Yu-En Lin

All Publications

• PathogenicLRRK2mutations cause loss of primary cilia and Neurturin in striatal parvalbumin interneurons. Life science alliance Lin, Y., Jaimon, E., Tonelli, F., Pfeffer, S. R. 2025; 8 (1)

  Abstract

  Parkinson's disease-associated, activating mutations in the LRRK2 kinase block primary cilium formation in cell culture and in specific cell types in the brain. In the striatum that is important for movement control, about half of astrocytes and cholinergic interneurons, but not the predominant medium spiny neurons, lose their primary cilia. Here, we show that mouse and human striatal parvalbumin interneurons that are inhibitory regulators of movement also lose primary cilia. Without cilia, these neurons are not able to respond to Sonic hedgehog signals that normally induce the expression of Patched RNA, and their numbers decrease. In addition, in mouse, glial cell line-derived neurotrophic factor-related Neurturin RNA is significantly decreased. These experiments highlight the importance of parvalbumin neurons in cilium-dependent, neuroprotective signaling pathways and show that LRRK2 activation correlates with decreased Neurturin production, resulting in less neuroprotection for dopamine neurons.

  View details for DOI 10.26508/lsa.202402922

  View details for PubMedID 39537338

• Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America Khan, S. S., Jaimon, E., Lin, Y. E., Nikoloff, J., Tonelli, F., Alessi, D. R., Pfeffer, S. R. 2024; 121 (32): e2402206121

  Abstract

  Activating leucine-rich repeat kinase 2 (LRRK2) mutations cause Parkinson's and phosphorylation of Rab10 by pathogenic LRRK2 blocks primary ciliogenesis in cultured cells. In the mouse brain, LRRK2 blockade of primary cilia is highly cell type specific: For example, cholinergic interneurons and astrocytes but not medium spiny neurons of the dorsal striatum lose primary cilia in LRRK2-pathway mutant mice. We show here that the cell type specificity of LRRK2-mediated cilia loss is also seen in human postmortem striatum from patients with LRRK2 pathway mutations and idiopathic Parkinson's. Single nucleus RNA sequencing shows that cilia loss in mouse cholinergic interneurons is accompanied by decreased glial-derived neurotrophic factor transcription, decreasing neuroprotection for dopamine neurons. Nevertheless, LRRK2 expression differences cannot explain the unique vulnerability of cholinergic neurons to LRRK2 kinase as much higher LRRK2 expression is seen in medium spiny neurons that have normal cilia. In parallel with decreased striatal dopaminergic neurite density, LRRK2 G2019S neurons show increased autism-linked CNTN5 adhesion protein expression; glial cells show significant loss of ferritin heavy chain. These data strongly suggest that loss of cilia in specific striatal cell types decreases neuroprotection for dopamine neurons in mice and human Parkinson's.

  View details for DOI 10.1073/pnas.2402206121

  View details for PubMedID 39088390

• Anti-depressive-like and cognitive impairment alleviation effects of Gastrodia elata Blume water extract is related to gut microbiome remodeling in ApoE−/− mice exposed to unpredictable chronic mild stress Journal of Ethnopharmacology Huang*, H., Lin*, Y., Panyod, S., Chen, R., Lin, Y., Chai, M. L., Hsu, C., Wu, W., Lu, K., Huang, Y., Sheen, L. 2023; 302: 115872

  View details for DOI 10.1016/j.jep.2022.115872

• Genotoxicity and 28-day repeated dose oral toxicity study of garlic essential oil in mice. Journal of traditional and complementary medicine Lin, Y. E., Lin, M. H., Yeh, T. Y., Lai, Y. S., Lu, K. H., Huang, H. S., Peng, F. C., Liu, S. H., Sheen, L. Y. 2022; 12 (6): 536-544

  Abstract

  Garlic essential oil (GEO) isolated from Garlic (Allium sativum L.) exerts biological activities in disease prevention, particularly in metabolic and liver diseases, and is used for a dietary therapy for centuries. However, due to the side effects associated with the excessive consumption of GEO, there is a need to evaluate the safety of the GEO.Ames test using five Salmonella typhimurium strains (TA98, TA100, TA102, TA1535, and TA1537) and Chinese hamster ovary (CHO-K1) cells with or without metabolic activation (S9 system), and mammalian erythrocyte micronucleus test were used to assess the genotoxicity and clastogenic effects of GEO. A repeated dose of GEO (15, 25, and 50 mg/kg body weight, p.o.) were administrated to ICR mice for 28 days to ascertain the subacute toxicity of GEO.The results of the Ames test with or without S9 system indicated that GEO did not induce mutagenicity nor have clastogenic effects in CHO-K1 cells with or without S9 activation. Furthermore, GEO did not affect the ratio of immature to total erythrocytes or the number of micronuclei in immature erythrocytes of ICR mice after 24 and 48 h. In a 28-day oral toxicity assessment, GEO (15, 25, and 50 mg/kg body weight, p.o.)-fed ICR mice exhibited normal behaviors, mortality, body weight, daily intake, hematology, clinical biochemistry, and organ weight. GEO shows no genotoxicity, and the no-observed-adverse-effect level (NOAEL) for GEO is considered to be greater than 50 mg/kg bw/day orally for 28 days in mice.

  View details for DOI 10.1016/j.jtcme.2022.05.001

  View details for PubMedID 36325240

  View details for PubMedCentralID PMC9618392

• Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Ravinther, A., Dewadas, H., Tong, S., Foo, C., Lin, Y., Chien, C., Lim, Y. 2022; 23 (19)

  Abstract

  Parkinson's disease is one of the most common neurodegenerative diseases affecting the ageing population, with a prevalence that has doubled over the last 30 years. As the mechanism of the disease is not fully elucidated, the current treatments are unable to effectively prevent neurodegeneration. Studies have found that mutations in Leucine-rich-repeat-kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). Moreover, aberrant (higher) LRRK2 kinase activity has an influence in idiopathic PD as well. Hence, the aim of this review is to categorize and synthesize current information related to LRRK2-linked PD and present the factors associated with LRRK2 that can be targeted therapeutically. A systematic review was conducted using the databases PubMed, Medline, SCOPUS, SAGE, and Cochrane (January 2016 to July 2021). Search terms included "Parkinson's disease", "mechanism", "LRRK2", and synonyms in various combinations. The search yielded a total of 988 abstracts for initial review, 80 of which met the inclusion criteria. Here, we emphasize molecular mechanisms revealed in recent in vivo and in vitro studies. By consolidating the recent updates in the field of LRRK2-linked PD, researchers can further evaluate targets for therapeutic application.

  View details for DOI 10.3390/ijms231911744

  View details for Web of Science ID 000867823600001

  View details for PubMedID 36233046

  View details for PubMedCentralID PMC9569706

• Dietary Exposure to Antibiotic Residues Facilitates Metabolic Disorder by Altering the Gut Microbiota and Bile Acid Composition MSYSTEMS Chen, R., Wu, W., Panyod, S., Liu, P., Chuang, H., Chen, Y., Lyu, Q., Hsu, H., Lin, T., Shen, T., Yang, Y., Zou, H., Huang, H., Lin, Y., Chen, C., Ho, C., Lai, H., Wu, M., Hsu, C., Sheen, L. 2022; 7 (3): e0017222

  Abstract

  Antibiotics used as growth promoters in livestock and animal husbandry can be detected in animal-derived food. Epidemiological studies have indicated that exposure to these antibiotic residues in food may be associated with childhood obesity. Herein, the effect of exposure to a residual dose of tylosin-an antibiotic growth promoter-on host metabolism and gut microbiota was explored in vivo. Theoretical maximal daily intake (TMDI) doses of tylosin were found to facilitate high-fat-diet-induced obesity, induce insulin resistance, and perturb gut microbiota composition in mice. The obesity-related phenotypes were transferrable to germfree recipient mice, indicating that the effects of a TMDI dose of tylosin on obesity and insulin resistance occurred mainly via alteration of the gut microbiota. Tylosin TMDI exposure restricted to early life, the critical period of gut microbiota development, altered the abundance of specific bacteria related to host metabolic homeostasis later in life. Moreover, early-life exposure to tylosin TMDI doses was sufficient to modify the ratio of primary to secondary bile acids, thereby inducing lasting metabolic consequences via the downstream FGF15 signaling pathway. Altogether, these findings demonstrate that exposure to very low doses of antibiotic residues, whether continuously or in early life, could exert long-lasting effects on host metabolism by altering the gut microbiota and its metabolites. IMPORTANCE This study demonstrates that even with limited exposure in early life, a residual dose of tylosin might cause long-lasting metabolic disturbances by altering the gut microbiota and its metabolites. Our findings reveal that the gut microbiota is susceptible to previously ignored environmental factors.

  View details for DOI 10.1128/msystems.00172-22

  View details for Web of Science ID 000810483900001

  View details for PubMedID 35670534

  View details for PubMedCentralID PMC9239188

• Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson's disease ELIFE Lin, Y., Lin, C., Ho, E., Ke, Y., Petridi, S., Elliott, C. H., Sheen, L., Chien, C. 2021; 10

  Abstract

  The most frequent missense mutations in familial Parkinson's disease (PD) occur in the highly conserved LRRK2/PARK8 gene with G2019S mutation. We previously established a fly model of PD carrying the LRRK2-G2019S mutation that exhibited the parkinsonism-like phenotypes. An herbal medicine, Gastrodia elata Blume (GE), has been reported to have neuroprotective effects in toxin-induced PD models. However, the underpinning molecular mechanisms of GE beneficiary to G2019S-induced PD remain unclear. Here, we show that these G2019S flies treated with water extracts of GE (WGE) and its bioactive compounds, gastrodin and 4-HBA, displayed locomotion improvement and dopaminergic neuron protection. WGE suppressed the accumulation and hyperactivation of G2019S proteins in dopaminergic neurons and activated the antioxidation and detoxification factor Nrf2 mostly in the astrocyte-like and ensheathing glia. Glial activation of Nrf2 antagonizes G2019S-induced Mad/Smad signaling. Moreover, we treated LRRK2-G2019S transgenic mice with WGE and found that the locomotion declines, the loss of dopaminergic neurons, and the number of hyperactive microglia were restored. WGE also suppressed the hyperactivation of G2019S proteins and regulated the Smad2/3 pathways in the mice brains. We conclude that WGE prevents locomotion defects and the neuronal loss induced by G2019S mutation via glial Nrf2/Mad signaling, unveiling a potential therapeutic avenue for PD.

  View details for DOI 10.7554/eLife.73753.sa2

  View details for Web of Science ID 000730832000001

  View details for PubMedID 34779396

  View details for PubMedCentralID PMC8660019

• Gastrodia elata Blume water extract modulates neurotransmitters and alters the gut microbiota in a mild social defeat stress-induced depression mouse model PHYTOTHERAPY RESEARCH Huang, Y., Choong, L., Panyod, S., Lin, Y., Huang, H., Lu, K., Wu, W., Sheen, L. 2021; 35 (9): 5133-5142

  Abstract

  Gastrodia elata Blume has multiple bioactive functions, such as antioxidant and antidepressant activities, immune modulation, neuroplasticity, and neuroprotection. We previously found that the water extract of G. elata exerts antidepressant-like effects in unpredictable chronic mild stress models and animals exposed to the forced swimming test. We aimed to investigate the mechanisms by which the water extract of G. elata protects against subchronic- and mild-social defeat-stress-induced dysbiosis. After a 10-day subchronic and mild-social-defeat-stress program, oral treatment with the water extract of G. elata (500 mg/kg bw) resulted in reversal of depression-like behavior. In addition, monoamine analyses showed that the water extract of G. elata normalized the 5-hydroxyindoleacetic acid:5-HT ratio in the prefrontal cortex and colon and reduced the defeat-stress-induced kynurenine:tryptophan ratio in the colon. After the 10-day subchronic and mild social-defeat-stress program, the water extract of G. elata altered the intestinal microbiome by increasing Actinobacteria levels, modulating intestinal inflammation, and shifting the relative abundances of multiple bacterial groups in the gut. Our results suggest that the water extract of G. elata exhibits a potent antidepressant-like effect via the regulation of monoaminergic neurotransmission and alteration of gut microbiota composition and function, and that it may be an effective prevention for depression.

  View details for DOI 10.1002/ptr.7091

  View details for Web of Science ID 000679127200001

  View details for PubMedID 34327733

• Antidepressant-like effects of water extract of Cordyceps militaris (Linn.) Link by modulation of ROCK2/PTEN/Akt signaling in an unpredictable chronic mild stress-induced animal model JOURNAL OF ETHNOPHARMACOLOGY Lin, Y., Chen, Y., Lu, K., Huang, Y., Panyod, S., Liu, W., Yang, S., Lu, Y., Chen, M., Sheen, L. 2021; 276: 114194

  Abstract

  Cordyceps militaris (Linn.) Link (CM) is a medicinal mushroom traditionally used in tonics for treating several neurological disorders, including epilepsy and anxiety, in Asia. Reports have shown that CM has anti-inflammatory and anti-oxidative effects and may be beneficial for depression management.This study aimed to investigate the potential of CM as an antidepressant for a long-term unpredictable chronic mild stress (UCMS) rodent models and explore its underlying mechanisms.Rats were orally administered with 125 (low, L), 250 (medium, M), and 500 (high, H) mg/kg bodyweight (bw) of the water extract of CM (WCM) for 35 consecutive days in the UCMS protocol. The levels of cerebral serotonin (5-HT), dopamine (DA), and metabolites in the frontal cortex of the rats were measured. Blood was collected to investigate the levels of proinflammatory cytokines, and the brain was dissected to assay the stress-associated ROCK2/PTEN/Akt signaling.All doses of the WCM prevented abnormal behaviors induced by UCMS, including anhedonia and hypoactivity. The LWCM treatment reduced the turnover rate of 5-HT, and all doses of the WCM reduced the turnover rate of DA in the frontal cortex. The LWCM also attenuated the elevation of serum IL-1β induced by chronic stress. All doses of the WCM attenuated the ROCK2 protein hyperactivation, and the LWCM further increased the down-regulation of p-Akt/Akt signaling.The WCM has antidepressant-like effects, which may result from the regulation of the stress-related ROCK2/PTEN/Akt pathway. Therefore, the WCM may be developed and used for the complementary treatment of depression.

  View details for DOI 10.1016/j.jep.2021.114194

  View details for Web of Science ID 000660251400006

  View details for PubMedID 33974945

• Water extract of Armillaria mellea (Vahl) P. Kumm. Alleviates the depression-like behaviors in acute- and chronic mild stress-induced rodent models via anti-inflammatory action JOURNAL OF ETHNOPHARMACOLOGY Lin, Y., Wang, H., Lu, K., Huang, Y., Panyod, S., Liu, W., Yang, S., Chen, M., Lu, Y., Sheen, L. 2021; 265: 113395

  Abstract

  Armillaria mellea (Vahl) P. Kumm. (AM) is an edible mushroom that has been reported as treatment for several neurological disorders, such as dizziness and epilepsy in Asia. Importantly, AM shares a symbiotic relationship with Gastrodia elata Blume (GE), a medicinal herb with antidepressant-like properties. Researchers believe that AM may possess pharmacological properties similar to GE due to their symbiosis, however, few studies have investigated the pharmacological effect of AM.The aim of this study was to explore the potential of AM as an antidepressant in forced-swimming test (FST) and unpredictable chronic mild stress (UCMS) rodent models and investigate its possible underlying mechanism.Rats were orally administrated with 250, 500, and 1000 mg/kg body weight (bw) water extract of AM (WAM) for 28 and 35 consecutive days prior to the FST and UCMS protocols, respectively. The cerebral serotonin (5-HT) and the metabolites in the frontal cortex of rats were measured. The brain was dissected and the blood was collected to investigate the levels of inflammatory-related signaling pathway.All doses of WAM reduced the immobility time in the FST without disturbing autonomic locomotion. All doses of WAM prevented stress-induced abnormal behaviors in the UCMS model, including decreased sucrose preference and hypoactivity. 500 and 1000 mg/kg bw WAM attenuated the stress-induced increases in IL-1β and TNF-α in the serum and cerebrum. 1000 mg/kg bw WAM alleviated brain inflammation by reducing the protein expression of ionized calcium binding adaptor molecule 1.WAM exhibited acute and chronic antidepressant-like effects, and may result from the anti-inflammatory actions. Therefore, the development of AM as a dietary therapy or adjuvant for depression treatment should be considered.

  View details for DOI 10.1016/j.jep.2020.113395

  View details for Web of Science ID 000583286600070

  View details for PubMedID 32956757

• Poria cocos water extract ameliorates the behavioral deficits induced by unpredictable chronic mild stress in rats by down-regulating inflammation JOURNAL OF ETHNOPHARMACOLOGY Huang, Y., Hsu, N., Lu, K., Lin, Y., Lin, S., Lu, Y., Liu, W., Chen, M., Sheen, L. 2020; 258: 112566

  Abstract

  Poria cocos is a medicinal mushroom of the Polyporaceae family with antioxidant and anti-inflammatory activities, which has been used for its sedative, diuretic and tonic effects in traditional medicine for several hundred years.Considering that depression is an inflammatory related mental disease, this study investigated the antidepressant-like effects of water extract of P. cocos in a rodent animal model.Rats that were exposed to a forced swimming test (FST) for 28 consecutive days, and unpredictable chronic mild stress (UCMS) for five weeks underwent treatment with P. cocos water extract (PCW) (doses: 100, 300 and 900 mg/kg body weight [bw]; administered by gavage). Dopamine (DA), serotonin (5-HT) and their metabolites in the frontal cortex of rats were measured.Our results firstly showed that sucrose preference during the UCMS paradigm was increased and immobility time in the FST was reduced with administration of PCW. In addition, PCW significantly attenuated UCMS-induced turnover rate of DA and 5-HT in the frontal cortex. Moreover, PCW inhibited UCMS-induced activated inflammatory response, reflected by reduced expression in the frontal cortex of p38, NF-κB and TNF-α.Our results strongly suggest that PCW exhibits a potent antidepressant-like effect via regulation of monoaminergic neurotransmission and inactivation of inflammation, and that P. cocos may be considered as a traditional herbal potential medicine for the treatment of depression.

  View details for DOI 10.1016/j.jep.2020.112566

  View details for Web of Science ID 000536887800028

  View details for PubMedID 31926986

• Allicin Modifies the Composition and Function of the Gut Microbiota in Alcoholic Hepatic Steatosis Mice JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY Panyod, S., Wu, W., Lu, K., Liu, C., Chu, Y., Ho, C., Hsiao, W., Lai, Y., Chen, W., Lin, Y., Lin, S., Wu, M., Sheen, L. 2020; 68 (10): 3088-3098

  Abstract

  The intestinal microbiome plays an important role in the pathogenesis of liver diseases. Alcohol intake induces gut microbiota dysbiosis and alters its function. This study investigated the antibiotic effect of allicin in mice with hepatic steatosis. Male C57BL/6 mice were administered an ethanol diet supplemented with allicin (5 and 20 mg/(kg bw day)) for 4 weeks. Allicin modified the gut microbiota composition. Cecal microbiota exhibited a positive correlation with alcohol and hepatic triacylglycerol, but were suppressed with allicin. Ethanol diet with 5 mg of allicin induced a lower intestinal permeability compared to the ethanol diet alone. Allicin mediated the lipopolysaccharide (LPS)-CD14-toll-like receptor 4 (TLR4)-induced hepatic inflammation pathway by reducing LPS, CD14, TLR4, and pro-inflammatory cytokines-tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. However, hepatic inflammation primarily resulted from alcohol toxicity rather than LPS production in the gut. The prediction of functional profiles from metagenomic 16S ribosomal RNA (rRNA) data revealed different functional profiles in each group. The predicted aldehyde dehydrogenase tended to increase in alcoholic mice administered allicin. The predicted LPS-related pathway and LPS biosynthesis protein results exhibited a similar trend as plasma LPS levels. Thus, alcohol and allicin intake shapes the gut microbiota and its functional profile and improves the CD14-TLR4 pathway to alleviate inflammation in the liver.

  View details for DOI 10.1021/acs.jafc.9b07555

  View details for Web of Science ID 000526397800025

  View details for PubMedID 32050766

• Garlic essential oil mediates acute and chronic mild stress-induced depression in rats via modulation of monoaminergic neurotransmission and brain-derived neurotrophic factor levels FOOD & FUNCTION Huang, Y., Lu, K., Lin, Y., Panyod, S., Wu, H., Chang, W., Sheen, L. 2019; 10 (12): 8094-8105

  Abstract

  Garlic essential oil (GEO) and its major organosulfur component (diallyl disulfide, DADS) possess diverse biological properties; however, limited information on their antidepressant-like effects is available. This study is the first to investigate these effects of GEO using the forced swimming test (FST) and unpredictable chronic mild stress (UCMS) induced depression in rats. After oral administration for 28 consecutive days, GEO (25 and 50 mg per kg bw) significantly reduced the immobility time in the FST. Additionally, GEO and DADS significantly reversed the sucrose preference index decrease induced by 5 weeks of UCMS. GEO (25 mg per kg bw) effectively decreased the frontal cortex turnover ratio of serotonin (5-HT) and dopamine (DA), thus increasing the 5-HT and DA levels, with no hippocampal effects. Chronic GEO treatment increased hippocampal brain-derived neurotrophic factor (BDNF), c-AMP response element binding protein (CREB), and protein kinase B (AKT) expression, exhibiting its effects via monoamine neurotransmitter modulation and the BDNF-related signaling pathway.

  View details for DOI 10.1039/c9fo00601j

  View details for Web of Science ID 000507643700041

  View details for PubMedID 31735946

• Antidepressant-like effects of water extract of Gastrodia elata Blume on neurotrophic regulation in a chronic social defeat stress model JOURNAL OF ETHNOPHARMACOLOGY Lin, Y., Chou, S., Lin, S., Lu, K., Panyod, S., Lai, Y., Ho, C., Sheen, L. 2018; 215: 132-139

  Abstract

  Gastrodia elata Blume (GE) is a traditional Chinese medicine commonly used to treat dizziness, epilepsy, paralysis and some emotional symptoms in east Asia. We previously showed that the water extract of Gastrodia elata Blume (WGE) possesses anti-depression like effects in a forced swimming test and chronic mild stress model.The aim of this study was to investigate the antidepressant-like effects of WGE and potential mechanisms related to brain-derived neurotrophic factor (BDNF) regulation in mice exposed to chronic social defeat stress (CSDS) model.Fifty C57BL/6 mice were divided into 5 groups as follows: a control (CTL) group, CSDS group, and 3 WGE groups receiving 250, 500 or 1000mg/kg body weight in the CSDS model. Mice were administered WGE for 24 days by oral gavage, and the social defeat stress paradigm began on day 14, except for the control group. A social interaction test was conducted to evaluate the antidepressant-like effects of WGE. Blood samples were collected to measure serum corticosterone levels, and the brain was dissected to investigate the expression of BDNF-related signaling pathway proteins using western blotting.Oral administration of WGE improved depression-like behaviors and stress-induced elevations of corticosterone. Further, WGE increased the protein expression of BDNF and promoted the hippocampal protein phosphorylation ratio of cAMP response element binding protein (CREB) and protein kinase B (Akt).WGE exerts antidepressant-like effects on mice in a CSDS model, likely through activating of the BDNF/CREB/Akt pathway. Therefore, WGE has potential as a supplement or an adjuvant to prevent or treat clinical depressive disorders.

  View details for DOI 10.1016/j.jep.2017.12.044

  View details for Web of Science ID 000427213500013

  View details for PubMedID 29288827

• Recent Research Progress on the Antidepressant-like Effect and Neuropharmacological Potential of Gastrodia elata Blume Current Pharmacology Reports Lin, Y., Lu, K., Sheen, L. 2018; 4: 220-237

  View details for DOI 10.1007/s40495-018-0137-2

• Diet Supplementation with Allicin Protects against Alcoholic Fatty Liver Disease in Mice by Improving Anti-inflammation and Antioxidative Functions JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY Panyod, S., Wu, W., Ho, C., Lu, K., Liu, C., Chu, Y., Lai, Y., Chen, W., Lin, Y., Lin, S., Sheen, L. 2016; 64 (38): 7104-7113

  Abstract

  This study investigated the liver-protective effects of allicin, an active compound in fresh garlic, against alcoholic fatty liver disease (AFLD) and liver inflammation. Its effects were investigated in an AFLD model in male C57BL/6 mice, which were fed Lieber-DeCarli liquid diet containing ethanol. Allicin (5 and 20 mg/kg bw/day) was orally administered daily in the AFLD mice for 4 weeks. The results indicate that allicin promotes hepatoprotection by significantly reducing aspartate transaminase (AST) and alanine transaminase (ALT) levels (p < 0.05) in the plasma, which are key indicators of liver damage. Allicin reduced fat accumulation, increased glutathione and catalase levels, and decreased microsomal protein cytochrome P450 2E1 (CYP2E1) expression (p < 0.05) in the livers of the AFLD mice. Furthermore, allicin supplementation significantly decreased the levels of proinflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 and suppressed the expression of sterol regulatory element-binding protein-1 (SREBP-1) (p < 0.05). Additionally, it improved the hepatic alcohol dehydrogenase (ADH) activity (p < 0.05). Collectively, these findings demonstrate that allicin attenuates liver oxidative stress and inflammation.

  View details for DOI 10.1021/acs.jafc.6b02763

  View details for Web of Science ID 000384518200007

  View details for PubMedID 27584700

• Antidepressant-like effects of water extract of Gastrodia elata Blume in rats exposed to unpredictable chronic mild stress via modulation of monoamine regulatory pathways JOURNAL OF ETHNOPHARMACOLOGY Lin, Y., Lin, S., Chen, W., Ho, C., Lai, Y., Panyod, S., Sheen, L. 2016; 187: 57-65

  Abstract

  Gastrodia elata Blume (GE) is a traditional herbal medicine belonging to the Orchidaceae family, and has been used to manage neurological disorders for centuries. We have previously reported that its water extract (WGE) could improve the depressive-like behaviours in the forced swimming test (FST), an animal model of depression.To investigate the antidepressant-like effects of WGE in rats exposed to unpredictable chronic mild stress (UCMS) model, and to explore its possible molecular mechanisms.UCMS rats were orally administered with WGE (0.5g/kg body weight) daily within the 4 weeks UCMS procedure. The sucrose preference test and the open field test were conducted to assess anhedonia and spontaneous behaviours, respectively. The cerebral turnover rates of monoamine neurotransmitters and the serum corticosterone levels were measured. In vitro direct and indirect monoamine oxidase A (MAO-A) inhibitory assays were employed to assess the possible antidepressant-like mechanisms of WGE (0.5mg/mL) and its major component, gastrodin (GAS, 15, 30 and 60μg/mL). Western blot was used to examine the expression of protein related to monoamine regulation, such as MAO-A and tyrosine hydroxylase (TH).WGE significantly reversed the sucrose preference and other abnormal behaviours induced by 4 weeks of UCMS. WGE significantly restored the cerebral turnover rates of serotonin and dopamine and decreased serum corticosterone levels. WGE and gastrodin inhibited the activity and protein expression of MAO-A, and increased TH levels in PC12 cells.The antidepressant-like effects of WGE and gastrodin might be mediated by the regulation of monoamine neurotransmitters, and therefore were beneficial in depression treatment as a complementary approach.

  View details for DOI 10.1016/j.jep.2016.04.032

  View details for Web of Science ID 000378190400007

  View details for PubMedID 27109341

• Anti-depressant effects of Gastrodia elata Blume and its compounds gastrodin and 4-hydroxybenzyl alcohol, via the monoaminergic system and neuronal cytoskeletal remodeling JOURNAL OF ETHNOPHARMACOLOGY Chen, W., Lai, Y., Lin, S., Lu, K., Lin, Y., Panyod, S., Ho, C., Sheen, L. 2016; 182: 190-199

  Abstract

  Gastrodia elata Blume is a highly valuable traditional Chinese medicine used in the treatment of depression. However, compounds with antidepressant effects in water extracts of G. elata Bl. (WGE) have not been identified. The aims of this study were to determine the major antidepressant compound in WGE and to evaluate the antidepressant effects of WGE and its active compounds which involved the monoaminergic system and neuronal cytoskeletal remodeling.Gastrodin (GAS) and 4-hydroxybenzyl alcohol (HBA) in WGE, were analyzed with high-performance liquid chromatography (HPLC)-ultraviolet detection. The forced swimming test (FST) was used to induce depression-like symptoms in 9 weeks old male Sprague-Dawley rats. The open field test (OFT) was used to measure anxiety after WGE, GAS, and HBA treatments. The levels of monoamine such as serotonin (5-HT), dopamine (DA), and their metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured using HPLC-electrochemical detection. Western blotting was used to examine the 5-HT1A receptor and the neuronal cytoskeleton remodeling-related proteins, Slit, dihydropyrimidinase-related protein 2 (DPYSL2, also called CRMP2), Ras homologous member A (RhoA), and profilin 1 (PFN1) in vivo. Slit1 expression was evaluated in Hs683 cell line after treated with WGE (0.5mg/mL), GAS (50, 100 and 100μM), and HBA (50, 100 and 100μM).Oral administration of WGE (500mg/kg bw), GAS (100mg/kg bw), and HBA (100mg/kg bw) exhibited the anti-depressant effect by significantly reducing the immobility time in FST, monoamine metabolism including the 5-HT to 5-HIAA in the hippocampus and DA to DOPAC and HVA ratios in the frontal cortex, amygdala, and hippocampus. In the hippocampus, the expression of the neuronal cytoskeleton remodeling-related negative regulators Slit1 and RhoA were significantly down-regulated. In addition, the positive regulators CRMP2 and PFN1 were significantly up-regulated following GAS, HBA, and WGE treatments. Moreover, WGE, GAS, and HBA were directly down-regulated Slit1 expression in Hs683 cells.WGE, GAS, and HBA exhibited potential anti-depressant effects in rats by decreasing monoamine metabolism and modulated cytoskeleton remodeling-related protein expression in the Slit-Robo pathway. These results suggest that WGE can be used as agent for depressive prevention.

  View details for DOI 10.1016/j.jep.2016.02.001

  View details for Web of Science ID 000373411100020

  View details for PubMedID 26899441

• Ginger Essential Oil Ameliorates Hepatic Injury and Lipid Accumulation in High Fat Diet-Induced Nonalcoholic Fatty Liver Disease JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY Lai, Y., Lee, W., Lin, Y., Ho, C., Lu, K., Lin, S., Panyod, S., Chu, Y., Sheen, L. 2016; 64 (10): 2062-2071

  Abstract

  The objective of this study was to investigate the hepatoprotective efficacy and mechanism of action of ginger essential oil (GEO) against the development of nonalcoholic fatty liver disease (NAFLD). Mice were maintained on either a control diet or high-fat diet (HFD) supplemented with GEO (12.5, 62.5, and 125 mg/kg) or citral (2.5 and 25 mg/kg) for 12 weeks. We demonstrated that GEO and its major component (citral) lowered HFD-induced obesity in a dose-dependent manner, accompanied by anti-hyperlipidemic effects by reducing serum free fatty acid, triglyceride, and total cholesterol levels. Moreover, liver histological results showed that administration of 62.5 and 125 mg/kg GEO and 25 mg/kg citral significantly reduced hepatic lipid accumulation. Further assessment by Western blotting and investigation of the lipid metabolism revealed that hepatic protein expression of sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and cytochrome P450 2E1 (CYP2E1) were down-regulated by GEO and citral, indicating that GEO and citral suppressed HFD-stimulated lipid biosynthesis and oxidative stress. Furthermore, GEO and citral effectively enhanced the antioxidant capacities and reduced inflammatory response in mouse liver, which exerted protective effects against steatohepatitis. Collectively, GEO and citral exhibited potent hepatoprotective effects against NAFLD induced by HFD in obese mice. Thus, GEO might be an effective dietary supplement to ameliorate NAFLD-related metabolic diseases, and citral could play a vital role in its management.

  View details for DOI 10.1021/acs.jafc.5b06159

  View details for Web of Science ID 000372478300004

  View details for PubMedID 26900108