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Fulltext The immunomodulatory effects of Tualang and Kelulut honey on microglial cell activities

Ooi, Yin Yin, Soyza, R. M., Low, Z. X., Tan, K. L.

Malaysian Journal of Medicine and Health Sciences, 2019;15(102):35-35.
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Introduction: Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) have become increasingly prevalent in recent years. Microglia, the resident myeloid cells of the Central Nervous System (CNS) are primarily responsible for the production of inflammatory mediators that accumulate and become toxic during a chronic inflammatory response. The accumulation of inflammatory mediators over time inadvertently contributes to the functional impairment of surrounding neurons. Hence, suppressing microglial cell activation can be a solution to control the progress of neurodegenerative disorders. Symptomatic treatments are available, but no curative treatment is currently available, and some are linked to several side effects associated with their use. Honey is a natural product derived from the nectar harvested and modified by honeybees. Its therapeutic effects are widely documented, have been tested and verified extensively in literature. Honey is recognized in modern medicine for its varied pharmacological activities. While the medicinal properties of honeys such as Manuka honey are well established, further investigation is required to elucidate the medicinal properties of locally sourced honeys, namely Tualang (TH) and Kelulut (KH) honeys. In this study, we investigated the immunomodulatory effects of local TH and KH honey on microglial cell activities. Methods: BV2 cells, an immortalized microglial cell line was used in this in vitro study to assess the cell survival when treated with the TH and KH honey. Expression of CD40, CD11b and CD86 were measured using flowcytometry. Results: BV2 cells incubated with TH at concentrations of 0.1% and 0.5%, and KH at concentrations of 0.1% and 0.25% for 24 and 48 hours showed cell survivability above 75%. Both TH and KH decreased ROS production significantly on LPS-induced BV2 cells, but increased ROS production on unstimulated BV2 cells. Additionally, the expression levels of CD40, CD11b and CD86 were also reduced on honey- treated LPS-induced BV2 cells. Conclusion: These results have demonstrated that both TH and KH are capable of suppressing microglial activation. Therefore, we propose the idea of utilizing these honeys as a complementary treatment to suppress the progression of neurodegenerative diseases.
Fulltext Mesenchymal stem cells exert anti-proliferative effect on lipopolysaccharide-stimulated BV2 microglia by reducing tumour necrosis factor-α levels

Jose S, Tan SW, Ooi YY, Ramasamy R, Vidyadaran S

J Neuroinflammation, 2014;11:149.
PMID: 25182840 DOI: 10.1186/s12974-014-0149-8

Progression of neurodegenerative diseases occurs when microglia, upon persistent activation, perpetuate a cycle of damage in the central nervous system. Use of mesenchymal stem cells (MSC) has been suggested as an approach to manage microglia activation based on their immunomodulatory functions. In the present study, we describe the mechanism through which bone marrow-derived MSC modulate the proliferative responses of lipopolysaccharide-stimulated BV2 microglia.
Fulltext Immunophenotype and differentiation capacity of bone marrow-derived mesenchymal stem cells from CBA/Ca, ICR and Balb/c mice

Ooi YY, Rahmat Z, Jose S, Ramasamy R, Vidyadaran S

World J Stem Cells, 2013 Jan 26;5(1):34-42.
PMID: 23362438 DOI: 10.4252/wjsc.v5.i1.34

To assess the capacity to isolate and expand mesenchymal stem cells (MSC) from bone marrow of CBA/Ca, ICR and Balb/c mice.
Effects of macrophage colony-stimulating factor on microglial responses to lipopolysaccharide and beta amyloid

Vidyadaran S, Ooi YY, Subramaiam H, Badiei A, Abdullah M, Ramasamy R, et al.

Cell Immunol, 2009;259(1):105-10.
PMID: 19577228 DOI: 10.1016/j.cellimm.2009.06.005

A challenge for studies involving microglia cultures is obtaining sufficient cells for downstream experiments. Macrophage colony-stimulating factor (M-CSF) has been used to improve yield of microglia in culture. However, the effects of M-CSF on activation profiles of microglia cultures are still unclear. Microglia activation is characterised by upregulation of co-stimulatory molecules and an inflammatory phenotype. The aim of this study is to demonstrate whether M-CSF supplementation alters microglial responses in resting and activated conditions. Microglia derived from mixed glia cultures and the BV-2 microglia cell line were cultivated with/without M-CSF and activated with lipopolysaccharide (LPS) and beta amyloid (Abeta). We show M-CSF expands primary microglia without affecting microglial responses to LPS and Abeta, as shown by the comparable expression of MHC class II and CD40 to microglia grown without this growth factor. M-CSF supplementation in BV-2 cells had no effect on nitric oxide (NO) production. Therefore, M-CSF can be considered for improving microglia yield in culture without introducing activation artefacts.
Bone marrow-derived mesenchymal stem cells modulate BV2 microglia responses to lipopolysaccharide

Ooi YY, Ramasamy R, Rahmat Z, Subramaiam H, Tan SW, Abdullah M, et al.

Int Immunopharmacol, 2010 Dec;10(12):1532-40.
PMID: 20850581 DOI: 10.1016/j.intimp.2010.09.001

The immunoregulatory properties of mesenchymal stem cells (MSC) have been demonstrated on a wide range of cells. Here, we describe the modulatory effects of mouse bone marrow-derived MSC on BV2 microglia proliferation rate, nitric oxide (NO) production and CD40 expression. Mouse bone marrow MSC were co-cultured with BV2 cells at various seeding density ratios and activated with lipopolysaccharide (LPS). We show that MSC exert an anti-proliferative effect on microglia and are potent producers of NO when stimulated by soluble factors released by LPS-activated BV2. MSC suppressed proliferation of both untreated and LPS-treated microglia in a dose-dependent manner, significantly reducing BV2 proliferation at seeding density ratios of 1:0.2 and 1:0.1 (p
Immunotherapies for Parkinson's Disease: Progression of Clinical Development

Teng JS, Ooi YY, Chye SM, Ling APK, Koh RY

CNS Neurol Disord Drug Targets, 2021;20(9):802-813.
PMID: 34042040 DOI: 10.2174/1871527320666210526160926

Parkinson's disease is a common neurodegenerative disease affecting the movement and well-being of most elderly. The manifestations of Parkinson's disease often include resting tremor, stiffness, bradykinesia, and muscular rigidity. The typical hallmark of Parkinson's disease is the destruction of neurons in the substantia nigra and the presence of Lewy bodies in different compartments of the central nervous system. Due to various limitations to the currently available treatments, immunotherapies have emerged to be the new approach to Parkinson's disease treatment. This approach shows some positive outcomes on the efficacy by removing the aggregated species of alpha-synuclein, which is believed to be one of the causes of Parkinson's disease. In this review, an overview of how alpha-synuclein contributes to Parkinson's disease and the effects of a few new immunotherapeutic treatments, including BIIB054 (cinpanemab), MEDI1341, AFFITOPE, and PRX002 (prasinezumab) that are currently under clinical development, will be discussed.
Response Profiles of BV2 Microglia to IFN-γ and LPS Co-Stimulation and Priming

Pan ML, Ahmad Puzi NN, Ooi YY, Ramasamy R, Vidyadaran S

Biomedicines, 2023 Sep 27;11(10).
PMID: 37893022 DOI: 10.3390/biomedicines11102648

(1) Background: The latest research illustrates that microglia phenotype is not the binary 'resting' and 'activated' profiles. Instead, there is wide diversity in microglia states. Similarly, when testing different stimulation protocols for BV2 microglia, we discovered differences in the response of the cells in terms of the production of intracellular ROS (iROS), nitric oxide (NO), CD40 expression, and migratory capacity. (2) Methods: BV2 microglia were treated with single interferon gamma (IFN-γ) stimulation, LPS/IFN-γ co-stimulation, and priming with IFN-γ followed by stimulation with LPS for 24 h. The responses of BV2 microglia were then assessed using the H2DCFDA test for iROS, the Griess assay for NO, immunophenotyping for CD40/CD11b/MHC II, and migration using a transwell apparatus. (3) Results: Single stimulation with IFN-γ induced NO but not ROS in BV2 microglia. Co-stimulation with LPS200IFN-γ2.5 induced a higher iROS production (a 9.2-fold increase) and CD40 expression (28031 ± 8810.2 MFI), compared to priming with primedIFN-γ50LPS100 (a 4.0-fold increase in ROS and 16764 ± 1210.8 MFI of CD40). Co-stimulation also induced cell migration. On the other hand, priming BV2 microglia (primedIFN-γ50LPS100) resulted in a higher NO production (64 ± 1.4 µM) compared to LPS200IFN-γ2.5 co-stimulation (44 ± 1.7 µM). Unexpectedly, priming inhibited BV2 migration. (4) Conclusions: Taken together, the findings from this project reveal the ability of co-stimulation and priming in stimulating microglia into an inflammatory phenotype, and the heterogeneity of microglia responses towards different stimulating approaches.
Increased SPRY1 expression activates NF-κB signaling and promotes pancreatic cancer progression by recruiting neutrophils and macrophages through CXCL12-CXCR4 axis

Shi T, Li X, Zheng J, Duan Z, Ooi YY, Gao Y, et al.

Cell Oncol (Dordr), 2023 Aug;46(4):969-985.
PMID: 37014552 DOI: 10.1007/s13402-023-00791-z

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high mortality rate, in which about 90% of patients harbor somatic oncogenic point mutations in KRAS. SPRY family genes have been recognized as crucial negative regulators of Ras/Raf/ERK signaling. Here, we investigate the expression and role of SPRY proteins in PDAC.
METHODS: Expression of SPRY genes in human and mice PDAC was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus datasets, and by immunohistochemistry analysis. Gain-of-function, loss-of-function of Spry1 and orthotopic xenograft model were adopted to investigate the function of Spry1 in mice PDAC. Bioinformatics analysis, transwell and flowcytometry analysis were used to identify the effects of SPRY1 on immune cells. Co-immunoprecipitation and K-ras4B G12V overexpression were used to identify molecular mechanism.
RESULTS: SPRY1 expression was remarkably increased in PDAC tissues and positively associated with poor prognosis of PDAC patients. SPRY1 knockdown suppressed tumor growth in mice. SPRY1 was found to promote CXCL12 expression and facilitate neutrophil and macrophage infiltration via CXCL12-CXCR4 axis. Pharmacological inhibition of CXCL12-CXCR4 largely abrogated the oncogenic functions of SPRY1 by suppressing neutrophil and macrophage infiltration. Mechanistically, SPRY1 interacted with ubiquitin carboxy-terminal hydrolase L1 to induce activation of nuclear factor κB signaling and ultimately increase CXCL12 expression. Moreover, SPRY1 transcription was dependent on KRAS mutation and was mediated by MAPK-ERK signaling.
CONCLUSION: High expression of SPRY1 can function as an oncogene in PDAC by promoting cancer-associated inflammation. Targeting SPRY1 might be an important approach for designing new strategy of tumor therapy.