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Fulltext A Precise Prediction Method for the Properties of API-Containing Tablets Based on Data from Placebo Tablets

Hayashi Y, Shirotori K, Kosugi A, Kumada S, Leong KH, Okada K, et al.

Pharmaceutics, 2020 Jun 28;12(7).
PMID: 32605318 DOI: 10.3390/pharmaceutics12070601

We previously reported a novel method for the precise prediction of tablet properties (e.g., tensile strength (TS)) using a small number of experimental data. The key technique of this method is to compensate for the lack of experimental data by using data of placebo tablets collected in a database. This study provides further technical knowledge to discuss the usefulness of this prediction method. Placebo tablets consisting of microcrystalline cellulose, lactose, and cornstarch were prepared using the design of an experimental method, and their TS and disintegration time (DT) were measured. The response surfaces representing the relationship between the formulation and the tablet properties were then created. This study investigated tablets containing four different active pharmaceutical ingredients (APIs) with a drug load ranging from 20-60%. Overall, the TS of API-containing tablets could be precisely predicted by this method, while the prediction accuracy of the DT was much lower than that of the TS. These results suggested that the mode of action of APIs on the DT was more complicated than that on the TS. Our prediction method could be valuable for the development of tablet formulations.
Fulltext A Time-Domain NMR Study of the State of Water in Wet Granules with Different Fillers and Its Contribution to the Wet Granulation Process and to the Characteristics of Granules

Ito T, Okada K, Leong KH, Hirai D, Hayashi Y, Kumada S, et al.

Chem Pharm Bull (Tokyo), 2019;67(3):271-276.
PMID: 30828004 DOI: 10.1248/cpb.c18-00888

The different states of water incorporated in wet granules were studied by a low-field benchtop 1H-NMR time-domain NMR (TD-NMR) instrument. Wet granules consisting different fillers [cornstarch (CS), microcrystalline cellulose (MCC), and D-mannitol (MAN)] with different water contents were prepared using a high-speed granulator, and then their spin-spin relaxation time (T2) was measured using the NMR relaxation technique. The experimental T2 relaxation curves were analyzed by the two-component curve fitting, and then the individual T2 relaxation behaviors of solid and water in wet granules were identified. According to the observed T2 values, it was confirmed that the molecular mobility of water in CS and MCC granules was more restricted than that in the MAN granule. The state of water appeared to be associated with the drying efficiency and moisture absorption capacity of wet granules. Thus, it was confirmed that the state of water significantly affected the wet granulation process and the characteristics of the resultant granules. In the final phase of this study, the effects of binders on the molecular mobility of water in granulation fluids and wet granules were examined. The state of water in granulation fluids was substantially changed by changing the binders. The difference was still detected in wet granules prepared by addition of these fluids to the fillers. In conclusion, TD-NMR can offer valuable knowledge on wet granulation from the viewpoint of molecular mobility of water.
A novel mycelial pellet applied to remove polycyclic aromatic hydrocarbons: High adsorption performance & its mechanisms

Zou JJ, Dai C, Hu J, Tong WK, Gao MT, Zhang Y, et al.

Sci Total Environ, 2024 Apr 20;922:171201.
PMID: 38417506 DOI: 10.1016/j.scitotenv.2024.171201

Mycelial pellets formed by Penicillium thomii ZJJ were applied as efficient biosorbents for the removal of polycyclic aromatic hydrocarbons (PAHs), which are a type of ubiquitous harmful hydrophobic pollutants. The live mycelial pellets were able to remove 93.48 % of pyrene at a concentration of 100 mg/L within 48 h, demonstrating a maximum adsorption capacity of 285.63 mg/g. Meanwhile, the heat-killed one also achieved a removal rate of 65.01 %. Among the six typical PAHs (pyrene, phenanthrene, fluorene, anthracene, fluoranthene, benzo[a]pyrene), the mycelial pellets preferentially adsorbed the high molecular weight PAHs, which also have higher toxicity, resulting in higher removal efficiency. The experimental results showed that the biosorption of mycelial pellets was mainly a spontaneous physical adsorption process that occurred as a monolayer on a homogeneous surface, with mass transfer being the key rate-limiting step. The main adsorption sites on the surface of mycelia were carboxyl and N-containing groups. Extracellular polymeric substances (EPS) produced by mycelial pellets could enhance adsorption, and its coupling with dead mycelia could achieve basically the same removal effect to that of living one. It can be concluded that biosorption by mycelial pellets occurred due to the influence of electrostatic and hydrophobic interactions, consisting of five steps. Furthermore, the potential applicability of mycelial pellets has been investigated considering diverse factors. The mycelia showed high environmental tolerance, which could effectively remove pyrene across a wide range of pH and salt concentration. And pellets diameters and humic acid concentration had a significant effect on microbial adsorption effect. Based on a cost-effectiveness analysis, mycelium pellets were found to be a low-cost adsorbent. The research outcomes facilitate a thorough comprehension of the adsorption process of pyrene by mycelial pellets and their relevant applications, proposing a cost-effective method without potential environmental issues (heat-killed mycelial pellets plus EPS) to removal PAHs.
A potent alpha-glucosidase inhibitor from Myristica cinnamomea King

Sivasothy Y, Loo KY, Leong KH, Litaudon M, Awang K

Phytochemistry, 2016 Feb;122:265-269.
PMID: 26712615 DOI: 10.1016/j.phytochem.2015.12.007

A dimeric acylphenol and a potent α-glucosidase inhibitor, giganteone D (IC50 5.05μM), was isolated and characterized from the bark of Myristica cinnamomea King. The bark also yielded an acylphenol with an unprecedented skeleton for which the name cinnamomeone A (IC50 358.80μM) was proposed. Their structures were established by means of NMR and MS spectrometric analyses. The Lineweaver-Burk plot of giganteone D indicated that it was a mixed-type inhibitor. This is the first report on the α-glucosidase inhibiting potential of acylphenols.
Accelerated organics degradation by peroxymonosulfate activated with biochar co-doped with nitrogen and sulfur

Oh WD, Zaeni JRJ, Lisak G, Lin KA, Leong KH, Choong ZY

Chemosphere, 2021 Aug;277:130313.
PMID: 33780679 DOI: 10.1016/j.chemosphere.2021.130313

Engineered biochar is increasingly regarded as a cost-effective and eco-friendly peroxymonosulfate (PMS) activator. Herein, biochar doped with nitrogen and sulfur moieties was prepared by pyrolysis of wood shavings and doping precursor. The doping precursor consists of either urea, thiourea or 1:1 w/w mixture of urea and thiourea (denoted as NSB-U, NSB-T and NSB-UT, respectively). The physicochemical properties of the NSBs were extensively characterized, revealing that they are of noncrystalline carbon with porous structure. The NSBs were employed as PMS activator to degrade organic pollutants particularly methylene blue (MB). It was found that NSB-UT exhibited higher MB removal rate with kapp = 0.202 min-1 due to its relatively high surface area and favorable intrinsic surface moieties (combination of graphitic N and thiophenic S). The effects of catalyst loading, PMS dosage and initial pH were evaluated. Positive enhancement of the MB removal rate can be obtained by carefully increasing the catalyst loading or PMS dosage. Meanwhile, the MB removal rate is greatly influenced by pH due to electrostatic interactions and pH dependent reactions. The NSB-UT can be reused for several cycles to some extent and its catalytic activity can be restored by thermal treatment. Based on the radical scavenger study and XPS analysis, the nonradical pathway facilitated by the graphitic N and thiophenic S active sites are revealed to be the dominant reaction pathway. Overall, the results of this study show that engineered biochar derived from locally available biowaste can be transformed into PMS activator for environmental applications.
Accelerated sunlight photocatalysis through improved electron mobility between g-C3N4 and BiPO4 nanomaterial

Ng JJ, Sim LC, Oh WD, Saravanan P, Tan B, Leong KH

Environ Sci Pollut Res Int, 2022 Dec;29(57):86068-86076.
PMID: 34523092 DOI: 10.1007/s11356-021-16449-y

Herein, we report a detailed study on creating heterojunction between graphitic carbon nitride (g-C3N4) and bismuth phosphate (BiPO4), enhancing the unpaired free electron mobility. This leads to an accelerated photocatalysis of 2,4-dichlorophenols (2,4-DCPs) under sunlight irradiation. The heterojunction formation was efficaciously conducted via a modest thermal deposition technique. The function of g-C3N4 plays a significant role in generating free electrons under sunlight irradiation. Together, the generated electrons at the g-C3N4 conduction band (CB) are transferred and trapped by the BiPO4 to form active superoxide anion radicals (•O2-). These active radicals will be accountable for the photodegradation of 2,4-DCPs. The synthesized composite characteristics were methodically examined through several chemical and physical studies. Due to the inimitable features of both g-C3N4 and BiPO4, its heterojunction formation, 2.5wt% BiPO4/g-C3N4 achieved complete 2,4-DCP removal (100%) in 90 min under sunlight irradiation. This is due to the presence of g-C3N4 that enhanced electron mobility through the formation of heterojunctions that lengthens the electron-hole pairs' lifetime and maximizes the entire solar spectrum absorption to generate active electrons at the g-C3N4 conduction band. Thus, this formation significantly draws the attention for future environmental remediation, especially in enhancing the entire solar spectrum's harvesting.
Activation of Intrinsic Apoptosis and G1 Cell Cycle Arrest by a Triazole Precursor, N-(4-chlorophenyl)-2-(4-(3,4,5-trimethoxybenzyloxy)benzoyl)-hydrazinecarbothioamide in Breast Cancer Cell Line

Arulnathan SB, Leong KH, Ariffin A, Kareem HS, Cheah KKH

Anticancer Agents Med Chem, 2020;20(9):1072-1086.
PMID: 32188392 DOI: 10.2174/1871520620666200318100051

BACKGROUND: Oxadiazoles, triazoles, and their respective precursors have been shown to exhibit various pharmacological properties, namely antitumour activities. Cytotoxic activity was reported for these compounds in various cancer cell lines.
AIM AND OBJECTIVES: In this study, we aim at investigating the mechanism of apoptosis by N-(4-chlorophenyl)-2-(4- (3,4,5-trimethoxybenzyloxy)benzoyl)-hydrazinecarbothioamide, a triazole precursor, henceforth termed compound P7a, in breast cancer cell line, MCF-7. We first screen a series of analogues containing (3,4,5-trimethoxybenzyloxy) phenyl moiety in breast cancer cell lines (MCF-7 and MDA-MB-231) to select the most cytotoxic compound and demonstrate a dose- and time-dependent cytotoxicity. Then, we unravel the mechanism of apoptosis of P7a in MCF-7 as well as its ability to cause cell cycle arrest.
METHODS: Synthesis was performed as previously described by Kareem and co-workers. Cytotoxicity of analogues containing (3,4,5-trimethoxybenzyloxy)phenyl moiety against MCF-7 and MDA-MB-231 cell lines was evaluated using the MTS assay. Flow cytometric analyses was done using Annexin V/PI staining, JC-1 staining and ROS assay. The activity of caspases using a chemoluminescence assay and western blot analysis was conducted to study the apoptotic pathway induced by the compound in MCF-7 cells. Lastly, cell cycle analysis was conducted using flow cytometry.
RESULTS: Upon 48 hours of treatment, compound P7a inhibited the proliferation of human breast cancer cells with IC50 values of 178.92 ± 12.51μM and 33.75 ± 1.20μM for MDA-MB-231 and MCF-7, respectively. Additionally, compound P7a showed selectivity towards the cancer cell line, MCF-7 compared to the normal breast cell line, hTERT-HME1, an advantage against current anticancer drugs (tamoxifen and vinblastine). Flow cytometric analyses using different assays indicated that compound P7a significantly increased the proportion of apoptotic cells, increased mitochondria membrane permeabilisation and caused generation of ROS in MCF-7. In addition, cell cycle analysis showed that cell proliferation was arrested at the G1 phase in the MCF-7 cell line. Furthermore, upon treatment, the MCF-7 cell line showed increased activity of caspase-3/7, and caspase-9. Lastly, the western blot analysis showed the up-regulation of pro-apoptotic proteins along with up-regulation of caspase-7 and caspase-9, indicating that an intrinsic pathway of apoptosis was induced.
CONCLUSION: The results suggest that compound P7a could be a potential chemotherapeutic agent for breast cancer.
Activation of death receptor, DR5 and mitochondria-mediated apoptosis by a 3,4,5-trimethoxybenzyloxy derivative in wild-type and p53 mutant colorectal cancer cell lines

Chan ZCK, Leong KH, Kareem HS, Norazit A, Noor SM, Ariffin A

Naunyn Schmiedebergs Arch Pharmacol, 2020 03;393(3):405-417.
PMID: 31641820 DOI: 10.1007/s00210-019-01730-2

The rationale of designing compounds containing a (3,4,5-trimethoxybenzyloxy) phenyl moiety is largely due to its potential antioxidant and cytotoxic activities. A previous study focused on its antioxidant mechanism, whereas in this study, we investigated the cytotoxicity of a series of 28 analogues and the mechanism of apoptosis of the most cytotoxic compound against wild-type (HCT-116) and p53 mutant (HT-29) colorectal cancer cell lines. The series of analogues comprise of different families, namely hydrazone, oxadiazole, thiosemicarbazides and triazoles. In the initial cytotoxicity screening, N-(3,4,5-trimethoxybenzylidene)-4-(3,4,5-trimethoxybenzyloxy) benzohydrazide, henceforth known as, P5H, was found to be most cytotoxic against human colorectal cancer cell lines (IC50 for HCT-116 = 11.79 μM and HT-29 = 18.52 μM). Additionally, P5H was found to have some degree of selectivity towards cancer cells compared to normal human colon cells (CCD-112 CoN). Subsequent investigation had brought insight on P5H ability to induce apoptosis in both HCT-116 and HT-29 cell lines. Cell cycle analysis showed both cell lines were arrested at the G2/M phase upon treatment. Our study concluded that P5H induced the death receptor, DR5 in HCT-116 and mitochondria-mediated apoptosis pathway in HT-29. Therefore, P5H may be a promising candidate as a chemotherapy agent against colon cancer. Graphical abstract The apoptotic pathways induced in HT-29 and HCT-116 cells upon P5H treatment.
Amalgamation of N-graphene quantum dots with nanocubic like TiO2: an insight study of sunlight sensitive photocatalysis

Lim PF, Leong KH, Sim LC, Abd Aziz A, Saravanan P

Environ Sci Pollut Res Int, 2019 Feb;26(4):3455-3464.
PMID: 30515688 DOI: 10.1007/s11356-018-3821-1

In this work, a sunlight-sensitive photocatalyst of nanocubic-like titanium dioxide (TiO2) and N-doped graphene quantum dots (N-GQDs) is developed through a simple hydrothermal and physical mixing method. The successful amalgamation composite photocatalyst characteristics were comprehensively scrutinized through various physical and chemical analyses. A complete removal of bisphenol A (BPA) is attained by a synthesized composite after 30 min of sunlight irradiation as compared to pure TiO2. This clearly proved the unique contribution of N-GQDs that enhanced the ability of light harvesting especially under visible light and near-infrared region. This superior characteristic enables it to maximize the absorbance in the entire solar spectrum. However, the increase of N-GQDs weight percentage has created massive oxygen vacancies that suppress the generation of active radicals. This resulted in a longer duration for a complete removal of BPA as compared to lower weight percentage of N-GQDs. Hence, this finding can offer a new insight in developing effective sunlight-sensitive photocatalysts for various complex organic pollutants degradation.
Antiplasmodial and antioxidant isoquinoline alkaloids from Dehaasia longipedicellata

Zahari A, Cheah FK, Mohamad J, Sulaiman SN, Litaudon M, Leong KH, et al.

Planta Med, 2014 May;80(7):599-603.
PMID: 24723007 DOI: 10.1055/s-0034-1368349

The crude extract of the bark of Dehaasia longipedicellata exhibited antiplasmodial activity against the growth of Plasmodium falciparum K1 isolate (resistant strain). Phytochemical studies of the extract led to the isolation of six alkaloids: two morphinandienones, (+)-sebiferine (1) and (-)-milonine (2); two aporphines, (-)-boldine (3) and (-)-norboldine (4); one benzlyisoquinoline, (-)-reticuline (5); and one bisbenzylisoquinoline, (-)-O-O-dimethylgrisabine (6). Their structures were determined on the basis of 1D and 2D NMR, IR, UV, and LCMS spectroscopic techniques and upon comparison with literature values. Antiplasmodial activity was determined for all of the isolated compounds. They showed potent to moderate activity with IC50 values ranging from 0.031 to 30.40 µM. (-)-O-O-dimethylgrisabine (6) and (-)-milonine (2) were the two most potent compounds, with IC50 values of 0.031 and 0.097 µM, respectively, that were comparable to the standard, chloroquine (0.090 µM). The compounds were also assessed for their antioxidant activities with di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium (IC50 = 18.40-107.31 µg/mL), reducing power (27.40-87.40 %), and metal chelating (IC50 = 64.30 to 257.22 µg/mL) having good to low activity. (-)-O-O-dimethylgrisabine (6) exhibited a potent antioxidant activity of 44.3 % reducing power, while di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium and metal chelating activities had IC50 values of 18.38 and 64.30 µg/mL, respectively. Thus it may be considered as a good reductant with the ability to chelate metal and prevent pro-oxidant activity. In addition to the antiplasmodial and antioxidant activities, the isolated compounds were also tested for their cytotoxicity against a few cancer and normal cell lines. (-)-Norboldine (4) exhibited potent cytotoxicity towards pancreatic cancer cell line BxPC-3 with an IC50 value of 27.060 ± 1.037 µM, and all alkaloids showed no toxicity towards the normal pancreatic cell line (hTERT-HPNE).
Fulltext Bee Inspired Novel Optimization Algorithm and Mathematical Model for Effective and Efficient Route Planning in Railway System

Leong KH, Abdul-Rahman H, Wang C, Onn CC, Loo SC

PLoS One, 2016;11(12):e0166064.
PMID: 27930659 DOI: 10.1371/journal.pone.0166064

Railway and metro transport systems (RS) are becoming one of the popular choices of transportation among people, especially those who live in urban cities. Urbanization and increasing population due to rapid development of economy in many cities are leading to a bigger demand for urban rail transit. Despite being a popular variant of Traveling Salesman Problem (TSP), it appears that the universal formula or techniques to solve the problem are yet to be found. This paper aims to develop an optimization algorithm for optimum route selection to multiple destinations in RS before returning to the starting point. Bee foraging behaviour is examined to generate a reliable algorithm in railway TSP. The algorithm is then verified by comparing the results with the exact solutions in 10 test cases, and a numerical case study is designed to demonstrate the application with large size sample. It is tested to be efficient and effective in railway route planning as the tour can be completed within a certain period of time by using minimal resources. The findings further support the reliability of the algorithm and capability to solve the problems with different complexity. This algorithm can be used as a method to assist business practitioners making better decision in route planning.
Characterization of Powder- and Tablet Properties of Different Direct Compaction Grades of Mannitol Using a Kohonen Self-organizing Map and a Lasso Regression Model

Kosugi A, Leong KH, Tsuji H, Hayashi Y, Kumada S, Okada K, et al.

J Pharm Sci, 2020 Aug;109(8):2585-2593.
PMID: 32473211 DOI: 10.1016/j.xphs.2020.05.010

The purpose of this study was to accumulate enhanced technical knowledge about the powder properties of direct compaction grades of mannitol that could lead to new tablet formulations. Fifteen different commercial direct compaction grades of mannitol were tested. Ten different powder properties representing flowability, particle size, specific surface area and manufacturing properties were measured. In addition, model tablets of each mannitol grade were prepared, and their disintegration time, friability, and tensile strength were measured. The data were analyzed by principle component analysis and a Kohonen self-organizing map to find correlations between powder properties. Self-organizing map clustering successfully classified the test grades into 5 distinct clusters having different powder properties. Each cluster was well characterized by statistical profiling. Subsequently, the contribution of the powder properties to the tablet properties was investigated by a least absolute shrinkage- and selection operator (Lasso) regression model. Mannitol grades with a larger particle size (D90) were prone to produce tablets with longer disintegration time, while a larger specific surface area of the particles was positively associated with tablets with higher mechanical strength. Our findings provide valuable information for the design of tablet formulations.
Characterization of the Salt and Free Base of Active Pharmaceutical Ingredients Based on NMR Relaxometry Measured by Time Domain NMR

Chiba Y, Okada K, Hayashi Y, Leong KH, Kumada S, Onuki Y

Chem Pharm Bull (Tokyo), 2022;70(2):162-168.
PMID: 35110437 DOI: 10.1248/cpb.c21-00975

NMR relaxometry measurement by time domain NMR (TD-NMR) is a promising technique for characterizing the properties of active pharmaceutical ingredients (APIs). This study is dedicated to identifying the salt and free base of APIs by NMR relaxometry measured by the TD-NMR technique. Procaine (PC) and tetracaine (TC) were selected as model APIs to be tested. By using conventional methods including powder X-ray diffraction and differential scanning calorimetry, this study first confirmed that the salt and free base of the tested APIs differ from each other in their crystalline form. Subsequently, measurements of T1 and T2 relaxation were performed on the tested APIs using TD-NMR. The results demonstrated that these NMR relaxometry measurements have sufficient capacity to distinguish the difference between the free base and salt of the tested APIs. Furthermore, quantification of the composition of the binary powder blends consisting of salt and free bases was conducted by analyzing the acquired T1 and T2 relaxation curves. The analysis of the T1 relaxation curves provided a partly acceptable estimation: a good estimation of the composition was observed from PC powders, whereas for TC powders the estimation accuracy changed with the free base content in the binary blends. For the analysis on T2 relaxation curves, a precise estimation of the composition was observed from all the samples. From these findings, the NMR relaxometry measurement by TD-NMR, in particular the T2 relaxation measurement, is effective for evaluating the properties of APIs having different crystalline forms.
Contamination levels of selected organochlorine and organophosphate pesticides in the Selangor River, Malaysia between 2002 and 2003

Leong KH, Tan LL, Mustafa AM

Chemosphere, 2007 Jan;66(6):1153-9.
PMID: 17027062

In Malaysia, rivers are the main source of public water supplies. This study was conducted from 2002 to 2003 to determine the levels of selected organochlorine and organophosphate pesticides in the Selangor River in Malaysia. Surface water samples have been collected seasonally from nine sites along the river. A liquid-liquid extraction followed by gas chromatography-mass spectrometry technique was used to determine the trace levels of these pesticide residues. The organochlorine pesticides detected were lindane, heptachlor, endosulfan, dieldrin, endosulfan sulfate, o,p'-DDT, p,p'-DDT, o,p'-DDE and p,p'-DDE whereas for organophosphate pesticides, they were chlorpyrifos and diazinon. At the river upstream where a dam is located for public water supply, incidents of pesticide levels exceeding the European Economic Community Directive of water quality standards have occurred. Furthermore, the wetland ecosystems located at the downstream of the river which houses the fireflies community is being threatened by occasional pesticide levels above EPA limits for freshwater aquatic organisms. The occurrence of these residual pesticides in the Selangor River can be attributed to the intense agriculture and urban activity.
Fulltext Continuous Monitoring of the Hydration Behavior of Hydrophilic Matrix Tablets Using Time-Domain NMR

Tsuji T, Ono T, Taguchi H, Leong KH, Hayashi Y, Kumada S, et al.

Chem Pharm Bull (Tokyo), 2023;71(7):576-583.
PMID: 37394606 DOI: 10.1248/cpb.c23-00214

Time-domain NMR (TD-NMR) was used for continuous monitoring of the hydration behavior of hydrophilic matrix tablets. The model matrix tablets comprised high molecular weight polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG). The model tablets were immersed in water. Their T2 relaxation curves were acquired by TD-NMR with solid-echo sequence. A curve-fitting analysis was conducted on the acquired T2 relaxation curves to identify the NMR signals corresponding to the nongelated core remaining in the samples. The amount of nongelated core was estimated from the NMR signal intensity. The estimated values were consistent with the experiment measurement values. Next, the model tablets immersed in water were monitored continuously using TD-NMR. The difference in hydration behaviors of the HPMC and PEO matrix tablets was then characterized fully. The nongelated core of the HPMC matrix tablets disappeared more slowly than that of the PEO matrix tablets. The behavior of HPMC was significantly affected by the PEG content in the tablets. It is suggested that the TD-NMR method has potential to be utilized to evaluate the gel layer properties, upon replacement of the immersion medium: purified (nondeuterated) water is replaced with heavy (deuterated) water. Finally, drug-containing matrix tablets were tested. Diltiazem hydrochloride (a highly water-soluble drug) was employed for this experiment. Reasonable in vitro drug dissolution profiles, which were in accordance with the results from TD-NMR experiments, were observed. We concluded that TD-NMR is a powerful tool to evaluate the hydration properties of hydrophilic matrix tablets.
Fulltext Cycloart-24-ene-26-ol-3-one, a New Cycloartane Isolated from Leaves of Aglaia exima Triggers Tumour Necrosis Factor-Receptor 1-Mediated Caspase-Dependent Apoptosis in Colon Cancer Cell Line

Leong KH, Looi CY, Loong XM, Cheah FK, Supratman U, Litaudon M, et al.

PLoS One, 2016;11(4):e0152652.
PMID: 27070314 DOI: 10.1371/journal.pone.0152652

Plants in the Meliaceae family are known to possess interesting biological activities, such as antimalaral, antihypertensive and antitumour activities. Previously, our group reported the plant-derived compound cycloart-24-ene-26-ol-3-one isolated from the hexane extracts of Aglaia exima leaves, which shows cytotoxicity towards various cancer cell lines, in particular, colon cancer cell lines. In this report, we further demonstrate that cycloart-24-ene-26-ol-3-one, from here forth known as cycloartane, reduces the viability of the colon cancer cell lines HT-29 and CaCO-2 in a dose- and time-dependent manner. Further elucidation of the compound's mechanism showed that it binds to tumour necrosis factor-receptor 1 (TNF-R1) leading to the initiation of caspase-8 and, through the activation of Bid, in the activation of caspase-9. This activity causes a reduction in mitochondrial membrane potential (MMP) and the release of cytochrome-C. The activation of caspase-8 and -9 both act to commit the cancer cells to apoptosis through downstream caspase-3/7 activation, PARP cleavage and the lack of NFkB translocation into the nucleus. A molecular docking study showed that the cycloartane binds to the receptor through a hydrophobic interaction with cysteine-96 and hydrogen bonds with lysine-75 and -132. The results show that further development of the cycloartane as an anti-cancer drug is worthwhile.
Fulltext Cytotoxic and antioxidant compounds from the stem bark of Goniothalamus tapisoides Mat Salleh

Kim RP, Bihud V, Bin Mohamad K, Leong KH, Bin Mohamad J, Bin Ahmad F, et al.

Molecules, 2012 Dec 21;18(1):128-39.
PMID: 23344192 DOI: 10.3390/molecules18010128

Eleven compounds:goniomicin A (1), goniomicin B (2), goniomicin C (3), goniomicin D (4), tapisoidin (5), goniothalamin (6), 9-deoxygoniopypyrone (7), pterodondiol (8), liriodenine (9), benzamide (10) and cinnamic acid (11), were isolated from the stem bark of Goniothalamus tapisoides. All compounds were identified by spectroscopic analysis and, for known compounds, by comparison with published data. Goniothalamin (6) exhibited mild cytotoxic activity towards a colon cancer cell line (HT-29), with an IC(50)value of 64.17 ± 5.60 µM. Goniomicin B (2) give the highest antioxidant activity in the DPPH assay among all compounds tested, with an IC(50) of 0.207 µM.
Fulltext D-Amino acids differentially trigger an inflammatory environment in vitro

Yap SH, Lee CS, Zulkifli ND, Suresh D, Hamase K, Das KT, et al.

Amino Acids, 2024 Feb 03;56(1):6.
PMID: 38310167 DOI: 10.1007/s00726-023-03360-8

Studies in vivo have demonstrated that the accumulation of D-amino acids (D-AAs) is associated with age-related diseases and increased immune activation. However, the underlying mechanism(s) of these observations are not well defined. The metabolism of D-AAs by D-amino oxidase (DAO) produces hydrogen peroxide (H2O2), a reactive oxygen species involved in several physiological processes including immune response, cell differentiation, and proliferation. Excessive levels of H2O2 contribute to oxidative stress and eventual cell death, a characteristic of age-related pathology. Here, we explored the molecular mechanisms of D-serine (D-Ser) and D-alanine (D-Ala) in human liver cancer cells, HepG2, with a focus on the production of H2O2 the downstream secretion of pro-inflammatory cytokine and chemokine, and subsequent cell death. In HepG2 cells, we demonstrated that D-Ser decreased H2O2 production and induced concentration-dependent depolarization of mitochondrial membrane potential (MMP). This was associated with the upregulation of activated NF-кB, pro-inflammatory cytokine, TNF-α, and chemokine, IL-8 secretion, and subsequent apoptosis. Conversely, D-Ala-treated cells induced H2O2 production, and were also accompanied by the upregulation of activated NF-кB, TNF-α, and IL-8, but did not cause significant apoptosis. The present study confirms the role of both D-Ser and D-Ala in inducing inflammatory responses, but each via unique activation pathways. This response was associated with apoptotic cell death only with D-Ser. Further research is required to gain a better understanding of the mechanisms underlying D-AA-induced inflammation and its downstream consequences, especially in the context of aging given the wide detection of these entities in systemic circulation.
Effect of the molecular mobility of water adsorbed by disintegrants on storage-induced hydrolytic degradation of acetylsalicylic acid incorporated into tablets under humid conditions

Ougi K, Okada K, Leong KH, Hayashi Y, Kumada S, Onuki Y

Eur J Pharm Sci, 2020 Nov 01;154:105502.
PMID: 32750421 DOI: 10.1016/j.ejps.2020.105502

The purpose of this study was to investigate the effect of molecular mobility of water adsorbed by disintegrants on the hydrolytic degradation of active pharmaceutical ingredients (APIs). Fourteen different disintegrants were tested. First, powdered disintegrants were stored at conditions of 40 °C/75% relative humidity ("humid conditions") and their T2 relaxation times were measured by time-domain nuclear magnetic resonance for examination of the molecular mobility of water adsorbed by the disintegrant. From the observed T2 values, the water molecular mobility was fully characterized. In particular, the molecular mobility of water adsorbed by crospovidones was much higher than the molecular mobility of water adsorbed by the other test disintegrants because of longer T2 values. The next study examined the hydrolytic degradation of acetylsalicylic acid (ASA), a model moisture-sensitive API, stored under humid conditions. Physical mixtures of ASA and disintegrants or their model tablets were used as test samples, and they were stored for 7 d. The disintegrants contained in the samples clearly affected the ASA degradation: the most significant ASA degradation was observed for the crospovidone-containing samples. Finally, we analyzed the effect of the molecular mobility of water adsorbed by disintegrants on the ASA degradation by the least absolute shrinkage and selection operator (Lasso) regression techniques. As in the T2 experiment, various properties of disintegrants (i.e., water content, pH, and water activity) were used in this experiment as the explanatory variables. From the Lasso analysis, we successfully showed that the higher molecular mobility of water adsorbed by disintegrants significantly enhanced ASA degradation. These findings provide profound insights into the chemical stability of moisture-sensitive APIs in tablets.
Effects of EDTA on adsorption of Cd(II) and Pb(II) by soil minerals in low-permeability layers: batch experiments and microscopic characterization

You X, Liu S, Dai C, Zhong G, Duan Y, Guo Y, et al.

Environ Sci Pollut Res Int, 2020 Nov;27(33):41623-41638.
PMID: 32691313 DOI: 10.1007/s11356-020-10149-9

Ethylenediaminetetraacetic acid (EDTA) can serve as a washing agent in the remediation of low-permeability layers contaminated by heavy metals (HMs). Therefore, batch adsorption experiments, where pure quartz (SM1) and mineral mixtures (SM2) were used as typical soil minerals (SMs) in low-permeability layers, were implemented to explore the effects of different EDTA concentrations, pH, and exogenous chemicals on the HM-SM-EDTA adsorption system. As the EDTA concentration increased, it gradually cut down the maximum Cd adsorption capacities of SM1 and SM2 from approximately 135 to 55 mg/kg and 2660 to 1453 mg/kg; and the maximum Pb adsorption capacities of SM1 and SM2 were reduced from 660 to 306 mg/kg and 19,677 to 19,262 mg/kg, respectively. When the initial mole ratio (MR = moles of HM ions/sum of moles of HM ions and EDTA) was closer to 0.5, the effect of EDTA was more effective. Additionally, EDTA worked well at pH below 7.0 and 4.0 for Cd and Pb, respectively. Low-molecular-weight organic acids (LMWOAs) affected the system mainly by bridging, complexation, adsorption site competition, and reductive dissolution. Cu2+, Fe2+ ions could significantly increase the Cd and Pb adsorption onto SM2. Notably, there were characteristic changes in mineral particles, including attachment of EDTA and microparticles, agglomeration, connection, and smoother surfaces, making the specific surface area (SSA) decrease from 16.73 to 12.59 m2/g. All findings indicated that EDTA could effectively and economically reduce the HM adsorption capacity of SMs at the reasonable MR value, contact time, and pH; EDTA reduced the HM adsorption capacity of SMs not only by complexation with HM ions but also by decreasing SSA and blocking active sites. Hence, the acquired insight from the presented study can help to promote the remediation of contaminated low-permeability layers in groundwater.

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