Type II diabetes mellitus (T2DM) is a chronic non‐communicable disease due to abnormal insulin actions causing uncontrolled hyperglycaemia. The treatment for T2DM, for instance, metformin and ...incretin mimetic, mainly focuses on the restoration of insulin sensitivity and secretion. Exendin‐4 is a short incretin‐mimetic peptide consisting of 39 amino acids. It is discovered in the venom of Heloderma suspectum as a full agonist for the glucagon‐like peptide 1 (GLP‐1) receptor and produces insulinotropic effects. It is more resistant to enzymatic degradation by dipeptidyl‐peptidase‐4 and has a longer half‐life than the endogenous GLP‐1; thus, it is further developed as an incretin hormone analogue used to treat T2DM. The helical region of the peptide first interacts with the extracellular N‐terminal domain (NTD) of GLP‐1 receptor while the C‐terminal extension containing the tryptophan cage further enhances its binding affinity. After binding to the NTD of the receptor, it may cause the receptor to switch from its auto‐inhibited state of the receptor to its auto‐activated state. Exendin‐4 enhances the physiological functions of β‐cells and the up‐regulation of GLP‐1 receptors, thus reducing the plasma glucose levels. Moreover, exendin‐4 has also been found to ameliorate neuropathy, nephropathy and ventricular remodelling. The therapeutic effects of exendin‐4 have also been extrapolated into several clinical trials. Although exendin‐4 has a reasonable subcutaneous bioavailability, its half‐life is rather short. Therefore, several modifications have been undertaken to improve its pharmacokinetics and insulinotropic potency. This review focuses on the pharmacology of exendin‐4 and the structure‐function relationships of exendin‐4 with GLP‐1 receptor. The review also highlights some challenges and future directions in the improvement of exendin‐4 as an anti‐diabetic drug.
Experiential learning is compromised in meeting the educational demands of our students during the challenging time of the COVID‐19 pandemic. A more inclusive, flexible, and objective‐oriented ...experiential learning environment is required. In this context, module‐based experiential learning that is executable on a digital platform was designed. The learning module focused on protein biochemistry, contained a combination of asynchronous and synchronous activities categorized into ‘Knowledge Hub’ and ‘Lab‐based Movie’, across 5 weeks. Digital and module‐based experiential learning provides equitable, inclusive, and flexible access to students at remote locations. Furthermore, it is an objective‐oriented and highly organized experiential learning framework that encourages students to engage and participate more in the learning process.
Approximate 70% of cobra venom is composed of cytotoxin (CTX), which is responsible for the dermonecrotic symptoms of cobra envenomation. However, CTX is generally low in immunogenicity, and the ...antivenom is ineffective in attenuating its in vivo toxicity. Furthermore, little is known about its epitope properties for empirical antivenom therapy. This study aimed to determine the epitope sequences of CTX using the immunoinformatic analyses and epitope-omics profiling. A conserved CTX was used in this study to determine its T-cell and B-cell epitope sequences using immunoinformatic tools and molecular docking simulation with different Human Leukocyte Antigens (HLAs). The potential T-cell and B-cell epitopes were 'KLVPLFY,' 'CPAGKNLCY,' 'MFMVSTPTK,' and 'DVCPKNSLL.' Molecular docking simulations disclosed that the HLA-B62 supertype exhibited the greatest binding affinity towards cobra venom cytotoxin. The namely L7, G18, K19, N20, M25, K33, V43, C44, K46, N47, and S48 of CTX exhibited prominent intermolecular interactions with HLA-B62. The multi-enzymatic-limited-digestion/liquid chromatography-mass spectrometry (MELD/LC-MS) also revealed three potential epitope sequences as 'LVPLFYK,' 'MFMVS,' and 'TVPVKR'. From different epitope mapping approaches, we concluded four potential epitope sites of CTX as 'KLVPLFYK', 'AGKNL', 'MFMVSTPKVPV' and 'DVCPKNSLL'. Site-directed mutagenesis of these epitopes confirmed their locations at the functional loops of CTX. These epitope sequences are crucial to CTX's structural folding and cytotoxicity. The results concluded the epitopes that resided within the functional loops constituted potential targets to fabricate synthetic epitopes for CTX-targeted antivenom production.
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•A. lappa root extract had potent anticancer effect against Jurkat T cells.•The root extract induced formation of apoptotic bodies in Jurkat T cells.•The extract caused a ...concentration-dependent elevated caspase-3/7 in treated cells.•There was an alteration of mitochondrial membrane potential in treated cells.•DNA fragmentation was observed in root extract treated Jurkat T cells.
Arctium lappa L. is a perennial herb traditionally consumed to improve well-being. It has been widely reported for its antioxidant properties; however, very little is known for its exact mechanisms underlying the anticancer activity. This study aimed to investigate the mechanisms of anticancer action for different A. lappa root extracts. Arctium lappa root was extracted with ethanol, hexane and ethyl acetate, then examined for in vitro anticancer activity against cancerous HeLa, MCF-7, Jurkat cell lines and non-cancerous 3T3 cell lines. Induction of apoptosis was determined by cellular morphological changes, mitochondrial membrane potential (ΔΨm), caspase-3/7 activity and DNA fragmentation. The active compounds present in the most potent root extracts were identified by LC-ESI-MS. Among all the extracts, ethyl acetate root extract has the highest potency with IC50 of 102.2 ± 42.4 μg/ml, followed by ethanolic root extract in Jurkat T cells, at 24 h. None of the extracts were cytotoxic against 3T3 cells, suggesting that the extracts were selective against cancerous cells only. Both ethyl acetate and ethanolic root extracts exhibited significant morphological changes in Jurkat T cells, including the detachment from adjacent cells, appearance of apoptotic bodies and cells shrinkage. The extracts treated cells also displayed an increase in caspase-3/7 activity and alteration in mitochondrial membrane potential. Only ethyl acetate root extract at IC50 induced DNA fragmentation in Jurkat T cells. LC-ESI-MS analysis of the extract revealed the presence of 8 compounds, of which only 6 compounds with various biological activities reported. These findings suggest that the ethyl acetate extract of A. lappa had strong anticancer potential and induced intrinsic apoptosis via loss of ΔΨm and activation of caspase-3/7 This study can provide new insight to the discovery of new promising lead compound in chemopreventive and chemotherapeutic strategies.
Cobra venom cytotoxin (CTX) is a non-enzymatic three-finger toxin that constitutes 40–60% of cobra venom. Thus, it plays an important role in the pathophysiology of cobra envenomation, especially in ...local dermonecrosis. The three-finger hydrophobic loops of CTX determine the cytotoxicity. Nevertheless, the actual mechanisms of cytotoxicity are not fully elucidated as they involve not only cytolytic actions but also intracellular signalling-mediated cell death pathways. Furthermore, the possible transition cell death pattern remains to be explored. The actual molecular mechanisms require further studies to unveil the relationship between different CTXs from different cobra species and cell types which may result in differential cell death patterns. Here, we discuss the biophysical interaction of CTX with the cell membrane involving four binding modes: electrostatic interaction, hydrophobic partitioning, isotropic phase, and oligomerisation. Oligomerisation of CTX causes pore formation in the membrane lipid bilayer. Additionally, the CTX-induced apoptotic pathway can be executed via death receptor-mediated extrinsic pathways and mitochondrial-mediated intrinsic pathways. We also discuss lysosomal-mediated necrosis and the occurrence of necroptosis following CTX action. Collectively, we provided an insight into concentration-dependent transition of cell death pattern which involves different mechanistic actions. This contributes a new direction for further investigation of cytotoxic pathways activated by the CTXs for future development of biotherapeutics targeting pathological effects caused by CTX.
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•Cytotoxin exhibits biophysical interaction with cell membrane.•Cytotoxin induces caspase-dependent extrinsic and intrinsic apoptosis.•Cytotoxin triggers lysosomal-mediated necrosis.•The occurrence of necroptosis has also been observed in cytotoxin-treated cells.•Transition of cell death pattern from apoptosis to necrosis or necroptosis is concentration-dependent.
There is growing evidence to suggest the importance of self-regulatory practices amongst older adults to sustain mobility. However, the decision to self-regulate driving is a complex interplay ...between an individual's preference and the influence of their social networks including spouse. To our best knowledge, the influence of an older adult's spouse on their decisions during driving transition has not been explored.
This qualitative descriptive study was conducted amongst married older adults aged 60 years and above. All interview responses were transcribed verbatim and examined using thematic approach and interpretative description method.
A total of 11 married couples were interviewed. Three major themes emerged: 1 Our roles in driving; 2 Challenges to continue driving; and, 3 Our driving strategies to ensure continued driving. Older couples adopted driving strategies and regulated their driving patterns to ensure they continued to drive safely. Male partners often took the active driving role as the principal drivers, while the females adopted a more passive role, including being the passenger to accompany the principal drivers or becoming the co-driver to help in navigation. Other coping strategies include sharing the driving duties as well as using public transportation or mixed mode transportation.
Our findings suggest spouse play a significant role in their partners' decision to self-regulate driving. This underscores a need to recognise the importance of interdependency amongst couples and its impact on their driving decisions and outcomes.
Microalgae are unicellular photosynthetic microorganisms that are commonly found in saline or freshwater environments. Over the years, microalgae represent promising sources of sustainable ...bioactivities with past literatures reflecting a growing interest in algae-based dietary supplements in the form of whole biomass. Notably, the bioactive molecules that can be identified and extracted in microalgae have scientifically proven to contain therapeutic properties which can be beneficial to human health. With the increasing occurrence of global health threats such as antimicrobial resistance and cancer, this has resulted in considerable attention for microalgae study especially in the medicinal field. Although studies have proved the therapeutic potentials of high-value bioproducts in microalgae, however, there is still room to understand their potential therapeutic properties on humans’ health, discovering novel microalgae-derived bioactive compounds, as well as translating the lab-based evidence to clinical trial studies. This review will focus on accessing the biochemical compositions of commercialised microalgae species from 2007 to 2020, and the activity of their biologically active molecules in eliciting selected therapeutic potentials which are anti-oxidative, anti-inflammatory, anti-microbial and anti-cancer properties. This review article will also be looking at the research gaps in addition to the above four major selected therapeutic potentials, and future prospective.
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Cyanobacteria bioactive compounds are chemical treasure troves for product discovery and development. The wound healing effects and antioxidant capacities of water extracts from
Nostoc
...NIES-2111_MUM004 were evaluated via in vitro wound scratch assay and three antioxidant assays respectively. Results showed that the water extracts were protein-rich and exhibited good antioxidant properties in ABTS radical scavenging (11.27 ± 0.205 mg TAE g
−1
extract), Ferric reducing antioxidant power (1652.71 ± 110.71 mg TAE g
−1
extract) and β-carotene bleaching assay (354.90 ± 31.80 mg TAE g
−1
extract). Also, extracts were non-cytotoxic in concentrations up to 250 µg/mL as reflected in cytotoxicity assay. Importantly, water extracts showed considerable proliferation and migration activity at 125 µg/mL with wound closure rate as high as 42.67%. Statistical correlation revealed no significant relationship (
p
> 0.05) between protein fraction and the wound healing properties, confirming that phycobiliproteins were not solely responsible for wound healing activities. Subsequent Q-TOF-LCMS analysis identified six protein families involved in enhancing the proliferation and migration of epithelial cells. These findings are antecedent in the uncovering of continuous supplies of bioactive compounds from new and sustainable sources. Ultimately, enriching the microalgae menu for applications in pharmaceutical, nutraceutical and cosmeceuticals.
The phospholipase A2 (PLA2) and l-amino acid oxidase (LAAO) are two major enzymes found in the venoms from most snake species. These enzymes have been structurally and functionally characterised for ...their pharmacological activities. Both PLA2 and LAAO from different venoms demonstrate considerable cytotoxic effects on cancer cells via induction of apoptosis, cell cycle arrest and suppression of proliferation. These enzymes produce more pronounced cytotoxic effects in cancer cells than normal cells, thus they can be potential sources as chemotherapeutic agents. It is proposed that PLA2 and LAAO contribute to an elevated oxidative stress due to their catalytic actions, for instance, the ability of PLA2 to produce reactive oxygen species during lipolysis and formation of H2O2 from LAAO catalytic activity which consequently lead to cell death. Nonetheless, the cell-death signalling pathways associated with exposure to these enzymatic toxins are not fully elucidated yet. Here in this review, we will discuss the cytotoxic effects of PLA2 and LAAO in relationship to their catalytic mechanisms and the underlying mechanisms of cytotoxic actions.
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