Publications by authors named "Naushad Ali"

44 Publications

It takes a village: microbiota, parainflammation, paligenosis and bystander effects in colorectal cancer initiation.

Dis Model Mech 2021 May 10;14(5). Epub 2021 May 10.

Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Sporadic colorectal cancer (CRC) is a leading cause of worldwide cancer mortality. It arises from a complex milieu of host and environmental factors, including genetic and epigenetic changes in colon epithelial cells that undergo mutation, selection, clonal expansion, and transformation. The gut microbiota has recently gained increasing recognition as an additional important factor contributing to CRC. Several gut bacteria are known to initiate CRC in animal models and have been associated with human CRC. In this Review, we discuss the factors that contribute to CRC and the role of the gut microbiota, focusing on a recently described mechanism for cancer initiation, the so-called microbiota-induced bystander effect (MIBE). In this cancer mechanism, microbiota-driven parainflammation is believed to act as a source of endogenous mutation, epigenetic change and induced pluripotency, leading to the cancerous transformation of colon epithelial cells. This theory links the gut microbiota to key risk factors and common histologic features of sporadic CRC. MIBE is analogous to the well-characterized radiation-induced bystander effect. Both phenomena drive DNA damage, chromosomal instability, stress response signaling, altered gene expression, epigenetic modification and cellular proliferation in bystander cells. Myeloid-derived cells are important effectors in both phenomena. A better understanding of the interactions between the gut microbiota and mucosal immune effector cells that generate bystander effects can potentially identify triggers for parainflammation, and gain new insights into CRC prevention.
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http://dx.doi.org/10.1242/dmm.048793DOI Listing
May 2021

Multivariate analysis for various quantitative traits in wheat advanced lines.

Saudi J Biol Sci 2021 Jan 15;28(1):347-352. Epub 2020 Oct 15.

Department Horticulture, The University of Haripur, Pakistan.

Genetic diversity play key role in the germplasm improvement which is directly correlated with the crop production. Various statistical techniques have been used to study diversity among different genotypes. Among these techniques multivariate is most frequently used one for the genetic association of genotypes. In the present study a total of 64 advance lines included one check cultivar were evaluated under the field conditions of Cereal Crop Research Institute, Pirsabaq Nowshera, Pakistan during September 2017. Data were recorded for nine different parameters. Multivariate analysis divided the total 64 genotypes into four groups. The first five PCs with Eigen values > 1 contributed 86.95% of the variability amongst genotypes. Characters with maximum values in PC1 were Spikelets spike (SPPS) (0.732), spike length (SPL) (0.722) and biological yield (BY) (0.607), PC2 comprised of 100-grain weight (TGW) (0.605), grain yield (GY) (0.482) while days to heading (DH) (0.393), for PC3 major contributors were BY (0.550) and number of tillers meter square (NTPS) (0.289), the contribution of PC4 were flag leaf area (FLA) (0.716) and SPL (0.298) and the maximum values for various traits in PC5 were SPPS (0.732), SPL (0.722) and BY (0.607). From the findings of present study best performing lines can be directly recommended for general cultivation or to be used in future breeding programs.
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http://dx.doi.org/10.1016/j.sjbs.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783652PMC
January 2021

Comparative evaluation of push-out bond strength of gutta-percha using different sealers with lateral condensation and thermoplasticized obturation technique: An study.

J Conserv Dent 2019 Nov-Dec;22(6):593-597. Epub 2020 Aug 20.

Department of Conservative Dentistry and Endodontics, College of Dental Science and Hospital, Indore, Madhya Pradesh, India.

Aim: The study aimed to evaluate and compare the push-out bond strength of gutta-percha using AH plus, Endosequence BC, and Roeko seal sealer with lateral condensation and thermoplasticized obturation technique.

Materials And Methods: Sixty single-rooted premolars were instrumented and samples were randomly assigned into three groups based on the sealer used (Group A-AH Plus, Group B-Endosequence BC, Group C-Roeko Seal) which were further divided into two subgroups-A1, B1, and C1 were obturated by the lateral condensation technique and A2, B2, and C2 using the thermoplasticized technique. Each sample was sectioned horizontally using a diamond disc, representing apical, middle, and coronal thirds, respectively. Root segments were then mounted on an acrylic block, and push-out bond strength of each sample was tested using the universal testing machine.

Statistical Analysis: One-way ANOVA, Tukey's test, and unpaired -test.

Results: For mandibular premolar teeth with a single canal using lateral condensation technique, the highest push-out bond strength was found in the A1 group (7.30 ± 0.61 MPa) at the apical level. While using the thermoplasticized technique, the highest push-out bond strength was found in the B2 group (3.71 ± 0.81 MPa) at the apical level. Overall results showed that the lateral condensation technique showed significantly higher push-out bond strength than thermoplasticized technique ( < 0.028).

Conclusions: The push-out bond strength of AH Plus sealer was higher than the Endosequence BC sealer and Roeko seal sealer. Lateral condensation technique has shown higher push-out bond strength than the thermoplasticized technique.
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http://dx.doi.org/10.4103/JCD.JCD_553_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542076PMC
August 2020

Doublecortin-like kinase 1 promotes hepatocyte clonogenicity and oncogenic programming via non-canonical β-catenin-dependent mechanism.

Sci Rep 2020 06 29;10(1):10578. Epub 2020 Jun 29.

Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.

Chronic liver injury is a risk factor for cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms that regulate the decision between normal injury repair and neoplastic initiation are unclear. Doublecortin-like kinase 1 (DCLK1), a tumor stem cell marker, is induced during cirrhosis and HCC. Here, we demonstrate that DCLK1-overexpressing primary human hepatocytes formed spheroids in suspension cultures. Spheroids derived from DCLK1-overexpressing hepatoma cells showed high level expression of active β-catenin, α-fetoprotein, and SOX9, suggesting that DCLK1 overexpression induces clonogenicity and dedifferentiated phenotypes in hepatoma cells. DCLK1 overexpression in hepatoma cells also increased phosphorylation of GSK-3β at Ser. This was associated with an induction of a 48-kDa active β-catenin with a preserved hypophosphorylated N-terminus that interacted with nuclear TCF-4 resulting in luciferase reporter activity and cyclin D1 expression. DCLK1 downregulation inhibited 48-kDa β-catenin expression. The proteasome inhibitor bortezomib did not block the 48-kDa β-catenin, instead, caused a threefold accumulation, suggesting a proteasome-independent mechanism. Liver tissues from patients with cirrhosis and HCC revealed epithelial co-staining of DCLK1 and active β-catenin, and cleaved E-cadherin. Repopulated DCLK1-overexpressing primary human hepatocytes in humanized FRG mouse livers demonstrated active β-catenin. In conclusion, DCLK1 regulates oncogenic signaling and clonogenicity of hepatocytes by a novel non-canonical/atypical β-catenin-dependent mechanism.
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http://dx.doi.org/10.1038/s41598-020-67401-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324569PMC
June 2020

Integrated multisectoral strategy to improve girls' and women's nutrition before conception, during pregnancy and after birth in India (Swabhimaan): protocol for a prospective, non-randomised controlled evaluation.

BMJ Open 2019 11 18;9(11):e031632. Epub 2019 Nov 18.

Department of Paediatrics, Sitaram Bhartia Institute of Science and Research, New Delhi, India.

Introduction: Swabhimaan is a community-based programme to improve adolescent girls' and women's nutrition in the rural areas of three Indian states-Bihar, Chhattisgarh and Odisha with high prevalence of undernutrition.

Methods And Analysis: Swabhimaan has a nested prospective, non-randomised controlled evaluation. Since 2017, five intervention sites receive community-led interventions through national government's livelihood mission supported women's self-help group federations and five control sites will initiate these activities 36 months later, in 2020. Community-led activities aim to improve coverage of 18 interventions including adequacy of food consumed, prevention of micronutrient deficiencies, access to basic health services and special care of nutritionally 'at risk' girls and women, improving hygiene and access to water and sanitation services and access to family planning services. The evaluation includes baseline (2016-2017), midline (2018-2019) and endline (2020-2021) surveys covering 6638 adolescent girls, 2992 pregnant women and 8755 mothers of children under 2. The final impact analysis will be by intention to treat, comparing primary and secondary outcomes in five intervention areas and five control areas. The primary outcomes are: (1) a 15% reduction in the proportion of adolescent girls with a body mass index (BMI) <18.5 kg/m; (2) a 15% reduction in the proportion of mothers of children under two with a BMI <18.5 kg/m and (3) and a 0.4 cm improvement in mean mid-upper arm circumference among pregnant women.

Ethics And Dissemination: All procedures involving human subjects were approved by the Institutional Ethics Committee of the All India Institute of Medical Sciences, Bihar, Chhattisgarh and Odisha and in compliance with guidelines laid down in the Declaration of Helsinki. Evidence will inform maternal and preconception nutrition policy at national and state level.

Trial Registration Number: 58261b2f46876 and CTRI/2016/11/007482; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-031632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886981PMC
November 2019

Cisplatin bioconjugated enzymatic GNPs amplify the effect of cisplatin with acquiescence.

Sci Rep 2019 09 25;9(1):13826. Epub 2019 Sep 25.

Nanomedicine & Nanobiotechnology Lab, Department of Biosciences, Integral University, Lucknow, India.

Enzymatic gold nanoparticles (B-GNPs) have been synthesized using a natural anticancer agent bromelain (a cysteine protease) and these nanoparticles were used to bioconjugate Cisplatin (highly effective against osteosarcoma and lung cancer). Cisplatin bioconjugated bromelain encapsulated gold nanoparticles (B-C-GNPs) were found profoundly potent against same cancers at much lower concentration with minimum side effects due to the synergistic effect of bromelain. The B-C-GNPs have been observed to inhibit the proliferation of osteosarcoma cell lines Saos-2 and MG-63 with IC estimation of 4.51 µg/ml and 3.21 µg/ml, respectively, and against small lung cancer cell line A-549 with IC 2.5 µg/ml which is lower than IC of cisplatin against same cell lines. The B-GNPs/B-C-GNPs were characterized by TEM, UV-Visible spectroscopy, Zeta potential and DLS to confirm the production, purity, crystalline nature, stability of nanoemulsion, size and shape distribution. The change in 2D and 3D conformation of bromelain after encapsulation was studied by Circular Dichroism and Fluorometry, respectively. It was found that after encapsulation, a 19.4% loss in secondary structure was observed, but tertiary structure was not altered significantly and this loss improved the anticancer activity. The confirmation of bioconjugation of cisplatin with B-GNPs was done by UV-Visible spectroscopy, TEM, FTIR, 2D H NMR DOSY and ICP-MS. Further, it was found that almost ~4 cisplatin molecules bound with each B-GNPs nanoparticle.
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http://dx.doi.org/10.1038/s41598-019-50215-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761153PMC
September 2019

Beetroot juice alleviates isoproterenol-induced myocardial damage by reducing oxidative stress, inflammation, and apoptosis in rats.

3 Biotech 2019 Apr 23;9(4):147. Epub 2019 Mar 23.

6Department Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451 Saudi Arabia.

Beetroot ( L.) juice (BRJ) is a good source of betalain (betacyanins and betaxanthin) pigments and exhibits antioxidant, anti-inflammatory, and chemo-preventive activities in vitro and in vivo. The current study was performed to determine the cardioprotective effect of BRJ on lipid peroxidation, antioxidant defense, functional impairment, and histopathology in rats with isoproterenol (ISP)-induced myocardial injury. Myocardial ischemia was induced by ISP (85 mg/kg) s.c. injection at 24 h intervals, followed by oral administration of BRJ for 28 days at doses of 150 and 300 mg/kg. ISP-induced myocardial damage was confirmed by an increase in heart weight to body weight ratio, % infarction size, serum cardiac indices (AST, ALT, GGT, ALP, LDH and CK-MB), and histological alterations in the myocardium. Pretreatment with BRJ (150 and 300 mg/kg) followed by ISP induction reduced oxidative/nitrosative stress and restored the cardiac endogenous antioxidants in rats. ISP augmented cardiac inflammatory cytokines (TNF-α, IL-6 and IL-10), myeloperoxidase activity, NF-κB DNA binding and protein expression of NF-κB (p65), and the hyperlipidemia level was significantly reduced by the BRJ pretreatment. Furthermore, the BRJ pretreatment significantly reduced caspase-3, Bax, and MMP-9 protein expression, enhanced the Bcl-2 antiapoptotic protein expression, alleviated the extent of histological damage, myonecrosis, and edema, and maintained the architecture of cardiomyocytes. These findings suggest that BRJ pretreatment mitigates cardiac dysfunction and structural damages by decreasing oxidative stress, inflammation, and apoptosis in cardiac tissues. These results further support the use of BRJ in traditional medicine against cardiovascular diseases.
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http://dx.doi.org/10.1007/s13205-019-1677-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430824PMC
April 2019

Effects of sinapic acid on hepatic cytochrome P450 3A2, 2C11, and intestinal P-glycoprotein on the pharmacokinetics of oral carbamazepine in rats: Potential food/herb-drug interaction.

Epilepsy Res 2019 07 22;153:14-18. Epub 2019 Mar 22.

Quality Assurance Unit, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Dietary supplements, herbal medicines, and other foods may affect the pharmacokinetics and/or pharmacodynamics of carbamazepine (CBZ), which may possibly lead to potential drug-drug/herb-drug interactions, as CBZ has a narrow therapeutic window. Sinapic acid (SA) is a bioactive phytoconstituent used as a dietary supplement for the treatment of epilepsy. This study determined the effects of SA on the pharmacokinetics of CBZ and proposed a possible interaction mechanism in twenty-four male wistar rats (180-210 g). A single CBZ dose (80 mg/kg) was administered orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The CBZ concentration in plasma samples was determined by using a sensitive reversed-phase high-performance liquid chromatography assay. The pharmacokinetic parameters were calculated by using non-compartmental analysis. Significance was determined through Dunnett's multiple comparison test or one-way analysis of variance as appropriate; p < 0.05 were considered significant. The change in the pharmacokinetic parameters (C, T, AUC, AUC, T, and k) of CBZ was evaluated after the administration of CBZ alone or after CBZ co-administration with SA pretreatment. The plasma concentration of CBZ was higher after SA pretreatment than that without pretreatment. The pharmacokinetics of orally administered CBZ were found to be significantly altered (p < 0.05) in rats pretreated with SA compared to those in rats administered CBZ alone. The increases in the C, AUC, T, and MRT of CBZ were 29.79%, 57.18%, 77.18%, and 58.31%, respectively, whereas the k and apparent oral CL/F were significantly reduced (p < 0.05) in rats pretreated with SA compared to those in rats not pretreated with SA (43.87% and 42.50%, respectively). However, no significant change was observed in the T of CBZ in rats pretreated with SA compared to that in rats that did not receive pretreatment. The enhancement in Cmax, AUC, T and MRT and the reduction in K and CL/F values resulted from the significant inhibition of CYP3 A2, the CYP2C11-mediated metabolism of CBZ in the liver, and the inhibition of intestinal P-glycoprotein/MDR1, which enhanced the rate of CBZ absorption. Further studies are required to determine the clinical relevance of these observations.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.03.012DOI Listing
July 2019

Effect of sinapic acid on aripiprazole pharmacokinetics in rats: Possible food drug interaction.

J Food Drug Anal 2019 01 3;27(1):332-338. Epub 2018 Jul 3.

Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Dietary supplements and foods can interact with various drugs, leading to possible clinical concerns. This study aimed to investigate the effect of orally administered sinapic acid (SA) on the pharmacokinetics of aripiprazole (APZ) in rats and its possible modulatory effects on hepatic cytochrome P450 (CYP3A2 and CYP2D6) expression in the liver tissues. Single dose and multiple dose parallel groups of wistar rats were categorized into six groups (n = 6 each) which abstained from food for 12 h prior to the experiment, while water was allowed ad libitum. The investigation was carried out for single dose: Group I was treated with normal saline orally for 15 days (normal control). Group II was administered normal saline orally for 15 days and received APZ (3 mg/kg p.o.) on day 15. Group III received SA (20 mg/kg p.o.) for 15 days and received APZ (3 mg/kg p.o.) on day 15. Group IV was treated with SA (20 mg/kg p.o.) for 15 days. For the multiple dose study, Group I was treated with normal saline orally for 15 days (normal control); Group II received APZ (3 mg/kg p.o.) daily for 15 days; Group III was administered with SA (20 mg/kg p.o.) and APZ (3 mg/kg p.o.) for 15 days and Group IV received SA (20 mg/kg p.o.) for 15 days. The group I and IV were kept common in single and multiple dose groups. After last APZ dose, plasma samples were collected and APZ concentrations were determined using an UPLC-MS/MS technique. The pharmacokinetic parameters were calculated using a non-compartmental analysis. The concomitant administration of APZ with SA (as single or multiple dose) resulted in an increase in APZ absorption and a decrease on its systemic clearance. This was associated with a reduction in CYP3A2 and CYP2D6 protein expressions by 33-43% and -71-68% after the single and multiple co-administration, which are two enzymes responsible of the metabolism of APZ. Therefore, a reduction in the metabolic clearance appears to be the mechanism underlying the drug interaction of dietary supplement containing SA with APZ. Therefore, the concomitant administration of SA and APZ should be carefully viewed. Further investigations are required to assess the clinical significance of such observations in humans.
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http://dx.doi.org/10.1016/j.jfda.2018.06.002DOI Listing
January 2019

Sinapic acid ameliorates bleomycin-induced lung fibrosis in rats.

Biomed Pharmacother 2018 Dec 13;108:224-231. Epub 2018 Sep 13.

Quality Research Unit, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Background: Pulmonary fibrosis is a multifaceted disease with high mortality and morbidity, and it is commonly nonresponsive to conventional therapy.

Purpose: We explore the possible discourse of sinapic acid (SA) against the prevention of bleomycin (BLM)-instigated lung fibrosis in rats through modulation of Nrf2/HO-1 and NF-κB signaling pathways.

Design/methods: Lung fibrosis was persuaded in Sprague-Dawley rats by a single intratracheal BLM (6.5 U/kg) injection. Then, these rats were treated with SA (10 and 20 mg/kg, p.o.) for 28 days. The normal control rats provided saline as a substitute of BLM. The lung function and biochemical, histopathological, and molecular alterations were studied in serum, bronchoalveolar lavage fluid (BALF), and the lungs tissues.

Results: SA treatment significantly restored BLM-induced alterations in body weight index and serum biomarkers [lactate dehydrogenase (LDH) and alkaline phosphatase (ALP)]. SA (10 and 20 mg/kg) treatment appeared to show a pneumoprotective effect through upregulation of antioxidant status, downregulation of inflammatory cytokines and MMP-7 expression, and reduction of collagen accumulation (hydroxyproline). Nrf2, HO-1, and TGF-β expression was downregulated in BLM-induced fibrosis model, while the reduced expression levels were significantly and dose-dependently upregulated by SA (10 and 20 mg/kg) treatment. We demonstrated that SA ameliorates BLM-induced lung injuries through inhibition of apoptosis and induction of Nrf2/HO-1-mediated antioxidant enzymes via NF-κB inhibition. The histopathological findings also revealed that SA treatment (10 and 20 mg/kg) significantly ameliorated BLM-induced lung injury.

Conclusion: The present results showed the ability of SA to restore the antioxidant system and to inhibit oxidative stress, proinflammatory cytokines, extracellular matrix, and TGF-β. This is first report demonstrating that SA amoleriates BLM induced lung injuries through inhibition of apoptosis and induction of Nrf2 and HO-1 mediated antioxidant enzyme via NF-κB inhibition. The histopathological finding reveals that SA treatment (10 and 20 mg/kg) significantly ameliorates BLM induced lung injuries.
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http://dx.doi.org/10.1016/j.biopha.2018.09.032DOI Listing
December 2018

Momordica charantia polysaccharides ameliorate oxidative stress, inflammation, and apoptosis in ethanol-induced gastritis in mucosa through NF-kB signaling pathway inhibition.

Int J Biol Macromol 2018 May 4;111:193-199. Epub 2018 Jan 4.

Quality Assurance Unit, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

This study investigated the therapeutic role of polysaccharides from M. charantia and their mechanism of action against ethanol-induced gastric ulcers in rats. Their effects were determined through macroscopic evaluation of the gastric cavity (gastric ulcer index [GUI]), changes in PGE, lipid peroxidation (malondialdehyde), antioxidant systems (catalase and reduced glutathione), inflammatory markers (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and myeloperoxidase [MPO]), apoptotic markers (caspase 3, Bax, and Bcl-2), nuclear factor-κB (NF-κB [p65]), and histopathological staining (H&E and PAS). Pretreatment with MCP (300mg/kg p.o.) attenuated the severity of ethanol-induced gastric mucosal damage, reductions in GUI, histopathologic aberrations, and neutrophil invasion, and PGE upregulation. These actions were similar to those of omeprazole, a reference anti-ulcer drug. MCP repressed gastric inflammation through the reduction of MPO, TNF-α, and IL-6, and prevented gastric oxidative stress through the inhibition of lipid peroxides with the concomitant enhancement of glutathione and catalase activity. Apoptotic markers indicated that MCP suppressed Bax and caspase-3 activity and enhanced the anti-apoptotic protein Bcl-2, which favored cell survival. MCP downregulated NF-κB and upregulated IκBα. Our study results suggested that the prophylactic administration of MCP reduced ethanol-induced gastric injury in rats through the suppression of gastric inflammation and oxidative stress, predominantly via NF-κB inhibition.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.01.008DOI Listing
May 2018

Magnetic, structural and magnetocaloric properties of Ni-Si and Ni-Al thermoseeds for self-controlled hyperthermia.

Int J Hyperthermia 2017 11 17;33(7):779-784. Epub 2017 Apr 17.

a Department of Physics , Southern Illinois University , Carbondale , IL , USA.

Self-controlled hyperthermia is a non-invasive technique used to kill or destroy cancer cells while preserving normal surrounding tissues. We have explored bulk magnetic Ni-Si and Ni-Al alloys as a potential thermoseeds. The structural, magnetic and magnetocaloric properties of the samples were investigated, including saturation magnetisation, Curie temperature (T), and magnetic and thermal hysteresis, using room temperature X-ray diffraction and magnetometry. The annealing time, temperature and the effects of homogenising the thermoseeds were studied to determine the functional hyperthermia applications. The bulk Ni-Si and Ni-Al binary alloys have Curie temperatures in the desired range, 316 K-319 K (43 °C-46 °C), which is suitable for magnetic hyperthermia applications. We have found that T strictly follows a linear trend with doping concentration over a wide range of temperature. The magnetic ordering temperature and the magnetic properties can be controlled through substitution in these binary alloys.
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http://dx.doi.org/10.1080/02656736.2017.1312562DOI Listing
November 2017

Environment effects for earliness and grain yield traits in F diallel populations of maize (Zea mays L.).

J Sci Food Agric 2017 Oct 14;97(13):4408-4418. Epub 2017 Jun 14.

Department of Agricultural Sciences, University of Haripur, Haripur, Pakistan.

Background: Five maize inbred lines, 20 F diallel hybrids and two check genotypes were evaluated through genotype × environment interaction (GEI) and GGE biplot for earliness and yield traits at four locations.

Results: Genotype, environment and GEI showed highly significant differences for all the traits. In total sum of squares, environment and genotype played a primary role, followed by GEI. Larger effects of environment and genotype to total variation influence the earliness and yield traits. However, according to the GGE biplot, the first two principal components (PC1 and PC2) explained 95% of the variation caused by GEI. GGE biplot confirmed the differential response of genotypes across environments. F hybrid SWAJK-1 × FRHW-3 had better stability, with a good yield, and was considered an ideal genotype. F hybrid FRHW-2 × FRHW-1 showed more earliness at CCRI and Haripur, followed by PSEV3 × FRHW-2 and its reciprocal at Swat and Mansehra, respectively. F hybrids FRHW-1 × SWAJK-1, PSEV3 × SWAJK-1 and SWAJK-1 × FRHW-3 at Mansehra and Swat produced maximum grain yield, followed by SWAJK-1 × FRHW-1 and PSEV3 × FRHW-1 at Haripur and CCRI, respectively.

Conclusion: Overall, maize genotypes showed early maturity in plain areas (CCRI and Haripur) but higher yield in hilly areas (Mansehra and Swat). © 2017 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.8420DOI Listing
October 2017

Dclk1, a tumor stem cell marker, regulates pro-survival signaling and self-renewal of intestinal tumor cells.

Mol Cancer 2017 02 1;16(1):30. Epub 2017 Feb 1.

Division of Digestive Diseases and Nutrition, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.

Background: More than 80% of intestinal neoplasia is associated with the adenomatous polyposis coli (APC) mutation. Doublecortin-like kinase 1 (Dclk1), a kinase protein, is overexpressed in colorectal cancer and specifically marks tumor stem cells (TSCs) that self-renew and increased the tumor progeny in Apc mice. However, the role of Dclk1 expression and its contribution to regulating pro-survival signaling for tumor progression in Apc mutant cancer is poorly understood.

Methods: We analyzed DCLK1 and pro-survival signaling gene expression datasets of 329 specimens from TCGA Colon Adenocarcinoma Cancer Data. The network of DCLK1 and pro-survival signaling was analyzed utilizing the GeneMANIA database. We examined the expression levels of Dclk1 and other stem cell-associated markers, pro-survival signaling pathways, cell self-renewal in the isolated intestinal epithelial cells of Apc mice with high-grade dysplasia and adenocarcinoma. To determine the functional role of Dclk1 for tumor progression, we knocked down Dclk1 and determined the pro-survival signaling pathways and stemness. We used siRNA technology to gene silence pro-survival signaling in colon cancer cells in vitro. We utilized FACS, IHC, western blot, RT-PCR, and clonogenic (self-renewal) assays.

Results: We found a correlation between DCLK1 and pro-survival signaling expression. The expression of Dclk1 and stem cell-associated markers Lgr5, Bmi1, and Musashi1 were significantly higher in the intestinal epithelial cells of Apc mice than in wild-type controls. Intestinal epithelial cells of Apc mice showed increased expression of pro-survival signaling, pluripotency and self-renewal ability. Furthermore, the enteroids formed from the intestinal Dclk1 cells of Apc mice display higher pluripotency and pro-survival signaling. Dclk1 knockdown in Apc mice attenuates intestinal adenomas and adenocarcinoma, and decreases pro-survival signaling and self-renewal. Knocking down RELA and NOTCH1 pro-survival signaling and DCLK1 in HT29 and DLD1 colon cancer cells in vitro reduced the tumor cells' ability to self-renew and survive.

Conclusion: Our results indicate that Dclk1 is essential in advancing intestinal tumorigenesis. Knocking down Dclk1 decreases tumor stemness and progression and is thus predicted to regulate pro-survival signaling and tumor cell pluripotency. This study provides a strong rationale to target Dclk1 as a treatment strategy for colorectal cancer.
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http://dx.doi.org/10.1186/s12943-017-0594-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286867PMC
February 2017

Intestinal tuft cells regulate the ATM mediated DNA Damage response via Dclk1 dependent mechanism for crypt restitution following radiation injury.

Sci Rep 2016 11 23;6:37667. Epub 2016 Nov 23.

Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Crypt epithelial survival and regeneration after injury require highly coordinated complex interplay between resident stem cells and diverse cell types. The function of Dclk1 expressing tuft cells regulating intestinal epithelial DNA damage response for cell survival/self-renewal after radiation-induced injury is unclear. Intestinal epithelial cells (IECs) were isolated and purified and utilized for experimental analysis. We found that small intestinal crypts of Villin;Dclk1 mice were hypoplastic and more apoptotic 24 h post-total body irradiation, a time when stem cell survival is p53-independent. Injury-induced ATM mediated DNA damage response, pro-survival genes, stem cell markers, and self-renewal ability for survival and restitution were reduced in the isolated intestinal epithelial cells. An even greater reduction in these signaling pathways was observed 3.5 days post-TBI, when peak crypt regeneration occurs. We found that interaction with Dclk1 is critical for ATM and COX2 activation in response to injury. We determined that Dclk1 expressing tuft cells regulate the whole intestinal epithelial cells following injury through paracrine mechanism. These findings suggest that intestinal tuft cells play an important role in regulating the ATM mediated DNA damage response, for epithelial cell survival/self-renewal via a Dclk1 dependent mechanism, and these processes are indispensable for restitution and function after severe radiation-induced injury.
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http://dx.doi.org/10.1038/srep37667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120335PMC
November 2016

APSA Awardee Submission: Tumor/cancer stem cell marker doublecortin-like kinase 1 in liver diseases.

Exp Biol Med (Maywood) 2017 02 4;242(3):242-249. Epub 2016 Oct 4.

2 Section of Digestive Diseases and Nutrition, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Liver diseases are the fourth leading cause of mortality among adults in the United States. Patients with chronic liver diseases such as viral hepatitis, fibrosis, and cirrhosis have significantly higher risks of developing hepatocellular carcinoma (HCC). With a dismal five-year survival rate of 11%, HCC is the third most common cause of cancer-related deaths worldwide. Regardless of the underlying cause, late presentation and a lack of effective therapy are the major impediments for successful treatment of HCC. Therefore, there is a considerable interest in developing new strategies for the prevention and treatment of chronic liver diseases at the early stages. Cancer stem cells (CSCs), a small cell subpopulation in a tumor, exhibit unlimited self-renewal and differentiation capacity. These cells are believed to play pivotal roles in the initiation, growth, metastasis, and drug-resistance of tumors. In this review, we will briefly discuss pivotal roles of the CSC marker doublecortin-like kinase 1 (DCLK1) in hepatic tumorigenesis. Recent evidence suggests that anti-DCLK1 strategies hold promising clinical potential for the treatment of cancers of the liver, pancreas, and colon.
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http://dx.doi.org/10.1177/1535370216672746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384496PMC
February 2017

(Z)-3,5,4'-Trimethoxystilbene Limits Hepatitis C and Cancer Pathophysiology by Blocking Microtubule Dynamics and Cell-Cycle Progression.

Cancer Res 2016 08 10;76(16):4887-96. Epub 2016 Jun 10.

Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Chronic hepatitis C virus (HCV) infection causes induction of several tumors/cancer stem cell (CSC) markers and is known to be a major risk factor for development of HCC. Therefore, drugs that simultaneously target viral replication and CSC properties are needed for a risk-free treatment of advanced stage liver diseases, including HCC. Here, we demonstrated that (Z)-3,5,4'-trimethoxystilbene (Z-TMS) exhibits potent antitumor and anti-HCV activities without exhibiting cytotoxicity to human hepatocytes in vitro or in mice livers. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl4) extensively induced expression of DCLK1 (a CSC marker) in the livers of C57BL/6 mice following hepatic injury. Z-TMS exhibited hepatoprotective effects against DEN/CCl4-induced injury by reducing DCLK1 expression and improving histologic outcomes. The drug caused bundling of DCLK1 with microtubules and blocked cell-cycle progression at G2-M phase in hepatoma cells via downregulation of CDK1, induction of p21(cip1/waf1) expression, and inhibition of Akt (Ser(473)) phosphorylation. Z-TMS also inhibited proliferation of erlotinib-resistant lung adenocarcinoma cells (H1975) bearing the T790M EGFR mutation, most likely by promoting autophagy and nuclear fragmentation. In conclusion, Z-TMS appears to be a unique therapeutic agent targeting HCV and concurrently eliminating cells with neoplastic potential during chronic liver diseases, including HCC. It may also be a valuable drug for targeting drug-resistant carcinomas and cancers of the lungs, pancreas, colon, and intestine, in which DCLK1 is involved in tumorigenesis. Cancer Res; 76(16); 4887-96. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-2722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987271PMC
August 2016

In vitro antimicrobial activities of different solvent extracted samples from Iris germinica.

Pak J Pharm Sci 2016 Jan;29(1):145-50

Department of Agriculture, University of Haripur, KPK, Pakistan.

Antibacterial and antifungal activities of different solvents extracted samples of Iris germinica were carried out through disc diffusion assay. For this purpose five different solvent extracts were prepared with two concentrations (1 and 2 mg disc(-1)) and their antimicrobial activity was tested using disc diffusion assay against eight pathogenic bacteria viz. Staphylococcus aureus, B. subtilis, Bacillus atrophaeus, Escherichia coli, Pseudomonas aeruginosa, Erwinia carotovara, Klebsiella pneumoniae, Salmonella typhi and one fungal specie (Candida albicans). Butanol and ethyl acetate fraction were more effective to control the growth of different pathogens followed by chloroform, hexane and aqueous fractions respectively. C. albicans, S. aureus E. carotovara, B. atrophaeus and E. coli were comparatively susceptible inhibited by all extracts of I. germinica compared with the rest of microbes. Maximum activity was shown by ethyl acetate extracted samples against B. atrophaeus followed by the same solvent against E. carotovara. Butanol extracted samples were effective against B. subtilis showing 62% reduction in growth at 1 or 2mg disc(-1) concentration. From these results it can be concluded that different solvent extracted samples from the leaves of I. germinica possess varying degree of antimicrobial against different micro-organisms and can be a good sources of antibiotics for the treatment of certain bacterial and fungal diseases.
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January 2016

Antioxidant Potential and In Situ Analysis of Major and Trace Element Determination of Ood-saleeb, a Known Unani Herbal Medicine by ICP-MS.

Biol Trace Elem Res 2016 Aug 13;172(2):521-527. Epub 2016 Jan 13.

Department of Pharmaceutics, College of Pharmacy, King Saud University, PO Box 2457, Riyadh, 11451, Saudi Arabia.

The intention of the present research work was to investigate the antioxidant activity and trace element analysis of Ood-saleeb, a known herbal medicine. Preliminary screening of phytochemicals showed that the extract of Ood-saleeb had flavonoids and phenolics. The significant activities in all antioxidant assays were observed in the extract of Ood-saleeb in comparison with the standard antioxidant with respect to dose of Ood-saleeb. Incredible activities to scavenge reactive oxygen species were also observed by the extract of Ood-saleeb. The IC50 values of all factors were determined using ascorbic acid as a standard. The inductive coupled plasma-mass spectroscopy (ICP-MS) was employed for the estimation of trace elements in Ood-saleeb extract. The concentrations of up to 18 elements were detected successfully. Silicon was found in high concentration (85.3 μg/g) while lithium was in low concentration (3 ng/g). The trace elements in the sample were found at different percentage levels which play a key role in the treatment of diseases.
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http://dx.doi.org/10.1007/s12011-015-0607-xDOI Listing
August 2016

The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism.

J Biol Chem 2016 Feb 23;291(7):3254-67. Epub 2015 Dec 23.

From the Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, North Chicago, Illinois 60064 and

Hepatitis C virus (HCV) relies on host lipids and lipid droplets for replication and morphogenesis. The accumulation of lipid droplets in infected hepatocytes manifests as hepatosteatosis, a common pathology observed in chronic hepatitis C patients. One way by which HCV promotes the accumulation of intracellular lipids is through enhancing de novo lipogenesis by activating the sterol regulatory element-binding proteins (SREBPs). In general, activation of SREBPs occurs during cholesterol depletion. Interestingly, during HCV infection, the activation of SREBPs occurs under normal cholesterol levels, but the underlying mechanisms are still elusive. Our previous study has demonstrated the activation of the inflammasome complex in HCV-infected human hepatoma cells. In this study, we elucidate the potential link between chronic hepatitis C-associated inflammation and alteration of lipid homeostasis in infected cells. Our results reveal that the HCV-activated NLRP3 inflammasome is required for the up-regulation of lipogenic genes such as 3-hydroxy-3-methylglutaryl-coenzyme A synthase, fatty acid synthase, and stearoyl-CoA desaturase. Using pharmacological inhibitors and siRNA against the inflammasome components (NLRP3, apoptosis-associated speck-like protein containing a CARD, and caspase-1), we further show that the activation of the NLRP3 inflammasome plays a critical role in lipid droplet formation. NLRP3 inflammasome activation in HCV-infected cells enables caspase-1-mediated degradation of insulin-induced gene proteins. This subsequently leads to the transport of the SREBP cleavage-activating protein·SREBP complex from the endoplasmic reticulum to the Golgi, followed by proteolytic activation of SREBPs by S1P and S2P in the Golgi. Typically, inflammasome activation leads to viral clearance. Paradoxically, here we demonstrate how HCV exploits the NLRP3 inflammasome to activate SREBPs and host lipid metabolism, leading to liver disease pathogenesis associated with chronic HCV.
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http://dx.doi.org/10.1074/jbc.M115.694059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751372PMC
February 2016

Plasma DCLK1 is a marker of hepatocellular carcinoma (HCC): Targeting DCLK1 prevents HCC tumor xenograft growth via a microRNA-dependent mechanism.

Oncotarget 2015 Nov;6(35):37200-15

Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Tumor stem cell marker Doublecortin-like kinase1 (DCLK1) is upregulated in several solid tumors. The role of DCLK1 in hepatocellular carcinoma (HCC) is unclear. We immunostained tissues from human livers with HCC, cirrhosis controls (CC), and non-cirrhosis controls (NCC) for DCLK1. Western blot and ELISA analyses for DCLK1 were performed with stored plasma samples. We observed increased immunoreactive DCLK1 in epithelia and stroma in HCC and CCs compared with NCCs, and observed a marked increase in plasma DCLK1 from patients with HCC compared with CC and NCC. Analysis of the Cancer Genome Atlas' HCC dataset revealed that DCLK1 is overexpressed in HCC tumors relative to adjacent normal tissues. High DCLK1-expressing cells had more epithelial-mesenchymal transition (EMT). Various tumor suppressor miRNAs were also downregulated in HCC tumors. We evaluated the effects of DCLK1 knockdown on Huh7.5-derived tumor xenograft growth. This was associated with growth arrest and a marked downregulation of cMYC, and EMT transcription factors ZEB1, ZEB2, SNAIL, and SLUG via let-7a and miR-200 miRNA-dependent mechanisms. Furthermore, upregulation of miR-143/145, a corresponding decrease in pluripotency factors OCT4, NANOG, KLF4, and LIN28, and a reduction of let-7a, miR-143/145, and miR-200-specific luciferase activity was observed. These findings suggest that the detection of elevated plasma DCLK1 may provide a cost-effective, less invasive tool for confirmation of clinical signs of cirrhosis, and a potential companion diagnostic marker for patients with cirrhosis and HCC. Our results support evaluating DCLK1 as a biomarker for detection and as a therapeutic target for eradicating HCC.
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http://dx.doi.org/10.18632/oncotarget.5808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741924PMC
November 2015

Dclk1+ small intestinal epithelial tuft cells display the hallmarks of quiescence and self-renewal.

Oncotarget 2015 Oct;6(31):30876-86

Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

To date, no discrete genetic signature has been defined for isolated Dclk1+ tuft cells within the small intestine. Furthermore, recent reports on the functional significance of Dclk1+ cells in the small intestine have been inconsistent. These cells have been proposed to be fully differentiated cells, reserve stem cells, and tumor stem cells. In order to elucidate the potential function of Dclk1+ cells, we FACS-sorted Dclk1+ cells from mouse small intestinal epithelium using transgenic mice expressing YFP under the control of the Dclk1 promoter (Dclk1-CreER;Rosa26-YFP). Analysis of sorted YFP+ cells demonstrated marked enrichment (~6000 fold) for Dclk1 mRNA compared with YFP- cells. Dclk1+ population display ~6 fold enrichment for the putative quiescent stem cell marker Bmi1. We observed significantly greater expression of pluripotency genes, pro-survival genes, and quiescence markers in the Dclk1+ population. A significant increase in self-renewal capability (14-fold) was observed in in vitro isolated Dclk1+ cells. The unique genetic report presented in this manuscript suggests that Dclk1+ cells may maintain quiescence, pluripotency, and metabolic activity for survival/longevity. Functionally, these reserve characteristics manifest in vitro, with Dclk1+ cells exhibiting greater ability to self-renew. These findings indicate that quiescent stem-like functionality is a feature of Dclk1-expressing tuft cells.
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http://dx.doi.org/10.18632/oncotarget.5129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741574PMC
October 2015

Ablation of Doublecortin-Like Kinase 1 in the Colonic Epithelium Exacerbates Dextran Sulfate Sodium-Induced Colitis.

PLoS One 2015 18;10(8):e0134212. Epub 2015 Aug 18.

Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, United States of America; Department of Veterans Affairs Medical Center, Oklahoma City, OK, 73104, United States of America; Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK, 73104, United States of America; COARE Biotechnology, Oklahoma City, OK, 73104, United States of America.

Doublecortin-like kinase 1 (Dclk1), a microtubule-associated kinase, marks the fifth lineage of intestinal epithelial cells called tuft cells that function as tumor stem cells in Apc mutant models of colon cancer. In order to determine the role of Dclk1 in dextran sulfate sodium (DSS) induced colonic inflammation both intestinal epithelial specific Dclk1 deficient (VillinCre;Dclk1f/f) and control (Dclk1f/f) mice were fed 3% DSS in drinking water for 9 days, allowed to recover for 2 days, and killed. The clinical and histological features of DSS-induced colitis were scored and immunohistochemical, gene expression, pro-inflammatory cytokines/chemokines, and immunoblotting analyses were used to examine epithelial barrier integrity, inflammation, and stem and tuft cell features. In DSS-induced colitis, VillinCre;Dclk1f/f mice demonstrated exacerbated injury including higher clinical colitis scores, increased epithelial barrier permeability, higher levels of pro-inflammatory cytokines and chemokines, decreased levels of Lgr5, and dysregulated Wnt/b-Catenin pathway genes. These results suggest that Dclk1 plays an important role in regulating colonic inflammatory response and colonic epithelial integrity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134212PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540568PMC
May 2016

Dietary Pectin Increases Intestinal Crypt Stem Cell Survival following Radiation Injury.

PLoS One 2015 13;10(8):e0135561. Epub 2015 Aug 13.

Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America; Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, United States of America; The Peggy and Charles Stephenson Cancer Center, Oklahoma City, Oklahoma, United States of America.

Gastrointestinal (GI) mucosal damage is a devastating adverse effect of radiation therapy. We have recently reported that expression of Dclk1, a Tuft cell and tumor stem cell (TSC) marker, 24h after high dose total-body gamma-IR (TBI) can be used as a surrogate marker for crypt survival. Dietary pectin has been demonstrated to possess chemopreventive properties, whereas its radioprotective property has not been studied. The aim of this study was to determine the effects of dietary pectin on ionizing radiation (IR)-induced intestinal stem cell (ISC) deletion, crypt and overall survival following lethal TBI. C57BL/6 mice received a 6% pectin diet and 0.5% pectin drinking water (pre-IR mice received pectin one week before TBI until death; post-IR mice received pectin after TBI until death). Animals were exposed to TBI (14 Gy) and euthanized at 24 and 84h post-IR to assess ISC deletion and crypt survival respectively. Animals were also subjected to overall survival studies following TBI. In pre-IR treatment group, we observed a three-fold increase in ISC/crypt survival, a two-fold increase in Dclk1+ stem cells, increased overall survival (median 10d vs. 7d), and increased expression of Dclk1, Msi1, Lgr5, Bmi1, and Notch1 (in small intestine) post-TBI in pectin treated mice compared to controls. We also observed increased survival of mice treated with pectin (post-IR) compared to controls. Dietary pectin is a radioprotective agent; prevents IR-induced deletion of potential reserve ISCs; facilitates crypt regeneration; and ultimately promotes overall survival. Given the anti-cancer activity of pectin, our data support a potential role for dietary pectin as an agent that can be administered to patients receiving radiation therapy to protect against radiation-induces mucositis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135561PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536042PMC
May 2016

Inflammatory and oncogenic roles of a tumor stem cell marker doublecortin-like kinase (DCLK1) in virus-induced chronic liver diseases.

Oncotarget 2015 Aug;6(24):20327-44

Department of Internal Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. We previously showed that a tumor/cancer stem cell (CSC) marker, doublecortin-like kinase (DCLK1) positively regulates hepatitis C virus (HCV) replication, and promotes tumor growth in colon and pancreas. Here, we employed transcriptome analysis, RNA interference, tumor xenografts, patient's liver tissues and hepatospheroids to investigate DCLK1-regulated inflammation and tumorigenesis in the liver. Our studies unveiled novel DCLK1-controlled feed-forward signaling cascades involving calprotectin subunit S100A9 and NFκB activation as a driver of inflammation. Validation of transcriptome data suggests that DCLK1 co-expression with HCV induces BRM/SMARCA2 of SW1/SNF1 chromatin remodeling complexes. Frequently observed lymphoid aggregates including hepatic epithelial and stromal cells of internodular septa extensively express DCLK1 and S100A9. The DCLK1 overexpression also correlates with increased levels of S100A9, c-Myc, and BRM levels in HCV/HBV-positive patients with cirrhosis and HCC. DCLK1 silencing inhibits S100A9 expression and hepatoma cell migration. Normal human hepatocytes (NHH)-derived spheroids exhibit CSC properties. These results provide new insights into the molecular mechanism of the hepatitis B/C-virus induced liver inflammation and tumorigenesis via DCLK1-controlled networks. Thus, DCLK1 appears to be a novel therapeutic target for the treatment of inflammatory diseases and HCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653008PMC
http://dx.doi.org/10.18632/oncotarget.3972DOI Listing
August 2015

Doublecortin-like kinase 1 is elevated serologically in pancreatic ductal adenocarcinoma and widely expressed on circulating tumor cells.

PLoS One 2015 27;10(2):e0118933. Epub 2015 Feb 27.

Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Department of Veterans Affairs Medical Center, Oklahoma City, OK, United States of America; Peggy and Charles Stephenson Oklahoma Cancer Center, Oklahoma City, OK, United States of America; COARE Biotechnology Inc., Oklahoma City, OK, United States of America.

Doublecortin-like kinase 1 (DCLK1) is a putative pancreatic stem cell marker and is upregulated in pancreatic cancer, colorectal cancer, and many other solid tumors. It marks tumor stem cells in mouse models of intestinal neoplasia. Here we sought to determine whether DCLK1 protein can be detected in the bloodstream and if its levels in archived serum samples could be quantitatively assessed in pancreatic cancer patients. DCLK1 specific ELISA, western blotting, and immunohistochemical analyses were used to determine expression levels in the serum and staining intensity in archived tumor tissues of pancreatic ductal adenocarcinoma (PDAC) patients and in pancreatic cancer mouse models. DCLK1 levels in the serum were elevated in early stages of PDAC (stages I and II) compared to healthy volunteers (normal controls). No differences were observed between stages III/IV and normal controls. In resected surgical tissues, DCLK1 expression intensity in the stromal cells was significantly higher than that observed in tumor epithelial cells. Circulating tumor cells were isolated from KPCY mice and approximately 52% of these cells were positive for Dclk1 staining. Dclk1 levels in the serum of KPC mice were also elevated. We have previously demonstrated that DCLK1 plays a potential role in regulating epithelial mesenchymal transition (EMT). Given the increasingly recognized role of EMT derived stem cells in cancer progression and metastasis, we hypothesize that DCLK1 may contribute to the metastatic process. Taken together, our results suggest that DCLK1 serum levels and DCLK1 positive circulating tumor cells should be further assessed for their potential diagnostic and prognostic significance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118933PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344195PMC
November 2015

DCLK1 facilitates intestinal tumor growth via enhancing pluripotency and epithelial mesenchymal transition.

Oncotarget 2014 Oct;5(19):9269-80

Department of Medicine, University of Oklahoma Health Sciences center, Oklahoma City, OK 73104, USA. OU Cancer Institute, University of Oklahoma Health Sciences center, Oklahoma City, OK 73104, USA. Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA.

Doublecortin-like kinase 1 (Dclk1) is overexpressed in many cancers including colorectal cancer (CRC) andit specifically marks intestinal tumor stem cells. However, the role of Dclk1 in intestinal tumorigenesis in Apc mutant conditions is still poorly understood. We demonstrate that Dclk1 expression and Dclk1+ cells are significantly increased in the intestinal epithelium of elderly ApcMin/+ mice compared to young ApcMin/+ mice and wild type mice. Intestinal epithelial cells of ApcMin/+ mice demonstrate increased pluripotency, self-renewing ability, and EMT. Furthermore, miRNAs are dysregulated, expression of onco-miRNAs are significantly increased with decreased tumor suppressor miRNAs. In support of these findings, knockdown of Dclk1 in elderly ApcMin/+ mice attenuates intestinal adenomas and adenocarcinoma by decreasing pluripotency, EMT and onco-miRNAs indicating that Dclk1 overexpression facilitates intestinal tumorigenesis. Knocking down Dclk1 weakens Dclk1-dependent intestinal processes for tumorigenesis. This study demonstrates that Dclk1 is critically involved in facilitating intestinal tumorigenesis by enhancing pluripotency and EMT factors in Apc mutant intestinal tumors and it also provides a potential therapeutic target for the treatment of colorectal cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253433PMC
http://dx.doi.org/10.18632/oncotarget.2393DOI Listing
October 2014

Small molecule kinase inhibitor LRRK2-IN-1 demonstrates potent activity against colorectal and pancreatic cancer through inhibition of doublecortin-like kinase 1.

Mol Cancer 2014 May 6;13:103. Epub 2014 May 6.

Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Background: Doublecortin-like kinase 1 (DCLK1) is emerging as a tumor specific stem cell marker in colorectal and pancreatic cancer. Previous in vitro and in vivo studies have demonstrated the therapeutic effects of inhibiting DCLK1 with small interfering RNA (siRNA) as well as genetically targeting the DCLK1+ cell for deletion. However, the effects of inhibiting DCLK1 kinase activity have not been studied directly. Therefore, we assessed the effects of inhibiting DCLK1 kinase activity using the novel small molecule kinase inhibitor, LRRK2-IN-1, which demonstrates significant affinity for DCLK1.

Results: Here we report that LRRK2-IN-1 demonstrates potent anti-cancer activity including inhibition of cancer cell proliferation, migration, and invasion as well as induction of apoptosis and cell cycle arrest. Additionally we found that it regulates stemness, epithelial-mesenchymal transition, and oncogenic targets on the molecular level. Moreover, we show that LRRK2-IN-1 suppresses DCLK1 kinase activity and downstream DCLK1 effector c-MYC, and demonstrate that DCLK1 kinase activity is a significant factor in resistance to LRRK2-IN-1.

Conclusions: Given DCLK1's tumor stem cell marker status, a strong understanding of its biological role and interactions in gastrointestinal tumors may lead to discoveries that improve patient outcomes. The results of this study suggest that small molecule inhibitors of DCLK1 kinase should be further investigated as they may hold promise as anti-tumor stem cell drugs.
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http://dx.doi.org/10.1186/1476-4598-13-103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030036PMC
May 2014

XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism.

Cancer Lett 2014 Aug 28;351(1):151-61. Epub 2014 May 28.

Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, United States; The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, United States. Electronic address:

XMD8-92 is a kinase inhibitor with anti-cancer activity against lung and cervical cancers, but its effect on pancreatic ductal adenocarcinoma (PDAC) remains unknown. Doublecortin-like kinase1 (DCLK1) is upregulated in various cancers including PDAC. In this study, we showed that XMD8-92 inhibits AsPC-1 cancer cell proliferation and tumor xenograft growth. XMD8-92 treated tumors demonstrated significant downregulation of DCLK1 and several of its downstream targets (including c-MYC, KRAS, NOTCH1, ZEB1, ZEB2, SNAIL, SLUG, OCT4, SOX2, NANOG, KLF4, LIN28, VEGFR1, and VEGFR2) via upregulation of tumor suppressor miRNAs let-7a, miR-144, miR-200a-c, and miR-143/145; it did not however affect BMK1 downstream genes p21 and p53. These data taken together suggest that XMD8-92 treatment results in inhibition of DCLK1 and downstream oncogenic pathways (EMT, pluripotency, angiogenesis and anti-apoptotic), and is a promising chemotherapeutic agent against PDAC.
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http://dx.doi.org/10.1016/j.canlet.2014.05.011DOI Listing
August 2014