Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues.

Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrPSc) that forms insoluble amyloids to impair brain function. PrPSc interacts with the non-pathogenic, cellular prion protein (PrPC) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrPSc but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC50 = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC50 = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrPSc in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.

Infection-Induced Rhabdomyolysis in a Pregnant Woman with Undiagnosed Myotonic Dystrophy: A Case Report.

A 34-year-old nulliparous gravid female presented with acute bilateral pyelonephritis at 29 + 5 weeks gestation. The patient was relatively well until two weeks ago when a slight increase in amniotic fluid was noted. Further investigation revealed myoglobinuria and significantly elevated levels of creatine phosphokinase. The patient was subsequently diagnosed with rhabdomyolysis. Twelve hours after admission, the patient noted reduced fetal movements. A non-stress test revealed fetal bradycardia and non-reassuring variability in fetal heart rate. An emergency cesarean section was performed, and a "floppy" female child was delivered. Genetic testing revealed congenital myotonic dystrophy, and the mother was also diagnosed with myotonic dystrophy. Rhabdomyolysis has a very low incidence in pregnancy. Herein, we report a rare case of myotonic dystrophy with rhabdomyolysis in a gravid female with no history of myotonic dystrophy. Acute pyelonephritis is a causative agent of rhabdomyolysis that results in preterm birth.

Perinatal Outcomes and Neurodevelopment 1 Year after Birth in Discordant Twins According to Chorionicity.

Background and Objectives: This study aimed to compare maternal complications, perinatal outcomes, and neurodevelopment 1 year after the birth between concordant and discordant twins in monochorionic and dichorionic twins. Materials and Methods: This retrospective study included twin pregnancies delivered between 24 + 1 and 38 + 2 weeks of gestation between January 2011 and September 2019. Chorionicity was confirmed by ultrasonography and was categorized into monochorionic and dichorionic. Each was then divided into two groups (concordant and discordant) according to birth weight discordancy. Maternal complications and neonatal outcomes, including neurodevelopmental delays, were compared between the two groups. Results: A total of 298 pairs of twin pregnancies were enrolled, of which 58 (19.26%) women were pregnant with monochorionic diamniotic twins and 240 (80.54%) with dichorionic diamniotic twins. In both monochorionic and dichorionic twins, the discordant twins had a greater incidence of emergency deliveries because of iatrogenic causes than the concordant twins. Among dichorionic twins, discordant twins had lower birth weight rates and higher hospitalization rates and morbidities than concordant twins. Among monochorionic twins, discordant twins had a lower birth weight and higher neonatal mortality than concordant twins. The neonatal size was not a predictor of neurodevelopment in this group. Based on the logistic regression analysis, male sex, respiratory distress syndrome, and bronchopulmonary dysplasia were risk factors for the neurodevelopmental delay; birth weight discordancy was significant only in dichorionic twins. Conclusions: Perinatal outcomes in discordant twins may be poor, and neurodevelopment 1 year after birth was worse in discordant twins than in concordant twins. Discordancy in twins can be a risk factor for neurodevelopmental delay.

Altered distribution, activation and increased IL-17 production of mucosal-associated invariant T cells in patients with acute respiratory distress syndrome.

OBJECTIVE: Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that are engaged in a number of diseases, but their roles in acute respiratory distress syndrome (ARDS) are not fully examined yet. This study aimed to examine levels and functions of MAIT cells in patients with ARDS. METHODS: Peripheral blood samples from patients with ARDS (n=50) and healthy controls (HCs, n=50) were collected. Levels of MAIT cells, cytokines, CD69, programmed cell death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) were measured by flow cytometry. RESULTS: Circulating MAIT cell levels were significantly reduced in patients with ARDS than in HCs. MAIT cell levels were inversely correlated with disease severity and mortality. Cytokine production profiles in MAIT cells showed that percentages of interleukin (IL)-17 producing MAIT cell were significantly higher in patients with ARDS than in HCs. Patients with ARDS exhibited higher expression levels of CD69, PD-1 and LAG-3 in circulating MAIT cells. Moreover, levels of MAIT cells and expression levels of CD69, PD-1 and IL-17 in MAIT cells were higher in bronchoalveolar lavage fluid samples than in peripheral blood samples. Our in vitro experiments showed that MAIT cells triggered macrophages to produce proinflammatory cytokines such as tumour necrosis factor-α, IL-1ß and IL-8. CONCLUSIONS: This study demonstrates that circulating MAIT cells are numerically deficient in patients with ARDS. In addition, MAIT cells were found to be activated, migrate into lung, secrete IL-17 and then stimulate macrophages. These findings suggest that MAIT cells contribute to the worsening of inflammation in the lung of patients with ARDS.

Acute Twin-to-Twin Transfusion Syndrome Resulting in Fetal Bradycardia and Neonatal Death: A Case Report.

In monochorionic twins with no evidence of chronic twin-to-twin transfusion syndrome or twin anemia-polycythemia sequence, a sudden onset of fetal transfusion syndrome after the second trimester of pregnancy is defined as acute twin-to-twin transfusion syndrome. Labor pain, change in the fetal position, and birth order are known risk factors for this condition, and the hemoglobin level of the donor twin is usually reported to be <12 g/dL. We report a recent case of acute twin-to-twin transfusion syndrome without effective labor pain causing cervical changes, resulting in fetal bradycardia and neonatal death after birth; however, the anemia of the donor twin was not as severe as has been reported previously in twin-to-twin transfusion syndrome cases.

6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists.

A series of N-[{2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl}methyl] N'-(6,6-fused heterocyclic) ureas have been investigated as hTRPV1 antagonists. Among them, compound 15 showed highly potent TRPV1 antagonism to capsaicin, with Ki(ant)=0.2nM, as well as antagonism to other activators, and it was efficacious in a pain model. A docking study of 15 with our hTRPV1 homology model indicates that there is crucial hydrogen bonding between the ring nitrogen and the receptor, contributing to its potency.

α-Lipoic acid attenuates coxsackievirus B3-induced ectopic calcification in heart, pancreas, and lung.

Ectopic mineralization of soft tissues is known to be a typical response to systemic imbalance of various metabolic factors as well as tissue injury, leading to severe clinical consequences. In this study, coxsackievirus B3 (CVB3) infection in mice resulted in significant tissue injury, especially in the heart and pancreas. Inflammatory damage and apoptotic cell death were observed in CVB3-infected heart and pancreas tissues. Along with tissue damage, substantial ectopic calcification was detected in CVB3-infected heart, pancreas, and lung tissues, as determined by von Kossa staining and calcium content quantification. In addition, CVB3 infection induced upregulation of osteogenic signals, including six genes (BMP2, SPARC, Runx2, osteopontin, collagen type I, and osterix) in the heart, three genes (SPARC, osteopontin, and collagen type I) in the pancreas, and two genes (BMP2 and alkaline phosphatase) in the lung, as determined by quantitative real-time PCR analysis. Intriguingly, we showed that α-lipoic acid diminished CVB3-mediated inflammatory and apoptotic tissue damage, subsequently ameliorating ectopic calcification via the suppression of osteogenic signals. Collectively, our data provide evidence that ectopic calcification induced by CVB3 infection is implicated in the induction of osteogenic propensity, and α-lipoic acid may be a potential therapeutic agent to ameliorate pathologic calcification.

Histone deacetylases inhibitor trichostatin A modulates the extracellular release of APE1/Ref-1.

Apurinic/apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) can be acetylated via post-translational modification. We investigated the effect of an inhibitor of histone deacetylases on the extracellular release of APE1/Ref-1 in HEK293 cells. Trichostatin A (TSA), an inhibitor of histone deacetylases, induced APE1/Ref-1 secretion without changing cell viability. In a fluorescence quantitative assay, the secreted APE1/Ref-1 was estimated to be about 10 ng/mL in response to TSA (1 µM). However, TSA did not induce the secretion of lysine-mutated APE1/Ref-1 (K6R/K7R). TSA also caused nuclear to cytoplasmic translocation of APE1/Ref-1. Taken together, these findings suggest that APE1/Ref-1 is a protein whose secretion is governed by lysine acetylation.

Rates and subsequent clinical course of fetal congenital anomalies detected by prenatal targeted ultrasonography of 137 cases over 5 years in a single institute: a retrospective observational study.

BACKGROUND: With the establishment of international guidelines and changes in insurance policies in Korea, the role of targeted ultrasonography has increased. This study aimed to identify the rates and clinical course of anomalies detected using prenatal targeted ultrasonography. METHODS: This study was a retrospective analysis of all pregnancies with targeted ultrasonography performed in a single secondary medical center over 5 years. RESULTS: Fetal anomalies were detected by targeted ultrasonography in 137 of the 8,147 cases (1.7%). The rates of anomalies were significantly higher in female fetuses (2.0% vs. 1.3%). In cases of female fetuses, the rate of anomalies was significantly higher in the advanced maternal age group (2.4% vs. 1.2%). In cases of male fetuses, the rate of anomalies was significantly higher in nulliparous (2.4% vs. 1.5%) and twin (5.7% vs. 1.9%) pregnancies. Pulmonary anomalies were significantly more common in the multiparity group (17.6% vs. 5.8%). Among the 137 cases, 17.5% terminated the pregnancy, 16.8% were diagnosed as normal after birth, and 42.3% were diagnosed with anomalies after birth or required follow-up. CONCLUSION: Through the first study on the rates and clinical course of anomalies detected by targeted ultrasonography at a single secondary center in Korea, we found that artificial abortions were performed at a high rate, even for relatively mild anomalies or anomalies with good prognosis. We suggest the necessity of a nationwide study to establish clinical guidelines based on actual incidences or prognoses.

Impact of vaccination and the omicron variant on COVID-19 severity in pregnant women.

We compared the clinical course of pregnant women with coronavirus disease 2019 (COVID-19) before and after the emergence of the omicron variant and based on vaccination status. We retrospectively reviewed the electronic medical charts of 224 patients and 82 deliveries from November 1, 2020, to March 7, 2022; of these, 42% were diagnosed during the omicron dominance period. Disease severity and morbidity of COVID-19 were significantly decreased during the omicron era. The vaccination rates among the patients were higher after omicron emergence (31.9%) than before (6.9%). Overall, 4.1% and 25% of patients had severe symptoms, and 2.6% and 16.2% required oxygen therapy in the vaccination and non-vaccination groups, respectively. Overall, patients had a more favorable clinical course in the omicron era; moreover, vaccinated patients were better protected than non-vaccinated patients, indicating the importance of vaccination against COVID-19.

Chemical Chaperones to Inhibit Endoplasmic Reticulum Stress: Implications in Diseases.

The endoplasmic reticulum (ER) is responsible for structural transformation or folding of de novo proteins for transport to the Golgi. When the folding capacity of the ER is exceeded or excessive accumulation of misfolded proteins occurs, the ER enters a stressed condition (ER stress) and unfolded protein responses (UPR) are triggered in order to rescue cells from the stress. Recovery of ER proceeds toward either survival or cell apoptosis. ER stress is implicated in many pathologies, such as diabetes, cardiovascular diseases, inflammatory diseases, neurodegeneration, and lysosomal storage diseases. As a survival or adaptation mechanism, chaperone molecules are upregulated to manage ER stress. Chemical versions of chaperone have been developed in search of drug candidates for ER stress-related diseases. In this review, synthetic or semi-synthetic chemical chaperones are categorized according to potential therapeutic area and listed along with their chemical structure and activity. Although only a few chemical chaperones have been approved as pharmaceutical drugs, a dramatic increase in literatures over the recent decades indicates enormous amount of efforts paid by many researchers. The efforts warrant clearer understanding of ER stress and the related diseases and consequently will offer a promising drug discovery platform with chaperone activity.

Gene transfer of redox factor-1 inhibits neointimal formation: involvement of platelet-derived growth factor-beta receptor signaling via the inhibition of the reactive oxygen species-mediated Syk pathway.

The role of apurinic/apyrimidinic endonuclease-1/redox factor-1 (Ref-1) in vascular smooth muscle cells has yet to be clearly elucidated. Therefore, we attempted to determine the roles of Ref-1 in the migration induced by platelet-derived growth factor (PDGF)-BB and in its signaling in rat aortic smooth muscle cells (RASMCs). Cellular migration, superoxide (O(2)(-*)) production, Rac-1 activity, and neointima formation were determined in cells transfected with adenoviruses encoding for Ref-1 (AdRef-1) and small interference RNA of Ref-1. Overexpression of Ref-1 induced by treatment with RASMCs coupled with AdRef-1 inhibited the migration induced by PDGF-BB. PDGF-BB also increased the phosphorylation of the PDGFbeta receptor, spleen tyrosine kinase (Syk), mitogen-activated protein kinase, and heat shock protein 27, but these increases were significantly inhibited by AdRef-1 treatment. PDGF-BB increased O(2)(-*) production and Rac-1 activity, and these were diminished in cells transfected with AdRef-1. In contrast, RASMC migration, phosphorylation of Syk and O(2)(-*) production in response to PDGF-BB were increased by the knock down of Ref-1 with small interference RNA. The phosphorylation of PDGFbeta receptor in response to PDGF-BB was inhibited completely by the Syk inhibitor and was partly attenuated by a NADPH oxidase inhibitor. PDGF-BB increased the sprout outgrowth of the aortic ring ex vivo, which was inhibited in the AdRef-1-infected RASMCs as compared with the controls. Balloon injury-induced neointimal formation was significantly attenuated by the gene transfer of AdRef-1. These results indicate that Ref-1 inhibits the PDGF-mediated migration signal via the inhibition of reactive oxygen species-mediated Syk activity in RASMCs.

Circulating Plasmacytoid and Conventional Dendritic Cells Are Numerically and Functionally Deficient in Patients With Scrub Typhus.

Background: Dendritic cells (DCs) are specialized antigen-presenting cells known to bridge innate and adaptive immune reactions. However, the relationship between circulating DCs and Orientia tsutsugamushi infection is unclear. Therefore, this study aimed to examine the level and function of plasmacytoid DCs (pDCs) and conventional DCs (cDCs), two subsets of circulating DCs, in scrub typhus patients. Methods: The study included 35 scrub typhus patients and 35 healthy controls (HCs). pDC and cDC levels, CD86 and CD274 expression, and cytokine levels were measured using flow cytometry. Results: Circulating pDC and cDC levels were found to be significantly reduced in scrub typhus patients, which were correlated with disease severity. The patients displayed increased percentages of CD86+ pDCs, CD274+ pDCs, and CD274+ cDCs in the peripheral blood. The alterations in the levels and surface phenotypes of pDCs and cDCs were recovered in the remission state. In addition, the production of interferon (IFN)-α and tumor necrosis factor (TNF)-α by circulating pDCs, and interleukin (IL)-12 and TNF-α by circulating cDCs was reduced in scrub typhus patients. Interestingly, our in vitro experiments showed that the percentages of CD86+ pDCs, CD274+ pDCs, and CD274+ cDCs were increased in cultures treated with cytokines including IFN-γ, IL-12, and TNF-α. Conclusions: This study demonstrates that circulating pDCs and cDCs are numerically deficient and functionally impaired in scrub typhus patients. In addition, alterations in the expression levels of surface phenotypes of pDCs and cDCs could be affected by pro-inflammatory cytokines.

Corrigendum to "WS-5 Extract of Curcuma longa, Chaenomeles sinensis, and Zingiber officinale Contains Anti-AChE Compounds and Improves ß-Amyloid-Induced Memory Impairment in Mice".

[This corrects the article DOI: 10.1155/2019/5160293.].

Clinical outcomes of hysterectomy for benign diseases in the female genital tract: 6 years' experience in a single institute.

BACKGROUND: Hysterectomy is one of the major gynecologic surgeries. Historically, several surgical procedures have been used for hysterectomy. The present study aims to evaluate the surgical trends and clinical outcomes of hysterectomy performed for benign diseases at the Yeungnam University Hospital. METHODS: We retrospectively reviewed patients who underwent a hysterectomy for benign diseases from 2013 to 2018. Data included the patients' demographic characteristics, surgical indications, hysterectomy procedures, postoperative pathologies, and perioperative outcomes. RESULTS: A total of 809 patients were included. The three major indications for hysterectomy were uterine leiomyoma, pelvic organ prolapse, and adenomyosis. The most common procedure was total laparoscopic hysterectomy (TLH, 45.2%), followed by open hysterectomy (32.6%). During the study period, the rate of open hysterectomy was nearly constant (29.4%-38.1%). The mean operative time was the shortest in the single-port laparoscopic assisted vaginal hysterectomy (LAVH, 89.5 minutes), followed by vaginal hysterectomy (VH, 96.8 minutes) and TLH (105 minutes). The mean decrease in postoperative hemoglobin level was minimum in single-port LAVH (1.8 g/dL) and VH (1.8 g/dL). Conversion to open surgery or multi-port surgery occurred in five cases (0.6%). Surgical complications including wound dehiscence, organ injuries, and conditions requiring reoperation were observed in 52 cases (6.4%). CONCLUSION: Minimally invasive approach was used for most hysterectomies for benign diseases, but the rate of open hysterectomy has mostly remained constant. Single-port LAVH and VH showed the most tolerable outcomes in terms of operative time and postoperative drop in hemoglobin level in selected cases.

Clinical and histopathologic analysis of gynecological cancer: a single institute experience over 7 years.

BACKGROUND: Approximately 100,000 women are diagnosed with cancer each year in Korea. According to a survey by the Korean central cancer registry in 2016, uterine cervical cancer, uterine corpus cancer, and ovarian cancer were the 5th, 7th, and 8th most prevalent cancers respectively among Korean women. The present study aims to review the clinico-pathologic characteristics of patients who were treated for major gynecological malignancies at Yeungnam University Medical Center. METHODS: Patients with invasive gynecological cancers from January 2012 to February 2019 were retrospectively identified. We analyzed the clinical features, demographic profiles, pathologic data, treatment modality used, adjuvant treatment used, complications, recurrence, and survival outcomes. RESULTS: A total of 287 patients (cervical cancer 115; corporal cancer 86; and ovarian, tubal, or primary peritoneal cancer 90) were included. Most cervical (82.7%) and corporal cancers (89.5%) were diagnosed in the early stages (stage I or II), while more than half (58.9%) the cases of ovarian, tubal or peritoneal cancers were diagnosed in the advanced stages (stage III or IV). Surgical complications were observed in 12.2% of cervical cancers, 16.3% of uterine corpus cancers, and 11.1% of ovarian, tubal, and peritoneal cancers, respectively. The 5-year overall survival rate was 94.1%, 91.0%, and 77.1% for cervical, corporal, and ovarian, tubal, or peritoneal cancers, respectively. CONCLUSION: Surgical treatment was satisfactory in terms of the incidence of complications, and survival outcomes were generally good. Clinicians should be aware of the clinical and histopathological characteristics of patients with gynecological cancers to be able to provide optimal strategies and counseling.

Endothelial nitric oxide synthase activation contributes to post-exercise hypotension in spontaneously hypertensive rats.

We investigated the role that endothelial nitric oxide synthase plays in post-exercise hypotension in spontaneously hypertensive rats. To accomplish this, rats were subjected to a single bout of dynamic exercise on a treadmill at 15 m/min for 20 min. L-nitroarginine methyl ester (L-NAME, 40 mg/kg, i.p.) significantly inhibited post-exercise hypotension (25+/-11 and 5+/-3 mm Hg, respectively; P<0.05). In addition, the superoxide anion generation was decreased, while the plasma nitrite production and serine phosphorylation of endothelial nitric oxide synthase were significantly elevated in spontaneously hypertensive rats at 30 min after the termination of exercise. Taken together, these data demonstrate that the increased phosphorylation of endothelial nitric oxide synthase plays a crucial role in the reduction of arterial pressure following a single bout of dynamic exercise in spontaneously hypertensive rats.

Midazolam inhibits tumor necrosis factor-alpha-induced endothelial activation: involvement of the peripheral benzodiazepine receptor.

BACKGROUND: Midazolam is widely used as an intravenous sedative. However, the role of midazolam on vascular endothelial activation is still unknown. The present study explores the action of midazolam on endothelial activation and its role to peripheral benzodiazepine receptor (PBR) in cultured human umbilical vein endothelial cells. METHODS: Intracellular localization of PBR in human umbilical vein endothelial cells was visualized with immunofluorescent staining. Monocyte adhesion and vascular cell adhesion molecule-1 expression were measured with monocyte adhesion assay and Western blot analysis. Involvement of PBR was assessed by using specific antagonists and small interfering RNA against PBR. RESULTS: PBR was localized in the mitochondria of human umbilical vein endothelial cells. Midazolam significantly inhibited tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 and monocyte adhesion in a dose-dependent manner (1-30 microM). The midazolam-mediated suppression on the tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression and monocyte adhesion were inhibited by the pretreatment of PK11195 and not inhibited by the flumazenil. Transfection of small interfering RNA for PBR decreased the expression of PBR (18 kDa) in human umbilical vein endothelial cells. Midazolam-mediated suppression on the tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression was abrogated by the transfection of small interfering RNA for PBR. CONCLUSION: These results suggest that midazolam has an inhibitory action on the endothelial activation and that its action is related to the activation of peripheral benzodiazepine receptor localized in mitochondria of the endothelial cells.

2,3,7,8-TCDD neurotoxicity in neuroblastoma cells is caused by increased oxidative stress, intracellular calcium levels, and tau phosphorylation.

One of the most notorious environmental toxicants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), easily accumulates in the environment and most organisms, including humans, because of its high lipophilicity and resistance to degradation. TCDD exposure causes a variety of adverse health effects in humans including immunotoxicity, hepatotoxicity, neurotoxicity, and carcinogenesis. For the most part, studies regarding the adverse effects of TCDD on the central nervous system (CNS) have been limited to neurodevelopmental processes. In this study, we investigated the neurotoxicity of TCDD in neuronal cells using a neuroblastoma cell line (clone N2a) and explored the possible mechanisms of action. MTT and Comet assays were conducted to determine if TCDD is cytotoxic and if it causes DNA damage, respectively. The results of these assays revealed that treatment with 100, 300, 500 and 1000 nM TCDD decreased the viability of N2a cells and increased DNA damage in a dose-dependent manner compared to controls. Additionally, a malondialdehyde (MDA) assay was performed to determine if TCDD induces lipid peroxidation. The results of this assay revealed that 100, 300 and 500 nM TCDD induced lipid peroxidation in a dose-dependent manner. Finally, TCDD neurotoxicity (300 nM or higher) in N2a cells was accompanied by elevated intracellular calcium levels. These increased calcium levels increased the phosphorylation of tau via up-regulation of phospho-glycogen synthase kinase-3beta (GSK-3beta). Taken together, these results indicate that TCDD exposure induces neurotoxicity in N2a cells by increasing DNA damage, oxidative stress and intracellular calcium levels. The TCDD-mediated increase of tau phosphorylation in particular indicates an important role for tau hyperphosphorylation in TCDD-induced neurotoxicity.

Protective effect of caffeic acid against beta-amyloid-induced neurotoxicity by the inhibition of calcium influx and tau phosphorylation.

AIMS: The progressive accumulation of beta-amyloid peptide (Abeta), in the form of senile plaques, has been recognized as one of the major causes of Alzheimer's disease (AD) pathology. Increased production of Abeta and the aggregation of Abeta to oligomers have been reported to trigger neurotoxicity, oxidative damage and inflammation. Furthermore, Abeta-induced tau hyperphosphorylation and neurotoxicity are downstream of Abeta. Therefore, we studied the possible neuroprotective effects of caffeic acid against Abeta-induced toxicity. MAIN METHODS: Treatment of PC12 cells with 10 microM Abeta (25-35) for 24 h significantly decreased the cell viability; this was accompanied by an increase in intracellular calcium levels and tau phosphorylation with GSK-3beta (glycogen synthase kinase-3beta) activation (phosphorylation). KEY FINDINGS: However, pretreatment of the PC12 cells with 10 and 20 microg/ml of caffeic acid, for 1 h prior to Abeta, significantly reversed the Abeta-induced neurotoxicity by attenuating the elevation of intracellular calcium levels and tau phosphorylation. SIGNIFICANCE: Taken together, these results suggest that caffeic acid protected the PC12 cells against Abeta-induced toxicity. In addition, the neuroprotective mechanisms of caffeic acid against Abeta attenuated intracellular calcium influx and decreased tau phosphorylation by the reduction of GSK-3beta activation.