Search results for: tumor necrosis factor-related apoptosis-inducing ligand

Authors: Somdutt Mujwar, Kamal Raj Pardasani

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Cholera pandemics are caused by facultative pathogenic Vibrio cholera bacteria persisting in the countries having warmer climatic conditions as well as the presence of large water bodies with huge amount of organic matter, it is responsible for the millions of deaths annually. Presently the available therapy for cholera is Oral Rehydration Therapy (ORT) with an antibiotic drug. Excessive utilization of life saving antibiotics drugs leads to the development of resistance by the infectious micro-organism against the antibiotic drugs resulting in loss of effectiveness of these drugs. Also, many side effects are also associated with the use of these antibiotic drugs. This riboswitch is explored as an alternative drug target for Vibrio cholera bacteria to overcome the problem of drug resistance as well as side effects associated with the antibiotics drugs. The bacterial riboswitch is virtually screened with 24407 legends to get possible drug candidates. The 10 ligands showing best binding with the riboswitch are selected to design a pharmacophore, which can be utilized to design lead molecules by using the phenomenon of bioisosterism.

Keywords: cholera, drug design, ligand, riboswitch, pharmacophore

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Authors: Axel Mancebo, Ana M. Bada, Angel Casacó, Bárbara González, Avelina León, María E. Arteaga, Consuelo González, Belinda Sánchez, Adriana Carr, Nuris Ledón, Arianna Iglesias

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Despite the many preventive and therapeutic modalities aimed at curing cancer, it remains as a serious world health problem. Promising recent developments suggest that cancer immunotherapy may be the next great hope for cancer treatment. EGFRs are receptor tyrosine kinases and it is considered an important therapeutic target related with tumor progression, and several types of molecular therapies, including monoclonal antibodies, small molecules, and vaccines, have been developed to target the HER family of receptors. On the other hand, gangliosides are membrane glycosphingolipids that contain two variants of sialic acid, the N-acetylated (NeuAc) and the N-glycolylated (NeuGc) variant. The high expression of this antigen-specific molecule has been associated with malignant tumor progression and immunosuppressive mechanisms, so ganglioside could be considered as the target for cancer immunotherapy. We have been working for several years in the safety evaluation of cancer vaccines targeting these two systems, the EGF receptor and ganglioside. We presented in this work results of repeated dose toxicity studies performed in Sprague Dawley rats and Cynomolgus monkeys, including clinical observations, body weight and rectal temperature measuring, clinical pathology analysis, gross necropsy and histological examination in rodent studies, and immunological evaluation. Immunizations were capable of inducing mainly inflammatory effects at the injection site, with findings largely attributable to the adjuvants used and probably enhanced by the immunological properties of the antigens. In general, these vaccines were shown to be well tolerated, and these studies in relevant species allow treating cancer patients with tumors during long periods with relative weight safety margin.

Keywords: cancer vaccines, safety, toxicology, rats, non human primates

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Authors: Inna Kornienko, Svetlana Guryeva, Natalia Danilova, Elena Petersen

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Drug toxicity often goes undetected until clinical trials, the most expensive and dangerous phase of drug development. Both human cell culture and animal studies have limitations that cannot be overcome by improvements in drug testing protocols. Tissue engineering is an emerging alternative approach to creating models of human malignant tumors for experimental oncology, personalized medicine, and drug discovery studies. This new generation of bioengineered tumors provides an opportunity to control and explore the role of every component of the model system including cell populations, supportive scaffolds, and signaling molecules. An area that could greatly benefit from these models is cancer research. Recent advances in tissue engineering demonstrated that decellularized tissue is an excellent scaffold for tissue engineering. Decellularization of donor organs such as heart, liver, and lung can provide an acellular, naturally occurring three-dimensional biologic scaffold material that can then be seeded with selected cell populations. Preliminary studies in animal models have provided encouraging results for the proof of concept. Decellularized Organs preserve organ microenvironment, which is critical for cancer metastasis. Utilizing 3D tumor models results greater proximity of cell culture morphological characteristics in a model to its in vivo counterpart, allows more accurate simulation of the processes within a functioning tumor and its pathogenesis. 3D models allow study of migration processes and cell proliferation with higher reliability as well. Moreover, cancer cells in a 3D model bear closer resemblance to living conditions in terms of gene expression, cell surface receptor expression, and signaling. 2D cell monolayers do not provide the geometrical and mechanical cues of tissues in vivo and are, therefore, not suitable to accurately predict the responses of living organisms. 3D models can provide several levels of complexity from simple monocultures of cancer cell lines in liquid environment comprised of oxygen and nutrient gradients and cell-cell interaction to more advanced models, which include co-culturing with other cell types, such as endothelial and immune cells. Following this reasoning, spheroids cultivated from one or multiple patient-derived cell lines can be utilized to seed the matrix rather than monolayer cells. This approach furthers the progress towards personalized medicine. As an initial step to create a new ex vivo tissue engineered model of a cancer tumor, optimized protocols have been designed to obtain organ-specific acellular matrices and evaluate their potential as tissue engineered scaffolds for cultures of normal and tumor cells. Decellularized biomatrix was prepared from animals’ kidneys, urethra, lungs, heart, and liver by two decellularization methods: perfusion in a bioreactor system and immersion-agitation on an orbital shaker with the use of various detergents (SDS, Triton X-100) in different concentrations and freezing. Acellular scaffolds and tissue engineered constructs have been characterized and compared using morphological methods. Models using decellularized matrix have certain advantages, such as maintaining native extracellular matrix properties and biomimetic microenvironment for cancer cells; compatibility with multiple cell types for cell culture and drug screening; utilization to culture patient-derived cells in vitro to evaluate different anticancer therapeutics for developing personalized medicines.

Keywords: 3D models, decellularization, drug discovery, drug toxicity, scaffolds, spheroids, tissue engineering

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Authors: Parcha Sreenivasa Rao, P. Lakshmi

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Diabetes Mellitus is metabolic disorder, characterized by high glucose levels in the blood due to one of the reason i.e., the death of β cells. The lack of β cells leads to the reduced insulin levels. The β cell death generally occurs due to apoptosis induced by the several cytokines. IL-1β, IFN- ϒ and TNF –α cytokines that are generally cause apoptosis to the β cell. The nutrient based apoptosis is generally seen with high glucose and free fatty acids. It is also noted that the β cell death triggered by Fas ligand and its receptor Fas at the surface of the activated CD8+ T- lymphocytes. Reports also reveal that the β cell apoptosis is under control of the transcription factors NF-kB and STAT- 1. The arresting or opposing of the β cell apoptosis can be overcome by the different growth factors like GLP-1, growth hormone, prolactin, VEGF, Dipeptidyl peptidase-4, Vildagliptin, suberoylanilidehydroxamic acid, trichistatin-A, XIAP, Bcl-2, FGF-21. Present investigation explains antiapoptotic property of the β cells derived from the mesenchymal stem cells of umbilical cord.

Keywords: stem cells, umblical cord, diabetes, apoptosis

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Authors: H. Yousefnia, A. Aghanejad, A. Mirzaei, R. Enayati, A. R. Jalilian, S. Zolghadri

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Bone metastases occur in many cases at an early stage of the tumour disease; however, their symptoms are recognized rather late. The aim of this study was the preparation and quality control of 111In-BPAMD for diagnostic purposes. 111In was produced at the Agricultural, Medical, and Industrial Research School (AMIRS) by means of 30 MeV cyclotron via natCd(p,x)111In reaction. Complexion of In‐111 with BPAMD was carried out by using acidic solution of 111InCl3 and BPAMD in absolute water. The effect of various parameters such as temperature, ligand concentration, pH, and time on the radiolabeled yield was studied. 111In-BPAMD was prepared successfully with the radiochemical purity of 95% at the optimized condition (100 µg of BPAMD, pH=5, and at 90°C for 1 h) which was measured by ITLC method. The final solution was injected to wild-type mice and biodistribution was determined up to 72 h. SPECT images were acquired after 2 and 24 h post injection. Both the biodistribution studies and SPECT imaging indicated high bone uptake while accumulation in other organs was approximately negligible. The results show that 111In-BPAMD can be used as an excellent tracer for diagnosis of bone metastases by SPECT imaging.

Keywords: biodistribution, BPAMD, 111In, SPECT

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Authors: Noura Kichou, Manel Tafergguenit, Nabila Ghechtouli, Zakia Hank

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The aim of this work is to synthesize, characterize and evaluate the biological activity of two Ligands : glyoxime and dimethylglyoxime, and their metal Ni(II) chelates. The newly chelates were characterized by elemental analysis, IR, EPR, nuclear magnetic resonances (1H and 13C), and biological activity. The antibacterial and antifungal activities of the ligands and its metal complexes were screened against bacterial species (Staphylococcus aureus, Bacillus subtilis, and Escherichia coli) and fungi (Candida albicans). Ampicillin and amphotericin were used as references for antibacterial and antifungal studies. The activity data show that the metal complexes have a promising biological activity comparable with parent free ligand against bacterial and fungal species. A structural, energetic, and electronic theoretical study was carried out using the DFT method, with the functional B3LYP and the gaussian program 09. A complete optimization of geometries was made, followed by a calculation of the frequencies of the normal modes of vibration. The UV spectrum was also interpreted. The theoretical results were compared with the experimental data.

Keywords: glyoxime, dimetylglyoxime, nickel, antibacterial activity

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Authors: Noura Kichou, Manel Tafergguenit, Nabila Ghechtouli, Zakia Hank

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The aim of this work is to synthesize, characterize and evaluate the biological activity of two Ligands: glyoxime and dimethylglyoxime, and their metal Ni(II) chelates. The newly chelates were characterized by elemental analysis, IR, EPR, nuclear magnetic resonances (1H and 13C), and biological activity. The antibacterial and antifungal activities of the ligands and its metal complexes were screened against bacterial species (Staphylococcus aureus, Bacillus subtilis, and Escherichia coli) and fungi (Candida albicans). Ampicillin and amphotericin were used as references for antibacterial and antifungal studies. The activity data show that the metal complexes have a promising biological activity comparable with parent free ligand against bacterial and fungal species. A structural, energetic, and electronic theoretical study was carried out using the DFT method, with the functional B3LYP and the gaussian program 09. A complete optimization of geometries was made, followed by a calculation of the frequencies of the normal modes of vibration. The UV spectrum was also interpreted. The theoretical results were compared with the experimental data.

Keywords: glyoxime, dimetylglyoxime, nickel, antibacterial activity

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Authors: Amesh P, Suneesh A S, Venkatesan K A

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The magnetic solid-phase extraction is a relatively new method among the other solid-phase extraction techniques for the separating of metal ions from aqueous solutions, such as mine water and groundwater, contaminated wastes, etc. However, the bare magnetic particles (Fe3O4) exhibit poor selectivity due to the absence of target-specific functional groups for sequestering the metal ions. The selectivity of these magnetic particles can be remarkably improved by covalently tethering the task-specific ligands on magnetic surfaces. The magnetic particles offer a number of advantages such as quick phase separation aided by the external magnetic field. As a result, the solid adsorbent can be prepared with the particle size ranging from a few micrometers to the nanometer, which again offers the advantages such as enhanced kinetics of extraction, higher extraction capacity, etc. Conventionally, the magnetite (Fe3O4) particles were prepared by the hydrolysis and co-precipitation of ferrous and ferric salts in aqueous ammonia solution. Since the covalent linking of task-specific functionalities on Fe3O4 was difficult, and it is also susceptible to redox reaction in the presence of acid or alkali, it is necessary to modify the surface of Fe3O4 by silica coating. This silica coating is usually carried out by hydrolysis and condensation of tetraethyl orthosilicate over the surface of magnetite to yield a thin layer of silica-coated magnetite particles. Since the silica-coated magnetite particles amenable for further surface modification, it can be reacted with task-specific functional groups to obtain the functionalized magnetic particles. The surface area exhibited by such magnetic particles usually falls in the range of 50 to 150 m2.g-1, which offer advantage such as quick phase separation, as compared to the other solid-phase extraction systems. In addition, the magnetic (Fe3O4) particles covalently linked on mesoporous silica matrix (MCM-41) and task-specific ligands offer further advantages in terms of extraction kinetics, high stability, longer reusable cycles, and metal extraction capacity, due to the large surface area, ample porosity and enhanced number of functional groups per unit area on these adsorbents. In view of this, the present paper deals with the synthesis of uranium specific diethylenetriamine ligand (DETA) ligand anchored on silica-coated magnetite (Fe-DETA) as well as on magnetic mesoporous silica (MCM-Fe-DETA) and studies on the extraction of uranium from aqueous solution spiked with uranium to mimic the mine water or groundwater contaminated with uranium. The synthesized solid-phase adsorbents were characterized by FT-IR, Raman, TG-DTA, XRD, and SEM. The extraction behavior of uranium on the solid-phase was studied under several conditions like the effect of pH, initial concentration of uranium, rate of extraction and its variation with pH and initial concentration of uranium, effect of interference ions like CO32-, Na+, Fe+2, Ni+2, and Cr+3, etc. The maximum extraction capacity of 233 mg.g-1 was obtained for Fe-DETA, and a huge capacity of 1047 mg.g-1 was obtained for MCM-Fe-DETA. The mechanism of extraction, speciation of uranium, extraction studies, reusability, and the other results obtained in the present study suggests Fe-DETA and MCM-Fe-DETA are the potential candidates for the extraction of uranium from mine water, and groundwater.

Keywords: diethylenetriamine, magnetic mesoporous silica, magnetic solid-phase extraction, uranium extraction, wastewater treatment

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Authors: Salem El-Tohami Ashoor

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Here we show that the reduction of [Cr(ArN(CH2)3NAr)2Cl2] (1) where (Ar = 2,6-Pri2C6H3) and in presence of NaCp (2) (Cp= C5H5 = cyclopentadien), with a center coordination η5 interaction between Cp as co-ligand and chromium metal center, this was optimization by using density functional theory (DFT) and then was comparing with experimental data, also other possibility of Cp interacted with ion metal were tested like η1 ,η2 ,η3 and η4 under optimization system. These were carried out under investigation of density functional theory (DFT) calculation, and comparing together. Other methods, explicitly including electron correlation, are necessary for more accurate calculations; MB3LYP ( Becke)( Lee–Yang–Parr ) level of theory often being used to obtain more exact results. These complexes were estimated of electronic energy for molecular system, because it accounts for all electron correlation interactions. The optimised of [Cr(ArN(CH2)3NAr)2(η5-Cp)] (Ar = 2,6-Pri2C6H3 and Cp= C5H5) was found to be thermally more stable than others of chromium cyclopentadienyl. By using Dewar-Chatt-Duncanson model, as a basis of the molecular orbital (MO) analysis and showed the highest occupied molecular orbital (HOMO) and lowest occupied molecular orbital LUMO.

Keywords: Chromium(III) cyclopentadienyl complexes, DFT, MO, HOMO, LUMO

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Authors: Neelesh Papineni

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Aim: Piezosurgery is a relatively new technique for osteotomy and osteoplasty that uses ultrasonic vibration. The conventional method of treating periodontal cases are by conventional surgeries. However, in this advancing field the use of motor-driven instruments is being considered less invasive. Out of these motor-driven instruments, piezo-electric device has been introduced to the field of periodontics and oral implantology. This article discusses about the wide range of application of piezo-electric device in periodontology, its advantages over conventional surgical therapies and other motor-driven instruments. Results: Piezo- electric has shown better results in aspect of osteotomy, osteoplasty, implants, and any procedure which includes conserving the bone. Also piezo-electric does not cause any kind of damage to the surrounding soft tissue and eliminates the risk of bone necrosis which is a risk factor in other motor driven instruments. Conclusion: In this era of modern dentistry , a successful periodontal and implant surgery requires a sound osseous support. This review gives a pictorial representation about the wide range of application of piezo-electric device in periodontology.

Keywords: piezo-electric, osteotomy, osteoplasty, implantology

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Authors: Afiqah Shafify Amran, Siti Aisyah Shamsudin, Nurul Yuziana Mohd Yusof

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Cadmium Sulphide (CdS) from group II-IV quantum dots with good optical properties was successfully synthesized by using the simple colloidal method. Capping them with ligand Polyethylinamine (PEI) alters the surface defect of CdS while, thioglycolic acid (TGA) was added to the reaction as a stabilizer. Due to their cytotoxicity, we decided to conjugate them with the protein cage nanoparticles. In this research, we used capsid of Cowpea Chlorotic Mottle Virus (CCMV) to package the CdS because they have the potential to serve in drug delivery, cell targeting and imaging. Adding Sodium Hydroxide (NaOH) changes the pH of the systems hence the isoelectric charge is adjusted. We have characterized and studied the morphology and the optical properties of CdS and CdS-CCMV by transmitted electron microscopic (TEM), UV-Vis spectroscopy, photoluminescence spectroscopy, UV lamp and Fourier transform infrared spectroscopy (FTIR), respectively. The results obtained suggest that the protein cage nanoparticles do not affect the optical properties of CdS.

Keywords: cadmium sulphide, cowpea chlorotic mottle virus, protein cage nanoparticles, quantum dots

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Authors: Lubna Azmi, Ila Shukla, Shyam Sundar Gupta, Padam Kant, C. V. Rao

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To investigate the chemoprotective potential of NBRIQU16 chemotype isolated from Argyreia speciosa (Family: Convolvulaceae) on N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and NaCl-induced gastric carcinomas in Wistar rats. Forty-six male 6-week-old Wistar rats were divided into two groups. Thirty rats in group A were fed with a diet supplemented with 8 % NaCl for 20 weeks and simultaneously given N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) in drinking water at a concentration of 100 ug/ml for the first 17 weeks. After administration of the carcinogen, 200 and 400 mg/kg of NBRIQU16 were administered orally once a day throughout the study. From week 18, these rats were given normal water. From week 21, these rats were fed with a normal diet for 15 weeks. Group B containing 16 rats was fed standard diet for thirty-five days. It served as control. Ten rats from group A were sacrificed after 20 weeks. Scarification of remaining animals was conducted after 35 weeks. Entire stomach and some part of the duodenum were incised parallel to the greater curvature, and the samples were collected. After opening the stomach location and size of tumors were recorded. The number of tumors with their locations and sizes were recorded. Expression of survivin was examined by recording the Immunohistochemistry of the specimens. The treatment with NBRIQU16 significantly reduced the nodule incidence and nodule multiplicity in the rats after MNNG administration. Surviving expression in glandular stomachs of normal rats, of rats in middle induction period, in adenocarcinomas and NBRIQU16 treated tissues adjacent to tumor were 0, 42.0 %, 79.3%, and 36.4 %, respectively. Expression of survivin was significantly different as compared to the normal rats. Histological observations of stomach tissues too correlated with the biochemical observations.These finding powerfully supports that NBRIQU16 chemopreventive effect by suppressing the tumor burden and restoring the activities of gastric cancer marker enzymes on MNNG and NaCl-induced gastric carcinomas in Wistar rats.

Keywords: Argyreia speciosa, gastric carcinoma, immunochemistry, NBRIQU16

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Authors: Christy Rosaline, Rathankar Roa, Waheeta Hopper

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Persistence of tuberculosis, emergence of multidrug-resistance and extensively drug-resistant forms of the disease, has increased the interest in developing new antitubercular drugs. Developing inhibitors for 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase from Mycobacterium tuberculosis (MtbDAH7Ps), an enzyme involved in shikimate pathway, gives a selective target for antitubercular agents. MtbDAH7Ps was screened against ZINC database, and shortlisted compounds were subjected to induce fit docking. Prime/Molecular Mechanics Generalized Born Surface Area calculation was used to validate the binding energy of ligand-protein complex. Molecular Dynamics analysis for of the lead compounds–MtbDAH7Ps complexes showed that the backbone of MtbDAH7Ps in their complexes were stable. These results suggest that the shortlisted lead compounds ZINC04097114, ZINC15163225, ZINC16857013, ZINC06275603, and ZINC05331260 could be developed into novel drug leads to inhibit DAH7Ps in Mycobacterium tuberculosis.

Keywords: MtbDAH7Ps, Mycobacterium tuberculosis, HTVS, molecular dynamics

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Authors: Prasamsha Panta, Da Yeon Kim, Ja Yong Jang, Min Jae Kim, Jae Ho Kim, Moon Suk Kim

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Introduction: Among the many anticancer drugs used clinically, doxorubicin (Dox), was one of widely used drugs to treat many types of solid tumors such as liver, colon, breast, or lung. Intratumoral injection of chemotherapeutic agents is a potentially more effective alternative to systemic administration because direct delivery of the anticancer drug to the target may improve both the stability and efficacy of anticancer drugs. Injectable in situ-forming gels have attracted considerable attention because they can achieve site specific drug delivery, long term action periods, and improved patient compliance. Objective: Objective of present study is to confirm clinical benefit of intratumoral chemotherapy using injectable in situ-forming poly(ethylene glycol)-b-polycaprolactone diblock copolymer (MP) and Dox with increase in efficacy and reducing the toxicity in patients with cancer diseases. Methods and methodology: We prepared biodegradable MP hydrogel and measured viscosity for the evaluation of thermo-sensitive property. In vivo antitumor activity was performed with normal saline, MP only, single free Dox, repeat free Dox, and Dox-loaded MP gel. The remaining amount of Dox drug was measured using HPLC after the mouse was sacrified. For cytotoxicity studies WST-1 assay was performed. Histological analysis was done with H&E and TUNEL processes respectively. Results: The works in this experiment showed that Dox-loaded MP have biodegradable drug depot property. Dox-loaded MP gels showed remarkable in vitro cytotoxicity activities against cancer cells. Finally, this work indicates that injection of Dox-loaded MP allowed Dox to act effectively in the tumor and induced long-lasting supression of tumor growth. Conclusion: This work has examined the potential clinical utility of intratumorally injected Dox-loaded MP gel, which shows significant effect of higher local Dox retention compared with systemically administered Dox.

Keywords: injectable in-situ forming hydrogel, anticancer, doxorubicin, intratumoral injection

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Authors: Juliana A. B. Silva, Caio H. T. L. Albuquerque, Leonardo L. dos Santos, Cristiane K. Oliveira, Ivani Malvestiti, Fernando Hallwass, Ricardo L. Longo

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Complexes with lanthanide ions have been extensively studied due to their applications as luminescent, magnetic and catalytic materials as molecular or extended crystals, thin films, glasses, polymeric matrices, ionic liquids, and in solution. NMR chemical shift data in solution have been reported and suggest fluxional structures in a wide range of coordination compounds with rare earth ions. However, the fluxional mechanisms for these compounds are still not established. This structural fluxionality may affect the photophysical, catalytic and magnetic properties in solution. Thus, understanding the structural interconversion mechanisms may aid the design of coordination compounds with, for instance, improved (electro)luminescence, catalytic and magnetic behaviors. The [Eu(btfa)₃bipy] complex, where btfa= 4,4,4-trifluoro-1-phenyl-1,3-butanedionate and bipy= 2,2’-bipiridyl, has a well-defined X-ray crystallographic structure and preliminary 1H NMR data suggested a structural fluxionality. Thus, we have investigated a series of coordination compounds with lanthanide ions [Ln(btfa)₃L], where Ln = La, Eu, Gd or Yb and L= bipy or phen (phen=1,10-phenanthroline) using a combined theoretical-experimental approach. These complexes were synthesized and fully characterized, and detailed NMR measurements were obtained. They were also studied by quantum chemical computational methods (DFT-PBE0). The aim was to determine the relevant factors in the structure of these compounds that favor or not the fluxional behavior. Measurements of the 1H NMR signals at variable temperature in CD₂Cl₂ of the [Eu(btfa)₃L] complexes suggest that these compounds have a fluxional structure, because the crystal structure has non-equivalent btfa ligands that should lead to non-equivalent hydrogen atoms and thus to more signals in the NMR spectra than those obtained at room temperature, where all hydrogen atoms of the btfa ligands are equivalent, and phen ligand has an effective vertical symmetry plane. For the [Eu(btfa)₃bipy] complex, the broadening of the signals at –70°C provides a lower bound for the coalescence temperature, which indicates the energy barriers involved in the structural interconversion mechanisms are quite small. These barriers and, consequently, the coalescence temperature are dependent upon the radii of the lanthanide ion as well as to their paramagnetic effects. The PBE0 calculated structures are in very good agreement with the crystallographic data and, for the [Eu(btfa)₃bipy] complex, this method provided several distinct structures with almost the same energy. However, the energy barrier for structural interconversion via dissociative pathways were found to be quite high and could not explain the experimental observations. Whereas the pseudo-rotation pathways, involving the btfa and bipy ligands, have very small activation barriers, in excellent agreement with the NMR data. The results also showed an increase in the activation barrier along the lanthanide series due to the decrease of the ionic radii and consequent increase of the steric effects. TD-DFT calculations showed a dependence of the ligand donor state energy with different structures of the complex [Eu(btfa)₃phen], which can affect the energy transfer rates and the luminescence. The energy required to promote the structural fluxionality may also enhance the luminescence quenching in solution. These results can aid in the design of more luminescent compounds and more efficient devices.

Keywords: computational chemistry, lanthanide-based compounds, NMR, structural fluxionality

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Authors: Rui Sang, Fei Deng, Alexander Engel, Ewa M. Goldys, Wei Deng

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In this study, we brought together X-ray induced photodynamic therapy (X-PDT) and chemo-drug (5-FU) for the treatment on colorectal cancer cells. This was achieved by developing a lipid-polymer hybrid nanoparticle delivery system (FA-LPNPs-VP-5-FU). It was prepared by incorporating a photosensitizer (verteporfin), chemotherapy drug (5-FU), and a targeting moiety (folic acid) into one platform. The average size of these nanoparticles was around 100 nm with low polydispersity. When exposed to clinical doses of 4 Gy X-ray radiation, FA-LPNPs-VP-5-FU generated sufficient amounts of reactive oxygen species, triggering the apoptosis and necrosis pathway of cancer cells. Our combined X-PDT and chemo-drug strategy was effective in inhibiting cancer cells’ growth and proliferation. Cell cycle analyses revealed that our treatment induced G2/M and S phase arrest in HCT116 cells. Our results indicate that this combined treatment provides better antitumour effect in colorectal cancer cells than each of these modalities alone. This may offer a novel approach for effective colorectal cancer treatment with reduced off-target effect and drug toxicity.

Keywords: pdt, targeted lipid-polymer nanoparticles, verteporfin, colorectal cancer

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Authors: Parthasarathi Pramanik

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Body packing is a way of transfer drugs across the international border or any drug prohibited area. The drugs are usually hidden in body packets inside the anatomical body cavities like mouth, intestines, rectum, ear, vagina etc. Cocaine is a very common drug for body packing across the world. A 48 year old male was reported dead in his hotel after complaining of chest pain and vomiting. At autopsy, there were eighty-two white cylindrical body packs in the stomach, small and large intestines. Seals of few of the packets were opened. Toxicological examination revealed presence of cocaine in the stomach, liver, kidney and hair samples. Microscopically, presence of myocardial necrosis with interstitial oedema along with hypertrophy and fibrosis of the myocardial fibre suggested heart failure due to cocaine cardio toxicity. However, focal lymphocyte infiltration and perivascular fibrosis in the myocardium also indicated chronic cocaine toxicity of the deceased. After careful autopsy examination it was considered the victim was died due congestive heart failure secondary to acute and chronic cocaine poisoning.

Keywords: cardiac failure, cocaine, body packer, sudden death

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Authors: Nadia Naseem, Farwa Batool, Nasir Mehmood, AbdulHannan Nagi

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Background: The incidence and mortality of breast cancer vary significantly in geographically distinct populations. In Pakistan, breast cancer has shown an increase in incidence in young females and is characterized by more aggressive behavior. The tumor suppressor TP53 gene is a crucial genetic factor that plays a significant role in breast carcinogenesis. This study investigated the TP53 mutations in molecular subtypes of both nodes negative and positive breast cancer in young Pakistani patients. Material and Methods: p53, Estrogen Receptor (ER), Progesterone Receptor (PR), Her-2 neu and Ki 67 expressions were analyzed immunohistochemically in a series of 75 node negative (A) and 75 node positive (B) young (aged: 19-40 years) breast cancer patients diagnosed between 2014 to 2017 at two leading hospitals of Punjab, Pakistan. Tumor tissue specimens and peripheral blood samples were examined for TP53 mutations by direct sequencing of the gene (exons 4-9). The relation of TP53 mutations to these markers and clinicopathological data was investigated. Results: Mean age of the patients was 32.4 + 9.1 SD. Invasive breast carcinoma was the most frequent histological variant (A=92%, B=94.6%). Grade 3 carcinoma was the commonest grade (A=72%, B=81.3%). Triple negative cases (ER-, PR-, Her-2) formed most of the molecular subtypes (A=44%, B=50.6%). A total of 17.2% (A: 6.6%, B: 10.6%) patients showed TP53 mutations. Mutations were significantly more frequent in triple negative cases (A: 74.8%, B: 62.2%) compared to HER2-positive patients (P < 0.0001). In the multivariate analysis of the whole patient group, the independent prognosticator were triple negative cases (P=0.021), TP53 overexpression by IHC (P=0.001) and advanced-stage disease (P=0.007). No statistically significant correlation between TP53 mutations and clinicopathological parameters was found (P < 0.05). Conclusions: It is concluded that TP53 mutations are infrequently present in breast carcinoma of young Pakistani population and there was no significant correlation between p53 mutation and early onset disease. Immunohistochemically detected TP53 expression in our resource-constrained to set up can be beneficial in predicting mutations at the younger age in our population.

Keywords: immunohistochemistry (IHC), invasive breast carcinoma (IBC), Pakistan, TP53

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Authors: Zakaria Baka, Halima Alem

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Cancer is a major worldwide health problem that has caused around ten million deaths in 2020. In addition, efforts to develop new anti-cancer drugs still face a high failure rate. This is partly due to the lack of preclinical models that recapitulate in-vivo drug responses. Indeed conventional cell culture approach (known as 2D cell culture) is far from reproducing the complex, dynamic and three-dimensional environment of tumors. To set up more in-vivo-like cancer models, 3D bioprinting seems to be a promising technology due to its ability to achieve 3D scaffolds containing different cell types with controlled distribution and precise architecture. Moreover, the introduction of microfluidic technology makes it possible to simulate in-vivo dynamic conditions through the so-called “cancer-on-chip” platforms. Whereas several cancer types have been modeled through the cancer-on-chip approach, such as lung cancer and breast cancer, only a few works describing ovarian cancer models have been described. The aim of this work is to combine 3D bioprinting and microfluidic technics with setting up a 3D dynamic model of ovarian cancer. In the first phase, alginate-gelatin hydrogel containing SKOV3 cells was used to achieve tumor-like structures through an extrusion-based bioprinter. The desired form of the tumor-like mass was first designed on 3D CAD software. The hydrogel composition was then optimized for ensuring good and reproducible printability. Cell viability in the bioprinted structures was assessed using Live/Dead assay and WST1 assay. In the second phase, these bioprinted structures will be included in a microfluidic device that allows simultaneous testing of different drug concentrations. This microfluidic dispositive was first designed through computational fluid dynamics (CFD) simulations for fixing its precise dimensions. It was then be manufactured through a molding method based on a 3D printed template. To confirm the results of CFD simulations, doxorubicin (DOX) solutions were perfused through the dispositive and DOX concentration in each culture chamber was determined. Once completely characterized, this model will be used to assess the efficacy of anti-cancer nanoparticles developed in the Jean Lamour institute.

Keywords: 3D bioprinting, ovarian cancer, cancer-on-chip models, microfluidic techniques

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Authors: Marina Shurupova, Victor Anisimov, Alexander Latanov

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Background: The cerebellar lesions inevitably provoke oculomotor impairments in patients of different age. Symptoms of subtentorial tumors, particularly medulloblastomas, include static and dynamic coordination disorders (ataxia, asynergia, imbalance), hypo-muscle tonus, disruption of the cranial nerves, and within the oculomotor system - nystagmus (fine or gross). Subtentorial tumors can also affect the areas of cerebellum that control the oculomotor system. The noninvasive eye-tracking technology allows obtaining multiple oculomotor characteristics such as the number of fixations and their duration, amplitude, latency and velocity of saccades, trajectory and scan path of gaze during the process of the visual field navigation. Eye tracking could be very useful in clinical studies serving as convenient and effective tool for diagnostics. The aim: We studied the dynamics of oculomotor system functioning in patients undergoing remission from cerebellar tumors removal surgeries and following neurocognitive rehabilitation. Methods: 38 children (23 boys, 15 girls, 9-17 years old) that have recovered from the cerebellar tumor-removal surgeries, radiation therapy and chemotherapy and were undergoing course of neurocognitive rehabilitation participated in the study. Two tests were carried out to evaluate oculomotor performance - gaze stability test and counting test. The monocular eye movements were recorded with eye tracker ArringtonResearch (60 Hz). Two experimental sessions with both tests were conducted before and after rehabilitation courses. Results: Within the final session of both tests we observed remarkable improvement in oculomotor performance: 1) in the gaze stability test the spread of gaze positions significantly declined compared to the first session, and 2) the visual path in counting test significantly shortened both compared to the first session. Thus, neurocognitive rehabilitation improved the functioning of the oculomotor system in patients following the cerebellar tumor removal surgeries and subsequent therapy. Conclusions: The experimental data support the effectiveness of the utilization of the eye tracking technique as diagnostic tool in the field of neurooncology.

Keywords: eye tracking, rehabilitation, cerebellar tumors, oculomotor system

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Authors: Hurtado Zuñiga Yonel Marcos, Ferreira Joao Tiago

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Introduction: Leiomyoma is a benign smooth muscle tumor. It is predominantly found between 40-49 years with a small prevalence in men. It is commonly found in the uterus, stomach, and in areas with smooth muscle. It presents as nodular, solitary, variable size, slow growing, and asymptomatic. It is classified into solid, vascular, and epithelioid leiomyoma. Vascular leiomyoma is the most common in the oral cavity. Oral leiomyomas are very rare because a smooth muscle in the oral cavity isn’t common. The most frequent areas of this pathologyaretongue, lip, buccal mucosa, and palate. It may be derived from the vascular walls or excretory ducts of the salivary glands. The diagnosis is made by histologically analysis. The treatment of choice is complete excision. Recurrence is rare. Objective: To report the case of a solid leiomyoma on the dorsum of the tongue and review the literature. Case description: A 78-year-old female patient presented a nodular (ovoid) elevation of 8x6mm, brownish color, with irregular limits and firm consistency located in the dorsal part of the tongue with slight symptoms. An excisional biopsy was performed, photographic record, and 3 weeks post-surgical follow-up. Result: The surgical specimen was submitted to an anatomopathological analysis, resulting in a benign nodule with defined limits compatible with solid leiomyoma of the tongue. Discussion: It is a pathology that presents in a solitary, nodular, well-defined, asymptomatic form; in the oral cavity, leiomyomas are found in the tongue, lip, buccal mucosa, and palate; as in our patient, it was nodular and, in the tongue, with a difference only in the symptomatology. The most prevalent age is 40-49 years and with small predominance in men, unlike our female patient with 78 years. Conclusions: Oral leiomyoma is a rare benign lesion that presents as a solitary nodular nodule; for its diagnosis, an anatomopathological analysis should be performed, and the treatment of choice is total excision with little recurrence.

Keywords: tongue, bening tumor, oral leiomyoma, leiomyoma

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Authors: Kuladip Jana

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Benzo(a)pyrene [B(a)P] is an environmental toxicant present mostly in cigarette smoke and car exhaust, is an aryl hydrocarbon receptor (AhR) ligand that exerts its toxic effects on both male and female reproductive systems. In this study, the effect of B(a)P at different doses (0.1, 0.25, 0.5, 1 and 5 mg /kg body weight) was studied on male reproductive system of rat. A significant decrease in cauda epididymal sperm count and motility along with the presence of sperm head abnormalities and altered epididymal and testicular histology were documented following B(a)P treatment. B(a)P treatment resulted apoptotic sperm cells as observed by TUNEL and Annexin V-PI assay with increased ROS, altered sperm mitochondrial membrane potential (ΔΨm) with a simultaneous decrease in the activity of antioxidant enzymes and GSH status. TUNEL positive apoptotic cells also observed in testis as well as isolated germ and Leydig cells following B(a)P exposure. Western Blot analysis revealed the activation of p38MAPK, cytosolic translocation of cytochrome-c, up-regulation of Bax and inducible nitric oxide synthase (iNOS) with cleavage of PARP and down-regulation of BCl2 in testis upon B(a)P treatment. The protein and mRNA levels of testicular key steroidogenesis regulatory proteins like StAR, cytochrome P450 IIA1 (CYPIIA1), 3β HSD, 17β HSD showed a significant decrease in a dose dependent manner while an increase in the expression of cytochrome P450 1A1 (CYP1A1), Aryl hydrocarbon Receptor (AhR), active caspase- 9 and caspase- 3 following B(a)P exposure. We conclude that exposure of benzo(a)pyrene caused testicular gamatogenic and steroidogenic disorders by induction of oxidative stress, inhibition of StAR and other steroidogenic enzymes along with activation of p38MAPK and initiated caspase-3 mediated germ and Leydig cell apoptosis.The possible protective role of naturally occurring phytochemicals against B(a)P induced testicular toxicity needs immediate consideration. Curcumin and resveratrol separately were found to protect against B(a)P induced germ cell apoptosis, and their combinatorial effect was more significant. Our present study in isolated testicular germ cell population from adult male Wistar rats, highlighted their synergistic protective effect against B(a)P induced germ cell apoptosis. Curcumin-resveratrol co-treatment decreased the expression of pro-apoptotic proteins like cleaved caspase 3,8,9, cleaved PARP, Apaf1, FasL, tBid. Curcumin-resveratrol co-treatment decreased Bax/Bcl2 ratio, mitochondria to cytosolic translocation of cytochrome c and activated the survival protein Akt. Curcumin-resveratrol decreased the expression of p53 dependent apoptotic genes like Fas, FasL, Bax, Bcl2, Apaf1.Curcumin-resveratrol co-treatment thus prevented B(a)P induced germ cell apoptosis. B(a)P induced testicular ROS generation and oxidative stress were significantly ameliorated with curcumin and resveratrol. Curcumin-resveratrol co-treatment prevented B(a)P induced nuclear translocation of AhR and CYP1A1 production. The combinatorial treatment significantly inhibited B(a)P induced ERK 1/2, p38 MAPK and JNK 1/2 activation. B(a)P treatment increased the expression of p53 and its phosphorylation (p53 ser 15). Curcumin-resveratrol co-treatment significantly decreased p53 level and its phosphorylation (p53 ser 15). The study concludes that curcumin-resveratrol synergistically modulated MAPKs and p53, prevented oxidative stress, regulated the expression of pro and anti-apoptotic proteins as well as the proteins involved in B(a)P metabolism thus protected germ cells from B(a)P induced apoptosis.

Keywords: benzo(a)pyrene, germ cell, apoptosis, oxidative stress, resveratrol, curcumin

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Authors: Sajeli A. Begum, Ameer Basha, Kirti Hira, Rukaiyya Khan

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Cyclic dipeptides are simple diketopiperazine derivatives being investigated by several scientists for their biological effects which include anticancer, antimicrobial, haematological, anticonvulsant, immunomodulatory effect, etc. They are potentially active microbial metabolites having been synthesized too, for developing into drug candidates. Cultures of Pseudomonas species have earlier been reported to produce cyclic dipeptides, helping in quorum sensing signals and bacterial–host colonization phenomena during infections, causing cell anti-proliferation and immunosuppression. Fluorescing Pseudomonas species have been identified to secrete lipid derivatives, peptides, pyrroles, phenazines, indoles, aminoacids, pterines, pseudomonic acids and some antibiotics. In the present work, results of investigation on the cyclic dipeptide metabolites secreted by the culture broth of Pseudomonas species as potent pro-inflammatory cytokine inhibitors are discussed. The bacterial strain was isolated from the rhizospheric soil of groundnut crop and identified as Pseudomonas aeruginosa by 16S rDNA sequence (GenBank Accession No. KT625586). Culture broth of this strain was prepared by inoculating into King’s B broth and incubating at 30 ºC for 7 days. The ethyl acetate extract of culture broth was prepared and lyophilized to get a dry residue (EEPA). Lipopolysaccharide (LPS)-induced ELISA assay proved the inhibition of tumor necrosis factor-alpha (TNF-α) secretion in culture supernatant of RAW 264.7 cells by EEPA (IC50 38.8 μg/mL). The effect of oral administration of EEPA on plasma TNF-α level in rats was tested by ELISA kit. The LPS mediated plasma TNF-α level was reduced to 45% with 125 mg/kg dose of EEPA. Isolation of the chemical constituents of EEPA through column chromatography yielded ten cyclic dipeptides, which were characterized using nuclear magnetic resonance and mass spectroscopic techniques. These cyclic dipeptides are biosynthesized in microorganisms by multifunctional assembly of non-ribosomal peptide synthases and cyclic dipeptide synthase. Cyclo (Gly-L-Pro) was found to be more potentially (IC50 value 4.5 μg/mL) inhibiting TNF-α production followed by cyclo (trans-4-hydroxy-L-Pro-L-Phe) (IC50 value 14.2 μg/mL) and the effect was equal to that of standard immunosuppressant drug, prednisolone. Further, the effect was analyzed by determining mRNA expression of TNF-α in LPS-stimulated RAW 264.7 macrophages using quantitative real-time reverse transcription polymerase chain reaction. EEPA and isolated cyclic dipeptides demonstrated diminution of TNF-α mRNA expression levels in a dose-dependent manner under the tested conditions. Also, they were found to control the expression of other pro-inflammatory cytokines like IL-1β and IL-6, when tested through their mRNA expression levels in LPS-stimulated RAW 264.7 macrophages under LPS-stimulated conditions. In addition, significant inhibition effect was found on Nitric oxide production. Further all the compounds exhibited weak toxicity to LPS-induced RAW 264.7 cells. Thus the outcome of the study disclosed the effectiveness of EEPA and the isolated cyclic dipeptides in down-regulating key cytokines involved in pathophysiology of autoimmune diseases.In another study led by the investigators, microbial cyclic dipeptides were found to exhibit excellent antimicrobial effect against Fusarium moniliforme which is an important causative agent of Sorghum grain mold disease. Thus, cyclic dipeptides are emerging small molecular drug candidates for various autoimmune diseases.

Keywords: cyclic dipeptides, cytokines, Fusarium moniliforme, Pseudomonas, TNF-alpha

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Authors: Shreya Sara Ittycheria, K. C. Sivakumar, Shijulal Nelson Sathi, Priya Srinivas

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hCG, a heterodimer composed of α and β subunits, is a peptide hormone having numerous biological functions. Although hCG is expressed by placenta during pregnancy, ectopic β-hCG secretion is observed in many non-trophoblastic tumors including that of breast. In-vitro and in-vivo studies done in the lab, have proved that BRCA1 defective cancers express β-hCG and when β-hCG is expressed or supplemented, it promotes tumor progression and exhibits resistance to carboplatin and ABT888, in such cancers but not in BRCA1 wild type cancers. In cancer cells, instead of binding to its regular receptor, LH-CGR, β-hCG binds with Transforming Growth Factor Receptor 2 (TGFβRII) and phosphorylates it resulting in faster tumor progression through the Smad signaling pathway. Targeting β-hCG could be a potential therapeutic strategy for managing BRCA1 defective cancers. Here, molecular docking and dynamic simulation studies were done to identify potential small molecule inhibitors against β-hCG as there are currently no such inhibitors reported. The binding sites of TGFβRII on β-hCG were identified from the top 10 predicted complexes from Z Dock. Virtual screening of selected commercially available small molecules from various libraries such as ZINC, NCI and Life Chemicals amounting to a total of 50,025 molecules were done. Four potential small molecule inhibitors were identified, RgcbPs-1, RgcbPs-2, RgcbPs-3 and RgcbPs-4 with binding affinities -60.778 kcal/mol, -45.447 kcal/mol, -65.2268 kcal/mol and -82.040 kcal/mol respectively. Further, 100ns Molecular Dynamics (MD) simulation showed that these molecules form stable complexes with β-hCG. RgcbPs-1 maintains hydrogen bonds with Q54, L52, Q46, C100, G36, C57, C38 residues, RgcbPs-2 maintains hydrogen bonds with A83 residue, RgcbPs-3 maintains hydrogen bonds with C57, Y58, R94, G101 residues and RgcbPs-4 maintains hydrogen bonds with G36, C38, T40, C57, D99, C100, G101 and L104 residues of β-hCG all of which coincide with the TGFβRII binding site on β-hCG. These results show that these two inhibitors could be used either singly or in combination for inhibiting β-hCG from binding to TGFβRII and thereby directly inhibiting the tumorigenesis pathway.

Keywords: β-hCG, breast cancer, dynamic simulations, molecular docking, small molecule inhibitors, virtual screening.

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Authors: E. Mosiniewicz-Szablewska, P. Suchocki, P. C. Morais

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Despite the significant progress in cancer treatment, there is a need to search for new therapeutic methods in order to minimize side effects. Chemotherapy, the main current method of treating cancer, is non-selective and has a number of limitations. Toxicity to healthy cells is undoubtedly the biggest problem limiting the use of many anticancer drugs. The problem of how to kill cancer without harming a patient can be solved by using organic selenium (IV) compounds. Organic selenium (IV) compounds are a new class of materials showing a strong anticancer activity. They are first organic compounds containing selenium at the +4 oxidation level and therefore they eliminate the multidrug-resistance for all tumor cell lines tested so far. These materials are capable of selectively killing cancer cells without damaging the healthy ones. They are obtained by the incorporation of selenous acid (H2SeO3) into molecules of fatty acids of sunflower oil and therefore, they are inexpensive to manufacture. Attaching these compounds to magnetic carriers enables their precise delivery directly to the tumor area and the simultaneous application of the magnetic hyperthermia, thus creating a huge opportunity to effectively get rid of the tumor without any side effects. Polylactic-co-glicolic acid (PLGA) nanocapsules loaded with maghemite (-Fe2O3) nanoparticles and organic selenium (IV) compounds are successfully prepared by nanoprecipitation method. In vitro antitumor activity of the nanocapsules were evidenced using murine melanoma (B16-F10), oral squamos carcinoma (OSCC) and murine (4T1) and human (MCF-7) breast lines. Further exposure of these cells to an alternating magnetic field increased the antitumor effect of nanocapsules. Moreover, the nanocapsules presented antitumor effect while not affecting normal cells. Magnetic properties of the nanocapsules were investigated by means of dc magnetization, ac susceptibility and electron spin resonance (ESR) measurements. The nanocapsules presented a typical superparamagnetic behavior around room temperature manifested itself by the split between zero field-cooled/field-cooled (ZFC/FC) magnetization curves and the absence of hysteresis on the field-dependent magnetization curve above the blocking temperature. Moreover, the blocking temperature decreased with increasing applied magnetic field. The superparamagnetic character of the nanocapsules was also confirmed by the occurrence of a maximum in temperature dependences of both real ′(T) and imaginary ′′ (T) components of the ac magnetic susceptibility, which shifted towards higher temperatures with increasing frequency. Additionally, upon decreasing the temperature the ESR signal shifted to lower fields and gradually broadened following closely the predictions for the ESR of superparamagnetoc nanoparticles. The observed superparamagnetic properties of nanocapsules enable their simple manipulation by means of magnetic field gradient, after introduction into the blood stream, which is a necessary condition for their use as magnetic drug carriers. The observed anticancer and superparamgnetic properties show that the magnetic nanocapsules loaded with organic selenium (IV) compounds should be considered as an effective material system for magnetic drug delivery and magnetohyperthermia inductor in antitumor therapy.

Keywords: cancer treatment, magnetic drug delivery system, nanomaterials, nanotechnology

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Authors: Razieh Zarei, Hassan zm, Abolghasem Ajami, Darush Moslemi, Narges Afsary, Amrollah Mostafa-zade

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Introduction: IL-23 is responsible for the differentiation and expansion of Th17/ThIL-17 cells from naive CD4+ T cells. Therefore, may be IL-23/IL17 axis involve in a variety of allergic and autoimmune diseases, such as RA, MS, inflammatory bowel disease (IBD), and asthma. TGF-β is also share for the differentiation Th17 producing IL-17 and CD4+CD25+Foxp3hiT regulatory cells from naïve CD4+ T cells which are involved in the regulation of immune response, maintaining immunological self-tolerance and immune homeostasis ,and the control of autoimmunity and cancer surveillance. Therefore, T regulatory cells play a key role in autoimmunity, allergy, cancer, infectious disease, and the induction of transplantation tolerance. Vitamin A and it's derivatives (retinoids) inhibit or reverse the carcinogenic process in some types of cancers in oral cavity,head and neck, breast, skin, liver, and blood cells. Shark is a murine organism and its cartilage has antitumor peptides to prevent angiogenesis, in vitro. Our purpose is whether simultaneous oral treatment vitamin A and shark cartilage can modulate IL-23/IL-17 and CD4CD25Foxp3 T regulatory cell/TGF-β pathways and Th1/Th2 immunity in patients with gastric cancer. Materials and Methods: First investigated an imbalanced supernatant of cytokines exist in patients with gastric cancer by ELISA. Associated with cytokines measuring such as IL-23,IL-17,TGF-β,IL-4 and γ-IFN, then flow cytometry was employed to determine whether the peripheral blood mononuclear cells such as CD4+CD25+Foxp3highT regulatory cells in patients with gastric cancer were changed correspondingly. Results: An imbalance between IL-17 secretion and TGF-β/Foxp3 t regulatory cell pathway and so, Th1 immunity (γ-IFN production) and TH2 immunity (IL-4 secretion) was not seen in patients with gastric cancer treated by vitamin A and shark cartilage. But, the simultaneously presented down-regulation of IL-23 indicated, at least cytokine level. Conclusion: Il-23, as a pro-angiogenesis cytokine, probably, help to tumor growth. Hence, suggested that down-regulation of IL-23, at least cytokine level, is useful for anti-tumor immune responses in patients with gastric cancer.

Keywords: IL-23/IL17 axis, TGF-β/CD4CD25Foxp3 T regulatory pathway, γ-IFN, IL-4, shark cartilage and gastric cancer

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Authors: Menna Ewida, Dalal Abou El-Ella, Dina Lasheen, Huessin El-Subbagh

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Introduction: Vascular Endothelial Growth Factor receptor (VEGF) is a signal protein produced by cells that stimulates vasculogenesis to create new blood vessels. VEGF family binds to three trans-membrane tyrosine kinase receptors,Dihydrofolate reductase (DHFR) is an enzyme of crucial importance in medicinal chemistry. DHFR catalyzes the reduction 7,8 dihydro-folate to tetrahydrofolate and intimately couples with thymidylate synthase which is a pivotal enzyme that catalysis the reductive methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) utilizing N5,N10-methylene tetrahydrofolate as a cofactor which functions as the source of the methyl group. Purpose: Novel substituted Thiazole agents were designed as DHFR and VEGF-TK inhibitors with increased synergistic activity and decreased side effects. Methods: Five series of compounds were designed with a rational that mimic the pharmacophoric features present in the reported active compounds that target DHFR & VEGFR. These molecules were docked against Methotrexate & Sorafenib as controls. An in silico ADMET study was also performed to validate the bioavailability of the newly designed compounds. The in silico molecular docking & ADMET study were also applied to the non-classical antifolates for comparison. The interaction energy comparable to that of MTX for DHFRI and Sorafenib for VEGF-TKI activity were recorded. Results: Compound 5 exhibited the highest interaction energy when docked against Sorafenib, While Compound 9 showed the highest interaction energy when docked against MTX with the perfect binding mode. Comparable results were also obtained for the ADMET study. Most of the compounds showed absorption within (95-99) zone which varies according to the type of substituents. Conclusions: The Substituted Thiazole Analogues could be a suitable template for antitumor drugs that possess enhanced bioavailability and act as DHFR and VEGF-TK inhibitors.

Keywords: anti-tumor agents, DHFR, drug design, molecular modeling, VEGFR-TKIs

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Authors: Alldila Hendy, Agi Satria

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Background: A colostomy procedure is an important part in the management of surgical procedures in some diseases involving the gastrointestinal tract. So it is necessary to find the factors that influence the occurrence of complications. Methods: This is a retrospective cross-sectional analytic study in Cipto Mangunkusumo Hospital noting medical records of patients after the colostomy from January 2012 to December 2014 at the Division of Digestive Surgery. Results: In 136 cases of post-colostomy, 66 cases have complications, 14 is early-onset, and 52 is late-onset. 70 is without complications. Most complications are dermatitis, which is 31 (22.8%), cases of infection/abscess/fistula and intestinal obstruction are 13 (9.6%) and 5 patients (4.4%). A rare complication is colostomy retraction by 2 patients (1.5%), colostomy prolapse and necrosis/gangrene, which is only 3 patients (2.2%). A colostomy procedure in emergency surgery is riskier than elective surgery for complications after colostomy (p < 0.007, OR 2.85), Based on the operator who performs a colostomy procedure, the consultant had a lower risk of complications than fellow or resident (p < 0.0001). Based on the age factor, where the age of about 50 years has a risk of complications after colostomy (p < 0.018). Conclusion: The timing of operation (emergency or elective), age, and operator who perform a colostomy procedure have a significant relationship with an increased prevalence of complications after colostomy in RSCM.

Keywords: colostomy, complications, factors, procedure

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Authors: Hailiang Liu, Yan Ni, Jie Zheng, Xiaoyan Jiang, Min Hong

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Allergic contact dermatitis (ACD) is a commonly clinical type IV allergic skin disease, with the pathological features of infiltration by mononuclear cells and tissue necrosis. Traditional Chinese medicine Radix Saposhnikoviae (RS) is traditionally employed to treat exogenous evils, rubella, itching, rheumatism and tetanus. Meanwhile, it is an important component of the commonly used anti-allergy compound. It’s now widely used as an immuno-modulating agent in mixed herbal decoctions to treat inflammation. However, its mechanism of anti-allergy remains unknown. RS was found to reduce ear thickness, as well as the infiltration of eosinophils. The proliferation of T lymphocytes was inhibited significantly by RS, markedly decreased IFN-γ levels in the supernatant of cells cultured and serum were detected with the treatment of RS. RS significantly decreased the amount of DCs in the mouse lymph nodes, and inhibited the expression of CD4 0 and CD86. Meanwhile, T-bet mRNA expression was down remarkably regulated by RS. These results indicate that RS cures Th1-induced allergic skin inflammation by regulating Th1/Th2 balance with decreasing Th1 differentiation, which might be associated with DCs.

Keywords: allergic contact dermatitis, Radix saposhnikoviae, dendritic cells, T-bet, GATA-3, CD4+ CD25+ Foxp3+ treg cells

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Authors: Kalimullah Khan, Samina Roohi, Mohammad Rafi, Rizwana Zahoor

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Labeling of 5-Aminolevulinic acid (5-ALA) with 99 mTc was achieved by using tin chloride dihydrate (Sncl2.2H2O) as reducing agent. Radiochemical purity and labeling efficiency was determined by Whattman paper No.3 and instant thin layer chromatographic strips impregnated with silica gel (ITLC/SG). Labeling efficiency was dependent on many parameters such as amount of ligand, reducing agent, pH, and incubation time. Therefore, optimum conditions for maximum labeling were selected. Stability of 99 mTc- 5-ALA was also checked in fresh human serum. Tissue bio-distribution of 99 mTc-5-ALA was evaluated in Spargue Dawley rats. 5-ALA was 98% labeled with 99 mTc under optimum conditions, i.e. 100µg of 5-ALA, pH: 4, 10µg of Sncl2.2H2O and 30 minutes incubation at room temperature. 99 mTc labelled 5- ALA remained stable for 24 hours in human serum. Bio-distribution study (%ID/gm) in rats revealed that maximum accumulation of 99 mTc-5-ALA was in liver, spleen, stomach and intestine after half hour, 4 hours, and 24 hours. Significant activity in bladder and urine indicated urinary mode of excretion.

Keywords: 99mTc-ALA, aminolevulinic acid, quality control, radiopharmaceuticals

Procedia PDF Downloads 384