Displaying publications 101 - 120 of 155 in total

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  1. Fulltext A combination of doxycycline and ribavirin alleviated chikungunya infection
    Rothan HA, Bahrani H, Mohamed Z, Teoh TC, Shankar EM, Rahman NA, et al.
    PLoS One, 2015;10(5):e0126360.
    PMID: 25970853 DOI: 10.1371/journal.pone.0126360
    Lack of vaccine and effective antiviral drugs against chikungunya virus (CHIKV) outbreaks have led to significant impact on health care in the developing world. Here, we evaluated the antiviral effects of tetracycline (TETRA) derivatives and other common antiviral agents against CHIKV. Our results showed that within the TETRA derivatives group, Doxycycline (DOXY) exhibited the highest inhibitory effect against CHIKV replication in Vero cells. On the other hand, in the antiviral group Ribavirin (RIBA) showed higher inhibitory effects against CHIKV replication compared to Aciclovir (ACIC). Interestingly, RIBA inhibitory effects were also higher than all but DOXY within the TETRA derivatives group. Docking studies of DOXY to viral cysteine protease and E2 envelope protein showed non-competitive interaction with docking energy of -6.6±0.1 and -6.4±0.1 kcal/mol respectively. The 50% effective concentration (EC50) of DOXY and RIBA was determined to be 10.95±2.12 μM and 15.51±1.62 μM respectively, while DOXY+RIBA (1:1 combination) showed an EC50 of 4.52±1.42 μM. When compared, DOXY showed higher inhibition of viral infectivity and entry than RIBA. In contrast however, RIBA showed higher inhibition against viral replication in target cells compared to DOXY. Assays using mice as animal models revealed that DOXY+RIBA effectively inhibited CHIKV replication and attenuated its infectivity in vivo. Further experimental and clinical studies are warranted to investigate their potential application for clinical intervention of CHIKV disease.
    Matched MeSH terms: Mice, Inbred ICR
  2. Effect of green and ripe Carica papaya epicarp extracts on wound healing and during pregnancy
    Anuar NS, Zahari SS, Taib IA, Rahman MT
    Food Chem Toxicol, 2008 Jul;46(7):2384-9.
    PMID: 18468758 DOI: 10.1016/j.fct.2008.03.025
    The traditional use of papaya to treat many diseases, especially skin conditions and its prohibition for consumption during pregnancy has prompted us to determine whether papaya extracts both from green and ripe fruits improve wound healing and also produce foetal toxicity. Aqueous extracts of green papaya epicarp (GPE) and ripe papaya epicarp (RPE) were applied on induced wounds on mice. GPE treatment induced complete healing in shorter periods (13 days) than that required while using RPE (17 days), sterile water (18 days) and Solcoseryl ointment (21 days). Extracts were administered orally (1 mg/g body weight/day) to pregnant mice from day 10 and onwards after conception. 3 (n=7) mice and 1 (n=6) mice given RPE and misoprostol, an abortive drug, respectively experienced embryonic resorption while this effect was observed in none of the mice given GPE (n=5) and water (n=5). The average body weight of live pups delivered by mice given GPE (1.12+/-0.04 g) was significantly lower than those delivered by mice given water (1.38+/-0.02 g). In SDS-PAGE, proteins were distributed in three bands (Mr range approximately 8-29 kDa). Band intensity at Mr approximately 28-29 kDa was higher in GPE than in RPE. In contrast, band intensity at low Mr (approximately 8 kDa) was found to be higher in RPE than in GPE. Notably, the band corresponding to Mr approximately 23-25 kDa was absent in RPE. These differences in composition may have contributed to the different wound healing and abortive effects of green and ripe papaya.
    Matched MeSH terms: Mice, Inbred ICR
  3. Fulltext Methanol Extract of Dicranopteris linearis Leaves Attenuate Pain via the Modulation of Opioid/NO-Mediated Pathway
    Zakaria ZA, Roosli RAJ, Marmaya NH, Omar MH, Basir R, Somchit MN
    Biomolecules, 2020 02 12;10(2).
    PMID: 32059475 DOI: 10.3390/biom10020280
    Dicranopteris linearis leaf has been reported to exert antinociceptive activity. The present study elucidates the possible mechanisms of antinociception modulated by the methanol extract of D. linearis leaves (MEDL) using various mouse models. The extract (25, 150, and 300 mg/kg) was administered orally to mice for 30 min priot to subjection to the acetic acid-induced writhing-, hot plate- or formalin-test to establish the antinociceptive profile of MEDL. The most effective dose was then used in the elucidation of possible mechanisms of action stage. The extract was also subjected to the phytochemical analyses. The results confirmed that MEDL exerted significant (p < 0.05) antinociceptive activity in those pain models as well as the capsaicin-, glutamate-, bradykinin- and phorbol 12-myristate 13-acetate (PMA)-induced paw licking model. Pretreatment with naloxone (a non-selective opioid antagonist) significantly (p < 0.05) reversed MEDL effect on thermal nociception. Only l-arginine (a nitric oxide (NO) donor) but not N(ω)-nitro-l-arginine methyl ester (l-NAME; a NO inhibitor) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a specific soluble guanylyl cyclase inhibitor) significantly (p < 0.05) modified MEDL effect on the writhing test. Several polyphenolics and volatile antinociceptive compounds were detected in MEDL. In conclusion, MEDL exerted the opioid/NO-mediated antinociceptive activity, thus, justify D. linearis as a potential source for new analgesic agents development.
    Matched MeSH terms: Mice, Inbred ICR
  4. Bone marrow-derived mesenchymal stem cells modulate BV2 microglia responses to lipopolysaccharide
    Ooi YY, Ramasamy R, Rahmat Z, Subramaiam H, Tan SW, Abdullah M, et al.
    Int Immunopharmacol, 2010 Dec;10(12):1532-40.
    PMID: 20850581 DOI: 10.1016/j.intimp.2010.09.001
    The immunoregulatory properties of mesenchymal stem cells (MSC) have been demonstrated on a wide range of cells. Here, we describe the modulatory effects of mouse bone marrow-derived MSC on BV2 microglia proliferation rate, nitric oxide (NO) production and CD40 expression. Mouse bone marrow MSC were co-cultured with BV2 cells at various seeding density ratios and activated with lipopolysaccharide (LPS). We show that MSC exert an anti-proliferative effect on microglia and are potent producers of NO when stimulated by soluble factors released by LPS-activated BV2. MSC suppressed proliferation of both untreated and LPS-treated microglia in a dose-dependent manner, significantly reducing BV2 proliferation at seeding density ratios of 1:0.2 and 1:0.1 (p
    Matched MeSH terms: Mice, Inbred ICR
  5. Fulltext Noni (Morinda citrifolia L.) fruit extract attenuates the rewarding effect of heroin in conditioned place preference but not withdrawal in rodents
    Narasingam M, Pandy V, Mohamed Z
    Exp Anim, 2016 May 20;65(2):157-64.
    PMID: 26744024 DOI: 10.1538/expanim.15-0088
    The present study was designed to investigate the effect of a methanolic extract of Morinda citrifolia Linn. fruit (MMC) on the rewarding effect of heroin in the rat conditioned place preference (CPP) paradigm and naloxone-precipitated withdrawal in mice. In the first experiment, following a baseline preference test (preconditioning score), the rats were subjected to conditioning trials with five counterbalanced escalating doses of heroin versus saline followed by a preference test conducted under drug-free conditions (post-conditioning score) using the CPP test. Meanwhile, in the second experiment, withdrawal jumping was precipitated by naloxone administration after heroin dependence was induced by escalating doses for 6 days (3×/ day). The CPP test results revealed that acute administration of MMC (1, 3, and 5 g/kg body weight (bw), p.o.), 1 h prior to the CPP test on the 12th day significantly reversed the heroin-seeking behavior in a dose-dependent manner, which was similar to the results observed with a reference drug, methadone (3 mg/kg bw, p.o.). On the other hand, MMC (0.5, 1, and 3 g/kg bw, p.o.) did not attenuate the heroin withdrawal jumps precipitated by naloxone. These findings suggest that the mechanism by which MMC inhibits the rewarding effect of heroin is distinct from naloxone-precipitated heroin withdrawal.
    Matched MeSH terms: Mice, Inbred ICR
  6. Fulltext Modulation of interleukin-18 release produced positive outcomes on parasitaemia development and cytokines production during malaria in mice
    Basir R, Hasballah K, Jabbarzare M, Gam LH, Abdul Majid AM, Yam MF, et al.
    Trop Biomed, 2012 Sep;29(3):405-21.
    PMID: 23018504 MyJurnal
    The involvement of interleukin-18 (IL-18) and the effects of modulating its release on the course of malaria infection were investigated using Plasmodium berghei ANKA infection in ICR mice as a model. Results demonstrated that plasma IL-18 concentrations in malarial mice were significantly elevated and positively correlated with the percentage parasitaemia development. Significant expressions of IL-18 were also observed in the brain, spleen and liver tissues. Slower development of parasitaemia was observed significantly upon inhibition and neutralization of IL-18, whereas faster development of parasitaemia was recorded when the circulating levels of IL-18 were further augmented during the infection. Inhibition and neutralization of IL-18 production also resulted in a significant decrease of plasma concentrations of pro-inflammatory cytokines (TNFα, IFNγ, IL-1α and IL-6), whereas the anti-inflammatory cytokine, IL-10, was significantly increased. Augmenting the release of IL- 18 during the infection on the other hand resulted in the opposite. Early mortality in malarial mice was also observed when the circulating levels of IL-18 were further augmented. Results proved the important role of IL-18 in immune response against malaria and suggest that IL-8 is pro-inflammatory in nature and may involve in mediating the severity of the infection through a pathway of elevating the pro-inflammatory cytokine and limiting the release of anti-inflammatory cytokine.
    Matched MeSH terms: Mice, Inbred ICR
  7. Fulltext Suppression of Plasmodium berghei parasitemia by LiCl in an animal infection model
    Nurul Aiezzah Z, Noor E, Hasidah MS
    Trop Biomed, 2010 Dec;27(3):624-31.
    PMID: 21399604 MyJurnal
    Malaria, caused by the Plasmodium parasite is still a health problem worldwide due to resistance of the pathogen to current anti-malarials. The search for new anti-malarial agents has become more crucial with the emergence of chloroquine-resistant Plasmodium falciparum strains. Protein kinases such as mitogen-activated protein kinase (MAPK), MAPK kinase, cyclin-dependent kinase (CDK) and glycogen synthase kinase- 3(GSK-3) of parasitic protozoa are potential drug targets. GSK-3 is an enzyme that plays a vital role in multiple cellular processes, and has been linked to pathogenesis of several diseases such as type II diabetes and Alzheimer's disease. In the present study, the antiplasmodial property of LiCl, a known GSK-3 inhibitor, was evaluated in vivo for its antimalarial effect against mice infected with Plasmodium berghei. Infected ICR mice were intraperitoneally administered with LiCl for four consecutive days before (prophylactic test) and after (suppressive test) inoculation of P. berghei-parasitised erythrocytes. Results from the suppressive test (post-infection LiCl treatment) showed inhibition of erythrocytic parasitemia development by 62.06%, 85.67% and 85.18% as compared to nontreated controls for the 100 mg/kg, 300 mg/kg and 600 mg/kg dosages respectively. Both 300 mg/kg and 600 mg/kg LiCl showed similar significant (P<0.05) suppressive values to that obtained with chloroquine-treated mice (86% suppression). The prophylactic test indicated a significantly (P<0.05) high protective effect on mice pre-treated with LiCl with suppression levels relatively comparable to chloroquine (84.07% and 86.26% suppression for the 300 mg/kg and 600 mg/kg LiCl dosages respectively versus 92.86% suppression by chloroquine). In both the suppressive and prophylactic tests, LiCl-treated animals survived longer than their non-treated counterparts. Mortality of the non-treated mice was 100% within 6 to 7 days of parasite inoculation whereas mice administered with LiCl survived beyond 9 days. Healthy non-infected mice administered with 600 mg/ kg LiCl for four consecutive days also showed decreased mortality compared to animals receiving lower doses of LiCl; three of the seven mice intraperitoneally injected with the former dose of LiCl did not survive more than 24 h after administration of LiCl whereas animals given the lower LiCl doses survived beyond four days of LiCl administration. To date, no direct evidence of anti-malarial activity in vivo or in vitro has been reported for LiCl. Evidence of anti-plasmodial activity of lithium in a mouse infection model is presented in this study.
    Matched MeSH terms: Mice, Inbred ICR
  8. Anti-malarial and cytokine-modulating effects of andrographolide in a murine model of malarial infection
    Hassan WRM, Basir R, Ali AH, Embi N, Sidek HM
    Trop Biomed, 2019 Sep 01;36(3):776-791.
    PMID: 33597499
    Malarial pathogenesis involves among others, uncontrolled or excessive cytokine production arising from dysregulated immune responses mounted by the host to eliminate the plasmodial parasite. The ubiquitous serine/threonine kinase, glycogen synthase kinase3β (GSK3β) is a crucial regulator of the balance between pro- and anti-inflammatory cytokine productions in the inflammatory response to pathogenic infections. Andrographolide, a bioactive compound in Andrographis paniculata, displays GSK3- inhibitory effects. A previous study elsewhere has shown that this compound has antimalarial activity but the molecular basis of its action is yet to be elucidated. Here we aimed to study the anti-malarial activity of andrographolide in a murine model of malarial infection to investigate whether its mechanism of action involves cytokine modulation and inhibition of GSK3β. Andrographolide showed strong and selective anti-plasmodial activity (IC50 = 13.70±0.71 µM; SI = 30.43) when tested against cultures of P. falciparum 3D7. Intraperitoneal administration of andrographolide (5 mg/kg body weight (bw)) into P. berghei NK65-infected ICR mice resulted in chemo-suppression of 60.17±2.12%, and significantly (P<0.05) improved median survival time of infected mice compared to nontreated control. In addition, andrographolide treatment significantly (P<0.05) decreased the level of serum pro-inflammatory cytokine, IFN-γ (1.4-fold) whilst the anti-inflammatory cytokines, IL-10 and IL-4 were increased 2.3- and 2.6-fold respectively. Western blot analyses revealed that andrographolide treatment of P. berghei NK65-infected mice resulted in an increased level of phosphorylated GSK3β (Ser9) in liver of infected mice. Andrographolide administration also decreased the levels of phosphorylated NF-κB p65 (Ser536) and phosphorylated Akt (Ser473) in liver of malaria- infected animals. Taken together, our findings demonstrate that the cytokine-modulating effect of andrographolide in experimental malarial infection involves at least in part inhibition of NF-κB activation as a consequence of GSK3β inhibition. Based on its cytokine-modulating effects, andrographolide is thus a plausible candidate for adjunctive therapy in malaria subject to clinical evaluations.
    Matched MeSH terms: Mice, Inbred ICR
  9. Morinda citrifolia leaf enhanced performance by improving angiogenesis, mitochondrial biogenesis, antioxidant, anti-inflammatory & stress responses
    Mohamad Shalan NA, Mustapha NM, Mohamed S
    Food Chem, 2016 Dec 01;212:443-52.
    PMID: 27374554 DOI: 10.1016/j.foodchem.2016.05.179
    Morinda citrifolia fruit, (noni), enhanced performances in athletes and post-menopausal women in clinical studies. This report shows the edible noni leaves water extract enhances performance in a weight-loaded swimming animal model better than the fruit or standardized green tea extract. The 4weeks study showed the extract (containing scopoletin and epicatechin) progressively prolonged the time to exhaustion by threefold longer than the control, fruit or tea extract. The extract improved (i) the mammalian antioxidant responses (MDA, GSH and SOD2 levels), (ii) tissue nutrient (glucose) and metabolite (lactate) management, (iii) stress hormone (cortisol) regulation; (iv) neurotransmitter (dopamine, noradrenaline, serotonin) expressions, transporter or receptor levels, (v) anti-inflammatory (IL4 & IL10) responses; (v) skeletal muscle angiogenesis (VEGFA) and (v) energy and mitochondrial biogenesis (via PGC, UCP3, NRF2, AMPK, MAPK1, and CAMK4). The ergogenic extract helped delay fatigue by enhancing energy production, regulation and efficiency, which suggests benefits for physical activities and disease recovery.
    Matched MeSH terms: Mice, Inbred ICR
  10. Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug-drug interaction in mice
    Liew MH, Ng S, Chew CC, Koo TW, Chee YL, Chee EL, et al.
    Invest New Drugs, 2017 04;35(2):145-157.
    PMID: 28070719 DOI: 10.1007/s10637-016-0415-y
    The sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60 mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC0→∞, 31% and 27% lower liver and kidney AUC0→∞ and 2.2-fold higher AUC0→∞ in brain (all p mice. Paracetamol decreased 29% plasma AUC0→∞ (p mice and remained unchanged in female mice. In male and female mice, it decreased liver (15%, 9%), kidney (15%, 20%) and brain (47%, 50%) AUC0→∞ (p mice (p 
    Matched MeSH terms: Mice, Inbred ICR
  11. Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice
    Chew CC, Ng S, Chee YL, Koo TW, Liew MH, Chee EL, et al.
    Invest New Drugs, 2017 08;35(4):399-411.
    PMID: 28285369 DOI: 10.1007/s10637-017-0447-y
    Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC0→∞ 38% in plasma (p mice. In brain, sunitinib exposure decreased 46% (p mice and 30% in kidney (p mice, probably owing to effects on efflux transporters. Sunitinib displayed sex-divergent DDI with diclofenac with probable clinical translatability due to potential different effects in male and female patients requiring careful selection of the NSAID and advanced TDM to implement a personalized treatment.
    Matched MeSH terms: Mice, Inbred ICR
  12. Fulltext Protective effect of α-asarone against nicotine-induced seizures in mice, but not by its interaction with nicotinic acetylcholine receptors
    Chellian R, Pandy V
    Biomed Pharmacother, 2018 Dec;108:1591-1595.
    PMID: 30372861 DOI: 10.1016/j.biopha.2018.09.137
    Alpha-asarone is one of the bioactive phytochemicals present in the rhizomes of Acorus species and demonstrated its anticonvulsant activity in rodents. Alpha-asarone protected mice from the gamma-aminobutyric acid (GABA) type A receptor antagonist or N-methyl-d-aspartate (NMDA) receptor agonist-induced seizures. In our recent study, α-asarone attenuated the nicotine withdrawal-induced depression-like behavior in mice. The seizures induced by nicotine is mediated through the activation of nicotinic acetylcholine receptors (nAChRs) and stimulation of NMDA receptors. Therefore, we hypothesized that α-asarone might be effective against nicotine-induced seizures. Also, the interaction of α-asarone with nAChRs is unknown. In this study, we investigated the effect of α-asarone on the locomotor activity and body temperature in mice. In addition, we studied the effect of α-asarone on nicotine-induced seizures in mice. Finally, we assessed in vivo pharmacodynamic interaction of α-asarone with nAChRs using nicotine-induced hypomotility and hypothermia tests in mice. The results of this study showed that the α-asarone (50-200 mg/kg, i.p.) and diazepam (5 mg/kg, i.p.) treatment significantly decreased the locomotor activity and body temperature in mice. Furthermore, α-asarone (50-200 mg/kg, i.p.) and diazepam (5 mg/kg, i.p.) pretreatment significantly prolonged the onset time of nicotine-induced seizures in mice. However, α-asarone (30 and 50 mg/kg, i.p.) pretreatment did not inhibit the nicotine-induced hypomotility or hypothermia in mice. Conversely, mecamylamine (1 mg/kg, s.c.) pretreatment completely blocked the nicotine-induced seizures and significantly prevents the nicotine-induced hypomotility and hypothermia in mice. Overall, these results suggest that the protective effect of α-asarone against nicotine-induced seizures did not mediate through the antagonism of nAChRs. We also postulated that the GABAergic and glutamatergic activities of α-asarone could be involved in its protective effect against nicotine-induced seizures and based on this aspect further studies are required.
    Matched MeSH terms: Mice, Inbred ICR
  13. Japanese Encephalitis Virus Infects the Thalamus Early Followed by Sensory-Associated Cortex and Other Parts of the Central and Peripheral Nervous Systems
    Fu TL, Ong KC, Tan SH, Wong KT
    J. Neuropathol. Exp. Neurol., 2019 12 01;78(12):1160-1170.
    PMID: 31675093 DOI: 10.1093/jnen/nlz103
    Japanese encephalitis (JE) is a known CNS viral infection that often involves the thalamus early. To investigate the possible role of sensory peripheral nervous system (PNS) in early neuroinvasion, we developed a left hindlimb footpad-inoculation mouse model to recapitulate human infection by a mosquito bite. A 1-5 days postinfection (dpi) study, demonstrated focal viral antigens/RNA in contralateral thalamic neurons at 3 dpi in 50% of the animals. From 4 to 5 dpi, gradual increase in viral antigens/RNA was observed in bilateral thalami, somatosensory, and piriform cortices, and then the entire CNS. Infection of neuronal bodies and adjacent nerves in dorsal root ganglia (DRGs), trigeminal ganglia, and autonomic ganglia (intestine, etc.) was also observed from 5 dpi. Infection of explant organotypic whole brain slice cultures demonstrated no viral predilection for the thalamus, while DRG and intestinal ganglia organotypic cultures confirmed sensory and autonomic ganglia susceptibility to infection, respectively. Early thalamus and sensory-associated cortex involvement suggest an important role for sensory pathways in neuroinvasion. Our results suggest that JE virus neuronotropism is much more extensive than previously known, and that the sensory PNS and autonomic system are susceptible to infection.
    Matched MeSH terms: Mice, Inbred ICR
  14. Fulltext Electrostatic interactions at the five-fold axis alter heparin-binding phenotype and drive enterovirus A71 virulence in mice
    Tee HK, Tan CW, Yogarajah T, Lee MHP, Chai HJ, Hanapi NA, et al.
    PLoS Pathog, 2019 11;15(11):e1007863.
    PMID: 31730673 DOI: 10.1371/journal.ppat.1007863
    Enterovirus A71 (EV-A71) causes hand, foot and mouth disease epidemics with neurological complications and fatalities. However, the neuropathogenesis of EV-A71 remains poorly understood. In mice, adaptation and virulence determinants have been mapped to mutations at VP2-149, VP1-145 and VP1-244. We investigate how these amino acids alter heparin-binding phenotype and shapes EV-A71 virulence in one-day old mice. We constructed six viruses with varying residues at VP1-98, VP1-145 (which are both heparin-binding determinants) and VP2-149 (based on the wild type 149K/98E/145Q, termed KEQ) to generate KKQ, KKE, KEE, IEE and IEQ variants. We demonstrated that the weak heparin-binder IEE was highly lethal in mice. The initially strong heparin-binding IEQ variant acquired an additional mutation VP1-K244E, which confers weak heparin-binding phenotype resulting in elevated viremia and increased virus antigens in mice brain, with subsequent high virulence. IEE and IEQ-244E variants inoculated into mice disseminated efficiently and displayed high viremia. Increasing polymerase fidelity and impairing recombination of IEQ attenuated the virulence, suggesting the importance of population diversity in EV-A71 pathogenesis in vivo. Combining in silico docking and deep sequencing approaches, we inferred that virus population diversity is shaped by electrostatic interactions at the five-fold axis of the virus surface. Electrostatic surface charges facilitate virus adaptation by generating poor heparin-binding variants for better in vivo dissemination in mice, likely due to reduced adsorption to heparin-rich peripheral tissues, which ultimately results in increased neurovirulence. The dynamic switching between heparin-binding and weak heparin-binding phenotype in vivo explained the neurovirulence of EV-A71.
    Matched MeSH terms: Mice, Inbred ICR
  15. Annona muricata leaves extracts prevent DMBA/TPA-induced skin tumorigenesis via modulating antioxidants enzymes system in ICR mice
    Md Roduan MR, Hamid RA, Sulaiman H, Mohtarrudin N
    Biomed Pharmacother, 2017 Oct;94:481-488.
    PMID: 28779710 DOI: 10.1016/j.biopha.2017.07.133
    Annona muricata, locally known as soursop has been reported to exhibit antiproliferative activities against various cancer cell lines. In this current study, we have investigated the antitumor promotion of various fractions of Annona muricata leaves (AML); hexane (AMLH), dichloromethane (AMLD) and methanol (AMLM) fraction respectively on 7, 12-dimethylbenz[α]anthracene (DMBA) induced and 12-0-tetradecaboylphorbol-13-acetate (TPA) promoted skin tumorigenesis in mice via morphological assessment, biochemical analysis and histopathological evaluation. The results of the study revealed significant inhibition in tumor incidence, tumor burden and tumor volume in the groups received AMLH and AMLD, respectively, and suppressive effects in group received AMLM compared with carcinogen control group at week 21. Superoxide dismutase, catalase, and lipid peroxidation levels were returned to near normal by administration of AML to DMBA/TPA-induced mice. The above findings were supported by histopathological studies, in which the extensive epidermal hyperplasia in carcinogen control group was restored to normal in AML treated groups. Whilst, annonacin, a major annaonaceous acetogenin was found to be the highest in AMLH and AMLD. From the present study, it can be inferred that AML supressed DMBA/TPA-induced skin tumor and this antitumor-promoting activity may be linked to the antioxidant/free radical-scavenging constituents of the extract and annonacin contained in the extracts.
    Matched MeSH terms: Mice, Inbred ICR
  16. Fulltext Methanol leaf extract ofActinodaphne sesquipedalis(Lauraceae) enhances gastric defense against ethanol-induced ulcer in rats
    Omar H, Nordin N, Hassandarvish P, Hajrezaie M, Azizan AHS, Fadaeinasab M, et al.
    Drug Des Devel Ther, 2017;11:1353-1365.
    PMID: 28496305 DOI: 10.2147/DDDT.S120564
    Actinodaphne sesquipedalis
    Hook. F. Var. Glabra (Kochummen), also known as "Medang payung" by the Malay people, belongs to the Lauraceae family. In this study, methanol leaf extract ofA. sesquipedaliswas investigated for their acute toxicity and gastroprotective effects to reduce ulcers in rat stomachs induced by ethanol. The rats were assigned to one of five groups: normal group (group 1), ulcer group (group 2), control positive drug group (group 3) and two experimental groups treated with 150 mg/kg (group 4) and 300 mg/kg (group 5) of leaf extract. The rats were sacrificed an hour after pretreatment with extracts, and their stomach homogenates and tissues were collected for further evaluation. Macroscopic and histological analyses showed that gastric ulcers in rats pretreated with the extract were significantly reduced to an extent that it allowed leukocytes penetration of the gastric walls compared with the ulcer group. In addition, an ulcer inhibition rate of >70% was detected in rats treated with both doses ofA. sesquipedalisextract, showing a notable protection of gastric layer. Severe destruction of gastric mucosa was prevented with a high production of mucus and pH gastric contents in both omeprazole-treated and extract-treated groups. Meanwhile, an increase in glycoprotein uptake was observed in pretreated rats through accumulation of magenta color in Periodic Acid Schiff staining assay. Analysis of gastric homogenate from pretreated rats showed a reduction of malondialdehyde and elevation of nitric oxide, glutathione, prostaglandin E2, superoxide dismutase and protein concentration levels in comparison with group 2. Suppression of apoptosis in gastric tissues by upregulation of Hsp70 protein and downregulation of Bax protein was also observed in rats pretreated with extract. Consistent results of a reduction of gastric ulcer and the protection of gastric wall were obtained for rats pretreated withA. sesquipedalisextract, which showed its prominent gastroprotective potential in rats' stomach against ethanol-induced ulcer.
    Matched MeSH terms: Mice, Inbred ICR
  17. Fulltext Unraveling the cytotoxicity and metabolic pathways of binary natural deep eutectic solvent systems
    Mbous YP, Hayyan M, Wong WF, Looi CY, Hashim MA
    Sci Rep, 2017 02 01;7:41257.
    PMID: 28145498 DOI: 10.1038/srep41257
    In this study, the anticancer potential and cytotoxicity of natural deep eutectic solvents (NADESs) were assessed using HelaS3, PC3, A375, AGS, MCF-7, and WRL-68 hepatic cell lines. NADESs were prepared from choline chloride, fructose, or glucose and compared with an N,N-diethyl ethanolammonium chloride:triethylene glycol DES. The NADESs (98 ≤ EC50 ≥ 516 mM) were less toxic than the DES (34 ≤ EC50 ≥ 120 mM). The EC50 values of the NADESs were significantly higher than those of the aqueous solutions of their individual components but were similar to those of the aqueous solutions of combinations of their chief elements. Due to the uniqueness of these results, the possibility that NADESs could be synthesized intracellularly to counterbalance the cytotoxicity of their excess principal constituents must be entertained. However, further research is needed to explore this avenue. NADESs exerted cytotoxicity by increasing membrane porosity and redox stress. In vivo, they were more destructive than the DES and induced liver failure. The potential of these mixtures was evidenced by their anticancer activity and intracellular processing. This infers that they can serve as tools for increasing our understanding of cell physiology and metabolism. It is likely that we only have begun to comprehend the nature of NADESs.
    Matched MeSH terms: Mice, Inbred ICR
  18. Lactobacilli-fermented cow's milk attenuated lipopolysaccharide-induced neuroinflammation and memory impairment in vitro and in vivo
    Musa NH, Mani V, Lim SM, Vidyadaran S, Abdul Majeed AB, Ramasamy K
    J Dairy Res, 2017 Nov;84(4):488-495.
    PMID: 29154736 DOI: 10.1017/S0022029917000620
    Nutritional interventions are now recommended as strategies to delay Alzheimer's disease (AD) progression. The present study evaluated the neuroprotective effect (anti-inflammation) of lactic acid bacteria (either Lactobacillus fermentum LAB9 or L. casei LABPC) fermented cow's milk (CM) against lipopolysaccharide (LPS)-activated microglial BV2 cells in vitro. The ability of CM-LAB in attenuating memory deficit in LPS-induced mice was also investigated. ICR mice were orally administered with CM-LAB for 28 d before induction of neuroinflammation by LPS. Learning and memory behaviour were assessed using the Morris Water Maze Test. Brain tissues were homogenised for measurement of acetylcholinesterase (AChE), antioxidative, lipid peroxidation (malondialdehyde (MDA)) and nitrosative stress (NO) parameters. Serum was collected for cytokine analysis. CM-LAB9 and CM-LABPC significantly (P < 0·05) decreased NO level but did not affect CD40 expression in vitro. CM-LAB attenuated LPS-induced memory deficit in mice. This was accompanied by significant (P < 0·05) increment of antioxidants (SOD, GSH, GPx) and reduction of MDA, AChE and also pro-inflammatory cytokines. Unfermented cow's milk (UCM) yielded greater cytokine lowering effect than CM-LAB. The present findings suggest that attenuation of LPS-induced neuroinflamation and memory deficit by CM-LAB could be mediated via anti-inflammation through inhibition of AChE and antioxidative activities.
    Matched MeSH terms: Mice, Inbred ICR
  19. Sunitinib DDI with paracetamol, diclofenac, mefenamic acid and ibuprofen shows sex-divergent effects on the tissue uptake and distribution pattern of sunitinib in mice
    Tan SY, Wong MM, Tiew AL, Choo YW, Lim SH, Ooi IH, et al.
    Cancer Chemother Pharmacol, 2016 10;78(4):709-18.
    PMID: 27495788 DOI: 10.1007/s00280-016-3120-9
    PURPOSE: Pharmacokinetic interaction of sunitinib with diclofenac, paracetamol, mefenamic acid and ibuprofen was evaluated due to their P450 mediated metabolism and OATP1B1, OATP1B3, ABCB1, ABCG2 transporters overlapping features.

    METHODS: Male and female mice were administered 6 sunitinib doses (60 mg/kg) PO every 12 h and 30 min before the last dose were administered vehicle (control groups), 250 mg/kg paracetamol, 30 mg/kg diclofenac, 50 mg/kg mefenamic acid or 30 mg/kg ibuprofen (study groups), euthanized 6 h post last administration and sunitinib plasma, liver, kidney, brain concentrations analyzed.

    RESULTS: Ibuprofen halved sunitinib plasma concentration in female mice (p mice (p mice showed 45 and 25 % higher plasma concentrations than male mice which were 27 % lower in mefenamic acid female mice. Paracetamol increased 2.2 (p mice that were lower in female mice (p mice that were higher than in female mice (p mice had 35 % higher sunitinib brain concentration than male mice but the concentration decreased 37, 33, 10 and 57 % in the diclofenac, paracetamol, mefenamic acid and ibuprofen (p mice (liver, brain) and female mice (liver, kidney).

    CONCLUSIONS: These results portray gender-based sunitinib pharmacokinetic differences and NSAIDs selective effects on male or female mice, with potential clinical translatability.

    Matched MeSH terms: Mice, Inbred ICR
  20. Fulltext α6GABAA Receptor Positive Modulators Alleviate Migraine-like Grimaces in Mice via Compensating GABAergic Deficits in Trigeminal Ganglia
    Tzeng HR, Lee MT, Fan PC, Knutson DE, Lai TH, Sieghart W, et al.
    Neurotherapeutics, 2021 Jan;18(1):569-585.
    PMID: 33111258 DOI: 10.1007/s13311-020-00951-1
    Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) play an important role. This hyperactivity might originate from an underfunctional GABAergic system in TG. To investigate this possibility, we adapted a mouse model of migraine by inducing migraine-like grimaces in male mice via repeated injections of nitroglycerin (NTG, 10 mg/kg, i.p.), once every 2 days, for up to 5 sessions. Migraine-like facial pain scores were measured using the mouse grimace scale. Repeated NTG treatments in mice caused significant increases in migraine-like grimaces that were aborted and prevented by two anti-migraine agents sumatriptan and topiramate, respectively. After 5 sessions of NTG injections, the GABA-synthesizing enzyme, 65-kDa glutamate decarboxylase (GAD65), but not the GABA transporter 1 (GAT1) or the α6 subunit-containing GABAA receptors (α6GABAARs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG α6GABAAR expression in NTG-treated mice, we demonstrated that an α6GABAAR-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both abortive and prophylactic effects, comparable to those of sumatriptan and topiramate, respectively, in this migraine-mimicking mouse model. The brain-impermeable furosemide significantly prevented the effects of DK-I-56-1, suggesting its peripheral site of action, likely via preventing α6GABAAR modulation in TG. Results suggest that a decreased GABA synthesis caused by the reduced GAD65 expression in TG contributes to the trigeminovascular activation in this repeated NTG-induced migraine-mimicking model and that the unaltered α6GABAARs in TG are potential targets for migraine treatment. Thus, α6GABAAR-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies.
    Matched MeSH terms: Mice, Inbred ICR
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