur in all patients, two patients were diagnosed with metachronous cancer. Overall, the survival rate was 100%. Thus, endoscopic submucosal dissection followed by concurrent chemoradiotherapy may be a feasible treatment for early esophageal cancer in patients with a high risk of lymph node metastasis. Future prospective large-scale studies are warranted to confirm our results.

Huge Intramural Duodenal Hematoma Complicated with Obstructive Jaundice following Endoscopic Hemostasis.

Intramural hematoma of the duodenum is a relatively unusual complication associated with the endoscopic treatment of bleeding peptic ulcers. Intramural hematomas are typically resolved spontaneously with conservative treatment alone. We report a case of an intramural duodenal hematoma following endoscopic hemostasis with epinephrine injection therapy, which was associated with transient obstructive jaundice in a patient undergoing hemodialysis. The patient developed biliary sepsis due to obstruction of the common bile duct secondary to the huge hematoma. He was treated with fluoroscopy-guided drainage catheter insertion, which spontaneously resolved the biliary sepsis through conservative treatment in 6 weeks. Fluoroscopy-guided drainage may impact the treatment of intramural hematomas that involve life-threatening complications.

Management of Le Fort I fracture.

Among the classification of maxillary fracture, the Le Fort classification is the best-known categorization. Le Fort (1901) completed experiments that determined the maxilla areas of structural weakness which he designated as the "lines of weakness". According to these results, there are three basic fracture line patterns (transverse, pyramidal and craniofacial disjunction). A transverse fracture is a Le Fort I fracture that is above the level of the apices of the maxillary teeth section, including the entire alveolar process of the maxilla, vault of the palate and inferior ends of the pterygoid processes in a single block from the upper craniofacial skeleton. Le Fort fractures result in both a cosmetic and a functional deficit if treated inappropriately. In this article, authors review the management of a Le Fort I fracture with a case-based discussion.

Chronological changes in the expression of phosphorylated tau and 5­AMP­activated protein kinase in the brain of senescence­accelerated P8 mice.

Senescence-accelerated mouse prone 8 (SAMP8), a non­transgenic animal model used for researching sporadic Alzheimer's disease (AD), presents AD pathologies and overall dysregulation in brain energy metabolism, which is one of the early pathogenic characteristics of AD. In the present study, the authors examined chronological changes in the expression patterns of phosphorylated tau and of proteins related to energy metabolism to evaluate the association of tau phosphorylation and metabolism, using young­ (2­months­old), middle­ (5­months­old) and old­aged (10­months­old) SAMP8. The levels of phosphorylated 5'­AMP activated protein kinase at Thr172 (p­AMPK) and phosphorylated glycogen synthase kinase 3ß (p­GSK3ßS9) in the cortex of SAMP8 at 2 months were significantly higher than those in senescence­accelerated mouse resistant 1 (SAMR1). The differences were not detected at 5 and 10 months of age, which were concurrent with the changes in levels of phosphorylated tau at Ser396 (p­tauS396), but not with p­tauS262. The level of p­tauS262 was considerably higher in the cortex of middle­aged SAMP8 when compared with that of SAMR1 and sustained in old­aged SAMP8, but not in the young cortex. The levels of cortical sirtuin1 (Sirt1) and insulin receptor substrate 1 (IRS­1) expression of young SAMP8 were significantly lower, when compared with those in SAMR1. However, in the hippocampus of SAMP8, the patterns of chronological changes and levels of p­tau, p­AMPK, Sirt1 and IRS­1 relative to SAMR1 were different from those in the cortex. Taken together, the results suggested that regulation of tau phosphorylation via the AMPK­GSK3ß pathway concurrent with dysregulation of energy metabolism may precede the pathological tau hyperphosphorylation in the cortex of SAMP8, and that the regulation of AMPK­GSK3ß­mediated tau phosphorylation may be dependent on phosphor­epitope in tau or the region of brain.

Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells.

Cancer therapies attempt to destroy the entire tumor, but this tends to require toxic compounds and high doses of radiation. Recently, considerable attention has focused on therapy-induced senescence (TIS), which can be induced in cancer cells by low doses of therapeutic drugs or radiation and provides a barrier to tumor development. However, the molecular mechanisms governing TIS remain elusive. Special attention has been paid to the potential chemopreventive effect of aspirin against human colorectal cancer. In this study, we investigated the effects of aspirin on TIS of human colorectal carcinoma (CRC) cells and show that it occurs via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), two key regulators of cellular metabolism. Aspirin increased the senescence of CRC cells, increased the protein levels of SIRT1, phospho-AMPK (T172), and phospho-acetyl CoA carboxylase (S79), and reduced the cellular level of ATP. Small-interfering RNA-mediated downregulation or pharmacological inhibition of SIRT1 or AMPK significantly attenuated the aspirin-induced cellular senescence in CRC cells. In contrast, treatment with a SIRT1 agonist or an AMP analog induced cellular senescence. Remarkably, SIRT1 knockdown abrogated the aspirin-induced activation of AMPK, and vice versa. During the progression of aspirin-induced cellular senescence in CRC cells, SIRT1 showed increased deacetylase activity at a relatively early time point but was characterized by decreased activity with increased cytoplasmic localization at a later time point. Collectively, these novel findings suggest that aspirin could provide anticancer effects by inducing senescence in human CRC cells through the reciprocal regulation of SIRT1-AMPK pathways.

Activation of the 5'-AMP-Activated Protein Kinase in the Cerebral Cortex of Young Senescence-Accelerated P8 Mice and Association with GSK3ß- and PP2A-Dependent Inhibition of p-tau396 Expression.

The 5'-AMP-activated protein kinase (AMPK), which is a sensor of cellular energy, regulates neuronal survival and energy homeostasis. However, the roles of AMPK in the pathogenesis of Alzheimer's disease (AD) are unclear. The senescence-accelerated mouse prone 8 (SAMP8) strain is characterized by deficits in learning and memory, exhibits pathological characteristics of AD as early as 5 months of age, and is being increasingly recognized as a model of AD. Here, we investigated the relationship between AMPK activation and phosphorylation of the tau protein in the brain of young (2-month-old) SAMP8 animals and in differentiated SH-SY5Y cells. Upregulation of p-AMPK, p-ACC, and p-GSK3ßS9 and downregulation of p-tau396 and sirtuin 1 (Sirt1) were observed in the cerebral cortex of young SAMP8 mice compared with that of age-matched SAMR1 animals. The hippocampal levels of p-AMPK and p-tau396 in SAMP8 animals were not significantly different from those of SAMR1, whereas upregulation of p-GSK3ßS9 and downregulation of sirt1 was observed in the hippocampus of SAMP8 mice. Consistent with in vivo findings in the cortex, AMPK activation in SH-SY5Y cells upregulated p-GSK3ßS9 but downregulated p-tau396, whereas it had no significant effect on p-tau262 expression. In addition, the AMPK-mediated inhibition of p-tau396 expression was attenuated by okadaic acid, a protein phosphatase 2A (PP2A) inhibitor. Taken together, our data showed that AMPK activation inhibits p-tau396 expression in a GSK3ß- and PP2A-dependent manner, and suggest that differential regulation of tau phosphorylation in young SAMP8 mice by AMPK plays a compensatory role against accelerated senescence in this AD animal model.