Search results for: Liver X receptor (LXR)

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: Christopher Leung, Guillermo Becerril-Martinez

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Amyloidosis is a rare systemic disease where abnormal proteins invade various organs and impede their function. Occasionally, they can manifest in a solidary organ such as the heart, lung, and nervous systems; rarely do they manifest in the gallbladder. Diagnosis often requires biopsy of the affected area and histopathology shows deposition of abnormally folded globular proteins called amyloid proteins. This case presents a 69-year-old male with a 3-month history of RUQ pain, diarrhea and non-specific symptoms of tiredness, etc. On imaging, both his US and CT abdomen showed gallbladder wall thickening and pericholecystic fluid, which may represent acute cholecystitis with hypodense lesions around the gallbladder, possibly representing liver abscesses. Given his symptoms of abdominal pain and imaging findings, this gentleman eventually had a laparoscopic cholecystectomy showing a gangrenous gallbladder with a mass on the liver bed. On histopathology, it showed amorphous hyaline eosinophilic material, which Congo-stained confirmed amyloidosis. Amyloidosis explained his non-specific symptoms, he avoided further biopsy, and he was commenced immediately on Lenalidomide. Involvement of the gallbladder is extremely rare, with less than 30 cases around the world. Half of the cases are reported as primary amyloidosis. This case adds to the current literature regarding primary gallbladder amyloidosis. Importantly, this case highlights how laparoscopic cholecystectomy can help with the diagnosis of gallbladder amyloidosis.

Keywords: amyloidosis, cholecystitis, gangrenous cholecystitis, gallbladder, systemic amyloidosis

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Authors: K. A. Gladkova, N. P. Babushkina, E. Y. Bragina

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Purpose: Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the major public health problems worldwide. It is clear that the immune response to M. tuberculosis infection is a relationship between inflammatory and anti-inflammatory responses in which Tumour Necrosis Factor-α (TNF-α) plays key roles as a pro-inflammatory cytokine. TNF-α involved in various cell immune responses via binding to its two types of membrane-bound receptors, TNFRSF1A and TNFRSF1B. Importantly, some variants of the TNFRSF1B gene have been considered as possible markers of host susceptibility to TB. However, the possible impact of such TNF-α and its receptor genes polymorphism on TB cases in Tomsk is missing. Thus, the purpose of our study was to investigate polymorphism of TNF-α (rs1800629) and its receptor TNFRSF1B (rs652625 and rs525891) genes in population of Tomsk and to evaluate their possible association with the development of pulmonary TB. Materials and Methods: The population distribution features of genes polymorphisms were investigated and made case-control study based on group of people from Tomsk. Human blood was collected during routine patients examination at Tomsk Regional TB Dispensary. Altogether, 234 TB-positive patients (80 women, 154 men, average age is 28 years old) and 205 health-controls (153 women, 52 men, average age is 47 years old) were investigated. DNA was extracted from blood plasma by phenol-chloroform method. Genotyping was carried out by a single-nucleotide-specific real-time PCR assay. Results: First, interpopulational comparison was carried out between healthy individuals from Tomsk and available data from the 1000 Genomes project. It was found that polymorphism rs1800629 region demonstrated that Tomsk population was significantly different from Japanese (P = 0.0007), but it was similar with the following Europeans subpopulations: Italians (P = 0.052), Finns (P = 0.124) and British (P = 0.910). Polymorphism rs525891 clear demonstrated that group from Tomsk was significantly different from population of South Africa (P = 0.019). However, rs652625 demonstrated significant differences from Asian population: Chinese (P = 0.03) and Japanese (P = 0.004). Next, we have compared healthy individuals versus patients with TB. It was detected that no association between rs1800629, rs652625 polymorphisms, and positive TB cases. Importantly, AT genotype of polymorphism rs525891 was significantly associated with resistance to TB (odds ratio (OR) = 0.61; 95% confidence interval (CI): 0.41-0.9; P < 0.05). Conclusion: To the best of our knowledge, the polymorphism of TNFRSF1B (rs525891) was associated with TB, while genotype AT is protective [OR = 0.61] in Tomsk population. In contrast, no significant correlation was detected between polymorphism TNF-α (rs1800629) and TNFRSF1B (rs652625) genes and alveolar TB cases among population of Tomsk. In conclusion, our data expands the molecular particularities associated with TB. The study was supported by the grant of the Russia for Basic Research #15-04-05852.

Keywords: polymorphism, tuberculosis, TNF-α, TNFRSF1B gene

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Authors: Mudassar Iqbal, Riaz Hussain, Khalid Mehmood, Farah Ali, Fazal Mahmood, Abdul Ghaffar

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Corynebacterium pseudotuberculosis is an important cause of caseous lymphadenitis (CL), a complex, chronic devastating and destructive disease of small ruminants. In present study, postmortem examination of Chinkara deer (n=25) was conducted in year 2014. Pus samples suggestive of CL were collected from the superficial lymph nodes, liver, spleen and lungs during necropsy and subjected to standard microbiological procedures for isolation and molecular analysis of bacterial pathogens. Pus samples collected from carcasses (25) presenting clinical lesions of C. pseudotuberculosis infection was identified in 19 (76%) carcasses on the basis of culture characteristics. The frequency of C. pseudotuberculosis bacterium was higher in older animals as compared to young animals. Grossly, multiple tubercles of variable size having caseous material were observed in liver, lungs, spleen and lymph nodes. Histopathologically, tissue sections from all the visceral organs were extensively plugged with abscess. In present study specific prolineiminopeptidase (PIP) gene of the C. pseudotuberculosis was amplified by the Polymerase chain reaction technique (PCR) in 17(25) cases. The efficient and reliable molecular analysis along with necropsy findings in present study can be used as valuable approach for diagnosis of caseous lymphadenitis in small ruminants.

Keywords: Chinkara deer, Corynebacterium pseudotuberculosis, Caseous lymphadenitis, PCR

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Authors: B. Sadek, N. Khan, Shreesh K. Ojha, Adel Sadeq, D. Lazewska, K. Kiec-Kononowicz

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The involvement of Histamine H3 receptors (H3Rs) in memory and the potential role of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer disease (AD) is well established. Therefore, the memory-enhancing effects of the H3R antagonist DL77 on MK801-induced cognitive deficits were evaluated in passive avoidance paradigm (PAP) and novel object recognition (NOR) tasks in adult male rats, applying donepezil (DOZ) as a reference drug. Animals pretreated with acute systemic administration of DL77 (2.5, 5, and 10 mg/kg, i.p.) were significantly ameliorated in regard to MK801-induced memory deficits in PAP. The ameliorative effect of most effective dose of DL77 (5 mg/kg, i.p.) was abrogated when animals were pretreated with a co-injection with the H3R agonist R-(α)-methylhistamine (RAMH, 10 mg/kg, i.p.). Moreover, and in the NOR paradigm, DL77 (5 mg/kg, i.p.) reversed MK801-induced deficits long-term memory (LTM), and the DL77-provided procognitive effect was comparable to that of reference drug DOZ, and was reversed when animals were co-injected with RAMH (10 mg/kg, i.p.). However, DL77(5 mg/kg, i.p.) failed to alter short-term memory (STM) impairment in NOR test. Furthermore, DL77 (5 mg/kg) failed to induce any alterations of anxiety and locomotor behaviors of animals naive to elevated-plus maze (EPM), indicating that the ameliorative effects observed in PAP or NOR tests were not associated to alterations in emotions or in natural locomotion of tested animals. These results reveal the potential contribution of H3Rs in modulating CNS neurotransmission systems associated with neurodegenerative disorders, e.g., AD.

Keywords: histamine H3 receptor, antagonist, learning and memory, Alzheimer's disease, neurodegeneration, passive avoidance paradigm, novel object recognition, behavioral research

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Authors: Belgherbi Aicha, Hadjidj Ismahen, Bessaid Abdelhafid

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Interpretation of medical images benefits from anatomical and physiological priors to optimize computer-aided diagnosis applications. Segmentation of liver, spleen and kidneys is regarded as a major primary step in the computer-aided diagnosis of abdominal organ diseases. In this paper, a semi-automated method for medical image data is presented for the abdominal organ segmentation data using mathematical morphology. Our proposed method is based on hierarchical segmentation and watershed algorithm. In our approach, a powerful technique has been designed to suppress over-segmentation based on mosaic image and on the computation of the watershed transform. Our algorithm is currency in two parts. In the first, we seek to improve the quality of the gradient-mosaic image. In this step, we propose a method for improving the gradient-mosaic image by applying the anisotropic diffusion filter followed by the morphological filters. Thereafter, we proceed to the hierarchical segmentation of the liver, spleen and kidney. To validate the segmentation technique proposed, we have tested it on several images. Our segmentation approach is evaluated by comparing our results with the manual segmentation performed by an expert. The experimental results are described in the last part of this work.

Keywords: anisotropic diffusion filter, CT images, morphological filter, mosaic image, simultaneous organ segmentation, the watershed algorithm

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Authors: Sara A. Al-Jaberi, Salma Ben-Salem, Meriam Messedi, Fatma Ayadi, Lihadh Al-Gazali, Bassam R. Ali

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Background: The chemokine receptor components play crucial roles in the immune system and some of them serve as co-receptors for the HIV virus. Several studies have documented those variants in chemokine receptors are correlated with susceptibility and resistance to infection with HIV virus. For example, mutations in the chemokine receptor 5 gene (CCR5) resulting in loss-of-function (such as the homozygous CCR5Δ32) confer high degree of resistance to HIV infection. Heterozygotes for these variants exhibit slow progression to AIDS. The prevalence of CCR5 polymorphisms varies among ethnic and geographical groups. For example, the CCR5 Δ32 variant is present in 10–15% of north Europeans but is rarely encountered among Africans. This study aims to identify the prevalence of some CCR5 variants in two geographically distant Arab populations (namely Emiratis and Tunisians). Methodology: The prevalence of CCR5 gene variants including CCR5Δ32, FS299, C101X, A29S and C178R has been determined using PCR and direct DNA sequencing. A total of 403 unrelated healthy individuals (253 Emiratis and 150 Tunisians) were genotyped for the CCR5Δ32 variant using PCR amplification and gel electrophoresis. In addition, 200 Emiratis have been screened for other SNPs using Sanger DNA sequencing. Results: Among Emiratis, the allele frequency of the CCR5Δ32 variant has been found to be 0.002. In addition, two variants L55Q and A159 were found at a frequency of 0.002.Moreover, the prevalence of the CCR5Δ32 variant in Tunisians was estimated to be 0.013 which is relatively higher than its frequency in Emiratis but lower than Europeans. Conclusion: We conclude that the allele frequency of the most critical CCR5 polymorphism (Δ32) is extremely low among Emiratis compared to other Arabs and North Europeans. In addition, very low allele frequencies of other CCR5 polymorphisms have been detected among Emiratis.

Keywords: chemokine receptors, CCR5Δ32, CCR5 polymorphisms, Emiratis, Arab populations

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Authors: M. G. Tanga, P. B. Telefo, D. N. Tarla

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Even though the WHO, the EPA and other regulatory bodies have recognized the effects of acute pesticide poisoning little data exists on health effects after long-term low-dose exposures especially in Africa and Cameroon. The aim of this study was to evaluate the impact of pesticides on the hepatic functions of market gardeners in the Western Region of Cameroon by studying some biochemical parameters. Sixty six male market gardeners in Foumbot, Massangam, and Bantoum were interviewed on their health status, habits and pesticide use in agriculture, including the spray frequency, application method, and pesticide dosage. Thirty men with no history of pesticide exposure were recruited as control group. Thereafter, their blood samples were collected for assessment of hepatic function biomarkers (ALT, AST, and albumin). The results showed that 56 pesticides containing 25 active ingredients were currently used by market gardeners enrolled in our study and most of their symptoms (headache, fatigue, skin rashes, eye irritation, and nausea) were related to the use of these chemicals. Compared to the control subjects market gardeners’ ALT levels (32.9 ± 7.19 UL-1 vs. 82.11 ± 35.40 UL-1; P < 0.001) and, AST levels (40.63 ± 6.52 UL-1 vs. 112.11 UL-1 ± 47.15 UL-1; P < 0.001) were significantly increased. These results suggest that liver function tests can be used as biomarkers to indicate toxicity before overt clinical signs occur. The market gardeners’ chronic exposure to pesticides due to poor application measures could lead to hepatic function impairment. Further research on larger scale is needed to confirm these findings and to establish a mechanism of toxicity.

Keywords: biomarkers, liver, pesticides, occupational exposure

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Authors: Shiliang Wu, Huanxin Zhang

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Mercury has been well-known for its negative effects on wildlife, public health as well as the ecosystem. Once emitted into atmosphere, mercury can be transformed into different forms or enter the ecosystem through dry deposition or wet deposition. Some fraction of the mercury will be reemitted back into the atmosphere and be subject to the same cycle. In addition, the relatively long lifetime of elemental mercury in the atmosphere enables it to be transported long distances from source regions to receptor regions. Global change such as climate change and land use/land cover change impose significant challenges for mercury pollution control besides the efforts to regulate mercury anthropogenic emissions. In this study, we use a global chemical transport model (GEOS-Chem) to examine the potential impacts from changes in climate and land use/land cover on the global budget of mercury as well as its atmospheric transport, chemical transformation, and deposition. We carry out a suite of sensitivity model simulations to separate the impacts on atmospheric mercury associated with changes in climate and land use/land cover. Both climate change and land use/land cover change are found to have significant impacts on global mercury budget but through different pathways. Land use/land cover change primarily increase mercury dry deposition in northern mid-latitudes over continental regions and central Africa. Climate change enhances the mobilization of mercury from soil and ocean reservoir to the atmosphere. Also, dry deposition is enhanced over most continental areas while a change in future precipitation dominates the change in mercury wet deposition. We find that 2000-2050 climate change could increase the global atmospheric burden of mercury by 5% and mercury deposition by up to 40% in some regions. Changes in land use and land cover also increase mercury deposition over some continental regions, by up to 40%. The change in the lifetime of atmospheric mercury has important implications for long-range transport of mercury. Our case study shows that changes in climate and land use and cover could significantly affect the source-receptor relationships for mercury.

Keywords: mercury, toxic pollutant, atmospheric transport, deposition, climate change

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Authors: Chutamas Thepmalee, Aussara Panya, Mutita Junking, Jatuporn Sujjitjoon, Nunghathai Sawasdee, Pa-Thai Yenchitsomanus

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Cholangiocarcinoma (CCA) is an aggressive malignancy of bile duct epithelial cells in which the standard treatments, including surgery, radiotherapy, chemotherapy, and targeted therapy are partially effective. Many solid tumors including CCA escape host immune responses by creating tumor microenvironment and generating immunosuppressive cytokines such as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β). These cytokines can inhibit dendritic cell (DC) differentiation and function, leading to decreased activation and response of effector CD4+ and CD8+ T cells for cancer cell elimination. To overcome the effects of these immunosuppressive cytokines and to increase ability of DC to activate effector CD4+ and CD8+ T cells, we generated self-differentiated DCs (SD-DCs) with down-regulation of IL-10 and TGF-β receptors for activation of effector CD4+ and CD8+ T cells. Human peripheral blood monocytes were initially transduced with lentiviral particles containing the genes encoding GM-CSF and IL-4 and then secondly transduced with lentiviral particles containing short-hairpin RNAs (shRNAs) to knock-down mRNAs of IL-10 and TGF-β receptors. The generated SD-DCs showed up-regulation of MHC class II (HLA-DR) and co-stimulatory molecules (CD40 and CD86), comparable to those of DCs generated by convention method. Suppression of IL-10 and TGF-β receptors on SD-DCs by specific shRNAs significantly increased levels of IFN-γ and also increased cytolytic activity of DC-activated effector T cells against CCA cell lines (KKU-213 and KKU-100), but it had little effect to immortalized cholangiocytes (MMNK-1). Thus, SD-DCs with down-regulation of IL-10 and TGF-β receptors increased activation of effector T cells, which is a recommended method to improve DC function for the preparation of DC-activated effector T cells for adoptive T-cell therapy.

Keywords: cholangiocarcinoma, IL-10 receptor, self-differentiated dendritic cells, TGF-β receptor

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Authors: P. Afsharian, S. Mousazadeh, M. Shahhoseini, R. Aflatoonian

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Introduction: Matrix MetalloProteinases (MMPs) degrade extracellular matrix components to provide normal remodeling and contribute to pathological tissue destruction and cell migration in endometriosis. It is accepted that MMPs are resistant to suppression by progesterone in endometriotic tissues. The physiological effects of progesterone are mediated by its two progesterone receptor (PGR) isoforms, namely PGR-A and PGR-B. The capacity of progesterone affect to gene expression is dependent on the PGR-A/PGR-B ratio. The imbalance ratio in endometriotic tissue may be an important mechanism to be resulted in Progesterone resistance and modify progesterone action via differential regulation of specific progesterone response genes and improve endometriosis disease. Material and methods: RNA was extracted from twenty ectopic (endometriotic) and eutopic (endometrial) tissue samples of women undergoing laparoscopy for endometriosis and 20 healthy fertile women at Royan Institute, Tehran, Iran. Analysis of PGR-A, PGR-B, MMP-2 and MMP-9 mRNA expression was performed using Real-time PCR in ectopic and eutopic tissues. Then, Statistical analysis was calculated according to the 2-ΔΔCT equation for all samples. Results: Quantitative RT–PCR analyses of PGR-A and PGR-B mRNA revealed that there were differences in both isoformes of PGRs mRNA expressions between ectopic and control eutopic tissues. We were able to demonstrate low expression levels of PGR-B isoforms in ectopic tissues. Although, PGR-A expression was significantly higher in the same ectopic samples compare to controls.This method permitted us to demonstrate significant overexpression of MMP-2 and MMP-9 in ectopic samples compared to control endometrial tissues, as well. Conclusions: Our data suggest that low expression levels of PGR-B and overexpression of PGR-A can alter PGR-A/PGR-B ratio in endometriotic ectopic tissues. Imbalance ratio of PGRs in endometriotic tissue may be able to consequence MMP-2 and MMP-9 overexpression which can be important in pathogenesis and treatment of disease.

Keywords: endometriosis, matrix metalloproteinases, progesterone receptor -A and -B, PGR-A/PGR-B ratio

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Authors: Umme Shahera, Saifullah Munshi, Munira Jahan, Afzalun Nessa, Shahinul Alam, Shahina Tabassum

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The development of HCC is a multi-stage process. Several extrinsic factors, such as aflatoxin, HBV, nutrition, alcohol, and trace elements are thought to initiate or/and promote the hepatocarcinogenesis. Alteration of p53 status is an important intrinsic factor in this process as p53 is essential for preventing inappropriate cell proliferation and maintaining genome integrity following genotoxic stress. This study was designed to assess the correlation of p53 gene expression with HBV-DNA and serum Alanine transaminase (ALT) in patients with cirrhosis and HCC. The study was conducted among 60 patients. The study population were divided into four groups (15 in each groups)-HBV positive cirrhosis, HBV negative cirrhosis, HBV positive HCC and HBV negative HCC. Expression of p53 gene was observed using real time PCR. P53 gene expressions in the above mentioned groups were correlated with serum ALT level and HBV viral load. p53 gene was significantly higher in HBV-positive patients with HCC than HBV-positive cirrhosis. Similarly, the expression of p53 was significantly higher in HBV-positive HCC than HBV-negative HCC patients. However, the expression of p53 was reduced in HBV-positive cirrhosis in comparison with HBV-negative cirrhosis. P53 gene expression in liver was not correlated with the serum levels of ALT in any of the study groups. HBV- DNA load also did not correlated with p53 gene expression in HBV positive HCC and HBV positive cirrhosis patients. This study shows that there was no significant change with the expression of p53 gene in any of the study groups with ALT level or viral load, though differential expression of p53 gene were observed in cirrhosis and HCC patients.

Keywords: P53, ALT, HBV-DNA, liver cirrhosis, hepatocellular carcinoma

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Authors: Seyyed Javad Ziaolhagh

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Background: The purpose of present study was to investigate, the effects of anabolic steroid Boldenone (BOL) with eight weeks of resistance training on structural changes in rat liver. Method: 21 Male adult Wistar rats, 12 weeks old and 228/53±7/94 g initial body weight were randomly assigned to three groups: group1: Control+ Placebo (C), group2: training+ Placebo (T), group3: Boldenone intramuscular injections 5mg/kg (B). The endurance training protocol consisted three exercise sessions weekly started by a 30-minute run with the speed of 12 m/min and lasted by 60min run with the speed of 30 m/min in 8 weeks. At the end of the experiment, for light microscopic study Slides were prepared. Results: Sections stained of rat's livers showed no any cell degeneration and cytoplasmic lipid vacuoles in all groups, but few samples were seen. Indeed, congested blood sinusoids, cell infiltration and degeneration were seen in the Boldenone-treated group. Hepatotoxic effects were severe in group treatment received 5 mg/kg and directly depended on the doses. Indeed, training group was no any hepatocyte degeneration, inflammation and congestion. Conclusion: The present results showed that BOL has a marked adverse effect on the liver tissue, even with low– dose and endurance training. As a result, athletes should aware of Boldenone dosage consumption.

Keywords: anabolic androgenic steroids, Boldenone, blood congestion, cellular inflammation, cellular degeneration, lipid vocuolations, endurance training

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Authors: Scott A. Ochsner, Christopher M. Watkins, Apollo McOwiti, David L. Steffen Lauren B. Becnel, Neil J. McKenna

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Understanding signaling by nuclear receptors (NRs) requires an appreciation of their cognate ligand- and tissue-specific transcriptomes. While target gene regulation data are abundant in this field, they reside in hundreds of discrete publications in formats refractory to routine query and analysis and, accordingly, their full value to the NR signaling community has not been realized. One of the mandates of the Nuclear Receptor Signaling Atlas (NURSA) is to facilitate access of the community to existing public datasets. Pursuant to this mandate we are developing a freely-accessible community web resource, Transcriptomine, to bring together the sum total of available expression array and RNA-Seq data points generated by the field in a single location. Transcriptomine currently contains over 25,000,000 gene fold change datapoints from over 1200 contrasts relevant to over 100 NRs, ligands and coregulators in over 200 tissues and cell lines. Transcriptomine is designed to accommodate a spectrum of end users ranging from the bench researcher to those with advanced bioinformatic training. Visualization tools allow users to build custom charts to compare and contrast patterns of gene regulation across different tissues and in response to different ligands. Our resource affords an entirely new paradigm for leveraging gene expression data in the NR signaling field, empowering users to query gene fold changes across diverse regulatory molecules, tissues and cell lines, target genes, biological functions and disease associations, and that would otherwise be prohibitive in terms of time and effort. Transcriptomine will be regularly updated with gene lists from future genome-wide expression array and expression-sequencing datasets in the NR signaling field.

Keywords: target gene database, informatics, gene expression, transcriptomics

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Authors: Luana N. Cardozo, Debora A. S. Coutinho, Fabiola Lagher, Bruno J. G. Silva, Ivonilce Venture, Mainara Tesser, Graciela Venera

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Ostrich oil is used as food in Brazil, and it has been the subject of scientific research because it contains essential fatty acids (Omega 3, 6, 7, and 9), which provide benefits to human health. Alkylglycerols are lipid ethers consisted of a saturated or unsaturated hydrocarbon chain joined by ether-type bonding to one of the glycerol hydroxyls. It is known that supplementation with alkylglycerols can act significantly on the functioning of immune system cells, both in pathological situations and in homeostasis. Objective: Analyze the presence of alkylglycerols in ostrich oil. Methods: The ostrich oil was bought from an industry that manufactures the product for sale as food, located in Mirante da Serra, northern Brazil. The samples were sent for analysis to the chemistry department of the Federal University of Paraná, where they were analyzed by the gas chromatography method. Results: The analysis of the ostrich oil presented alkylglycerols in area 514505154. Comparison, it is possible to observe that shark liver oil contains the area 26190196, and the difference between both is highly significant. Conclusion: The importance of alkylglycerol supplementation for the immune system is known. The analysis of the results made it possible to verify the presence of alkylglycerols in the ostrich oil, which is five times higher than in the shark liver oil, that would be the largest source food, but was surpassed by the ostrich oil until the present time. The present study emphasizes that ostrich oil can be considered a food source of alkylglycerols and may play a promising role in the immune system because it contains such substance, but further studies are needed to prove its performance in the body.

Keywords: ostrich oil, nutritional composition, alkylglycerols, food

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Authors: H. M. El-Rafie, A. H. Abou Zeid, R. S. Mohammed, A. A. Sleem

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Acrocarpus is a genus of flowering plants in the legume family Fabaceae which considered as a large and economically important family. This study aimed to investigate the phytoconstituents of the petroleum ether extract (PEE) of Acrocarpus fraxinofolius bark by Gas chromatography coupled with mass spectrometry (GC/MS) analysis of its fractions (fatty acid and unsaponifiable matter). Concerning this, identification of 52 compounds constituting 97.03 % of the total composition of the unsaponifiable matter fraction. Cycloeucalenol was found to be the major compound representing 32.52% followed by 4a, 14a-dimethyl-A8~24(28)-ergostadien (26.50%) and ß-sitosterol(13.74%), furthermore Gas liquid chromatography (GLC) analysis of the sterol fraction revealed the identification of cholesterol (7.22 %), campesterol (13.30 %), stigmasterol (10.00 %) and β - sitosterol (69.48 %). Meanwhile, the identification of 33 fatty acids representing 90.71% of the total fatty acid constituents. Methyl-9,12-octadecadienoate (40.39%) followed by methyl hexadecanoate (23.64%) were found to be the major compounds. On the other hand, column chromatography and Thin layer chromatography (TLC) fractionation of PEE separate the triterpenoid: 21β-hydroxylup-20(29)-en-3-one and β- amyrin which were structurally identified by spectroscopic analysis (NMR, MS and IR). PEE has been biologically evaluated for 1: management of diabetes in alloxan induced diabetic rats 2: cytotoxic activity against four human tumor cell lines (Cervix carcinoma cell line[HELA], Breast carcinoma cell line [MCF7], Liver carcinoma cell line[HEPG2] and Colon carcinoma cell line[HCT-116] 3: hepatoprotective activity against CCl4-induced hepatotoxicity in rats and the activity was studied by assaying the serum marker enzymes like AST, ALT, and ALP. Concerning this, the anti-diabetic activity exhibited by 100mg of PEE extract was 74.38% relative to metformin (100% potency). It also showed a significant anti-proliferative activity against MCF-7 (IC50= 2.35µg), Hela(IC50=3.85µg) and HEPG-2 (IC50= 9.54µg) compared with Doxorubicin as reference drug. The hepatoprotective activity was evidenced by significant decrease in liver function enzymes, i.e. AST, ALT and ALP by (29.18%, 28.26%, and 34.11%, respectively using silymarin as the reference drug, compared to their concentration levels in an untreated group with liver damage induced by CCl₄. This study was performed for the first time on the bark of this species.

Keywords: Acrocarpus fraxinofolius, antidiabetic, cytotoxic, hepatoprotective

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Authors: Abdulmalik Altuwayjiri, Milad Pirhadi, Sina Taghvaee, Constantinos Sioutas

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A significant portion of PM₂.₅ mass concentration is carbonaceous matter (CM), which majorly exists in the form of organic carbon (OC). Ambient OC originates from a multitude of sources and plays an important role in global climate effects, visibility degradation, and human health. In this study, positive matrix factorization (PMF) was utilized to identify and quantify the long-term contribution of PM₂.₅ sources to total OC mass concentration in central Los Angeles (CELA) and Riverside (i.e., receptor site), using the chemical speciation network (CSN) database between 2005 and 2015, a period during which several state and local regulations on tailpipe emissions were implemented in the area. Our PMF resolved five different factors, including tailpipe emissions, non-tailpipe emissions, biomass burning, secondary organic aerosol (SOA), and local industrial activities for both sampling sites. The contribution of vehicular exhaust emissions to the OC mass concentrations significantly decreased from 3.5 µg/m³ in 2005 to 1.5 µg/m³ in 2015 (by about 58%) at CELA, and from 3.3 µg/m³ in 2005 to 1.2 µg/m³ in 2015 (by nearly 62%) at Riverside. Additionally, SOA contribution to the total OC mass, showing higher levels at the receptor site, increased from 23% in 2005 to 33% and 29% in 2010 and 2015, respectively, in Riverside, whereas the corresponding contribution at the CELA site was 16%, 21% and 19% during the same period. The biomass burning maintained an almost constant relative contribution over the whole period. Moreover, while the adopted regulations and policies were very effective at reducing the contribution of tailpipe emissions, they have led to an overall increase in the fractional contributions of non-tailpipe emissions to total OC in CELA (about 14%, 28%, and 28% in 2005, 2010 and 2015, respectively) and Riverside (22%, 27% and 26% in 2005, 2010 and 2015), underscoring the necessity to develop equally effective mitigation policies targeting non-tailpipe PM emissions.

Keywords: PM₂.₅, organic carbon, Los Angeles megacity, PMF, source apportionment, non-tailpipe emissions

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Authors: Jelena Nedeljković Trailović, Marko Vasiljević, Jog Raj, Hunor Farkaš, Branko Petrujkić, Stamen Radulović, Gorana Popvić

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The experiment was performed on a total of 99 one-day-old broilers of Cob 500 provenance, which were divided into IX equal groups. Broilers of the E-I group were fed 0.25 mg T-2 toxin/kg feed, E-II and E-III groups 0.25 mg T-2 toxin/kg feed with the addition of 1 kg/t and 3 kg/t of the mycotoxin detoxification agent MDA, respectively. The E-IV group received 1 mg of T-2 toxin/kg of feed, and the broilers of E-V and E-VI groups received 1 mg of T-2 toxin/kg of feed with the addition of 1 kg/t and 3 kg/t of the MDA detoxification preparation, respectively. The E-VII group received commercial feed without toxins and additives, the E-VIII and E-IX groups received feed with 1kg/t and 3kg/t of the MDA detoxification preparation. The trial lasted 42 days. Observing the results obtained on the 42nd day of the experiment, we can conclude that the change in the absolute mass of the spleen occurred in the broilers of the E-IV group (1.66±0.14)g, which was statistically significantly lower compared to the broilers of the E-V and E-VI groups (2.58±0.15 and 2.68±0.23)g. Heart mass was significantly statistically lower in broilers of group E-IV (9.1±0.38)g compared to broilers of group E-V and E-VI (12.23±0.5 and 11.43±0.51)g. It can be concluded that the broilers that received 1 kg/t and 3 kg/t of the detoxification preparation had an absolute mass of organs within physiological limits. Broilers of the E-IV group achieved the lowest BM during the experiment (on the 42nd day of the experiment 1879±52.73)g, they were significantly statistically lower than the BW of broilers of all experimental groups. This trend is observed from the beginning to the end of the experiment. The protective effect of the detoxification preparation can be seen in broilers of the E-V group, that had a significantly statistically higher BM on the 42nd day of the experiment (2225±58.81)g compared to broilers of group E-IV. Broilers of E-VIII group (2452±46.71) g, which received commercial feed with the addition of 1 kg/t MDA preparation, had the highest BMI at the end of the experiment. At the end of the trial on the 42nd day, blood samples were collected from broilers of the experimental groups that received T-2 toxin and MR detoxification preparations in different concentrations. Also, liver and breast musculature samples were collected for testing for the presence and content of T-2 toxin, HT-2 toxin, T-2 tetraol and T-2 triol. Due to very rapid elimination from the blood, no remains of T-2 toxin and its metabolites were detected in the blood of broilers of groups E-I to E-VI. In the breast muscles, T-2 toxin residues below LoQ < 0.2 (μg/kg) were detected in all groups that received T-2 toxin in food, the highest value was recorded in the E-IV group (0.122 μg/kg and the lowest in E -VI group 0.096 μg/kg). No T-2 toxin residues were detected in the liver. Remains of HT-2 were detected in the breast muscles and livers of broilers from E-IV, E-V and E-VI groups, LoQ < 1 (μg/kg); for the breast muscles: 0.054, 0.044 and 0.041 μg/kg, and for the liver: 0.473, 0.231 and 0.185 μg/kg. Summing up all the results, a partial protective effect of the detoxification preparation, added to food in the amount of 1kg/t, can be seen.

Keywords: T-2 toxin, bloiler, MDA, mycotoxuns

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Authors: Nahida Sultana

Abstract:

Globally, an estimated 58 million people have chronic hepatitis C virus infection, with about 1.5 million new infections occurring per year. The hepatitis C virus is a blood-borne virus, and most infections occur through exposure to blood from unsafe injection practices, unsafe health care, unscreened blood transfusion, injection drug use, and sexual practices that lead to exposure to blood. Hepatitis C virus (HCV) causes chronic infections that mainly affect the liver leading to liver diseases. This study aimed to determine whether there is any significant association between HCV transmission risk factors in relation to genotypes in HCV-infected Bangladeshi patients. After quantification of HCV viral load, 36 samples were randomly selected for HCV genotyping and risk factor measurement. A greater proportion of genotype 1 (p > 0.05) patients (40%) underwent blood transfusion compared to patients (22.6%) with genotype 3 infections. More genotype 1 patient underwent surgery and invasive procedures (20%), and rather than those with genotype 3 patients (16.1%). The history of IDUs (25.8%) and sexual exposure (3.2%) are only prevalent in genotype 3 patients and absent in patients with genotype 1 (p >0.05). There was no significant statistical difference found in HCV transmission risk factors (blood transfusion, IDUs, Surgery& interventions, sexual transmission) between patients infected with genotypes 1 and 3. In HCV infection, genotype may have no relation to transmission risk factors among Bangladeshi patients.

Keywords: HCV genotype, alanine aminotransferase (ALT), HCV viral load, IDUs

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Authors: Amira ben Hassine, A. Valverde, V. Serafín, C. Muñoz-San Martín, M. Garranzo-Asensio, M. Gamella, R. Barderas, M. Pedrero, N. Raouafi, S. Campuzano, P. Yáñez-Sedeño, J. M. Pingarrón

Abstract:

This work describes the development of a dual electrochemical immunosensing platform for accurate determination of two target proteins, IL-13 Receptor α2 (IL-13Rα2) and E-cadherin (E-cad). The proposed methodology is based on the use of sandwich immunosensing approaches (involving horseradish peroxidase-labeled detector antibodies) implemented onto magnetic microbeads (MBs) and amperometric transduction at screen-printed dual carbon electrodes (SPdCEs). The magnetic bioconjugates were captured onto SPdCEs and the amperometric transduction was performed using the H2O2/hydroquinone (HQ) system. Under optimal experimental conditions, the developed bio platform demonstrates linear concentration ranges of 1.0–25 and 5.0-100 ng mL-1, detection limits of 0.28 and 1.04 ng mL-1 for E-cad and IL-13Rα2, respectively, and excellent selectivity against other non-target proteins. The developed immuno-platform also offers a good reproducibility among amperometric responses provided by nine different sensors constructed in the same manner (Relative Standard Deviation values of 3.1% for E-cad and 4.3% for IL-13Rα2). Moreover, obtained results confirm the practical applicability of this bio-platform for the accurate determination of the endogenous levels of both extracellular receptors in colon cancer cells (both intact and lysed) with different metastatic potential and serum and tissues from patients diagnosed with colorectal cancer at different grades. Interesting features in terms of, simplicity, speed, portability and sample amount required to provide quantitative results, make this immuno-platform more compatible than conventional methodologies with the clinical diagnosis and prognosis at the point of care.

Keywords: electrochemistry, mmunosensors, biosensors, E-cadherin, IL-13 receptor α2, cancer colorectal

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Authors: Hanan A. Soliman, Mohamed A. El-Desouky, Walaa G. Hozayen, Rasha R. Ahmed, Amal K . Khaliefa

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Aim: The objective of this study is to investigate the hypoglycemic, hypolipidemic, and hepatoprotective effects of the aqueous extract of parsley, basil, and chicory whole plant in normal and dexamethasone (Dex) rats. Materials and Methods: 50 female albino rats were used in this study and divided into 5 groups (for each 10). Group (1) fed basal diet and maintained as negative control group. Group (2) received Dex in a dose of (0.1 mg/kg b. wt.). Groups 3, 4, and 5 were treated with Dex along with three different plant extracts of parsley, basil, and chicory (2 g/kg b. wt.), (400 mg/kg b. wt.), and (100 mg/kg b. wt.), respectively. Results: All these groups were treated given three times per week for 8 consecutive weeks. Dex-induced alterations in the levels of serum glucose, triglyceride, cholesterol, low-density lipoprotein-cholesterol levels and cardiovascular indices and serum alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase activities, liver thiobarbituric acid (TBARS) levels increased, while high-density lipoprotein-cholesterol, total protein, albumin, and liver glutathione (GSH) levels decreased. On the other hand, plant extracts succeeded to modulate these observed abnormalities resulting from Dex as indicated by the reduction of glucose, cholesterol, TBARS, and the pronounced improvement of the investigated biochemical and antioxidant parameters. Conclusions: It was concluded that probably, due to its antioxidant property, parsley, basil, and chicory extracts have hepatoprotective effects in Dex-induced in rats.

Keywords: antioxidants, dexamethasone, hyperglycemia, hyperlipidemia

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Authors: V. K. Rajaletchumy, S. L. Chia, M. I. Setyawati, M. S. Muthu, S. S. Feng, D. T. Leong

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Triple negative breast cancers (TNBC) can be classified as one of the most aggressive with a high rate of local recurrences and systematic metastases. TNBCs are insensitive to existing hormonal therapy or targeted therapies such as the use of monoclonal antibodies, due to the lack of oestrogen receptor (ER) and progesterone receptor (PR) and the absence of overexpression of human epidermal growth factor receptor 2 (HER2) compared with other types of breast cancers. The absence of targeted therapies for selective delivery of therapeutic agents into tumours, led to the search for druggable targets in TNBC. In this study, we developed a targeted micellar system of cetuximab-conjugated micelles of D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS) for targeted delivery of docetaxel as a model anticancer drug for the treatment of TNBCs. We examined the efficacy of our micellar system in xenograft models of triple negative breast cancers and explored the effect of the micelles on post-treatment tumours in order to elucidate the mechanism underlying the nanomedicine treatment in oncology. The targeting micelles were found preferentially accumulated in tumours immediately after the administration of the micelles compare to normal tissue. The fluorescence signal gradually increased up to 12 h at the tumour site and sustained for up to 24 h, reflecting the increases in targeted micelles (TPFC) micelles in MDA-MB-231/Luc cells. In comparison, for the non-targeting micelles (TPF), the fluorescence signal was evenly distributed all over the body of the mice. Only a slight increase in fluorescence at the chest area was observed after 24 h post-injection, reflecting the moderate uptake of micelles by the tumour. The successful delivery of docetaxel into tumour by the targeted micelles (TPDC) exhibited a greater degree of tumour growth inhibition than Taxotere® after 15 days of treatment. The ex vivo study has demonstrated that tumours treated with targeting micelles exhibit enhanced cell cycle arrest and attenuated proliferation compared with the control and with those treated non-targeting micelles. Furthermore, the ex vivo investigation revealed that both the targeting and non-targeting micellar formulations shows significant inhibition of cell migration with migration indices reduced by 0.098- and 0.28-fold, respectively, relative to the control. Overall, both the in vivo and ex vivo data increased the confidence that our micellar formulations effectively targeted and inhibited EGF-overexpressing MDA-MB-231 tumours.

Keywords: biodegradable polymers, cancer nanotechnology, drug targeting, molecular biomaterials, nanomedicine

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Authors: Enjie Xu, Zhen Huang, Kunpeng Zhu, Jianping Hu, Xiaolong Ma, Yongjie Wang, Jiazhuang Zhu, Chunlin Zhang

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Abstract: Hypoxia and dedifferentiation of osteosarcoma (OS) cells leads to poor prognosis. We plan to identify the role of hypoxia on dedifferentiation and the associated signaling pathways. We performed a sphere formation assay and determined spheroid cells as dedifferentiated cells by detecting stem cell-like markers. RNAi assay was used to explore the expression relationship between hypoxia inducible factor 1 subunit alpha (HIF1A) and platelet derived growth factor receptor beta (PDGFRB). We obtained PDGFRB knockdown and overexpression cells through lentiviral infection experiments and the effects of PDGFRB on cytoskeleton rearrangement and cell adhesion were explored by immunocytochemistry. Wound-healing experiments, transwell assays, and animal trials were employed to investigate the effect of PDGFRB on OS metastasis. Dedifferentiated OS cells were found to exhibit high expression of HIF1A and PDGFRB, and HIF1A promoted the expression of PDGFRB, subsequently activated ras homolog family member A (RhoA), and increased the phosphorylation of myosin light chain (MLC). PDGFRB also enhanced the phosphorylation of focal adhesion kinase (FAK). The OS cell morphology and vinculin distribution were altered by PDGFRB. PDGFRB also promoted cell dedifferentiation and had a significant impact on the metastasis of OS cells both in vitro and in vivo. Our results demonstrated that HIF1A up-regulated PDGFRB under hypoxic conditions, and PDGFRB regulated the actin cytoskeleton by activating RhoA and subsequently phosphorylating MLC, thereby promoting OS dedifferentiation and pulmonary metastasis.

Keywords: osteosarcoma, dedifferentiation, metastasis, cytoskeleton rearrangement, PDGFRB, hypoxia

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Authors: Zaide Montes Ortiz, Jorge Alberto Molina, Alejandro Reyes

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Insects are extremely successful organisms. A sophisticated olfactory system is in part responsible for their survival and reproduction. The detection of volatile organic compounds can positively or negatively affect many behaviors in insects. Compounds such as carbon dioxide (CO2), ammonium, indol, and lactic acid are essential for many species of mosquitoes like Anopheles gambiae in order to locate vertebrate hosts. For instance, in A. gambiae, the olfactory receptor AgOR2 is strongly activated by indol, which accounts for almost 30% of human sweat. On the other hand, in some insects of agricultural importance, the detection and identification of pheromone receptors (PRs) in lepidopteran species has become a promising field for integrated pest management. For example, with the disruption of the pheromone receptor, BmOR1, mediated by transcription activator-like effector nucleases (TALENs), the sensitivity to bombykol was completely removed affecting the pheromone-source searching behavior in male moths. Then, the detection and identification of olfactory receptors in the genomes of insects is fundamental to improve our understanding of the ecological interactions, and to provide alternatives in the integrated pests and vectors management. Hence, the objective of this study is to propose a bioinformatic workflow to enhance the detection and identification of potential olfactory receptors in genomes of relevant insects. Applying Hidden Markov models (Hmms) and different computational tools, potential candidates for pheromone receptors in Tuta absoluta were obtained, as well as potential carbon dioxide receptors in Rhodnius prolixus, the main vector of Chagas disease. This study showed the validity of a bioinformatic workflow with a potential to improve the identification of certain olfactory receptors in different orders of insects.

Keywords: bioinformatic workflow, insects, olfactory receptors, protein prediction

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Authors: Osama M. Ahmed, Walaa G. Hozayen, Haidy Tamer Abo Sree

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Doxorubicin (DOX), an anthracycline antibiotic is a broad-spectrum antineoplastic agent, which is commonly used in the treatment of uterine, ovarian, breast and lung cancers, Hodgkin's disease and soft tissue sarcomas as well as in several other cancer types. The effect of doxorubicin (4 mg/kg b.w.week) without or with oral administration of ethanolic purslane (Portulaca oleracea) shoot (leaves and stems) extract (50 mg/kg b.w. day) or ethanolic purslane seeds extract (50 mg/kg b.w.day) co-treatments for 6 weeks was evaluated in adult male rats. Serum ALT, AST, ALP, GGT, total bilirubin, total protein, and albumin levels were assayed. Lipid peroxidation (indexed by MDA) and antioxidants like hepatic glutathine, glutathione transferase, peroxidase, SOD, and CAT were assessed. There was an increase in serum levels of ALT, AST, ALP, GGT and total bilirubin. In addition, hepatic glutathine, glutathione transferase, peroxidase, SOD, and CAT activities were decreased while lipid peroxidation in the liver was increased. Co-administration of ethanolic purslane and seed extracts successfully improved the adverse changes in the liver functions with an increase in antioxidants activities and reduction of lipid peroxidation. In conclusion, it can be supposed that dietary purslane extract supplementation may provide a cushion for a prolonged therapeutic option against DOX hepatopathy without harmful side effects. However, further clinical studies are required to assess the safety and efficacy of these extract in human beings.

Keywords: doxorubicin, purslane, hepatotoxicity, antioxidants

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Authors: Hasan Frookh Jamal

Abstract:

This is a case of a 36-year-old Bahraini gentleman diagnosed to have Cushing's Syndrome with a large anterior mediastinal mass. He was sent abroad to the Speciality hospital in Jordan, where he underwent diagnostic video-assisted thoracoscopy, partial thymectomy and pericardial fat excision. Histopathology of the mass was reported to be an Atypical carcinoid tumor with a low Ki67 proliferation index of 5%, the mitotic activity of 4 MF/10HPF and pathological stage classification(pTNM): pT1aN1. MRI of the pituitary gland showed an ill-defined non-enhancing focus of about 3mm on the Rt side of the pituitary on coronal images, with a similar but smaller one on the left side, which could be due to enhancing pattern rather than a real lesion as reported. The patient underwent Ga68 Dotate PET/CT scan post-operatively, which showed multiple somatostatin receptor-positive lesions seen within the tail, body and head of the pancreas and positive somatostatin receptor lymph nodes located between the pancreatic head and IVC. There was no uptake detected at the anterior mediastinum nor at the site of thymic mass resection. There was no evidence of any positive somatostatin uptake at the soft tissue or lymph nodes. The patient underwent IPSS, which proved that the source is, in fact, an ectopic source of ACTH secretion. Unfortunately, the patient's serum cortisol remained elevated after surgery and failed to be suppressed by 1 mg ODST and by 2 days LLDST with a high ACTH value. The patient was started on Osilodrostat for treatment of hypercortisolism for the time being and his future treatment plan with Lutetium-177 Dotate therapy vs. bilateral adrenalectomy is to be considered in an MDT meeting.

Keywords: cushing syndrome, neuroendocrine tumur, carcinoid tumor, Thymoma

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Authors: Y. Z. Gad

Abstract:

Disorders of Sex Development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. The DSD are relatively prevalent in Egypt. In spite of that, the relative rarity of the individual disease types or their molecular pathologies frequently resulted in reporting on single or few cases. This augmented the challenging nature of phenotype-genotype correlation in this disease group and its utilization in the management of such medical emergency. Through critical assessment of the published DSD reports, the current review aims at analyzing the clinical characteristics of the various DSD forms in relation to the underlying molecular pathologies. A systematic literature search was done in Pubmed, using relevant keywords (Egypt versus DSD, genital ambiguity or ambiguous genitalia, the old terms of 'intersex, hermaphroditism and pseudohermaphroditism', and a list of the DSD entities and their related genes). The search yielded 24 reports of molecular data in Egyptian patients presenting with ambiguous genitalia. However, only 21 publications fulfilled the criteria of inclusion of detailed clinical descriptions and definitive molecular diagnoses of individual patients. Curation of the data yielded a total of 53 cases that were ascertained from 40 families. Fifty-one patients present with ambiguous genitalia only while 2 had multiple congenital anomalies. Parental consanguinity was noted in 60% of cases. Sex of rearing at initial presentation was female in 75% and 60% in 46,XY and 46,XX DSD cases, respectively. The external genital phenotype in 2/3 of the 46,XY DSD cases showed moderate undermasculinization [Quigley scores 3 & 4] and 1/3 had severe presentations [scores 5 & 6]. For 46,XX subjects, 1 had severe virilization of the external genitalia while 8 had moderate phenotype. Hormonal data were inconclusive or contradictory to final diagnosis in a forth of cases. Collectively, 31 families [31/40, 77.5%] with 46,XY DSD had molecular defects in the genes, 5 alpha reductase 2 (SRD5A2) [12/31], 17 beta-hydroxysteroid dehydrogenase 3 [8/31], androgen receptor [7/31], Steroidogenic factor 1 [2/31], luteinizing hormone receptor [1/31], and fibroblast growth factor receptor 1 [1/31]. In a multiethnic study, 9 families afflicted with 46,XX DSD due to 11 beta hydroxylase (CYP11B1) deficiency were documented. Two recurrent mutations, G34R and N160D, in SRD5A2 were present, respectively, in 42 and 17% of cases. Similarly, 4 recurrent mutations resulted in 89% of the CYP11B1 presentations. In conclusion, this analysis highlights the importance of autosomal recessive inheritance and inbreeding among DSD presentations, the importance of founder effect in at least 2 disorders, the difficulties in relating the genotype with the indeterminate genital phenotype, the under-reporting of some DSD subtypes, and the notion that the reported mutational profiles among Egyptian DSD cases are relatively different from those reported in other ethnic groups.

Keywords: disorders of sex development, genital ambiguity, mutation, molecular diagnosis, Egypt

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Authors: Eqbal M. A. Dauqan, A. Aminah

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The aim of the present study was to evaluate the blood lipid profile and liver lipid peroxidation in normal rat fed with different concentrations of Acacia senegal and Acacia seyal. Thirty six Sprague Dawley male rats each weighing between 180-200g were randomly divided into two groups. Each group contains eighteen rats and were divided into three groups of 6 rats per group. The rats were fed ad libitum with commercial rat’s feed and tap water containing different concentrations of Acacia senegal and Acacia seyal (3% and 6%) for 4 weeks. The results at 4 weeks showed that there was no significant difference (p≤0.05) in the total cholesterol (TC) and triglycerides (TG) between the control group and treated groups while the results for the high density lipoprotein (HDL-C) showed a significant decrease (P≥0.05) at the 3% and 6% of gum arabic treated groups compared to control group. There was a significant increase (P≥0.05) in low density lipoprotein (LDL-C) with 3% and 6% of gum Arabic (GA) groups compared to the control group. The study indicated that there was no significant (p≤0.05) effect on TC and TG but there was significant effect (P≥0.05) on HDL-C and LDL-C in blood lipid profile of normal rat. The results showed that after 4 weeks of treatment the malondialdehyde (MDA) value in rat fed with 6% of A. seyal group was significantly higher (P≥0.05) than control or other treated groups of A. seyal and A. senegal studied. Thus, the two species of gum arabic did not have beneficial effect on blood lipid profile and lipid peroxidation.

Keywords: Acacia senegal, acacia seyal, lipid profile, lipid peroxidation, malondialdehyde (MDA)

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Authors: Carolina N. França, Jônatas B. do Amaral, Maria C.O. Izar, Ighor L. Teixeira, Francisco A. Fonseca

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Introduction: Atherosclerosis is a progressive disease, characterized by lipid and fibrotic element deposition in large-caliber arteries. Conditions related to the development of atherosclerosis, as dyslipidemia, hypertension, diabetes, and smoking are associated with endothelial dysfunction. There is a frequent recurrence of cardiovascular outcomes after acute myocardial infarction and, at this sense, cycles of mobilization of monocyte subtypes (classical, intermediate and nonclassical) secondary to myocardial infarction may determine the colonization of atherosclerotic plaques in different stages of the development, contributing to early recurrence of ischemic events. The recruitment of different monocyte subsets during inflammatory process requires the expression of chemokine receptors CCR2, CCR5, and CX3CR1, to promote the migration of monocytes to the inflammatory site. The aim of this study was to evaluate the effect of lipid-lowering treatment by six months in the monocyte phenotype and chemokine receptor levels of patients after Acute Myocardial Infarction (AMI). Methods: This is a PROBE (prospective, randomized, open-label trial with blinded endpoints) study (ClinicalTrials.gov Identifier: NCT02428374). Adult patients (n=147) of both genders, ageing 18-75 years, were randomized in a 2x2 factorial design for treatment with rosuvastatin 20 mg/day or simvastatin 40 mg/day plus ezetimibe 10 mg/day as well as ticagrelor 90 mg 2x/day and clopidogrel 75 mg, in addition to conventional AMI therapy. Blood samples were collected at baseline, after one month and six months of treatment. Monocyte subtypes (classical - inflammatory, intermediate - phagocytic and nonclassical – anti-inflammatory) were identified, quantified and characterized by flow cytometry, as well as the expressions of the chemokine receptors (CCR2, CCR5 and CX3CR1) were also evaluated in the mononuclear cells. Results: After six months of treatment, there was an increase in the percentage of classical monocytes and reduction in the nonclassical monocytes (p=0.038 and p < 0.0001 Friedman Test), without differences for intermediate monocytes. Besides, classical monocytes had higher expressions of CCR5 and CX3CR1 after treatment, without differences related to CCR2 (p < 0.0001 for CCR5 and CX3CR1; p=0.175 for CCR2). Intermediate monocytes had higher expressions of CCR5 and CX3CR1 and lower expression of CCR2 (p = 0.003; p < 0.0001 and p = 0.011, respectively). Nonclassical monocytes had lower expressions of CCR2 and CCR5, without differences for CX3CR1 (p < 0.0001; p = 0.009 and p = 0.138, respectively). There were no differences after the comparison between the four treatment arms. Conclusion: The data suggest a time-dependent modulation of classical and nonclassical monocytes and chemokine receptor levels. The higher percentage of classical monocytes (inflammatory cells) suggest a residual inflammatory risk, even under preconized treatments to AMI. Indeed, these changes do not seem to be affected by choice of the lipid-lowering strategy.

Keywords: acute myocardial infarction, chemokine receptors, lipid-lowering treatment, monocyte subtypes

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Authors: Raj Raghupathy

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Recurrent Spontaneous Miscarriage (RSM) is a common form of pregnancy loss, 50% of which are due to ‘unexplained’ causes. Evidence exists to suggest that RSM may be caused by immunologic factors such as cytokines which are critical molecules of the immune system, with an impressive array of capabilities. An association appears to exist between Th2-type reactivity (mediated by Th2 or anti-inflammatory cytokines) and normal, successful pregnancy, and between unexplained RSM and Th1 cytokine dominance. If pro-inflammatory cytokines are indeed associated with pregnancy loss, the suppression of these cytokines, and thus the ‘redirection’ of maternal reactivity, may help prevent cytokine-mediated pregnancy loss. The objective of this study was to explore the possibility of modulating cytokine production using Dydrogesterone (Duphaston®), an orally-administered progestogen. Peripheral blood mononuclear cells from 34 women with a history of at least 3 unexplained recurrent miscarriages were stimulated in vitro with a mitogen (to elicit cytokine production) in the presence and absence of dydrogesterone. Levels of selected pro- and anti-inflammatory cytokines produced by peripheral blood mononuclear cells were measured after exposure to these progestogens. Dydrogesterone down-regulates the production of pro-inflammatory cytokines and up-regulates the production of anti-inflammatory cytokines. The ratios of Th2 to Th1 cytokines are markedly elevated in the presence of dydrogesterone, indicating a shift from potentially harmful maternal Th1 reactivity to a more pregnancy-conducive Th2 profile. We used a progesterone receptor antagonist to show that this cytokine-modulating effect of dydrogesterone is mediated via the progesterone receptor. Dydrogesterone also induces the production of the Progesterone-Induced Blocking Factor (PIBF); lymphocytes exposed to PIBF produce higher levels of Th2 cytokines, affecting a Th1 → Th2 cytokine shift which could be favourable to the success of pregnancy. We conclude that modulation of maternal cytokine production profiles is possible with dydrogesterone which has the merits that it can be administered orally and that it is safe.

Keywords: cytokines, dydrogesterone, progesterone, recurrent spontaneous miscarriage

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