Displaying publications 1 - 20 of 24 in total

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  1. Choudhury H, Pandey M, Chin PX, Phang YL, Cheah JY, Ooi SC, et al.
    Drug Deliv Transl Res, 2018 10;8(5):1545-1563.
    PMID: 29916012 DOI: 10.1007/s13346-018-0552-2
    Treatment of glioblastoma multiforme (GBM) is a predominant challenge in chemotherapy due to the existence of blood-brain barrier (BBB) which restricts delivery of chemotherapeutic agents to the brain together with the problem of drug penetration through hard parenchyma of the GBM. With the structural and mechanistic elucidation of the BBB under both physiological and pathological conditions, it is now viable to target central nervous system (CNS) disorders utilizing the presence of transferrin (Tf) receptors (TfRs). However, overexpression of these TfRs on the GBM cell surface can also help to avoid restrictions of GBM cells to deliver chemotherapeutic agents within the tumor. Therefore, targeting of TfR-mediated delivery could counteract drug delivery issues in GBM and create a delivery system that could cross the BBB effectively to utilize ligand-conjugated drug complexes through receptor-mediated transcytosis. Hence, approach towards successful delivery of antitumor agents to the gliomas has been making possible through targeting these overexpressed TfRs within the CNS and glioma cells. This review article presents a thorough analysis of current understanding on Tf-conjugated nanocarriers as efficient drug delivery system.
  2. Mak KK, Epemolu O, Pichika MR
    Drug Discov Today, 2021 Nov 10.
    PMID: 34774767 DOI: 10.1016/j.drudis.2021.11.005
    The successful regulatory authority approval rate of drug candidates in the drug development pipeline is crucial for determining pharmaceutical research and development (R&D) efficiency. Regulatory authorities include the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceutical and Food Safety Bureau Japan (PFSB), among others. Optimal drug metabolism and pharmacokinetics (DMPK) properties influence the progression of a drug candidate from the preclinical to the clinical phase. In this review, we provide a comprehensive assessment of essential concepts, methods, improvements, and challenges in DMPK science and its significance in drug development. This information provides insights into the association of DMPK science with pharmaceutical R&D efficiency.
  3. Lai CM, Mak KK, Watanabe H, Jeong J, Kim D, Bahar N, et al.
    Public Health, 2015 Sep;129(9):1224-36.
    PMID: 26343546 DOI: 10.1016/j.puhe.2015.07.031
    OBJECTIVES: This study examines the associations of Internet addiction with social anxiety, depression, and psychosocial well-being among Asian adolescents. A self-medication model conceptualizing Internet addiction as a mediating role in relating depression and social anxiety to negative psychosocial well-being was tested.
    STUDY DESIGN: A cross-sectional survey.
    METHODS: In the Asian Adolescent Risk Behavior Survey (AARBS), 5366 adolescents aged 12-18 years from six Asian countries (China, Hong Kong, Japan, South Korea, Malaysia, and Philippines) completed a questionnaire with items of the Internet Addiction Test (IAT), Social Anxiety Scale for Adolescents (SAS-A), Center for Epidemiological Studies Depression Scale (CESD), Self-Rated Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA-SR) in the 2012-2013 school year. Structural equation modelling was used to examine the mediating role of Internet addiction in depression, social anxiety, and subjective psychosocial well-being.
    RESULTS: Significant differences on the scores of IAT, SAS-A, CESD, and HoNOSCA-SR across the six countries were found. The proposed self-medication model of Internet addiction received satisfactory goodness-of-fit with data of all countries. After the path from social anxiety to Internet addiction had been discarded in the revised model, there was a significant improvement of the goodness-of-fit in the models for Japan, South Korea, and the Philippines.
    CONCLUSIONS: Depression and social anxiety reciprocally influenced, whereas depression associated with poorer psychosocial well-being directly and indirectly through Internet addiction in all six countries. Internet addiction mediated the association between social anxiety and poor psychosocial well-being in China, Hong Kong, and Malaysia.
    KEYWORDS: Adolescents; Asian; Depression; Internet addiction; Social anxiety; Structural equation modelling
  4. Lasing T, Phumee A, Siriyasatien P, Chitchak K, Vanalabhpatana P, Mak KK, et al.
    Bioorg Med Chem, 2020 01 01;28(1):115187.
    PMID: 31761725 DOI: 10.1016/j.bmc.2019.115187
    In a search for potent antileishmanial drug candidates, eighteen rhodacyanine analogues bearing fluorine or perfluoroalkyl substituents at various positions were synthesized. These compounds were tested for their inhibitory activities against Leishmania martiniquensis and L. orientalis. This 'fluorine-walk' analysis revealed that the introduction of fluorine atom at C-5, 6, 5', or 6' on the benzothiazole units led to significant enhancement of the activity, correlating with the less negative reduction potentials of the fluorinated analogues confirmed by the electrochemical study. On the other hand, CF3 and OCF3 groups were found to have detrimental effects, which agreed with the poor aqueous solubility predicted by the in silico ADMET analysis. In addition, some of the analogues including the difluorinated species showed exceptional potency against the promastigote and axenic amastigote stages (IC50 = 40-85 nM), with the activities surpassing both amphotericin B and miltefosine.
  5. Bapat RA, Muthusamy SK, Sidhu P, Mak KK, Parolia A, Pichika MR, et al.
    Macromol Biosci, 2021 Dec 06.
    PMID: 34870895 DOI: 10.1002/mabi.202100326
    Novel 3D-biomaterial scaffold is constructed having a combination of a new quaternary ammonium silane (k21) antimicrobial impregnated in 3D collagen printed scaffolds cross linked with Riboflavin in presence of d-alpha-tocopheryl poly(ethyleneglycol)-1000-succinate. Groups of "0.1% and 0.2% k21", and "0.1% and 0.2% Chlorhexidine (CHX)" are prepared. k21/CHX with neutralized collagen is printed with BioX. Riboflavin is photo-activated and examined using epifluorescence for Aggregatibacter actinomycetemcomitans (7-days). Collagen is examined using TEM and measured for porosity, and shape-fitting. Raman and tandem mass/solid-state are performed with molecular-docking and circular-dichroism. X-ray diffractions, rheological tests, contact angle, and ninhydrin assay are conducted. k21 samples demonstrated collagen aggregates while 0.1% CHX and 0.2% CHX showed irregularities. Porosity of control and "0.1% and 0.2% k21" scaffolds show no differences. Low contact angle, improved elastic-modulus, rigidity, and smaller strain in k21 groups are seen. Bacteria are reduced and strong organic intensities are seen in k21 scaffolds. Simulation shows hydrophobicity/electrostatic interaction. Crosslinking is observed in 0.2% CHX/79% and 0.2% k21/80%. Circular dichroism for k21 are suggestive of triple helix. XRD patterns appear at d = 5.97, 3.03, 2.78, 2.1, and 2.90 A°. 3D-printing of collagen impregnated with quaternary ammonium silane produces a promising scaffold with antimicrobial potency and structural stability.
  6. Shiming Z, Mak KK, Balijepalli MK, Chakravarthi S, Pichika MR
    Biomed Pharmacother, 2021 Jul;139:111576.
    PMID: 33862494 DOI: 10.1016/j.biopha.2021.111576
    Diabetes mellitus or type-2 diabetes, commonly referred as diabetes, is a metabolic disorder that results in high blood sugar level. Despite the availability of several antidiabetic drugs in the market, they still do not adequately regulate blood sugar levels. Thus, in general people prefer to use herbal supplements/medicines along with antidiabetic drugs to control blood sugar levels. One of such herbal medicine is Swietenia macrophylla seeds. It is widely used in Asia for controlling blood sugar levels. One of the major bioactive compounds, Swietenine, is reported to be responsible for controlling blood glucose levels. However, there were no studies on its efficacy in controlling the blood glucose in diabetic rats. In this study, we evaluated the antihyperglycemic activity of Swietenine and its pharmacodynamic interaction with Metformin in Streptozotocin induced diabetes in rats. The activity of Swietenine was investigated at three different doses: 10, 20 and 40 mg/kg body weight (bw). Metformin (50 mg/kg bw) was used as a standard drug. Swietenine (20 and 40 mg/kg bw) and Metformin (50 mg/kg bw) showed significant effect in reducing the glucose, cholesterol, triglycerides, low-density lipoprotein, urea, creatinine, alanine transaminase, alkaline phosphatase, aspartate transaminase, alanine transaminase, and malondialdehyde level in serum while it had increased the high-density lipoprotein, glutathione, and total antioxidant capacity level. In addition, Swietenine (20 and 40 mg/kg) had shown significant synergistic effect with Metformin. Administration of Swietenine at 10 mg/kg bw neither showed activity nor influenced Metformin's activity. The results from this study confirmed the beneficial effects of Swietenine and its synergistic action with Metformin in controlling the dysregulated serum parameters in Streptozotocin induced diabetes in rats.
  7. Mak KK, Zhang S, Chellian J, Mohd Z, Epemolu O, Dinkova-Kostova AT, et al.
    Antioxidants (Basel), 2023 Feb 27;12(3).
    PMID: 36978843 DOI: 10.3390/antiox12030595
    Our previous studies have reported the effect of swietenine (a major bioactive component of Swietenia macrophylla seeds) in reversing and potentiating the effect of metformin in hyperglycemia and hyperlipidaemia in diabetic rats. Moreover, we reported that the anti-inflammatory effect of swietenine is mediated via the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). This study evaluated the effect of swietenine and its mechanisms in nonalcoholic fatty liver disease (NAFLD) in high-fat diet/streptozotocin-induced diabetic mice. The effect was assessed by determining blood biochemical parameters (glucose, cholesterol, triglycerides, alanine transaminase (ALT), asparate transaminase (AST), alkaline phosphatase (ALP), glutathione (GSH), total antioxidant capacity (TAC), and malondialdehyde (MDA)) and liver biochemical parameters (liver index, cholesterol, and triglycerides). Hepatic lipid accumulation (initial causative factor in NAFLD) was determined by oil-O-red staining. Gene expression (qPCR) and immunohistochemical studies were performed to elucidate the mechanism of swietenine's effect in NAFLD. The critical regulators (genes and proteins) involved in lipogenesis (ACLY, ACC1, FASN, SREBP1c, and ChREBPβ) and oxidative stress (Nrf2, NQO-1 and HO-1) pathways were determined. In mice fed with a high-fat diet followed by streptozotocin injection, the liver cholesterol, triglycerides, and lipids were elevated. These increases were reversed by the oral administration of swietenine, 80 mg/kg body weight, on alternate days for eight weeks. Gene expression and immunohistochemical studies showed that swietenine reversed the elevated levels of crucial enzymes of lipogenesis (ACLY, ACC1 and FASN) and their master transcription factors (SREBP1c and ChREBPβ). Furthermore, swietenine activated the Nrf2 antioxidant defense mechanism, as evidenced by the upregulated levels of Nrf2, NQO-1, and HO-1. It is concluded that swietenine shows beneficial effects in diabetes-induced NAFLD via inhibiting lipogenesis and activating the Nrf2 pathway.
  8. Mak KK, Balijepalli MK, Pichika MR
    Expert Opin Drug Discov, 2022 Jan;17(1):79-92.
    PMID: 34553659 DOI: 10.1080/17460441.2022.1985108
    INTRODUCTION: Artificial intelligence (AI) in drug discovery and development (DDD) has gained more traction in the past few years. Many scientific reviews have already been made available in this area. Thus, in this review, the authors have focused on the success stories of AI-driven drug candidates and the scientometric analysis of the literature in this field.

    AREA COVERED: The authors explore the literature to compile the success stories of AI-driven drug candidates that are currently being assessed in clinical trials or have investigational new drug (IND) status. The authors also provide the reader with their expert perspectives for future developments and their opinions on the field.

    EXPERT OPINION: Partnerships between AI companies and the pharma industry are booming. The early signs of the impact of AI on DDD are encouraging, and the pharma industry is hoping for breakthroughs. AI can be a promising technology to unveil the greatest successes, but it has yet to be proven as AI is still at the embryonic stage.

  9. Chellian J, Mak KK, Chellappan DK, Krishnappa P, Pichika MR
    Sci Rep, 2022 Dec 10;12(1):21393.
    PMID: 36496468 DOI: 10.1038/s41598-022-25739-5
    The antidiabetic effects of quercetin and metformin are well known. However, their synergistic effect in reversing the symptoms of diabetes-induced endothelial dysfunction remains unknown. In this study, we have investigated their synergistic effect in streptozotocin (STZ)-nicotinamide induced diabetic rats. Seventy-five rats were divided into five groups; normal control, diabetic control, treatment groups (10 mg/kg quercetin, 180 mg/kg metformin, and combined). The plasma glucose and lipid levels, liver enzymes, ex-vivo studies on aortic rings, histology of liver, kidney, pancreas, abdominal aorta and thoracic aorta, and immunohistochemical studies were carried out. The findings revealed that the combination of quercetin and metformin showed a greater antidiabetic effect than either drug, and rendered protection to the endothelium. The combination effectively reversed the hyperglycemia-induced endothelial dysfunction in diabetic rats. Furthermore, it also reversed the dysregulated expression of eNOS, 3-nitrotyrosine, VCAM-1, CD31 and SIRT-1. Overall, the present study's findings demonstrate that quercetin potentiates the activity of metformin to control the complications associated with diabetes.
  10. Bapat RA, Mak KK, Pichika MR, Pang JC, Lin SL, Khoo SP, et al.
    BMC Oral Health, 2024 Mar 25;24(1):382.
    PMID: 38528501 DOI: 10.1186/s12903-024-04069-0
    AIMS AND OBJECTIVES: To analyze anti-MMP mode of action of Quaternary Ammonium Silane (QAS, codenamed as k21) by binding onto specific MMP site using computational molecular simulation and Anti-Sortase A (SrtA) mode of action by binding onto specific site using computational molecular simulation.

    MATERIALS AND METHODS: In silico Molecular Dynamics (MD) was used to determine the interactions of K21 inside the pocket of the targeted protein (crystal structure of fibroblast collagenase-1 complexed to a diphenyl-ether sulphone based hydroxamic acid; PDB ID: 966C; Crystal structure of MMP-2 active site mutant in complex with APP-derived decapeptide inhibitor. MD simulations were accomplished with the Desmond package in Schrödinger Drug Discovery Suite. Blood samples (~ 0.5 mL) collected into K2EDTA were immediately transferred for further processing using the Litron MicroFlow® PLUS micronucleus analysis kit for mouse blood according to the manufacturer's instructions. Bacterial Reverse Mutation Test of K21 Molecule was performed to evaluate K21 and any possible metabolites for their potential to induce point mutations in amino acid-requiring strains of Escherichia coli (E. coli) (WP2 uvrA (tryptophan-deficient)).

    RESULTS: Molecular Simulation depicted that K21 has a specific pocket binding on various MMPs and SrtA surfaces producing a classical clouting effect. K21 did not induce micronuclei, which are the result of chromosomal damage or damage to the mitotic apparatus, in the peripheral blood reticulocytes of male and female CD-1 mice when administered by oral gavage up to the maximum recommended dose of 2000 mg/kg. The test item, K21, was not mutagenic to Salmonella typhimurium (S. typhimurium) strains TA98, TA100, TA1535 and TA1537 and E. coli strain WP2 uvrA in the absence and presence of metabolic activation when tested up to the limit of cytotoxicity or solubility under the conditions of the test.

    CONCLUSION: K21 could serve as a potent protease inhibitor maintaining the physical and biochemical properties of dental structures.

  11. Daood U, Omar H, Qasim S, Nogueira LP, Pichika MR, Mak KK, et al.
    J Mech Behav Biomed Mater, 2020 10;110:103927.
    PMID: 32957222 DOI: 10.1016/j.jmbbm.2020.103927
    OBJECTIVE: Here we describe a novel formulation, based on quaternary ammonium (QA) and riboflavin (RF), which combines antimicrobial activities and protease inhibitory properties with collagen crosslinking without interference to bonding capabilities, was investigated.

    METHODS: Experimental adhesives modified with different fractions of dioctadecyldimethyl ammonium bromide quaternary ammonium and riboflavin (QARF) were formulated. Dentine specimens were bonded to resincomposites with control or the experimental adhesives to be evaluated for bond strength, interfacial morphology, micro-Raman analysis, nano-CT and nano-leakage expression. In addition, the antibacterial and biocompatibilities of the experimental adhesives were investigated. The endogenous proteases activities and their molecular binding-sites were studied.

    RESULTS: Modifying the experimental adhesives with QARF did not adversely affect micro-tensile bond strength or the degree of conversion along with the demonstration of anti-proteases and antibacterial abilities with acceptable biocompatibilities. In general, all experimental adhesives demonstrated favourable bond strength with increased and improved values in 1% QARF adhesive at 24 h (39.2 ± 3.0 MPa) and following thermocycling (34.8 ± 4.3 MPa).

    SIGNIFICANCE: It is possible to conclude that the use of QARF with defined concentration can maintain bond strength values when an appropriate protocol is used and have contributed in ensuring a significant decrease in microbial growth of biofilms. Incorporation of 1% QARF in the experimental adhesive lead to simultaneous antimicrobial and anti-proteolytic effects with low cytotoxic effects, acceptable bond strength and interfacial morphology.

  12. Daood U, Gopinath D, Pichika MR, Mak KK, Seow LL
    Molecules, 2021 Apr 12;26(8).
    PMID: 33921378 DOI: 10.3390/molecules26082214
    To determine whether quaternary ammonium (k21) binds to Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) spike protein via computational molecular docking simulations, the crystal structure of the SARS-CoV-2 spike receptor-binding domain complexed with ACE-2 (PDB ID: 6LZG) was downloaded from RCSB PD and prepared using Schrodinger 2019-4. The entry of SARS-CoV-2 inside humans is through lung tissues with a pH of 7.38-7.42. A two-dimensional structure of k-21 was drawn using the 2D-sketcher of Maestro 12.2 and trimmed of C18 alkyl chains from all four arms with the assumption that the core moiety k-21 was without C18. The immunogenic potential of k21/QA was conducted using the C-ImmSim server for a position-specific scoring matrix analyzing the human host immune system response. Therapeutic probability was shown using prediction models with negative and positive control drugs. Negative scores show that the binding of a quaternary ammonium compound with the spike protein's binding site is favorable. The drug molecule has a large Root Mean Square Deviation fluctuation due to the less complex geometry of the drug molecule, which is suggestive of a profound impact on the regular geometry of a viral protein. There is high concentration of Immunoglobulin M/Immunoglobulin G, which is concomitant of virus reduction. The proposed drug formulation based on quaternary ammonium to characterize affinity to the SARS-CoV-2 spike protein using simulation and computational immunological methods has shown promising findings.
  13. Lai CM, Mak KK, Cheng C, Watanabe H, Nomachi S, Bahar N, et al.
    Cyberpsychol Behav Soc Netw, 2015 Oct;18(10):609-17.
    PMID: 26468915 DOI: 10.1089/cyber.2015.0069
    There has been increased research examining the psychometric properties on the Internet Addiction Test (IAT) in different populations. This population-based study examined the psychometric properties and measurement invariance of the IAT in adolescents from three Asian countries. In the Asian Adolescent Risk Behavior Survey (AARBS), 2,535 secondary school students (55.9% girls) aged 12-18 years from Hong Kong (n=844), Japan (n=744), and Malaysia (n=947) completed a survey in 2012-2013 school year. A nested hierarchy of hypotheses concerning the IAT cross-country invariance was tested using multigroup confirmatory factor analyses. Replicating past findings in Hong Kong adolescents, the construct of the IAT is best represented by a second-order three-factor structure in Malaysian and Japanese adolescents. Configural, metric, scalar, and partial strict factorial invariance was established across the three samples. No cross-country differences on Internet addiction were detected at the latent mean level. This study provided empirical support for the IAT as a reliable and factorially stable instrument, and valid to be used across Asian adolescent populations.
  14. Low JS, Mak KK, Zhang S, Pichika MR, Marappan P, Mohandas K, et al.
    Fitoterapia, 2021 Oct;154:105026.
    PMID: 34480992 DOI: 10.1016/j.fitote.2021.105026
    Wounds still pose a huge burden on human health and healthcare systems in many parts of the world. Phytomedicines are being used to heal the wounds since ancient times. Now-a-days also many researchers are exploring the wound healing activity of phytomedicines. Wound healing is a complex process thus, it is always a question mark regarding the best test model (in vivo, ex vivo and in vitro) model to assess the wound healing activity of phytomedicines. In general, the researchers would opt for in vivo model - probably because of closer physiological relevance to human wounds. However, in vivo experimental models are not suitable for high throughput screening and not ethical in terms of initial screening of the phytomedicines. The in vivo models are associated with difficulties in obtaining the ethical approvals, requires huge budget, and resources. We argue that judicious selection of cell types would serve the purpose of developing a physiologically relevant in vitro experimental model. A lot of progress has been made in molecular biology techniques to bridge the gap between in vitro models and their physiological relevance. The in vitro models are the best suited for high throughput screening and to elucidate the molecular mechanisms. The main aim of this review is to provide insights on selection of the cell types for developing physiologically relevant in vitro wound healing assays, which can be used to improve the value of phytomedicines further.
  15. Mak KK, Lai CM, Watanabe H, Kim DI, Bahar N, Ramos M, et al.
    Cyberpsychol Behav Soc Netw, 2014 Nov;17(11):720-8.
    PMID: 25405785 DOI: 10.1089/cyber.2014.0139
    Internet addiction has become a serious behavioral health problem in Asia. However, there are no up-to-date country comparisons. The Asian Adolescent Risk Behavior Survey (AARBS) screens and compares the prevalence of Internet behaviors and addiction in adolescents in six Asian countries. A total of 5,366 adolescents aged 12-18 years were recruited from six Asian countries: China, Hong Kong, Japan, South Korea, Malaysia, and the Philippines. Participants completed a structured questionnaire on their Internet use in the 2012-2013 school year. Internet addiction was assessed using the Internet Addiction Test (IAT) and the Revised Chen Internet Addiction Scale (CIAS-R). The variations in Internet behaviors and addiction across countries were examined. The overall prevalence of smartphone ownership is 62%, ranging from 41% in China to 84% in South Korea. Moreover, participation in online gaming ranges from 11% in China to 39% in Japan. Hong Kong has the highest number of adolescents reporting daily or above Internet use (68%). Internet addiction is highest in the Philippines, according to both the IAT (5%) and the CIAS-R (21%). Internet addictive behavior is common among adolescents in Asian countries. Problematic Internet use is prevalent and characterized by risky cyberbehaviors.
  16. Parolia A, Kumar H, Ramamurthy S, Madheswaran T, Davamani F, Pichika MR, et al.
    Molecules, 2021 Jan 30;26(3).
    PMID: 33573147 DOI: 10.3390/molecules26030715
    To determine the antibacterial effect of propolis nanoparticles (PNs) as an endodontic irrigant against Enterococcus faecalis biofilm inside the endodontic root canal system. Two-hundred-ten extracted human teeth were sectioned to obtain 6 mm of the middle third of the root. The root canal was enlarged to an internal diameter of 0.9 mm. The specimens were inoculated with E. faecalis for 21 days. Following this, specimens were randomly divided into seven groups, with 30 dentinal blocks in each group including: group I-saline; group II-propolis 100 µg/mL; group III-propolis 300 µg/mL; group IV-propolis nanoparticle 100 µg/mL; group V-propolis nanoparticle 300µg/mL; group VI-6% sodium hypochlorite; group VII-2% chlorhexidine. Dentin shavings were collected at 200 and 400 μm depths, and total numbers of CFUs were determined at the end of one, five, and ten minutes. The non-parametric Kruskal-Wallis and Mann-Whitney tests were used to compare the differences in reduction in CFUs between all groups, and probability values of p < 0.05 were set as the reference for statistically significant results. The antibacterial effect of PNs as an endodontic irrigant was also assessed against E. faecalis isolates from patients with failed root canal treatment. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) were also performed after exposure to PNs. A Raman spectroscope, equipped with a Leica microscope and lenses with curve-fitting Raman software, was used for analysis. The molecular interactions between bioactive compounds of propolis (Pinocembrin, Kaempferol, and Quercetin) and the proteins Sortase A and β-galactosidase were also understood by computational molecular docking studies. PN300 was significantly more effective in reducing CFUs compared to all other groups (p < 0.05) except 6% NaOCl and 2% CHX (p > 0.05) at all time intervals and both depths. At five minutes, 6% NaOCl and 2% CHX were the most effective in reducing CFUs (p < 0.05). However, no significant difference was found between PN300, 6% NaOCl, and 2% CHX at 10 min (p > 0.05). SEM images also showed the maximum reduction in E. faecalis with PN300, 6% NaOCl, and 2% CHX at five and ten minutes. CLSM images showed the number of dead cells in dentin were highest with PN300 compared to PN100 and saline. There was a reduction in the 484 cm-1 band and an increase in the 870 cm-1 band in the PN300 group. The detailed observations of the docking poses of bioactive compounds and their interactions with key residues of the binding site in all the three docking protocols revealed that the interactions were consistent with reasonable docking and IFD docking scores. PN300 was equally as effective as 6% NaOCl and 2% CHX in reducing the E. faecalis biofilms.
  17. Kandasamy M, Mak KK, Devadoss T, Thanikachalam PV, Sakirolla R, Choudhury H, et al.
    BMC Chem, 2019 Dec;13(1):117.
    PMID: 31572984 DOI: 10.1186/s13065-019-0633-4
    Background: The transcription factor Nuclear factor erythroid-2-related factor 2 (NRF2) and its principal repressive regulator, Kelch-like ECH-associated protein 1 (KEAP1), are perilous in the regulation of inflammation, as well as maintenance of homeostasis. Thus, NRF2 activation is involved in cytoprotection against many inflammatory disorders. N'-Nicotinoylquinoxaline-2-carbohdyrazide (NQC) was structurally designed by the combination of important pharmacophoric features of bioactive compounds reported in the literature.

    Methods: NQC was synthesised and characterised using spectroscopic techniques. The compound was tested for its anti-inflammatory effect using Lipopolysaccharide from Escherichia coli (LPSEc) induced inflammation in mouse macrophages (RAW 264.7 cells). The effect of NQC on inflammatory cytokines was measured using enzyme-linked immune sorbent assay (ELISA). The Nrf2 activity of the compound NQC was determined using 'Keap1:Nrf2 Inhibitor Screening Assay Kit'. To obtain the insights on NQC's activity on Nrf2, molecular docking studies were performed using Schrödinger suite. The metabolic stability of NQC was determined using mouse, rat and human microsomes.

    Results: NQC was found to be non-toxic at the dose of 50 µM on RAW 264.7 cells. NQC showed potent anti-inflammatory effect in an in vitro model of LPSEc stimulated murine macrophages (RAW 264.7 cells) with an IC50 value 26.13 ± 1.17 µM. NQC dose-dependently down-regulated the pro-inflammatory cytokines [interleukin (IL)-1β (13.27 ± 2.37 μM), IL-6 (10.13 ± 0.58 μM) and tumor necrosis factor (TNF)-α] (14.41 ± 1.83 μM); and inflammatory mediator, prostaglandin E2 (PGE2) with IC50 values, 15.23 ± 0.91 µM. Molecular docking studies confirmed the favourable binding of NQC at Kelch domain of Keap-1. It disrupts the Nrf2 interaction with kelch domain of keap 1 and its IC50 value was 4.21 ± 0.89 µM. The metabolic stability studies of NQC in human, rat and mouse liver microsomes revealed that it is quite stable with half-life values; 63.30 ± 1.73, 52.23 ± 0.81, 24.55 ± 1.13 min; microsomal intrinsic clearance values; 1.14 ± 0.31, 1.39 ± 0.87 and 2.96 ± 0.34 µL/min/g liver; respectively. It is observed that rat has comparable metabolic profile with human, thus, rat could be used as an in vivo model for prediction of pharmacokinetics and metabolism profiles of NQC in human.

    Conclusion: NQC is a new class of NRF2 activator with potent in vitro anti-inflammatory activity and good metabolic stability.

  18. Bijle MN, Pichika MR, Mak KK, Parolia A, Babar MG, Yiu C, et al.
    Molecules, 2021 Oct 31;26(21).
    PMID: 34771014 DOI: 10.3390/molecules26216605
    This study's objective was to examine L-arginine (L-arg) supplementation's effect on mono-species biofilm (Streptococcus mutans/Streptococcus sanguinis) growth and underlying enamel substrates. The experimental groups were 1%, 2%, and 4% arg, and 0.9% NaCl was used as the vehicle control. Sterilised enamel blocks were subjected to 7-day treatment with test solutions and S. mutans/S. sanguinis inoculum in BHI. Post-treatment, the treated biofilms stained for live/dead bacterial cells were analysed using confocal microscopy. The enamel specimens were analysed using X-ray diffraction crystallography (XRD), Raman spectroscopy (RS), and transmission electron microscopy (TEM). The molecular interactions between arg and MMP-2/MMP-9 were determined by computational molecular docking and MMP assays. With increasing arg concentrations, bacterial survival significantly decreased (p < 0.05). The XRD peak intensity with 1%/2% arg was significantly higher than with 4% arg and the control (p < 0.05). The bands associated with the mineral phase by RS were significantly accentuated in the 1%/2% arg specimens compared to in other groups (p < 0.05). The TEM analysis revealed that 4% arg exhibited an ill-defined shape of enamel crystals. Docking of arg molecules to MMPs appears feasible, with arg inhibiting MMP-2/MMP-9 (p < 0.05). L-arginine supplementation has an antimicrobial effect on mono-species biofilm. L-arginine treatment at lower (1%/2%) concentrations exhibits enamel hydroxyapatite stability, while the molecule has the potential to inhibit MMP-2/MMP-9.
  19. Mak KK, Ho CS, Zhang MW, Day JR, Ho RC
    Asian J Psychiatr, 2013 Oct;6(5):373-9.
    PMID: 24011683 DOI: 10.1016/j.ajp.2013.03.011
    Overdosing is an accessible method adopted by people attempting suicide in city settings.
  20. Jogi H, Maheshwari R, Raval N, Kuche K, Tambe V, Mak KK, et al.
    Nanomedicine (Lond), 2018 May;13(10):1187-1220.
    PMID: 29905493 DOI: 10.2217/nnm-2017-0397
    Cancer is estimated to be a significant health problem of the 21st century. The situation gets even tougher when it comes to its treatment using chemotherapy employing synthetic anticancer molecules with numerous side effects. Recently, there has been a paradigm shift toward the adoption of herbal drugs for the treatment of cancer. In this context, a suitable delivery system is principally warranted to deliver these herbal biomolecules specifically at the tumorous site. To achieve this goal, carbon nanotubes (CNTs) have been widely explored to deliver anticancer herbal molecules with improved therapeutic efficacy and safety. This review uniquely expounds the biopharmaceutical, clinical and safety aspects of different anticancer herbal drugs delivered through CNTs with a cross-talk on their outcomes. This review will serve as a one-stop-shop for the readers on various anticancer herbal drugs delivered through CNTs as a futuristic delivery device.
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