Aerial part of Houttuynia cordata reverses memory impairment by regulating amyloid beta accumulation and neuroinflammation in Alzheimer's disease model.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by amyloid-ß (Aß) deposition, accompanied by neuroinflammation and memory dysfunction. Houttuyniae Herba (aerial parts of Houttuynia cordata, also known as fish mint; HH), an herbal medicine traditionally used to treat fever, urinary disorders, and pus, is revealed to protect neurons from Aß toxicity and regulate cholinergic dysfunction in AD models. In this study, we aimed to investigate the effects of HH on excessive accumulation of Aß followed by neuroinflammation, synaptic degeneration, and memory impairment. Two-month-old 5xFAD transgenic mice were administered HH at 100 mg/kg for 4 months. We observed that HH treatment ameliorated memory impairment and reduced Aß deposits in the brains of the mice. HH directly inhibited Aß aggregation in vitro using the Thioflavin T assay and indirectly suppressed the amyloidogenic pathway by increasing alpha-secretase expression in the mice brain. In addition, HH exerted antineuroinflammatory effects by reducing of glial activation and p38 phosphorylation. Moreover, HH treatment increased the expression of synaptophysin, a presynaptic marker protein. Overall, HH alleviates memory impairment in AD by facilitating nonamyloidogenic pathway and inhibiting neuroinflammation. Therefore, we suggest that HH can be a promising herbal drug for patients with AD requiring multifaceted improvement.

DA-9805, a Herbal Mixture, Restores Motor Manifestations in 6-Hydroxydopamine-induced Parkinson's Disease Mouse Model by Regulating Striatal Dopamine and Acetylcholine Levels.

Loss of dopamine (DA) is one of the primary features of Parkinson's disease (PD); however, imbalances of non-dopaminergic neurotransmitters significantly contribute to the disabilities noted in advanced PD patients. DA-9805 is the ethanolic extraction of the root bark of Paeonia × suffruticosa Andrews (Paeoniaceae), the root of Angelica dahurica (Hoffm.) Benth. and Hook.f. ex Franch. and Sav. (Apiaceae) and the root of Bupleurum falcatum L. (Apiaceae), which have been widely utilized as an enhancer of motor function in East Asia. This study aimed to investigate whether DA-9805 modified motor dysfunctions and imbalances associated with DA and other neurotransmitters in a 6-hydroxydopamine-induced PD mouse. We confirmed the expressions of proteins related with neurotransmissions in the striatum. In addition, we measured the striatal neurotransmitters using HPLC and analyzed their correlation. DA-9805 significantly improved motor impairments and restored the altered levels of neurotransmitters in the striatum. Moreover, DA-9805 improved the altered expressions of tyrosine hydroxylase (TH), DA transporter, and choline acetyltransferase (ChAT) in the ipsilateral part of mouse striatum or SNpc, which implies the neuroprotection. We also found that the level of striatal acetylcholine (Ach) has the moderate negative correlation with motor functions and TH expression in the SNpc. This study indicates that DA-9805 restores motor dysfunctions by normalizing the increased levels of striatal Ach via modulating DA transmission and ChAT expressions as well as its neuroprotective effects.

The novel anti-neuroinflammatory functional food CCL01, a mixture of Cuscuta seed extracts and Lactobacillus paracasei NK112.

Neuroinflammation, which occurs due to microglia, is related to the pathogenesis of neurodegenerative disorders. Recently, the development of functional foods that down-regulate over-activated microglial cells to prevent the progression of neurodegenerative disorders has been proposed, since over-activated microglia induce a chronic source of neurotoxic factors and reduce neuronal survival. Thus, the anti-neuroinflammatory effects of a functional food mixture (CCL01) including Cuscuta seeds and Lactobacillus paracasei NK112 on lipopolysaccharide (LPS)-induced experimental models were investigated. In LPS-induced in vitro models, the expression levels of inflammatory mediators (e.g., inducible nitric oxide synthase, cyclooxygenase-2, nitric oxide, and prostaglandin E2) and pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6) were decreased upon CCL01 treatment. CCL01 showed an anti-neuroinflammatory effect in LPS-induced microglial cells via the inhibition of the mitogen-activated protein kinase (MAPK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and the activation of the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. In the LPS-treated in vivo mouse models, the increased expression of ionized calcium binding adaptor molecule 1 (Iba-1), which indicates microglial activity, was markedly decreased upon treatment with CCL01 (50 and 200 mg kg-1) in the hippocampus and cortex areas of the mouse brains in comparison with the LPS-injected group. In addition, the groups to which CCL01 was administered had significantly decreased plasma levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in the LPS-injected mouse models. Our data suggest that CCL01 may be a potential anti-neuroinflammatory agent that can prevent microglia overactivation, and it could be useful for developing functional foods.

DA-9801, a standardized Dioscorea extract, improves memory function via the activation of nerve growth factor-mediated signaling.

OBJECTIVES: Nerve growth factor (NGF) is a neurotrophin that plays a critical role in mammalian learning and memory functions. NGF also regulates neuronal cell differentiation and neurite outgrowth by activating ERK/CREB signaling. This present study examined the effects of a standardized Dioscorea extract (DA-9801), which is composed of Dioscorea japonica Thunb and Dioscorea nipponica Makino on memory function via its NGF-potentiating activities using an in vitro and in vivo paradigm. METHODS: Cells were incubated with or without different concentrations of DA-9801 (10, 25, and 50 µg/ml) extract for 24 h. The cultured conditioned medium from C6 glioma cells was used for NGF production assay, and neurite length in N2a cells was measured after every 2 h. Mice were orally treated with DA-9801 (10 and 100 mg/kg/day) once daily for 7 days. They were subjected to passive avoidance test to evaluate memory functions. The question of whether DA-9801 induced NGF synthesis was assessed by measuring the levels of NGF in the mouse cortical and hippocampal tissues. Hippocampal cell differentiation and NGF-mediated ERK/CREB signaling were evaluated by performing immunohistochemical analysis using BrdU, ki67, DCX, phosphorylated ERK and CREB in the mouse hippocampus. RESULTS: DA-9801 treatment increased the NGF contents and neurite length, respectively. Mice with DA-9801 administration showed memory enhancement in the passive avoidance test. DA-9801 also increased newborn cell differentiation, neurite length, NGF secretion, and ERK/CREB phosphorylation in the mouse hippocampus. DISCUSSION: These results suggest that DA-9801 treatment could improve memory function by inducing hippocampal NGF synthesis and ERK/CREB signaling.

A novel nutritional mixture, MBN, prevents memory impairment via inhibiting NLRP3 inflammasome formation in 5xFAD transgenic mice.

OBJECTIVES: Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological factor of Alzheimer's disease (AD), which results in memory impairment. Inhibition of excessive neuroinflammation mediated by Aß is considered a promising strategy to ameliorate AD symptoms. To regulate the inflammatory response, nutritional and dietary supplements have been used for centuries. Based on this idea, we investigated whether MBN, a novel nutritional mixture including cassia bark, turmeric root, and ginkgo leaf, can prevent AD progression through neuroinflammatory regulation. METHODS: MBN (10, 30, or 100 µg/ml) and Aß1-42 monomer were incubated together, and the degree of Aß aggregation was measured using Thioflavin T assay. The effects of MBN on Aß pathology in vivo were evaluated by orally administering MBN (40 mg/kg/day for 16 weeks) to five familial AD (5xFAD) mice. RESULTS: We found that treatment with MBN inhibited Aß aggregation in vitro. Next, MBN treatment significantly inhibited the activation of microglia induced by aggregated Aß in 5xFAD mice. Caspase-1 activation, which plays an important role in the maturation of interleukin-1ß, was markedly reduced by MBN. We also found that oral administration of MBN in 5xFAD mice alleviated memory decline. Taken together, our findings demonstrate that MBN suppresses neuroinflammation by downregulating the caspase-1 expression, thereby ameliorating memory impairment in 5xFAD mice. DISCUSSION: Based on these results, we suggest that MBN may be a preventive and therapeutic supplement for AD through the regulation of neuroinflammation.

Artemisiae Iwayomogii Herba inhibits lipopolysaccharide-induced neuroinflammation by regulating NF-κB and MAPK signaling pathways.

BACKGROUND: Neuroinflammation plays a major role in the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The regulation of microglia is an efficient therapeutic approach to controlling neuroinflammation. PURPOSE: In this study, we aimed to determine whether Artemisiae Iwayomogii Herba (AIH), which is herbal medicine traditionally used for inflammation-related disorders, controls neuroinflammatory responses by regulating the microglia-mediated signaling pathway. METHODS: BV-2 microglial cells were treated with AIH and lipopolysaccharides (LPS), then various pro-inflammatory mediators were analyzed using griess reaction, quantitative reverse-transcription polymerase chain reaction, or western blotting. C57BL/6 J mice were orally administered by AIH for 17 days and intraperitoneally injected with LPS for the last 14 days. The brains were collected and the microglial activation and nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) expression in the cortex and hippocampus were analyzed using immunohistochemistry or western blotting. RESULTS: In BV-2 microglial cells, we found that AIH inhibited nitric oxide (NO) production induced by LPS. AIH also suppressed the expressions of pro-inflammatory mediators, including inducible NO synthase, cyclooxygenase-2, tumor necrosis factor-α, and interleukin-6. The study also revealed that the effects of AIH are related to the regulation of the nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, we found that AIH prevented the formation of NLRP3 inflammasomes. Consistent with the results of in vitro studies on the brains of LPS-injected mice, we observed that AIH suppressed microglial activation and NLRP3 expression. CONCLUSION: Taken together, these results suggest that AIH attenuates neuroinflammation by regulating the NF-κB and MAPK pathways, and it may be used for treating neurological diseases.

Artemisiae Iwayomogii Herba Inhibits Growth, Motility, and the PI3K/AKT/mTOR Signaling Pathway in Hepatocellular Carcinoma Cells.

Artemisia gmelinii (Artemisia iwayomogi) has been used in traditional medicine to cure various infectious diseases such as cholecystitis, hepatitis, and jaundice. In this study, the Artemisiae Iwayomogii Herba ethanol extract was investigated for the ability to inhibit growth of hepatocellular carcinoma and its underlying mechanism involved. The antiproliferative effect of Artemisiae Iwayomogii Herba ethanol extract was evaluated using cell viability and proliferation assays. The effect of Artemisiae Iwayomogii Herba ethanol extract on apoptosis was measured using western blotting, terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling staining, JC-1 staining, cytochrome c release, immunohistochemistry, and immunofluorescence in ex vivo mouse xenografts. Artemisiae Iwayomogii Herba ethanol extract inhibited hepatocellular carcinoma cell growth and proliferation in a dose-dependent manner. The apoptotic effect of Artemisiae Iwayomogii Herba ethanol extract was observed via increased levels of cleaved caspase-3 and cleaved PARP, as well as elevated numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling-positive apoptotic cells. Artemisiae Iwayomogii Herba ethanol extract also decreased XIAP and Mcl-1 expression via loss of mitochondrial membrane potential. Additionally, Artemisiae Iwayomogii Herba ethanol extract inhibited hepatocellular carcinoma cell invasion and migration. In the ex vivo model, Artemisiae Iwayomogii Herba ethanol extract significantly inhibited tumor cell proliferation and increased the number of apoptotic cells with more activated cleaved caspase-3. A mechanistic study revealed that Artemisiae Iwayomogii Herba ethanol extract effectively suppressed the PI3K/AKT/mTOR signaling pathway in hepatocellular carcinoma cells. Our findings demonstrate that Artemisiae Iwayomogii Herba ethanol extract can efficiently induce apoptosis and inhibit the growth, migration, and invasion of human hepatocellular carcinoma cells, and simultaneously block PI3K/AKT/mTOR pathway. We therefore suggest Artemisiae Iwayomogii Herba ethanol extract as a novel natural agent for prevention and therapy of hepatocellular carcinoma.

The Mixture of Gotu Kola, Cnidium Fruit, and Goji Berry Enhances Memory Functions by Inducing Nerve-Growth-Factor-Mediated Actions Both In Vitro and In Vivo.

Nerve growth factor (NGF), a typical neurotrophin, has been characterized by the regulation of neuronal cell differentiation and survival involved in learning and memory functions. NGF has a main role in neurite extension and synapse formation by activating the cyclic adenosine monophosphate-response-element-binding protein (CREB) in the hippocampus. The purpose of this study was to determine whether a mixture of Gotu Kola, Cnidium fruit, and Goji berry (KYJ) enhances memory function by inducing NGF-mediated actions both in vitro and in vivo. The KYJ combination increased NGF concentration and neurite length in C6 glioma and N2a neuronal cells, respectively. Additionally, we discovered memory-enhancing effects of KYJ through increased NGF-mediated synapse maturation, CREB phosphorylation, and cell differentiation in the mouse hippocampus. These findings suggest that this combination may be a potential nootropic cognitive enhancer via the induction of NGF and NGF-dependent activities.

Ginger and 6-shogaol protect intestinal tight junction and enteric dopaminergic neurons against 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine in mice.

Objective: Ginger and its compound, 6-shogaol, have been known for improving gastrointestinal (GI) function and reducing inflammatory responses in GI tract. Recently, the treatment of GI dysfunction has been recognized as an important part of the management of neurodegenerative diseases, especially for Parkinson's disease (PD). In this study, we investigated whether ginger and 6-shogaol attenuate disruptions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the intestinal barrier and the enteric dopaminergic neurons.Methods: C57BL/6J mice received MPTP (30 mg/kg) for 5 days to induce GI alterations. Ginger (30, 100, 300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 15 days including the period of MPTP injection.Results: Ginger and 6-shogaol protected intestinal tight junction proteins disrupted by MPTP in mouse colon. In addition, ginger and 6-shogaol suppressed the increase of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α and IL-1ß activated by macrophage. Moreover, ginger and 6-shogaol suppressed the MPTP-induced enteric dopaminergic neuronal damage via increasing the cell survival signaling pathway.Conclusion: These results indicate that ginger and 6-shogaol restore the disruption of intestinal integrity and enteric dopaminergic neurons in an MPTP-injected mouse PD model by inhibiting the processes of inflammation and apoptosis, suggesting that they may attenuate the GI dysfunction in PD patients.

Cuscutae Japonicae Semen Ameliorates Memory Dysfunction by Rescuing Synaptic Damage in Alzheimer's Disease Models.

Alzheimer's disease (AD) is the most common type of dementia in the elderly. It is characterized by the accumulation of amyloid-beta (Aß) and progressive cognitive impairment. To alleviate the symptoms of AD, functional foods and nutrients have been used for centuries. In this study, we investigated whether Cuscutae Japonicae Semen (CJS), a medicinal food traditionally used in East Asia, has effects on memory improvement and synapse protection in AD. We orally administered CJS to 5x familiar AD (5xFAD) transgenic mice and performed the Morris water maze test. The results showed that CJS treatment ameliorated the decline of memory function. Then, we demonstrated that CJS attenuated the degeneration of pre- and post-synaptic proteins in the hippocampi of 5xFAD mice. To demonstrate the effects of CJS in vitro, we treated Aß in primary neuronal culture with CJS and observed that CJS rescued the loss of functional synapses. The protective effects of CJS on the synapse were due to the inhibition of activated caspase-3 expression. Additionally, CJS inhibited the phosphorylation of glycogen synthase kinase-3ß and tau proteins, which contribute to synaptic dysfunction. Taken together, our results suggest that CJS is efficient in alleviating memory loss by rescuing caspase-3-mediated synaptic damage in AD treatment.

Protective effects of DA-9805 on dopaminergic neurons against 6-hydroxydopamine-induced neurotoxicity in the models of Parkinson's disease.

With the elderly population rapidly growing, the prevalence of Parkinson's disease (PD) is quickly increasing because neurodegenerative disorders are usually late-onset. Herbal medicines and formula are adjuvant therapies of conventional PD agents, which result in serious side effects with long-term use. This study evaluated the neuroprotective effects of DA-9805, a standardized herbal formula that consists of an ethanolic extract of Moutan Cortex Radix, Angelica Dahuricae Radix, and Bupleuri Radix against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in vitro and in vivo. In PC12 cells, DA-9805 at concentrations of 1 and 10 µg/mL ameliorated cell viability, which was reduced by 6-OHDA. In addition, DA-9805 activated the extracellular-regulated kinase-nuclear transcription factor-erythroid 2-related factor 2 pathway, subsequently stimulating antioxidative enzymes such as NAD(P)H:quinone oxidoreductase 1 and catalase and suppressing apoptosis. Furthermore, DA-9805 prevented 6-OHDA-induced movement impairment, as well as a decrease of dopaminergic neurons and dopamine transmission in rodents. Taken together, these results suggest that the mixed herbal formula DA-9805 may be a pharmaceutical agent for preventing or improving PD.

Protective effects of Belamcandae Rhizoma against skin damage by ameliorating ultraviolet-B-induced apoptosis and collagen degradation in keratinocytes.

Ultraviolet-B light (UV-B) is a major cause of skin photoaging, inducing cell death and extracellular matrix collapse by generating reactive oxygen species (ROS). Belamcandae Rhizoma (BR), the rhizome of Belamcanda chinensis Leman, exhibits antioxidant properties, but it remains unknown whether BR extract ameliorates UV-B-induced skin damage. In this study, we evaluated the effects of a standardized BR extract on UV-B-induced apoptosis and collagen degradation in HaCaT cells. BR was extracted using four different methods. We used radical-scavenging assays to compare the antioxidative activities of the four extracts. Cells were irradiated with UV-B and treated with BR boiled in 70% (vol/vol) ethanol (BBE). We measured cell viability, intracellular ROS levels, the expression levels of antioxidative enzymes, and apoptosis-related and collagen degradation-related proteins. The irisflorentin and tectorigenin levels were measured via high-performance liquid chromatography. BBE exhibited the best radical-scavenging and cell protective effects of the four BR extracts. BBE inhibited intracellular ROS generation and induced the synthesis of antioxidative enzymes such as catalase and glutathione. BBE attenuated apoptosis by reducing the level of caspase-3 and increasing the Bcl-2/Bax ratio. BBE reduced the level of matrix metalloproteinase-1 and increased that of type I collagen. The irisflorentin and tectorigenin contents were 0.23% and 0.015%, respectively. From these results, BBE ameliorated UV-B-induced apoptosis and collagen degradation by enhancing the expression of antioxidative enzymes. It may be a useful treatment for UV-B-induced skin damage.

Z-ligustilide and n-Butylidenephthalide Isolated from the Aerial Parts of Angelica tenuissima Inhibit Lipid Accumulation In Vitro and In Vivo.

Abnormal lipid metabolism, such as increased fatty acid uptake and esterification, is associated with nonalcoholic fatty liver disease (NAFLD). The aqueous extract of the aerial part of Angelica tenuissima Nakai (ATX) inhibited high-fat diet-induced hepatic steatosis in mice as well as oleic acid-induced neutral lipid accumulation in HepG2 cells. ATX decreased the mRNA and protein levels of CD36 and diglyceride acyltransferase 2 (DGAT2), the maturation of sterol regulatory element-binding proteins (SREBP), and the expression of the lipogenic target genes fasn and scd1. The ATX components, Z-ligustilide and n-butylidenephthalide, inhibited the expression of FATP5 and DGAT2 and thus oleic acid-induced lipid accumulation in HepG2 cells. These results suggest that ATX and its active components Z-ligustilide and n-butylidenephthalide inhibit fatty acid uptake and esterification in mice and have potential as therapeutics for NAFLD.

Tectorigenin, a Flavonoid-Based Compound of Leopard Lily Rhizome, Attenuates UV-B-Induced Apoptosis and Collagen Degradation by Inhibiting Oxidative Stress in Human Keratinocytes.

Ultraviolet (UV) light, a major risk factor for external skin photoaging, induces oxidative stress in skin. UV causes a breakdown of skin homeostasis by impairing the extracellular matrix and inducing cell death. Tectorigenin, a constituent of leopard lily (Belamcanda chinensis L.) rhizome, has been reported to possess antioxidant, hair-darkening, and anti-inflammatory activities; however, the effect of tectorigenin on UV-B-induced skin damage is unknown. Here, we investigated the anti-skin-damage effects of tectorigenin against UV-B-stimulated oxidative stress in human keratinocytes. We irradiated HaCaT cells with UV-B (25 mJ/cm²), followed by treatment with tectorigenin for 24 h. We found that tectorigenin decreased the levels of intracellular reactive oxygen species by increasing the expression of anti-oxidative enzymes, such as glutathione and catalase. Furthermore, tectorigenin inhibited apoptosis by reducing caspase-3- and Bcl-2-associated protein-X levels, and increasing Bcl-2 protein levels. Tectorigenin also decreased matrix metalloproteinase-1 levels and increased type 1 collagen levels, thus preventing collagen degradation. These data demonstrate that tectorigenin exerts anti-skin-damage effects in human keratinocytes by attenuating UV-B-induced hyper-oxidation, apoptosis, and collagen degradation.

Peucedani Japonici Radix ameliorates lipopolysaccharide-induced neuroinflammation by regulating microglial responses.

Neuroinflammation is an inflammatory process within the central nervous system that is mediated by microglial activation, which releases pro-inflammatory mediators leading to neurodegeneration. In this study, we investigated the effects of Peucedani Japonici Radix (PJR), a medicinal herb traditionally used in East Asia to treat neuroinflammation both in vitro and in vivo. First, we examined the effects of PJR on pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. The results showed that PJR suppressed the LPS-induced increase of several inflammatory factors, such as nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, prostaglandin E2, interleukin-1ß, and tumor necrosis factor-α. We also revealed that PJR inhibited the nuclear factor kappa B (NF-κB) pathway, which is the upstream modulator of inflammatory processes. Furthermore, to confirm the regulatory effects of PJR on microglia in vivo, we measured the number of ionized calcium-binding adapter molecule 1-positive cells in mouse brains and found that PJR treatment reduced microglial activation. Taken together, these results suggest that PJR inhibits microglia-mediated neuroinflammation through the modulation of NF-κB signaling and has the therapeutic potential to prevent inflammation-related neurodegenerative diseases.

An ethyl acetate fraction of Artemisia capillaris (ACE-63) induced apoptosis and anti-angiogenesis via inhibition of PI3K/AKT signaling in hepatocellular carcinoma.

In cancer treatment, herbal medicines may be a good choice because of the reduced risk of adverse side effects. Artemisia capillaris has been recognized as a promising candidate due to its hepatoprotective effects. Herein, we investigated whether A. capillaris-derived fraction (ACE-63) could inhibit the progression of hepatocellular carcinoma (HCC) and its underlying mechanism. In this study, ACE-63 effectively inhibited the growth and proliferation of HCC cells. ACE-63 induced apoptosis, as observed using Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, which was accompanied with increases in cleaved Poly (ADP-ribose) polymerase (PARP) and caspase-3 in HCC cells. Additionally, the pro-apoptotic effect of ACE-63 was demonstrated by a decrease in the expression of the X-linked inhibitor of apoptosis protein (XIAP) and survivin via a loss of mitochondrial membrane potential. In an ex vivo model, ACE-63 significantly inhibited tumor cell growth and induced apoptosis by increasing the expression of cleaved caspase-3 and DNA fragmentation. In addition, ACE-63 decreased the expression of hypoxia-inducible factor-1α and vascular endothelial growth factor and inhibited tube formation of human umbilical vein endothelial cells. A mechanistic study revealed that ACE-63 effectively suppressed the PI3K/AKT/mTOR signaling pathways, which were observed as a target signaling by phosphokinase array. Taken together, our findings demonstrate that ACE-63 could not only efficiently induce apoptosis but also inhibit the growth/angiogenesis of human HCC cells by blocking the PI3K/AKT/mTOR signaling pathway, suggesting that ACE-63 may be a new chemotherapeutic candidate against HCC.

Butterbur Leaves Attenuate Memory Impairment and Neuronal Cell Damage in Amyloid Beta-Induced Alzheimer's Disease Models.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and is characterized by the accumulation of amyloid beta (Aß) as a pathological hallmark. Aß plays a central role in neuronal degeneration and synaptic dysfunction through the generation of excessive oxidative stress. In the present study, we explored whether leaves of Petasites japonicus (Siebold & Zucc.) Maxim. (PL), called butterbur and traditionally used in folk medicine, show neuroprotective action against Aß25⁻35 plaque neurotoxicity in vitro and in vivo. We found that PL protected Aß25⁻35 plaque-induced neuronal cell death and intracellular reactive oxygen species generation in HT22 cells by elevating expression levels of phosphorylated cyclic AMP response element-binding protein, heme oxygenase-1, and NAD(P)H quinine dehydrogenase 1. These neuroprotective effects of PL were also observed in Aß25⁻35 plaque-injected AD mouse models. Moreover, administration of PL diminished Aß25⁻35 plaque-induced synaptic dysfunction and memory impairment in mice. These findings lead us to suggest that PL can protect neurons against Aß25⁻35 plaque-induced neurotoxicity and thus may be a potential candidate to regulate the progression of AD.

Inhibitory effects of Aconiti Lateralis Radix Preparata on chronic intermittent cold-induced inflammation in the mouse hypothalamus.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconiti Lateralis Radix Preparata (AR) is the most frequently used herb to generate heat and treat symptoms associated with coldness in Asia. AIMS OF THE STUDY: The hypothalamus is one of the master regulators to maintain constant core body temperature. Chronic exposure to cold stress disturbs homeostatic regulation, gradually resulting in hypothalamic inflammation. This study investigate the effects of AR, on the chronic intermittent cold (CIC)-induced release of pro-inflammatory signaling molecules in the mouse hypothalamus. MATERIALS AND METHODS: Aconiti Lateralis Radix Preparata extract (ARE) were solubilized in distilled water and diluted with saline before administration. Male ICR mice (7 weeks old, 30-32g) were divided randomly into 6 groups: (1) control, (2) cold stress, (3) ARE 30, (4) ARE 100, (5) ARE 300, and (6) ARE 1000mg/kg groups. Groups (2)-(6) were exposed to CIC stress once a day for 14 days. CIC stress was achieved by exposing the mice to 4°C and 60 ± 10% humidity for 120min once a day. Rectal temperature was measured after terminating cold stress. Cortisol levels were measured from serum. Hypothalamus tissue was used for western blot analysis, and IL-9, IL-13, PGE1, and PGE2 levels were assessed. RESULTS: ARE treatment prevented the CIC-induced decrease in rectal temperature and increase in serum cortisol level. ARE-treated CIC-exposed mice demonstrated decrease in nuclear c-Fos levels dose-dependently compared to CIC-exposed mice. Nuclear NF-kB expression showed significant increase in CIC-exposed mice. ARE treatment significantly blunted the increase in nuclear NF-kB expression. CIC-exposed mice had significantly increased levels of both IL-9 and IL-13. Treatment with ARE suppressed the elevated IL-9 and IL-13 levels. Between control and CIC-exposed mice PGE1 levels showed no difference. However ARE (1000mg/kg)-treated CIC-exposed mice had a significant increase in PGE1 level compared to CIC-exposed mice. PGE2 levels were significantly higher in CIC-exposed mice compared to control mice. ARE treatment significantly attenuated the increase in PGE2 levels. CONCLUSIONS: Our findings suggest CIC stress disturbs the anti-inflammatory effect of cortisol and maintenance of the body temperature. Thus AR contributes to suppress the activated proinflammatory factors, IL-9, IL-13, and PGE-2, and to increase the heat production.

Pharmacotherapeutic potential of ginger and its compounds in age-related neurological disorders.

Age-related neurological disorders (ANDs), including neurodegenerative diseases, are multifactorial disorders with a risk that increases with aging. ANDs are generally characterized by common neuropathological conditions of the central nervous system, such as oxidative stress, neuroinflammation, and protein misfolding. Recently, efforts have been made to overcome ANDs because of the increase in age-dependent prevalence. Ginger, the rhizome of Zingiber officinale Roscoe, is a popular food spice and has a long history of use in traditional medicine for treating various disease symptoms. The structure-activity relationships of ginger phytochemicals show that ginger can be used to treat ANDs by targeting different ligand sites. This review shows that ginger and its constituents, such as 6-gingerol, 6-shogaol, 6-paradol, zingerone, and dehydrozingerone, are effective for ameliorating the neurological symptoms and pathological conditions of ANDs through by modulating cell death or cell survival signaling molecules. From this review, we conclude that the active ingredients in ginger have therapeutic potential in ANDs.

Optimized-SopungSunkiwon, a Herbal Formula, Attenuates Aß Oligomer-Induced Neurotoxicity in Alzheimer's Disease Models.

Alzheimer's disease (AD), the most common form of dementia, is an age-related neurodegenerative disease that is characterized by memory dysfunction, neuronal cell damage, and neuroinflammation. It is believed that AD-related pathology is mostly due to the overproduction of Aß, especially the oligomeric form (AßO), in the brain. Evidence of the effects of multifunctional medicinal herbs in the treatment of AD has been steadily increasing. Optimized-SopungSunkiwon (OSS), a multiherbal formulation that is composed of six medicinal herbs derived from SopungSunkiwon, is a traditional medicine that is prescribed for neurodegenerative disorders in elderly patients. We previously reported that OSS showed an antiamnesic and memory enhancing effect in mice, but it is unknown whether OSS has a protective effect against AßO neurotoxicity. In this study, we investigated the effects of OSS in AD models induced by AßO in vitro and in vivo. We found that OSS protected neuronal cells and inhibited the generation of nitric oxide and reactive oxygen species against AßO toxicity in vitro. These results were confirmed by in vivo data that oral administration of OSS for 14 days attenuated memory impairments and neuronal cell death by modulating gliosis, glutathione depletion, and synaptic damage in the mouse hippocampus induced by AßO.