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Fulltext Biological Activities of Snowdrop (Galanthus spp., Family Amaryllidaceae)

Kong CK, Low LE, Siew WS, Yap WH, Khaw KY, Ming LC, et al.

Front Pharmacol, 2020;11:552453.
PMID: 33679383 DOI: 10.3389/fphar.2020.552453

Snowdrop is an iconic early spring flowering plant of the genus Galanthus (Amaryllidaceae). Galanthus species (Galanthus spp.) are economically important plants as ornaments. Galanthus spp has gained significance scientific and commercial interest due to the discovery of Galanthamine as symptomatic treatment drug for Alzhiermer disease. This review aims to discuss the bioactivities of Galanthus spp including anticholinesterase, antimicrobial, antioxidant and anticancer potential of the extracts and chemical constituents of Galanthus spp. This review highlights that Galanthus spp. as the exciting sources for drug discovery and nutraceutical development.
In vitro evaluation of the involvement of Nrf2 in maslinic acid-mediated anti-inflammatory effects in atheroma pathogenesis

Ooi BK, Phang SW, Yong PVC, Chellappan DK, Dua K, Khaw KY, et al.

Life Sci, 2021 Aug 01;278:119658.
PMID: 34048809 DOI: 10.1016/j.lfs.2021.119658

AIMS: Maslinic acid (MA) is a naturally occurring pentacyclic triterpene known to exert cardioprotective effects. This study aims to investigate the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) for MA-mediated anti-inflammatory effects in atheroma pathogenesis in vitro, including evaluation of tumor necrosis factor-alpha (TNF-α)-induced monocyte recruitment, oxidized low-density lipoprotein (oxLDL)-induced scavenger receptors expression, and nuclear factor-kappa B (NF-ĸB) activity in human umbilical vein endothelial cells (HUVECS) and human acute monocytic leukemia cell line (THP-1) macrophages.
MATERIALS AND METHODS: An in vitro monocyte recruitment model utilizing THP-1 and HUVECs was developed to evaluate TNF-α-induced monocyte adhesion and trans-endothelial migration. To study the role of Nrf2 for MA-mediated anti-inflammatory effects, Nrf2 inhibitor ML385 was used as the pharmacological inhibitor. The expression of Nrf2, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 36 (CD36), and scavenger receptor type A (SR-A) in HUVECs and THP-1 macrophages were investigated using RT-qPCR and Western blotting. The NF-κB activity was determined using NF-κB (p65) Transcription Factor Assay Kit.
KEY FINDINGS: The results showed opposing effects of MA on Nrf2 expression in HUVECs and THP-1 macrophages. MA suppressed TNF-α-induced Nrf2 expression in HUVECs, but enhanced its expression in THP-1 macrophages. Combined effects of MA and ML385 suppressed MCP-1, VCAM-1, and SR-A expressions. Intriguingly, at the protein level, ML385 selectively inhibited SR-A but enhanced CD36 expression. Meanwhile, ML385 further enhanced MA-mediated inhibition of NF-κB activity in HUVECs. This effect, however, was not observed in THP-1 macrophages.
SIGNIFICANCE: MA attenuated foam cell formation by suppressing VCAM-1, MCP-1, and SR-A expression, as well as NF-κB activity, possibly through Nrf2 inhibition. The involvement of Nrf2 for MA-mediated anti-inflammatory effects however differs between HUVECs and macrophages. Future investigations are warranted for a detailed evaluation of the contributing roles of Nrf2 in foam cells formation.
Unraveling the Immunopathogenesis and Genetic Variants in Vasculitis Toward Development of Personalized Medicine

Yap BJM, Lai-Foenander AS, Goh BH, Ong YS, Duangjai A, Saokaew S, et al.

Front Cardiovasc Med, 2021;8:732369.
PMID: 34621800 DOI: 10.3389/fcvm.2021.732369

Leukocytoclastic vasculitis (LCV) is a systemic autoimmune disease characterized by the inflammation of the vascular endothelium. Cutaneous small vessel vasculitis (CSVV) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are two examples of LCV. Advancements in genomic technologies have identified risk haplotypes, genetic variants, susceptibility loci and pathways that are associated with vasculitis immunopathogenesis. The discovery of these genetic factors and their corresponding cellular signaling aberrations have enabled the development and use of novel therapeutic strategies for vasculitis. Personalized medicine aims to provide targeted therapies to individuals who show poor response to conventional interventions. For example, monoclonal antibody therapies have shown remarkable efficacy in achieving disease remission. Here, we discuss pathways involved in disease pathogenesis and the underlying genetic associations in different populations worldwide. Understanding the immunopathogenic pathways in vasculitis and identifying associated genetic variations will facilitate the development of novel and targeted personalized therapies for patients.
Fibroblast-derived matrices-based human skin equivalent as an in vitro psoriatic model for drug testing

Yap WH, Cheah TY, Yong LC, Chowdhury SR, Ng MH, Kwan Z, et al.

J Biosci, 2021;46.
PMID: 34475316

Psoriasis is a chronic skin disease characterized by thickening and disorganization of the skin's protective barrier. Although current models replicate some aspects of the disease, development of therapeutic strategies have been hindered by absence of more relevant models. This study aimed to develop and characterize an in vitro psoriatic human skin equivalent (HSE) using human keratinocytes HaCat cell line grown on fibroblasts-derived matrices (FDM). The constructed HSEs were treated with cytokines (IL-1α, TNF-α, IL-6, and IL22) to allow controlled induction of psoriasis-associated features. Histological stainings showed that FDMHSE composed of a fully differentiated epidermis and fibroblast-populated dermis comparable to native skin and rat tail collagen-HSE. Hyperproliferation (CK16 and Ki67) and inflammatory markers (TNF-α and IL-6) expression were significantly enhanced in the cytokine-induced FDM- and rat tail collagen HSEs compared to non-treated HSE counterparts. The characteristics were in line with those observed in psoriasis punch biopsies. Treatment with all-trans retinoic acid (ATRA) has shown to suppress these effects, where HSE models treated with both ATRA and cytokines exhibit histological characteristics, hyperproliferation and differentiation markers expression like non-treated control HSEs. Cytokine-induced FDM-HSE, constructed entirely from human cell lines, provides an excellent opportunity for psoriasis research and testing new therapeutics.
Fulltext Resveratrol-Potential Antibacterial Agent against Foodborne Pathogens

Ma DSL, Tan LT, Chan KG, Yap WH, Pusparajah P, Chuah LH, et al.

Front Pharmacol, 2018;9:102.
PMID: 29515440 DOI: 10.3389/fphar.2018.00102

Bacterial foodborne pathogens are a significant health burden and the recent emergence of pathogenic resistant strains due to the excessive use of antibiotics makes it more difficult to effectively treat infections as a result of contaminated food. Awareness of this impending health crisis has spurred the search for alternative antimicrobials with natural plant antimicrobials being among the more promising candidates as these substances have good acceptability and likely low toxicity levels as they have long been used in traditional medicines. Resveratrol (3,5,4'-trihydroxystilbene) is a naturally occurring stilbenoid which has been gaining considerable attention in medical field due to its diverse biological activities - it has been reported to exhibit antioxidant, cardioprotective, anti-diabetic, anticancer, and antiaging properties. Given that resveratrol is phytoalexin, with increased synthesis in response to infection by phytopathogens, there has been interest in exploring its antimicrobial activity. This review aims to provide an overview of the published data on the antibacterial activity of resveratrol against foodborne pathogens, its mechanisms of action as well as its possible applications in food packing and processing; in addition we also summarize the current data on its potential synergism with known antibacterials and future research and applications.
Fulltext Harnessing the Potential of CRISPR/Cas in Atherosclerosis: Disease Modeling and Therapeutic Applications

Siew WS, Tang YQ, Kong CK, Goh BH, Zacchigna S, Dua K, et al.

Int J Mol Sci, 2021 Aug 05;22(16).
PMID: 34445123 DOI: 10.3390/ijms22168422

Atherosclerosis represents one of the major causes of death globally. The high mortality rates and limitations of current therapeutic modalities have urged researchers to explore potential alternative therapies. The clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system is commonly deployed for investigating the genetic aspects of Atherosclerosis. Besides, advances in CRISPR/Cas system has led to extensive options for researchers to study the pathogenesis of this disease. The recent discovery of Cas9 variants, such as dCas9, Cas9n, and xCas9 have been established for various applications, including single base editing, regulation of gene expression, live-cell imaging, epigenetic modification, and genome landscaping. Meanwhile, other Cas proteins, such as Cas12 and Cas13, are gaining popularity for their applications in nucleic acid detection and single-base DNA/RNA modifications. To date, many studies have utilized the CRISPR/Cas9 system to generate disease models of atherosclerosis and identify potential molecular targets that are associated with atherosclerosis. These studies provided proof-of-concept evidence which have established the feasibility of implementing the CRISPR/Cas system in correcting disease-causing alleles. The CRISPR/Cas system holds great potential to be developed as a targeted treatment for patients who are suffering from atherosclerosis. This review highlights the advances in CRISPR/Cas systems and their applications in establishing pathogenetic and therapeutic role of specific genes in atherosclerosis.
Fulltext Angelicin-A Furocoumarin Compound With Vast Biological Potential

Mahendra CK, Tan LTH, Lee WL, Yap WH, Pusparajah P, Low LE, et al.

Front Pharmacol, 2020;11:366.
PMID: 32372949 DOI: 10.3389/fphar.2020.00366

Angelicin, a member of the furocoumarin group, is related to psoralen which is well known for its effectiveness in phototherapy. The furocoumarins as a group have been studied since the 1950s but only recently has angelicin begun to come into its own as the subject of several biological studies. Angelicin has demonstrated anti-cancer properties against multiple cell lines, exerting effects via both the intrinsic and extrinsic apoptotic pathways, and also demonstrated an ability to inhibit tubulin polymerization to a higher degree than psoralen. Besides that, angelicin too demonstrated anti-inflammatory activity in inflammatory-related respiratory and neurodegenerative ailments via the activation of NF-κB pathway. Angelicin also showed pro-osteogenesis and pro-chondrogenic effects on osteoblasts and pre-chondrocytes respectively. The elevated expression of pro-osteogenic and chondrogenic markers and activation of TGF-β/BMP, Wnt/β-catenin pathway confirms the positive effect of angelicin bone remodeling. Angelicin also increased the expression of estrogen receptor alpha (ERα) in osteogenesis. Other bioactivities, such as anti-viral and erythroid differentiating properties of angelicin, were also reported by several researchers with the latter even displaying an even greater aptitude as compared to the commonly prescribed drug, hydroxyurea, which is currently on the market. Apart from that, recently, a new application for angelicin against periodontitis had been studied, where reduction of bone loss was indirectly caused by its anti-microbial properties. All in all, angelicin appears to be a promising compound for further studies especially on its mechanism and application in therapies for a multitude of common and debilitating ailments such as sickle cell anaemia, osteoporosis, cancer, and neurodegeneration. Future research on the drug delivery of angelicin in cancer, inflammation and erythroid differentiation models would aid in improving the bioproperties of angelicin and efficacy of delivery to the targeted site. More in-depth studies of angelicin on bone remodeling, the pro-osteogenic effect of angelicin in various bone disease models and the anti-viral implications of angelicin in periodontitis should be researched. Finally, studies on the binding of angelicin toward regulatory genes, transcription factors, and receptors can be done through experimental research supplemented with molecular docking and molecular dynamics simulation.
Fulltext Hydroxychloroquine: Key therapeutic advances and emerging nanotechnological landscape for cancer mitigation

Low LE, Kong CK, Yap WH, Siva SP, Gan SH, Siew WS, et al.

Chem Biol Interact, 2023 Dec 01;386:110750.
PMID: 37839513 DOI: 10.1016/j.cbi.2023.110750

Hydroxychloroquine (HCQ) is a unique class of medications that has been widely utilized for the treatment of cancer. HCQ plays a dichotomous role by inhibiting autophagy induced by the tumor microenvironment (TME). Preclinical studies support the use of HCQ for anti-cancer therapy, especially in combination with conventional anti-cancer treatments since they sensitize tumor cells to drugs, potentiating the therapeutic activity. However, clinical evidence has suggested poor outcomes for HCQ due to various obstacles, including non-specific distribution, low aqueous solubility and low bioavailability at target sites, transport across tissue barriers, and retinal toxicity. These issues are addressable via the integration of HCQ with nanotechnology to produce HCQ-conjugated nanomedicines. This review aims to discuss the pharmacodynamic, pharmacokinetic and antitumor properties of HCQ. Furthermore, the antitumor performance of the nanoformulated HCQ is also reviewed thoroughly, aiming to serve as a guide for the HCQ-based enhanced treatment of cancers. The nanoencapsulation or nanoconjugation of HCQ with nanoassemblies appears to be a promising method for reducing the toxicity and improving the antitumor efficacy of HCQ.
Fulltext Prioritising topics for developing e-learning resources in healthcare curricula: A comparison between students and educators using a modified Delphi survey

Lim HM, Ng CJ, Teo CH, Lee PY, Kassim PSJ, Nasharuddin NA, et al.

PLoS One, 2021;16(6):e0253471.
PMID: 34166432 DOI: 10.1371/journal.pone.0253471

BACKGROUND: Engaging students in the e-learning development process enhances the effective implementation of e-learning, however, students' priority on the topics for e-learning may differ from that of the educators. This study aims to compare the differences between the students and their educators in prioritising the topics in three healthcare curricula for reusable e-learning object (RLO) development.
METHOD: A modified Delphi study was conducted among students and educators from University Malaya (UM), Universiti Putra Malaysia (UPM) and Taylor's University (TU) on three undergraduate programmes. In Round 1, participants were asked to select the topics from the respective syllabi to be developed into RLOs. Priority ranking was determined by using frequencies and proportions. The first quartile of the prioritised topics was included in Round 2 survey, which the participants were asked to rate the level of priority of each topic using a 5-point Likert scale. The mean score of the topics was compared between students and educators.
RESULT: A total of 43 educators and 377 students participated in this study. For UM and TU Pharmacy, there was a mismatch in the prioritised topics between the students and educators. For UPM, both the educators and students have prioritised the same topics in both rounds. To harmonise the prioritisation of topics between students and educators for UM and TU Pharmacy, the topics with a higher mean score by both the students and educators were prioritised.
CONCLUSION: The mismatch in prioritised topics between students and educators uncovered factors that might influence the prioritisation process. This study highlighted the importance of conducting needs assessment at the beginning of eLearning resources development.
Fulltext Knowledge transfer of eLearning objects: Lessons learned from an intercontinental capacity building project

Lim HM, Ng CJ, Wharrad H, Lee YK, Teo CH, Lee PY, et al.

PLoS One, 2022;17(9):e0274771.
PMID: 36126036 DOI: 10.1371/journal.pone.0274771

BACKGROUND: Effective knowledge transfer of eLearning objects can hasten the adoption and dissemination of technology in teaching and learning. However, challenges exist which hinder inter-organisational knowledge transfer, particularly across continents. The ACoRD project aimed to transfer knowledge on digital learning development from UK/EU (provider) to Malaysian (receiver) higher education institutions (HEIs). This study explores the challenges encountered during the knowledge transfer process and lessons learned.
METHODS: This is a qualitative study involving both the knowledge providers and receivers in focus group discussions (n = 25). Four focus group discussions were conducted in the early (n = 2) and mid-phase (n = 2) of the project by trained qualitative researchers using a topic guide designed to explore experiences and activities representing knowledge transfer in multi-institutional and multi-cultural settings. The interviews were audio-recorded, transcribed verbatim, and checked. The transcripts were analysed using thematic analysis.
RESULTS: Five main themes emerged from this qualitative study: mismatched expectations between providers and receivers; acquiring new knowledge beyond the professional "comfort zone"; challenges in cascading newly acquired knowledge to colleagues and management; individual and organisational cultural differences; and disruption of knowledge transfer during the COVID-19 pandemic.
CONCLUSION: This study highlights the need to create a conducive platform to facilitate continuous, timely and bi-directional needs assessment and feedback; this should be done in the early phase of the knowledge transfer process. The challenges and strategies identified in this study could guide more effective knowledge transfer between organisations and countries.

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