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Effect of melatonin supplementation and cross-fostering on renal glutathione system and development of hypertension in spontaneously hypertensive rats

Siew-Keah L, Sundaram A, Sirajudeen KN, Zakaria R, Singh HJ

J Physiol Biochem, 2014 Mar;70(1):73-9.
PMID: 23975651 DOI: 10.1007/s13105-013-0282-3

Antenatal and postnatal environments are hypothesised to influence the development of hypertension. This study investigates the synergistic effect of cross-fostering and melatonin supplementation on the development of hypertension and renal glutathione system in spontaneously hypertensive rats (SHR). In one experiment, 1-day-old male SHR pups were fostered to either SHR (shr-SHR) or Wistar-Kyoto rats, (shr-WKY). In a concurrent experiment, SHR dams were given melatonin in drinking water (10 mg/kg body weight) from day 1 of pregnancy. Immediately following delivery, 1-day-old male pups were fostered either to SHR (Mel-shr-SHR) or WKY (Mel-shr-WKY) dams receiving melatonin supplementation until weaning on day 21. Upon weaning, melatonin supplementation was continued to these pups until the age of 16 weeks. Systolic blood pressures (SBP) were recorded at the age of 4, 6, 8, 12 and 16 weeks. Renal antioxidant activities were measured. Mean SBP of shr-WKY, Mel-shr-SHR and Mel-shr-WKY was significantly lower than that in shr-SHR until the age of 8 weeks. At 12 and 16 weeks of age, mean SBP of Mel-shr-WKY was lower than those in non-treated shr-SHR and shr-WKY pups but was not significantly different from that in Mel-shr-SHR. Renal glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities were significantly higher in Mel-shr-SHR and Mel-shr-WKY at 16 weeks of age. It appears that combination of cross-fostering and melatonin supplementation exerts no synergistic effect on delaying the rise in blood pressure in SHR. The elevated GPx and GST activities are likely to be due to the effect of melatonin supplementation.

Matched MeSH terms: Drug Evaluation, Preclinical
Chalcones and bis-chalcones: As potential α-amylase inhibitors; synthesis, in vitro screening, and molecular modelling studies

Tajudeen Bale A, Mohammed Khan K, Salar U, Chigurupati S, Fasina T, Ali F, et al.

Bioorg Chem, 2018 09;79:179-189.
PMID: 29763804 DOI: 10.1016/j.bioorg.2018.05.003

Despite of a diverse range of biological activities associated with chalcones and bis-chalcones, they are still neglected by the medicinal chemist for their possible α-amylase inhibitory activity. So, the current study is based on the evaluation of this class for the identification of new leads as α-amylase inhibitors. For that purpose, a library of substituted chalcones 1-13 and bis-chalcones 14-18 were synthesized and characterized by spectroscopic techniques EI-MS and 1H NMR. CHN analysis was carried out and found in agreement with the calculated values. All compounds were evaluated for in vitro α-amylase inhibitory activity and demonstrated good activities in the range of IC50 = 1.25 ± 1.05-2.40 ± 0.09 µM as compared to the standard acarbose (IC50 = 1.04 ± 0.3 µM). Limited structure-activity relationship (SAR) was established by considering the effect of different groups attached to aryl rings on varying inhibitory activity. SMe group in chalcones and OMe group in bis-chalcones were found more influential on the activity than other groups. However, in order to predict the involvement of different groups in the binding interactions with the active site of α-amylase enzyme, in silico studies were also conducted.

Matched MeSH terms: Drug Evaluation, Preclinical
Benzoxazinone-thiosemicarbazones as antidiabetic leads via aldose reductase inhibition: Synthesis, biological screening and molecular docking study

Shehzad MT, Imran A, Njateng GSS, Hameed A, Islam M, Al-Rashida M, et al.

Bioorg Chem, 2019 06;87:857-866.
PMID: 30551808 DOI: 10.1016/j.bioorg.2018.12.006

Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC50 values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC50 values of 0.52 ± 0.04 and 0.19 ± 0.03 μM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC50 value of 3.14 ± 0.02 μM).

Matched MeSH terms: Drug Evaluation, Preclinical
Isolate resistance of Blastocystis hominis to metronidazole

Haresh K, Suresh K, Khairul Anus A, Saminathan S

Trop Med Int Health, 1999 Apr;4(4):274-7.
PMID: 10357863

Isolates of Blastocystis hominis from infected immigrant workers from Indonesia, Bangladesh and infected individuals from Singapore and Malaysia were assessed for growth pattern and degree of resistance to different concentrations of metronidazole. Viability of the cells was assessed using eosin-brillian cresyl blue which stained viable cells green and nonviable cells red. The Bangladeshi and Singaporean isolates were nonviable even at the lowest concentration of 0.01 mg/ml, whereas 40% of the initial inoculum of parasites from the Indonesian isolate at day one were still viable in cultures with 1.0 mg/ml metronidazole. The study shows that isolates of B. hominis of different geographical origin have different levels of resistance to metronidazole. The search for more effective drugs to eliminate th parasite appears inevitable, especially since surviving parasites from metronidazole cultures show greater ability to multiply in subcultures than controls.

Matched MeSH terms: Drug Evaluation, Preclinical
Antiviral activity of selected flavonoids against Chikungunya virus

Lani R, Hassandarvish P, Shu MH, Phoon WH, Chu JJ, Higgs S, et al.

Antiviral Res, 2016 Sep;133:50-61.
PMID: 27460167 DOI: 10.1016/j.antiviral.2016.07.009

This study focuses on the antiviral activity of selected flavonoids against the Chikungunya virus (CHIKV), a mosquito-transmitted virus that can cause incapacitating arthritis in infected individuals. Based on the results of screening on Vero cells, the tested compounds were evaluated further with various assays, including cytotoxicity assay, virus yield assay by quantitative reverse transcription polymerase chain reaction (qRT-PCR), virus RNA replication assay with a CHIKV replicon cell line, Western blotting, and quantitative immunofluorescence assay. Baicalein, fisetin, and quercetagetin displayed potent inhibition of CHIKV infection, with 50% inhibitory concentrations [IC50] of 1.891 μg/ml (6.997 μM), 8.444 μg/ml (29.5 μM), and 13.85 μg/ml (43.52 μM), respectively, and with minimal cytotoxicity. The time-of-addition studies and various antiviral assays demonstrated that baicalein and quercetagetin mainly inhibited CHIKV binding to the Vero cells and displayed potent activity against extracellular CHIKV particles. The qRT-PCR, immunofluorescence assay, and Western blot analyses indicated that each of these flavonoids affects CHIKV RNA production and viral protein expression. These data provide the first evidence of the intracellular anti-CHIKV activity of baicalein, fisetin, and quercetagetin.

Matched MeSH terms: Drug Evaluation, Preclinical
Synthesis, spectral analysis and biological evaluation of sulfamoyl and 1,3,4-oxadiazole derivatives of 3-pipecoline

Rehman A, Aslam SJ, Abbasi MA, Siddiqui SZ, Rasool S, Shah SAA

Pak J Pharm Sci, 2019 May;32(3):987-996.
PMID: 31278711

Heterocyclic chemistry is an important field of organic chemistry due to therapeutic potential. The minor modification in the structure of poly-functional compounds has great effect on therapeutic ability. In the presented research work, substituted 1,3,4-oxadiazole derivatives, 8a-p, have been synthesized by the reaction of 1-(4-bromomethylbenzenesulfonyl)-3-methylpiperidine (7) and 5-substituted-1,3,4-oxadiazole-2-thiol (4a-p). The 5-substituted-1,3,4-oxadiazole-2-thiol were synthesized by converting carboxylic acids correspondingly into esters, hydrazides and oxadiazoles. Secondly the electrophile, 1-(4-Bromomethylbenzenesulfonyl)-3-methylpiperidine (7), was prepared by the reaction of 3-methylpiperidine with 4-bromomethylbenzenesulfonyl chloride in the presence of water and Na2CO3 under pH of 9-10. The compounds were structurally corroborated through spectroscopic data analysis of IR, EI-MS and 1H-NMR. The screening for antibacterial activity revealed the compounds to be moderate to excellent inhibitors against bacteria under study. Anti-enzymatic activity was assessed against urease enzyme and 1-{[4-({[5-(3-nitrophenyl)-1,3,4-oxadiazol-2-yl]sulfanyl}methyl)phenyl]sulfonyl}-3-methylpiperidine (8d) was the most active one.

Matched MeSH terms: Drug Evaluation, Preclinical
Thraatchathi Chooranam, protects cardiomyocytes against oxidative stress

Ganapathy R, Mani S, Hanumanth Rao BR, Tunku K, Ray B, Bhat A, et al.

Front Biosci (Elite Ed), 2018 03 01;10:437-448.
PMID: 29293467

Thraatchathi Chooranam (TC), is a polyphenol-rich Indian traditional medicine. Present study was undertaken to investigate the effects of TC against H2O2 induced oxidative stress and apoptotic damage in H9C2 cardiomyocytes. Cell viability assay indicated relative safety (IC50= 488.10±12.04 mg/ml) of TC. Pretreatment of cells with TC upregulated anti-apoptotic Bcl2, and anti-oxidants TRX1 and TRXR and downregulated Bax and HIF-α and inflammatory genes iNOS and TNF-α. Together, these findings show that TC has both anti-oxidant and anti-apoptotic properties. Further studies may be considered to identify the bioactive principle(s) and precise mechanisms of action of TC.

Matched MeSH terms: Drug Evaluation, Preclinical
Screening of microfilaricidal effects of plant extracts against Dirofilaria immitis

Merawin LT, Arifah AK, Sani RA, Somchit MN, Zuraini A, Ganabadi S, et al.

Res Vet Sci, 2010 Feb;88(1):142-7.
PMID: 19500810 DOI: 10.1016/j.rvsc.2009.05.017

Canine dirofilariasis is a common tropical parasitic disease of companion animals, caused by infestation of Dirofilaria immitis filarids within the pulmonary arteries and extending into the right heart. Increased reports of adverse reactions elicited by current microfilaricidal agents against D. immitis such as neurological disorders, circulatory collapse and potential resistance against these agents, warrant the search for new agents in forms of plant extracts. The use of plant extracts in therapeutic medicine is commonly met with scepticism by the veterinary community, thus the lack of focus on its medical potential. This study evaluated the presence of microfilaricidal activities of the aqueous extracts of Zingiber officinale, Andrographis paniculata and Tinospora crispa Miers on D. immitisin vitro at different concentrations; 10mg/ml, 1mg/ml, 100 microg/ml, 10 microg/ml and 1 microg/ml within 24h, by evaluation of relative microfilarial motility as a measure of microfilaricidal activity. All extracts showed microfilaricidal activity with Z. officinale exhibiting the strongest activity overall, followed by A. paniculata and T. crispa Miers. It is speculated that the microfilaricidal mechanism exhibited by these extracts is via spastic paralysis based upon direct observation of the microfilarial motility.

Matched MeSH terms: Drug Evaluation, Preclinical
Fulltext Effect of germinated brown rice extracts on pancreatic lipase, adipogenesis and lipolysis in 3T3-L1 adipocytes

Lim SM, Goh YM, Kuan WB, Loh SP

Lipids Health Dis, 2014 Nov 03;13:169.
PMID: 25367070 DOI: 10.1186/1476-511X-13-169

BACKGROUND: This study investigated anti-obesity effects of seven different solvent (n-hexane, toluene, dicholoromethane, ethyl acetate, absolute methanol, 80% methanol and deionized water) extracts of germinated brown rice (GBR) on pancreatic lipase activity, adipogenesis and lipolysis in 3T3-L1 adipocytes.
METHODS: GBR were extracted separately by employing different solvents with ultrasound-assisted. Pancreatic lipase activity was determined spectrophotometrically by measuring the hydrolysis of p-nitrophenyl butyrate (p-NPB) to p-nitrophenol at 405 nm. Adipogenesis and lipolysis were assayed in fully differentiated 3T3-L1 adipocytes by using Oil Red O staining and glycerol release measurement.
RESULTS: GBR extract using hexane showed the highest inhibitory effect (13.58 ± 0.860%) at concentration of 200 μg/ml followed by hexane extract at 100 μg/ml (9.98 ± 1.048%) while ethyl acetate extract showed the lowest (2.62 ± 0.677%) at concentration of 200 μg/ml on pancreatic lipase activity. Water extract at 300 μg/ml showed 61.55 ± 3.824% of Oil Red O staining material (OROSM), a marker of adipogenesis. It significantly decrease (p

Matched MeSH terms: Drug Evaluation, Preclinical
Fulltext Molecular screening of phytocompounds targeting the interface between influenza A NS1 and TRIM25 to enhance host immune responses

Suleman M, Sayaf AM, Khan A, Khan SA, Albekairi NA, Alshammari A, et al.

J Infect Public Health, 2024 Jul;17(7):102448.
PMID: 38815532 DOI: 10.1016/j.jiph.2024.05.005

BACKGROUND: Influenza A virus causes severe respiratory illnesses, especially in developing nations where most child deaths under 5 occur due to lower respiratory tract infections. The RIG-I protein acts as a sensor for viral dsRNA, triggering interferon production through K63-linked poly-ubiquitin chains synthesized by TRIM25. However, the influenza A virus's NS1 protein hinders this process by binding to TRIM25, disrupting its association with RIG-I and preventing downstream interferon signalling, contributing to the virus's evasion of the immune response.
METHODS: In our study we used structural-based drug designing, molecular simulation, and binding free energy approaches to identify the potent phytocompounds from various natural product databases (>100,000 compounds) able to inhibit the binding of NS1 with the TRIM25.
RESULTS: The molecular screening identified EA-8411902 and EA-19951545 from East African Natural Products Database, NA-390261 and NA-71 from North African Natural Products Database, SA-65230 and SA- 4477104 from South African Natural Compounds Database, NEA- 361 and NEA- 4524784 from North-East African Natural Products Database, TCM-4444713 and TCM-6056 from Traditional Chinese Medicines Database as top hits. The molecular docking and binding free energies results revealed that these compounds have high affinity with the specific active site residues (Leu95, Ser99, and Tyr89) involved in the interaction with TRIM25. Additionally, analysis of structural dynamics, binding free energy, and dissociation constants demonstrates a notably stronger binding affinity of these compounds with the NS1 protein. Moreover, all selected compounds exhibit exceptional ADMET properties, including high water solubility, gastrointestinal absorption, and an absence of hepatotoxicity, while adhering to Lipinski's rule.
CONCLUSION: Our molecular simulation findings highlight that the identified compounds demonstrate high affinity for specific active site residues involved in the NS1-TRIM25 interaction, exhibit exceptional ADMET properties, and adhere to drug-likeness criteria, thus presenting promising candidates for further development as antiviral agents against influenza A virus infections.

Matched MeSH terms: Drug Evaluation, Preclinical
Trigonelline attenuates the adipocyte differentiation and lipid accumulation in 3T3-L1 cells

Ilavenil S, Arasu MV, Lee JC, Kim DH, Roh SG, Park HS, et al.

Phytomedicine, 2014 Apr 15;21(5):758-65.
PMID: 24369814 DOI: 10.1016/j.phymed.2013.11.007

Trigonelline is a natural alkaloid mainly found in Trigonella Foenum Graecum (fenugreek) Fabaceae and other edible plants with a variety of medicinal applications. Therefore, we investigated the molecular mechanism of trigonelline (TG) on the inhibition of adipocyte differentiation and lipid accumulation in 3T3-L1 cells. Trigonelline suppressed lipid droplet accumulation in a concentration (75 and 100 μM) dependent manner. Treatment of adipocyte with of TG down regulates the peroxisome proliferator-activated receptor (PPARγ) and CCAAT element binding protein (C/EBP-α) mRNA expression, which leads to further down regulation of other gene such as adiponectin, adipogenin, leptin, resistin and adipocyte fatty acid binding protein (aP2) as compared with respective control cells on 5th and 10th day of differentiation. Further, addition of triognelline along with troglitazone to the adipocyte attenuated the troglitazone effects on PPARγ mediated differentiation and lipid accumulation in 3T3-L1 cells. Trigonelline might compete against troglitazone for its binding to the PPARγ. In addition, adipocyte treated with trigonelline and isoproterenol separately. Isoproterenol, a lipolytic agent which inhibits the fatty acid synthase and GLUT-4 transporter expression via cAMP mediated pathway, we found that similar magnitude response of fatty acid synthase and GLUT-4 transporter expression in trigonelline treated adipocyte. These results suggest that the trigonelline inhibits the adipogenesis by its influences on the expression PPARγ, which leads to subsequent down regulation of PPAR-γ mediated pathway during adipogenesis. Our findings provide key approach to the mechanism underlying the anti-adipogenic activity of trigonelline.

Matched MeSH terms: Drug Evaluation, Preclinical
Fulltext Evaluation of antiviral activities of four local Malaysian Phyllanthus species against herpes simplex viruses and possible antiviral target

Tan WC, Jaganath IB, Manikam R, Sekaran SD

Int J Med Sci, 2013;10(13):1817-29.
PMID: 24324358 DOI: 10.7150/ijms.6902

Nucleoside analogues such as acyclovir are effective antiviral drugs against herpes simplex virus infections since its introduction. However, with the emergence of acyclovir-resistant HSV strains particularly in immunocompromised patients, there is a need to develop an alternative antiherpetic drug and plants could be the potential lead. In this study, the antiviral activity of the aqueous extract of four Phyllanthus species were evaluated against herpes simplex virus type-1 (HSV-1) and HSV-2 in Vero cells by quantitative PCR. The protein expressions of untreated and treated infected Vero cells were studied by 2D-gel electrophoresis and Western blot. This is the first study that reported the antiviral activity of P. watsonii. P. urinaria was shown to demonstrate the strongest antiviral activity against HSV-1 and HSV-2, with SI >33.6. Time-of-addition studies suggested that the extract may act against the early infection stage and the replication stage. Protein expression studies indicated that cellular proteins that are involved in maintaining cytoskeletal structure could be potential target for development of antiviral drugs. Preliminary findings indicated that P. urinaria demonstrated potent inhibitory activity against HSV. Hence, further studies such as in vivo evaluation are required for the development of effective antiherpetic drug.

Matched MeSH terms: Drug Evaluation, Preclinical
Synthesis, antibacterial activity and cytotoxicity of new fused pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-c][1,2,4]triazine derivatives from new 5-aminopyrazoles

Al-Adiwish WM, Tahir MI, Siti-Noor-Adnalizawati A, Hashim SF, Ibrahim N, Yaacob WA

Eur J Med Chem, 2013 Jun;64:464-76.
PMID: 23669354 DOI: 10.1016/j.ejmech.2013.04.029

New 5-aminopyrazoles 2a-c were prepared in high yields from the reaction of known α,α-dicyanoketene-N,S-acetals 1a-c with hydrazine hydrate under reflux in ethanol. These compounds were utilized as intermediates to synthesize pyrazolo[1,5-a]-pyrimidines 3a-c, 4a-d, 5a-c, and 6a-c, as well as pyrazolo[5,1-c][1,2,4]triazines 7a-c and 8a-c, by the reaction of 2-[bis(methylthio)methylene]malononitrile, α,α-dicyanoketene-N,S-acetals 1a-b, acetylacetone, acetoacetanilide as well as acetylacetone, and malononitrile, respectively. Furthermore, cyclization of 2a-c with pentan-2,5-dione yielded the corresponding 5-pyrrolylpyrazoles 9a-c. Moreover, fusion of 2a-c with acetic anhydride resulted in the corresponding 1-acetyl-1H-pyrazoles 10a-c. The antibacterial activity and cytotoxicity against Vero cells of several selected compounds are also reported.

Matched MeSH terms: Drug Evaluation, Preclinical
Molecular characterization of Antarctic actinobacteria and screening for antimicrobial metabolite production

Lee LH, Cheah YK, Mohd Sidik S, Ab Mutalib NS, Tang YL, Lin HP, et al.

World J Microbiol Biotechnol, 2012 May;28(5):2125-37.
PMID: 22806035 DOI: 10.1007/s11274-012-1018-1

The present study aimed to isolate actinobacteria from soil samples and characterized them using molecular tools and screened their secondary metabolites for antimicrobial activities. Thirty-nine strains from four different location of Barrientos Island, Antarctica using 12 types of isolation media was isolated. The isolates were preceded to screening of secondary metabolites for antimicrobial and antifungal activities. Using high-throughput screening methods, 38% (15/39) of isolates produced bioactive metabolites. Approximately 18% (7/39), 18% (7/39), 10% (4/39) and 2.5% (1/39) of isolates inhibited growth of Candida albicans ATCC 10231(T), Staphylococcus aurues ATCC 51650(T), methicillin-resistant Staphylococcus aurues (MRSA) ATCC BAA-44(T) and Pseudomonas aeruginosa ATCC 10145(T), respectively. Molecular characterization techniques like 16S rRNA analysis, Enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR), Random amplified polymorphic DNA (RAPD) and composite analyses were used to characterize the actinobacteria strains. Analysis of 16S rRNA sequences is still one of the most powerful methods to determine higher taxonomic relationships of Actinobacteria. Both RAPD and ERIC-PCR fingerprinting have shown good discriminatory capability but RAPD proved to be better in discriminatory power than ERIC-PCR. Our results demonstrated that composite analysis of both fingerprinting generally increased the discrimination ability and generated best clustering for actinobacteria strains in this study.

Matched MeSH terms: Drug Evaluation, Preclinical
Fulltext Anti-inflammatory and antioxidant effects of Tualang honey in alkali injury on the eyes of rabbits: experimental animal study

Bashkaran K, Zunaina E, Bakiah S, Sulaiman SA, Sirajudeen K, Naik V

BMC Complement Altern Med, 2011;11:90.
PMID: 21982267 DOI: 10.1186/1472-6882-11-90

Alkali injury is one of the most devastating injuries to the eye. It results in permanent unilateral or bilateral visual impairment. Chemical eye injury is accompanied by an increase in the oxidative stress. Anti-inflammatory and antioxidant agents play a major role in the treatment of chemical eye injuries. The purpose of this study is to evaluate the anti-inflammatory (clinical and histopathological) and antioxidant effects of Tualang honey versus conventional treatment in alkali injury on the eyes of rabbits.

Matched MeSH terms: Drug Evaluation, Preclinical
Fulltext Screening of anti-dengue activity in methanolic extracts of medicinal plants

Tang LI, Ling AP, Koh RY, Chye SM, Voon KG

BMC Complement Altern Med, 2012;12:3.
PMID: 22244370 DOI: 10.1186/1472-6882-12-3

Dengue fever regardless of its serotypes has been the most prevalent arthropod-borne viral diseases among the world population. The development of a dengue vaccine is complicated by the antibody-dependent enhancement effect. Thus, the development of a plant-based antiviral preparation promises a more potential alternative in combating dengue disease.

Matched MeSH terms: Drug Evaluation, Preclinical
Differential effects of ketoconazole and primaquine on the pharmacokinetics and tissue distribution of imatinib in mice

Soo GW, Law JH, Kan E, Tan SY, Lim WY, Chay G, et al.

Anticancer Drugs, 2010 Aug;21(7):695-703.
PMID: 20629201

Imatinib, a selective inhibitor of c-KIT and Bcr-Abl tyrosine kinases, approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, shows further therapeutic potential for gliomas, glioblastoma, renal cell carcinoma, autoimmune nephritis and other neoplasms. It is metabolized by CYP3A4, is highly bound to alpha-1-acid glycoprotein and is a P-glycoprotein substrate limiting its brain distribution. We assess imatinib's protein binding interaction with primaquine, which also binds to alpha-1-acid glycoprotein, and its metabolic interaction with ketoconazole, which is a CYP3A4 inhibitor, on its pharmacokinetics and biodistribution. Male ICR mice, 9-12 weeks old were given imatinib PO (50 mg/kg) alone or co-administered with primaquine (12.5 mg/kg), ketoconazole (50 mg/kg) or both, and imatinib concentration in the plasma, kidney, liver and brain was measured at prescheduled time points by HPLC. Noncompartmental pharmacokinetic parameters were estimated. Primaquine increased 1.6-fold plasma AUC(0)--> infinity, C(Max) decreased 24%, T(Max) halved and t(1/2) and mean residence time were longer. Ketoconazole increased plasma AUC(0)-->infinity 64% and doubled the C(Max), but this dose did not affect t(1/2) or mean residence time. When ketoconazole and primaquine were co-administered, imatinib AUC(0)-->infinity and C(Max) increased 32 and 35%, respectively. Ketoconazole did not change imatinib's distribution efficiency in the liver and kidney, primaquine increased it two-fold and it was larger when both the drugs were co-administered with imatinib. Ketoconazole did not change brain penetration but primaquine increased it approximately three-fold. Ketoconazole and primaquine affect imatinib clearance, bioavailability and distribution pattern, which could improve the treatment of renal and brain tumors, but also increase toxicity. This would warrant hepatic and renal functions monitoring.

Matched MeSH terms: Drug Evaluation, Preclinical
Phyllanthus spp. Exerts Anti-Angiogenic and Anti-Metastatic Effects Through Inhibition on Matrix Metalloproteinase Enzymes

Tang YQ, Jaganath IB, Manikam R, Sekaran SD

Nutr Cancer, 2015;67(5):783-95.
PMID: 25996262 DOI: 10.1080/01635581.2015.1040518

Tumor angiogenesis and metastasis are the major causes for high morbidity and mortality rates in cancer patient. Modulation on tumor angiogenesis and metastasis provides opportunities to halt progression of cancer. From our previous findings, Phyllanthus plant possesses antiproliferative effects on melanoma and prostate cancer cell lines and induction of apoptosis. The main aims of the present work were further investigated on the antimetastatic and antiangiogenic effects on cancer cells (MeWo and PC-3) and human umbilical vein endothelial cells (HUVECs) of 4 Phyllanthus species (P.amarus, P.niruri, P.urinaria and P.watsonii). Phyllanthus extracts significantly inhibited cell adhesion, migration, invasion, and transendothelial migration activities of cancer (MeWo and PC-3) cells in a dose-dependent manner (P < 0.05) by cell-matrix adhesion, Transwell migration, invasion, and transendothelial migration assays. Phyllanthus extracts were exhibited low cytotoxicity on HUVECs up to a concentration of 500.0 μg/ml by MTS reduction assay. Phyllanthus extracts also exhibited antiangiogenic effects through inhibition of migration, invasion, and microcapillary like-tube structure formation in HUVECs. These observations were due to alteration in activities of matrix metalloproteinase (MMP) -2, -7, -9, and -26 in treated-endothelial and cancer cells by zymographies. These findings suggest that Phyllanthus plant has the potential to inhibit tumour metastasis and angiogenesis through the suppression of MMP enzymes.

Matched MeSH terms: Drug Evaluation, Preclinical
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: Drug Evaluation, Preclinical
Fulltext Resveratrol affects Zika virus replication in vitro

Mohd A, Zainal N, Tan KK, AbuBakar S

Sci Rep, 2019 10 04;9(1):14336.
PMID: 31586088 DOI: 10.1038/s41598-019-50674-3

Zika virus (ZIKV) infection is a serious public health concern. ZIKV infection has been associated with increased occurrences of microcephaly among newborns and incidences of Guillain-Barré syndrome among adults. No specific therapeutics or vaccines are currently available to treat and protect against ZIKV infection. Here, a plant-secreted phytoalexin, resveratrol (RES), was investigated for its ability to inhibit ZIKV replication in vitro. Several RES treatment regimens were used. The ZIKV titers of mock- and RES-treated infected cell cultures were determined using the focus-forming assay and the Zika mRNA copy number as determined using qRT-PCR. Our results suggested that RES treatment reduced ZIKV titers in a dose-dependent manner. A reduction of >90% of virus titer and ZIKV mRNA copy number was achieved when infected cells were treated with 80 µM of RES post-infection. Pre-incubation of the virus with 80 µM RES showed >30% reduction in ZIKV titers and ZIKV mRNA copy number, implying potential direct virucidal effects of RES against the virus. The RES treatment reduced >70% virus titer in the anti-adsorption assay, suggesting the possibility that RES also interferes with ZIKV binding. However, there was no significant decrease in ZIKV titer when a short-period of RES treatment was applied to cells before ZIKV infection (pre-infection) and after the virus bound to the cells (virus internalization inhibition), implying that RES acts through its continuous presence in the cell cultures after virus infection. Overall, our results suggested that RES exhibited direct virucidal activity against ZIKV and possessed anti-ZIKV replication properties, highlighting the need for further exploration of RES as a potential antiviral molecule against ZIKV infection.

Matched MeSH terms: Drug Evaluation, Preclinical

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