فهرست مطالب نویسنده:
farnaz safavifar
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Introduction
Glioblastoma is an aggressive human brain malignancy with poorly understood pathogenesis. Voltage-gated potassium (Kv) channels and Matrix Metalloproteinases (MMPs) are highly expressed in malignant tumors and involved in the progression and metastasis of glioblastoma. This study aimed to determine whether a voltage-dependent potassium channel blocker could modulate astrocytes as a cell involved in the immunopathogenesis of glioblastoma.
MethodsThe cytotoxic effect of 4-Aminopyridine (4-AP) at different doses in the cell model of glioblastoma was measured by MTT assay. The ELISA technique and gelatin zymography were used to assess cytokine levels and MMP-9 after 4-AP treatment.
ResultsCytotoxicity analysis data indicated that cell viability reduced by increasing 4-AP level and cell growth decreased gradually by removing 4-AP from the cell medium. 4-AP inhibits the secretion of IL-6 and IL-1 (P<0.05). MMP9 activity significantly inhibits with increased 4-AP dose, compared to non-treated cells.
ConclusionThe reduction of cell viability, IL-6 secretion, and MMP-9 activity in an in vitro model of glioblastoma might be assumed 4-AP as an agent for chemoprevention of cancer.
Keywords: Glioblastoma, Interleukin-6, 4-Aminopyridine, Matrix metalloproteinases, Potassium channels, Voltage-gated -
BackgroundCurcumin and resveratrol are two polyphenolic compounds extensively investigated for their medicinal effects on inflammatory signaling. However, there is a paucity of information on the Adenosine-3’, 5’-cyclic monophosphate (cAMP) kinetics following administration of curcumin and resveratrol in biological systems. In this study, kinetic modulation of cAMP as a target detection messenger in pro-inflammatory pathways was assessed by co-administration of curcumin and resveratrol using a cellular sensor model.
MethodsTo evaluate their putative activity, curcumin and resveratrol compounds were administered alone or in combination on the media culture of cAMP EPAC (exchange protein directly activated by cAMP) bioluminescence resonance energy transfer (BRET) biosensor. The study was performed at the following two centers at Tehran University of Medical Sciences (TUMS): 1- Biotechnology Research Center, and, 2- Endocrinology and Metabolism Research Institute (EMRI) in 2017. Time course kinetic of cAMP response signals were plotted. Forskolin and IBMX were used to stabilize the cAMP signals.ResultsWhen we treated HEK-293T biosensor cells at 10uM concentration, curcumin and resveratrol upregulated cAMP signaling. Co-administration of resveratrol and curcumin revealed an augmented cAMP level, as compared to treatments with the compounds alone.ConclusionCo-administration of curcumin and resveratrol leverage cAMP kinetic response in a time-course manner. The presented methodology can be readily adopted for drug development and novel biopharmaceutical functional analyses.Keywords: cAMP, Cellular biosensor, Curcumin, Inflammation, Resveratrol -
سابقه و هدفهپاتوسلولار کارسینوما (HCC) سرطانی شایع است و تحریک سیستم ایمنی از طریق 9-TLR (Toll-like receptors) به وسیله 2006 CpG-ODN می تواند در درمان آن کارآیی داشته باشد. هدف این مطالعه بررسی اثر تیمار هم زمان سیلیبینین و 2006 CpG-ODN بر رشد و تکثیر مدل سلولی HCC می باشد.مواد و روش هادر این مطالعه تجربی، اثر بازدارندگی دوزهای متفاوت سیلیبینین و 2006 CpG-ODN بر رشد سلول های 2HepG و تعیین بهترین غلظت برای تیمار هم زمان به روش MTT سنجیده شد. میزان بیان ژن های MMP2 و TLR9 به روش Real-Time PCR سنجیده شد. فعالیت ماتریکس متالوپروتییناز MMP2 با روش زایموگرافی اندازه گیری گردید.یافته هابه ترتیب، غلظت های μM 100 و nM 100 از سیلیبینین و 2006 CpG-ODN برای انجام تیمار هم زمان انتخاب شدند که اثرات ایستایی شدیدی بر رشد سلول داشتند (05/0< P). نتایج Real-Time PCR تفاوت معنی داری در Ct تکثیر ژن ها نشان نداد (05/0> P).استنتاجحتی غلظت های پایین CpG در این پژوهش، اثربخشی سیلیبینین بر سلول سرطان کبد را به طور مشخصی افزایش داده اند. با توجه به اهمیت استفاده از دوزهای پایین دارو و فعال سازی مکانسیم های ایمنی، تجویز توام این دو دارو می تواند چشم انداز روشنی را برای روش های درمانی ترکیبی آینده داشته باشد.کلید واژگان: سیلیبینین, اولیگوداکسی نوکلئوتیدهای CpG, MMP2, TLR9, HepG-2Background and purposeHepatocellular carcinoma (HCC) is a most common liver malignancy and TLR9 (Toll-like receptor) is essential for CpG DNA-induced immune responses. The aim of this study was to assess the anti-metastatic effects of combined administration of silibinin and CpG-ODN2006 on human hepatocellular carcinoma HepG-2 cell line model.Materials and methodsInhibitory effects of various different concentrations of silibinin and CpG-ODN2006 on HepG-2 cells growth and detection of best dosages for simultaneously treatment were assessed by MTT method. Expression of MMP2 and TLR9 genes was analyzed by real- time PCR. Gelatin zymography was used to determine the activity of MMP2.ResultsInhibitory effects of determined concentrations of silibinin (100 μM) and CpG-ODN2006 (100 nM) on HepG-2 cells growth was significant (p<0.05). Real-Time PCR showed no significant differences between Ct of the genes expression analyses.ConclusionCollectively, the data in this study supports the idea of combined silibinin-CpG administration in hepatic cancer customized therapeutic modalities. However, more investigations to assess immunomodulatory effects and safety analyses would be very informative steps in advance of randomized clinical trials.Keywords: silibinin, CpG-oligodeoxynucleotides, MMP2, TLR9, HepG-2
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BackgroundHigh temperatures have destructive effects on cancer cells by damaging proteins and structures within cells. Gold nanoparticles (AuNPs) can act as drug delivery vehicles, especially for cancer therapy. Due to the selective intake of asparagine molecules into malignant cells, AuNPs were coated with asparagine; and CCRF-CEM human T-cell leukemia cells were treated with the new combination, Asn-AuNPs, at 39 °C.MethodsThe co-authors from a number of collaborative labs located at Tehran University of Medical Sciences, Tehran, Iran, have initiated the idea and preliminary design of this study in 2011. Hydroxyl surfaced AuNPs were preliminary prepared by tannin free ethanol extract of black tea leaves. These biogenic AuNPs were further capped with asparagines to form asparagine-gold nanoparticle conjugates (Asn-AuNP conjugates). Then CCRF-CEM human T-cell leukemia cells were separately treated with different concentrations of AuNPs and Asn-AuNP conjugates (3, 30, 300 µg/mL). MTT assay and zymography analysis were carried out, and the apoptotic and necrotic effects of Asn-AuNPs were determined in comparison with AuNPs, using flow cytometry assay.ResultsAsn-AuNP conjugates at 300 µg/mL significantly inhibited MMPs at 39 °C, compared to AuNPs. In terms of cytotoxicity, a remarkable decrease was observed in the percentage of viable cells treated with Asn-AuNP conjugates, rather than AuNPs. Moreover, the AuNPs and Asn-AuNP conjugates enhanced the level of apoptosis at almost similar rates.ConclusionAuNPs are coated with asparagine molecules and the temperature is slightly increased by 2 °C, the apoptosis is not only enhanced among cells but also shifts to necrosis in higher concentrations of Asn-AuNP conjugates. More investigations should be carried out to explain the exact mechanism underlying the necrotic effects of Asn-AuNPs.Keywords: Gold nanoparticles, Asparagine, Acute lymphoblastic leukemia, CCRF-CEM cells
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There exists compelling evidence that Toll-like receptor 3 (TLR3) agonists can directly affect human cancer cells. The aim of this study was to investigate anti-cancer effects of TLR3 agonist in human breast cell line.We assessed potential effects of poly (A:U) on human breast cell line (MDA-MB-231) on a dose-response and time-course basis. Human breast cell line MDA-MB-231 was treated with different concentrations of poly (A:U) and lipopolysaccharide (LPS). Then, the following assays were performed on the treated cells: dose-response and time-course cytotoxicity using colorimetric method; matrix metalloproteinase-2 (MMP-2) activity using gelatin zymography method; apoptosis using annexin-v flowcytometry method; and relative expression of TLR3 and MMP-2 mRNA using reverse transcriptase polymerase chain reaction (RT-PCR) method. Following treatments, dose- response and time-course cytotoxicity using a colorimetric method, (MMP-2) activity (using gelatin zymography), apoptosis (using annexin-v flowcytometry method) assays and expression of TLR3 and MMP-2 genes (using PCR method) were performed.Cytotoxicity and flowcytometry analysis of poly (A:U) showed that poly (A:U) do not have any cytotoxic and apoptotic effects in different concentrations used. MMP-2 activity analysis showed significant decrease in higher concentrations (50 and 100 μg/ ml) between treated and untreated cells. Moreover, poly A:U treated cells demonstrated decreased expression of MMP-2 gene in higher concentrations.Collectively, our data indicated that human breast cancer cell line (MDA-MB-231) was highly responsive to poly (A:U). The antimetastatic effect of direct poly (A:U) and TLR3 interactions in MDA-MB-231 cells could provide new approaches in malignant tumor therapeutic strategy.Keywords: MDA, MB, 231, MMP, 2, Poly (A:U), TLR3
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سابقه و هدفیکی از روش های درمانی مفید و موثر در بیماران مبتلا به لنفوم غیرهوچکین (عود کرده یا با پاسخ نسبی به درمان اولیه) پیوند اتولوگ سلول های بنیادی خون محیطی یا مغز استخوان است و یکی از فاکتورهای مهم در بازده پیوند، نوع رژیم آماده سازی ((conditioning می باشد. این مطالعه به منظور بررسی اثر رژیم آماده سازی CEAM در پیوند اتولوگ بیماران مبتلا به لنفوم غیر هوچکین در مرکز تحقیقات هماتولوژی، آنکولوژی و پیوند مغز استخوان بیمارستان شریعتی، دانشگاه علوم پزشکی تهران به انجام رسید.مواد و روش هادر این مطالعه بقا، تعداد 25 بیمار براساس فاکتورهای ورود ذیل؛ سن 60-14 سال مبتلا به NHL با بهبودی کامل یا نسبی در هر مرحله و درجه همراه با عملکرد مناسب مغز استخوان، قلب، ریه، کلیه و کبد و وضعیت عملکردی خوب، انتخاب شدند. پس از دریافت رژیم موبیلیزان که با استفاده از سیکلوفسفامید به اضافه G-CSF یا G-CSF به تنهایی انجام می شد و نیز استخراج سلول های بنیادی مغز استخوان، تحت شیمی درمانی با رژیم CEAM قرار گرفتند. پس از انجام پیوند، تمامی این بیماران از نظر میزان عفونت، مدت و سرعت بهبودی هماتولوژیک و میزان عوارض رژیم بررسی شدند. همچنین، میزان دریافت واحدهای خون و پلاکت مورد بررسی قرار گرفت. پس از ترخیص از بخش نیز بیماران به طور دوره ای از نظر علایم (نشانه های B) و معاینه بالینی (وجود لنفادنوپاتی جدید) و تست های آزمایشگاهی ارزیابی می شدند.نتایجدر بین این تعداد فقط یک نفر پیوند اتولوگ خود را از سلول های بنیادی مغز استخوان و مابقی از سلول های بنیادی خون محیطی(PBSCT [1]) دریافت کردند. هنگام پیوند 6 نفر(24 درصد) در بهبودی کامل اول، 11 نفر (44 درصد) در بهبودی کامل دوم، 6 نفر (24 درصد) در بهبودی کامل سوم و 2 نفر (8 درصد) در بهبودی نسبی بودند. مدت بستری پس از انجام BMT [2] یا PBSCT به طور متوسط 5/25 روز بود. از میان 25 نفر که تحت پیوند اتولوگ قرار گرفتند، 16 نفر (64 درصد) عود نداشتند ولی 8 نفر (32 درصد) دچار عود شدند. یک نفر نیز اصلا هیچ گونه پاسخی به پیوند نداد. میزان مرگ و میر در طی این مطالعه، 5 نفر (20درصد) بود. احتمال بقاء کلی ([3] OS) یک ساله 6/8 ± 4/78 درصد بود و OS دو ساله نیز نتیجه مشابه داشت. بقاء بدون بیماری (DFS [4]) یک ساله 5/9 ± 70 درصد و DFS دو ساله 7/10 ± 1/59 درصد بود. در ضمن، بقاء بدون بیماری در بهبودی کامل اول طی یک سال، 3/83 درصد و در دو سال نیز همین مقدار بود، ولی در بهبودی کامل دوم یا بیشتر، و نیز در بهبودی نسبی در یک سال، 7/11 ± 65 درصد و در دو سال 6/13 ± 1/48 درصد بود. عوارض هماتولوژیک و گوارشی در همه موارد دیده شد. گرانولوسیتوپنی و آنمی و ترومبوسیتوپنی درجه 4 به ترتیب در 96، 20 و 52 درصد افراد مشاهده شد. بیشترین درجه موکوزیت در گرید 1 (40 درصد)، اسهال و تهوع و استفراغ در گرید 2 (به ترتیب 44 و 52 درصد) مشاهده شد. تب و عفونت با یا بدون کشت مثبت در 96 درصد بیماران در طی دوران بستری به وقوع پیوست. در نهایت سمیت های ناشی از درمان به خوبی تحمل شد.نتیجه گیریهمراه با اجرای رژیم CEAM مدت دوره تجویز دارو به 4 روز کاهش می یابد و همچنین، نیاز به مصرف داروی BCNU که مستلزم رعایت زنجیره سرد در انتقال دارو می باشد، نیست. با توجه به موارد فوق و همچنین نتایج بهتر DFS یک ساله نسبت به رژیم آماده سازی قبلی مورد استفاده در این مرکز (70 درصد در مقابل30 درصد) و قابل تحمل بودن مسمومیت ناشی از درمان، لذا رژیم CEAM با این شرایط به عنوان یک رژیم جایگزین مناسب برای رژیم BEAM می تواند مطرح باشد.
کلید واژگان: رژیم آماده سازی, لنفوم غیرهوچکین, پیوند اتولوگ, رد پیوند, بقاء کلی, بقاء بدون بیماری, سمیت ناشی از درمانBackgroundAn effective and useful therapy for NHL patients (relapsed or with incomplete response) is autologous bone marrow/peripheral blood stem cell transplantation (SCT). In this case, the type of conditioning regimen is an important factor for transplant outcome. This study carried out for evaluating the results of CEAM regimen as a conditioning regimen for autologous stem cell transplantation in 25 patients with NHL in Dr Shariati hospital bone marrow transplantation research center, Tehran University of medical sciences.Materials And MethodsIn this survival study 25 patients were selected according to inclusion criteria: ages between 14-60 years old, in complete or partial remission, in any stage and grade, with good function of bone marrow, heart, kidney and liver, and good performance status. After introducing mobilization regimen with G-CSF alone or with cyclophosphamide, the conditioning regimen (CEAM) was applied to the patients. After transplantation all patients were evaluated for rate of infection, hematologic engraftment, conditioning related organ toxicities and number of transfused packed cell and platelet units. In follow-up period after discharge, patients had regular examinations for B symptoms, lymph nodes and laboratory tests.ResultsThe peripheral blood was the stem cell source of all patients except one. At transplantation time, 6 (24%) were in the first complete remission, 11 (44%) in the second, 6 (26%) in third and 2 (8%) in partial remission. The mean duration of hospitalization after SCT was 25.5 days. From 25 person under going autologous transplantation, 16 (64%) did not have relapse 8 (32%) had relapse, and one person never had any response to transplant. Mortality rate in this study was 5(20%). One-year overall survival (OS) was 78.4% (SE=8.6%) two-year overall survival was the same. One-year and two-year disease free survival (DFS) were 70% (SE=9.5%) and 59.1% (SE=10.7%), respectively. The most common different organ toxicity in admission interval was as follow: Hematologic and gastrointestinal toxicities were seen in 100%. The grade IV hematologic toxicities were 96% granulocytopenia, 20% anemia and 52% thrombocytopenia. The greatest part of mucositis in grade I (40%), nausea and vomiting in grade II (respectively 44% and 52%) were seen. Fever and infection, with or without positive culture, occurred during hospitalization in all patients except one (96%). Overally the patients well tolerated the toxicities.ConclusionAccording to the results, CEAM regimen can be suggest the as a good alternative for BEAM regimen with the added benefits of shorter duration of conditioning regimen (4 days vs. 6 days), no need for stem cell cryopreservation, no need for cold chain required for BCNU replaced by CCNU, better one year DFS result than previous conditioning regimen in this center (70% vs 30%) and tolerable treatment associated toxicities. -
BackgroundAlthough pyrimethamine (Tindurin™) appears to be effective in the prevention and treatment of some infectious diseases, very little information exists on its unpredictable properties. We design this study to evaluate its anti-tumoral effect on a model of cell line.MethodsThe cytotoxic influence of Pyrimethamine on prostate cell line was investigated using an in vitro colometric assay. The potential modulatory effects on metastasis, apoptosis, and immortality characteristics of cells were assessed with gelatin zymography, terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and telomeric repeat amplification protocol, respectively.ResultsCytotoxicity analysis of pyrimethamine revealed a dose- dependent fashion. An apoptotic influence of pyrimethamine was also confirmed by data obtained from TUNEL assay. Dose-dependent inhibitory effect on matrix metalloproteinases (MMP) was seen in pyrimethamine. A potent inhibitory effect of pyrimethamine was also established by data achieved from TRAPeze telomerase detection kit.ConclusionsCollectively, as induction of apoptosis together with MMP and telomerase inhibition could be indicative of cancer treatment, pyrimethamine might be considered as a chemopreventative agent in cancer. Iran. Biomed. J. 11 (4): 223-228, 2007
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Recent reports have indicated different effects of immunostimulatory sequences containing CpG-Oligodeoxynucleotides (ODN) on various immune cells. However, the exact role of CpG-ODN in the human gut is unclear. In the present study, we assessed potential effects of CpG-ODN on non lymphoid cell (intestinal epithelial cell line HT-29) on a dose-response and time-course basis. Intestinal epithelial cell line HT-29 was treated with CpG-ODN (CpG 2006) and lipopolysaccharide (LPS) at 5, 10, 25, 50 μg/ ml and 1, 5, 10 μg/ ml concentrations, respectively. Following treatments, dose- response and time-course cytotoxicity using a colorimetric method, Metaloproteinase-2 (MMP-2) activity (using gelatin zymography) and apoptosis (using annexin-v flowcytometry method) assays were performed. Chloroquine treatment was also used for its inhibitory effect on endosomal acidification process to verify specific CpG-ODN and Toll Like Receptor 9 (TLR9) interactions. Cytotoxicity analysis of CpG-ODN showed that CpG-ODN increased significantly the proliferation of CpG-ODN treated cells, as compared to untreated cells, at concentrations of 10-25 μg/ml (p< 0.05). Overall MMP-2 activity analysis showed significant differences between treated and untreated cells. However, minimal changes were observed when MMP-2 activity was assessed per cell. Moreover, CpG-ODN treated cells demonstrated an increasing apoptosis rate of 0.8 %, 6.46 % and 14.21% at concentrations of 5, 10, 25 μg/ml, respectively. Collectively, our data indicated that intestinal epithelial cell line HT-29 is highly responsive to CpG effect in vitro and exhibits modified activities. The direct CpG-ODN and TLR-9 interactions in HT-29 cells could provide new approaches in malignant tumor therapeutic strategies.
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This study was conducted to examine if allergic contact dermatitis (ACD) alters the expression of MMPs in human dermal fibroblasts. Fibroblasts are the primary source for MMP and matrix production in skin. MMPs are known to involve in a number of physiological and pathological processes. Some published data indicated a gelatinase-like activity in acute and chronic phases of allergic contact dermatitis. However, no exact source of gelatinase activity was demonstrated. Moreover, little is known about the role of MMPs in immune responses.To study and predict the pathophysiological effects of (MMP-2) in allergic contact dermatitic (ACD) patients, we established an in vitro tissue culture survey based on fibroblast explanted from ACD wounds and normal tissues respectively. We also employed a precise proliferation assay [i.e. MTT; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to analyze and compare three ACD vs. three normal cell strains. Parallel to MTT assay, we assessed the activity as well as the kinetics of gelatinase (MMP-2) in conditioned media using a zymogeraphy analysis. There was a significant difference in proliferation capacity between mean ACD fibroblast strains vs. mean normal cells, particularly in days 6 to 8 post explantation, 492.5±6.6 vs. 361.75±8.25 respectively. Zymoanalyses indicated significant differences between ACD cells and normal fibroblasts both in time-course and MMP-2 activity per cell fashions, 163.7±16.21 for mean ACD fibroblasts vs. 130±9.09 for normal cells respectively. These data suggest that fibroblasts overproliferated in the process of ACD. Moreover, simultaneous overexpression of MMPs observed in ACD fibroblasts vs. normal strains, is indicative of altered fibroblast functionality in the process of allergic contactdermatitis. The activity per cell analysis showed that MMP-2 expression in ACD fibroblasts is independent of cell number, suggesting that either intra- or inter-cellular control signals are also altered and that ACD fibroblasts exhibit hyper-responsiveness to mitogenic or fibrogenic stimulants. Altogether, these data address the chronocity and non-healing tendency of ACD wounds. However, more studies are required to examine possible MMPs inhibition and differential expression of mytogenic, fibrogenic and antifibrogenic cytokines in ACD wound beds. In particular, MMP-2 is postulated to be an aim for further gene therapy protocols
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