Publications by authors named "Ayman M Saleh"

27 Publications

  • Page 1 of 1

SARS-CoV-2 PCR positivity rate and seroprevalence of related antibodies among a sample of patients in Cairo: Pre-wave 2 results of a screening program in a university hospital.

PLoS One 2021 15;16(7):e0254581. Epub 2021 Jul 15.

President of Ain-Shams University, Cairo, Egypt.

Background: Research has revealed that asymptomatic and pre-symptomatic infections are important contributors to the transmission of SARS-CoV-2 in populations. In Egypt, the true prevalence of infections is veiled due to the low number of screening tests. The aim of this study was to determine the SARS-CoV-2 PCR positivity rate as well the seroprevalence of the SARS-CoV-2 antibodies before the ultimate development of a second wave of the epidemic in Cairo, Egypt.

Methods: Our study was carried out between May 5 and the end of October 2020. It included all patients requiring admission to Ain Shams University hospitals. An interview questionnaire was used to collect demographic and clinical data. Laboratory tests for all participants included RT-PCR and total antibody assay for SARS-CoV-2.

Results: A total of 4,313 subjects were enrolled in our study, with females representing 56% of the sample. Adults and middle-aged individuals represented around 60% of the study sample. The positivity rate of SARS-CoV-2 PCR was 3.84% (95% CI 3.29-4.48), and the SARS-CoV-2 antibody seroprevalence was 29.82% (95% CI: 28.16-31.51). Males showed a higher risk for getting the COVID-19 infection, while middle-age group had significantly higher antibody seroprevalence rates.

Conclusion: SARS-CoV-2 infection imposes a high burden on the community as detected by high seroprevalence rates.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254581PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282003PMC
July 2021

Dose Issues in Cancer Chemotherapy.

Oncology 2020 5;98(8):520-527. Epub 2020 May 5.

Interdisciplinary Research Centre in Biomedical Materials (IRCBM), COMSATS University Islamabad, Lahore Campus, Lahore, Pakistan.

In this review, human methotrexate dosing regimens, as well as their relationship to data from in vitro cell culture and in vivo animal and human studies, are discussed. Low-dose, intermediate-dose, and high-dose therapies are covered. Since in vitro and in vivo screenings of potential cancer drugs are commonplace in the development of cancer chemotherapy, comparisons of the three criteria for effectiveness are important.
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http://dx.doi.org/10.1159/000506705DOI Listing
August 2020

Chemical constituents of the aerial parts of Boiss. from Jordan.

Nat Prod Res 2020 Oct 4;34(20):2981-2985. Epub 2019 Jun 4.

Department of Chemistry, Faculty of Science, Yarmouk University, Irbid, Jordan.

Investigation of the chemical constituents of growing wild in Jordan led to the isolation and identification of 15 known compounds. These included: luteolin-3'-methyl ether (), indole-3-carboxyaldehyde (), -hydroxybenzaldehyde (), tricin (), apigenin (), methyl isoferuloyl-7-(3,4-dihydroxyphenyl) lactate (), methyl rosmarinate (, rosmarinic acid (), salvigenin (), -sitosterol (), 3, 28-dihydroxyurs-12-ene (), cirsilineol (), 2,3-dihydroxyurs-12-en-28-oic acid (), -sitosteryl glucoside (), and tormentic acid (). Compounds and exhibited strong radical scavenging and chelating activities as compared to α-tocopherol and ascorbic acid, compound showed a 2-fold greater antioxidant activity as compared to compound . Furthermore, low doses of compounds and were able to inhibit the growth of leukemic (HL-60, Jurkat, K562 and CCRF-SB) and solid tumor cells (MCF-7, MDA-MB-231 and Caco-2). Compound showed a ca. 3-4-fold stronger cytotoxicity against the tested cells as compared to compound .
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http://dx.doi.org/10.1080/14786419.2019.1597349DOI Listing
October 2020

Rheumatoid Arthritis: A Brief Overview of the Treatment.

Med Princ Pract 2018 2;27(6):501-507. Epub 2018 Sep 2.

Larkin Community Hospital, Miami, Florida, USA.

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease, affecting the joints with varying severity among patients. The risk factors include age, gender, genetics, and environmental exposure (cigarette smoking, air pollutants, and occupational). Many complications can follow, such as permanent joint damage requiring arthroplasty, rheumatoid vasculitis, and Felty syndrome requiring splenectomy if it remains unaddressed. As there is no cure for RA, the treatment goals are to reduce the pain and stop/slow further damage. Here, we present a brief summary of various past and present treatment modalities to address the complications associated with RA.
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http://dx.doi.org/10.1159/000493390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422329PMC
August 2019

Antibody responses to P. falciparum Apical Membrane Antigen 1(AMA-1) in relation to haemoglobin S (HbS), HbC, G6PD and ABO blood groups among Fulani and Masaleit living in Western Sudan.

Acta Trop 2018 Jun 24;182:115-123. Epub 2018 Feb 24.

Department of clinical Immunology, PaLMS-Sheikh Khalifa Medical City, P.O. Box 51900, Abu Dhabi, United Arab Emirates; Department of Microbiology and Immunology, Faculty of Medicine, University of Khartoum, Sudan.

Fulani and Masaleit are two sympatric ethnic groups in western Sudan who are characterised by marked differences in susceptibility to Plasmodium falciparum malaria. It has been demonstrated that Glucose-6-phosphate dehydrogenase (G6PD) deficiency and Sickle cell trait HbAS carriers are protected from the most severe forms of malaria. This study aimed to investigate a set of specific IgG subclasses against P. falciparum Apical Membrane Antigen 1 (AMA-1 3D7), haemoglobin variants and (G6PD) in association with malaria susceptibility among Fulani ethnic group compared to sympatric ethnic group living in Western Sudan. A total of 124 children aged 5-9 years from each tribe living in an area of hyper-endemic P. falciparum unstable malaria transmission were recruited and genotyped for the haemoglobin (Hb) genes, (G6PD) and (ABO) blood groups. Furthermore, the level of plasma IgG antibody subclasses against P. falciparum antigen (AMA-1) were measured using enzyme linked immunosorbent assays (ELISA). Higher levels of anti-malarial IgG1, IgG2 and IgG3 but not IgG4 antibody were found in Fulani when compared to Masaleit. Individuals carrying the HbCC phenotype were significantly associated with higher levels of IgG1 and IgG2. Furthermore, individuals having the HbAS phenotype were associated with higher levels of specific IgG2 and IgG4 antibodies. In addition, patients with G6PD A/A genotype were associated with higher levels of specific IgG2 antibody compared with those carrying the A/G and G/G genotypes. The results indicate that the Fulani ethnic group show lower frequency of HbAS, HbSS and HbAC compared to the Masaleit ethnic group. The inter-ethnic analysis shows no statistically significant difference in G6PD genotypes (P value = 0.791). However, the intra-ethnic analysis indicates that both ethnic groups have less A/A genotypes and (A) allele frequency of G6PD compared to G/G genotypes, while the HbSA genotype was associated with higher levels of IgG2 (AMA-1) and IgG4 antibodies. In addition, patients carrying the G6PD A/A genotype were associated with higher levels of specific IgG2 antibody compared with those carrying the A/G and G/G genotypes. The present results revealed that the Fulani ethnic group has statistically significantly lower frequency of abnormal haemoglobin resistant to malaria infection compared to the Masaleit ethnic group.
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http://dx.doi.org/10.1016/j.actatropica.2018.02.030DOI Listing
June 2018

Applications of nanoparticle systems in drug delivery technology.

Saudi Pharm J 2018 Jan 25;26(1):64-70. Epub 2017 Oct 25.

Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center (KAIMRC), King Abdulaziz Medical City, National Guard Health Affairs, Mail Code 6610, P. O. Box 9515, Jeddah 21423, Saudi Arabia.

The development of nanoparticle-based drug formulations has yielded the opportunities to address and treat challenging diseases. Nanoparticles vary in size but are generally ranging from 100 to 500 nm. Through the manipulation of size, surface characteristics and material used, the nanoparticles can be developed into smart systems, encasing therapeutic and imaging agents as well as bearing stealth property. Further, these systems can deliver drug to specific tissues and provide controlled release therapy. This targeted and sustained drug delivery decreases the drug related toxicity and increase patient's compliance with less frequent dosing. Nanotechnology has proven beneficial in the treatment of cancer, AIDS and many other disease, also providing advancement in diagnostic testing.
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http://dx.doi.org/10.1016/j.jsps.2017.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783816PMC
January 2018

Protective effect of metoclopramide against organophosphate-induced apoptosis in the murine skin fibroblast L929.

J Appl Toxicol 2018 03 13;38(3):329-340. Epub 2017 Oct 13.

King Abdullah International Medical Research Center (KAIMRC), King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, Kingdom of Saudi Arabia.

This study was performed to evaluate the protective efficacy of metoclopramide (MCP) against the organophosphates paraoxon (POX)- and malathion (MLT)-induced apoptosis in the murine L929 skin fibroblasts. L929 cells were exposed to either POX (10 nm) or 1.0 μm MLT in the absence and presence of increased concentrations of MCP. The protective effect of MCP on these organophosphate-stimulated apoptotic events was evaluated by flow cytometry analysis after staining with annexin-V/propidium iodide, processing and activation of the executioner caspase-3, cleavage of the poly-ADP ribose polymerase, fragmentation of the nucleosomal DNA and disruption of the mitochondrial membrane potential (Δψ). Our results showed that increased doses of MCP alone (≥10 μm) did not induce apoptosis or activation of caspase-3. Pretreatment of the cells with MCP attenuated all the apoptotic events triggered by the organophosphate compounds in a dose-dependent manner reaching ~70-80% protection when they were preincubated at 1 and 5 μm of the drug before the addition of POX and MLT, respectively. Interestingly, MCP did not offer a significant protective effect against the cytotoxicity of tumor necrosis factor-α, cisplatinum, etoposide or paclitaxel, which stimulate apoptosis by various mechanisms, suggesting that the anti-apoptotic effect of the drug is specific to organophosphates. The strong and specific anti-apoptotic activity of subclinical doses of MCP against the cytotoxicity of organophosphate compounds suggests its potential clinical application in treating their poisoning.
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http://dx.doi.org/10.1002/jat.3543DOI Listing
March 2018

Towards personalized medicine of colorectal cancer.

Crit Rev Oncol Hematol 2017 Oct 26;118:70-78. Epub 2017 Aug 26.

King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Office of the Chief Executive Officer, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia. Electronic address:

Efforts in colorectal cancer (CRC) research aim to improve early detection and treatment for metastatic stages which could translate into better prognosis of this disease. One of the major challenges that hinder these efforts is the heterogeneous nature of CRC and involvement of diverse molecular pathways. New large-scale 'omics' technologies are making it possible to generate, analyze and interpret biological data from molecular determinants of CRC. The developments of sophisticated computational analyses would allow information from different omics platforms to be integrated, thus providing new insights into the biology of CRC. Together, these technological advances and an improved mechanistic understanding might allow CRC to be clinically managed at the level of the individual patient. This review provides an account of the current challenges in CRC management and an insight into how new technologies could allow the development of personalized medicine for CRC.
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http://dx.doi.org/10.1016/j.critrevonc.2017.08.007DOI Listing
October 2017

Comprehensive Analysis of the Chemical Composition and In Vitro Cytotoxic Mechanisms of Pallines Spinosa Flower and Leaf Essential Oils Against Breast Cancer Cells.

Cell Physiol Biochem 2017 11;42(5):2043-2065. Epub 2017 Aug 11.

Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), and King Abdullah International Medical Research Center (KAIMRC), King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia.

Background/aims: In our quest for new natural anticancer agents, we studied the cytotoxicity of the essential oils extracted from flowers and leaves of Pallines spinosa.

Methods: The essential oils were extracted by hydrodistillation and solid phase microextraction (SPME) from flowers and leaves of the plant and their composition was determined by GC/GC-MS. The cytotoxicity of the oils was evaluated against MCF-7 and MDA-MB-231 breast adenocarcinomas, and the non-cancerous MCF-10-2A cells, using a flow cytometry-based assay Apoptosis was evaluated by flow cytometry, nuclear staining, caspases activation, and Western blotting techniques, and cell cycle by measuring DNA contents.

Results: The hydrodistilled flower oil contained mainly sesquiterpenes (96.39%), while the leaf sample was dominated by oxygenated-sesquiterpenes (51.60%) and sesquiterpene-hydrocarbons (34.06%). In contrast, the SPME oil contained mainly monoterpene-hydrocarbons (44.09%) and sesquiterpene-hydrocarbons (34.15%) in the flower and leaf samples, respectively. The cytotoxicity of the flower oil against MCF-7 (IC50 0.25 ± 0.03 µg/mL) and MDA-MB-231 (IC50 0.21 ± 0.03 µg/mL) was much stronger than the leaf oil (IC50 2.4 ± 0.5 µg/mL and 1.5 ± 0.1 µg/mL, respectively). The toxicity of the flower oil was ∼5 to 8-times less in normal MCF-10-2A (IC50 1.3 ± 0.2 µg/mL) and blood mononuclear cells (2.80 ± 0.45 µg/mL) as compared to breast and hematological cancer cells, respectively. Both oils induced a caspase-dependent and -independent apoptosis in MCF-7 and MDA-MB-231 cells, and altered the levels of Bcl-2 and Bax proteins. In addition, the oils arrested cell cycle in both cancer cell lines at G0/G1 phase by modulating the expression of cyclin D1, CDK4 and p21 proteins.

Conclusion: The cytotoxicity of P. spinosa oils were mediated by apoptosis and cell cycle arrest, suggesting the potential use of their bioactive compounds as natural anticancer compounds.
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http://dx.doi.org/10.1159/000479900DOI Listing
November 2017

Composition, Antioxidant, and Cytotoxic Activities of the Essential Oils from Fresh and Air-Dried Aerial Parts of Pallenis spinosa.

Chem Biodivers 2017 Aug 11;14(8). Epub 2017 Jul 11.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, P.O. Box 926592, Amman, Jordan.

This study was performed to determine the chemical composition, antioxidant and cytotoxic effects of essential oils extracted from the aerial parts of fresh (F-PSEO) and air-dried (D-PSEO) Pallenis spinosa. The composition of the oils was analyzed by gas chromatography (GC) and GC/mass spectrometry, the antioxidant activity by free radical scavenging and metal chelating assays, and their cytotoxicity by a flow cytometry analysis. The primary components in both oils were sesquiterpene hydrocarbons and oxygentated sesquiterpenes. F-PSEO contained 36 different compounds; α-cadinol (16.48%), germacra-1(10),5-diene-3,4-diol (14.45%), γ-cadinene (12.03%), and α-muurolol (9.89%) were the principal components. D-PSEO contained 53 molecules; α-cadinol (19.26%), δ-cadinene (13.93%), α-muurolol (12.88%), and germacra-1(10),5-diene-3,4-diol (8.41%) constituted the highest percentages. Although both oils exhibited a weak radical scavenging and chelating activity, compared to α-tocopherol and ascorbic acid, D-PSEO showed a 2-fold greater antioxidant activity than F-PSEO. Furthermore, low doses of F-PSEO were able to inhibit the growth of leukemic (HL-60, K562, and Jurkat) and solid tumor cells (MCF-7, HepG2, HT-1080, and Caco-2) with an IC range of 0.25 - 0.66 μg/ml and 0.50 - 2.35 μg/ml, respectively. F-PSEO showed a ca. 2 - 3-fold stronger cytotoxicity against the tested cells than D-PSEO. The potent growth inhibitory effect of the plant essential oil encourages further studies to characterize the molecular mechanisms of its cytotoxicity.
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http://dx.doi.org/10.1002/cbdv.201700146DOI Listing
August 2017

New flavonol glycoside from Scabiosa prolifera L. aerial parts with in vitro antioxidant and cytotoxic activities.

Nat Prod Res 2017 Dec 24;31(24):2865-2874. Epub 2017 Mar 24.

d School of Science, Department of Chemistry , The University of Jordan , Amman , Jordan.

Phytochemical investigation of the chemical constituents of the aerial parts of Scabiosa prolifera L. led to the isolation of one new flavonol glycoside, kaempferol-3-O-(4″,6″-di-E-p-coumaroyl)-β-D-galactopyranoside (1), along with ten other known compounds including luteolin-7-O-(2″-O-ethyl-β-glucopyranoside), β-sitosterol, β-sitosterylglucoside, ursolic acid, corosolic acid, ursolic acid 3-O-β-D-arabinopyranoside, apigenin, methyl-α-D-glucopyranoside, luteolin-7-O-β-glucopyranoside and isoorientin. The structures of all isolated compounds were established using chemical methods and spectroscopic methods including IR, UV, NMR (1D and 2D) and HRESIMS. All compounds were isolated for the first time from the plant. The antioxidant and cytotoxic activities of compounds 1 and 2 were also investigated.
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http://dx.doi.org/10.1080/14786419.2017.1305377DOI Listing
December 2017

Utility of cytokine, adhesion molecule and acute phase proteins in early diagnosis of neonatal sepsis.

J Nat Sci Biol Med 2017 Jan-Jun;8(1):32-39

Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center (KAIMRC) National Guard Health Affairs, Riyadh, Saudi Arabia.

Background And Aim: Neonatal infection, including bacterial sepsis, is a major health care issue with an annual global mortality in excess of one million lives. Therefore, this study aimed to evaluate the potential diagnostic value of C-reactive protein (CRP), E-selectin, procalcitonin (PCT), interleukins-6 (IL-6), and tumor necrosis factor-α (TNF-α) both independently and in combination for the diagnosis of neonatal sepsis in its earliest stages.

Materials And Methods: A total of 320 subjects were included in this study. A prospective cross-sectional study was conducted among neonates admitted to Neonatal Intensive Care Unit at King Abdulaziz Medical City, Riyadh, KSA during January 2013 to August 2015, the study based on three study groups categorized according to clinical symptoms and blood culture result. Study groups include healthy control neonates ( = 80), clinical sepsis (CS) group ( = 80) with clinical signs of sepsis but their blood culture was negative, and sepsis group with clinical signs of sepsis and their blood culture was positive.

Results: The study observed significant difference in plasma levels of CRP, IL-6, TNF-α, E-selectin, and PCT in patients group when compared with control group ( < 0.001). Furthermore, the levels are significantly different between patient groups including CS and neonatal sepsis group. Moreover, result observed significant difference in CRP and IL-6 in early onset sepsis (EOS) when compared with late onset sepsis (LOS) neonates ( < 0.001 and 0.01), respectively, while there were no significant difference in TNF-α, E-selectin, and PCT between EOS and LOS ( = 0.44, 0.27 and 0.24), respectively. Regarding biomarkers accuracy, the result showed that CRP has the best diagnostic accuracy with cutoff value of 3.6 ng/ml (sensitivity 78% and specificity of 70%). The best combination is shown with CRP and IL-6 in which sensitivity increased to 89% and specificity to 79%.

Conclusion: It was concluded that infected new-born babies have a higher E-selectin, PCT, IL-6, TNF-α, and CRP compared with the neonates with CS and control. IL-6, TNF-α, and CRP should be measured in combination for mare diagnostic accuracy in neonatal sepsis. Likewise, PCT should be investigated as a part of sepsis screening for all suspected neonates.
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http://dx.doi.org/10.4103/0976-9668.198362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320820PMC
March 2017

Cytotoxic activity of the novel heterocyclic compound G-11 is primarily mediated through intrinsic apoptotic pathway.

Apoptosis 2016 07;21(7):873-86

Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University (NSU), Fort Lauderdale, FL, 33328, USA.

Natural and chemically synthesized heterocyclic compounds have been explored for their potential use as anticancer agents. We had synthesized non-natural heterocyclic analogs and evaluated their anti-tumor activity by measuring effect on cell proliferation and induction of apoptosis in different cell lines. Previously, we identified a pyrazole-containing compound (G-11) showing cytotoxic effect towards leukemia and lymphoma cell lines. In this study, we further investigated the mechanistic aspects of anticancer properties of G-11 in HL-60 cell line. We demonstrated that cytotoxic effect of G-11 is mediated by caspase-dependent apoptosis. However, the involvement of mitochondrial dysfunction induced by G-11 was independent of caspases. G-11 triggered generation of ROS, caused disruption of mitochondrial transmembrane potential, increased release of cytochrome c to the cytosol, and altered the expression of Bcl-2 and Bax proteins. These results suggest significant involvement of intrinsic apoptotic pathway. This study comprehensively details the possible mechanisms of action of a novel heterocyclic compound which could find its potential use as an anticancer agent.
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http://dx.doi.org/10.1007/s10495-016-1248-zDOI Listing
July 2016

Novel anticancer compound [trifluoromethyl-substituted pyrazole N-nucleoside] inhibits FLT3 activity to induce differentiation in acute myeloid leukemia cells.

Cancer Lett 2016 Jun 23;375(2):199-208. Epub 2016 Feb 23.

Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University (NSU), Fort Lauderdale, FL 33328, United States.

Anticancer properties of chemically synthesized compounds have continuously been optimized for better efficacy and selectivity. Derivatives of heterocyclic compounds are well known to have selective antiproliferative effect against many types of cancer. In this study, we investigated the ability of an indigenously synthesized anticancer molecule, G-11 [1-(2",3",4",6"-Tetra-O-acetyl-β-D-glucopyranosyl)-4-(3'-trifluoromethylphenylhydrazono)-3-trifluoromethyl-1,4-dihydropyrazol-5-one], to cause selective cytotoxicity and induce differentiation in the acute myeloid leukemia HL-60 cells. G-11 was able to exert cytotoxic effect on hematological (Jurkat, U937, K562, HL-60, CCRF-SB) and solid tumor (MCF-7, HepG2, HeLa, Caco-2) cell lines, with IC50 values significantly lower than noncancerous cells (HEK-293, BJ and Vero) and normal peripheral blood mononuclear cells. G-11 induced differentiation of HL-60 cells to granulocytes and monocytes/macrophages by inhibiting the activation of FLT3 (CD135 tyrosine kinase). ITD-FLT3 mutation found in many acute myeloid leukemia patients could also be targeted by G-11 as exhibited by its inhibitory effect on MOLM-13 and MV4-11 cell lines. Molecular docking studies suggest the involvement of Leu616, Asp698, Cys694 and Cys828 residues in binding of G-11 to FLT3. The ability of G-11 to cause selective cytotoxicity and induce differentiation in cancer cells could be clinically relevant for therapeutic gains.
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http://dx.doi.org/10.1016/j.canlet.2016.02.028DOI Listing
June 2016

Neurocysticercosis: A case report and brief review.

Asian Pac J Trop Med 2016 Jan 19;9(1):100-2. Epub 2015 Dec 19.

JAS Medical Management LLC, 6151 Miramar Pkwy, Miramar, FL 33023, USA. Electronic address:

Neurocysticercosis (NCC) is one of the seven neglected endemic zoonoses targeted by the World Health Organization. It is considered a common infection of the nervous system caused by the Taenia solium and is known to be the primary cause of preventable epilepsy in many developing countries. NCC is commonly resulted by the ingestion of Taenia solium eggs after consuming undercooked pork, or contaminated water. The parasite can grow in the brain and spinal cord within the nervous system, causing severe headache and seizures beside other pathological manifestations. Immigration and international travel to endemic countries has made this disease common in the United States. NCC can be diagnosed with computed tomography and magnetic resonance imaging of the brain. The treatment of the NCC including cysticidal drugs (e.g., albendazole and praziquantel), and neurosurgical procedure, depending upon the situation. A patient of Asian origin came to our clinic with complaints of dizziness, headaches and episodes seizures for the past twelve years without proper diagnosis. The computed tomography and magnetic resonance imaging scans indicated multilobulated cystic mass in the brain with the suspicion of neurocysticercosis.
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http://dx.doi.org/10.1016/j.apjtm.2015.12.020DOI Listing
January 2016

Altered Lamin A/C splice variant expression as a possible diagnostic marker in breast cancer.

Cell Oncol (Dordr) 2016 Apr 5;39(2):161-74. Epub 2016 Jan 5.

Department of Basic Medical Sciences, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia.

Background: Lamin A/C alternative splice variants (Lamin A, Lamin C, Lamin AΔ10 and Lamin AΔ50) have been implicated in cell cycle regulation, DNA replication, transcription regulation, cellular differentiation, apoptosis and aging. In addition, loss of Lamin A/C expression has been observed in several cancers, including breast cancer, and it has been found that Lamin A/C suppression may lead to cancer-like aberrations in nuclear morphology and aneuploidy. Based on these observations, we hypothesized that Lamin A/C transcript variant quantification might be employed for the diagnosis of breast cancer.

Methods: Newly designed TaqMan qRT-PCR assays for the analysis of Lamin A/C splice variants were validated and their use as biomarkers for the diagnosis of breast cancer was assessed using 16 normal breast tissues and 128 breast adenocarcinomas. In addition, the expression levels of the Lamin A/C transcript variants were measured in samples derived from seven other types of cancer.

Results: We found that the expression level of Lamin C was significantly increased in the breast tumors tested, whereas the expression levels of Lamin A and Lamin AΔ50 were significantly decreased. No significant change in Lamin AΔ10 expression was observed. Our data also indicated that the Lamin C : Lamin A mRNA ratio was increased in all clinical stages of breast cancer. Additionally, we observed increased Lamin C : Lamin A mRNA ratios in liver, lung and thyroid carcinomas and in colon, ovary and prostate adenocarcinomas.

Conclusions: From our data we conclude that the Lamin C : Lamin A mRNA ratio is increased in breast cancer and that this mRNA ratio may be of diagnostic use in all clinical stages of breast cancer and, possibly, also in liver, lung, thyroid, colon, ovary and prostate cancers.
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http://dx.doi.org/10.1007/s13402-015-0265-1DOI Listing
April 2016

New isoflavones from Gynandriris sisyrinchium and their antioxidant and cytotoxic activities.

Fitoterapia 2015 Dec 25;107:15-21. Epub 2015 Sep 25.

Department of Chemistry, Faculty of Science, Yarmouk University, Irbid, Jordan.

Chemical investigation of Gynandriris sisyrinchium (L.) Parl growing in Jordan resulted in the isolation and characterization of a total of twelve compounds two of which are reported here for the first time in nature. These new compounds included the isoflavones; 3'-methyl tenuifone (2) and gynandrinone (5). In addition, ten known compounds including; β-sitosterol (1), 7,3'-dimethoxy-5,6,4'-trihydroxyisoflavone (3), iristectorigenin (4), hispidulin (6), galangustin (7), 6-hydroxybiochanin A (8), ursolic acid (9), ladanetin (10), 4'-O-methylgenistein (11) and β-sitosterol glucoside (12) are also reported here for the first time from G. sisyrinchium. The isolated compounds were characterized by different spectroscopic methods including NMR (1D and 2D), UV, IR and MS (HRESIMS and EIMS). The antioxidant and cytotoxic activities of isoflavones 2, 3 and 5 were investigated. Compound 3 showed the highest antioxidant activity (IC50=17.3μg/mL), as compared to compounds 5 and 2 (IC50=26.7 and 51.7μg/mL, respectively). The cytotoxic activity against the human promyelocytic leukemia HL-60 cells revealed that compound 2 was the most active (40μM). The results indicate that the cytotoxicity of compound 2 is mediated by apoptosis.
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http://dx.doi.org/10.1016/j.fitote.2015.09.020DOI Listing
December 2015

Quantification of insulin receptor mRNA splice variants as a diagnostic tumor marker in breast cancer.

Cancer Biomark 2015 ;15(5):653-61

Department of Basic Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Kingdom of Saudi Arabia.

Background: The mature human insulin receptor (INSR) has two isoforms: The A isoform and the B isoform. INSR upregulation has been suggested to play a role in cancer.

Objective: To establish quantitative PCR method for INSR transcript variants and examine their differential expression as a diagnostic tumor marker in breast cancer.

Methods: The differential expression of IR-A and IR-B were evaluated by TaqMan qRT-PCR assay in the commercially available Breast Cancer Disease cDNA and Cancer Survey cDNA arrays.

Results: The mRNA expression levels of IR-A was statistically significantly higher in breast cancer when compared to normal breast tissue while IR-B mRNA expression was down regulated significantly in breast cancer. Stratification of patients into groups according to metastatic stages indicated statistically significantly higher levels of IR-A mRNA in clinical stage (CS)-IV, and lower IR-B levels in CS-IIA, CS-IIIB and CS-IIIC. However, IR-A:IR-B ratio showed a statistically significant increase in all stages. Cancer Survey cDNA array demonstrated lower levels of IR-B mRNA in breast adenocarcinoma, liver carcinoma and lung carcinoma only while IR-A expression was significantly altered in kidney carcinoma without any significant differences in IR-A:IR-B ratios.

Conclusions: The results demonstrate an increased IR-A:IR-B ratio in all clinical stages of breast cancer. Thus, IR-A:IR-B ratio may have a diagnostic biomarker utility in breast cancer.
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http://dx.doi.org/10.3233/CBM-150505DOI Listing
July 2016

Altered Sirtuin 7 Expression is Associated with Early Stage Breast Cancer.

Breast Cancer (Auckl) 2015 9;9:3-8. Epub 2015 Apr 9.

Department of Basic Medical Sciences, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia. ; Department of Microbiology, Faculty of Science and Technology, Al-Neelain University, Sudan.

Background: To evaluate sirtuin-7 (SirT7) mRNA expression status in breast cancer patients with different metastatic stages and survey SirT7 mRNA expression status in eight different types of cancer.

Methods: The expression of SirT7 in the commercially available TissueScan qPCR Breast Cancer Disease cDNA arrays containing 16 normal, 23 Stage I, 36 IIA, 22 IIB, 8 IIIA, 23 IIIA, 6 IIIB, 13 IIIC, and 5 IV were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Similar analysis was performed in TissueScan qPCR Cancer Survey cDNA array, which includes breast, colon, kidney, liver, lung, ovarian, prostate, and thyroid specimens.

Results: The mRNA expression levels of SirT7 were significantly higher in breast cancer samples compared to normal breast specimens (P < 0.001). Stratification of patients into groups according to metastatic stages indicated statistically significantly higher levels of SirT7 mRNA in CS-I, CS-II, and CS-III when compared to normal breast tissue (P < 0.05). Notably, SirT7 mRNA levels were higher in CS-I, CS-IIA, CS-IIB, and CS-IIIA (P < 0.05). Additionally, there were significantly lower SirT7 mRNA levels in thyroid carcinoma when compared to their corresponding normal tissue (P < 0.05).

Conclusions: Our results indicate an increase in the mRNA expression level of SirT7 in breast cancer, particularly in CS-I, CS-IIA, CS-IIB, and CS-IIIA. The relationship of altered SirT7 with breast cancer progression and patient survival should be prospectively explored in future studies.
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http://dx.doi.org/10.4137/BCBCR.S23156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396534PMC
April 2015

The pyridone-annelated isoindigo (5'-Cl) induces apoptosis, dysregulation of mitochondria and formation of ROS in leukemic HL-60 cells.

Cell Physiol Biochem 2015 27;35(5):1958-74. Epub 2015 Mar 27.

Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), National Guard Health Affairs, Riyadh, Kingdom of Saudi Arabia.

Background/aims: In our quest to develop an isoindigo with improved efficacy and bioavailability, we recently synthesized a series of novel substituted pyridone-annelated isoindigo and evaluated their antiproliferative effects. We identified the compound [(E)-1-(5'-Chloro-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f] quinoline-8-carboxylic acid], abbreviated as 5'-Cl, which shows selective antiproliferative activities against various cancer cell lines mediated through apoptosis. Here we have investigated the molecular mechanisms underlying the apoptotic activity of 5'-Cl in the human promyelocytic leukemia HL-60 cells.

Methods: We employed different methods to determine the apoptotic pathways triggered by 5'-Cl in HL-60 cells, using flow cytometry, nuclear staining, caspases activation, mitochondria functioning, generation of reactive oxygen species (ROS) and Western blotting techniques.

Results: Low concentrations (1-8 µM) of 5'-Cl inhibited the growth of HL-60 cells in a dose and time-dependent manner. Cytotoxicity of this compound is found to be mediated by a caspase-dependent apoptosis. Also, there were indications of caspase independent apoptosis as z-VAD-FMK failed to fully rescue the cells from 5'-Cl-induced apoptosis. In addition, the compound triggered generation of Reactive Oxygen Species (ROS), caused depolarization of the mitochondrial inner membrane, decreased the level of cellular ATP, modulated the expression and phosphorylation of Bcl-2 leading to loss of its association with Bax and increased the release of cytochrome c to the cytosol of treated cells. The effects of 5'-Cl on mitochondria and apoptosis were substantially blocked in the presence of a combination between z-VAD-FMK and either of the ROS scavenger N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC).

Conclusion: We demonstrated that the growth inhibitory effects of 5'-Cl in HL-60 cells involve multiple pathways of apoptosis and dysregulation of mitochondrial functions.
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http://dx.doi.org/10.1159/000374004DOI Listing
December 2015

The anticancer activity of the substituted pyridone-annelated isoindigo (5'-Cl) involves G0/G1 cell cycle arrest and inactivation of CDKs in the promyelocytic leukemia cell line HL-60.

Cell Physiol Biochem 2015 27;35(5):1943-57. Epub 2015 Mar 27.

Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), National Guard Health Affairs, Riyadh, Kingdom of Saudi Arabia.

Background/aims: The antileukemic potential of isoindigos make them desired candidates for understanding their mechanism of action. We have recently synthesized a novel group of pyridone-annelated isoindigos and identified the derivative 5'-Cl that is cytotoxic to various cancer cell lines. In the present study, we analyzed the effect of this compound on cell cycle of the promyelocytic leukemia cell line HL-60.

Methods: HL-60 cells were treated with 5'-Cl and its effect on cell cycle stages were determined by flow cytometry. Expression of cyclins, cyclin dependent kinases (CDKs) and cyclin kinase inhibitors (CKIs) were determined by Western blotting, and activation of CDKs was studied using kinase assays.

Results: 5'-Cl remarkably arrested cell cycle in HL-60 cells at the G0/G1 phase in a dose and time-dependent manner. Furthermore, 5'-Cl treatment significantly inhibited expression of D-cyclins, CDK2 and CDK4 and suppressed phosphorylation of the retinoblastoma protein Rb, whereas it increased the level of CKI p21. Molecular modelling experiments show that 5'-Cl may compete with ATP for binding to the catalytic subunit of CDK2 and CDK4 that could lead to inhibition of these enzymes. Indeed, 5'-Cl inhibited the kinase activity of CDK2 and CDK4 both in cell free systems and in treated cells. 5'-Cl also inhibited cell cycle progression in several other tumor cell lines.

Conclusion: We demonstrate the potent inhibitory effects of 5'-Cl on HL-60 cells could be mediated by arresting cells in the G0/G1 phase.
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http://dx.doi.org/10.1159/000374003DOI Listing
December 2015

Antiproliferative activity of the isoindigo 5'-Br in HL-60 cells is mediated by apoptosis, dysregulation of mitochondrial functions and arresting cell cycle at G0/G1 phase.

Cancer Lett 2015 Jun 16;361(2):251-61. Epub 2015 Mar 16.

Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University (NSU), Fort Lauderdale, Florida 33328, USA.

Our new compound, 5'-Br [(E)-1-(5'-bromo-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f]quinoline-8-carboxylic acid], had shown strong, selective antiproliferative activity against different cancer cell lines. Here, we aim to comprehensively characterize the mechanisms associated with its cytotoxicity in the human promyelocytic leukemia HL-60 cells. We focused at studying the involvement of apoptotic pathway and cell cycle effects. 5'-Br significantly inhibited proliferation by inducing caspase-dependent apoptosis. Involvement of caspase independent mechanism is also possible due to observed inability of z-VAD-FMK to rescue apoptotic cells. 5'-Br was found to trigger intrinsic apoptotic pathway as indicated by depolarization of the mitochondrial inner membrane, decreased level of cellular ATP, modulated expression and phosphorylation of Bcl-2 leading to loss of its association with Bax, and increased release of cytochrome c. 5'-Br treated cells were found arrested at G0/G1 phase with modulation in protein levels of cyclins, dependent kinases and their inhibitors. Expression and enzymatic activity of CDK2 and CDK4 was found inhibited. Retinoblastoma protein (Rb) phosphorylation was also inhibited whereas p21 protein levels were increased. These results suggest that the antiproliferative mechanisms of action of 5'-Br could involve apoptotic pathways, dysregulation of mitochondrial functions and disruption of cell cycle checkpoint.
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http://dx.doi.org/10.1016/j.canlet.2015.03.013DOI Listing
June 2015

Synthesis and biological evaluation of new pyridone-annelated isoindigos as anti-proliferative agents.

Molecules 2014 Aug 25;19(9):13076-92. Epub 2014 Aug 25.

Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), P.O. Box 3660, Riyadh 11481, Kingdom of Saudi Arabia.

A selected set of substituted pyridone-annelated isoindigos 3a-f has been synthesized via interaction of 5- and 6-substituted oxindoles 2a-f with 6-ethyl-1,2,9-trioxopyrrolo[3,2-f]quinoline-8-carboxylic acid (1) in acetic acid at reflux. Among these isoindigos, the 5'-chloro and 5'-bromo derivatives 3b and 3d show strong and selective antiproliferative activities against a panel of human hematological and solid tumor cell-lines, but not against noncancerous cells, suggesting their potential use as anticancer agents. In all the tested cell lines, compound 3b was a 25%-50% more potent inhibitor of cell growth than 3d, suggesting the critical role of the substitution at 5'-position of the benzo-ring E. The IC50 values after 48 hours incubation with the 5'-chloro compound 3b were 6.60 µM in K562, 8.21 µM in THP-1, 8.97 µM in HepG2, 11.94 µM in MCF-7 and 14.59 µM in Caco-2 cancer cells, while the IC50 values in noncancerous HEK-293 and L-929 were 30.65 µM and 40.40 µM, respectively. In addition, compound 3b induced higher levels apoptosis in K562 cells than 3d, as determined by annexin V/7-AAD flowcytometry analysis. Therefore, further characterization of the antitproliferative mechanisms of compounds 3b and 3d may provide a novel chemotherapeutic agents.
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http://dx.doi.org/10.3390/molecules190913076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271423PMC
August 2014

In vitro cytotoxicity of Artemisia vulgaris L. essential oil is mediated by a mitochondria-dependent apoptosis in HL-60 leukemic cell line.

BMC Complement Altern Med 2014 Jul 7;14:226. Epub 2014 Jul 7.

College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia.

Background: The essential oil (EO) of Artemisia vulgaris L. has been traditionally used worldwide for treating a large number of diseases. Although major components in A. vulgaris EO have been shown to inhibit growth of different cancer cells, as pure compounds or part of other plants extracted oil, no information is known about its anti-proliferative activities. Therefore, the current investigation has evaluated the toxicity of the plant extracted oil from buds (AVO-b) and leaves (AVO-l) and characterized their growth inhibitory effects on cancer cells.

Methods: AVO-b and AVO-l from A. vulgaris L. were extracted by hydrodistillation, and their effect on the viability of human HL-60 promyelocytic leukemia and various other cancer cell lines was tested using MTT assay. Flow cytometric analysis of apoptosis, DNA fragmentation assay, caspases enzymatic activities and Western blotting were used to determine the apoptotic pathway triggered by their action on HL-60 cells.

Results: Low concentrations of AVO-b and AVO-l inhibited the growth of HL-60 cells in a dose- and time-dependent manner. Employing flow cytometric, DNA fragmentation and caspase activation analyses, demonstrated that the cytotoxic effect of the oils is mediated by a caspase-dependent apoptosis. Kinetic studies in the presence and absence specific caspase inhibitors showed that activation of caspase-8 was dependent and subsequent to the activation of caspases-9 and -3. In addition, the essential oil caused a disruption of the mitochondrial transmembrane potential (ΔΨm), increased the release of cytochrome c to the cytosol, and altered the expression of certain members of Bcl-2 family (Bcl-2, Bax and Bid), Apaf-1 and XIAP. Interestingly, low doses of AVO-b and AVO-1 also induced apoptosis in various cancer cell lines, but not in noncancerous cells.

Conclusions: The results demonstrate that the EO-induced apoptosis in HL-60 cells is mediated by caspase-dependent pathways, involving caspases-3, -9, and -8, which are initiated by Bcl-2/Bax/Bid-dependent loss of ΔΨm leading to release of cytochrome c to the cytoplasm to activate the caspase cascade. The finding that AVO-b and AVO-l are more efficient to induce apoptosis in different cancer cell lines than noncancerous cells, suggests that A. vulgaris might be a promising source for new anticancer agents.
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http://dx.doi.org/10.1186/1472-6882-14-226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227289PMC
July 2014

Modulation of insulin/IGFs pathways by sirtuin-7 inhibition in drug-induced chemoreistance.

Diagn Pathol 2014 May 22;9:94. Epub 2014 May 22.

Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, P, O, Box 22490, Riyadh 11426, Kingdom of Saudi Arabia.

Background: Insulin and insulin-like growth factors (IGFs) are key regulators of metabolism and growth. Recent evidences suggest a key role of these pathways in non-classical tissues and the metabolic pathways by which these hormones exert their effects in neoplasia is unclear.

Aims: To study insulin/IGFs pathways in drug sensitive and resistant cancer cells representing breast cancer (MCF-7), osteosarcoma (SaOS-2), and ovarian cancer (A2780) and to examine the effect of Sirtuin-7 (Sirt7) inhibition on insulin/IGFs pathways in MCF-7 cell line.

Methods: Drug resistant cells were generated by continuous incubation of parental cell lines with stepwise increases in Doxorubicin or Cisplatin over a period of 3 to 6 months. MCF-7 cells were transfected with cloned hairpin siRNA template for Sirt7 using the Amaxa GmbH transfection system. mRNA expression of Sirt7, INSR, IRS-1, IRS-2, IRS-4, IGF-1, IGF-2, MDR-1, MRP-1, BCRP was measured by qPCR and Sirt7 by standard Western blotting. FITC-insulin uptake was imaged with Leica Confocal Microscope.

Results: Insulin receptor (INSR), insulin receptor substrate-1 (IRS-1) were inhibited in drug-induced resistance, whereas IRS-2 was significantly induced in all the chemoresistant cells tested when compared to their parental counterparts. IGF-1 and IGF-2 were also upregulated in all the drug resistant cells tested. Sirt7 was significantly reduced in all chemoresistant cells tested. Knockdown of Sirt7 expression in human breast MCF-7 cell line by siRNA induced premature senescence-like phenotype and multi-drug resistance, suggesting that this gene may play an active role in regulating cancer cell response to stress. Suppression of Sirt7 selectively inhibited INSR and IRS-1, whereas it had minimal effect on that of IRS-2. Sirt7 suppression in MCF-7 also inhibited insulin uptake. Additionally, Sirt7 inhibition upregulated IGF-1, IGF-2 and IGFR expression.

Conclusion: Our data demonstrate that stress-induced Sirt7 inhibition significantly increases stress resistance and modulates insulin/IGF-1 signaling pathways. More importantly, this study links Sir2 family proteins to insulin/IGF signaling in drug-induced stress resistance in neoplasia.

Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1135426681234493.
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http://dx.doi.org/10.1186/1746-1596-9-94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229859PMC
May 2014

Composition of the essential oil of wild growing Artemisia vulgaris from Erie, Pennsylvania.

Nat Prod Commun 2012 May;7(5):637-40

Department of Chemistry and Biochemistry, Mercyhurst University, Erie, PA 16546, USA.

Essential oil from wild growing Artemisia vulgaris L. originating in Erie, Pennsylvania was obtained by hydrodistillation of the aerial parts of the plant. Gas chromatographic-mass spectral analysis was used to identify the major volatiles present. Up to 22 components were detected in the essential oils. Germacrene D (25%), Caryophyllene (20%), alpha-Zingiberene (15%) and Borneol (11%) represent the major components of leaf oil, while the buds were rich in 1,8-Cineole (32%), Camphor (16%), Borneol (9%), and Caryophyllene (5%). trans-2-Hexenal was also detected in the aerial parts of the plant. alpha-Zingiberene and trans-2-Hexenal have not been previously reported for Artemisia vulgaris L. The major analytes are compared to those from Artemisia vulgaris L, originating outside of the United States.
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May 2012

Synthesis and antitumor activity of 5-trifluoromethyl-2,4- dihydropyrazol-3-one nucleosides.

Molecules 2004 Feb 28;9(3):109-16. Epub 2004 Feb 28.

Department of Chemistry, Faculty of Science, UAE University, Al-Ain P.O. Box 17551, UAE.

2,4-Dihydropyrazole glucosides 3a-3c were prepared and tested for their antitumor activity. The structures of these compounds were established by (1)H and (13)C-NMR spectroscopy. Glucoside 3b shows an in vitro IC(50) value of 16.4 muM against proliferation of the human promyelotic leukemia (HL60) cell line.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147422PMC
http://dx.doi.org/10.3390/90300109DOI Listing
February 2004
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