Targeting energy metabolism to eliminate cancer cells

Adaptive metabolic responses toward a low oxygen environment are essential to maintain rapid proliferation and are relevant for tumorigenesis. Reprogramming of core metabolism in tumors confers a selective growth advantage such as the ability to evade apoptosis and/or enhance cell proliferation and promotes tumor growth and progression. One of the mechanisms that contributes to tumor growth is the impairment of cancer cell metabolism. In this review, we outline the small-molecule inhibitors identified over the past decade in targeting cancer cell metabolism and the usage of some of these molecules in clinical trials

The cytotoxic effect and glucose uptake modulation of Baeckea frutescens on breast cancer cells

Background: Baeckea frutescens (B. frutescens) of the family Myrtaceae is a plant that has been used in traditionalmedicine. It is known to have antibacterial, antipyretic and cytoprotective properties. The objective of this study isto explore the mechanism of B. frutescens leaves extracts in eliminating breast cancer cells. Method: B. frutescens leaves extracts were prepared using Soxhlet apparatus with solvents of different polarity. The selective cytotoxicity of these extracts at various concentrations (20 to 160 μg/ml) were tested using cell viability assay after 24, 48 and 72 h of treatment. The IC50 value in human breast cancer (MCF-7 and MDA-MB-231) and mammary breast (MCF10A) cell lines were determined. Apoptotic study using AO/PI double staining was performed using fluorescent microscope. The glucose uptake was measured using 2-NBDG, a fluorescent glucose analogue. The phytochemical screening was performed for alkaloids, flavonoids, tannins, triterpenoids, and phenols. Results: B. frutescens leaves extracts showed IC50 value ranging from 10 -127μg/ml in MCF-7 cells after 72 h of treatment. Hexane extract had the lowest IC50 value (10μg/ml), indicating its potent selective cytotoxic activity. Morphology of MCF-7 cells after treatment with B. frutescens extracts exhibited evidence of apoptosis that included membrane blebbing and chromatin condensation. In the glucose uptake assay, B. frutescens extracts suppressed glucose uptake in cancer cells as early as 24 h upon treatment. The inhibition was significantly lower compared to the positive control WZB117 at their respective IC50 value after 72 h incubation. It was also shown that the glucose inhibition is selective towards cancer cells compared to normal cells. The phytochemical analysis of the extract using hexane as the solvent in particular gave similar quantities of tannin, triterpenoids, flavonoid and phenols. Presumably, these metabolites have a synergistic effect in the in vitro testing, producing the potent IC50 value and subsequently cell death. Conclusion: This study reports the potent selective cytotoxic effect of B. frutescens leaves hexane extract against MCF-7 cancer cells. B. frutescens extracts selectively suppressed cancer cells glucose uptake and subsequently induced cancer cell death. These findings suggest a new role of B. frutescens in cancer cell metabolis

Colonization of Methicillin-Resistant Staphylococcus aureus (MRSA) among medical students in tertiary institution in Central Malaysia

Methicillin-resistant Staphylococcus aureus or MRSA infection is virulent and presents with a broad spectrum of severity. Limited regional reports that specifically outlined the potential risk of medical students being part of the dissemination of MRSA in healthcare settings were noted. This study aims to assess the prevalence and contributory factors of colonization of MRSA on neckties, headscarves, and ID badges among medical students in a local medical university in Malaysia. A cross-sectional study was conducted involving 256 medical students. A validated questionnaire was used to collect the data, and sample swabs were collected between July and August 2013 by swabbing neckties, headscarves, or identification badges. The swabs were then streaked onto mannitol salt agar (MSA) and incubated at 37 °C overnight. Out of 433 samples taken, 40 swabs (9.24%) were positive for Staphylococcus aureus. Out of the 40 swabs, five (12.5%) isolates were MRSA (one culture was isolated from the headscarf of a preclinical student, one culture was isolated from the necktie of clinical students, while the remaining three were isolated from identification badges of clinical students. There was no significant association between age, gender, ethnicity, and phase of medical students with the colonization of MRSA (p > 0.05). There was a significant association between knowledge score on hand hygiene practice and phase of medical students. MRSA colonies were present on neckties, headscarves, and identification badges of medical students of all phases. The findings from this study suggest the need for improvement of hand hygiene knowledge and discontinuity of mandatory use of physical ID badges and neckties among medical students

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

Expression of autophagy and mitophagy markers in breast cancer tissues

Mitochondria play important roles in regulating cell bioenergetics status and reactive oxygen species (ROS) generation. ROS-induced mitochondrial damage is among the main intracellular signal inducers of autophagy. Autophagy is a cellular catabolic process that regulates protein and organelle turnover, while a selective form of autophagy, mitophagy, specifically targets dysfunctional mitochondrial degradation. This study aims to measure the levels of autophagy, mitophagy, oxidative stress, and apoptosis in invasive breast carcinoma tissues using immunohistochemistry (IHC). Tissue microarrays of 76 patients with breast cancer were stained with six IHC markers (MnSOD, Beclin-1, LC3, BNIP3, Parkin, and cleaved caspase 3). The expression intensity was determined for each tumor tissue and the adjacent tumor-matched control tissues. Intermediate and strong staining scores of MnSOD, Beclin-1, LC-3, BNIP-3, and Parkin were significantly higher in tumor tissues compared to the adjacent matched control. The scoring intensity was further classified into tissues with negative staining and positive staining, which showed that positive scores of Beclin-1 and Parkin were significantly high in tumor tissues compared to other markers. Positive association was also noted between BNIP-3 and Beclin-1 as well as LC-3 and cleaved caspase-3 immunostaining. To our knowledge, this is one of the first studies that measure both mitophagy and autophagy in the same breast cancer tissues and the adjacent matched control. The findings from this study will be of great potential in identifying new cancer biomarkers and inspire significant interest in applying anti-autophagy therapies as a possible treatment for breast cancer

The p53 response: a new mitochondrial role for cofactor strap

Strap is a DNA damage responsive p53 cofactor, reflecting its control by the DNA damage signalling pathway. This study identified Strap at the mitochondria where it is damage regulated and can augment p53-dependent cytochrome c release leading to apoptosis. Moreover, p53 and Strap facilitate each other’s localisation from the mitochondria to the nucleus during the DNA damage response. Two ATM/ATR phosphorylation consensus sites in Strap were identified by mass spectrometry and phosphorylation of all the ATM/ATR consensus sites resulted in mitochondrial localisation of Strap during DNA damage. Targeting Strap to the mitochondria depletes cellular ATP when cells favour energy production through oxidative phosphorylation and sensitises cells to p53-dependent damage-induced apoptosis. These results thus imply that Strap co-ordinates different arms of the p53 response, and might be responsible for integrating its mitochondrial and nuclear functions.</p

The p53 response: a new mitochondrial role for cofactor strap

Strap is a DNA damage responsive p53 cofactor, reflecting its control by the DNA damage signalling pathway. This study identified Strap at the mitochondria where it is damage regulated and can augment p53-dependent cytochrome c release leading to apoptosis. Moreover, p53 and Strap facilitate each other’s localisation from the mitochondria to the nucleus during the DNA damage response. Two ATM/ATR phosphorylation consensus sites in Strap were identified by mass spectrometry and phosphorylation of all the ATM/ATR consensus sites resulted in mitochondrial localisation of Strap during DNA damage. Targeting Strap to the mitochondria depletes cellular ATP when cells favour energy production through oxidative phosphorylation and sensitises cells to p53-dependent damage-induced apoptosis. These results thus imply that Strap co-ordinates different arms of the p53 response, and might be responsible for integrating its mitochondrial and nuclear functions.This thesis is not currently available in ORA

A systematic review of the effects of Equol (Soy Metabolite) on breast cancer

Equol is a soy isoflavone metabolite that can be produced by intestinal bacteria. It is lipophilic and resembles natural oestrogens with an affinity to oestrogen receptors. This review is focused on how equol affects breast cancer, as evidenced by in vivo and in vitro studies. Equol is considered chemoprotective in specific endocrine-related pathologies, such as breast cancer, prostate cancer, cardiovascular diseases, and menopausal symptoms. In humans, not everyone can produce equol from gut metabolism. It is postulated that equol producers benefit more than non-equol producers for all the endocrine-related effects. Equol exists in two enantiomers of R-equol and S-equol. Earlier studies, however, did not specify which enantiomer was being used. This review considers equol’s type and concentration variations, pathways affected, and its outcome in in vivo and in vitro studies

Systematic review on e-cigarette and its effects on weight gain and adipocytes.

Smoking and obesity are leading causes of morbidity and mortality worldwide. E-cigarette which was first introduced in 2000s is perceived as an effective alternative to conventional tobacco smoking. Limited knowledge is available regarding the risks and benefits of e-cigarettes. This study systematically reviews the current literature on the effects of e-cigarettes on body weight changes and adipocytes. The search was performed using OVID Medline and Scopus databases and studies meeting the inclusion criteria were independently assessed. This review included all English language, empirical quantitative and qualitative papers that investigated the effects of e-cigarettes on bodyweight or lipid accumulation or adipocytes. Literature searches identified 4965 references. After removing duplicates and screening for eligibility, thirteen references which involve human, in vivo and in vitro studies were reviewed and appraised. High prevalence of e-cigarette was reported in majority of the cross sectional studies conducted among respondent who are obese or overweight. More conclusive findings were identified in in vivo studies with e-cigarette causing weight decrease. However, these observations were not supported by in vitro data. Hence, the effect of e-cigarette on body weight changes warrants further investigations. Well-designed population and molecular studies are needed to further elucidate the role of e-cigarettes in obesity

A Systematic Review of the Effects of Equol (Soy Metabolite) on Breast Cancer

Equol is a soy isoflavone metabolite that can be produced by intestinal bacteria. It is lipophilic and resembles natural oestrogens with an affinity to oestrogen receptors. This review is focused on how equol affects breast cancer, as evidenced by in vivo and in vitro studies. Equol is considered chemoprotective in specific endocrine-related pathologies, such as breast cancer, prostate cancer, cardiovascular diseases, and menopausal symptoms. In humans, not everyone can produce equol from gut metabolism. It is postulated that equol producers benefit more than non-equol producers for all the endocrine-related effects. Equol exists in two enantiomers of R-equol and S-equol. Earlier studies, however, did not specify which enantiomer was being used. This review considers equol’s type and concentration variations, pathways affected, and its outcome in in vivo and in vitro studies