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Fulltext Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al.

Autophagy, 2016;12(1):1-222.
PMID: 26799652 DOI: 10.1080/15548627.2015.1100356
Fulltext The spatial configuration of local climate zones reveals effects on wayfinding in human walking

Fan PY, Chun KP, Tan ML, Mah DN, Mijic A, Strickert G, et al.

PLoS One, 2023;18(9):e0289780.
PMID: 37682889 DOI: 10.1371/journal.pone.0289780

The importance of easy wayfinding in complex urban settings has been recognized in spatial planning. Empirical measurement and explicit representation of wayfinding, however, have been limited in deciding spatial configurations. Our study proposed and tested an approach to improving wayfinding by incorporating spatial analysis of urban forms in the Guangdong-Hong Kong-Macau Great Bay Area in China. Wayfinding was measured by an indicator of intelligibility using spatial design network analysis. Urban spatial configurations were quantified using landscape metrics to describe the spatial layouts of local climate zones (LCZs) as standardized urban forms. The statistical analysis demonstrated the significant associations between urban spatial configurations and wayfinding. These findings suggested, to improve wayfinding, 1) dispersing LCZ 1 (compact high-rise) and LCZ 2 (compact mid-rise) and 2) agglomerating LCZ 3 (compact low-rise), LCZ 5 (open mid-rise), LCZ 6 (open low-rise), and LCZ 9 (sparsely built). To our knowledge, this study is the first to incorporate the LCZ classification system into the wayfinding field, clearly providing empirically-supported solutions for dispersing and agglomerating spatial configurations. Our findings also provide insights for human-centered spatial planning by spatial co-development at local, urban, and regional levels.
Functionalization of remote sensing and on-site data for simulating surface water dissolved oxygen: Development of hybrid tree-based artificial intelligence models

Tiyasha T, Tung TM, Bhagat SK, Tan ML, Jawad AH, Mohtar WHMW, et al.

Mar Pollut Bull, 2021 Sep;170:112639.
PMID: 34273614 DOI: 10.1016/j.marpolbul.2021.112639

Dissolved oxygen (DO) is an important indicator of river health for environmental engineers and ecological scientists to understand the state of river health. This study aims to evaluate the reliability of four feature selector algorithms i.e., Boruta, genetic algorithm (GA), multivariate adaptive regression splines (MARS), and extreme gradient boosting (XGBoost) to select the best suited predictor of the applied water quality (WQ) parameters; and compare four tree-based predictive models, namely, random forest (RF), conditional random forests (cForest), RANdom forest GEneRator (Ranger), and XGBoost to predict the changes of dissolved oxygen (DO) in the Klang River, Malaysia. The total features including 15 WQ parameters from monitoring site data and 7 hydrological components from remote sensing data. All predictive models performed well as per the features selected by the algorithms XGBoost and MARS in terms applied statistical evaluators. Besides, the best performance noted in case of XGBoost predictive model among all applied predictive models when the feature selected by MARS and XGBoost algorithms, with the coefficient of determination (R2) values of 0.84 and 0.85, respectively, nonetheless the marginal performance came up by Boruta-XGBoost model on in this scenario.
Megacities' environmental assessment for Iraq region using satellite image and geo-spatial tools

Tao H, Hashim BM, Heddam S, Goliatt L, Tan ML, Sa'adi Z, et al.

Environ Sci Pollut Res Int, 2023 Mar;30(11):30984-31034.
PMID: 36441299 DOI: 10.1007/s11356-022-24153-8

Urban areas are quickly established, and the overwhelming population pressure is triggering heat stress in the metropolitan cities. Climate change impact is the key aspect for maintaining the urban areas and building proper urban planning because spreading of the urban area destroyed the vegetated land and increased heat variation. Remote sensing-based on Landsat images are used for investigating the vegetation circumstances, thermal variation, urban expansion, and surface urban heat island or SUHI in the three megacities of Iraq like Baghdad, Erbil, and Basrah. Four satellite imageries are used aimed at land use and land cover (LULC) study from 1990 to 2020, which indicate the land transformation of those three major cities in Iraq. The average annually temperature is increased during 30 years like Baghdad (0.16 °C), Basrah (0.44 °C), and Erbil (0.32 °C). The built-up area is increased 147.1 km2 (Erbil), 217.86 km2 (Baghdad), and 294.43 km2 (Erbil), which indicated the SUHI affects the entire area of the three cities. The bare land is increased in Baghdad city, which indicated the local climatic condition and affected the livelihood. Basrah City is affected by anthropogenic activities and most areas of Basrah were converted into built-up land in the last 30 years. In Erbil, agricultural land (295.81 km2) is increased. The SUHI study results indicated the climate change effect in those three cities in Iraq. This study's results are more useful for planning, management, and sustainable development of urban areas.
Fulltext Machine learning-based country-level annual air pollutants exploration using Sentinel-5P and Google Earth Engine

Halder B, Ahmadianfar I, Heddam S, Mussa ZH, Goliatt L, Tan ML, et al.

Sci Rep, 2023 May 17;13(1):7968.
PMID: 37198391 DOI: 10.1038/s41598-023-34774-9

Climatic condition is triggering human health emergencies and earth's surface changes. Anthropogenic activities, such as built-up expansion, transportation development, industrial works, and some extreme phases, are the main reason for climate change and global warming. Air pollutants are increased gradually due to anthropogenic activities and triggering the earth's health. Nitrogen Dioxide (NO2), Carbon Monoxide (CO), and Aerosol Optical Depth (AOD) are truthfully important for air quality measurement because those air pollutants are more harmful to the environment and human's health. Earth observational Sentinel-5P is applied for monitoring the air pollutant and chemical conditions in the atmosphere from 2018 to 2021. The cloud computing-based Google Earth Engine (GEE) platform is applied for monitoring those air pollutants and chemical components in the atmosphere. The NO2 variation indicates high during the time because of the anthropogenic activities. Carbon Monoxide (CO) is also located high between two 1-month different maps. The 2020 and 2021 results indicate AQI change is high where 2018 and 2019 indicates low AQI throughout the year. The Kolkata have seven AQI monitoring station where high nitrogen dioxide recorded 102 (2018), 48 (2019), 26 (2020) and 98 (2021), where Delhi AQI stations recorded 99 (2018), 49 (2019), 37 (2020), and 107 (2021). Delhi, Kolkata, Mumbai, Pune, and Chennai recorded huge fluctuations of air pollutants during the study periods, where ~ 50-60% NO2 was recorded as high in the recent time. The AOD was noticed high in Uttar Pradesh in 2020. These results indicate that air pollutant investigation is much necessary for future planning and management otherwise; our planet earth is mostly affected by the anthropogenic and climatic conditions where maybe life does not exist.
Coupling SWAT and Bi-LSTM for improving daily-scale hydro-climatic simulation and climate change impact assessment in a tropical river basin

Yang S, Tan ML, Song Q, He J, Yao N, Li X, et al.

J Environ Manage, 2023 Mar 15;330:117244.
PMID: 36621311 DOI: 10.1016/j.jenvman.2023.117244

Global climate change has led to an increase in both the frequency and magnitude of extreme events around the world, the risk of which is especially imminent in tropical regions. Developing hydrological models with better capabilities to simulate streamflow, especially peak flow, is urgently needed to facilitate water resource planning and management as well as climate change mitigation efforts in the tropics. In view of the need, this paper explores the feasibility of improving streamflow simulation performance in the tropical Kelantan River Basin (KRB) of Peninsular Malaysia through coupling a conceptual process-based hydrological model - Soil and Water Assessment Tool (SWAT) with a deep learning model - Bidirectional Long Short-Term Memory (Bi-LSTM) in two ways. All SWAT parameters were set as their default values in one hybrid model (SWAT-D-LSTM), whereas three most sensitive SWAT parameters were calibrated in the other hybrid model (SWAT-T-LSTM). Comparison of daily streamflow simulation results have shown that SWAT-T-LSTM consistently performs better than SWAT-D-LSTM as well as the stand-alone SWAT and Bi-LSTM model throughout the simulation period. Particularly, SWAT-T-LSTM performs considerably better than the other three models in simulating daily peak flow. Based on the latest projection results of five GCMs from the Sixth Phase of the Coupled Model Intercomparison Project (CMIP6) under three emission scenarios (SSP1-2.6, SSP2-4.5, SSP5-8.5), the best-performed SWAT-T-LSTM was run to assess the potential impacts of climate change on streamflow in the KRB. Ensemble assessment results have concluded that both average and extreme streamflow is much likely to increase considerably in the already wet northeast monsoon season from November to January, which has surely raised the alarm for more frequent flood occurrence in the KRB.
Fulltext Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling

Hariono M, Choi SB, Roslim RF, Nawi MS, Tan ML, Kamarulzaman EE, et al.

PLoS One, 2019;14(1):e0210869.
PMID: 30677071 DOI: 10.1371/journal.pone.0210869

Dengue virus Type 2 (DENV-2) is predominant serotype causing major dengue epidemics. There are a number of studies carried out to find its effective antiviral, however to date, there is still no molecule either from peptide or small molecules released as a drug. The present study aims to identify small molecules inhibitor from National Cancer Institute database through virtual screening. One of the hits, D0713 (IC50 = 62 μM) bearing thioguanine scaffold was derivatised into 21 compounds and evaluated for DENV-2 NS2B/NS3 protease inhibitory activity. Compounds 18 and 21 demonstrated the most potent activity with IC50 of 0.38 μM and 16 μM, respectively. Molecular dynamics and MM/PBSA free energy of binding calculation were conducted to study the interaction mechanism of these compounds with the protease. The free energy of binding of 18 calculated by MM/PBSA is -16.10 kcal/mol compared to the known inhibitor, panduratin A (-11.27 kcal/mol), which corroborates well with the experimental observation. Results from molecular dynamics simulations also showed that both 18 and 21 bind in the active site and stabilised by the formation of hydrogen bonds with Asn174.
Fulltext Advanced Nanoparticle-Based Drug Delivery Systems and Their Cellular Evaluation for Non-Small Cell Lung Cancer Treatment

Mohtar N, Parumasivam T, Gazzali AM, Tan CS, Tan ML, Othman R, et al.

Cancers (Basel), 2021 Jul 15;13(14).
PMID: 34298753 DOI: 10.3390/cancers13143539

Lung cancers, the number one cancer killer, can be broadly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC being the most commonly diagnosed type. Anticancer agents for NSCLC suffer from various limitations that can be partly overcome by the application of nanomedicines. Nanoparticles is a branch within nanomedicine that can improve the delivery of anticancer drugs, whilst ensuring the stability and sufficient bioavailability following administration. There are many publications available in the literature exploring different types of nanoparticles from different materials. The effectiveness of a treatment option needs to be validated in suitable in vitro and/or in vivo models. This includes the developed nanoparticles, to prove their safety and efficacy. Many researchers have turned towards in vitro models that use normal cells or specific cells from diseased tissues. However, in cellular works, the physiological dynamics that is available in the body could not be mimicked entirely, and hence, there is still possible development of false positive or false negative results from the in vitro models. This article provides an overview of NSCLC, the different nanoparticles available to date, and in vitro evaluation of the nanoparticles. Different types of cells suitable for in vitro study and the important precautions to limit the development of false results are also extensively discussed.
Fulltext Polyunsaturated fatty acids (PUFAs) for children with specific learning disorders

Tan ML, Ho JJ, Teh KH

Cochrane Database Syst Rev, 2016 Sep 28;9:CD009398.
PMID: 27678554 DOI: 10.1002/14651858.CD009398.pub3

BACKGROUND: About 5% of school children have a specific learning disorder, defined as unexpected failure to acquire adequate abilities in reading, writing or mathematics that is not a result of reduced intellectual ability, inadequate teaching or social deprivation. Of these events, 80% are reading disorders. Polyunsaturated fatty acids (PUFAs), in particular, omega-3 and omega-6 fatty acids, which normally are abundant in the brain and in the retina, are important for learning. Some children with specific learning disorders have been found to be deficient in these PUFAs, and it is argued that supplementation of PUFAs may help these children improve their learning abilities.
OBJECTIVES: 1. To assess effects on learning outcomes of supplementation of polyunsaturated fatty acids (PUFAs) for children with specific learning disorders.2. To determine whether adverse effects of supplementation of PUFAs are reported in these children.
SEARCH METHODS: In November 2015, we searched CENTRAL, Ovid MEDLINE, Embase, PsycINFO, 10 other databases and two trials registers. We also searched the reference lists of relevant articles.
SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing PUFAs with placebo or no treatment in children younger than 18 years with specific learning disabilities, as diagnosed in accordance with the fifth (or earlier) edition of theDiagnostic and Statistical Manual of Mental Disorders (DSM-5), or the 10th (or earlier) revision of the International Classification of Diseases (ICD-10) or equivalent criteria. We included children with coexisting developmental disorders such as attention deficit hyperactivity disorder (ADHD) or autism.
DATA COLLECTION AND ANALYSIS: Two review authors (MLT and KHT) independently screened the titles and abstracts of articles identified by the search and eliminated all studies that did not meet the inclusion criteria. We contacted study authors to ask for missing information and clarification, when needed. We used the GRADE approach to assess the quality of evidence.
MAIN RESULTS: Two small studies involving 116 children, mainly boys between 10 and 18 years of age, met the inclusion criteria. One study was conducted in a school setting, the other at a specialised clinic. Both studies used three months of a combination of omega-3 and omega-6 supplements as the intervention compared with placebo. Although both studies had generally low risk of bias, we judged the risk of reporting bias as unclear in one study, and as high in the other study. In addition, one of the studies was funded by industry and reported active company involvement in the study.None of the studies reported data on the primary outcomes of reading, writing, spelling and mathematics scores, as assessed by standardised tests.Evidence of low quality indicates that supplementation of PUFAs did not increase the risk of gastrointestinal disturbances (risk ratio 1.43, 95% confidence interval 0.25 to 8.15; two studies, 116 children). Investigators reported no other adverse effects.Both studies reported attention deficit hyperactivity disorder (ADHD)-related behaviour outcomes. We were unable to combine the results in a meta-analysis because one study reported findings as a continuous outcome, and the other as a dichotomous outcome. No other secondary outcomes were reported.We excluded one study because it used a cointervention (carnosine), and five other studies because they did not provide a robust diagnosis of a specific learning disorder. We identified one ongoing study and found three studies awaiting classification.
AUTHORS' CONCLUSIONS: Evidence is insufficient to permit any conclusions about the effect of PUFAs on the learning abilities of children with specific learning disorders. Well-designed RCTs with clearly defined populations of children with specific learning disorders who have been diagnosed by standardised diagnostic criteria are needed.
Mitragynine and its potential blocking effects on specific cardiac potassium channels

Tay YL, Teah YF, Chong YM, Jamil MFA, Kollert S, Adenan MI, et al.

Toxicol Appl Pharmacol, 2016 08 15;305:22-39.
PMID: 27260674 DOI: 10.1016/j.taap.2016.05.022

Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac IKr current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, IK1, a Kir current mediated by Kir2.1 channel and IKACh, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC50 value of 1.62μM and 1.15μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit IKACh current with an IC50 value of 3.32μM but has no significant effects on IK1. Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks.
Fulltext Cytochrome P450 induction properties of food and herbal-derived compounds using a novel multiplex RT-qPCR in vitro assay, a drug-food interaction prediction tool

Koe XF, Tengku Muhammad TS, Chong AS, Wahab HA, Tan ML

Food Sci Nutr, 2014 Sep;2(5):500-20.
PMID: 25473508 DOI: 10.1002/fsn3.122

A multiplex RT-qPCR was developed to examine CYP1A2, CYP2D6, and CYP3A4 induction properties of compounds from food and herbal sources. The induction of drug metabolizing enzymes is an important pharmacokinetic interaction with unique features in comparison with inhibition of metabolizing enzymes. Cytochrome induction can lead to serious drug-drug or drug-food interactions, especially if the coadministered drug plasma level is critical as it can reduce therapeutic effects and cause complications. Using this optimized multiplex RT-qPCR, cytochrome induction properties of andrographolide, curcumin, lycopene, bergamottin, and resveratrol were determined. Andrographolide, curcumin, and lycopene produced no significant induction effects on CYP1A2, CYP2D6, and CYP3A4. However, bergamottin appeared to be a significant in vitro CYP1A2 inducer starting from 5 to 50 μmol/L with induction ranging from 60 to 100-fold changes. On the other hand, resveratrol is a weak in vitro CYP1A2 inducer. Examining the cytochrome induction properties of food and herbal compounds help complement CYP inhibition studies and provide labeling and safety caution for such products.
The mTOR signalling pathway in cancer and the potential mTOR inhibitory activities of natural phytochemicals

Tan HK, Moad AI, Tan ML

Asian Pac J Cancer Prev, 2014;15(16):6463-75.
PMID: 25169472

The mammalian target of rapamycin (mTOR) kinase plays an important role in regulating cell growth and cell cycle progression in response to cellular signals. It is a key regulator of cell proliferation and many upstream activators and downstream effectors of mTOR are known to be deregulated in various types of cancers. Since the mTOR signalling pathway is commonly activated in human cancers, many researchers are actively developing inhibitors that target key components in the pathway and some of these drugs are already on the market. Numerous preclinical investigations have also suggested that some herbs and natural phytochemicals, such as curcumin, resveratrol, timosaponin III, gallic acid, diosgenin, pomegranate, epigallocatechin gallate (EGCC), genistein and 3,3'-diindolylmethane inhibit the mTOR pathway either directly or indirectly. Some of these natural compounds are also in the clinical trial stage. In this review, the potential anti-cancer and chemopreventive activities and the current status of clinical trials of these phytochemicals are discussed.
Fulltext Analytical modeling of glucose biosensors based on carbon nanotubes

Pourasl AH, Ahmadi MT, Rahmani M, Chin HC, Lim CS, Ismail R, et al.

Nanoscale Res Lett, 2014 Jan 15;9(1):33.
PMID: 24428818 DOI: 10.1186/1556-276X-9-33

In recent years, carbon nanotubes have received widespread attention as promising carbon-based nanoelectronic devices. Due to their exceptional physical, chemical, and electrical properties, namely a high surface-to-volume ratio, their enhanced electron transfer properties, and their high thermal conductivity, carbon nanotubes can be used effectively as electrochemical sensors. The integration of carbon nanotubes with a functional group provides a good and solid support for the immobilization of enzymes. The determination of glucose levels using biosensors, particularly in the medical diagnostics and food industries, is gaining mass appeal. Glucose biosensors detect the glucose molecule by catalyzing glucose to gluconic acid and hydrogen peroxide in the presence of oxygen. This action provides high accuracy and a quick detection rate. In this paper, a single-wall carbon nanotube field-effect transistor biosensor for glucose detection is analytically modeled. In the proposed model, the glucose concentration is presented as a function of gate voltage. Subsequently, the proposed model is compared with existing experimental data. A good consensus between the model and the experimental data is reported. The simulated data demonstrate that the analytical model can be employed with an electrochemical glucose sensor to predict the behavior of the sensing mechanism in biosensors.
Andrographolide and 14-deoxy-11, 12-didehydroandrographolide inhibit cytochrome P450s in HepG2 hepatoma cells

Ooi JP, Kuroyanagi M, Sulaiman SF, Muhammad TS, Tan ML

Life Sci, 2011 Feb 28;88(9-10):447-54.
PMID: 21219911 DOI: 10.1016/j.lfs.2010.12.019

Cytochrome P450 (CYP) enzymes have been implicated in a large number of preventable drug-herb interactions. Andrographis paniculata Nees, a tropical herb widely used for various health conditions contains two major diterpenoids, andrographolide and 14-Deoxy-11, 12-Didehydroandrographolide. These compounds were evaluated systematically for their effects on CYP1A2, CYP2D6 and CYP3A4 expressions in HepG2 cells.
In vitro evaluation of cytochrome P450 induction and the inhibition potential of mitragynine, a stimulant alkaloid

Lim EL, Seah TC, Koe XF, Wahab HA, Adenan MI, Jamil MF, et al.

Toxicol In Vitro, 2013 Mar;27(2):812-24.
PMID: 23274770 DOI: 10.1016/j.tiv.2012.12.014

CYP450 enzymes are key determinants in drug toxicities, reduced pharmacological effect and adverse drug reactions. Mitragynine, an euphoric compound was evaluated for its effects on the expression of mRNAs encoding CYP1A2, CYP2D6 and CYP3A4 and protein expression and resultant enzymatic activity. The mRNA and protein expression of CYP450 isoforms were carried out using an optimized multiplex qRT-PCR assay and Western blot analysis. CYP1A2 and CYP3A4 enzyme activities were evaluated using P450-Glo™ assays. The effects of mitragynine on human CYP3A4 protein expression were determined using an optimized hCYP3A4-HepG2 cell-based assay. An in silico computational method to predict the binding conformation of mitragynine to the active site of the CYP3A4 enzyme was performed and further validated using in vitro CYP3A4 inhibition assays. Mitragynine was found to induce mRNA and protein expression of CYP1A2. For the highest concentration of 25 μM, induction of mRNA was approximately 70% that of the positive control and was consistent with the increased CYP1A2 enzymatic activity. Thus, mitragynine is a significant in vitro CYP1A2 inducer. However, it appeared to be a weak CYP3A4 inducer at the transcriptional level and a weak CYP3A4 enzyme inhibitor. It is therefore, unlikely to have any significant clinical effects on CYP3A4 activity.
14-Deoxy-11,12-didehydroandrographolide induces DDIT3-dependent endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma cells

Tan HK, Muhammad TST, Tan ML

Toxicol Appl Pharmacol, 2016 06 01;300:55-69.
PMID: 27049118 DOI: 10.1016/j.taap.2016.03.017

14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells.
Fulltext Cytotoxic data of 14-deoxy-11, 12-didehydroandrographolide (14-DDA), double transfection and DDIT3 silencing data in T-47D breast carcinoma cells

Tan HK, Tengku Muhammad TS, Tan ML

Data Brief, 2016 Jun;7:1506-10.
PMID: 27182548 DOI: 10.1016/j.dib.2016.04.046

The data presented in this article are related to the research article entitled "14-deoxy-11,12-didehydroandrographolide induces DDIT3-dependent endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma cells", which the mechanistic toxicology properties of 14-deoxy-11,12-didehydroandrographolide (14-DDA) were investigated (Tan et al., 2016 [1]). This article describes the derivation of cytotoxic parameters of 14-DDA, cell viability data after double transfection and DDIT3 silencing in T-47D cells.
Fulltext Immunohistochemical expression of MAP1LC3A and MAP1LC3B protein in breast carcinoma tissues

Othman EQ, Kaur G, Mutee AF, Muhammad TS, Tan ML

J Clin Lab Anal, 2009;23(4):249-58.
PMID: 19623642 DOI: 10.1002/jcla.20309

Autophagy is a protein degradation process within the cell and its deregulation has been linked to various diseases and the formation of cancer. One of the important proteins involved in the autophagy process is microtubule-associated protein 1 light chain 3 (MAP1LC3). The aims of this study were to determine the MAP1LC3A and MAP1LC3B protein expression in both normal and cancer breast tissues and to determine the relationship between the expression of these proteins and type of tissues. Immunohistochemistry assessments were carried out on tissue microarrays consisting of breast tissues. MAP1LC3A expression was detected in 52/56 of normal breast tissue cores and 65/67 of breast cancer tissue cores. MAP1LC3B expression was detected in 55/56 of normal breast tissue cores and 67/67 of breast cancer tissue cores. MAP1LC3A and MAP1LC3B protein are expressed in the majority of normal and cancer breast tissues. A large number of MAP1LC3A and MAP1LC3B positive breast cancer tissues cores have high proportion of stained cells (81-100%) as compared with normal breast tissues. However, a significantly higher number of breast cancer tissues were found to express the MAP1LC3A protein with strong immunoreactivity as compared with the normal tissues, suggesting that MAP1LC3A may play a role in breast cancer development.
Fulltext Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells

Tay YL, Amanah A, Adenan MI, Wahab HA, Tan ML

Sci Rep, 2019 12 24;9(1):19757.
PMID: 31874991 DOI: 10.1038/s41598-019-56106-6

Mitragyna speciosa Korth (M. speciosa) has been widely used as a recreational product, however, there are growing concerns on the abuse potentials and toxicity of the plant. Several poisoning and fatal cases involving kratom and mitragynine have been reported but the underlying causes remain unclear. The human ether-a-go-go-related gene 1 (hERG1) encodes the pore-forming subunit underlying cardiac rapidly delayed rectifier potassium current (IKr). Pharmacological blockade of the IKr can cause acquired long QT syndrome, leading to lethal cardiac arrhythmias. This study aims to elucidate the mechanisms of mitragynine-induced inhibition on hERG1a/1b current. Electrophysiology experiments were carried out using Port-a-Patch system. Quantitative RT-PCR, Western blot analysis, immunofluorescence and co-immunoprecipitation methods were used to determine the effects of mitragynine on hERG1a/1b expression and hERG1-cytosolic chaperones interaction. Mitragynine was found to inhibit the IKr current with an IC50 value of 332.70 nM. It causes a significant reduction of the fully-glycosylated (fg) hERG1a protein expression but upregulates both core-glycosylated (cg) expression and hERG1a-Hsp90 complexes, suggesting possible impaired hERG1a trafficking. In conclusion, mitragynine inhibits hERG1a/1b current through direct channel blockade at lower concentration, but at higher concentration, it upregulates the complexation of hERG1a-Hsp90 which may be inhibitory towards channel trafficking.
The inhibitory effects of mitragynine on P-glycoprotein in vitro

Rusli N, Amanah A, Kaur G, Adenan MI, Sulaiman SF, Wahab HA, et al.

Naunyn Schmiedebergs Arch Pharmacol, 2019 04;392(4):481-496.
PMID: 30604191 DOI: 10.1007/s00210-018-01605-y

Mitragynine is a major component isolated from Mitragyna speciosa Korth or kratom, a medicinal plant known for its opiate-like and euphoric properties. Multiple toxicity and fatal cases involving mitragynine or kratom have been reported but the underlying causes remain unclear. P-glycoprotein (P-gp) is a multidrug transporter which modulates the pharmacokinetics of xenobiotics and plays a key role in mediating drug-drug interactions. This study investigated the effects of mitragynine on P-gp transport activity, mRNA, and protein expression in Caco-2 cells using molecular docking, bidirectional assay, RT-qPCR, Western blot analysis, and immunocytochemistry techniques, respectively. Molecular docking simulation revealed that mitragynine interacts with important residues at the nucleotide binding domain (NBD) site of the P-gp structure but not with the residues from the substrate binding site. This was consistent with subsequent experimental work as mitragynine exhibited low permeability across the cell monolayer but inhibited digoxin transport at 10 μM, similar to quinidine. The reduction of P-gp activity in vitro was further contributed by the downregulation of mRNA and protein expression of P-gp. In summary, mitragynine is likely a P-gp inhibitor in vitro but not a substrate. Hence, concurrent administration of mitragynine-containing kratom products with psychoactive drugs which are P-gp substrates may lead to clinically significant toxicity. Further clinical study to prove this point is needed.

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