In vitro metabolic zonation through oxygen gradient on a chip

Abstract Among the multiple metabolic signals involved in the establishment of the hepatic zonation, oxygen could play a key role. Indeed, depending on hepatocyte position in the hepatic lobule, gene expression and metabolism are differently affected by the oxygen gradient present across the lobule. The aim of this study is to understand whether an oxygen gradient, generated in vitro in our developed device, is sufficient to instruct a functional metabolic zonation during the differentiation of human embryonic stem cells (hESCs) from endoderm toward terminally differentiated hepatocytes, thus mimicking the in vivo situation. For this purpose, a microfluidic device was designed for the generation of a stable oxygen gradient. The oxygen gradient was applied to differentiating hESCs at the pre-hepatoblast stage. The definitive endoderm and hepatic endoderm cells were characterized by the expression of the transcription factor SOX-17 and alpha-fetoprotein (AFP). Immature and mature hepatocytes were characterized by hepatocyte nuclear factor 4-alpha (HNF-4α) and albumin (ALB) expression and also analyzed for cytochrome P450 (CYP3A4) zonation and glycogen accumulation through PAS staining. Metabolic zonated genes expression was assessed through quantitative real time PCR. Application of the oxygen gradient during differentiation induced zonated glycogen storage, which was higher in the hepatocytes grown in high pO2 compared to those grown in low pO2. The mRNA levels of glutamine synthetase (GLUL), beta-catenin (CTNNB) and its direct target cyclin D1 (CCND1) showed significantly higher expression in the cells grown in low pO2 compared to those grown in high pO2. On the contrary, carbamoyl-phosphate synthetase 1 (CPS1), ALB, the proliferative marker ki67 (MKI67) and cyclin A (CCNA) resulted to be significantly higher expressed in cells cultured in high pO2 compared to those cultured in low pO2. These results indicate that the oxygen gradient generated in our device can instruct the establishment of a functional metabolic zonation in differentiating hESCs. The possibility to obtain differentiated hepatocytes in vitro may allow in the future to deepen our knowledge about the physiology/pathology of hepatocytes in relation to the oxygen content.

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4 GENE EXPRESSION IN CULTURES OF INNER CELL MASSES ISOLATED FROM IN VITRO-PRODUCED AND IN VIVO-DERIVED BOVINE BLASTOCYSTS

Reproduction Fertility and Development ◽

10.1071/rdv18n2ab4 ◽

2006 ◽

Vol 18 (2) ◽

pp. 110 ◽

Cited By ~ 6

Author(s):

D. Pant ◽

C. Keefer

Keyword(s):

Es Cells ◽

Primary Cultures ◽

Embryonic Stem ◽

Pcr Analysis ◽

Beta Catenin ◽

Rt Pcr ◽

Self Renewal ◽

Domestic Species

Genetic modification of embryonic stem (ES) cells derived from domestic species could be exploited to produce transgenic animals; however, fully validated ES have not been obtained in domestic species. Recent findings regarding key transcription factors and regulation of pluripotency and self-renewal in murine ES cells may provide keys to enable the derivation of ES in domestic species. The aim of this study was to identify and monitor the expression of candidate genes, which are known to be involved in the maintenance of self-renewal and pluripotency in mouse and human ES cells, during the critical first steps in establishment of primary cultures. Inner cell masses (ICMs) were isolated via manual dissection of 25 to 30 commercial in vitro-produced (IVP) blastocysts (Bomed, Inc., Madison, WI, USA) in each of three separate replicates and from 10 in vivo-derived Day 7-8 bovine blastocysts. On the day of ICM isolation (Day 0), 4-5 ICM clumps were collected for RT-PCR analysis. The remaining isolated ICMs were cultured (4-5 ICM clumps per well) on mitomycin C (Sigma-Aldrich, St. Louis, MO, USA)-inactivated mouse embryonic fibroblasts (STO, ATCC, Manassas, VA, USA). The ICM clumps were cultured in 12-well tissue culture dishes in ES medium consisting of Knockout DMEM (Invitrogen, Carlsbad, CA, USA) supplemented with 15% FCS (Hyclone, Logan, UT, USA), 2 mM l-glutamine (Invitrogen), 0.1 mM 2-mercaptoethanol (MP Biomedicals, Irvine, CA, USA), and non-essential amino acids (Sigma). Two to four cultured ICM clumps were collected for RT-PCR analysis on Days 1-4 from IVP embryos and on Days 2, 4, and 6 from in vivo-derived embryos. Total RNA was extracted from the collected samples using the Absolutely RNA Nanoprep Kit (Strategene, La Jolla, CA, USA). First-strand DNAs were synthesized using Superscript III (Invitrogen) and cDNAs were amplified with PfuUltra hotstart PCR mastermix (Stratagene). Primers were designed based on homology between human and mouse sequences and were validated using bovine tissues. In experiments spanning these critical first few days of culture, the pluripotency-related genes (Nanog, Oct-4, Sox-2) and components of the LIF (LIFR, Gp130), BMP (Bmpr1a, Id-1), and Wnt (Beta-catenin, Frizzled) pathways were expressed in the ICM cultures over the 4 days of IVP-ICM cultures and the 6 days of in vivo-derived ICM cultures. These results indicate that the markers of pluripotency and the components of signaling pathways implicated in the maintenance of murine embryonic stem cells are present in ICMs of Day 7-8 bovine blastocysts and continue to be expressed at least during the initial days of culture. Genes (NCAM, Lef1) associated with early differentiation, however, were also expressed. Whether their expression is an indicator of ICM differentiation or of residual contamination with trophectoderm remains to be determined. Further studies will determine whether stimulation of these pathways can facilitate efficient derivation and maintenance ruminant ES cells.

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Wnt/(beta)-catenin signaling regulates the expression of the homeobox gene Cdx1 in embryonic intestine

Development ◽

10.1242/dev.127.17.3805 ◽

2000 ◽

Vol 127 (17) ◽

pp. 3805-3813 ◽

Cited By ~ 2

Author(s):

H. Lickert ◽

C. Domon ◽

G. Huls ◽

C. Wehrle ◽

I. Duluc ◽

...

Keyword(s):

Signaling Pathway ◽

Intestinal Epithelium ◽

Es Cells ◽

Embryonic Stem ◽

Early Period ◽

Homeobox Gene ◽

Beta Catenin ◽

Mammalian Development

During mammalian development, the Cdx1 homeobox gene exhibits an early period of expression when the embryonic body axis is established, and a later period where expression is restricted to the embryonic intestinal endoderm. Cdx1 expression is maintained throughout adulthood in the proliferative cell compartment of the continuously renewed intestinal epithelium, the crypts. In this study, we provide evidence in vitro and in vivo that Cdx1 is a direct transcriptional target of the Wnt/(beta)-catenin signaling pathway. Upon Wnt stimulation, expression of Cdx1 can be induced in mouse embryonic stem (ES) cells as well as in undifferentiated rat embryonic endoderm. Tcf4-deficient mouse embryos show abrogation of Cdx1 protein in the small intestinal epithelium, making Tcf4 the likely candidate to transduce Wnt signal in this part of gut. The promoter region of the Cdx1 gene contains several Tcf-binding motifs, and these bind Tcf/Lef1/(beta)-catenin complexes and mediate (beta)-catenin-dependent transactivation. The transcriptional regulation of the homeobox gene Cdx1 in the intestinal epithelium by Wnt/(beta)-catenin signaling underlines the importance of this signaling pathway in mammalian endoderm development.

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Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice

PLoS ONE ◽

10.1371/journal.pone.0251911 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0251911

Author(s):

Alexandre Boyer ◽

Xiangfan Zhang ◽

Adrien Levasseur ◽

Nour Abou Nader ◽

Guillaume St-Jean ◽

...

Keyword(s):

Germ Cell ◽

Integration Site ◽

Cell Activity ◽

Cell Loss ◽

Beta Catenin ◽

Mrna Levels ◽

Self Renewal ◽

Important Regulator

Spermatogenesis requires that a careful balance be maintained between the self-renewal of spermatogonial stem cells (SSCs) and their commitment to the developmental pathway through which they will differentiate into spermatozoa. Recently, a series of studies employing various in vivo and in vitro models have suggested a role of the wingless-related MMTV integration site gene family/beta-catenin (WNT/CTNNB1) pathway in determining the fate of SSCs. However, conflicting data have suggested that CTNNB1 signaling may either promote SSC self-renewal or differentiation. Here, we studied the effects of sustained CTNNB1 signaling in SSCs using the Ctnnb1tm1Mmt/+; Ddx4-CreTr/+ (ΔCtnnb1) mouse model, in which a stabilized form of CTNNB1 is expressed in all germ cells. ΔCtnnb1 mice were found to have reduced testis weights and partial germ cell loss by 4 months of age. Germ cell transplantation assays showed a 49% reduction in total functional SSC numbers in 8 month-old transgenic mice. In vitro, Thy1-positive undifferentiated spermatogonia from ΔCtnnb1 mice formed 57% fewer clusters, which was associated with decreased cell proliferation. A reduction in mRNA levels of genes associated with SSC maintenance (Bcl6b, Gfra1, Plzf) and increased levels for markers associated with progenitor and differentiating spermatogonia (Kit, Rarg, Sohlh1) were detected in these cluster cells. Furthermore, RNAseq performed on these clusters revealed a network of more than 900 genes regulated by CTNNB1, indicating that CTNNB1 is an important regulator of spermatogonial fate. Together, our data support the notion that CTNNB1 signaling promotes the transition of SSCs to undifferentiated progenitor spermatogonia at the expense of their self-renewal.

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Nanocurcumin: A Double-Edged Sword for Microcancers

Current Pharmaceutical Design ◽

10.2174/1381612826666201118100045 ◽

2020 ◽

Vol 26 (45) ◽

pp. 5783-5792

Author(s):

Kholood Abid Janjua ◽

Adeeb Shehzad ◽

Raheem Shahzad ◽

Salman Ul Islam ◽

Mazhar Ul Islam

Keyword(s):

Intracellular Signaling ◽

Dosage Forms ◽

The Body ◽

In Vivo Studies ◽

Mrna Levels ◽

Anticancer Activities ◽

Road Map ◽

Anticancer Effects

There is compelling evidence that drug molecules isolated from natural sources are hindered by low systemic bioavailability, poor absorption, and rapid elimination from the human body. Novel approaches are urgently needed that could enhance the retention time as well as the efficacy of natural products in the body. Among the various adopted approaches to meet this ever-increasing demand, nanoformulations show the most fascinating way of improving the bioavailability of dietary phytochemicals through modifying their pharmacokinetics and pharmacodynamics. Curcumin, a yellowish pigment isolated from dried ground rhizomes of turmeric, exhibits tremendous pharmacological effects, including anticancer activities. Several in vitro and in vivo studies have shown that curcumin mediates anticancer effects through the modulation (upregulation and/or downregulations) of several intracellular signaling pathways both at protein and mRNA levels. Scientists have introduced multiple modern techniques and novel dosage forms for enhancing the delivery, bioavailability, and efficacy of curcumin in the treatment of various malignancies. These novel dosage forms include nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles. Nanocurcumin has shown improved anticancer effects compared to conventional curcumin formulations. This review discusses the underlying molecular mechanism of various nanoformulations of curcumin for the treatment of different cancers. We hope that this study will make a road map for preclinical and clinical investigations of cancer and recommend nano curcumin as a drug of choice for cancer therapy.

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Perilla frutescens Leaf Extract and Fractions: Polyphenol Composition, Antioxidant, Enzymes (α-Glucosidase, Acetylcholinesterase, and Tyrosinase) Inhibitory, Anticancer, and Antidiabetic Activities

Foods ◽

10.3390/foods10020315 ◽

2021 ◽

Vol 10 (2) ◽

pp. 315

Author(s):

Zhenxing Wang ◽

Zongcai Tu ◽

Xing Xie ◽

Hao Cui ◽

Kin Weng Kong ◽

...

Keyword(s):

Ethyl Acetate ◽

Animal Experiments ◽

Ethyl Acetate Fraction ◽

The Body ◽

Total Phenolic ◽

Antioxidant Power ◽

Glycogen Accumulation ◽

Inhibitory Ability

This study aims to evaluate the bioactive components, in vitro bioactivities, and in vivo hypoglycemic effect of P. frutescens leaf, which is a traditional medicine-food homology plant. P. frutescens methanol crude extract and its fractions (petroleum ether, chloroform, ethyl acetate, n-butanol fractions, and aqueous phase residue) were prepared by ultrasound-enzyme assisted extraction and liquid–liquid extraction. Among the samples, the ethyl acetate fraction possessed the high total phenolic (440.48 μg GAE/mg DE) and flavonoid content (455.22 μg RE/mg DE), the best antioxidant activity (the DPPH radical, ABTS radical, and superoxide anion scavenging activity, and ferric reducing antioxidant power were 1.71, 1.14, 2.40, 1.29, and 2.4 times higher than that of control Vc, respectively), the most powerful α-glucosidase inhibitory ability with the IC50 value of 190.03 μg/mL which was 2.2-folds higher than control acarbose, the strongest proliferative inhibitory ability against MCF-7 and HepG2 cell with the IC50 values of 37.92 and 13.43 μg/mL, which were considerable with control cisplatin, as well as certain inhibition abilities on acetylcholinesterase and tyrosinase. HPLC analysis showed that the luteolin, rosmarinic acid, rutin, and catechin were the dominant components of the ethyl acetate fraction. Animal experiments further demonstrated that the ethyl acetate fraction could significantly decrease the serum glucose level, food, and water intake of streptozotocin-induced diabetic SD rats, increase the body weight, modulate their serum levels of TC, TG, HDL-C, and LDL-C, improve the histopathology and glycogen accumulation in liver and intestinal tissue. Taken together, P. frutescens leaf exhibits excellent hypoglycemic activity in vitro and in vivo, and could be exploited as a source of natural antidiabetic agent.

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TRIM27 interacts with Iκbα to promote the growth of human renal cancer cells through regulating the NF-κB pathway

BMC Cancer ◽

10.1186/s12885-021-08562-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chengwu Xiao ◽

Wei Zhang ◽

Meimian Hua ◽

Huan Chen ◽

Bin Yang ◽

...

Keyword(s):

Cell Lines ◽

Prognostic Indicator ◽

The Cancer Genome Atlas ◽

Mrna Levels ◽

Loss Of Function ◽

Protein Levels ◽

Kaplan Meier ◽

Cancer Genome Atlas

Abstract Background The tripartite motif (TRIM) family proteins exhibit oncogenic roles in various cancers. The roles of TRIM27, a member of the TRIM super family, in renal cell carcinoma (RCC) remained unexplored. In the current study, we aimed to investigate the clinical impact and roles of TRIM27 in the development of RCC. Methods The mRNA levels of TRIM27 and Kaplan–Meier survival of RCC were analyzed from The Cancer Genome Atlas database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of TRIM27 both in vivo and in vitro. siRNA and TRIM27 were exogenously overexpressed in RCC cell lines to manipulate TRIM27 expression. Results We discovered that TRIM27 was elevated in RCC patients, and the expression of TRIM27 was closely correlated with poor prognosis. The loss of function and gain of function results illustrated that TRIM27 promotes cell proliferation and inhibits apoptosis in RCC cell lines. Furthermore, TRIM27 expression was positively associated with NF-κB expression in patients with RCC. Blocking the activity of NF-κB attenuated the TRIM27-mediated enhancement of proliferation and inhibition of apoptosis. TRIM27 directly interacted with Iκbα, an inhibitor of NF-κB, to promote its ubiquitination, and the inhibitory effects of TRIM27 on Iκbα led to NF-κB activation. Conclusions Our results suggest that TRIM27 exhibits an oncogenic role in RCC by regulating NF-κB signaling. TRIM27 serves as a specific prognostic indicator for RCC, and strategies targeting the suppression of TRIM27 function may shed light on future therapeutic approaches.

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MBRS-48. IDENTIFICATION OF NOVEL THERAPEUTIC APPROACHES FOR MYC-DRIVEN MEDULLOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.557 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii406-iii406

Author(s):

Kübra Taban ◽

David Pauck ◽

Mara Maue ◽

Viktoria Marquardt ◽

Hua Yu ◽

...

Keyword(s):

New Drugs ◽

Current Therapy ◽

Cancer Drug ◽

Mrna Levels ◽

Cell Models ◽

Therapeutic Approaches ◽

Group 3 ◽

Novel Therapeutic

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and is frequently metastatic at diagnosis. Treatment with surgery, radiation and multi-agent chemotherapy may leave survivors of these brain tumors with long-term deficits as a consequence. One of the four consensus molecular subgroups of MB is the MYC-driven group 3 MB, which is the most malignant type and has a poor prognosis under current therapy. Thus, it is important to discover more effective targeted therapeutic approaches. We conducted a high-throughput drug screening to identify novel compounds showing efficiency in group 3 MB using both clinically established inhibitors (n=196) and clinically-applicable compounds (n=464). More than 20 compounds demonstrated a significantly higher anti-tumoral effect in MYChigh (n=7) compared to MYClow (n=4) MB cell models. Among these compounds, Navitoclax and Clofarabine showed the strongest effect in inducing cell cycle arrest and apoptosis in MYChigh MB models. Furthermore, we show that Navitoclax, an orally bioavailable and blood-brain barrier passing anti-cancer drug, inhibits specifically Bcl-xL proteins. In line, we found a significant correlation between BCL-xL and MYC mRNA levels in 763 primary MB patient samples (Data source: “R2 https://hgserver1.amc.nl”). In addition, Navitoclax and Clofarabine have been tested in cells obtained from MB patient-derived-xenografts, which confirmed their specific efficacy in MYChigh versus MYClow MB. In summary, our approach has identified promising new drugs that significantly reduce cell viability in MYChigh compared to MYClow MB cell models. Our findings point to novel therapeutic vulnerabilities for MB that need to be further validated in vitro and in vivo.

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Grafts Derived from an α-Synuclein Triplication Patient Mediate Functional Recovery but Develop Disease-Associated Pathology in the 6-OHDA Model of Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-202366 ◽

2020 ◽

pp. 1-14

Author(s):

Shelby Shrigley ◽

Fredrik Nilsson ◽

Bengt Mattsson ◽

Alessandro Fiorenzano ◽

Janitha Mudannayake ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Lines ◽

Functional Recovery ◽

Embryonic Stem ◽

Hesc Line ◽

Alternative Source ◽

And Function

Background: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson’s disease (PD) and they provide the option of using the patient’s own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD. Objective: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control. Methods: Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo. Results: Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line. Conclusion: This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.

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Genome-Wide Binding Analyses of HOXB1 Revealed a Novel DNA Binding Motif Associated with Gene Repression

Journal of Developmental Biology ◽

10.3390/jdb9010006 ◽

2021 ◽

Vol 9 (1) ◽

pp. 6

Author(s):

Narendra Pratap Singh ◽

Bony De Kumar ◽

Ariel Paulson ◽

Mark E. Parrish ◽

Carrie Scott ◽

...

Keyword(s):

Dna Binding ◽

Target Genes ◽

Embryonic Stem ◽

Binding Motif ◽

Binding Assays ◽

Histone Marks ◽

Genome Wide ◽

Hox Cofactors

Knowledge of the diverse DNA binding specificities of transcription factors is important for understanding their specific regulatory functions in animal development and evolution. We have examined the genome-wide binding properties of the mouse HOXB1 protein in embryonic stem cells differentiated into neural fates. Unexpectedly, only a small number of HOXB1 bound regions (7%) correlate with binding of the known HOX cofactors PBX and MEIS. In contrast, 22% of the HOXB1 binding peaks display co-occupancy with the transcriptional repressor REST. Analyses revealed that co-binding of HOXB1 with PBX correlates with active histone marks and high levels of expression, while co-occupancy with REST correlates with repressive histone marks and repression of the target genes. Analysis of HOXB1 bound regions uncovered enrichment of a novel 15 base pair HOXB1 binding motif HB1RE (HOXB1 response element). In vitro template binding assays showed that HOXB1, PBX1, and MEIS can bind to this motif. In vivo, this motif is sufficient for direct expression of a reporter gene and over-expression of HOXB1 selectively represses this activity. Our analyses suggest that HOXB1 has evolved an association with REST in gene regulation and the novel HB1RE motif contributes to HOXB1 function in part through a repressive role in gene expression.

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Neuroprotective Effect of Optimized Yinxieling Formula in 6-OHDA-Induced Chronic Model of Parkinson’s Disease through the Inflammation Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/2529641 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Renrong Wei ◽

Cuiping Rong ◽

Qingfeng Xie ◽

Shouhai Wu ◽

Yuchao Feng ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Calcium Binding ◽

Dopaminergic Neurons ◽

Neuroprotective Effect ◽

Interleukin 1 ◽

Mrna Levels ◽

Cox 2

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN)-striatum circuit, which is associated with glial activation and consequent chronic neuroinflammation. Optimized Yinxieling Formula (OYF) is a Chinese medicine that exerts therapeutical effect and antiinflammation property on psoriasis. Our previous study has proven that pretreatment with OYF could regulate glia-mediated inflammation in an acute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Given that PD is a chronic degeneration disorder, this study applied another PD animal model induced by striatal injection of 6-hydroxydopamine (6-OHDA) to mimic the progressive damage of the SN-striatum dopamine system in rats. The OYF was administrated in the manner of pretreatment plus treatment. The effects of the OYF on motor behaviors were assessed with the apomorphine-induced rotation test and adjusting steps test. To confirm the effect of OYF on dopaminergic neurons and glia activation in this model, we analyzed the expression of tyrosine hydroxylase (TH) and glia markers, ionized calcium-binding adapter molecule 1 (Iba-1), and glial fibrillary acidic protein (GFAP) in the SN region of the rat PD model. Inflammation-associated factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were further evaluated in this model and in interferon-γ- (INF-γ-) induced murine macrophages RAW264.7 cells. The results from the in vivo study showed that OYF reversed the motor behavioral dysfunction in 6-OHDA-induced PD rats, upregulated the TH expression, decreased the immunoreactivity of Iba-1 and GFAP, and downregulated the mRNA levels of TNF-α and COX-2. The OYF also trended to decrease the mRNA levels of IL-1β and iNOS in vivo. The results from the in vitro study showed that OYF significantly decreased the mRNA levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2. Therefore, this study suggests that OYF exerts antiinflammatory effects, which might be related to the protection of dopaminergic neurons in 6-OHDA-induced chronic neurotoxicity.

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