Browsing by Author "Mousa, Shaker A."
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Item Alpha v beta 3 integrin antagonists enhance chemotherapy response in an orthotopic pancreatic cancer model(Frontiers Media, 2020-01-27) Sudha, Thangirala; Bharali, Dhruba J.; Davis, Paul J.; Mousa, Shaker A.; Coşkun, Melis Debreli; Çelikler, Serap; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Biyoloji Bölümü.; 0000-0002-4177-3478; CML-2517-2022; 57194630463; 8234554800Pancreatic cancer decreases survival time and quality of life because of drug resistance and peripheral neuropathy during conventional treatment. This study was undertaken to investigate whether alpha v beta 3 integrin receptor antagonist compounds NDAT and XT199 can suppress the development of cisplatin resistance and cisplatin-induced peripheral neuropathy in an orthotopic pancreatic SUIT2-luc cancer cell mouse model. Anticancer effects of these compounds and their combination with cisplatin were assessed in this tumor mouse model with bioluminescent signaling and histopathology, and a cytokine assay was used to examine expression of inflammatory cytokines IL-1 beta, IL-6, IL-10, and TNF-alpha from plasma samples. To determine the neuroprotective effects of the compounds on cisplatin-induced peripheral neuropathy, behavioral hind-limb posture of the mice was evaluated. The combination therapy of NDAT or XT199 with cisplatin elicited greater inhibition of tumor growth and increased tumor necrosis compared to cisplatin alone. NDAT and XT199 in combination with cisplatin significantly decreased expression of pro-inflammatory cytokines IL-1 beta, IL-6, and TNF-alpha and significantly increased expression of anti-inflammatory cytokine IL-10 in comparison to cisplatin alone. Cisplatin-treated groups showed stocking-glove hind-limb posture, whereas NDAT and XT199 with cisplatin-treated groups displayed normal hind-limb posture. Results clearly suggest that NDAT and XT199 treatment with cisplatin that inactivates NF-kappa B may contribute to increased antitumor and anti-inflammatory efficacy as well as alleviate cisplatin-mediated loss of motor function in this pancreatic tumor mouse model.Item Corrigendum to “Semisynthesis and pharmacological activities of thyroxine analogs: Development of new angiogenesis modulators” [Bioorg. Med. Chem. Lett. 20 (2010) 3394](Pergamon-Elsevier Science, 2010-09-15) Bridoux, Alexandre; Cui, Huadong; Dyskin, Evgeny; Schmitzer, Andreea Ruxandra; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veterinerlik Fakültesi/Temel Bilimler Bölümü.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Item Enzymatic generation of highly anticoagulant bovine intestinal heparin(Amer Chemical, 2017-10-26) Fu, Li; Li, Kevin; Hirakane, Makoto; Lin, Lei; Grover, Navdeep; Datta, Payel; Yu, Yanlei; Zhao, Jing; Zhang, Fuming; Mousa, Shaker A.; Dordick, Jonathan S.; Linhardt, Robert J.; Yalçın, Murat; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Unlike USP porcine heparin, bovine intestinal heparin (BIH) has a low anticoagulant activity. Treatment with 6-OST-1,-3, and/or 3-OST-1 afforded two remodeled heparins that met USP heparin activity and Mw specifications. We explored the pharmacodynamics and pharmacokinetics in a rabbit model. We conclude that a modest increase in the content of 3-O-sulfo groups in BIH increases the number of antithrombin III binding sites, making remodeled BIH behave similarly to pharmaceutical heparin.Item Fluorinated analog NMR s of organosulfur compounds from garlic (allium sativum): Synthesis, chemistry and anti-angiogenesis and antithrombotic studies(MDPI, 2017-11-24) Block, Eric; Bechand, Benjamin; Gundala, Sivaji; Vattekkatte, Abith; Wang, Kai; Mousa, Shaymaa S; Godugu, Kavitha; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734We describe the synthesis, reactivity, and antithrombotic and anti-angiogenesis activity of difluoroallicin (S-(2-fluoroallyl) 2-fluoroprop-2-ene-1-sulfinothioate) and S-2-fluoro-2-propenyl-l-cysteine, both easily prepared from commercially available 3-chloro-2-fluoroprop-1-ene, as well as the synthesis of 1,2-bis(2-fluoroallyl)disulfane, 5-fluoro-3-(1-fluorovinyl)-3,4-dihydro-1,2-dithiin, trifluoroajoene ((E,Z)-1-(2-fluoro-3-((2-fluoroallyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoroallyl)disulfane), and a bis(2-fluoroallyl)polysulfane mixture. All tested organosulfur compounds demonstrated effective inhibition of either FGF or VEG-mediated angiogenesis (anti-angiogenesis activity) in the chick chorioallantoic membrane (CAM) or the mouse Matrigel (R) models. No embryo mortality was observed. Difluoroallicin demonstrated greater inhibition (p < 0.01) versus organosulfur compounds tested. Difluoroallicin demonstrated dose-dependent inhibition of angiogenesis in the mouse Matrigel (R) model, with maximal inhibition at 0.01 mg/implant. Allicin and difluoroallicin showed an effective antiplatelet effect in suppressing platelet aggregation compared to other organosulfur compounds tested. In platelet/fibrin clotting (anti-coagulant activity), difluoroallicin showed concentration-dependent inhibition of clot strength compared to allicin and the other organosulfur compounds tested.Item Increased tumor uptake of chemotherapeutics and improved chemoresponse by novel non-anticoagulant low molecular weight heparin(Int Inst Anticancer Research, 2011-02) Phillips, Patricia G.; Cui, Huadong; Abdel, Hani Nabi; Sajjad, Munawwar; Bernacki, Ralph; Veith, Jean; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veterinerlik Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Background: Recent prospective clinical trials of low molecular weight heparins (LMWHs) have demonstrated that these agents may provide significant advantages in terms of progression-free and overall survival in certain subgroups of cancer patients. The mechanisms of improved survival associated with LMWHs are not known, and may involve direct and/or indirect effects on tumor growth. The purpose of this study was to investigate the effects of LMWH and a sulfated non-anticoagulant LMWH (S-NACH) on tumor chemotherapeutic uptake and chemoresponse. Materials and Methods: LMWH and S-NACH were tested for their ability to reduce tumor growth and tumor-associated angiogenesis using three different in vivo models. Biodistribution studies were undertaken to determine the effect of these agents on uptake of paclitaxel (PACL) and doxorubicin (Dox) by breast cancer tumor xenografts. Results: LMWH and S-NACH (10 mg/kg s.c. daily) effectively limited tumor growth of human A549 lung adenocarcinoma xenografts in the nude mouse. In an MDA453/LCC6 breast tumor xenograft model, PACL plus S-NACH showed significant (p<0.01) tumor growth suppression and improved survival when compared to PACL alone. LMWH increased [I124-]-PACL uptake into MDA453/LCC6 tumors, with tumor:muscle ratios several fold greater than that of [I124-]-PACL alone 24 h post-injection. Similarly, LMWH and S-NACH significantly (p<0.01) increased the uptake of Dox by 1.5-2 fold in MCF7 Dox-resistant tumor xenografts. Conclusion: Protocols utilizing adjuvant or neoadjuvant therapy with LMWH or S-NACH could lead to increased tumor chemo responsiveness, potentially overcoming tumor chemoresistance.Publication Lead-induced endothelial cell dysfunction: Protective effect of sulfated non-anticoagulant low molecular weight heparin(Korean Soc Environmental Risk Assessment & Health Science, 2021-04-12) Motawei, Shimaa M.; Sudha, Thangirala; Godugu, Kavitha; Mousa, Shaker A.; Yalçın, Murat; YALÇIN, MURAT; Bursa Uludağ Üniversitesi/Veteriner Fakültesi.; 0000-0002-5600-8162; AAG-6956-2021Objective The aim of this investigation is to determine the potential protective effect and mechanism of a novel non-anticoagulant heparin-derived product on lead (Pb) mediated endothelial cells (ECs) toxicity. Pb is known to have detrimental effects on human health by affecting the function of all systems of the human body due to its toxicity on ECs. Altered activities of the protective substances secreted by the vascular endothelium such as EC's tissue factor pathway inhibiter (TFPI), nitric oxide and other protective factors might increase the risk for vascular disorders. Heparin and its sulfated non-anticoagulant low molecular weight heparin (S-NACH) are known to enhance TFPI release from ECs, which is a protective mechanism for the ECs against thrombo-inflammation. Methods We examined 3-100 mu M Pb-induced dysfunction on ECs and the potential protective effect of 1-10 mu M S-NACH in returning the ECs' normal function. Methods included an in vitro tube formation assay and an in vivo Matrigel plug angiogenesis model in mice. Results We found that Pb-induced EC dysfunction by inhibiting EC viability. The cytotoxic effect of 3-100 mu M Pb on ECs inhibited angiogenesis in a dose-dependent manner. Pb disrupted ECs' normal physiological function by hindering the release of its endogenous vascular protective mediators TFPI-1 and TFPI-2. The impairment effect of 3-30 mu M Pb on ECs' release of both TFPIs was effectively reversed to normal levels by S-NACH in a concentration-dependent manner and combatted the harmful Pb effects on physiological angiogenesis. Conclusions Our data indicate that S-NACH, which is devoid of bleeding side effects, can effectively reverse potentially high-risk Pb-mediated endothelial cytotoxicity by reversing the physiological release of endogenous EC TFPIs.Item Models for assessing anti-angiogenesis agents: Appraisal of current techniques(Elsevier, 2017) Mousa, Shaker A.; Davis, Paul J.; Yalçın, Murat; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734A number of reproducible, technically satisfactory methods are available for experimentally measuring the anti- and proangiogenic activities of vascular growth factors, hormones, peptides, and pharmaceuticals. A group of widely used in vitro and in vivo assays for angiogenesis are reviewed here. The in vitro assays are the aortic ring, sprouting, and tube formation systems and the in vivo assays are the chick chorioallantoic membrane (CAM), the zebrafish, tumor xenografts in the immunocompromised mouse, and the Matrigel plug models. Human angiogenesis cannot be entirely reproduced in a single assay system. Thus, satisfactory preclinical anti- and proangiogenesis assay results do not assure clinical efficacy. Most of the assays discussed here, however, respond predictably to standard angiogenesis inhibitors and proangiogenesis factors and are cost effective.Publication Nanotetrac targets integrin αvβ3 on tumor cells to disorder cell defense pathways and block angiogenesis(Dove Medical Press Ltd, 2014-01-01) Davis, Paul J.; Lin, Hung-Yun; Sudha, Thangirala; Yalçın, Murat; Tang, Heng-Yuan; Hercbergs, Aleck; Leith, John T.; Luidens, Mary K.; Ashur-Fabian, Osnat; Incerpi, Sandra; Mousa, Shaker A.; YALÇIN, MURAT; Uludağ Üniversitesi/Tıp Fakültesi/Radyasyon Onkolojisi Anabilim Dalı; 0000-0002-5600-8162; AAG-6956-2021The extracellular domain of integrin alpha v beta 3 contains a receptor for thyroid hormone and hormone analogs. The integrin is amply expressed by tumor cells and dividing blood vessel cells. The proangiogenic properties of thyroid hormone and the capacity of the hormone to promote cancer cell proliferation are functions regulated nongenomically by the hormone receptor on alpha v beta 3. An L-thyroxine (T-4) analog, tetraiodothyroacetic acid (tetrac), blocks binding of T-4 and 3,5,3'-triiodo-L-thyronine (T-3) by alpha v beta 3 and inhibits angiogenic activity of thyroid hormone. Covalently bound to a 200 nm nanoparticle that limits its activity to the cell exterior, tetrac reformulated as Nanotetrac has additional effects mediated by alpha v beta 3 beyond the inhibition of binding of T-4 and T-3 to the integrin. These actions of Nanotetrac include disruption of transcription of cell survival pathway genes, promotion of apoptosis by multiple mechanisms, and interruption of repair of double-strand deoxyribonucleic acid breaks caused by irradiation of cells. Among the genes whose expression is suppressed by Nanotetrac are EGFR, VEGFA, multiple cyclins, catenins, and multiple cytokines. Nanotetrac has been effective as a chemotherapeutic agent in preclinical studies of human cancer xenografts. The low concentrations of alpha v beta 3 on the surface of quiescent nonmalignant cells have minimized toxicity of the agent in animal studies.Item Nf-kb ve oksidatif stresin inhibisyonu ile peripheral nöropatinin iyileştirilmesi ve kanser kemoterapi sonuçlarının geliştirilmesi(Uludağ Üniversitesi, 2017) Coşkun, Melis Debreli; Kasımoğulları, Serap Çelikler; Mousa, Shaker A.; Uludağ Üniversitesi/Fen Bilimleri Enstitüsü/Biyoloji Anabilim Dalı.Pankreas kanseri geleneksel tedavisinde meydana gelen ilaç direnci ve periferik nöropati sebebiyle sağ kalım süresini ve yaşam kalitesini düşürmektedir. Pankreas kanseri tedavisinde daha etkin, direnç geliştirmeyen ve nöropati oluşturmayacak yeni kemoterapötik ve kemopreventiflerin bulunması önem arz etmektedir. Bu tez çalışmasında kemoterapötik ilaçların indüklediği NF-κB/ROS aktivitesi inhibe edilerek, nöropatik ağrı gelişimini azaltmak ve kanser kemoterapi sonuçlarını iyileştirmek amacıyla NDAT, XT199, OT-404 ve EGCG bileşiklerinin etkilerinin klinik öncesi yöntemlerle (in vitro ve in vivo) değerlendirilmesi amaçlanmıştır. Kemoterapötik ilaçların (sisplatin ve gemsitabin) ve LPS'in indüklediği NF-κB/ROS aktivitesi üzerine, αvβ3 integrin reseptör antagonistleri (NDAT ve XT199) ve antioksidanların (EGCG ve OT-404) anti-inflamatuar etkileri HeLa ve THP1 hücrelerinde lusiferaz yöntemi ile araştırıldı. NDAT, XT199, EGCG ve OT-404'ün tek başına ve sisplatin ile kombine halde pankreas kanseri üzerine antitümör etkileri, ortotopik pankreas kanseri fare tümör modelinde, in vivo görüntüleme sistemi (IVIS) ve histopatolojik değerlendirme ile araştırıldı. NDAT, XT199, EGCG ve OT-404'ün tek başına ve sisplatin ile kombine halde anti-inflamatuar etkileri, nöropatik ağrı patogenezinde yer alan NF-κB ile ilişkili sitokinlerin (IL-1, IL-6, IL-10, IL-17, TNF- ve IFN-) ortotopik pankreas tümörlü farelerin plazma örneklerinden Bio-Plex sitokin yöntemi ile analiz edilmesi sonucu belirlendi. NDAT, XT199, EGCG ve OT-404'ün kemoterapinin-indüklediği periferik nöropati (CIPN) üzerindeki nöroprotektif etkilerini belirlemek adına farelerin arka-ayaklarının davranışsal duruş değerlendirmesi yapıldı. Bu tez çalışmasında, NDAT ve XT199'un pankreas kanseri tedavisinde NF-κB sinyal yolağı inhibitörü olarak, antitümör ve anti-inflamatuar etkili potansiyel kemoterapötik ajanlar OT-404'ün ise kemoprotektif bir ajan olabileceği in vitro ve in vivo çalışmalarla gösterilmiştir. Ayrıca bu bileşiklerin geleneksel kemoterapi ile gelişen ilaç direncinin üstesinden geldiği ve CIPN'yi azalttığı da belirlenmiştir. Sonuç olarak bu tez, pankreas kanseri tedavisinde ilaç direncini yıkan, periferik nöropatiyi iyileştiren yeni tedavi seçeneği sunan orijinal bir çalışmadır.Item OT-404, multi-targeted anti-cancer agent affecting tumor proliferation, chemo-resistance, and angiogenesis(Elsevier, 2013-05) Rebbaa, Abdelhadi; Patil, Ghanshyam; Sudha, Thangirala; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veterinerlik Fakültesi/Veteriner Hekimliği Temel Bilimler Bölümü.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734There is a need for a comprehensive anti-cancer strategy that simultaneously targets abnormal proliferation, angiogenesis rates, and development of chemotherapy resistance. We have identified a small molecule, OT-404, that effectively inhibited proliferation and angiogenesis of either chemo-sensitive or resistant human cancer cells and enhanced cancer cell sensitivity to different chemotherapy. In vivo studies of human tumor xenografts in nude mice showed that OT-404, used alone or encapsulated into nanoparticles, inhibited the growth of doxorubicin-resistant breast cancer MCF-7 by more than 80%, and by 95% when combined with doxorubicin. These findings provide evidence for the potential of OT-404 in cancer management.Item Pharmacokinetics, biodistribution, and anti-angiogenesis efficacy of diamino propane tetraiodothyroacetic acid-conjugated biodegradable polymeric nanoparticle(Nature, 2019-06-21) Li, Weikun; Bharali, Dhruba J.; Lin, Qishan; Godugu, Kavitha; Fujioka, Kazutoshi; Keating, Kelly A.; Mousa, Shaker A.; Yalçın, Murat; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734The anti-angiogenic agent, diamino propane tetraiodothyroacetic acid (DAT), is a thyro-integrin (integrin alpha v beta 3) antagonist anticancer agent that works via genetic and nongenetic actions. Tetraiodothyroacetic acid (tetrac) and DAT as thyroid hormone derivatives influence gene expression after they transport across cellular membranes. To restrict the action of DAT to the integrin alpha v beta 3 receptors on the cell surface, we used DAT-conjugated PLGA nanoparticles (NDAT) in an active targeting mode to bind to these receptors. Preparation and characterization of NDAT is described, and both in vitro and in vivo experiments were done to compare DAT to NDAT. Intracellular uptake and distribution of DAT and NDAT in U87 glioblastoma cells were evaluated using confocal microscopy and showed that DAT reached the nucleus, but NDAT was restricted from the nucleus. Pharmacokinetic studies using LC-MS/MS analysis in male C57BL/6 mice showed that administration of NDAT improved the area under the drug concentration curve AUC(()(0-)(48 h)) by 4-fold at a dose of 3 mg/kg when compared with DAT, and C-max of NDAT (4363 ng/mL) was 8-fold greater than that of DAT (548 ng/ mL). Biodistribution studies in the mice showed that the concentrations of NDAT were higher than DAT/Cremophor EL micelles in heart, lung, liver, spleen, and kidney. In another mouse model using female NCr nude homozygous mice with U87 xenografts, tumor growth was significantly decreased at doses of 1 and 3 mg/kg of NDAT. In the chick chorioallantoic membrane (CAM) assay used to measure angiogenesis, DAT (500 ng/CAM) resulted in 48% inhibition of angiogenesis levels. In comparison, NDAT at low dose (50 ng/CAM) showed 45% inhibition of angiogenesis levels. Our investigation of NDAT bridges the study of polymeric nanoparticles and anti-angiogenic agents and offers new insight for the rational design of anti-angiogenic agents.Item Response of human pancreatic cancer cell xenografts to tetraiodothyroacetic acid nanoparticles(Springer, 2013-06) Lin, Hungyung; Sudha, Thangirala; Bharali, Dhruba Jyoti; Meng, Ran; Tang, Hengyuan; Davis, Faith B.; Stain, Steven Charles; Davis, Paul J.; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Tetraiodothyroacetic acid (tetrac) and its nanoparticle formulation (Tetrac NP) act at an integrin cell surface receptor to inhibit tumor cell proliferation and tumor-related angiogenesis. Human pancreatic cancer cell (PANC-1 and MPanc96) xenografts were established in nude mice, and the effects of tetrac versus Tetrac NP on tumor growth and tumor angiogenesis were determined. The in vitro effects of tetrac and Tetrac NP were also determined by reverse transcription polymerase chain reaction or immunoblot on gene expression or gene products relevant to cell cycle arrest, apoptosis, or angiogenesis. Tetrac and Tetrac NP reduced both PANC-1 tumor mass by 45-55 % and PANC-1 tumor hemoglobin content, a marker of angiogenesis, by 50-60 % (*P < 0.05) in treated groups vs. controls by treatment day 15. Comparable results were obtained with tetrac and Tetrac NP in suppressing tumor growth and tumor angiogenesis in MPanc96 xenografts. In vitro studies showed that tetrac and Tetrac NP caused accumulation of pro-apoptotic protein BcLx-s. Tetrac NP was more effective than tetrac in increasing cellular abundance of mRNAs of pro-apoptotic p53 and p21 and anti-angiogenesis thrombospondin 1 protein in PANC-1 and MPanc96 cancer cell lines. Tetrac NP noticeably decreased expression of EGFR and of anti-apoptosis gene XIAP; tetrac did not affect EGFR and increased XIAP mRNA in both MPanc96 and PANC-1. In conclusion, tetrac or Tetrac NP effectively inhibited human pancreatic xenograft growth and tumor angiogenesis via a plasma membrane receptor that downstream modulated cellular abundance of proteins or mRNAs relevant to apoptosis and angiogenesis.Item Self-assembly of green tea catechin derivatives in nanoparticles for oral lycopene delivery(Elsevier, 2017-02-28) Li, Weikun; Lin, Qishan; Ardawi, Mohammed-Salleh M.; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Lycopene is a natural anti-oxidant that has attracted much attention due to its varied applications such as protection against loss of bonemass, chronic diseases, skin cancer, prostate cancer, and cardiovascular disease. However, high instability and extremely low oral bioavailability limit its further clinical development. We selected a green tea catechin derivative, oligomerized (-)-epigallocatechin-3-O-gallate (OEGCG) as a carrier for oral lycopene delivery. Lycopene-loaded OEGCG nanoparticles (NPs) were prepared by a nano-precipitation method, followed by coating with chitosan to form a shell. This method not only can easily control the size of the NP to be around 200 nm to improve its bioavailability, but also can effectively protect the lycopene against degradation due to EGCG's anti-oxidant property. OEGCG was carefully characterized with nuclearmagnetic resonance spectroscopy and mass spectrometry. Lycopene-loaded polylactic-co-glycolic acid (PLGA) NPs were prepared by the same method. Chitosan-coated OEGCG/lycopene NPs had a diameter of 152 +/- 32 nmand a.-potential of 58.3 +/- 4.2 mv as characterized with transmission electron microscopy and dynamic light scattering. The loading capacity of lycopene was 9% and encapsulation efficiency was 89%. FT-IR spectral analysis revealed electrostatic interaction between OEGCG and chitosan. Freeze drying of the NPs was also evaluated as a means to improve shelf life. Dynamic light scattering data showed that no aggregation occurred, and the size of the NP increased 1.2 times (S-f/S-i ratio) in the presence of 10% sucrose after freeze drying. The in vitro release study showed slow release of lycopene in simulated gastric fluid at acidic pH and faster release in simulated intestinal fluid. In an in vivo study in mice, lycopene pharmacokinetic parameters were improved by lycopene/OEGCG/chitosan NPs, but not improved by lycopene/PLGA/chitosan NPs. The self-assembled nanostructure of OEGCG combined with lycopene may be a promising application in oral drug delivery in various indications.Item Semisynthesis and pharmacological activities of tetrac analogs: Angiogenesis modulators(Pergamon-Elsevier Science, 2009-06-15) Bridoux, Alexandre; Cui, Huadong; Dyskin, Evgeny A.; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Novel Tetrac analogs were synthesized and then tested. Anti-angiogenesis efficacy was carried out using the Chick Chorioallantoic Membrane (CAM) model and the mouse matrigel model for angiogenesis. Pharmacological activities showed Tetrac can accommodate numerous modifications and maintain anti-angiogenesis activity.Item Semisynthesis and pharmacological activities of thyroxine analogs: Development of new angiogenesis modulators(Pergamon-Elsevier Science, 2010-06-01) Bridoux, Alexandre; Cui, Huadong; Dyskin, Evgeny; Schmitzer, Andreea Ruxandra; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veterinerlik Fakültesi/Temel Bilimler Bölümü.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Novel thyroxine analogs with hindered phenol, amino and carboxylic acid groups have been synthesized and the effects of the synthesized compounds on angiogenesis using the chick chorioallantoic membrane and mouse matrigel models have been tested. Pharmacological profiles revealed that thyroxine tolerates numerous modifications on the amino group and remains active. These results provide the rationale for the selection of a novel thyroxine nanoparticle precursor.Item Suppression of pancreatic cancer by sulfated non-anticoagulant low molecular weight heparin(Elsevier Ireland, 2014-08-01) Sudha, Thangirala; Lin, Thangirala; Elmetwally, Ahmed M.; Nazeer, Tipu; Arumugam, Thiruvengadam; Phillips, Patricia G.; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veterinerlik Fakültesi/Temel Bilimler Bölümü.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Sulfated non-anticoagulant heparins (S-NACHs) might be preferred for potential clinical use in cancer patients without affecting hemostasis as compared to low molecular weight heparins (LMWHs). We investigated anti-tumor effects, anti-angiogenesis effects, and mechanisms of S-NACH in a mouse model of pancreatic cancer as compared to the LMWH tinzaparin. S-NACH or tinzaparin with or without gemcitabine were administered, and tumor luminescent signal intensity, tumor weight, and histopathology were assessed at the termination of the study. S-NACH and LMWH efficiently inhibited tumor growth and metastasis, without any observed bleeding events with S-NACH as compared to tinzaparin. S-NACH distinctly increased tumor necrosis and enhanced gemcitabine response in the mouse pancreatic cancer models. These data suggest the potential implication of S-NACH as a neoadjuvant in pancreatic cancer.Item Synthesis of new analogs of tetraiodothyroacetic acid (tetrac) as novel angiogenesis inhibitors for treatment of cancer(Pergamon-Elsevier Science, 2018-02-24) Rajabi, Mehdi; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734In the angiogenesis process, integrins, which are members of a family of cell surface transmembrane receptors, play a critical role particularly in blood vessel formation and the local release of vascular growth factors. Thyroid hormones such as L-thyroxine (T-4) and 3,5,30-triiodo-L-thyronine (T-3) promote angiogenesis and tumor cell proliferation via integrin alpha v beta 3 receptor. At or near an arginine-glycine-aspartate (RGD) recognition site on the binding pocket of integrin avb3, tetraiodothyroacetic acid (tetrac, a deaminated derivative of T-4) is a thyrointegrin receptor antagonist and blocks the actions of T-3 and T-4 as well as different growth factors-mediated angiogenesis. In this study, we synthesized novel tetrac analogs by modifying the phenolic moiety of tetrac and tested them for their anti-angiogenesis activity using a Matrigel plug model for angiogenesis in mice. Pharmacological activity results showed that tetrac can accommodate numerous modifications and maintain its anti-angiogenesis activity.Item Tetraidothyroacetic acid (tetrac) and tetrac nanoparticles inhibit growth of human renal cell carcinoma xenografts(Int Inst Anticancer Research, 2009-10) Bharali, Dhruba; Lansing, Lawrence; Dyskin, E.; Mousa, Shaker A.; Hercbergs, Aleck; Davis, Faith; Davis, Paul J.; Mousa, Sheren Ali; Yalçın, Murat; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Renal cell carcinoma is the most lethal of the common urologic malignancies, with no available effective therapeutics. Tetrac (tetraiodothyroacetic acid) is a deaminated analogue of L-thyroxine (T-4) that blocks the proangiogenesis actions of T-4 and 3, 5, 3'-triiodo-L-thyronine as well as other growth factors at the cell surface receptor for thyroid hormone on integrin av beta 3. Since this integrin is expressed on cancer cells and also on endothelial and vascular smooth cells, the possibility exists that Tetrac may act on both cell types to block the proliferative effects of thyroid hormone on tumor growth and tumor-related angiogenesis. To test this hypothesis, we determined the effect of Tetrac on tumor cell proliferation and on related angiogenesis of human renal cell carcinoma (RCC). We used two models: tumor cell implants in the chick chorioallantoic membrane (CAM) system and xenografts in nude mice. To determine the relative contribution of the nuclear versus the plasma membrane action of Tetrac, we compared the effects of unmodified Tetrac to Tetrac covalently linked to poly (lactide-co-glycolide) as a nanoparticle (Tetrac NP) that acts exclusively at the cell surface through the integrin receptor. In the CAM model, Tetrac and Tetrac NP (both at 1 mu g/CAM) arrested tumor-related angiogenesis and tumor growth. In the mouse xenograft model, Tetrac and Tetrac NP promptly reduced tumor volume (p<0.91) when administered daily for up to 20 days. Animal weight gain was comparable in the control and treatment groups. Overall, the findings presented here provide evidence for the anti-angiogenic, and anti-tumor actions of Yetrac and Yetrac NP and suggest their potential utility in the treatment of renal cell carcinoma.Item Tetraiodothyroacetic acid and its nanoformulation inhibit thyroid hormone stimulation of non-small cell lung cancer cells in vitro and its growth in xenografts(Elsevier Ireland, 2012-04) Mousa, Shaker A.; Bharali, Dhruba J.; Meng, Ran; Tang, Heng-Yuan; Lin, Hung-Yun; Davis, Faith B.; Davis, Paul J.; Yalçın, Murat; Uludağ Üniversitesi/Veteriner Fakültesi/Fizyoloji Anabilim Dalı.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Thyroid hormone stimulates cell proliferation of several types of cancers and stimulates cancer-relevant angiogenesis. In the present study, we investigated the proliferative effect of thyroid hormone and the anti-proliferative and anti-angiogenic action of its nano-derivative, tetrac-NP, on human non-small cell lung cancer (NSCLC) H1299 cells in vitro and in xenografts. The anti-proliferative activity of unmodified tetrac and tetrac-NP against human H1299 cells was determined in three models: (a) cultured H1299 cells in vitro, (b) tumor cell implants in the fertilized chick chorioallantoic membrane (CAM) system and (c) xenografts in the nude mouse. An integrin alpha v beta 3 antibody inhibited thyroid hormone-induced cell proliferation in vitro, as did unmodified tetrac and tetrac-NP. Pharmacologic inhibition of the mitogen-activated protein kinase pathway also blocked NSCLC cell proliferation in response to thyroid hormone. Tetrac and tetrac-NP arrested tumor growth and tumor-related angiogenesis in H1299 cells grown in the CAM model and both agents prevented chick embryo mortality. Xenografts of H1299 cells were established in nude mice (n = 8, treatment and control groups) and when tumor volumes reached 250-300 mm(3), tetrac (1 mg/kg) or tetrac-NP (1 mg tetrac as the nanoparticle/kg) were administered intraperitoneally every 2 days. Tetrac and tetrac-NP significantly suppressed tumor growth and angiogenesis. Thus, both tetrac and tetrac-NP effectively arrest human NSCLC tumor cell proliferation in vitro and in the CAM assay and in murine xenograft models.Item Tetraiodothyroacetic acid and tetraiodothyroacetic acid nanoparticle effectively inhibit the growth of human follicular thyroid cell carcinoma(Mary Ann Liebert, 2010-03) Bharali, Druba Jyoti; Dyskin, Evgeny; Dier, Emmy; Lansing, Lawrence S.; Mousa, Shaymaa S.; Davis, Faith B.; Davis, Paul J.; Mousa, Shaker A.; Yalçın, Murat; Uludağ Üniversitesi/Veterinerlik Fakültesi/Veteriner Hekimliği Temel Bilimler Bölümü.; 0000-0002-5600-8162; AAG-6956-2021; 57192959734Background: Tetraiodothyroacetic acid (tetrac) is a deaminated analogue of L-thyroxine that blocks the actions of L-thyroxine and 3,5,3'-triiodo-L-thyronine at the cell surface receptor for thyroid hormone on integrin alpha v beta 3. Tetrac blocks the proliferative effects of thyroid hormone on tumor cells and the proangiogenesis actions of the hormone. In the absence of thyroid hormone, tetrac also blocks angiogenesis induced by various growth factors. Covalently linked to poly(lactide-co-glycolide), tetrac nanoparticles (tetrac NP) do not gain access to the cell interior and act exclusively at the integrin receptor. Here, the activity of tetrac and tetrac NP against follicular thyroid carcinoma (FTC)-236 cells was studied in two models: (1) tumor cell implants in the chick chorioallantoic membrane (CAM) system and (2) xenografts in the nude mouse. Methods: FTC-236 cells (10(6)) were implanted in the CAM (n = 8 each for control, and for tetrac and tetrac NP, both at 1 mu g/CAM) and the actions of tetrac and tetrac NP were determined after 8 days on tumor-related angiogenesis and tumor growth. Xenografts of 10(7) FTC-236 cells were implanted in nude mice (n = 8 per group). Tetrac or tetrac NP was administered intraperitoneal (1 mg/kg and 1 mg tetrac equivalent/kg, respectively) every other day for 32 days beginning on day 10, when tumor volume was 200-250 mm(3). Animals were monitored after discontinuation of treatment up to day 40. Results: In the CAM paradigm, tetrac and tetrac NP arrested tumor-related angiogenesis and tumor growth. In the xenograft model, tetrac and tetrac NP promptly and progressively reduced tumor volume (p < 0.01) over 32 days. There was some regrowth of tumor after interruption of tetrac treatment, but at day 40, tumor volume and tumor weight at sacrifice were 45-55% below those of controls (p < 0.01). Animal weight gain was comparable in the control and treatment groups of animals. Conclusions: Tetrac and tetrac NP effectively arrest FTC-236 cell tumor growth in the CAM and xenograft models, suggesting its potential utility against FTC.