Potential ability of phytochemical in inhibition of invadopodia formation and HIF-1α in cancer metastasis

Cancer metastasis is a multistep process, which results in cancer cells disseminating to other organs. The crucial metastasis step involves cancer invasion which occurs via actin-protrusion by invasive malignant cells, termed as invadopodia. In solid tumours, invadopodia formation increases as a result of hypoxia which is found to be resistant against chemotherapy and radiotherapy. Phytochemicals have been potentially identified as a prime source of effective conventional drugs for metastasis treatments, which target cancer cell invasion, particularly molecular components of the invadopodia formation. The Hypoxia-Inducible Factor-1α (HIF-1α) is an essential target in terms of treatment for hypoxic tumour, as well as helping to identify the mode of action for the drugs, particularly phytochemical compounds. The aim of this review is to highlight the current development with regards to the ability of phytochemicals in targeting cancer metastasis, as well as phytochemical compounds which are able to inhibit HIF-1α and invadopodia formation. The use of phytochemicals for targeting hypoxic cancer cells may open new prospects for reducing cancer metastasis

An insight into the anti-angiogenic and anti-metastatic effects of oridonin: current knowledge and future potential

Cancer is one of the leading causes of death worldwide, with a mortality rate of more than 9 million deaths reported in 2018. Conventional anti-cancer therapy can greatly improve survival however treatment resistance is still a major problem especially in metastatic disease. Targeted anti-cancer therapy is increasingly used with conventional therapy to improve patients’ outcomes in advanced and metastatic tumors. However, due to the complexity of cancer biology and metastasis, it is urgent to develop new agents and evaluate the anti-cancer efficacy of available treatments. Many phytochemicals from medicinal plants have been reported to possess anti-cancer properties. One such compound is known as oridonin, a bioactive component of Rabdosia rubescens. Several studies have demonstrated that oridonin inhibits angiogenesis in various types of cancer, including breast, pancreatic, lung, colon and skin cancer. Oridonin’s anti-cancer effects are mediated through the modulation of several signaling pathways which include upregulation of oncogenes and pro-angiogenic growth factors. Furthermore, oridonin also inhibits cell migration, invasion and metastasis via suppressing epithelial-to-mesenchymal transition and blocking downstream signaling targets in the cancer metastasis process. This review summarizes the recent applications of oridonin as an anti-angiogenic and anti-metastatic drug both in vitro and in vivo, and its potential mechanisms of action

Identification of potential chemical substrates as fuel for hypoxic tumors that may be linked to invadopodium formation in hypoxia-induced MDA-MB-231 breast-cancer cell line

Hypoxia plays a significant role in solid tumors by the increased expression of hypoxia-inducible factor-1α (HIF-1α), which is known to promote cancer invasion and metastasis. Cancer-cell invasion dynamically begins with the degradation of the extracellular matrix (ECM) via invadopodia formation. The chemical substrates that are utilized by hypoxic cells as fuel to drive invadopodia formation are still not fully understood. Therefore, the aim of the study was to maintain MDA-MB-231 cells under hypoxia conditions to allow cells to form a large number of invadopodia as a model, followed by identifying their nutrient utilization. The results of the study revealed an increase in the number of cells forming invadopodia under hypoxia conditions. Moreover, Western blot analysis confirmed that essential proteins for hypoxia and invadopodia, including HIF-1α, vascular endothelial growth factor (VEGF), metallopeptidase-2 (MMP-2), and Rho guanine nucleotide exchange factor 7 (β-PIX), significantly increased under hypoxia. Interestingly, phenotype microarray showed that only 11 chemical substrates from 367 types of substrates were significantly metabolized in hypoxia compared to in normoxia. This is thought to be fuel for hypoxia to drive the invasion process. In conclusion, we found 11 chemical substrates that could have potential energy sources for hypoxia-induced invadopodia formation of these cells. This may in part be a target in the hypoxic tumor and invadopodia formation. Additionally, these findings can be used as potential carrier targets in cancer-drug discovery, such as the usage of dextrin

Anti-allergic activity of 2,4,6-trihydroxy-3-geranylacetophenone (tHGA) via attenuation of IgE-mediated mast cell activation and inhibition of passive systemic anaphylaxis

tHGA, a geranyl acetophenone compound originally isolated from a local shrub called Melicope ptelefolia, has been previously reported to prevent ovalbumin-induced allergic airway inflammation in a murine model of allergic asthma by targeting cysteinyl leukotriene synthesis. Mast cells are immune effector cells involved in the pathogenesis of allergic diseases including asthma by releasing cysteinyl leukotrienes. The anti-asthmatic properties of tHGA could be attributed to its inhibitory effect on mast cell degranulation. As mast cell degranulation is an important event in allergic responses, this study aimed to investigate the anti-allergic effects of tHGA in cellular and animal models of IgE-mediated mast cell degranulation. For in vitro model of IgE-mediated mast cell degranulation, DNP-IgE-sensitized RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA to induce degranulation. For IgE-mediated passive systemic anaphylaxis, Sprague Dawley rats were sensitized by intraperitoneal injection of DNP-IgE before challenged with DNP-BSA. Both in vitro and in vivo models showed that tHGA significantly inhibited the release of preformed mediators (β-hexosaminidase and histamine) as well as de novo mediators (interleukin-4, tumour necrosis factor-α, prostaglandin D2 and leukotriene C4). Pre-treatment of tHGA also prevented IgE-challenged RBL-2H3 cells and peritoneal mast cells from undergoing morphological changes associated with mast cell degranulation. These findings indicate that tHGA possesses potent anti-allergic activity via attenuation of IgE-mediated mast cell degranulation and inhibition of IgE-mediated passive systemic anaphylaxis. Thus, tHGA may have the potential to be developed as a mast cell stabilizer for the treatment of allergic diseases in the future

LAT is essential for the mast cell stabilising effect of tHGA in IgE-mediated mast cell activation

Mast cells play a central role in the pathogenesis of allergic reaction. Activation of mast cells by antigens is strictly dependent on the influx of extracellular calcium that involves a complex interaction between signalling molecules located within the cells. We have previously reported that tHGA, an active compound originally isolated from a local shrub known as Melicope ptelefolia, prevented IgE-mediated mast cell activation and passive systemic anaphylaxis by suppressing the release of interleukin-4 (IL-4) and tumour necrosis factor (TNF)-α from activated rat basophilic leukaemia (RBL)-2H3 cells. However, the mechanism of action (MOA) as well as the molecular target underlying the mast cell stabilising effect of tHGA has not been previously investigated. In this study, DNP-IgE-sensitised RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA. To dissect the MOA of tHGA in IgE-mediated mast cell activation, the effect of tHGA on the transcription of IL-4 and TNF-α mRNA was determined using Real Time-Polymerase Chain Reaction (qPCR) followed by Calcium Influx Assay to confirm the involvement of calcium in the activation of mast cells. The protein lysates were analysed by using Western Blot to determine the effect of tHGA on various important signalling molecules in the LAT-PLCγ-MAPK and PI3K-NFκB pathways. In order to identify the molecular target of tHGA in IgE-mediated mast cell activation, the LAT and LAT2 genes in RBL-2H3 cells were knocked-down by using RNA interference to establish a LAT/LAT2 competition model. The results showed that tHGA inhibited the transcription of IL-4 and TNF-α as a result of the suppression of calcium influx in activated RBL-2H3 cells. The results from Western Blot revealed that tHGA primarily inhibited the LAT-PLCγ-MAPK pathway with partial inhibition on the PI3K-p65 pathway without affecting Syk. The results from RNAi further demonstrated that tHGA failed to inhibit the release of mediators associated with mast cell degranulation under the LAT/LAT2 competition model in the absence of LAT. Collectively, this study concluded that the molecular target of tHGA could be LAT and may provide a basis for the development of a mast cell stabiliser which targets LAT

A wake-up call: Covid-19 and its impact on reforming biosciences education towards resiliency and sustainability

COVID-19’s global pandemic has had a significant impact on bioscience education, which has switched to online learning. Every entity within the higher education ecosystem, whether technical, pedagogical, or social, has faced a number of challenges as a result of this. Regardless, biosciences education stakeholders have been fast to implement innovative strategies to maintain high standards and quality of biosciences online teaching and learning. This paper focuses on the biosciences education transition toward developing resiliency, as well as the technology resources and approaches that have been deployed in the current context to change biosciences education to be robust in the face of the COVID-19 upheaval. Finally, significant insights into ‘resilience sustainability’ approaches that may be employed in relation to the digitisation of biosciences education in a concerted effort to promote resiliency, adaptability and sustainability in biosciences education are presente

Hypoxia-induced neuroinflammation in Alzheimer’s disease: potential neuroprotective effects of Centella asiatica

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterised by the presence of extracellular beta-amyloid fibrillary plaques and intraneuronal neurofibrillary tau tangles in the brain. Recurring failures of drug candidates targeting these pathways have prompted research in AD multifactorial pathogenesis, including the role of neuroinflammation. Triggered by various factors, such as hypoxia, neuroinflammation is strongly linked to AD susceptibility and/or progression to dementia. Chronic hypoxia induces neuroinflammation by activating microglia, the resident immune cells in the brain, along with an increased in reactive oxygen species and pro-inflammatory cytokines, features that are common to many degenerative central nervous system (CNS) disorders. Hence, interests are emerging on therapeutic agents and plant derivatives for AD that target the hypoxia-neuroinflammation pathway. Centella asiatica is one of the natural products reported to show neuroprotective effects in various models of CNS diseases. Here, we review the complex hypoxia-induced neuroinflammation in the pathogenesis of AD and the potential application of Centella asiatica as a therapeutic agent in AD or dementia

Annexin A2 extracellular translocation and virus interaction: a potential target for antivirus‐drug discovery

Annexin A2 is a membrane scaffolding and binding protein, which mediated various cellular events. Its functions are generally affected by cellular localization. In the cytoplasm, they interacted with different phospholipid membranes in Ca2+‐dependent manner and play vital roles including actin binding, remodeling and dynamics, cytoskeletal rearrangement, and lipid‐raft microdomain formation. However, upon cell exposure to certain stimuli, annexin A2 translocates to the external leaflets of the plasma membrane where annexin A2 was recently reported to serve as a virus receptor, play an important role in the formation of virus replication complex, or implicated in virus assembly and budding. Here, we review some of annexin A2 roles in virus infections and the potentiality of targeting annexin A2 in the design of novel and promising antivirus agent that may have a broader consequence in virus therapy

Annexin II as a dengue virus serotype 2 interacting protein mediating virus interaction on Vero cells

Recent evidence has demonstrated that dengue virus requires active filopodia formation for a successful infection. However, the cellular factor involved in the interaction has not been fully elucidated. We used a combination of virus overlay protein binding assay and LC-MS/MS, and identified annexin II as a dengue virus serotype 2 (DENV2) interacting protein on Vero cells, upon filopodia induction. Flow cytometry analysis showed annexin II on the Vero cells surface increased when DENV2 was added. The amount of annexin II in the plasma membrane fraction was reduced as the infection progressed. Antibody-mediated inhibition of infection and siRNA-mediated knockdown of annexin II expression significantly reduced DENV2 infection and production levels. Collectively, we demonstrated that annexin II is one of the host factor involved in DENV2 binding on Vero cells

Zerumbone induces cytotoxicity and inhibits cell migration of human colon cancer cells

Colon cancer is the second leading cause of cancer death among males and females. Survival in colorectal cancer patients is poor and greatly affected by its metastasis. Zerumbone (ZER) is an active compound isolated from the essential volatile oil of an edible ginger plant, Zingiber zerumbet. It is known to exhibit anticancer properties which able to inhibit cancer cell proliferation and induce apoptosis in colon cancer. These findings led us to investigate the ability of ZER to inhibit cell migration in colon cancer cell line. From the MTT results, the IC50 values for HCT116 cells treated with ZER were 8.9 ± 0.3, 18.0 ± 1.2, and 21.3 ± 3.5 µg/mL at 24, 48, and 72 h of incubation, respectively. The results show that the IC 50 was significantly increased (p <0.05) in a time-dependent manner. The treatment of ZER at higher concentration (6 and 9 µg/mL) inhibited the migration of HCT116 cells at 1.5-fold higher compared to that of the untreated cells which reduced in the scratch gap. The characteristic of apoptosis such as cell shrinkage, membrane blabbing, and detachment of cells were observed on HCT116 cells treated with ZER, suggesting that the mode cell death induced by ZER on HCT116 cells might be due to apoptosis. Hence, it is concluded that ZER exhibits cytotoxic effects and inhibits cell migration in colon cancer cells