Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson's disease.

Mitochondria are essential organelles for cell survival that manage the cellular energy supply by producing ATP. Mitochondrial dysfunction is associated with various human diseases, including metabolic syndromes, aging, and neurodegenerative diseases. Among the diseases related to mitochondrial dysfunction, Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss and neuroinflammation. Recently, it was reported that mitochondrial transfer between cells occurred naturally and that exogenous mitochondrial transplantation was beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transfer on PD in vitro and in vivo. The results showed that PN-101 mitochondria isolated from human mesenchymal stem cells exhibited a neuroprotective effect against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and rotenone in dopaminergic cells and ameliorated dopaminergic neuronal loss in the brains of C57BL/6J mice injected 30 â€‹mg/kg of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally. In addition, PN-101 exhibited anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines in microglial cells and suppressing microglial activation in the striatum. Furthermore, intravenous mitochondrial treatment was associated with behavioral improvements during the pole test and rotarod test in the MPTP-induced PD mice. These dual effects of neuroprotection and anti-neuroinflammation support the potential for mitochondrial transplantation as a novel therapeutic strategy for PD.

Inulae Flos has Anti-Depressive Effects by Suppressing Neuroinflammation and Recovering Dysfunction of HPA-axis.

Depression is a debilitating mood disorder that causes persistent feelings of sadness, emptiness, and a loss of joy. However, the clinical efficacy of representative drugs for depression, such as selective serotonin reuptake inhibitors, remains controversial. Therefore, there is an urgent need for more effective therapies to treat depression. Neuroinflammation and the hypothalamic-pituitary-adrenal (HPA) axis are pivotal factors in depression. Inulae Flos (IF), the flower of Inula japonica Thunb, is known for its antioxidant and anti-inflammatory effects. This study explored whether IF alleviates depression in both in vitro and in vivo models. For in vitro studies, we treated BV2 and PC12 cells damaged by lipopolysaccharides or corticosterone (CORT) with IF to investigate the mechanisms of depression. For in vivo studies, C57BL/6 mice were exposed to chronic restraint stress and were administered IF at doses of 0, 100, and 300 mg/kg for 2 weeks. IF inhibited pro-inflammatory mediators, such as nitric oxide, inducible nitric oxide synthase, and interleukins in BV2 cells. Moreover, IF increased the viability of CORT-damaged PC12 cells by modulating protein kinase B, a mammalian target of the rapamycin pathway. Behavioral assessments demonstrated that IF reduced depression-like behaviors in mice. We found that IF reduced the activation of microglia and astrocytes, and regulated synapse plasticity in the mice brains. Furthermore, IF lowered elevated CORT levels in the plasma and restored glucocorticoid receptor expression in the hypothalamus. Collectively, these findings suggest that IF can alleviate depression by mitigating neuroinflammation and recovering dysfunction of the HPA-axis.

Trichosanthis Semen Exerts Neuroprotective Effects in Alzheimer's Disease Models by Inhibiting Amyloid-ß Accumulation and Regulating the Akt and ERK Signaling Pathways.

Background: Alzheimer's disease (AD), the most common form of dementia, is characterized by memory loss and the abnormal accumulation of senile plaques composed of amyloid-ß (Aß) protein. Trichosanthis Semen (TS) is a traditional herbal medicine used to treat phlegm-related conditions. While TS is recognized for various bioactivities, including anti-neuroinflammatory effects, its ability to attenuate AD remains unknown. Objective: To evaluate the effects of TS extract (TSE) on neuronal damage, Aß accumulation, and neuroinflammation in AD models. Methods: Thioflavin T and western blot assays were used to assess effects on Aß aggregation in vitro. TS was treated to PC12 cells with Aß to assess the neuroprotective effects. Memory functions and histological brain features were investigated in TSE-treated 5×FAD transgenic mice and mice with intracerebroventricularly injected Aß. Results: TSE disrupted Aß aggregation and increased the viability of cells and phosphorylation of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) in vitro. TSE treatment also suppressed the accumulation of Aß plaques in the brain of 5×FAD mice, protected neuronal cells in both the subiculum and medial septum, and upregulated Akt/ERK phosphorylation in the hippocampus. Moreover, TSE ameliorated the memory decline and glial overactivation observed in 5×FAD mice. As assessing whether TS affect Aß-induced neurotoxicity in the Aß-injected mice, the effects of TS on memory improvement and neuroinflammatory inhibition were confirmed. Conclusions: TSE disrupted Aß aggregation, protected neurons against Aß-induced toxicity, and suppressed neuroinflammation, suggesting that it can suppress the development of AD.

Inhibition of microfold cells ameliorates early pathological phenotypes by modulating microglial functions in Alzheimer's disease mouse model.

BACKGROUND: The gut microbiota has recently attracted attention as a pathogenic factor in Alzheimer's disease (AD). Microfold (M) cells, which play a crucial role in the gut immune response against external antigens, are also exploited for the entry of pathogenic bacteria and proteins into the body. However, whether changes in M cells can affect the gut environments and consequently change brain pathologies in AD remains unknown. METHODS: Five familial AD (5xFAD) and 5xFAD-derived fecal microbiota transplanted (5xFAD-FMT) naïve mice were used to investigate the changes of M cells in the AD environment. Next, to establish the effect of M cell depletion on AD environments, 5xFAD mice and Spib knockout mice were bred, and behavioral and histological analyses were performed when M cell-depleted 5xFAD mice were six or nine months of age. RESULTS: In this study, we found that M cell numbers were increased in the colons of 5xFAD and 5xFAD-FMT mice compared to those of wild-type (WT) and WT-FMT mice. Moreover, the level of total bacteria infiltrating the colons increased in the AD-mimicked mice. The levels of M cell-related genes and that of infiltrating bacteria showed a significant correlation. The genetic inhibition of M cells (Spib knockout) in 5xFAD mice changed the composition of the gut microbiota, along with decreasing proinflammatory cytokine levels in the colons. M cell depletion ameliorated AD symptoms including amyloid-ß accumulation, microglial dysfunction, neuroinflammation, and memory impairment. Similarly, 5xFAD-FMT did not induce AD-like pathologies, such as memory impairment and excessive neuroinflammation in Spib-/- mice. CONCLUSION: Therefore, our findings provide evidence that the inhibiting M cells can prevent AD progression, with therapeutic implications.

P. mirabilis-derived pore-forming haemolysin, HpmA drives intestinal alpha-synuclein aggregation in a mouse model of neurodegeneration.

BACKGROUND: Recent studies suggesting the importance of the gut-microbiome in intestinal aggregated alpha synuclein (α-syn) have led to the exploration of the possible role of the gut-brain axis in central nervous system degeneration. Proteus mirabilis (P. mirabilis), a gram-negative facultative anaerobic bacterium, has been linked to brain neurodegeneration in animal studies. We hypothesised that P. mirabilis-derived virulence factors aggregate intestinal α-synuclein and could prompt the pathogenesis of dopaminergic neurodegeneration in the brain. METHODS: We used vagotomised- and antibiotic-treated male murine models to determine the pathogenesis of P. mirabilis during brain neurodegeneration. The neurodegenerative factor that is driven by P. mirabilis was determined using genetically mutated P. mirabilis. The pathological functions and interactions of the virulence factors were determined in vitro. FINDINGS: The results showed that P. mirabilis-induced motor dysfunction and neurodegeneration are regulated by intestinal α-syn aggregation in vagotomised- or antibiotic-treated murine models. We deduced that the specific virulence factor, haemolysin A (HpmA), plays a role in the pathogenesis of P. mirabilis. HpmA is involved in α-synuclein oligomerisation and membrane pore formation, resulting in the activation of mTOR-mediated autophagy signalling in intestinal neuroendocrine cells. INTERPRETATION: Taken together, the results of the present study suggest that HpmA can interact with α-syn and act as a possible indicator of brain neurodegenerative diseases that are induced by P. mirabilis. FUNDING: This study was supported by a grant from the National Research Foundation of Korea.

Linderae Radix Ameliorates Cognitive Dysfunction by Inhibiting Neuroinflammation and Synaptic Damage in Alzheimer's Disease Models.

Neuroinflammation and synaptic damage are important etiologies associated with the progression of Alzheimer's disease (AD). Linderae Radix (LR) has antioxidant and anti-inflammatory properties. This study investigated whether LR attenuates microglia activation-mediated neuroinflammation and synaptic degeneration and improves AD pathological phenotypes induced by amyloid beta oligomers (AßO) or lipopolysaccharide (LPS) toxicity. For in vitro studies, we treated LR to AßO-stimulated HT22 cells or LR LPS-stimulated BV2 cells. For in vivo studies, we administered LR to mice and AßO was injected by stereotaxic to induce cognitive impairment, neuroinflammation, and synaptic loss. We found that LR increased the cell viability reduced by AßO. Moreover, LR inhibited pro-inflammatory mediators such as nitric oxide (NO), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2), and downregulated p38 mitogen-activated protein kinase (MAPK) signaling in BV2 cells. Behavioral assessments demonstrated that LR administration significantly improved cognitive decline induced by AßO-injection. Furthermore, we found that microglia activation increased, and the expression of synaptic proteins decreased in the hippocampus of the AßO-injected group, which was alleviated in the LR-treated group. These findings suggest that LR may be a potential candidate for protection against neuroinflammation and synaptic loss, and may prevent or delay AD progression.

Peripheral metabolic alterations associated with pathological manifestations of Parkinson's disease in gut-brain axis-based mouse model.

Introduction: Parkinson's disease (PD) is a representative neurodegenerative disease, and its diagnosis relies on the evaluation of clinical manifestations or brain neuroimaging in the absence of a crucial noninvasive biomarker. Here, we used non-targeted metabolomics profiling to identify metabolic alterations in the colon and plasma samples of Proteus mirabilis (P. mirabilis)-treated mice, which is a possible animal model for investigating the microbiota-gut-brain axis. Methods: We performed gas chromatography-mass spectrometry to analyze the samples and detected metabolites that could reflect P. mirabilis-induced disease progression and pathology. Results and discussion: Pattern, correlation and pathway enrichment analyses showed significant alterations in sugar metabolism such as galactose metabolism and fructose and mannose metabolism, which are closely associated with energy metabolism and lipid metabolism. This study indicates possible metabolic factors for P. mirabilis-induced pathological progression and provides evidence of metabolic alterations associated with P. mirabilis-mediated pathology of brain neurodegeneration.

Longan extract suppresses food intake through regulation of POMC/AgRP neuronal activities and endoplasmic reticulum stress in hypothalamus of db/db mice.

Type 2 diabetes mellitus (T2DM) is one of the biggest public health issues worldwide and closely related to development of other chronic diseases such as cardiovascular diseases, cancer and neurodegenerative diseases. Considerable percentage of T2DM patients undergo have suffered from binge eating disorder which exacerbates insulin resistance and metabolic challenges. Longan (Dimocarpus longan L.) and its constituents are reported for their various health benefits. However, it is still unknown whether longan fruit supplementation can ameliorate glucose homeostasis and binge eating disorder found in T2DM. The current study aimed to investigate whether longan fruit extract (LE) supplementation can improve diabetic hyperglycemia through modulation of feeding center located in hypothalamus of db/db T2DM mice. As a result, LE supplementation ameliorated fasting blood glucose levels and reduced excessive epididymal fat accumulation. In addition, LE administration improved glucose tolerance and insulin sensitivity in db/db mice. Especially, LE supplemented mice showed less food consumption which was in line with increase of pro-opiomelanocortin (POMC) neuronal activities and decrease of agouti-related peptide (AgRP) neuronal activities. Furthermore, LE supplementation reduced hypothalamic endoplasmic reticulum (ER) stress which was stimulated in db/db mice. As ER stress is a crucial factor involving in appetite control and glucose homeostasis, the effect of LE supplementation on circulating glucose levels and feeding behavior might be mediated by suppression of hypothalamic ER stress. Collectively, these findings suggest that LE could be a potential nutraceutical for improvement of T2DM as well as patients with satiety issues.

6-Shogaol, an Active Ingredient of Ginger, Improves Intestinal and Brain Abnormalities in Proteus Mirabilis-Induced Parkinson's Disease Mouse Model.

Parkinson's disease (PD) which has various pathological mechanisms, recently, it is attracting attention to the mechanism via microbiome-gut-brain axis. 6-Shogaol, a representative compound of ginger, have been known for improving PD phenotypes by reducing neuroinflammatory responses. In the present study, we investigated whether 6-shogaol and ginger attenuate degeneration induced by Proteus mirabilis (P. mirabilis) on the intestine and brain, simultaneously. C57BL/6J mice received P. mirabilis for 5 days. Ginger (300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 22 days including the period of P. mirabilis treatment. Results showed that 6-shogaol and ginger improved motor dysfunction and dopaminergic neuronal death induced by P. mirabilis treatment. In addition, they suppressed P. mirabilis-induced intestinal barrier disruption, pro-inflammatory signals such as toll-like receptor and TNF-α, and intestinal α-synuclein aggregation. Moreover, ginger and 6-shogaol significantly inhibited neuroinflammation and α-synuclein in the brain. Taken together, 6-shogaol and ginger have the potential to ameliorate PD-like motor behavior and degeneration of dopaminergic neurons induced by P. mirabilis in mice. Here, these findings are meaningful in that they provide the first experimental evidence that 6-shogaol might attenuate PD via regulating gut-brain axis.

5-Hydroxytryptophan Reduces Levodopa-Induced Dyskinesia via Regulating AKT/mTOR/S6K and CREB/ΔFosB Signals in a Mouse Model of Parkinson's Disease.

Long-term administration of levodopa (L-DOPA) to patients with Parkinson's disease (PD) commonly results in involuntary dyskinetic movements, as is known for L-DOPA-induced dyskinesia (LID). 5-Hydroxytryptophan (5-HTP) has recently been shown to alleviate LID; however, no biochemical alterations to aberrant excitatory conditions have been revealed yet. In the present study, we aimed to confirm its anti-dyskinetic effect and to discover the unknown molecular mechanisms of action of 5-HTP in LID. We made an LID-induced mouse model through chronic L-DOPA treatment to 6-hydroxydopamine-induced hemi-parkinsonian mice and then administered 5-HTP 60 mg/kg for 15 days orally to LID-induced mice. In addition, we performed behavioral tests and analyzed the histological alterations in the lesioned part of the striatum (ST). Our results showed that 5-HTP significantly suppressed all types of dyskinetic movements (axial, limb, orolingual and locomotive) and its effects were similar to those of amantadine, the only approved drug by Food and Drug Administration. Moreover, 5-HTP did not affect the efficacy of L-DOPA on PD motor manifestations. From a molecular perspective, 5-HTP treatment significantly decreased phosphorylated CREB and ΔFosB expression, commonly known as downstream factors, increased in LID conditions. Furthermore, we found that the effects of 5-HTP were not mediated by dopamine1 receptor (D1)/DARPP32/ERK signaling, but regulated by AKT/mTOR/S6K signaling, which showed different mechanisms with amantadine in the denervated ST. Taken together, 5-HTP alleviates LID by regulating the hyperactivated striatal AKT/mTOR/S6K and CREB/ΔFosB signaling.

Two Faces of Catechol-O-Methyltransferase Inhibitor on One-Carbon Metabolism in Parkinson's Disease: A Meta-Analysis.

Levodopa (L-dopa) and catechol-O-methyltransferase (COMT) inhibition are widely used therapeutics in Parkinson's disease (PD). Despite their therapeutic effects, it was raised that nutrients involved in one-carbon metabolism can be deteriorated by PD therapies. The aim of this meta-analysis was to investigate the impact of L-dopa and COMT inhibitors on levels of homocysteine (Hcy), vitamin B12 and folate in patients with PD. A total of 35 case-control studies from 14 different countries were selected through PubMed, MEDLINE and Google Scholar and were meta-analyzed. In the L-dopa group, the Hcy level was higher compared to the PD without L-dopa group (SMD: 5.11 µmol/L, 95% CI: 3.56 to 6.66). Moreover, vitamin B12 and folate levels in the L-dopa group were lower compared to the healthy control (SMD: -62.67 pg/mL, 95% CI: -86.53 to -38.81; SMD: -0.89 ng/mL, 95% CI: -1.44 to -0.33, respectively). The COMT inhibitor group showed lower levels of Hcy (SMD: -3.78 µmol/L, 95% CI: -5.27 to -2.29) and vitamin B12 (SMD: -51.01 pg/mL, 95% CI: -91.45 to -10.57), but higher folate levels (SMD: 1.78 ng/mL, 95% CI: -0.59 to 4.15) compared to the L-dopa group. COMT inhibitors may ameliorate L-dopa-induced hyper-homocysteine and folate deficiency but exacerbate vitamin B12 deficiency.

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.

Protective effects of CCL01 against Aß-induced neurotoxicity in 5xFAD transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common dementia characterized by the excessive accumulation of amyloid-beta (Aß) and tau aggregates, as well as neuronal damage and neuroinflammation. Metabolic disruption in AD has been noticed because metabolite alterations closely correlate with Aß neuropathology and behavioral phenotypes. Accordingly, controlling various neuropathological processes and metabolic disruption is an efficient therapeutic strategy for AD treatment. In this study, we evaluated the effects of a combination of Cuscuta seeds and Lactobacillus paracasei NK112 (CCL01) on AD neuropathology and altered metabolism in five familial AD (5xFAD) transgenic mice and neuronal cell cultures. First, we observed that CCL01 exerted neuroprotective effects in HT22 hippocampal neurons and primary cultured neurons. CCL01 ameliorated memory decline and protected synapses and neuronal survival in 5xFAD mice. These effects were related to the inhibition of tau phosphorylation. CCL01 also inhibited the activation of mitogen-activated protein kinase (MAPK) signaling and neuroinflammatory processes. Moreover, the metabolite profile-particularly characterized by altered phospholipid metabolism-was significantly changed in the 5xFAD group, while CCL01 partly restored the alteration. Lysophosphatidylcholine (lysoPC), the levels of which were higher in the brains of 5xFAD mice, exerted neurotoxicity in vitro, whereas CCL01 protected neurons from lysoPC-induced toxicity by regulating MAPK signaling. Additionally, CCL01 administration reduced gut inflammation in the 5xFAD mice. In summary, we demonstrated that CCL01 improved the memory function of 5xFAD mice by protecting neurons against Aß- and lysoPC-induced toxicity through the regulation of MAPK signaling, neuroinflammation, tau phosphorylation, and gut inflammation, suggesting the potential of CCL01 as treatment for AD.

Trichosanthis Semen and Zingiberis Rhizoma Mixture Ameliorates Lipopolysaccharide-Induced Memory Dysfunction by Inhibiting Neuroinflammation.

Neuroinflammation, a key pathological contributor to various neurodegenerative diseases, is mediated by microglial activation and subsequent secretion of inflammatory cytokines via the mitogen-activated protein kinase (MAPK) signaling pathway. Moreover, neuroinflammation leads to synaptic loss and memory impairment. This study investigated the inhibitory effects of PNP001, a mixture of Trichosanthis Semen and Zingiberis Rhizoma in a ratio of 3:1, on neuroinflammation and neurological deficits induced by lipopolysaccharide (LPS). For the in vitro study, PNP001 was administered in LPS-stimulated BV2 microglial cells, and reduced the pro-inflammatory mediators, such as nitric oxide, inducible nitric oxide synthase, and cyclooxygenase-2 by downregulating MAPK signaling. For the in vivo study, ICR mice were orally administered PNP001 for 18 consecutive days, and concurrently treated with LPS (1 mg/kg, i.p.) for 10 days, beginning on the 4th day of PNP001 administration. The remarkably decreased number of activated microglial cells and increased expression of pre- and post-synaptic proteins were observed more in the hippocampus of the PNP001 administered groups than in the LPS-treated group. Furthermore, daily PNP001 administration significantly attenuated long-term memory decline compared with the LPS-treated group. Our study demonstrated that PNP001 inhibits LPS-induced neuroinflammation and its associated memory dysfunction by alleviating microglial activation and synaptic loss.

Psychophysiological and Metabolomics Responses of Adults during Horticultural Activities Using Soil Inoculated with Streptomyces rimosus: A Pilot Study.

This study compared the physiological effects at a metabolomics level with autonomic nervous system responses in adults during soil mixing activities, based on the presence or absence of Streptomyces rimosus in the soil. Thirty adult participants performed soil mixing activities for 5 min using sterilized soil with culture media and Streptomyces rimosus, respectively. Blood samples were drawn twice from each participant after each activity. Electroencephalograms were measured during the activity. Serum metabolites underwent metabolite profiling by gas chromatography, followed by multivariate analyses. Serum brain-derived neurotrophic factor and C-reactive protein levels were measured by Enzyme-Linked Immunosorbent Assay. Soil-emitted volatile organic compounds were identified via solid-phase microextraction and gas chromatography-mass spectroscopy, followed by multivariate analyses. The volatile compound analysis revealed that the terpenoid and benzoid compounds, geosmin, and 2-methylisoborneol were greater in soil with Streptomyces rimosus. Serum metabolomics revealed that the treatment group (soil inoculated with Streptomyces rimosus) possessed relatively higher levels of serotonin compared to the control group (soil mixed with culture media), and serum C-reactive protein levels were significantly lower in the treatment group. In the treatment group, the electroencephalogram revealed that alpha band activity of the occipital lobe increased. This study concludes that Streptomyces rimosus soil contact can positively affect human metabolic and autonomic reactions. Therefore, this pilot study confirmed the possible role of soil microorganisms in horticultural activities for psychophysiological effects in humans.

Petasites japonicus leaf extract inhibits Alzheimer's-like pathology through suppression of neuroinflammation.

Neuroinflammation is a crucial pathogenic process involved in the development and deterioration of Alzheimer's disease (AD). Petasites japonicus is known for its beneficial effects on various disease states such as allergic reaction, oxidative stress and inflammation. However, it is still unknown whether P. japonicus has protective effects on neuroinflammation, especially microgliosis related to AD. The current study aimed to investigate whether an extract of P. japonicus (named KP-1) protects from microglial cell activation in vitro and in vivo. To demonstrate the anti-neuroinflammation effects of KP-1, the current study adopted the most widely used experimental models including the lipopolysaccharide (LPS)-induced microgliosis in vitro model and amyloid beta (Aß) oligomer (AßO)-induced neuroinflammation in vivo model, respectively. As a result, KP-1 pre-treatment reduced nitric oxide (NO) production, protein levels of inducible NO synthase (iNOS) and c-Jun N-terminal kinase (JNK) phosphorylation in BV2 cells which were significantly promoted by 100 ng ml-1 LPS treatment. Similarly, KP-1 administration protected mice from AßO-induced memory impairment scored by Y-maze and novel object recognition test (NORT). Moreover, KP-1 administration suppressed AßO-induced microglial cell activation measured by counting the number of ionized calcium binding adaptor molecule 1 (Iba-1)-positive cells in both the cortex and hippocampal dentate gyrus and measuring the mRNA expression of TNFα, IL-1ß and IL-6. Furthermore, AßO-induced synaptotoxicity was prevented by KP-1 administration which is in line with behavioral changes. Collectively, these findings suggest that KP-1 could be a potential functional food for protection against neuroinflammation, and prevents or delays the progression of AD.

Chemical Constituents from the Aerial Parts of Artemisia iwayomogi and Their Anti-Neuroinflammatory Activities.

Neuroinflammation, predominantly mediated by microglial activation, is a key immunological response in the pathogenesis of neurodegenerative disorders. In our preliminary study, the aerial part of Artemisia iwayomogi inhibits LPS-induced microglial activation. The present study aims to identify chemical constituents with anti-neuroinflammatory properties in the aerial parts of A. iwayomogi. Two new guaianolide sesquiterpenes, iwayomogins A and B (1 and 2), along with thirteen known sesquiterpene lactones (3-15), one diterpene glycoside (16), and nine phenolic compounds (17-25) were isolated from the aerial parts of A. iwayomogi by repeated chromatography. The structures of the isolates were elucidated by their spectroscopic data. All isolates were evaluated for their inhibitory activities on nitric oxide (NO) production in LPS-induced BV-2 microglial cells. 2,3-Dehydro-1-epi-asperilin (11) exhibited the strongest inhibitory effect on NO production (IC50 value of 1.78 µM). In the molecular docking study, three compounds (1, 2, and 11) showed good binding affinities with iNOS. Additionally, compounds 1, 2, and 11 inhibit pro-inflammatory cytokines (TNF-α and IL-6) in dose-dependent manners. The present study demonstrates that the chemical constituents from A. iwayomogi inhibit NO production and pro-inflammatory cytokine release in BV-2 cells. However, further evaluation with biological experiments utilizing in vivo models is necessary.

In vitro and in vivo neuroprotective effect of novel mPGES-1 inhibitor in animal model of Parkinson's disease.

mPGES-1 is found to be up-regulated in the dopaminergic neurons of the substantia nigra pars compacta (SNpc) of postmortem brain tissue from Parkinson's disease (PD) patients and neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. Since the genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE2 production and 6-OHDA-induced dopaminergic neurodegeneration in vitro and in vivo models, mPGES-1 enzyme has the potential to be an important target for PD therapy. In the present work, we investigated whether a small organic molecule as mPGES-1 inhibitor could exhibit the neuroprotective effects against 6-OHDA-induced neurotoxicity in in vitro and in vivo models. For this research goal, a new series of arylsulfonyl hydrazide derivatives was prepared and investigated whether these compounds may protect neurons against 6-OHDA-induced neurotoxicity in both in vitro and in vivo studies. Among them, compound 7s (MPO-0144) as a mPGES-1 inhibitor (PGE2 IC50 = 41.77 nM; mPGES-1 IC50 = 1.16 nM) exhibited a potent neuroprotection (ED50 = 3.0 nM) against 6-OHDA-induced in PC12 cells without its own neurotoxicity (IC50 = >10 µM). In a 6-OHDA-induced mouse model of PD, administration of compound 7s (1 mg/kg/day, for 7 days, i.p.) ameliorated motor impairments and dopaminergic neuronal damage. These significant biological effects of compound 7s provided the first pharmacological evidence that mPGES-1 inhibitor could be a promising therapeutic agent for PD patients.

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.

Sceptrin-Au nano-aggregates (SANA) for overcoming drug-resistant Gram-negative bacteria.

One of the recent advances in medical nanotechnology has been the development of nanoformulations to overcome drug-resistant bacterial infections. Herein, we disclose a new nano-antibiotic formulation based on sceptrin-Au nano-aggregates (SANA), which are drug-metal ion multiple complexes. Sceptrin is a natural compound from a marine organism (sponge) and was reported as a potential compound with drug activities. SANA consists of a sceptrin-Au ion and is a self-assembled nano-formation with electrostatic interaction. Interestingly, SANA showed superior antibiotic/antibiofilm activity toward carbapenem-resistant Gram-negative bacteria with low toxicity to red blood cells and endothelial cells. The working mechanism of SANA was identified with analysis of the extracellular reactive oxygen species level and membrane depolarization of bacteria. The feasibility of SANA as a new nano-antibiotic was demonstrated in CRPA-contaminated medical supplies where SANA inhibited the formation of biofilms as well as the growth of CRPA. This work presents a new concept for the development of next-generation nano-antibiotics and a more feasible clinical translational pathway.