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Fulltext Neuroprotective mechanisms of orientin against hydrogen peroxide-induced oxidative damage in SH-SY5Y cells

Lam, Kit Ying, Ling, Anna Pick Kiong, Sasmita, Andrew Octavian, Koh, Rhun Yian, Wong, Ying Pei, Voon, Kenny Gah Leong, et al.

Journal of Biochemistry, Microbiology and Biotechnology, 2018;6(1):10-18.
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Natural products or plant derivatives could be used to prevent or treat neurodegenerative diseases (ND). Oxidative stress has been highly implicated in the progression of ND;thus, this leads to the study on the effects of orientin in regulating Nrf2/Keap-1 redox signalling, PI3K/Akt survival and MAPK/ERK apoptosis pathways in the hydrogen peroxide (H2O2)-induced oxidative damage in SH-SY5Y cells. The cells were treated with half maximum non-toxic dose (½ MNTD) or maximum non-toxic dose (MNTD) of orientin and subsequently with H2O2. Cells were then subjected to the measurement of nitric oxide (NO), intracellular calcium (Ca2+), mitochondrial membrane potential (MMP) and annexin V/propidium iodide apoptosis assays. Regulation of the signalling pathways was analysed by Western blotting. Results showed that ½ MNTD of orientin reduced the NO levels. The intracellular Ca2+ level was also reduced by ½ MNTD and MNTD of orientin. The orientin treatment at ½ MNTD and MNTD restored the loss of MMP. Pre-treatment of orientin reduced the early and late apoptotic cells as well as necrotic cells. Orientin was found to up-regulate the Nrf2/Keap-1 and PI3K/Akt pathways whilst down-regulate the MAPK/ERK pathway. The findings from this study will be useful for the prevention of ND in the near future.
Biomarkers and therapeutic advances in glioblastoma multiforme

Sasmita AO, Wong YP, Ling APK

Asia Pac J Clin Oncol, 2018 Feb;14(1):40-51.
PMID: 28840962 DOI: 10.1111/ajco.12756

Glioblastoma multiforme (GBM) is a malignant tumor within the brain. Generally classified as primary and secondary with several different subtypes, ample molecular biomarkers have risen throughout the years which have garnered the attention of researchers. The advancements in genomics and proteomics have allowed researchers to gather prominent molecular biomarkers. All these biomarkers are gathered by means of biopsy or bodily fluid sample collection and are quantitatively analyzed by polymerase chain reaction coupled with other computational technologies. This review highlights the significance, regulation and prevalence of molecular biomarkers such as O6 -methylguanine-DNA methyltransferase, epidermal growth factor receptor vIII, isocitrate dehydrogenase mutation and several others which expressed differently in different types and molecular subtypes of GBM. The discoveries and roles of GBM-specific microRNAs including miR-21 and miR-10b as biomarkers with promising prognostic values were also delineated. The role and mechanism of biomarkers in GBM tumorigenesis are essential in the development of therapy for patients suffering from the disease itself. Thus, this review also discusses the mechanisms, effects and limitations of therapy such as temozolomide, viral gene transfer, biomarker-based vaccines or even engineered T cells for more specific responses. Biomarkers have displayed a high value and could eventually be utilized as drug targets. It is hoped that by combining different aspects of the disease which present with different biomarkers could lead to the development of a robust, effective and innovative take on GBM therapy.
Fulltext A Review on Medicinal Properties of Orientin

Lam KY, Ling AP, Koh RY, Wong YP, Say YH

Adv Pharmacol Sci, 2016;2016:4104595.
PMID: 27298620 DOI: 10.1155/2016/4104595

Medicinal plants continue to play an important role in modern medications and healthcare as consumers generally believe that most of them cause fewer or milder adverse effects than the conventional modern medicines. In order to use the plants as a source of medicinal agents, the bioactive compounds are usually extracted from plants. Therefore, the extraction of bioactive compounds from medicinal plants is a crucial step in producing plant-derived drugs. One of the bioactive compounds isolable from medicinal plants, orientin, is often used in various bioactivity studies due to its extensive beneficial properties. The extraction of orientin in different medicinal plants and its medicinal properties, which include antioxidant, antiaging, antiviral, antibacterial, anti-inflammation, vasodilatation and cardioprotective, radiation protective, neuroprotective, antidepressant-like, antiadipogenesis, and antinociceptive effects, are discussed in detail in this review.
Neuroprotective effects of orientin on hydrogen peroxide‑induced apoptosis in SH‑SY5Y cells

Law BN, Ling AP, Koh RY, Chye SM, Wong YP

Mol Med Rep, 2014 Mar;9(3):947-54.
PMID: 24366367 DOI: 10.3892/mmr.2013.1878

Neurodegenerative diseases remain a global issue which affects the ageing population. Efforts towards determining their aetiologies to understand their pathogenic mechanisms are underway in order to identify a pathway through which therapeutic measures can be applied. One such pathogenic mechanism, oxidative stress (OS), is widely considered to be involved in neurodegenerative disease. Antioxidants, most notably flavonoids, have promising potential for therapeutic use as shown in in vitro and in vivo studies. In view of the importance of flavonoids for combating OS, this study investigated the neuroprotective effects of orientin, which has been reported to be capable of crossing the blood‑brain barrier. The maximum non‑toxic dose (MNTD) of orientin against SH‑SY5Y neuroblastoma cells was determined using a 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide (MTT) assay. The effects of the MNTD and the half MNTD (½MNTD) of orientin on cell cycle progression and intracellular reactive oxygen species (ROS) levels, as well as the activity of caspases 3/7, 8 and 9 after exposure to 150 µM of hydrogen peroxide (H2O2) were also determined using flow cytometry, a 2',7'‑dichlorodihydrofluorescein‑diacetate (DCFH‑DA) assay and caspase assay kits, respectively. The results revealed that orientin at ≤20 µM was not cytotoxic to SH‑SY5Y cells. After treatment with orientin at the MNTD, the percentage of apoptotic cells was significantly reduced compared with that in cells treated with 150 µM H2O2 alone. The results also showed that, although orientin at the MNTD and ½MNTD did not reduce intracellular ROS levels, it significantly inhibited the activity of caspases 3/7. Caspase 9 was significantly inactivated with orientin at the MNTD. Findings from this study suggest that the neuroprotection conferred by orientin was the result of the intracellular mediation of caspase activity.
Madecassoside activates anti‑neuroinflammatory mechanisms by inhibiting lipopolysaccharide‑induced microglial inflammation

Sasmita AO, Ling APK, Voon KGL, Koh RY, Wong YP

Int J Mol Med, 2018 May;41(5):3033-3040.
PMID: 29436598 DOI: 10.3892/ijmm.2018.3479

Neurodegeneration is typically preceded by neuroinflammation generated by the nervous system to protect itself from tissue damage, however, excess neuroinflammation may inadvertently cause more harm to the surrounding tissues. Attenuating neuroinflammation with non‑steroidal anti‑inflammatory drugs can inhibit neurodegeneration. However, such treatments induce chronic side effects, including stomach ulcers. Madecassoside, a triterpene derived from Centella asiatica, is considered to be an alternative treatment of inflammation. In the present study, the anti‑neuroinflammatory properties of madecassoside were assessed in BV2 microglia cells, which were pre‑treated with madecassoside at a maximum non‑toxic dose (MNTD) of 9.50 µg/ml and a ½ MNTD of 4.75 µg/ml for 3 h and stimulated with 0.1 µg/ml lipopolysaccharide (LPS). The effect of madecassoside was assessed by determining reactive oxygen species (ROS) levels in all groups. Furthermore, the expression of pro‑ and anti‑neuroinflammatory genes and proteins were analyzed using reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that ROS levels in cells treated with the MNTD of madecassoside were significantly reduced compared with cells treated with LPS alone (P<0.05). The expression of pro‑neuroinflammatory genes, including inducible nitric oxide synthase, cyclooxygenase‑2, signal transducer and activator of transcription 1 and nuclear factor‑κB, were significantly downregulated in a dose‑independent manner following treatment with madecassoside. Conversely, the anti‑neuroinflammatory component heme oxygenase 1 was significantly upregulated by 175.22% in the MNTD‑treated group, compared with cells treated with LPS alone (P<0.05). The gene expression profiles of pro‑ and anti‑inflammatory genes were also consistent with the results of western blotting. The results of the present study suggest that madecassoside may be a potent anti‑neuroinflammatory agent. The antioxidative properties of madecassoside, which serve a major role in anti‑neuroinflammation, indicate that this compound may be a functional natural anti‑neuroinflammatory agent, therefore, further in vivo or molecular studies are required.
Fulltext Anti-neuroinflammatory of Chloroform Extract of Panax ginseng Root Culture on Lipopolysaccharide-stimulated BV2 Microglia Cells

Cheah CH, Ling APK, Wong YP, Koh RY, Hussein S

Rep Biochem Mol Biol, 2022 Apr;11(1):125-137.
PMID: 35765526 DOI: 10.52547/rbmb.11.1.125

BACKGROUND: It is believed that activation of microglia in the central nervous system upon detection of stimulus like lipopolysaccharides provokes neuroinflammation via the production of pro-inflammatory mediators and cytokines. The cytoprotective and anti-inflammatory properties of various folk medicine has been gaining attention as a strategy to combat various disease. This study aimed to assess the anti-neuroinflammatory properties of chloroform extract of in vitro Panax ginseng root culture based on nitric oxide and cytokines production.
METHODS: The study was initiated with the determination of maximum non-toxic dose (MNTD) of P. ginseng root culture chloroform extract using the MTT assay. The lipopolysaccharides-stimulated BV2 microglia cells were treated with MNTD and ½MNTD of the extract and its anti-neuroinflammatory properties were assessed by measuring the production of nitric oxide (NO) via Griess assay, as well as TNF-α, IL-6 and IL-10 using Quantikine ELISA.
RESULTS: It was found that the MNTD and ½MNTD of the extract did not play a significant role in the production of pro-inflammatory cytokines such as NO, TNF-α and IL-6. However, the MNTD and ½MNTD of chloroform extract significantly increased the anti-inflammatory IL-10 compared to the untreated cells.
CONCLUSION: With this, the chloroform extract of P. ginseng root culture potentially exerts anti-neuroinflammatory properties.