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Molecularly targeted therapies for asthma: Current development, challenges and potential clinical translation

Sulaiman I, Lim JC, Soo HL, Stanslas J

Pulm Pharmacol Ther, 2016 Oct;40:52-68.
PMID: 27453494 DOI: 10.1016/j.pupt.2016.07.005

Extensive research into the therapeutics of asthma has yielded numerous effective interventions over the past few decades. However, adverse effects and ineffectiveness of most of these medications especially in the management of steroid resistant severe asthma necessitate the development of better medications. Numerous drug targets with inherent airway smooth muscle tone modulatory role have been identified for asthma therapy. This article reviews the latest understanding of underlying molecular aetiology of asthma towards design and development of better antiasthma drugs. New drug candidates with their putative targets that have shown promising results in the preclinical and/or clinical trials are summarised. Examples of these interventions include restoration of Th1/Th2 balance by the use of newly developed immunomodulators such as toll-like receptor-9 activators (CYT003-QbG10 and QAX-935). Clinical trials revealed the safety and effectiveness of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists such as OC0000459, BI-671800 and ARRY-502 in the restoration of Th1/Th2 balance. Regulation of cytokine activity by the use of newly developed biologics such as benralizumab, reslizumab, mepolizumab, lebrikizumab, tralokinumab, dupilumab and brodalumab are at the stage of clinical development. Transcription factors are potential targets for asthma therapy, for example SB010, a GATA-3 DNAzyme is at its early stage of clinical trial. Other candidates such as inhibitors of Rho kinases (Fasudil and Y-27632), phosphodiesterase inhibitors (GSK256066, CHF 6001, roflumilast, RPL 554) and proteinase of activated receptor-2 (ENMD-1068) are also discussed. Preclinical results of blockade of calcium sensing receptor by the use of calcilytics such as calcitriol abrogates cardinal signs of asthma. Nevertheless, successful translation of promising preclinical data into clinically viable interventions remains a major challenge to the development of novel anti-asthmatics.
Fulltext Morphological and molecular datasets for Kaempferia species

Labrooy C, Abdullah TL, Stanslas J

Data Brief, 2018 Dec;21:1678-1685.
PMID: 30505900 DOI: 10.1016/j.dib.2018.10.097

This study compared morphological and molecular data for identification of Kaempferia species. Each species was deposited in Institute of Bioscience (IBS), Universiti Putra Malaysia (UPM) as voucher specimens and ITS sequences of each species deposited in NCBI (https://www.ncbi.nlm.nih.gov/) as GenBank accessions. DNA was extracted using a modified CTAB method and PCR amplification was completed using Internal Transcribed Spacer (ITS4 and ITS5) markers. PCR amplification of products were viewed under gel electrophoresis. Sequencing was performed and sequence characteristics of ITS rDNA in Kaempferia is shown. Qualitative and qualitative scoring of morphological characters and measuring techniques for Kaempferia species are included. In addition, a brief review of molecular markers used in phylogenetic studies of Zingiberaceae is included in this dataset.
NCI in vitro and in silico anticancer screen, cell cycle pertubation and apoptosis-inducing potential of new acylated, benzylidene and isopropylidene derivatives of andrographolide

Wong CC, Sagineedu SR, Sumon SH, Sidik SM, Phillips R, Lajis NH, et al.

Environ Toxicol Pharmacol, 2014 Sep;38(2):489-501.
PMID: 25168151 DOI: 10.1016/j.etap.2014.07.016

Andrographolide (AGP) is the main bioactive constituent isolated from the traditional medicinal, Andrographis paniculata which contributes towards its various biological activities, including anticancer property. In this study, a series of new AGP derivatives were semi-synthesised and screened against the NCI in vitro 60 cell lines. From the screening results, we had identified SRS07 as the most potent AGP derivative, against breast and colon cancer cell lines. Subsequently, SRS07 was tested for its capability to induce cell cycle arrest and apoptosis in MCF-7 and HCT116 cancer cells. SRS07 effectively induced G1 cell cycle arrest in both cell lines and ultimately apoptosis by inducing DNA fragmentation in HCT116 cells. The apoptotic cell death induced by SRS07 was confirmed via FITC Annexin-V double staining. Western blot analysis of SRS07-treated HCT116 cells revealed that the compound induced apoptosis be activating caspase 8 which in turn cleaved Bid to t-Bid to initiate cell death cascade. Prediction of the possible mode of action of SRS07 by utilising NCI COMPARE analysis failed to reveal a distinct mechanism category. Hence, it is speculated that SRS07 possesses novel mechanism of action. In conclusion, SRS07 demonstrated superior in vitro anticancer profiles and emerged as a potential lead anticancer candidate.
Nanoemulsion-based Parenteral Drug Delivery System of Carbamazepine: Preparation, Characterization, Stability Evaluation and Blood-Brain Pharmacokinetics

Tan SL, Stanslas J, Basri M, Abedi Karjiban RA, Kirby BP, Sani D, et al.

Curr Drug Deliv, 2015;12(6):795-804.
PMID: 26324229

Carbamzepine (CBZ) was encapsulated in a parenteral oil-in-water nanoemulsion, in an attempt to improve its bioavailability. The particle size, polydispersity index and zeta potential were measured using dynamic light scattering. Other parameters such as pH, osmolality, viscosity, drug loading efficiency and entrapment efficiency were also recorded. Transmission electron microscopy revealed that emulsion droplets were almost spherical in shape and in the nano-range. The in vitro release profile was best characterized by Higuchi's equation. The parenteral nanoemulsion of CBZ showed significantly higher AUC0→5, AUC0→∞, AUMC0→5, AUMC0→∞, Cmax and lower clearance than that of CBZ solution in plasma. Additionally, parenteral nanoemulsion of CBZ showed significantly higher AUC0→∞, AUMC0→∞ and Cmaxthan that of CBZ solution in brain. The parenteral nanoemulsion of CBZ could therefore use as a carrier, worth exploring further for brain targeting.
Naturally occurring labdane diterpene and benzofuran from Globba pendula

Maulidiani, Shaari K, Paetz C, Stanslas J, Abas F, Lajis NH

Nat Prod Commun, 2009 Aug;4(8):1031-6.
PMID: 19768978

Phytochemical investigation on Globba pendula resulted in the isolation of a new naturally occurring 16-oxo-(8)17-12-labdadien-15,11-olide 1 and benzofuran-2-carboxaldehyde 2. Other known compounds including isoandrographolide, indirubin, vanillin, vanillic acid, 2(3H)-benzoxazolone, as well as beta-sitosteryl-beta-D-glucopyranoside, beta-sitosterol, and 7alpha-hydroxysitosterol were also isolated. The structures were established based on spectroscopic data and comparison with the literature. Furthermore, the compound isoandrographolide has demonstrated strong cytotoxic properties towards a panel of cancer cell lines (MCF-7, PC-3, and H-460) with the IC50 values of 7.9, 8.7, and 9.0 microM, respectively.
New flavan and alkyl alpha,beta-lactones from the stem bark of Horsfieldia superba

Al-Mekhlafi NA, Shaaria K, Abas F, Jeyaraj EJ, Stanslas J, Khalivulla SI, et al.

Nat Prod Commun, 2013 Apr;8(4):447-51.
PMID: 23738449

In the present study phytochemical investigation of the methanol extract of the stem bark of Horsfieldia superba led to the isolation of twenty compounds (1-20), of which three (1-3) were new. However, compounds 2 and 3 were previously reported as synthetic alpha,beta-lactones. The compounds were characterized as (-)-3,4',7-trihydroxy-3'-methoxyflavan (1), (-)-5,6-dihydro-6-undecyl-2H-pyran-2-one (2), and (-)-5,6-dihydro-6-tridecyl-2H-pyran-2-one (3). Seventeen other known compounds were also isolated and identified as (-)-viridiflorol (4), hexacosanoic acid (5), beta-sitosterol (6), methyl 2,4-dihydroxy-6-methylbenzoate (methylorsellinate) (7), methyl 2,4-dihydroxy-3,6-dimethylbenzoate (8), (-)-4'-hydroxy-7-methoxyflavan (9), (-)-4',7-dihydroxyflavan (10), (-)-4',7-dihydroxy-3'-methoxyflavan (11), (+)-3,4',7-trihydroxyflavan (12), (-)-catechin (13), (-)-epicatechin (14), (-)-7-hydroxy-3',4'-methylenedioxyflavan (15), 2',3,4-trihydroxy-4'-methoxydihydrochalcone (16), 3',4',7-trihydroxyflavone (17), (+)-4'-hydroxy-7-methoxyflavanone (18), hexadecanoic acid (palmitic acid) (19) and 3,4-dihydroxybenzoic acid (20). The structures of the compounds were fully characterized by various physical methods (melting point, optical rotation), spectral (UV, IR, ID and 2D NMR) and mass spectrometric techniques. In vitro assay of compounds 2 and 3 demonstrated moderate cytotoxic activities against human prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer cells, while the chloroform and ethyl acetate fractions of H. superba were found to exhibit moderate AChE inhibitory activity (IC50 72 and 60 microg/mL).
Non-steroid receptor-mediated antiproliferative activity of styrylpyrone derivative in human breast cancer cell lines

Pihie AH, Stanslas J, Din LB

Anticancer Res, 1998 May-Jun;18(3A):1739-43.
PMID: 9673398

The antiproliferative activity of a styrylpyrone derivative (SPD) plant extract, was studied in three different human breast cancer cell lines in culture, and was compared with tamoxifen. The number of living cells was evaluated by Methylene Blue staining technique. SPD showed strong antiproliferative activity in estrogen receptor (ER) and progestin receptor (PgR) positive MCF-7 cells (EC50 = 6.30 x 10(-7) M) and receptor-negative MDA-MB-231 (EC50 = 5.62 x 10(-7) M), but it partially inhibited the high progestin receptor positive T47D cells (EC50 = 1.58 x 10(-6) M). Whereas tamoxifen, a nonsteroidal antiestrogen exhibited strong inhibition on MCF-7 cells (EC50 = 1.41 x 10(-6) M) and partial inhibition on T47D cells (EC50 = 2.5 x 10(-6) M), but did not affect the MDA-MB-231 cells in the concentration range 0.1 nM-1 microM (EC50 = 5.01 microM). At the same concentration range SPD and tamoxifen did not inhibit the proliferation of normal human liver cell line CCL 13 and normal bovine kidney MDBK; whereas adriamycin, a common chemotherapy drug for the treatment of advance cancer, caused 95% inhibition at 10(-6) M. Competitive binding studies showed SPD had no ability to inhibit the binding of [3H]estradiol and [3H]progesterone to ER and PgR, respectively but, tamoxifen exhibited affinity for ER. Therefore, it can be concluded that the antiproliferative activity of SPD was selective towards breast cancer cell lines and not mediated by ER or PgR.
Oestrogenic activity of mimosine on MCF-7 breast cancer cell line through the ERα-mediated pathway

Huq AM, Wai LK, Rullah K, Mohd Aluwi MFF, Stanslas J, Jamal JA

Chem Biol Drug Des, 2019 03;93(3):222-231.
PMID: 30251480 DOI: 10.1111/cbdd.13404

Hormone replacement therapy has been a conventional treatment for postmenopausal symptoms in women. However, it has potential risks of breast and endometrial cancers. The aim of this study was to evaluate the oestrogenicity of a plant-based compound, mimosine, in MCF-7 cells by in silico model. Cell viability and proliferation, ERα-SRC1 coactivator activity and expression of specific ERα-dependent marker TFF1 and PGR genes were evaluated. Binding modes of 17β-oestradiol and mimosine at the ERα ligand binding domain were compared using docking and molecular dynamics simulation experiments followed by binding interaction free energy calculation with molecular mechanics/Poisson-Boltzmann surface area. Mimosine showed increased cellular viability (64,450 cells/ml) at 0.1 μM with significant cell proliferation (120.5%) compared to 17β-oestradiol (135.2%). ER antagonist tamoxifen significantly reduced proliferative activity mediated by mimosine (49.9%). Mimosine at 1 μM showed the highest ERα binding activity through increased SRC1 recruitment at 186.9%. It expressed TFF1 (11.1-fold at 0.1 μM) and PGR (13.9-fold at 0.01 μM) genes. ERα-mimosine binding energy was -49.9 kJ/mol, and it interacted with Thr347, Gly521 and His524 of ERα-LBD. The results suggested that mimosine has oestrogenic activity.
Fulltext Pancreatic cancer treatment with targeted therapies: are we there yet?

Ngozi Nwaefulu O, Rao Sagineedu S, Kaisarul Islam M, Stanslas J

Eur Rev Med Pharmacol Sci, 2022 Jan;26(2):367-381.
PMID: 35113412 DOI: 10.26355/eurrev_202201_27861

OBJECTIVE: Pancreatic cancer (PaCa) is a disease that is extremely difficult to treat and is associated with a high fatality rate. The majority of patients present to hospitals with metastatic or end-stage cancer, making the ultimate cure impossible. End-stage PaCa has no specific treatment, though surgery, irradiation, and chemotherapy can help patients live longer. Consequently, it is vital to accumulate all information on potential targeted therapies for this cancer into a single report.
MATERIALS AND METHODS: This review has been compiled using relevant keywords and a thorough web search utilising PubMed, ScienceDirect, GoogleScholar, Scopus, MEDLINE, and SpringerLink.
RESULTS: Conventional medicines that target various biological processes have a significant negative impact on normal cells. As a result, targeted therapies are required, which include the use of small-molecule inhibitors and monoclonal antibodies to target cancer cell surface receptors, growth factors, and other proteins involved in disease progression. In this review, we summarize the known targeted PaCa therapies, which include inhibitors of the KRAS, mTOR, and PI3K/AKT signaling pathways, as well as PARP, hedgehog, EGFR/ErbB, and TGF-β signaling pathways, along with inhibitors of the neurotrophic tropomyosin receptor kinase (NTRK).
CONCLUSIONS: An adequate understanding of PaCa pathogenesis and the adoption of tailored medicines can increase patients' overall survival. We believe targeted therapy can help patients with PaCa to have a better prognosis. As such, more research is needed to find appropriate biomarkers to aid in early tumor diagnosis and to discover novel prospective therapeutics based on the drugs listed in this article.
Peptide-based and small molecule PD-1 and PD-L1 pharmacological modulators in the treatment of cancer

Islam MK, Stanslas J

Pharmacol Ther, 2021 11;227:107870.
PMID: 33895183 DOI: 10.1016/j.pharmthera.2021.107870

Cancer immunotherapy is an option to enhance physiological defence mechanism to fight cancer, where natural substances (e.g., antigen/antibody) or small synthetic molecule can be utilized to improve and restore the immune system to stop or slacken the development of malignant cells, stop metastasis and/or help the immune response with synthetic monoclonal antibodies (mAbs) and tumour-agnostic therapy to eliminate cancer cells. Interaction between the programmed cell death ligand 1 (PD-L1) and its receptor (programmed cell death protein 1, PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) linked signalling pathways have been identified as perilous towards the body's immune mechanism in regulating the progression of cancer. It is known that certain cancers use these pathways to evade the body's defence mechanism. The immune system is capable of responding to cancer by stalling these trails with specific synthetic antibodies or immune checkpoint inhibitors, which can ultimately either stop or slow cancer cell development. Recent findings and data suggested that using such inhibitors invigorated a new approach to cancer treatment. These inhibitors usually activate the immune system to identify and eliminate cancer cells rather than attacking tumour cells directly. PD-1/PD-L1 inhibitors have already been substantiated for their efficacy in over twenty variations of cancer through different clinical trials. Studies on molecular interaction with existing PD-1/PD-L1 inhibitors that are mainly dominated by antibodies are constantly generating new ideas to develop novel inhibitors. This review has summarised information on reported and/or patented small molecules and peptides for their ability to interact with the PD-1/PD-L1 as a potential anticancer strategy.
Pharmacogenetics of taxanes: impact of gene polymorphisms of drug transporters on pharmacokinetics and toxicity

Jabir RS, Naidu R, Annuar MA, Ho GF, Munisamy M, Stanslas J

Pharmacogenomics, 2012 Dec;13(16):1979-88.
PMID: 23215890 DOI: 10.2217/pgs.12.165

Interindividual variability in drug response and the emergence of adverse drug effects are the main causes of treatment failure in cancer therapy. Functional membrane drug transporters play important roles in altering pharmacokinetic profile, resistance to treatment, toxicity and patient survival. Pharmacogenetic studies of these transporters are expected to provide new approaches for optimizing therapy. Taxanes are approved for the treatment of various cancers. Circulating taxanes are taken up by SLCO1B3 into hepatocytes. The CYP450 enzymes CYP3A4, CYP3A5 and CYP2C8 are responsible for the conversion of taxanes into their metabolites. Ultimately, ABCB1 and ABCC2 will dispose the metabolites into bile canaliculi. Polymorphisms of genes encoding for proteins involved in the transport and clearance of taxanes reduce excretion of the drugs, leading to development of toxicity in patients. This review addresses current knowledge on genetic variations of transporters affecting taxanes pharmacokinetics and toxicity, and provides insights into future direction for personalized medicine.
Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti-Ras drugs

Quah SY, Tan MS, Teh YH, Stanslas J

Pharmacol Ther, 2016 06;162:35-57.
PMID: 27016467 DOI: 10.1016/j.pharmthera.2016.03.010

Oncogenic rat sarcoma (Ras) is linked to the most fatal cancers such as those of the pancreas, colon, and lung. Decades of research to discover an efficacious drug that can block oncogenic Ras signaling have yielded disappointing results; thus, Ras was considered "undruggable" until recently. Inhibitors that directly target Ras by binding to previously undiscovered pockets have been recently identified. Some of these molecules are either isolated from natural products or derived from natural compounds. In this review, we described the potential of these compounds and other inhibitors of Ras signaling in drugging Ras. We highlighted the modes of action of these compounds in suppressing signaling pathways activated by oncogenic Ras, such as mitogen-activated protein kinase (MAPK) signaling and the phosphoinositide-3-kinase (PI3K) pathways. The anti-Ras strategy of these compounds can be categorized into four main types: inhibition of Ras-effector interaction, interference of Ras membrane association, prevention of Ras-guanosine triphosphate (GTP) formation, and downregulation of Ras proteins. Another promising strategy that must be validated experimentally is enhancement of the intrinsic Ras-guanosine triphosphatase (GTPase) activity by small chemical entities. Among the inhibitors of Ras signaling that were reported thus far, salirasib and TLN-4601 have been tested for their clinical efficacy. Although both compounds passed phase I trials, they failed in their respective phase II trials. Therefore, new compounds of natural origin with relevant clinical activity against Ras-driven malignancies are urgently needed. Apart from salirasib and TLN-4601, some other compounds with a proven inhibitory effect on Ras signaling include derivatives of salirasib, sulindac, polyamine, andrographolide, lipstatin, levoglucosenone, rasfonin, and quercetin.
Phytochemicals from Phyllanthus niruri Linn. and their pharmacological properties: a review

Bagalkotkar G, Sagineedu SR, Saad MS, Stanslas J

J Pharm Pharmacol, 2006 Dec;58(12):1559-70.
PMID: 17331318

This review discusses the medicinal plant Phyllanthus niruri Linn. (Euphorbiaceae), its wide variety of phytochemicals and their pharmacological properties. The active phytochemicals, flavonoids, alkaloids, terpenoids, lignans, polyphenols, tannins, coumarins and saponins, have been identified from various parts of P. niruri. Extracts of this herb have been proven to have therapeutic effects in many clinical studies. Some of the most intriguing therapeutic properties include anti-hepatotoxic, anti-lithic, anti-hypertensive, anti-HIV and anti-hepatitis B. Therefore, studies relating to chemical characteristics and structural properties of the bioactive phytochemicals found in P. niruri are very useful for further research on this plant as many of the phytochemicals have shown preclinical therapeutic efficacies for a wide range of human diseases, including HIV/AIDS and hepatitis B.
Plasma alpha-1-acid glycoprotein as a potential predictive biomarker for non-haematological adverse events of docetaxel in breast cancer patients

Jabir RS, Ho GF, Annuar MABA, Stanslas J

Biomarkers, 2018 Mar;23(2):142-146.
PMID: 28554261 DOI: 10.1080/1354750X.2017.1334152

CONTEXT: Rash and oral mucositis are major non-haematological adverse events (AEs) of docetaxel, in addition to fatigue, nausea, vomiting and diarrhoea, which restrict the use of the drug in cancer therapy. Alpha-1-acid glycoprotein (AAG) is an acute phase reactant glycoprotein and is a primary carrier of docetaxel in the blood. Docetaxel has extensive binding (>98%) to plasma proteins such as AAG, lipoproteins and albumin.
OBJECTIVE: To study the association between plasma AAG level and non-haematological AEs of docetaxel in Malaysian breast cancer patients of three major ethnic groups (Malays, Chinese and Indians).
MATERIALS AND METHODS: One hundred and twenty Malaysian breast cancer patients receiving docetaxel as single agent chemotherapy were investigated for AAG plasma level using enzyme-linked immunosorbent assay technique. Toxicity assessment was determined using Common Terminology Criteria of Adverse Events v4.0. The association between AAG and toxicity were then established.
RESULTS: There was interethnic variation of plasma AAG level; it was 182 ± 85 mg/dl in Chinese, 237 ± 94 mg/dl in Malays and 240 ± 83 mg/dl in Indians. It was found that low plasma levels of AAG were significantly associated with oral mucositis and rash.
CONCLUSIONS: This study proposes plasma AAG as a potential predictive biomarker of docetaxel non-haematological AEs namely oral mucositis and rash.
Fulltext Possible Epigenetic Role of Vitexin in Regulating Neuroinflammation in Alzheimer's Disease

Yahaya MAF, Zolkiffly SZI, Moklas MAM, Hamid HA, Stanslas J, Zainol M, et al.

J Immunol Res, 2020;2020:9469210.
PMID: 32258178 DOI: 10.1155/2020/9469210

Alzheimer's disease (AD) has been clinically characterized by a progressive degeneration of neurons which resulted in a gradual and irreversible cognitive impairment. The accumulation of Aβ and τ proteins in the brain contribute to the severity of the disease. Recently, vitexin compound has been the talk amongst researchers due to its pharmacological properties as anti-inflammation and anti-AD. However, the epigenetic mechanism of the compound in regulating the neuroinflammation activity is yet to be fully elucidated. Hence, this review discusses the potential of vitexin compound to have the pharmacoepigenetic property in regulating the neuroinflammation activity in relation to AD. It is with hope that the review would unveil the potential of vitexin as the candidate in treating AD.
Fulltext Predictors of recurrence of major depressive disorder

Lye MS, Tey YY, Tor YS, Shahabudin AF, Ibrahim N, Ling KH, et al.

PLoS One, 2020;15(3):e0230363.
PMID: 32191745 DOI: 10.1371/journal.pone.0230363

A total of 201 patients with major depressive disorder from four hospitals in Malaysia were followed up for 5 years to determine the prognostic factors of recurrent major depressive disorder that could potentially contribute to improving the management of MDD patients. For each individual patient, at the time of recruitment as part of a case-control study, information was collected on recent threatening life events, personality and social and occupational functioning, while blood samples were collected to genotype single nucleotide polymorphisms of vitamin D receptor (VDR), zinc transporter-3 (ZnT3), dopamine transporter-1 (DAT1), brain-derived neurotropic factor (BDNF), serotonin receptor 1A (HT1A) and 2A (HT2A) genes. Kaplan-Meier and Cox-regression were used to estimate hazard functions for recurrence of major depressive disorder. Individuals with severe MDD in previous major depressive episodes had five and a half times higher hazard of developing recurrence compared to mild and moderate MDD (HR = 5.565, 95% CI = 1.631-18.994, p = 0.006). Individuals who scored higher on social avoidance had three and a half times higher hazard of recurrence of MDD (HR = 3.525, 95% CI = 1.349-9.209; p = 0.010). There was significant interaction between ApaI +64978C>A single nucleotide polymorphism and severity. The hazard ratio increased by 6.4 times from mild and moderate to severe MDD for A/A genotype while that for C/A genotype increased by 11.3 times. Social avoidance and severity of depression at first episode were prognostic of recurrence. Screening for personality factors at first encounter with MDD patients needs to be considered as part of the clinical practice. For those at risk of recurrence in relation to social avoidance, the psychological intervention prescribed should be customized to focus on this modifiable factor. Prompt and appropriate management of severe MDD is recommended to reduce risk of recurrence.
Fulltext Proximate Analysis and Safety Profile of Farmed Edible Bird's Nest in Malaysia and Its Effect on Cancer Cells

Tan SN, Sani D, Lim CW, Ideris A, Stanslas J, Lim CTS

Evid Based Complement Alternat Med, 2020;2020:8068797.
PMID: 32051689 DOI: 10.1155/2020/8068797

Edible bird's nest (EBN) which is solidified swiftlet's saliva contains high nutritional value. It is widely consumed in countries like Malaysia, Indonesia, and Thailand. However, previous proximate analysis of Malaysia EBN was not representative of all the regions in Malaysia. In recent years, safety issues such as high nitrate and nitrite contents, presence of heavy metal, adulteration, fungal infection, and cancer cell stimulation were associated with EBN. Hence, this study aimed to determine the proximate analysis, safety profile during normal weather and hazy periods, and its effect on cancer cells stimulation in Malaysia-farmed EBN. Seven raw cleaned EBN samples were sourced from 6 different regions in Malaysia. Proximate analysis and safety profile were performed using official AOCA methods and Malaysian Standard. High protein (53.03-56.37%) and carbohydrate content (27.97-31.68%) with an acceptable level of moisture (10.8-14.04%) and ash (2.22-3.38%) were reported. A good safety profile was obtained with low nitrite and nitrate levels, with undetectable heavy metals and no significant growth of pathogenic microorganism except mould. Epidermal growth factor was detected but below the quantification level with the chicken EGF ELISA kit. The microculture tetrazolium (MTT) assay was performed for growth stimulation assessment comparing human EGF and EBN. There was no significant cell growth observed in cancer cells after EBN treatment. In conclusion, EBN Malaysia has a good nutritional profile, free of heavy metals, and an acceptable level of nitrate, nitrite, and microorganism profile except for mould contents. Furthermore, the in vitro study indicated that EBN was not associated with cancer cell growth.
Fulltext Release behavior and toxicity profiles towards A549 cell lines of ciprofloxacin from its layered zinc hydroxide intercalation compound

Abdul Latip AF, Hussein MZ, Stanslas J, Wong CC, Adnan R

Chem Cent J, 2013;7:119.
PMID: 23849189 DOI: 10.1186/1752-153X-7-119

Layered hydroxides salts (LHS), a layered inorganic compound is gaining attention in a wide range of applications, particularly due to its unique anion exchange properties. In this work, layered zinc hydroxide nitrate (LZH), a family member of LHS was intercalated with anionic ciprofloxacin (CFX), a broad spectrum antibiotic via ion exchange in a mixture solution of water:ethanol.
Role of the IL8 rs4073 polymorphism in central nervous system toxicity in patients receiving multidrug-resistant tuberculosis treatment

Badamasi IM, Muhammad M, Umar AA, Madugu UM, Gadanya MA, Aliyu IA, et al.

J Bras Pneumol, 2024;50(1):e20230338.
PMID: 38359298 DOI: 10.36416/1806-3756/e20230338

OBJECTIVE: To determine the role of the IL8 rs4073 polymorphism in predicting the risk of central nervous system (CNS) toxicity in patients receiving standard pharmacological treatment for multidrug-resistant tuberculosis (MDR-TB).
METHODS: A cohort of 85 consenting MDR-TB patients receiving treatment with second-line antituberculosis drugs had their blood samples amplified for the IL8 (rs4073) gene and genotyped. All patients were clinically screened for evidence of treatment toxicity and categorized accordingly. Crude and adjusted associations were assessed.
RESULTS: The chief complaints fell into the following categories: CNS toxicity; gastrointestinal toxicity; skin toxicity; and eye and ear toxicities. Symptoms of gastrointestinal toxicity were reported by 59% of the patients, and symptoms of CNS toxicity were reported by 42.7%. With regard to the genotypes of IL8 (rs4073), the following were identified: AA, in 64 of the study participants; AT, in 7; and TT, in 11. A significant association was found between the dominant model of inheritance and CNS toxicity for the crude model (p = 0.024; OR = 3.57; 95% CI, 1.18-10.76) and the adjusted model (p = 0.031; OR = 3.92; 95% CI, 1.13-13.58). The AT+TT genotype of IL8 (rs4073) showed a 3.92 times increased risk of CNS toxicity when compared with the AA genotype.
CONCLUSIONS: The AT+TT genotype has a tendency to be associated with an increased risk of adverse clinical features during MDR-TB treatment.
SRJ09, a promising anticancer drug lead: Elucidation of mechanisms of antiproliferative and apoptogenic effects and assessment of in vivo antitumor efficacy

Wong CC, Lim SH, Sagineedu SR, Lajis NH, Stanslas J

Pharmacol Res, 2016 05;107:66-78.
PMID: 26940565 DOI: 10.1016/j.phrs.2016.02.024

SRJ09 (3,19-(2-bromobenzylidene)andrographolide), a semisynthetic andrographolide (AGP) derivative, was shown to induce G1 cell cycle arrest and eventually apoptosis in breast and colon cancer cell lines. The present investigation was carried out to elucidate the mechanisms cell cycle arrest and apoptosis and evaluate the in vivo antitumor activity of SRJ09. The in vitro growth inhibitory properties of compounds were assessed in colon (HCT-116) and breast (MCF-7) cancer cell lines. Immunoblotting was utilized to quantitate the protein levels in cells. The gene expressions were determined using reverse transcriptase PCR (RT-PCR). Pharmacokinetic investigation was carried out by determining SRJ09 levels in plasma of Balb/C mice using HPLC. In vivo antitumor activity was evaluated in athymic mice carrying HCT-116 colon tumor xenografts. SRJ09 displayed improved in vitro activity when compared with AGP by producing rapid cell killing effect in vitro. Its activity was not compromised in MES-SA/Dx5 multidrug resistant (MDR) cells expressing p-glycoprotein. Cells treated with SRJ09 (0.1-10μM) displayed increased p21 protein level, which corresponded with gene expression. Whereas CDK4 protein level and gene expression was suppressed. The treatment did not affect cyclin D1. Changes of these proteins paralleled G1 cell cycle arrest in both cell lines as determined by flow cytometry. Induction of apoptosis by SRJ09 in HCT-116 cells which occurred independent of p53 and bcl-2 was inhibited in the presence of caspase 8 inhibitor, implicating the extrinsic apoptotic pathway. A single dose (100mg/kg, i.p) of SRJ09 produced a plasma concentration range of 12-30.4μM. At 400mg/kg (q4dX3), it significantly retarded growth of tumor xenografts. The antitumor activity of SRJ09 is suggested mediated via the induction of p21 expression and suppression of CDK-4 expression without affecting cyclin D1 to trigger G1 arrest leading to apoptosis.

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