Search results for: oral kinase inhibitors

Authors: Shrestha Sharma, Jasjeet K. Sahni, Javed Ali, Sanjula Baboota

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Introduction: Rutin is a naturally occurring strong antioxidant molecule belonging to bioflavonoid category. Due to its free radical scavenging properties, it has been found to be beneficial in the treatment of various diseases including inflammation, cancer, diabetes, allergy, cardiovascular disorders and various types of microbial infections. Despite its beneficial effects, it suffers from the problem of low aqueous solubility which is responsible for low oral bioavailability. The aim of our study was to optimize and characterize self-nanoemulsifying drug delivery system (SNEDDS) of rutin using Box-Behnken design (BBD) combined with a desirability function. Further various antioxidant, pharmacokinetic and pharmacodynamic studies were performed for the optimized rutin SNEDDS formulation. Methodologies: Selection of oil, surfactant and co-surfactant was done on the basis of solubility/miscibility studies. Sefsol+ Vitamin E, Solutol HS 15 and Transcutol P were selected as oil phase, surfactant and co-surfactant respectively. Optimization of SNEDDS formulations was done by a three-factor, three-level (33)BBD. The independent factors were Sefsol+ Vitamin E, Solutol HS15, and Transcutol P. The dependent variables were globule size, self emulsification time (SEF), % transmittance and cumulative percentage drug released. Various response surface graphs and contour plots were constructed to understand the effect of different factor, their levels and combinations on the responses. The optimized Rutin SNEDDS formulation was characterized for various parameters such as globule size, zeta potential, viscosity, refractive index , % Transmittance and in vitro drug release. Ex vivo permeation studies and pharmacokinetic studies were performed for optimized formulation. Antioxidant activity was determined by DPPH and reducing power assays. Anti-inflammatory activity was determined by using carrageenan induced rat paw oedema method. Permeation of rutin across small intestine was assessed using confocal laser scanning microscopy (CLSM). Major findings:The optimized SNEDDS formulation consisting of Sefsol+ Vitamin E - Solutol HS15 -Transcutol HP at proportions of 25:35:17.5 (w/w) was prepared and a comparison of the predicted values and experimental values were found to be in close agreement. The globule size and PDI of optimized SNEDDS formulation was found to be 16.08 ± 0.02 nm and 0.124±0.01 respectively. Significant (p˂0.05) increase in percentage drug release was achieved in the case of optimized SNEDDS formulation (98.8 %) as compared to rutin suspension. Furthermore, pharmacokinetic study showed a 2.3-fold increase in relative oral bioavailability compared with that of the suspension. Antioxidant assay results indicated better efficacy of the developed formulation than the pure drug and it was found to be comparable with ascorbic acid. The results of anti-inflammatory studies showed 72.93 % inhibition for the SNEDDS formulation which was significantly higher than the drug suspension 46.56%. The results of CLSM indicated that the absorption of SNEDDS formulation was considerably higher than that from rutin suspension. Conclusion: Rutin SNEDDS have been successfully prepared and they can serve as an effective tool in enhancing oral bioavailability and efficacy of Rutin.

Keywords: rutin, oral bioavilability, pharamacokinetics, pharmacodynamics

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Authors: Andhiani Sharfina Arnellya, Mochammad Indra Permana, Dika Pramita Destiani, Ellin Febrina

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Health Research Data, Ministry of Health of Indonesia in 2007, showed coronary heart disease (CHD) or coronary artery disease (CAD) was the third leading cause of death in Indonesia after hypertension and stroke with 7.2% incidence rate. Antiplatelet is one of the important therapy in management of patients with CHD. In addition to therapeutic effect on patients, quality of life is one aspect of another assessment to see the success of antiplatelet therapy. The purpose of this study was to determine the quality of life of patients on oral antiplatelet therapy in outpatient cardiac department Dr. Hasan Sadikin central general hospital, Bandung, Indonesia. This research is a cross sectional by collecting data through quality of life questionnaire of patients which performed prospectively as primary data and secondary data from medical record of patients. The results of this study showed that 54.3% of patients had a good quality of life, 45% had a moderate quality of life, and 0.7% had a poor quality of life. There are no significant differences in quality of life-based on age, gender, diagnosis, and duration of drug use.

Keywords: antiplatelet, quality of life, coronary artery disease, coronary heart disease

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Authors: T. Almutairi, K. Naudi, N. Nairn, X. Ju, B. Eng, J. Whitters, A. Ayoub

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Purpose: At present Cone Beam Computed Tomography (CBCT) imaging does not record dental morphology accurately due to the scattering produced by metallic restorations and the reported magnification. The aim of this pilot study is the development and validation of a new method for the replacement of the distorted dentition of CBCT scans with the dental image captured by the digital intraoral camera. Materials and Method: Six dried skulls with orthodontics brackets on the teeth were used in this study. Three intra-oral markers made of dental stone were constructed which were attached to orthodontics brackets. The skulls were CBCT scanned, and occlusal surface was captured using TRIOS® 3D intraoral scanner. Marker based and surface based registrations were performed to fuse the digital intra-oral scan(IOS) into the CBCT models. This produced a new composite digital model of the skull and dentition. The skulls were scanned again using the commercially accurate Laser Faro® arm to produce the 'gold standard' model for the assessment of the accuracy of the developed method. The accuracy of the method was assessed by measuring the distance between the occlusal surfaces of the new composite model and the 'gold standard' 3D model of the skull and teeth. The procedure was repeated a week apart to measure the reproducibility of the method. Results: The results showed no statistically significant difference between the measurements on the first and second occasions. The absolute mean distance between the new composite model and the laser model ranged between 0.11 mm to 0.20 mm. Conclusion: The dentition of the CBCT can be accurately replaced with the dental image captured by the intra-oral scanner to create a composite model. This method will improve the accuracy of orthognathic surgical prediction planning, with the final goal of the fabrication of a physical occlusal wafer without to guide orthognathic surgery and eliminate the need for dental impression.

Keywords: orthognathic surgery, superimposition, models, cone beam computed tomography

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Authors: Regiane A. Oliveira, Carlos E. Vaz Rossell, Rubens Maciel Filho

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Lactic acid, besides a valuable chemical may be considered a platform for other chemicals. In fact, the feasibility of hemicellulosic sugars as feedstock for lactic acid production process, may represent the drop of some of the barriers for the second generation bioproducts, especially bearing in mind the 5-carbon sugars from the pre-treatment of sugarcane bagasse. Bearing this in mind, the purpose of this study was to use the hemicellulosic liquor from sugarcane bagasse as a substrate to produce lactic acid by fermentation. To release of sugars from hemicellulose it was made a pre-treatment with a diluted sulfuric acid in order to obtain a xylose's rich liquor with low concentration of inhibiting compounds for fermentation (≈ 67% of xylose, ≈ 21% of glucose, ≈ 10% of cellobiose and arabinose, and around 1% of inhibiting compounds as furfural, hydroxymethilfurfural and acetic acid). The hemicellulosic sugars associated with 20 g/L of yeast extract were used in a fermentation process with Lactobacillus plantarum to produce lactic acid. The fermentation process pH was controlled with automatic injection of Ca(OH)2 to keep pH at 6.00. The lactic acid concentration remained stable from the time when the glucose was depleted (48 hours of fermentation), with no further production. While lactic acid is produced occurs the concomitant consumption of xylose and glucose. The yield of fermentation was 0.933 g lactic acid /g sugars. Besides, it was not detected the presence of by-products, what allows considering that the microorganism uses a homolactic fermentation to produce its own energy using pentose-phosphate pathway. Through facultative heterofermentative metabolism the bacteria consume pentose, as is the case of L. plantarum, but the energy efficiency for the cell is lower than during the hexose consumption. This implies both in a slower cell growth, as in a reduction in lactic acid productivity compared with the use of hexose. Also, L. plantarum had shown to have a capacity for lactic acid production from hemicellulosic hydrolysate without detoxification, which is very attractive in terms of robustness for an industrial process. Xylose from hydrolyzed bagasse and without detoxification is consumed, although the hydrolyzed bagasse inhibitors (especially aromatic inhibitors) affect productivity and yield of lactic acid. The use of sugars and the lack of need for detoxification of the C5 liquor from sugarcane bagasse hydrolyzed is a crucial factor for the economic viability of second generation processes. Taking this information into account, the production of second generation lactic acid using sugars from hemicellulose appears to be a good alternative to the complete utilization of sugarcane plant, directing molasses and cellulosic carbohydrates to produce 2G-ethanol, and hemicellulosic carbohydrates to produce 2G-lactic acid.

Keywords: fermentation, lactic acid, hemicellulosic sugars, sugarcane

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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: Arghavan Tonkaboni, Shamsolmolouk Najafi, Mohmmad Taghi Kiani, Mehrzad Gholampour, Touraj Goli

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Introduction: Recurrent aphthous stomatitis (RAS) is a multifactorial recurrent oral lesion; which is an autoimmune disease. TH1 cytokines are the most important etiological factors. Autoimmune thyroid disease (ATD) is one of the most common autoimmune diseases and generally coexists with other autoimmune diseases. This study assessed the prevalence of thyroid disease in patients with recurrent aphthous stomatitis. Materials and Methods: This case control study assessed 100 known RAS patients who were diagnosed clinically by oral medicine specialists; venous blood samples were analyzed for thyroid stimulating hormone (TSH), free triiodothyronine (fT3), total thyroxine (fT4), thyroglobulin, anti-thyroid peroxidase antibody (anti-TPO) and anti-thyroglobulin antibody (anti-TG) levels. Results: Fifty patients with RAS aged between 18-42 years (28.5±5.8) and 50 healthy volunteers aged 19-45 years (27.3±5.4) participated. In RAS patients, fT3 and TSH levels were significantly higher (P=0.031, P=0.706); however, fT4 level was lower in the RAS group (P=0.447). Anti TG and anti-TPO levels were significantly higher in the RAS group (P=0.008, P=0.067). Conclusion: Our study showed that ATD prevalence was significantly higher in RAS patients. Based on this study, we recommend assessment of thyroid hormones and antibodies in RAS patients.

Keywords: recurrent aphthous stomatitis, thyroid antibodies, thyroid hormone, thyroid autoimmune disease

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Authors: Aulina R. Rahmi, Farid Yuristiawan, Annisa Ibifadillah, Ummu H. Amri, Hidayati Gunawan

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Glass ionomer cement is one of the filling material that often used on the field of dentistry because it is relatively less expensive and mostly available. Restoration materials could undergo changes in their clinical properties such as changes in roughness of the restoration`s surface. An increase of surface roughness accelerates bacterial colonization and plaque maturation. In the oral cavity, GIC was exposed to various substances, such as toothpaste, an oral care product used during toothbrushing. One of the popular toothpaste is whitening toothpaste. Abrasive and chemical agents such as hydrogen peroxide in whitening toothpaste could increase the surface roughness of restorative materials. Objective: To determine the differences on the surface roughness of glass ionomer cement that was brushed with whitening and conventional toothpaste. Method: This study was done using experimental laboratory method with pre and post test design. There were 36 samples which were divided into 2 groups. The first group was brushed with whitening toothpaste and the second group was brushed with conventional toothpaste, each for 2 minutes. Surface roughness value of the specimens was measured by using Roughness Tester test. Result: The data was analyzed by using independent t-test and the result of this study showed there was a significant difference between the surface of glass ionomer cement which was brushed with whitening and conventional toothpaste (p=0,000). Conclusion: Glass ionomer cement that was brushed with whitening toothpaste produced more roughness than conventional toothpaste.

Keywords: glass ionomer cement, surface roughness, toothpaste, roughness tester

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Authors: Timmis W., Simms M., Thomas C.

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This case discusses the management of two floors of mouth (FOM) Squamous Cell Carcinomas (SCC) not identified upon initial biopsy. A 51 year-old male presented with right FOM erythroleukoplakia. Relevant medical history included alcoholic dependence syndrome and alcoholic liver disease. Relevant drug therapy encompassed acamprosate, folic acid, hydroxocobalamin and thiamine. The patient had a 55.5 pack-year smoking history and alcohol dependence from age 14, drinking 16 units/day. FOM incisional biopsy and histopathological analysis diagnosed Carcinoma in situ. Treatment involved wide local excision. Specimen analysis revealed two separate foci of pT1 moderately differentiated SCCs. Carcinoma staging scans revealed no pathological lymphadenopathy, no local invasion or metastasis. SCCs had been excised in completion with narrow margins. MDT discussion concluded that in view of the field changes it would be difficult to identify specific areas needing further excision, although techniques such as Lugol’s Iodine were considered. Further surgical resection, surgical neck management and sentinel lymph node biopsy was offered. The patient declined intervention, primary management involved close monitoring alongside alcohol and smoking cessation referral. Narrow excisional margins can increase carcinoma recurrence risk. Biopsy failed to identify SCCs, despite sampling an area of clinical concern. For gross field change multiple incisional biopsies should be considered to increase chance of accurate diagnosis and appropriate treatment. Coupling of tobacco and alcohol has a synergistic effect, exponentially increasing the relative risk of oral carcinoma development. Tobacco and alcoholic control is fundamental in reducing treatment‑related side effects, recurrence risk and second primary cancer development.

Keywords: alcohol dependence, biopsy, oral carcinoma, tobacco

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Authors: Mazo Kone, Rachida Salah, Harir Noria

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Background and objectives: c-Cbl and Cbl-b are two members of the Cbl family proteins, with a crucial role of downregulation of tyrosine kinase receptors. They act as E3 ubiquitin ligases and are multivalent adaptor proteins, making them important in maintaining homeostasis in the body. This study investigated the expression level in thymus and testis in normal conditions. Methods: The expression level was assessed by immunochemistry of tissue microarrays of normal thymus and testis biopsies. Results: Cbl-b and c-Cbl proteins were found to be highly expressed in normal testis and thymus, indicated as yellowish brown granules in the cytomembrane and cytoplasm compared to controls. The c-Cbl appears to be more highly expressed than the Cbl-b in the thymus, while c-Cbl appears slightly stronger than Cbl-b in the testis. The thymus was found with a higher grade compared to the testis. Conclusion: In this work we concluded, that in normal condition, thymus tissue expresses more Cbl family proteins(c-Cbl and Cbl-b) than the testis tissue in humans.

Keywords: Human C-Cbl proteins, Human Cbl-b protein, Testis, Thymus

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Authors: Alireza Barari

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Physical activity and diet are factors that influence the body's structure. The purpose of this study was to compare the effects of four weeks of resistance training, and glutamine supplement consumption on growth hormone (GH), and Insulin-like growth factor 1 (IGF-1) Axis. 40 amateur male bodybuilders, participated in this study. They were randomly divided into four equal groups, Resistance (R), Glutamine (G), Resistance with Glutamine (RG), and Control (C). The R group was assigned to a four week resistance training program, three times/week, three sets of 10 exercises with 6-10 repetitions, at the 80-95% 1RM (One Repetition Maximum), with 120 seconds rest between sets), G group is consuming l-glutamine (0.1 g/kg^-1/day^-1), RG group resistance training with consuming L-glutamine, and C group continued their normal lifestyle without exercise training. GH, IGF1, IGFBP-III plasma levels were measured before and after the protocol. One-way ANOVA indicated significant change in GH, IGF, and IGFBP-III between the four groups, and the Tukey test demonstrated significant increase in GH, IGF1, IGFBP-III plasma levels in R, and RG group. Based upon these findings, we concluded that resistance training at 80-95% 1RM intensity, and resistance training along with oral glutamine shows significantly increase secretion of GH, IGF-1, and IGFBP-III in amateur males, but the addition of oral glutamine to the exercise program did not show significant difference in GH, IGF-1, and IGFBP-III.

Keywords: strength, glutamine, growth hormone, insulin-like growth factor 1

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Authors: Allaire Eric, Hauet Pascal, Floresco Jean, Beley Sebastien, Sussman Helene, Virag Ronald

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Background: Caverno-venous leakage (CVL) is devastating, although barely known disease, the first cause of major physical impairment in men under 25, and responsible for 50% of resistances to phosphodiesterase 5-inhibitors (PDE5-I), affecting 30 to 40% of users in this medication class. In this condition, too early blood drainage from corpora cavernosa prevents penile rigidity and penetration during sexual intercourse. The role of conservative surgery in this disease remains controversial. Aim: Assess complications and results of combined open surgery and embolization for CVL. Method: Between June 2016 and September 2021, 133 consecutive patients underwent surgery in our institution for CVL, causing severe erectile dysfunction (ED) resistance to oral medical treatment. Procedures combined vein embolization and ligation with microsurgical techniques. We performed a pre-and post-operative clinical (Erection Harness Scale: EHS) hemodynamic evaluation by duplex sonography in all patients. Before surgery, the CVL network was visualized by computed tomography cavernography. Penile EMG was performed in case of diabetes or suspected other neurological conditions. All patients were optimized for hormonal status—data we prospectively recorded. Results: Clinical signs suggesting CVL were ED since age lower than 25, loss of erection when changing position, penile rigidity varying according to the position. Main complications were minor pulmonary embolism in 2 patients, one after airline travel, one with Factor V Leiden heterozygote mutation, one infection and three hematomas requiring reoperation, one decreased gland sensitivity lasting for more than one year. Mean pre-operative pharmacologic EHS was 2.37+/-0.64, mean pharmacologic post-operative EHS was 3.21+/-0.60, p<0.0001 (paired t-test). The mean EHS variation was 0.87+/-0.74. After surgery, 81.5% of patients had a pharmacologic EHS equal to or over 3, allowing for intercourse with penetration. Three patients (2.2%) experienced lower post-operative EHS. The main cause of failure was leakage from the deep dorsal aspect of the corpus cavernosa. In a 14 months follow-up, 83.2% of patients had a clinical EHS equal to or over 3, allowing for sexual intercourse with penetration, one-third of them without any medication. 5 patients had a penile implant after unsuccessful conservative surgery. Conclusion: Open surgery combined with embolization for CVL is an efficient approach to CVL causing severe erectile dysfunction.

Keywords: erectile dysfunction, cavernovenous leakage, surgery, embolization, treatment, result, complications, penile duplex sonography

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Authors: Ila Shukla, Lubna Azmi, Shyam Sunder Gupta, C. V. Rao

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Treatments against Hepatitis-C virus (HCV) are already available, but the current high cost of such treatments limit them to wealthy patients only. Hence our current study is aimed at the rectification of HCV infection by using Lichen rangiferinus (LRE) extract in in vitro cultures. Anti-HCV activity of the given extract was evaluated using the virus grown in cell culture (HCVcc). Two control inhibitors, erlotinib and telaprevir, were systematically included in each experiment. At the end of the incubation period, we evaluated cell viability and viral replication. The LRE inhibited the growth of HCV in a dose dependent manner.

Keywords: Erlotinib, Hepatitis C, Lichen rangiferinus, Telaprevir

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Authors: Muhammad Asif Syed, Mirza Amir Baig

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Background: Pakistan is one of the two remaining polio-endemic countries, posing a significant public health challenge for global polio eradication due to failure to interrupt polio transmission. Country specific seroprevalence studies help in the evaluation of immunization program performance, the susceptibility of population against polio virus and identification of existing level of immunity with factors that affect seroconversion of the oral polio vaccine (OPV). The objective of the study was to find out factors associated with seroconversion of the OPV among children 6-59 months in Pakistan. Methods: A Hospital based cross-sectional serosurvey was undertaken in May-June 2015 at District Mirpurkhas, Sindh-Pakistan. Total 180 children aged 6–59 months were selected by using systematic random sampling from Muhammad Medical College Hospital, Mirpurkhas. Demographic, vaccination history and risk factors information were collected from the parents/guardian. Blood sample was collected and tested for the detection of poliovirus IgG antibodies by using ELISA Kit. The IgG titer <10 IU/ml, 50 to <150 IU/ml and >150 IU/ml was defined as negative, weak positive and positive immunity respectively. Pearson Chi-square test was used to determine the difference in seroprevalence in univariate analysis. Results: A total of 180 subjects were enrolled mean age was 23 months (7 -59 months). Off these 160 (89%) children were well and 18 (10%) partially protected against polio virus. Two (1.1%) children had no protection against polio virus as they had <10 IU/ml poliovirus IgG antibodies titer. Both negative cases belong from the female gender, age group 12-23 months, urban area and BMI <50 percentile. There was a difference between normal and the wasting children; it did attain statistical significance (χ2= 35.5, p=0.00). The difference in seroconversion was also observed in relation to the gender (χ2=6.23, p=0.04), duration of breast feeding (χ2=18.6, p=0.04), history of diarrheal disease before polio vaccine administration (χ2=7.7, p=0.02), and stunting (χ2= 114, p=0.00). Conclusion: This study demonstrated that near 90% children achieve seroconversion of OPV and well protected against polio virus. There is an urgent need to focus on factors like duration of breast feeding, diarrheal diseases and malnutrition (acute and chronic) among the children as an immunization strategy.

Keywords: seroconversion, oral polio vaccine, Polio, Pakistan

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Authors: Laura Gleason, Sahithi Talasila, Lauren Banner, Ladan Afifi, Neda Nikbakht

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Primary cutaneous anaplastic large cell lymphoma (pcALCL) accounts for 9% of all cutaneous T-cell lymphomas. pcALCL is classically characterized as a solitary papulonodule that often enlarges, ulcerates, and can be locally destructive, but overall exhibits an indolent course with overall 5-year survival estimated to be 90%. Distinguishing pcALCL from systemic ALCL (sALCL) is essential as sALCL confers a poorer prognosis with average 5-year survival being 40-50%. Although extremely rare, there have been several cases of ALK-positive ALCL diagnosed on skin biopsy without evidence of systemic involvement, which poses several challenges in the classification, prognostication, treatment, and follow-up of these patients. Objectives: We present a case of cutaneous ALK-positive ALCL without evidence of systemic involvement, and a narrative review of the literature to further characterize that ALK-positive ALCL limited to the skin is a distinct variant with a unique presentation, history, and prognosis. A 30-year-old woman presented for evaluation of an erythematous-violaceous papule present on her right chest for two months. With the development of multifocal disease and persistent lymphadenopathy, a bone marrow biopsy and lymph node excisional biopsy were performed to assess for systemic disease. Both biopsies were unrevealing. The patient was counseled on pursuing systemic therapy consisting of Brentuximab, Cyclophosphamide, Doxorubicin, and Prednisone given the concern for sALCL. Apropos of the patient we searched for clinically evident, cutaneous ALK-positive ALCL cases, with and without systemic involvement, in the English literature. Risk factors, such as tumor location, number, size, ALK localization, ALK translocations, and recurrence, were evaluated in cases of cutaneous ALK-positive ALCL. The majority of patients with cutaneous ALK-positive ALCL did not progress to systemic disease. The majority of cases that progressed to systemic disease in adults had recurring skin lesions and cytoplasmic localization of ALK. ALK translocations did not influence disease progression. Mean time to disease progression was 16.7 months, and significant mortality (50%) was observed in those cases that progressed to systemic disease. Pediatric cases did not exhibit a trend similar to adult cases. In both the adult and pediatric cases, a subset of cutaneous-limited ALK-positive ALCL were treated with chemotherapy. All cases treated with chemotherapy did not progress to systemic disease. Apropos of an ALK-positive ALCL patient with clinical cutaneous limited disease in the histologic presence of systemic markers, we discussed the literature data, highlighting the crucial issues related to developing a clinical strategy to approach this rare subtype of ALCL. Physicians need to be aware of the overall spectrum of ALCL, including cutaneous limited disease, systemic disease, disease with NPM-ALK translocation, disease with ALK and EMA positivity, and disease with skin recurrence.

Keywords: anaplastic large cell lymphoma, systemic, cutaneous, anaplastic lymphoma kinase, ALK, ALCL, sALCL, pcALCL, cALCL

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Authors: Ajay Pratap Singh Lodhi, Deepak Kumar

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Vegetable oil-based environmentally friendly metalworking fluids (MWFs) are formulated. The tribological performance, cytotoxicity, and corrosion resistance of the formulated fluids (FFs) are evaluated and benchmarked with commercial mineral oil-based MWFs (CF). Results show that FFs exhibited better machining characteristics (roughness, cutting forces, and surface morphology) during machining than CF. MTT assay and Live dead cell assay confirm the cytocompatibility nature of the FFs relative to the toxic CF. Electrochemical analysis shows that FFs and CF exhibited comparable corrosion current density.

Keywords: corrosion inhibitors, cytotoxicity, machining, MTT assay, Taguchi method, vegetable oil

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Authors: Agnieszka Krzemińska, Katarzyna Świderek, Vicente Molinier, Piotr Paneth

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In order to understand in details the interactions between ligands and the enzyme isotope effects were studied between clinically used drugs that bind in the active site of Human Immunodeficiency Virus Reverse Transcriptase, HIV-1 RT, as well as triazole-based inhibitor that binds in the allosteric pocket of this enzyme. The magnitudes and origins of the resulting binding isotope effects were analyzed. Subsequently, binding isotope effect of the same triazole-based inhibitor bound in the active site were analyzed and compared. Together, these results show differences in binding origins in two sites of the enzyme and allow to analyze binding mode and place of newly synthesized inhibitors. Typical protocol is described below on the example of triazole ligand in the allosteric pocket. Triazole was docked into allosteric cavity of HIV-1 RT with Glide using extra-precision mode as implemented in Schroedinger software. The structure of HIV-1 RT was obtained from Protein Data Bank as structure of PDB ID 2RKI. The pKa for titratable amino acids was calculated using PROPKA software, and in order to neutralize the system 15 Cl- were added using tLEaP package implemented in AMBERTools ver.1.5. Also N-terminals and C-terminals were build using tLEaP. The system was placed in 144x160x144Å3 orthorhombic box of water molecules using NAMD program. Missing parameters for triazole were obtained at the AM1 level using Antechamber software implemented in AMBERTools. The energy minimizations were carried out by means of a conjugate gradient algorithm using NAMD. Then system was heated from 0 to 300 K with temperature increment 0.001 K. Subsequently 2 ns Langevin−Verlet (NVT) MM MD simulation with AMBER force field implemented in NAMD was carried out. Periodic Boundary Conditions and cut-offs for the nonbonding interactions, range radius from 14.5 to 16 Å, are used. After 2 ns relaxation 200 ps of QM/MM MD at 300 K were simulated. The triazole was treated quantum mechanically at the AM1 level, protein was described using AMBER and water molecules were described using TIP3P, as implemented in fDynamo library. Molecules 20 Å apart from the triazole were kept frozen, with cut-offs established on range radius from 14.5 to 16 Å. In order to describe interactions between triazole and RT free energy of binding using Free Energy Perturbation method was done. The change in frequencies from ligand in solution to ligand bounded in enzyme was used to calculate binding isotope effects.

Keywords: binding isotope effects, molecular dynamics, HIV, reverse transcriptase

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Authors: M. R. Aher, R. B. Laware, G. S. Asane, B. S. Kuchekar

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Objective: Studies have shown that a new combination therapy with Artemisinin derivatives and curcumin is unique, with potential advantages over known ACTs. In present study an attempt was made to prepare microparticulate drug delivery system of Curcumin-Zn complex and evaluate it in combination with artemether for antimalarial activity. Material and method: Curcumin Zn complex was prepared and encapsulated using sodium alginate. Microparticles thus obtained are further coated with various enteric polymers at different coating thickness to control the release. Microparticles are evaluated for encapsulation efficiency, drug loading and in vitro drug release. Roentgenographic Studies was conducted in rabbits with BaSO 4 tagged formulation. Optimized formulation was screened for antimalarial activity using P. berghei-infected mice survival test and % paracetemia inhibition, alone (three oral dose of 5mg/day) and in combination with arthemether (i.p. 500, 1000 and 1500µg). Curcumin-Zn(II) was estimated in serum after oral administration to rats by using spectroflurometry. Result: Microparticles coated with Cellulose acetate phthalate showed most satisfactory and controlled release with 479 min time for 60% drug release. X-ray images taken at different time intervals confirmed the retention of formulation in GI tract. Estimation of curcumin in serum by spectroflurometry showed that drug concentration is maintained in the blood for longer time with tmax of 6 hours. The survival time (40 days post treatment) of mice infected with P. berghei was compared to survival after treatment with either Curcumin-Zn(II) microparticles artemether combination, curcumin-Zn complex and artemether. Oral administration of Curcumin-Zn(II)-artemether prolonged the survival of P.berghei-infected mice. All the mice treated with Curcumin-Zn(II) microparticles (5mg/day) artemether (1000µg) survived for more than 40 days and recovered with no detectable parasitemia. Administration of Curcumin-Zn(II) artemether combination reduced the parasitemia in mice by more than 90% compared to that in control mice for the first 3 days after treatment. Conclusion: Antimalarial activity of the curcumin Zn-artemether combination was more pronounced than mono therapy. A single dose of 1000µg of artemether in curcumin-Zn combination gives complete protection in P. berghei-infected mice. This may reduce the chances of drug resistance in malaria management.

Keywords: formulation, microparticulate drug delivery, antimalarial, pharmaceutics

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Authors: Adnan A. Kadi, Nasser S. Al-Shakliah, Haitham Al-Rabiah

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Zorifertinib is a novel, potent, oral, a small molecule used to treat non-small cell lung cancer (NSCLC). zorifertinib is an Epidermal Growth Factor Receptor (EGFR) inhibitor and has good blood–brain barrier permeability for (NSCLC) patients with EGFR mutations. zorifertinibis currently at phase II/III clinical trials. The current research reports the characterization and identification of in vitro, in vivo and reactive intermediates of zorifertinib. Prediction of susceptible sites of metabolism and reactivity pathways (cyanide and GSH) of zorifertinib were performed by the Xenosite web predictor tool. In-vitro metabolites of zorifertinib were performed by incubation with rat liver microsomes (RLMs) and isolated perfused rat liver hepatocytes. Extraction of zorifertinib and it's in vitro metabolites from the incubation mixtures were done by protein precipitation. In vivo metabolism was done by giving a single oral dose of zorifertinib(10 mg/Kg) to Sprague Dawely rats in metabolic cages by using oral gavage. Urine was gathered and filtered at specific time intervals (0, 6, 12, 18, 24, 48, 72,96and 120 hr) from zorifertinib dosing. A similar volume of ACN was added to each collected urine sample. Both layers (organic and aqueous) were injected into liquid chromatography ion trap mass spectrometry(LC-IT-MS) to detect vivozorifertinib metabolites. N-methyl piperizine ring and quinazoline group of zorifertinib undergoe metabolism forming iminium and electro deficient conjugated system respectively, which are very reactive toward nucleophilic macromolecules. Incubation of zorifertinib with RLMs in the presence of 1.0 mM KCN and 1.0 Mm glutathione were made to check reactive metabolites as it is often responsible for toxicities associated with this drug. For in vitro metabolites there were nine in vitro phase I metabolites, four in vitro phase II metabolites, eleven reactive metabolites(three cyano adducts, five GSH conjugates metabolites, and three methoxy metabolites of zorifertinib were detected by LC-IT-MS. For in vivo metabolites, there were eight in vivo phase I, tenin vivo phase II metabolitesofzorifertinib were detected by LC-IT-MS. In vitro and in vivo phase I metabolic pathways wereN- demthylation, O-demethylation, hydroxylation, reduction, defluorination, and dechlorination. In vivo phase II metabolic reaction was direct conjugation of zorifertinib with glucuronic acid and sulphate.

Keywords: in vivo metabolites, in vitro metabolites, cyano adducts, GSH conjugate

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Authors: Jineetkumar Gawad, Chandrakant Bonde

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Tuberculosis (TB) is a major worldwide concern whose control has been exacerbated by HIV, the rise of multidrug-resistance (MDR-TB) and extensively drug resistance (XDR-TB) strains of Mycobacterium tuberculosis. The interest for newer and faster acting antitubercular drugs are more remarkable than any time. To search potent compounds is need and challenge for researchers. Here, we tried to design lead for inhibition of Decaprenyl phosphoryl-β-D-ribose 2′-epimerase (DprE1) enzyme. Arabinose is an essential constituent of mycobacterial cell wall. DprE1 is a flavoenzyme that converts decaprenylphosphoryl-D-ribose into decaprenylphosphoryl-2-keto-ribose, which is intermediate in biosynthetic pathway of arabinose. Latter, DprE2 converts keto-ribose into decaprenylphosphoryl-D-arabinose. We had a selection of 23 compounds from azaindole series for computational study, and they were drawn using marvisketch. Ligands were prepared using Maestro molecular modeling interface, Schrodinger, v10.5. Common pharmacophore hypotheses were developed by applying dataset thresholds to yield active and inactive set of compounds. There were 326 hypotheses were developed. On the basis of survival score, ADRRR (Survival Score: 5.453) was selected. Selected pharmacophore hypotheses were subjected to virtual screening results into 1000 hits. Hits were prepared and docked with protein 4KW5 (oxydoreductase inhibitor) was downloaded in .pdb format from RCSB Protein Data Bank. Protein was prepared using protein preparation wizard. Protein was preprocessed, the workspace was analyzed using force field OPLS 2005. Glide grid was generated by picking single atom in molecule. Prepared ligands were docked with prepared protein 4KW5 using Glide docking. After docking, on the basis of glide score top-five compounds were selected, (5223, 5812, 0661, 0662, and 2945) and the glide docking score (-8.928, -8.534, -8.412, -8.411, -8.351) respectively. There were interactions of ligand and protein, specifically HIS 132, LYS 418, TRY 230, ASN 385. Pi-pi stacking was observed in few compounds with basic Imidazo [4,5-b] pyridine ring. We had basic azaindole ring in parent compounds, but after glide docking, we received compounds with Imidazo [4,5-b] pyridine as a basic ring. That might be the new lead in the process of drug discovery.

Keywords: DprE1 inhibitors, in silico drug designing, imidazo [4, 5-b] pyridine, lead, tuberculosis

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Authors: Kalyan S. Ghosh, B. L. Dhananjaya

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Snake bite causes fatal injuries in multi-organs and even many deaths due to several adverse physiological effects of various phospholipases (PLA2s) present in snake venom. Though these PLA2s bear highly homologues sequences and also structure but exhibit a different extent of those pharmacological effects. In this study, we have explored the difference in the neurotoxicity of two PLA2 namely PLA2-V, PLA2-VIIIa present in the venom from Vipera russellii. Bioinformatics studies on sequences of these two proteins along with detailed structural comparison enable us to explore the differences unambiguously. The identification of the residues involved in neurotoxicity will further lead towards proper designing of inhibitors against such killing effects of the venom.

Keywords: electrostatic potential, homology modeling, hydrophobicity, neurotoxicity, Phospholipase A2

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Authors: Parimelazhagan Thangaraj

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Natural products serves human kind as a source of all drugs and higher plants provide most of these therapeutic agents. These products are widely recognized in the pharmaceutical industry for their broad structural diversity as well as their wide range of pharmacological activities. Euphorbiaceae is one of the important families with significant pharmacological activities, of which many species has been used traditionally for the treatment of various ailments. Breynia retusa belongs to the family Euphorbiaceae is used to cure ailments like body pain, skin inflammation, hyperglycaemia, diarrhoea, dysentery and toothache. Flowers and young leaves of B. retusa are cooked and eaten, roots are used for meningitis. The juice of the stem is used in conjunctivtis and leaves as poultice to hasten suppuration. Based on the strong evidences of traditional uses of Breynia retusa, the present study was focused on neutraceuticals evaluation of the species with special reference to oxidative stress and diabetes. Both leaves and stem of B. retusa were extracted with different solvents and analyzed for radical scavenging ability wherein ABTS.+ (8396.95±1529.01 µM TEAC/g extract), phosphomolybdenum (17.34±0.08 g AAE/100 g extract) and FRAP (6075.66±414.28 µM Fe (II) E/mg extract) assays showed good radical scavenging activity in stem. Furthermore, leaf extracts showed good radical inhibition in DPPH (2.4 µg/mL), metal ion (27.44±0.09 mg EDTAE/g extract) scavenging methods. The α-amylase and α-glucosidase inhibitors are currently used for diabetic treatment as oral hypoglycemic agents. The inhibitory effects of the B. retusa leaf and stem ethyl acetate extracts showed good inhibition on α-amylase (96.25% and 95.69 respectively) and α-glucosidase (54.50% and 50.87% respectively) enzymes compared to standard acarbose. The proximate composition analysis of B. retusa leaves contains higher amount of total carbohydrates (14.08 g Glucose equivalents/100 g sample), ash (19.04 %) and crude fibre (0.52 %). The examination of mineral profile explored that the leaves was rich in calcium (1891 ppm), sulphur (1406 ppm), copper (2600 ppm) and magnesium (778 ppm). Leaves sample revealed very minimal amount of anti-nutrient contents like trypsin (14.08±0.03 TIU/mg protein) and tannin (0.011±0.001 mg TAE/g sample). The low anti nutritional factors may not pose any serious nutritional problems when these leaves are consumed. In conclusion, it is very clear that dietary compounds from B. retusa are suitable and promising for the development of safe food products and natural additives. Based on the studies, it may be concluded that nutritional composition, antioxidant and anti-diabetic activities this species can be used as future therapeutic medicine.

Keywords: Breynia retusa, nutraceuticals, antioxidant, anti diabetic

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Authors: Jeong Woo Kang, MiYoung Baek, Ki-Suk Kim, Kwang-Jick Lee, ByungJae So

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Introduction: A fast, easy and sensitive detection method was developed and validated by liquid chromatography tandem mass spectrometry for the determination of marbofloxacin in pig plasma which was further applied to study the pharmacokinetics of marbofloxacin. Materials and Methods: The plasma sample (500 μL) was mixed with 1.5 ml of 0.1% formic acid in MeCN to precipitate plasma proteins. After shaking for 20 min, The mixture was centrifuged at 5,000 × g for 30 min. It was dried under a nitrogen flow at 50℃. 500 μL aliquot of the sample was injected into the LC-MS/MS system. Chromatographic analysis was carried out mobile phase gradient consisting 0.1% formic acid in D.W. (A) and 0.1% formic acid in MeCN (B) with C18 reverse phase column. Mass spectrometry was performed using the positive ion mode and the selected ion monitoring (MRM). Results and Conclusions: The method validation was performed in the sample matrix. Good linearities (R2>0.999) were observed and the quantified average recoveries of marbofloxacin were 87 - 92% at level of 10 ng g-1 -100 ng g-1. The percent of coefficient of variation (CV) for the described method was less than 10 % over the range of concentrations studied. The limits of detection (LOD) and quantification (LOQ) were 2 and 5 ng g-1, respectively. This method has also been applied successfully to pharmacokinetic analysis of marbofloxacin after intravenous (IV), intramuscular (IM) and oral administration (PO). The mean peak plasma concentration (Cmax) was 2,597 ng g-1at 0.25 h, 2,587 ng g-1at 0.44 h and 2,355 ng g-1at 1.58 h for IV, IM and PO, respectively. The area under the plasma concentration-time curve (AUC0–t) was 24.8, 29.0 and 25.2 h μg/mL for IV, IM and PO, respectively. The elimination half-life (T1/2) was 8.6, 13.1 and 9.5 for IV, IM and PO, respectively. Bioavailability (F) of the marbofloxacin in pig was 117 and 101 % for IM and PO, respectively. Based on these result, marbofloxacin does not have any obstacles as therapeutics to develop the oral formulations such as tablets and capsules.

Keywords: marbofloxacin, LC-MS/MS, pharmacokinetics, chromatographic

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Authors: Dalia O. Saleha, Gehad A. Abdel Jaleela, Sally W. Al-Awdana

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Diabetes mellitus (DM) is known to exacerbate cerebral ischemic injury. The present study aimed to investigate the anti-oxidant and anti-inflammatory effects of oral supplementation of melatonin (MLN) on cerebral injury caused by middle cerebral artery occlusion and reperfusion (MCAO/Re) in streptozotocin (STZ)-induced hyperglycemic rats. Hyperglycemia was induced by a single injection of STZ (55mg/kg; i.p.), six weeks later the cerebral injury was induced by MCAO/Re. Twenty-four hours after the MCAO/Re the MLN (10 mg/kg) was injected for 14 consecutive days. Results of the present study revealed that MCAO/Re in STZ-induced hyperglycemia in rats causes an increase in the oxidative stress biomarkers; it increased brain lipid peroxidation (measured as malondialdehyde; MDA) and brain level of nitric oxide (NO). Moreover, MCAO/Reproduces a prominent increase in the brain inflammatory markers viz. interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis nuclear factor-alpha (TNF-α). Oral treatment of MCAO/Re in STZ-induced hyperglycemic rats with MLN (10 mg/kg) for two weeks restored the brain levels of MDA, GSH, NO, IL-6, IL-1β and the TNF-α. MLN succeeded to suppress the exacerbation of damage in the brain of hyperglycemic rats. These results suggest that daily intake of MLN attenuates the exacerbation of cerebral ischemic injury in a diabetic state, which may be attributed to anti-oxidant and anti-inflammatory effects in the brain.

Keywords: melatonin, brain injury, cerebral ischemia/reperfusion, hyperglycemia, rats

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Authors: Wenjun Zhang, Yunqing Du, Steven W. Cranford, Ming L. Wang

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The beginning of 21st century has witnessed new advancements in the design and use of new materials for biosensing applications, from nano to macro, protein to tissue. Traditional analytical methods lack a complete toolset to describe the complexities introduced by living systems, pathological relations, discrete hierarchical materials, cross-phase interactions, and structure-property dependencies. Materiomics – via systematic molecular dynamics (MD) simulation – can provide structure-process-property relations by using a materials science approach linking mechanisms across scales and enables oriented biosensor design. With this approach, DNA biosensors can be utilized to detect disease biomarkers present in individuals’ breath such as acetone for diabetes. Our wireless sensor array based on single-stranded DNA (ssDNA)-decorated single-walled carbon nanotubes (SWNT) has successfully detected trace amount of various chemicals in vapor differentiated by pattern recognition. Here, we present how MD simulation can revolutionize the way of design and screening of DNA aptamers for targeting biomarkers related to oral diseases and oral health monitoring. It demonstrates great potential to be utilized to build a library of DNDA sequences for reliable detection of several biomarkers of one specific disease, and as well provides a new methodology of creating, designing, and applying of biosensors.

Keywords: biosensor, DNA, biomarker, molecular dynamics simulation

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Authors: Jae-Hyeon Kim, Michael Lee

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Intrinsic and acquired resistance limits the therapeutic benefits of oncogenic BRAF inhibitors in melanoma. MicroRNAs (miRNA) regulate the expression of target mRNAs by repressing their translation. Thus, we investigated miRNA expression patterns in melanoma cell lines to identify candidate biomarkers for acquired resistance to BRAF inhibitor. Here, we used Affymetrix miRNA V3.0 microarray profiling platform to compare miRNA expression levels in three cell lines containing BRAF inhibitor-sensitive A375P BRAF V600E cells, their BRAF inhibitor-resistant counterparts (A375P/Mdr), and SK-MEL-2 BRAF-WT cells with intrinsic resistance to BRAF inhibitor. The miRNAs with at least a two-fold change in expression between BRAF inhibitor-sensitive and –resistant cell lines, were identified as differentially expressed. Averaged intensity measurements identified 138 and 217 miRNAs that were differentially expressed by 2 fold or more between: 1) A375P and A375P/Mdr; 2) A375P and SK-MEL-2, respectively. The hierarchical clustering revealed differences in miRNA expression profiles between BRAF inhibitor-sensitive and –resistant cell lines for miRNAs involved in intrinsic and acquired resistance to BRAF inhibitor. In particular, 43 miRNAs were identified whose expression was consistently altered in two BRAF inhibitor-resistant cell lines, regardless of intrinsic and acquired resistance. Twenty five miRNAs were consistently upregulated and 18 downregulated more than 2-fold. Although some discrepancies were detected when miRNA microarray data were compared with qPCR-measured expression levels, qRT-PCR for five miRNAs (miR-3617, miR-92a1, miR-1246, miR-1936-3p, and miR-17-3p) results showed excellent agreement with microarray experiments. To further investigate cellular functions of miRNAs, we examined effects on cell proliferation. Synthetic oligonucleotide miRNA mimics were transfected into three cell lines, and proliferation was quantified using a colorimetric assay. Of the 5 miRNAs tested, only miR-1246 altered cell proliferation of A375P/Mdr cells. The transfection of miR-1246 mimic strongly conferred PLX-4720 resistance to A375P/Mdr cells, implying that miR-1246 upregulation confers acquired resistance to BRAF inhibition. We also found that PLX-4720 caused much greater G2/M arrest in A375P/Mdr cells transfected with miR-1246mimic than that seen in scrambled RNA-transfected cells. Additionally, miR-1246 mimic partially caused a resistance to autophagy induction by PLX-4720. These results indicate that autophagy does play an essential death-promoting role inPLX-4720-induced cell death. Taken together, these results suggest that miRNA expression profiling in melanoma cells can provide valuable information for a network of BRAF inhibitor resistance-associated miRNAs.

Keywords: microRNA, BRAF inhibitor, drug resistance, autophagy

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Authors: Gayatri Swarnakar

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Paramphistomiasis and fascioliasis diseases have been prevalent due to presence of trematode parasites in the rumen and liver of domestic buffalo (Bubalus bubalis) in Udaipur, India. The trematode parasites such as Paramphistomum cervi, Gastrothylax crumenifer, Cotylophoron cotylophorum, Orthocoelium scoliocoelium, Fasciola hepatica and Fasciola gigantica were collected from infected rumen and liver of the freshly slaughtered buffaloes (Bubalus bubalis) at local zoo abattoir in Udaipur. Live trematodes were washed in normal saline, fixed in 0.2M cacodylate fixative, post fixed in osmium tetraoxide, dehydrated, dried, coated with gold sputter and observed under scanning electronic microscope (SEM). The surface tegument of Paramphistomum cervi was spineless with transverse folds, discontinuous with ridges and grooves. Two types of sensory papillae such as knob like and button shaped were also observed. The oral opening of Cotylophoron cotylophorum was surrounded by wrinkled and ridged tegument which formed concentric elevated rings. Tegument of Cotylophoron cotylophorum in acetabulum region was observed to be rough and bee-comb like structure. Genital sucker of this worm was surrounded by a tyre- shaped elevation of the tegument. Orthocoelium scoliocoelium showed circular and concentric rings of tegumental folds around the oral sucker. Genital pore had knob like papillae with radial tegumental folds. Surface topography of Fasciola gigantica and Fasciola hepatica were found to be rough due to occurrence of different types of spines, three types of sensory papillae, transverse folds and grooves. Oral and ventral suckers were spineless and covered with thick rims of transverse folds. Genital pore showed small scattered spines. Present research work would provide knowledge for ultrastructural characteristics of trematode parasites for chemotherapeutic measures and help us to evolve suitable strategy for the eradication of trematode parasites from the domestic buffalo (Bubalus bubalis).

Keywords: Domestic buffalo, tegument, trematode parasites, ultrastructure

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Authors: Sujata Sharma, Avinash Singh, Lovely Gautam, Pradeep Sharma, Mau Sinha, Asha Bhushan, Punit Kaur, Tej P. Singh

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Peptidyl-tRNA hydrolase (Pth) Pth is an essential bacterial enzyme that catalyzes the release of free tRNA and peptide moeities from peptidyl tRNAs during stalling of protein synthesis. In order to design inhibitors of Pth from Pseudomonas aeruginosa (PaPth), we have determined the structures of PaPth in its native state and in the bound states with two compounds, amino acylate-tRNA analogue (AAtA) and 5-azacytidine (AZAC). The peptidyl-tRNA hydrolase gene from Pseudomonas aeruginosa was amplified by Phusion High-Fidelity DNA Polymerase using forward and reverse primers, respectively. The E. coliBL21 (λDE3) strain was used for expression of the recombinant peptidyl-tRNA hydrolase from Pseudomonas aeruginosa. The protein was purified using a Ni-NTA superflow column. The crystallization experiments were carried out using hanging drop vapour diffusion method. The crystals diffracted to 1.50 Å resolution. The data were processed using HKL-2000. The polypeptide chain of PaPth consists of 194 amino acid residues from Met1 to Ala194. The centrally located β-structure is surrounded by α-helices from all sides except the side that has entrance to the substrate binding site. The structures of the complexes of PaPth with AAtA and AZAC showed the ligands bound to PaPth in the substrate binding cleft and interacted with protein atoms extensively. The residues that formed intermolecular hydrogen bonds with the atoms of AAtA included Asn12, His22, Asn70, Gly113, Asn116, Ser148, and Glu161 of the symmetry related molecule. The amino acids that were involved in hydrogen bonded interactions in case of AZAC included, His22, Gly113, Asn116, and Ser148. As indicated by fittings of two ligands and the number of interactions made by them with protein atoms, AAtA appears to be a more compatible with the structure of the substrate binding cleft. However, there is a further scope to achieve a better stacking than that of O-tyrosyl moiety because it is not still ideally stacked. These observations about the interactions between the protein and ligands have provided the information about the mode of binding of ligands, nature and number of interactions. This information may be useful for the design of tight inhibitors of Pth enzymes.

Keywords: peptidyl tRNA hydrolase, Acinetobacter baumannii, Pth enzymes, O-tyrosyl

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Authors: Atul Srivastava, D. V. Gowda

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Enterotoxigenic Escherichia coli (ETEC) infection is one of the major causes contributing to the development of diarrhoea in adults and children in developing countries. To date, no preventive/treatment strategy showed promising results, which could be due to the lack of potent vaccines, and/or due to the development of resistance of ETEC to antibiotics. Therefore, in the present investigation, a novel porous Sodium Alginate (SA) tablet formulation loaded with F4 fimbriae antigen was developed and tested for efficacy against ETEC infections in piglet models. Pre-compression parameters of the powder mixes and post compression parameters of tablets have been evaluated and results were found to be satisfactory. Loading of F4 fimbrial antigens in to the tablets was achieved by inducing pores in the tablets via the sublimation of camphor followed by incubation with purified F4 fimbriae. The loaded tablets have been coated with Eudragit L100 to protect the F4 fimbriae from (a) highly acidic gastric environment; (b) proteolytic cleavage by pepsin; and (c) to promote subsequent release in the intestine. Evaluation of developed F4 fimbrial tablets in a Pig model demonstrated induction of mucosal immunity, and a significant reduction of F4+ E. coli in faeces. Therefore, F4 fimbriae loaded porous tablets could be a novel oral vaccination candidate to induce mucosal and systemic immunity against ETEC infections.

Keywords: porous tablets, sublimation, f4 fimbriae, eudragit l100, vaccination

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Authors: Mathew O. Ayoola, Foluke Aderemi, Tunde E. Lawal, Opeyemi Oladejo, Micheal A. Abiola

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Food animals reared for meat require transportation during their life cycle. The transportation procedures could initiate stressors capable of disrupting the physiological homeostasis. Such stressors associated with transportation may include; loading and unloading, crowding, environmental temperature, fear, vehicle motion/vibration, feed / water deprivation, and length of travel. This may cause oxidative stress and damage to excess free radicals or reactive oxygen species (ROS). In recent years, the application of natural products as a substitute for synthetic electrolytes and tranquilizers as anti-stress agents during the transportation is yet under investigation. Sweet orange, a predominant fruit in humid tropics, has been reported to have a good content of vitamin C (Ascorbic acid). Vitamin C, which is an active ingredient in orange juice, plays a major role in the biosynthesis of Corticosterone, a hormone that enhances energy supply during transportation and heat stress. Ninety-six, 15weeks, Isa brown pullets were allotted to four (4) oral treatments; sterile water (T1), synthetic vit C (T2), 30ml orange/liter of water (T3), 50ml orange/1 liter (T4). Physiological parameters; body temperature (BTC), rectal temperature (RTC), respiratory rate (RR), and panting rate (PR) were measured pre and post-transportation. The birds were transported with a specialized vehicle for a distance of 50km at a speed of 60 km/hr. The average environmental THI and within the vehicle was 81.8 and 74.6, respectively, and the average wind speed was 11km/hr. Treatments and periods had a significant (p>0.05) effect on all the physiological parameters investigated. Birds on T1 are significantly (p<0.05) different as compared to T2, T3, and T4. Values recorded post-transportation are significantly (p<0.05) higher as compared to pre-transportation for all parameters. In conclusion, this study showed that transportation as a stressor can affect the physiological homeostasis of pullets. Oral supplementation of electrolytes or tranquilizers is essential as an anti-stress during transportation. The application of the organic product in form of sweet orange could serve as a suitable alternative for the synthetic vitamin C.

Keywords: physiological, pullets, sweet orange, transportation stress, and vitamin C

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Authors: Gokul Gaudel, Zhang Wen Hui, Dang Quang Hung, Le Thi Hien, Liang Xiao

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The community forests of Nepal serve as a major source of medicinal plants for majority of local people who are dependent on traditional health care system. This study aims to explore the ethnobotanical information of the medicinal plants used by five different community forest user groups of Parbat district of Nepal. The research was conducted during different periods of the year 2015, using semi-structured, open-ended questionnaires, formal and informal interviews, and group discussions. In total 145 different plant species within 77 families were documented, the majority of them being herb were found to be used to treat 84 different ailments. In terms of plant parts use: whole plants, barks, fruits, leaves were found to be in top priorities. Oral administration was the dominant route (57%), followed by both oral and dermal route (29%) and dermal only (14%). Females were found to have 24% more ethnobotanical knowledge than male. The knowledge of ethnobotanical medicinal plants was found excellent on age group 65-75. This study showed that community forests of Parbat district are rich in medicinal plants but the new generation was found less interested in using them. Easy access to modern medicines, lack of documentation and knowledge transfer to young generations are the major causes of diminishing utility of traditional medicinal practices.

Keywords: ailments, community forest, ethnobotany, medicinal plants, Parbat

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