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Fulltext Adipocytokine Regulation and Antiangiogenic Activity Underlie the Molecular Mechanisms of Therapeutic Effects of Phyllanthus niruri against Non-Alcoholic Fatty Liver Disease

Zarzour RHA, Alshawsh MA, Asif M, Al-Mansoub MA, Mohamed Z, Ahmad M, et al.

Nutrients, 2018 Aug 09;10(8).
PMID: 30096951 DOI: 10.3390/nu10081057

The growth of adipose tissues is considered angiogenesis-dependent during non-alcoholic fatty liver disease (NAFLD). We have recently reported that our standardized 50% methanolic extract (ME) of Phyllanthus niruri (50% ME of P. niruri) has alleviated NAFLD in Sprague⁻Dawley rats. This study aimed to assess the molecular mechanisms of action, and to further evaluate the antiangiogenic effect of this extract. NAFLD was induced by eight weeks of high-fat diet, and treatment was applied for four weeks. Antiangiogenic activity was assessed by aortic ring assay and by in vitro tests. Our findings demonstrated that the therapeutic effects of 50% ME among NAFLD rats, were associated with a significant increase in serum adiponectin, reduction in the serum levels of RBP4, vaspin, progranulin, TNF-α, IL-6, and significant downregulation of the hepatic gene expression of PPARγ, SLC10A2, and Collα1. Concomitantly, 50% ME of P. niruri has exhibited a potent antiangiogenic activity on ring assay, cell migration, vascular endothelial growth factor (VEGF), and tube formation, without any cytotoxic effect. Together, our findings revealed that the protective effects of P. niruri against NAFLD might be attributed to its antiangiogenic effect, as well as to the regulation of adipocytokines and reducing the expression of adipogenic genes.
Fulltext Human ACE2 orthologous peptide sequences show better binding affinity to SARS-CoV-2 RBD domain: Implications for drug design

Mahmoudi Azar L, Öncel MM, Karaman E, Soysal LF, Fatima A, Choi SB, et al.

Comput Struct Biotechnol J, 2023;21:4096-4109.
PMID: 37671240 DOI: 10.1016/j.csbj.2023.07.022

Computational methods coupled with experimental validation play a critical role in the identification of novel inhibitory peptides that interact with viral antigenic determinants. The interaction between the receptor binding domain (RBD) of SARS-CoV-2 spike protein and the helical peptide of human angiotensin-converting enzyme-2 (ACE2) is a necessity for the initiation of viral infection. Herein, natural orthologs of human ACE2 helical peptide were evaluated for competitive inhibitory binding to the viral RBD by use of a computational approach, which was experimentally validated. A total of 624 natural ACE2 orthologous 32-amino acid long peptides were identified through a similarity search. Molecular docking was used to virtually screen and rank the peptides based on binding affinity metrics, benchmarked against human ACE2 peptide docked to the RBD. Molecular dynamics (MD) simulations were done for the human reference and the Nipponia nippon peptide as it exhibited the highest binding affinity (Gibbs free energy; -14 kcal/mol) predicted from the docking results. The MD simulation confirmed the stability of the assessed peptide in the complex (-12.3 kcal/mol). The top three docked-peptides (from Chitinophaga sancti, Nipponia nippon, and Mus musculus) and the human reference were experimentally validated by use of surface plasmon resonance technology. The human reference exhibited the weakest binding affinity (Kd of 318-441 pM) among the peptides tested, in agreement with the docking prediction, while the peptide from Nipponia nippon was the best, with 267-538-fold higher affinity than the reference. The validated peptides merit further investigation. This work showcases that the approach herein can aid in the identification of inhibitory biosimilar peptides for other viruses.
Fulltext Analysis of viral diversity for vaccine target discovery

Khan AM, Hu Y, Miotto O, Thevasagayam NM, Sukumaran R, Abd Raman HS, et al.

BMC Med Genomics, 2017 12 21;10(Suppl 4):78.
PMID: 29322922 DOI: 10.1186/s12920-017-0301-2

BACKGROUND: Viral vaccine target discovery requires understanding the diversity of both the virus and the human immune system. The readily available and rapidly growing pool of viral sequence data in the public domain enable the identification and characterization of immune targets relevant to adaptive immunity. A systematic bioinformatics approach is necessary to facilitate the analysis of such large datasets for selection of potential candidate vaccine targets.
RESULTS: This work describes a computational methodology to achieve this analysis, with data of dengue, West Nile, hepatitis A, HIV-1, and influenza A viruses as examples. Our methodology has been implemented as an analytical pipeline that brings significant advancement to the field of reverse vaccinology, enabling systematic screening of known sequence data in nature for identification of vaccine targets. This includes key steps (i) comprehensive and extensive collection of sequence data of viral proteomes (the virome), (ii) data cleaning, (iii) large-scale sequence alignments, (iv) peptide entropy analysis, (v) intra- and inter-species variation analysis of conserved sequences, including human homology analysis, and (vi) functional and immunological relevance analysis.
CONCLUSION: These steps are combined into the pipeline ensuring that a more refined process, as compared to a simple evolutionary conservation analysis, will facilitate a better selection of vaccine targets and their prioritization for subsequent experimental validation.
Genomic analysis and biological characterization of a novel Schitoviridae phage infecting Vibrio alginolyticus

Tajuddin S, Khan AM, Chong LC, Wong CL, Tan JS, Ina-Salwany MY, et al.

Appl Microbiol Biotechnol, 2023 Feb;107(2-3):749-768.
PMID: 36520169 DOI: 10.1007/s00253-022-12312-3

Vibrio alginolyticus is a Gram-negative bacterium commonly associated with mackerel poisoning. A bacteriophage that specifically targets and lyses this bacterium could be employed as a biocontrol agent for treating the bacterial infection or improving the shelf-life of mackerel products. However, only a few well-characterized V. alginolyticus phages have been reported in the literature. In this study, a novel lytic phage, named ΦImVa-1, specifically infecting V. alginolyticus strain ATCC 17749, was isolated from Indian mackerel. The phage has a short latent period of 15 min and a burst size of approximately 66 particles per infected bacterium. ΦImVa-1 remained stable for 2 h at a wide temperature (27-75 °C) and within a pH range of 5 to 10. Transmission electron microscopy revealed that ΦImVa-1 has an icosahedral head of approximately 60 nm in diameter with a short tail, resembling those in the Schitoviridae family. High throughput sequencing and bioinformatics analysis elucidated that ΦImVa-1 has a linear dsDNA genome of 77,479 base pairs (bp), with a G + C content of ~ 38.72% and 110 predicted gene coding regions (106 open reading frames and four tRNAs). The genome contains an extremely large virion-associated RNA polymerase gene and two smaller non-virion-associated RNA polymerase genes, which are hallmarks of schitoviruses. No antibiotic genes were found in the ΦImVa-1 genome. This is the first paper describing the biological properties, morphology, and the complete genome of a V. alginolyticus-infecting schitovirus. When raw mackerel fish flesh slices were treated with ΦImVa-1, the pathogen loads reduced significantly, demonstrating the potential of the phage as a biocontrol agent for V. alginolyticus strain ATCC 17749 in the food. KEY POINTS: • A novel schitovirus infecting Vibrio alginolyticus ATCC 17749 was isolated from Indian mackerel. • The complete genome of the phage was determined, analyzed, and compared with other phages. • The phage is heat stable making it a potential biocontrol agent in extreme environments.
Raphanus sativus Seeds Oil Arrested in vivo Inflammation and Angiogenesis through Down-regulation of TNF-α

Asif M, Yousaf HM, Saleem M, Hussain L, Mahrukh, Zarzour RA, et al.

Curr Pharm Biotechnol, 2022;23(5):728-739.
PMID: 34225619 DOI: 10.2174/1389201022666210702120956

BACKGROUND: Raphanus sativus is traditionally used as an anti-inflammatory agent.
OBJECTIVES: The current study was designed to explore the in vivo anti-inflammatory and antiangiogenic properties of Raphanus sativus seeds oil.
METHODS: Cold press method was used for the extraction of oil (RsSO) and was characterised by using GC-MS techniques. Three in vitro antioxidant assays (DPPH, ABTS and FRAP) were performed to explore the antioxidant potential of RsSO. Disc diffusion methods were used to study in vitro antimicrobial properties. In vivo anti-inflammatory properties were studied in both acute and chronic inflammation models. In vivo chicken chorioallantoic membrane assay was performed to study antiangiogenic effects. Molecular mechanisms were identified using TNF-α ELISA kit and docking tools.
RESULTS: GC-MS analysis of RsSO revealed the presence of hexadecanoic and octadecanoic acid. Findings of DPPH, ABTS, and FRAP models indicated relatively moderate radical scavenging properties of RsSO. Oil showed antimicrobial activity against a variety of bacterial and fungal strains tested. Data of inflammation models showed significant (p < 0.05) anti-inflammatory effects of RsSO in both acute and chronic models. 500 mg/kg RsSO halted inflammation development significantly better (p < 0.05) as compared with lower doses. Histopathological evaluations of paws showed minimal infiltration of inflammatory cells in RsSO-treated animals. Findings of TNF-α ELSIA and docking studies showed that RsSO has the potential to down-regulate the expression of TNF-α, iNOS, ROS, and NF-κB respectively. Moreover, RsSO showed in vivo antiangiogenic effects.
CONCLUSION: Data of the current study highlight that Raphanus sativus seeds oil has anti-inflammatory, and antiangiogenic properties and can be used as an adjunct to standard NSAIDs therapy which may reduce the dose and related side effects.
Fulltext Recent updates in the treatment of neurodegenerative disorders using natural compounds

Rasool M, Malik A, Qureshi MS, Manan A, Pushparaj PN, Asif M, et al.

Evid Based Complement Alternat Med, 2014;2014:979730.
PMID: 24864161 DOI: 10.1155/2014/979730

Neurodegenerative diseases are characterized by protein aggregates and inflammation as well as oxidative stress in the central nervous system (CNS). Multiple biological processes are linked to neurodegenerative diseases such as depletion or insufficient synthesis of neurotransmitters, oxidative stress, abnormal ubiquitination. Furthermore, damaging of blood brain barrier (BBB) in the CNS also leads to various CNS-related diseases. Even though synthetic drugs are used for the management of Alzheimer's disease, Parkinson's disease, autism, and many other chronic illnesses, they are not without side effects. The attentions of researchers have been inclined towards the phytochemicals, many of which have minimal side effects. Phytochemicals are promising therapeutic agents because many phytochemicals have anti-inflammatory, antioxidative as well as anticholinesterase activities. Various drugs of either synthetic or natural origin applied in the treatment of brain disorders need to cross the BBB before they can be used. This paper covers various researches related to phytochemicals used in the management of neurodegenerative disorders.
Fulltext Do domestic innovations promote trade openness? Empirical evidence from emerging economies

Khan MN, Jan AA, Asif M, Lai FW, Shad MK, Shadab S

Heliyon, 2023 Dec;9(12):e22848.
PMID: 38076083 DOI: 10.1016/j.heliyon.2023.e22848

PURPOSE: Innovation activities have gained much importance due to their pivotal role in achieving economic growth - directly by increasing productivity and - indirectly by increasing the degree of trade openness. This study aims to focus on the indirect channel, a rarely explored area of research, especially in the context of emerging economies.
METHODOLOGY: To achieve the aim of the study, four proxies of innovation (resident patent applications, nonresident patent applications, scientific and technical journal articles, and research and development expenditures) are used to establish a robust relationship between innovation activities and trade openness in BRICS economies. Panel data from 2000 to 2020 is obtained from World Development Indicators and Penn World Tables. Econometric techniques of panel data such as fixed effect and generalized least squares are employed to extract results from the specified models.
FINDINGS: The findings of the study revealed that three proxies of innovation (i.e., resident patent applications, nonresident patent applications, scientific and technical journal articles) have a significant positive role in improving trade openness in the BRICS economies. However, the fourth proxy of innovation i.e., research and development expenditures had a negative impact on the degree of trade openness. Besides, innovation activities such as inflation rate and foreign direct investment have also influenced the degree of trade openness positively and significantly. Conversely, GDP per capita had a negative relationship with trade openness. Moreover, domestic investments showed a positive influence on the degree of trade openness while employment had a negative and insignificant influence on the degree of trade openness. Finally, the causality analysis revealed a one-way relationship running from innovations to trade openness.
IMPLICATIONS: In view of the results obtained, the policymakers of the BRICS economies might focus on encouraging innovation activities to enhance the degree of trade openness. Increased trade openness will consequently contribute to economic growth enormously and thus the attainment of sustainable development goals (SDG-8). Policymakers are also suggested to encourage FDI inflows and further ensure a moderate inflation rate to improve the degree of trade openness and hence accelerate economic growth.
ORIGINALITY: This study focused on examining the nexus between innovation activities and trade openness in emerging economies, which is indeed an interesting but rarely explored area of research. The findings of the study might help the policymakers of the BRICS economies in formulating policies regarding trade openness and innovation activities.
High dengue virus load differentially modulates human microvascular endothelial barrier function during early infection

Soe HJ, Khan AM, Manikam R, Samudi Raju C, Vanhoutte P, Sekaran SD

J Gen Virol, 2017 Dec;98(12):2993-3007.
PMID: 29182510 DOI: 10.1099/jgv.0.000981

Plasma leakage is the main pathophysiological feature in severe dengue, resulting from altered vascular barrier function associated with an inappropriate immune response triggered upon infection. The present study investigated functional changes using an electric cell-substrate impedance sensing system in four (brain, dermal, pulmonary and retinal) human microvascular endothelial cell (MEC) lines infected with purified dengue virus, followed by assessment of cytokine profiles and the expression of inter-endothelial junctional proteins. Modelling of changes in electrical impedance suggests that vascular leakage in dengue-infected MECs is mostly due to the modulation of cell-to-cell interactions, while this loss of vascular barrier function observed in the infected MECs varied between cell lines and DENV serotypes. High levels of inflammatory cytokines (IL-6 and TNF-α), chemokines (CXCL1, CXCL5, CXCL11, CX3CL1, CCL2 and CCL20) and adhesion molecules (VCAM-1) were differentially produced in the four infected MECs. Further, the tight junctional protein, ZO-1, was down-regulated in both the DENV-1-infected brain and pulmonary MECs, while claudin-1, PECAM-1 and VE-cadherin were differentially expressed in these two MECs after infection. Non-purified virus stock was also studied to investigate the impact of virus stock purity on dengue-specific immune responses, and the results suggest that virus stock propagated through cell culture may include factors that mask or alter the DENV-specific immune responses of the MECs. The findings of the present study show that high DENV load differentially modulates human microvascular endothelial barrier function and disrupts the function of inter-endothelial junctional proteins during early infection with organ-specific cytokine production.
Fulltext Cytokine expression profile of dengue patients at different phases of illness

Rathakrishnan A, Wang SM, Hu Y, Khan AM, Ponnampalavanar S, Lum LC, et al.

PLoS One, 2012;7(12):e52215.
PMID: 23284941 DOI: 10.1371/journal.pone.0052215

BACKGROUND: Dengue is an important medical problem, with symptoms ranging from mild dengue fever to severe forms of the disease, where vascular leakage leads to hypovolemic shock. Cytokines have been implicated to play a role in the progression of severe dengue disease; however, their profile in dengue patients and the synergy that leads to continued plasma leakage is not clearly understood. Herein, we investigated the cytokine kinetics and profiles of dengue patients at different phases of illness to further understand the role of cytokines in dengue disease.
METHODS AND FINDINGS: Circulating levels of 29 different types of cytokines were assessed by bead-based ELISA method in dengue patients at the 3 different phases of illness. The association between significant changes in the levels of cytokines and clinical parameters were analyzed. At the febrile phase, IP-10 was significant in dengue patients with and without warning signs. However, MIP-1β was found to be significant in only patients with warning signs at this phase. IP-10 was also significant in both with and without warning signs patients during defervescence. At this phase, MIP-1β and G-CSF were significant in patients without warning signs, whereas MCP-1 was noted to be elevated significantly in patients with warning signs. Significant correlations between the levels of VEGF, RANTES, IL-7, IL-12, PDGF and IL-5 with platelets; VEGF with lymphocytes and neutrophils; G-CSF and IP-10 with atypical lymphocytes and various other cytokines with the liver enzymes were observed in this study.
CONCLUSIONS: The cytokine profile patterns discovered between the different phases of illness indicate an essential role in dengue pathogenesis and with further studies may serve as predictive markers for progression to dengue with warning signs.
Fulltext Microencapsulation of fish oil using supercritical antisolvent process

Karim FT, Ghafoor K, Ferdosh S, Al-Juhaimi F, Ali E, Yunus KB, et al.

J Food Drug Anal, 2017 Jul;25(3):654-666.
PMID: 28911651 DOI: 10.1016/j.jfda.2016.11.017

In order to improve the encapsulation process, a newly supercritical antisolvent process was developed to encapsulate fish oil using hydroxypropyl methyl cellulose as a polymer. Three factors, namely, temperature, pressure, and feed emulsion rate were optimized using response surface methodology. The suitability of the model for predicting the optimum response value was evaluated at the conditions of temperature at 60°C, pressure at 150 bar, and feed rate at 1.36 mL/min. At the optimum conditions, particle size of 58.35 μm was obtained. The surface morphology of the micronized fish oil was also evaluated using field emission scanning electron microscopy where it showed that particles formed spherical structures with no internal voids. Moreover, in vitro release of oil showed that there are significant differences of release percentage of oil between the formulations and the results proved that there was a significant decrease in the in vitro release of oil from the powder when the polymer concentration was high.
Fulltext Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers

Lim WC, Marques Da Costa ME, Godefroy K, Jacquet E, Gragert L, Rondof W, et al.

Front Immunol, 2023;14:1265469.
PMID: 38318504 DOI: 10.3389/fimmu.2023.1265469

The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes in 576 children, adolescents and young adults with recurrent/refractory solid tumors from the MOSCATO-01 and MAPPYACTS trials, using normal and tumor whole exome and RNA sequencing data and benchmarked algorithms. There was no evidence for narrowed HLA allelic diversity but discordant homozygosity and allele frequencies across tumor types and subtypes, such as in embryonal and alveolar rhabdomyosarcoma, neuroblastoma MYCN and 11q subtypes, and high-grade glioma, and several alleles may represent protective or susceptibility factors to specific pediatric solid cancers. There was a paucity of somatic mutations in HLA and antigen processing and presentation (APP) genes in most tumors, except in cases with mismatch repair deficiency or genetic instability. The prevalence of loss-of-heterozygosity (LOH) ranged from 5.9 to 7.7% in HLA class I and 8.0 to 16.7% in HLA class II genes, but was widely increased in osteosarcoma and glioblastoma (~15-25%), and for DRB1-DQA1-DQB1 in Ewing sarcoma (~23-28%) and low-grade glioma (~33-50%). HLA class I and HLA-DR antigen expression was assessed in 194 tumors and 44 patient-derived xenografts (PDXs) by immunochemistry, and class I and APP transcript levels quantified in PDXs by RT-qPCR. We confirmed that HLA class I antigen expression is heterogeneous in advanced pediatric solid tumors, with class I loss commonly associated with the transcriptional downregulation of HLA-B and transporter associated with antigen processing (TAP) genes, whereas class II antigen expression is scarce on tumor cells and occurs on immune infiltrating cells. Patients with tumors expressing sufficient HLA class I and TAP levels such as some glioma, osteosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft-tissue sarcoma cases may more likely benefit from T cell-based approaches, whereas strategies to upregulate HLA expression, to expand the immunopeptidome, and to target TAP-independent epitopes or possibly LOH might provide novel therapeutic opportunities in others. The consequences of HLA class II expression by immune cells remain to be established. Immunogenetic profiling should be implemented in routine to inform immunotherapy trials for precision medicine of pediatric cancers.
Fulltext FNG-IE: an improved graph-based method for keyword extraction from scholarly big-data

Tahir N, Asif M, Ahmad S, Malik MSA, Aljuaid H, Butt MA, et al.

PeerJ Comput Sci, 2021;7:e389.
PMID: 33817035 DOI: 10.7717/peerj-cs.389

Keyword extraction is essential in determining influenced keywords from huge documents as the research repositories are becoming massive in volume day by day. The research community is drowning in data and starving for information. The keywords are the words that describe the theme of the whole document in a precise way by consisting of just a few words. Furthermore, many state-of-the-art approaches are available for keyword extraction from a huge collection of documents and are classified into three types, the statistical approaches, machine learning, and graph-based methods. The machine learning approaches require a large training dataset that needs to be developed manually by domain experts, which sometimes is difficult to produce while determining influenced keywords. However, this research focused on enhancing state-of-the-art graph-based methods to extract keywords when the training dataset is unavailable. This research first converted the handcrafted dataset, collected from impact factor journals into n-grams combinations, ranging from unigram to pentagram and also enhanced traditional graph-based approaches. The experiment was conducted on a handcrafted dataset, and all methods were applied on it. Domain experts performed the user study to evaluate the results. The results were observed from every method and were evaluated with the user study using precision, recall and f-measure as evaluation matrices. The results showed that the proposed method (FNG-IE) performed well and scored near the machine learning approaches score.
Fulltext APBioNet-transforming bioinformatics in the Asia-Pacific region

Khan AM, Tan TW, Schönbach C, Ranganathan S

PLoS Comput Biol, 2013 Oct;9(10):e1003317.
PMID: 24204244 DOI: 10.1371/journal.pcbi.1003317
Fulltext A short comparative study on modified Duckworth-Lewis methods

Asif M, Ahmadian A, Azeem M, Pansera BA

PLoS One, 2021;16(11):e0259423.
PMID: 34748588 DOI: 10.1371/journal.pone.0259423

In this paper, the Duckworth-Lewis-Stern (DLS) and Duckworth-Lewis-McHale-Asif (DLMA) methods of revising targets for a team batting in second innings in an interrupted Limited Overs International Cricket (LOI), are examined for fairness. The work discusses four significant points: flexibility, intuition, simplicity, and goodness-of-fit of the two mentioned methods. The research findings have shown that the DLMA method is better in every aspect than the DLS method. Further, the data of 1764 ODI matches played during 2004-2021 to investigate the compatibility of the DLMA for high run-scoring One-Day International matches. The results show that DLMA is compatible to the situation of the well-above run-scoring situation.
Fulltext Complementary effects of Orthosiphon stamineus standardized ethanolic extract and rosmarinic acid in combination with gemcitabine on pancreatic cancer

Yehya AHS, Asif M, Abdul Majid AMS, Oon CE

Biomed J, 2021 Dec;44(6):694-708.
PMID: 35166208 DOI: 10.1016/j.bj.2020.05.015

BACKGROUND: Pancreatic cancer is one of the most notorious cancers and is known for its highly invasive characteristics, drug resistance, and metastatic progression. Unfortunately, many patients with advanced pancreatic cancer become insensitive towards gemcitabine treatment. Orthosiphon stamineus (O.s) is used widely as a traditional medicine for the treatment of multiple ailments, including cancer in South East Asia. The present in vitro study was designed to investigate the complementary effects of an ethanolic extract of O.s (Et. O.s) or rosmarinic acid in combination with gemcitabine on Panc-1 pancreatic cancer cells.
METHOD: Cell viability and colony formation assays were used to determine the 50% inhibitory concentration (IC50) of Et. O.s, rosmarinic acid, and gemcitabine. Different doses of gemcitabine in combination with Et. O.s or rosmarinic acid were tested against Panc-1 to select the best concentrations which possessed synergistic effects. Elucidation of molecular mechanisms responsible for mediating chemo-sensitivity in Panc-1 was performed using Quantitative Real-time PCR (QPCR), flow cytometry and immunohistochemistry.
RESULTS: Et. O.s was found to significantly sensitise Panc-1 towards gemcitabine by reducing the gene expression of multidrug-resistant protein family (MDR) (MDR-1, MRP-4, and MRP-5) and molecules related to epithelial-mesenchymal transition (ZEB-1 and Snail-1). An induction of the human equilibrate nucleoside transporter-1 (hENT-1) gene was also found in cells treated with Et. O.s-gemcitabine. The Et. O.s-gemcitabine combination induced cellular senescence, cell death and cell cycle arrest in Panc-1. In addition, the inhibition of Notch signalling was demonstrated through the downregulation of Notch 1 intracellular domain in this treatment group. In contrast, rosmarinic acid-gemcitabine combination showed no additional effects on cellular senescence, apoptosis, epithelial mesenchymal transition (EMT) markers, the MRP-4 and MRP-5 multi-drug resistance protein family, hENT-1, and the Notch pathway through Notch 1 intracellular domain.
CONCLUSION: This study provides valuable insights on the use of Et. O.s to complement gemcitabine in targeting pancreatic cancer in vitro, suggesting its potential use as a novel complementary treatment in pancreatic cancer patients.
Fulltext Polymolecular botanical drug of Orthosiphon stamineus extract (C5OSEW5050ESA) as a complementary therapy to overcome gemcitabine resistance in pancreatic cancer cells

Yehya AHS, Asif M, Abdul Majid AMS, Oon CE

J Tradit Complement Med, 2023 Jan;13(1):39-50.
PMID: 36685076 DOI: 10.1016/j.jtcme.2022.10.002

BACKGROUND AND AIM: Gemcitabine remains the cornerstone of pancreatic cancer treatment, despite exhibiting a modest effect on patient survival due to the development of drug resistance. Nuvastatic™ polymolecular botanical drug Orthosiphon stamineus (O. stamineus) is a folklore Asian herbal medicine that is used for the treatment of a variety of ailments. However, little is known about the mechanism of actions of the Nuvastatic™ polymolecular botanical drug of O. stamineus as a complementary therapy in resistant pancreatic cancer. It is postulated that the proprietary O. stamineus extract formulation (ID: C5EOSEW5050ESA) in Nuvastatic™ may sensitise resistant pancreatic cancer cells to gemcitabine. This study was conducted to assess the cytotoxic activity and synergistic effects of C5EOSEW5050ESA in gemcitabine-resistant pancreatic cancer cells.
EXPERIMENTAL PROCEDURE: The effects of C5EOSEW5050ESA treatment on cell viability, multidrug-resistant genes, epithelial-mesenchymal transition, cellular senescence, cell death, and Notch signalling pathway were evaluated in gemcitabine-resistant Panc-1 cells.
RESULTS AND CONCLUSION: C5EOSEW5050ESA sensitised gemcitabine resistant cells towards C5EOSEW5050ESA-gemcitabine combination treatment by reducing the expression of multidrug-resistant genes and epithelial-mesenchymal transition markers in gemcitabine-resistant cells compared to the control group, possibly through the inhibition of Notch signalling. This study provides valuable insight into using C5EOSEW5050ESA as a potential complementary treatment for resistant pancreatic cancer.
Fulltext Anti-tumour activity and toxicological studies of combination treatment of Orthosiphon stamineus and gemcitabine on pancreatic xenograft model

Yehya AHS, Subramaniam AV, Asif M, Kaur G, Abdul Majid AMS, Oon CE

World J Gastroenterol, 2022 Aug 28;28(32):4620-4634.
PMID: 36157930 DOI: 10.3748/wjg.v28.i32.4620

BACKGROUND: Pancreatic cancer is the most aggressive cancer type. Gemcitabine is the first line chemo-drug used for pancreatic cancer but exerts a broad spectrum of organ toxicities and adverse effects in patients.
AIM: To evaluate the anti-tumour activity and toxicological effects of Orthosiphon stamineus extract formulation (ID: C5EOSEW5050ESA trademarked as Nuva-staticTM), and gemcitabine combination on pancreatic xenograft model.
METHODS: Mice were randomly divided into six groups of 6 mice each (n = 6) and given different treatments for 28 d. The study design consisted of a 2 x 3 factorial treatment structure, with gemcitabine (yes/no) by oral (at 1200 and 400 mg/kg per day). Human pancreatic cancer cells were injected subcutaneously into the flanks of athymic nude mice. C5EOSEW5050ESA (200 or 400 mg/kg per day) was administered orally, while gemcitabine (10 mg/kg per 3 d) was given intraperitoneally either alone or in combination treatment. Histopathological analyses of vital organs, tumour tissues, and incidence of lethality were analysed. Analyses of tumour necrosis and proliferation were determined by haematoxylin-eosin staining and immunohistochemistry for Ki-67, respectively.
RESULTS: No signs of toxicity or damage to vital organs were observed in all treatment groups compared to the untreated group. C5EOSEW5050ESA at 200 mg/kg and gemcitabine combination had no additive antitumor effects compared to a single treatment. Remarkably, a comparably greater response in a reduction in tumour growth, Ki-67 protein expression, and necrosis was demonstrated by 400 mg/kg of C5EOSEW5050ESA and gemcitabine combination than that of the individual agents.
CONCLUSION: These results highlighted the synergistic activity of C5EOSEW5050ESA with gemcitabine to reduce pancreatic tumour growth in mice compared to a single treatment. Thus, this study provides valuable insights into using C5EOSEW5050ESA as a complementary treatment with gemcitabine for pancreatic cancer.
Fulltext Toxicological studies of Orthosiphon stamineus (Misai Kucing) standardized ethanol extract in combination with gemcitabine in athymic nude mice model

Yehya AHS, Asif M, Kaur G, Hassan LEA, Al-Suede FSR, Abdul Majid AMS, et al.

J Adv Res, 2019 Jan;15:59-68.
PMID: 30581613 DOI: 10.1016/j.jare.2018.05.006

Pancreatic cancer has the highest mortality rate among cancers due to its aggressive biology and lack of effective treatment. Gemcitabine, the first line anticancer drug has reduced efficacy due to acquired resistance. The current study evaluates the toxicological effects of Orthosiphon stamineus (O.s) and its marker compound (rosmarinic acid) in combination with gemcitabine. O.s (200 or 400 mg/kg/day) and rosmarinic acid (32 mg/kg/day) were administered orally and gemcitabine (10 mg/kg/3 days) intraperitoneally either alone or in combination treatment for fourteen days. Parameters including blood serum biochemistry, hematology, myeloid-erythroid ratio, incident of lethality, and histopathological analysis of liver, kidney, and spleen tissues were studied. Neither, individual drugs/extract nor chemo-herbal combinations at tested doses induced any toxicity and damage to organs in nude mice when compared to control group. Toxicological data obtained from this study will help to select the best doses of chemo-herbal combination for future pancreatic xenograft tumor studies.
Fulltext Advancing Personalized Medicine Through the Application of Whole Exome Sequencing and Big Data Analytics

Suwinski P, Ong C, Ling MHT, Poh YM, Khan AM, Ong HS

Front Genet, 2019;10:49.
PMID: 30809243 DOI: 10.3389/fgene.2019.00049

There is a growing attention toward personalized medicine. This is led by a fundamental shift from the 'one size fits all' paradigm for treatment of patients with conditions or predisposition to diseases, to one that embraces novel approaches, such as tailored target therapies, to achieve the best possible outcomes. Driven by these, several national and international genome projects have been initiated to reap the benefits of personalized medicine. Exome and targeted sequencing provide a balance between cost and benefit, in contrast to whole genome sequencing (WGS). Whole exome sequencing (WES) targets approximately 3% of the whole genome, which is the basis for protein-coding genes. Nonetheless, it has the characteristics of big data in large deployment. Herein, the application of WES and its relevance in advancing personalized medicine is reviewed. WES is mapped to Big Data "10 Vs" and the resulting challenges discussed. Application of existing biological databases and bioinformatics tools to address the bottleneck in data processing and analysis are presented, including the need for new generation big data analytics for the multi-omics challenges of personalized medicine. This includes the incorporation of artificial intelligence (AI) in the clinical utility landscape of genomic information, and future consideration to create a new frontier toward advancing the field of personalized medicine.
Treatment of novel IL17A inhibitor in glioblastoma implementing 3rd generation co-culture cell line and patient-derived tumor model

Khan MSS, Asif M, Basheer MKA, Kang CW, Al-Suede FS, Ein OC, et al.

Eur J Pharmacol, 2017 May 15;803:24-38.
PMID: 28322833 DOI: 10.1016/j.ejphar.2017.03.031

Despite many treatment options, cancer remains a growing problem and has become the second leading cause of death globally. Here, we present fluorescence molecular tomography (FMT) data regarding the reversion of third generation co-cultured U87+DBTRG and patient-derived GBM tumor model after treatment with novel IL17A inhibitor named FLVM and FLVZ (organic derivatives of caffeic acid). FMT was used to determine tumor angiogenesis volume (assessment of number of blood vessel; the expression of angiogenic factors CD34 and other angiogenic cancer bio-markers) in U87+DBTRG and patient-derived gliomas. Immunohistochemistry was used to determine microvessel density [CD34], and cell proliferation [Ki67]. Western blot was used to assess the interleukin 17A [IL17A], vascular endothelial growth factor [VEGF] and hypoxia-inducible factor-1α [HIF-1α]. Antibody array was used to assess the cancer bio-markers in co-cultured U87+DBTRG gliomas. Animal survival was found to be significantly increased (P<0.0001) after FLVM treatment compared with control-IL17A. After FMT detection, FLVM, administered orally, was found to decrease tumor growth (P<0.0001). FLVM and FLVZ administration resulted in significant decreases in tumor hypoxia [HIF-1α (P<0.05)], angiogenesis [CD34 (P<0.05)], VEGF, IL17A and cell proliferation [Ki67 (P<0.05)] and caused a significant increase of Bax, caspase and FasL (P<0.05), compared with untreated animals. Additionally, Leptin, LPL (P<0.01), FFA (P<0.05) and adipogenesis were downregulated and no additive toxicity was found in mice except calorie-restriction like effect. Use of FLVM can be considered as a novel inhibitor of IL17A for the treatment of human gliomas.

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