Correction: Samsuzzaman et al. A Synthetic Derivative SH 66 of Homoisoflavonoid from Liliaceae Exhibits Anti-Neuroinflammatory Activity against LPS-Induced Microglial Cells. Molecules 2024, 29, 3037.

Error in Figure [...].

A Synthetic Derivative SH 66 of Homoisoflavonoid from Liliaceae Exhibits Anti-Neuroinflammatory Activity against LPS-Induced Microglial Cells.

Naturally occurring homoisoflavonoids isolated from some Liliaceae plants have been reported to have diverse biological activities (e.g., antioxidant, anti-inflammatory, and anti-angiogenic effects). The exact mechanism by which homoisoflavonones exert anti-neuroinflammatory effects against activated microglia-induced inflammatory cascades has not been well studied. Here, we aimed to explore the mechanism of homoisoflavonoid SH66 having a potential anti-inflammatory effect in lipopolysaccharide (LPS)-primed BV2 murine microglial cells. Microglia cells were pre-treated with SH66 followed by LPS (100 ng/mL) activation. SH66 treatment attenuated the production of inflammatory mediators, including nitric oxide and proinflammatory cytokines, by down-regulating mitogen-activated protein kinase signaling in LPS-activated microglia. The SH66-mediated inhibition of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex and the respective inflammatory biomarker-like active interleukin (IL)-1ß were noted to be one of the key pathways of the anti-inflammatory effect. In addition, SH66 increased the neurite length in the N2a neuronal cell and the level of nerve growth factor in the C6 astrocyte cell. Our results demonstrated the anti-neuroinflammatory effect of SH66 against LPS-activated microglia-mediated inflammatory events by down-regulating the NLRP3 inflammasome complex, with respect to its neuroprotective effect. SH66 could be an interesting candidate for further research and development regarding prophylactics and therapeutics for inflammation-mediated neurological complications.

Anti-Glucotoxicity Effect of Phytoconstituents via Inhibiting MGO-AGEs Formation and Breaking MGO-AGEs.

The therapeutic benefits of phytochemicals in the treatment of various illnesses and disorders are well documented. They show significant promise for the discovery and creation of novel medications for treating a variety of human diseases. Numerous phytoconstituents have shown antibiotic, antioxidant, and wound-healing effects in the conventional system. Traditional medicines based on alkaloids, phenolics, tannins, saponins, terpenes, steroids, flavonoids, glycosides, and phytosterols have been in use for a long time and are crucial as alternative treatments. These phytochemical elements are crucial for scavenging free radicals, capturing reactive carbonyl species, changing protein glycation sites, inactivating carbohydrate hydrolases, fighting pathological conditions, and accelerating the healing of wounds. In this review, 221 research papers have been reviewed. This research sought to provide an update on the types and methods of formation of methylglyoxal-advanced glycation end products (MGO-AGEs) and molecular pathways induced by AGEs during the progression of the chronic complications of diabetes and associated diseases as well as to discuss the role of phytoconstituents in MGO scavenging and AGEs breaking. The development and commercialization of functional foods using these natural compounds can provide potential health benefits.

Antidepressive Effect of Natural Products and Their Derivatives Targeting BDNF-TrkB in Gut-Brain Axis.

Modern neurological approaches enable detailed studies on the pathophysiology and treatment of depression. An imbalance in the microbiota-gut-brain axis contributes to the pathogenesis of depression. This extensive review aimed to elucidate the antidepressive effects of brain-derived neurotrophic factor (BDNF)-targeting therapeutic natural products and their derivatives on the gut-brain axis. This information could facilitate the development of novel antidepressant drugs. BDNF is crucial for neuronal genesis, growth, differentiation, survival, plasticity, and synaptic transmission. Signaling via BDNF and its receptor tropomyosin receptor kinase B (TrkB) plays a vital role in the etiopathogenesis of depression and the therapeutic mechanism of antidepressants. This comprehensive review provides information to researchers and scientists for the identification of novel therapeutic approaches for neuropsychiatric disorders, especially depression and stress. Future research should aim to determine the possible causative role of BDNF-TrkB in the gut-brain axis in depression, which will require further animal and clinical research as well as the development of analytical approaches.

Nitric Oxide as a Target for Phytochemicals in Anti-Neuroinflammatory Prevention Therapy.

Nitric oxide (NO) is a neurotransmitter that mediates the activation and inhibition of inflammatory cascades. Even though physiological NO is required for defense against various pathogens, excessive NO can trigger inflammatory signaling and cell death through reactive nitrogen species-induced oxidative stress. Excessive NO production by activated microglial cells is specifically associated with neuroinflammatory and neurodegenerative conditions, such as Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, ischemia, hypoxia, multiple sclerosis, and other afflictions of the central nervous system (CNS). Therefore, controlling excessive NO production is a desirable therapeutic strategy for managing various neuroinflammatory disorders. Recently, phytochemicals have attracted considerable attention because of their potential to counteract excessive NO production in CNS disorders. Moreover, phytochemicals and nutraceuticals are typically safe and effective. In this review, we discuss the mechanisms of NO production and its involvement in various neurological disorders, and we revisit a number of recently identified phytochemicals which may act as NO inhibitors. This review may help identify novel potent anti-inflammatory agents that can downregulate NO, specifically during neuroinflammation and neurodegeneration.

Effects of Aloe vera Flower Extract and Its Active Constituent Isoorientin on Skin Moisturization via Regulating Involucrin Expression: In Vitro and Molecular Docking Studies.

Skin moisturization is very crucial for maintaining the flexibility, viscoelasticity, and differentiation of the epidermis and its deprivation causes several diseases from dry skin to dermatitis. Aloe vera, a miracle plant having diverse medicinal properties including skin moisturization effects. This study investigated for the first time the molecular mechanism targeting skin moisturization effects of the Aloe vera flower and its major active constituent. By treating human epidermal keratinocytes (HaCaT cells) with Aloe vera flower water extract (AFWE), we found that AFWE upregulated epidermal involucrin by activating the expression of protein kinase C, p38, and ERK 1/2. Additionally, it modulated filaggrin, increased aquaporin expression, and hyaluronan synthesis via a balanced regulation of HAS1 and HYAL1 protein. Similarly, it was able to protect UVB-induced photodamage. Western blot analysis, ELISA, and qRT- PCR were performed to evaluate various epidermal differentiation markers and moisturization-related factors on human epidermal keratinocytes (HaCaT cells). TLC and HPLC were used to detect and analyze the chemical constituents. Among them, we found that an active component of Aloe vera flower, isoorientin (IO) has a high binding affinity to all of its targeted proteins such as involucrin, PKC, P38, etc. through molecular docking assay. This study indicated that the Aloe vera flower and its active constituent, IO can be used as a prominent ingredient to enhance skin barrier function and improve its related pathologies.

Metabolomic Comparison of Guava (Psidium guajava L.) Leaf Extracts Fermented by Limosilactobacillus fermentum and Lactiplantibacillus plantarum and Their Antioxidant and Antiglycation Activities.

Probiotic fermentation of plant-based materials can lead to the generation of various bioactive substances via bacterial metabolites and the biotransformation of phenolic compounds. We compared the metabolic differences between fermentation by Limosilactobacillus fermentum KCTC15072BP (LFG) and fermentation by Lactiplantibacillus plantarum KGMB00831 (LPG) in guava leaf extract (0%, 0.5%, and 2% (w/v))-supplemented medium via non-targeted metabolite profiling. By performing multivariate statistical analysis and comparing the different guava leaf extract groups, 21 guava-derived and 30 bacterial metabolites were identified. The contents of guava-derived glucogallin, gallic acid, and sugar alcohols were significantly higher in LFG than they were in LPG. Similarly, significantly higher contents of guava-derived pyrogallol, vanillic acid, naringenin, phloretin, and aromatic amino acid catabolites were obtained with LPG than with LFG. LFG led to significantly higher antioxidant activities than LPG, while LPG led to significantly higher antiglycation activity than LFG. Interestingly, the fermentation-induced increase in the guava-leaf-extract-supplemented group was significantly higher than that in the control group. Thus, the increased bioactivity induced by guava fermentation with the Lactobacillaceae strain may be influenced by the synergistic effects between microbial metabolites and plant-derived compounds. Overall, examining the metabolic changes in plant-based food fermentation by differentiating the origin of metabolites provides a better understanding of food fermentation.

Fucoidan from Undaria pinnatifida induces apoptosis in A549 human lung carcinoma cells.

Fucoidan, a sulfated polysaccharide, has various biological activities, such as anticancer, antiangiogenic and antiinflammatory effects; however, the mechanisms of action of fucoidan on anticancer activity have not been fully elucidated. The anticancer effects of fucoidan from Undaria pinnatifida on A549 human lung carcinoma cells were examined. Treatment of A549 cells with fucoidan resulted in potent antiproliferative activity. Also, some typical apoptotic characteristics, such as chromatin condensation and an increase in the population of sub-G1 hypodiploid cells, were observed. With respect to the mechanism underlying the induction of apoptosis, fucoidan reduced Bcl-2 expression, but the expression of Bax was increased in a dose-dependent manner compared with the controls. Furthermore, fucoidan induced caspase-9 activation, but decreased the level of procaspase-3. Cleavage of poly-ADP-ribose polymerase (PARP), a vital substrate of effector caspase, was found. The study further investigated the role of the MAPK and PI3K/Akt pathways with respect to the apoptotic effect of fucoidan, and showed that fucoidan activates ERK1/2 in A549 cells. Unlike ERK1/2, however, treatment with fucoidan resulted in the down-regulation of phospho-p38 expression. In addition, fucoidan resulted in the down-regulation of phospho-PI3K/Akt. Together, these results indicate that fucoidan induces apoptosis of A549 human lung cancer cells through down-regulation of p38, PI3K/Akt, and the activation of the ERK1/2 MAPK pathway.

Ameliorative Effect of Annona muricata (Graviola) Extract on Hyperglycemia Induced Hepatic Damage in Type 2 Diabetic Mice.

Annona muricata (AM) is evergreen plant of the Annonaceae family and known to have anticancer and antidiabetic effects. However, anti-diabetic mechanisms of AM extracts (AME) associated with hepatic glucose regulation and lipid metabolism remain unclear. In this study, we investigated the protective effect of AME extracted on hepatic damage in diabetic mice. Diabetes was induced by a high-fat diet with two-times streptozotocin (STZ) injection (60 mg/kg BW) in C57BL/6 male mice. The diabetic mice were daily administered with AME (50 or 100 mg/kg BW) by gavage for 9 weeks. Biomarkers related to energy metabolism and insulin signaling were examined to identify the effect of AME on hyperglycemia induced hepatic damage. AME supplementation reduced levels of FBG, HbA1c, HOMA-IR and hepatic lipid profiles as well as enhanced insulin signaling by increased the protein levels of IRS-1 accompanied GLUT2 in diabetic mice. Especially low dose of AME showed the beneficial effect of reducing oxidative stress (4-HNE, protein carbonyls, Nrf2, NQO1) and improved hepatic morphology demonstrated by lipid droplets along with upregulation of lipophagy (pAMPK, p-mTOR/mTOR, LC3-2/LC3-1) in diabetic mice. Moreover, AME supplementation ameliorated hepatic lipid metabolism (FAS, SREBP1c, C/EBPα, PPARγ, CPT1A, PPARα) and energy metabolism (pAMPK, PGC1α) in diabetic mice. Taken together, this study suggested that AME could be helpful to prevent hepatic abnormality by regulation of insulin signaling associated with energy metabolism and autophagy in diabetes.

Protective effects of a novel herbal decoction on focal cerebral ischemia in a rodent model.

BACKGROUND: Herbs have been used to treat stroke and coma patient in traditional Korean medicine (TKM). The novel decoction, Guhpoongchungsimhwan (GCH), was developed on the basis of clinical data and TKM theory. METHODS: We examined the neuroprotective effect of GCH on cerebral ischemia. The middle cerebral artery occlusion (MCAO) model was used to produce cerebral ischemia in Sprague-Dawley rats. Subjects were treated with GCH (50 or 200 mg/kg) or vehicle alone (controls) 0 and 2 hours after MCAO. The functional status was tested 24 hours after MCAO by neurological examination (clinical score) and by series of motor function tasks (foot placement and parallel bar crossing). RESULTS: The infarct volume was determined by 2,3,5-triphenyltetrazolium chloride staining 24 hours after surgery, and the expression of cyclooxygenase-2 was determined by immunohistochemistry. The clinical score of the GCH-treated group (200 mg/kg) was significantly lower than that of the control group (p<0.05), indicating fewer neurological deficits. The impairment of motor functions induced by MCAO was significantly reduced by the administration of GCH (p<0.05). The infarct volume was significantly smaller in the GCH-treated group (203.1 +/- 40.2 mm(3), p<0.05), as compared to the control group (377.8 +/- 32.6 mm(3)). The level of motor function in the GCH-treated group was associated with reduced infarct volume. In the analysis of immunohistochemistry, GCH treatment markedly inhibited the ischemia-induced expression of PTGS2 (prostaglandin-endoperoxidase synthase 2) or cyclooxygenase 2 (COX2), which plays an important role in ischemic neuronal cell death. CONCLUSION: The results showed that GCH reduced the infarct size and the functional deficits in MCAO rats.

Effect of honey bee venom on microglial cells nitric oxide and tumor necrosis factor-alpha production stimulated by LPS.

Abnormal activation of microglial cells has been implicated in various neurodegenerative diseases. Results showed that venom (KBV) produced and purified in Korea regulated lipopolysaccharides (LPS)-induced nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) in the murine microglia, BV-2 cell line. The production of proinflammatory cytokines, NO, and TNF-alpha was examined by LPS in BV-2 cell. The effect of KBV on the expression of inducible nitric oxide synthase (iNOS) and TNF-alpha was investigated by Western blot and RT-PCR in LPS-stimulated BV-2 cells. KBV suppressed the NO, iNOS, and TNF-alpha production, and decreased the levels of iNOS and TNF-alpha mRNA. These results suggest that KBV has anti-inflammatory properties that inhibit iNOS and TNF-alpha expression. KBV could be useful in inhibiting the production of inflammatory cytokine and NO production in neurodegenerative diseases. Further studies on the pharmacological aspects of the individual components of KBV are recommended.

Fermented Pueraria Lobata extract ameliorates dextran sulfate sodium-induced colitis by reducing pro-inflammatory cytokines and recovering intestinal barrier function.

Inflammatory bowel disease is a chronic inflammatory disorder occurring in the gastrointestinal track. However, the efficacy of current therapeutic strategies has been limited and accompanied by side effects. In order to eliminate the limitations, herbal medicines have recently been developed for treatment of IBD. Peuraria Lobata (Peuraria L.) is one of the traditional herbal medicines that have anti-inflammatory effects. Bioavailability of Peuraria L., which is rich in isoflavones, is lower than that of their fermented forms. In this study, we generated fermented Peuraria L. extracts (fPue) and investigated the role of fPue in inflammation and intestinal barrier function in vitro and in vivo. As the mice or intestinal epithelial cells were treated with DSS/fPue, mRNA expression of pro-inflammatory cytokines was reduced and the architecture and expression of tight junction proteins were recovered, compared to the DSS-treated group. In summary, fPue treatment resulted in amelioration of DSS-induced inflammation in the colon, and the disrupted intestinal barrier was recovered as the expression and architecture of tight junction proteins were retrieved. These results suggest that use of fPue could be a new therapeutic strategy for treatment of IBD.

Long-term Treatment with Oriental Medicinal Herb Artemisia princeps Alters Neuroplasticity in a Rat Model of Ovarian Hormone Deficiency.

Artemisia princeps (AP) is a flowering perennial used as a traditional medicine and dietary supplement across East Asia. No study has yet assessed its effects on synaptic plasticity in hippocampus and much less in a model of ovarian hormone deficiency. We examined the influence of chronic oral AP ethanol extract treatment in ovariectomized rats on the induction of long-term depression in a representative synapse (CA3-CA1) of the hippocampus. Ovariectomized rats demonstrated lower trabecular mean bone mineral densities than sham, validating the establishment of pathology. Against this background of pathology, AP-treated ovariectomized rats exhibited attenuated long-term depression (LTD) in CA1 relative to water-treated controls as measured by increased field excitatory post-synaptic potentials (fEPSP) activation averages over the post-stimulation period. While pathological significance of long-term depression (LTD) in ovariectomized rats is conflicting, that AP treatment significantly affected its induction offers justification for further study of its influences on plasticity and its related disorders.

Alkaloid fraction of Uncaria rhynchophylla protects against N-methyl-D-aspartate-induced apoptosis in rat hippocampal slices.

Uncaria rhynchophylla is a medicinal herb which has sedative and anticonvulsive effects and has been applied in the treatment of epilepsy in Oriental medicine. In this study, the effect of alkaloid fraction of U. rhynchophylla against N-methyl-D-aspartate (NMDA)-induced neuronal cell death was investigated. Pretreatment with an alkaloid fraction of U. rhynchophylla for 1 h decreased the degree of neuronal damage induced by NMDA exposure in cultured hippocampal slices and also inhibited NMDA-induced enhanced expressions of apoptosis-related genes such as c-jun, p53, and bax. In the present study, the alkaloid fraction of U. rhynchophylla was shown to have a protective property against NMDA-induced cytotoxicity by suppressing the NMDA-induced apoptosis in rat hippocampal slices.

Anxiolytic effects of Julibroside C1 isolated from Albizzia julibrissin in mice.

Julibroside C1 is a saponin-containing compound isolated from Albizzia julibrissin Durazz. In this study, we investigated the putative anxiolytic effects of Julibroside C1 using the elevated plus maze (EPM) in mice. Julibroside C1 at doses of 0.5 and 1 mg/kg significantly increased the time spent in the open arms and the number of entries into the open arms of the EPM compared to the control group. Moreover, the anxiolytic-like effects of Julibroside C1 (0.5 mg/kg) were blocked by WAY-100635 (5-HT1A receptor antagonist), bicuculline (GABA(A) receptor antagonist), and flumazenil (antagonist of the GABA(A) receptor benzodiazepine site). However, Julibroside C1 did not change locomotor activity or induce myorelaxant effects. We used quantitative receptor autoradiography to investigate the effects of Julibroside C1 on alterations in mouse brain receptors. After acute treatment with Julibroside C1 (0.5 mg/kg), [(3)H]-8-OH-DPAT binding was significantly decreased in the CA1 region of the hippocampus and [(3)H]-flunitrazepam binding was decreased remarkably in the cingulate cortex region. However, [(3)H]-muscimol binding did not show a significant change in any brain region. Taken together, our findings suggest that Julibroside C1 shows anxiolytic-like effects, which might be mediated by the 5-HT1A and GABA(A)-benzodiazepine receptor systems.

3-[2-(3,5-Dimethoxyphenyl)vinyl]furan protects hippocampal neurons against ischemic damage.

Resveratrol, an ingredient in grapes, has been reported to exhibit anti-cancer activity, anti-inflammatory activity, and cardiovascular protection property. Interestingly, resveratrol has been recently reported to have neuroprotective effect. This study reports the neuroprotective effect of a resveratrol derivative, 3-[2-(3,5-dimethoxyphenyl)vinyl]furan (DPVF). This synthetic DPVF conferred more protection than resveratrol against neuronal cell damage induced by oxygen and glucose deprivation in a rat hippocampal slice culture. In addition, DPVF inhibited ATP depletion following oxygen and glucose deprivation in the adult hippocampal slice. Moreover, we found that DPVF is neuroprotective against ischemic damage in rats. DPVF showed potent neuroprotection on a 4-velssel-occusion model and inhibited iron-induced malondialdehyde (MDA) formation in the rat brain tissue. These results demonstrate that DPVF might be a useful agent in reducing ischemic neuronal damage.

5-HT(1A) receptor binding in the dorsal raphe nucleus is implicated in the anxiolytic-like effects of Cinnamomum cassia.

Previously we reported that the 50% EtOH extract of Cinnamomum cassia (C. cassia) possesses anxiolytic-like activity in the mouse elevated plus maze (EPM) test. This activity was blocked by the 5-HT(1A) receptor antagonist, WAY 100635. Therefore, in order to investigate the effect of C. cassia on 5-HT(1A) receptor binding, quantitative autoradiography of 5-HT(1A) receptors was carried out in brains of mice treated acutely and repeatedly with C. cassia. Binding of [(3)H]8-OH-DPAT to the 5-HT(1A) receptor was investigated in the mouse brain. After a single treatment of C. cassia (750 mg/kg, p.o.), [(3)H]8-OH-DPAT binding showed a significant increase in the dorsal raphe nucleus (DRN). After repeated treatment with C. cassia (100mg/kg, once a day for 5 days, p.o.), [(3)H]8-OH-DPAT binding showed no significant change in any brain region. Taken together, the anxiolytic-like effect of the 50% EtOH extract of C. cassia might be mediated by region specific change of 5-HT(1A) receptors in the dorsal raphe nucleus.

Lonicera japonica THUNB. protects 6-hydroxydopamine-induced neurotoxicity by inhibiting activation of MAPKs, PI3K/Akt, and NF-κB in SH-SY5Y cells.

In this study, we investigated the neuroprotective effects of Lonicera japonica THUNB. extract (LJ) on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. We found that LJ significantly increased cell viability decrease, lactate dehydrogenase release (LDH), morphological changes, nuclear condensation, fragmentation, and reactive oxygen species (ROS) production induced by 6-OHDA in SH-SY5Y cells. The cytoprotection afforded by pretreatment with LJ was associated with increases of the glutathione (GSH) level, superoxide dismutase (SOD) activity, and catalase (CAT) activity in 6-OHDA-induced SH-SY5Y cells. In addition, LJ strikingly inhibited 6-OHDA-induced mitochondrial dysfunctions including reduction of mitochondria membrane potential (MMP) and activation of cleaved poly-ADP-ribose polymerase (PARP), cleaved caspase-3, cleaved caspase-9, increased Bax, as well as decreased Bcl-2 and Bcl-xL. Additionally, LJ dramatically attenuated 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK 1/2), and phosphoinositide 3-kinase (PI3K)/Akt. Meanwhile, LJ counteracted nuclear factor-κB (NF-κB) activation by blocking its translocation to the nucleus. These findings suggest that LJ has a potent anti-parkinsonism; this effect was mediated, at least in part, by inhibition of neurotoxicity, apoptotic cascade events, and oxidative stress via activation of MAPKs, PI3K/Akt, and NF-κB.

Anxiolytic-Like Effects of Chrysanthemum indicum Aqueous Extract in Mice: Possible Involvement of GABAA Receptors and 5-HT1A Receptors.

Chrysanthemum indicum Linne is an ancient herbal medicine used to treat bone and muscle deterioration, ocular infl ammation, headache, and anxiety in Korea, China, and Japan. Furthermore, tea derived from Chrysanthemum indicum Linne has been used to treat anxiety by facilitating relaxation and curing insomnia. However, no reports exist on the anxiolytic-like effects of Chrysanthemum indicum Linne water extract (CWE) in mice. In the present study, we investigated the anxiolytic-like effects of CWE using the elevated plus-maze (EPM) test in mice. CWE, at a dose of 500 mg/kg (p.o.), signifi cantly increased the time spent in the open arms of the EPM compared to a vehicle-injected control group. Moreover, the effect of CWE (500 mg/kg) was blocked by bicuculline (a selective GABAA receptor antagonist) and WAY 100635 (a selective 5-HT1A receptor antagonist). Taken together, these fi ndings suggest that the anxiolytic-like effects of CWE might be mediated by the GABAA receptor and the 5-HT1A receptor.

Eucommia ulmoides Oliv. Bark. protects against hydrogen peroxide-induced neuronal cell death in SH-SY5Y cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Eucommia ulmoides Oliv. Bark. (EUE), has commonly been used to fortify the muscles and lungs, lower blood pressure, prevent miscarriage, improve the tone of liver and kidneys, and promote longevity the traditional tonic medicines of Korea, China, and Japan. AIM OF THE STUDY: In this study, we investigated that the neuroprotective activities and possible mechanisms of EUE aqueous extract in hydrogen peroxide (H(2)O(2))-induced neuronal cell death in human SH-SY5Y neuroblastoma cells. MATERIAL AND METHOD: We examined the effects of EUE against H(2)O(2)-induced cytotoxicity, DNA condensation, the production of reactive oxygen species (ROS), loss of mitochondria membrane potential (MMP), the proteolysis of cleaved poly-ADP-ribose polymerase (PARP), and the expression of Bcl-2, Bcl-xL, cleaved caspase-3, and release of cytochrome c. Moreover, we attempted to determine whether EUE suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK 1/2), and phosphoinositide 3-kinase (PI3K)/Akt. RESULTS: Pretreatment with EUE increased cell viability and inhibited cytotoxicity and DNA condensation. EUE also attenuated the increase in ROS production and MMP reduction. Western blot data revealed that EUE inhibited H(2)O(2)-induced up- or down-regulation of cleaved PARP, cleaved caspase-3, Bcl-2, and Bcl-xL. The EUE inhibited release of cytochrome c from mitochondria to the cytosol, and significantly attenuated H(2)O(2)-induced phosphorylation of JNK, p38 MAPK, ERK 1/2, and PI3K/Akt. CONCLUSION: The potent neuroprotective capacity of EUE, shown in these experiments, may potentially be applied in the prevention or treatment of neurodegenerative diseases such as Alzheimer's disease (AD).