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Volumen 8, Ausgabe 4 (2014)

Rezensionsartikel

Viral Disease, Tissue Injury, Repair and Regeneration

Nicholas Ten, Deisy Contreras, Vidhya Kanagavel and Vaithilingaraja Arumugaswami

 

Adult stem cells present in various tissues play key roles in tissue repair and regeneration upon injury. The inflammatory responses associated with tissue damage that are caused by physical, chemical, infectious, nutritional and genetic factors activate stem cells to proliferate and differentiate. The severity and duration of the injury influence the outcome of tissue repair. Viral diseases are major public health problems and over 500 million people worldwide are affected with viral hepatitis. Virus infection of acute or chronic nature could disrupt the tissue homeostasis by altering cell function and architecture. Little is known about the effect of viral diseases on resident stem or progenitor cell population during tissue repair and the regeneration process. This review summarizes the liver-specific inflammatory and healing responses to injury and provides a detailed overview of the cellular and molecular basis of tissue regeneration following viral diseases. Understanding the behavior of resident stem or progenitor cells in response to tissue injury caused by infectious agents such as viruses can allow for the development of small molecule and cell-based therapy for tissue regeneration.

Kleiner Rückblick

Biochemical Alterations in Diabetic Neuropathy

Subhashree Venugopal

Type 2 Diabetes mellitus is a disease which manifests with a variety of cardiovascular risk factors, including hypertension, dyslipidemia and overweight or obesity that contributes to development of long term complications termed diabetic related ailments. Diabetic peripheral neuropathy (DPN) is a debilitating condition affecting as many as one half of all patients with diabetes during the course of their disease. Several metabolic and vascular pathways have been identified as contributors to the pathogenesis of diabetic neuropathy. Diabetic neuropathy encompasses a wide range of clinical and subclinical syndromes from pain to complete loss of sensation. Metabolic and therapeutic approaches have focused on aldose reductase, poly (ADP- Ribose) polymerase, protein kinase C, advanced Glycation end products. Novel approaches to identify targets for treatment of diabetic peripheral neuropathy require cross links between molecular and computational biology methods.

Forschungsartikel

Matrin 3 Augments the Transcriptional Activity of an SV40 Promoter-Mediated Luciferase Gene with a Highly Repetitive DNA Component

Shinya Kamiuchi, Mutsumi Fukaya, Tatsuhiro Usui, Naohiro Iwata, Mari Okazaki, Hirokazu Matsuzaki, Katsuyoshi Sunaga and Yasuhide Hibino

We examined the transcriptional augmentation of matrin 3, a nuclear matrix protein, of the SV40 promotermediated luciferase gene (pGL3) following transient transfection of recombinant plasmids into cells. It has been reported that the interaction of the Xmn I fragment, a highly repetitive DNA component as one of a typical matrix- or scaffold-attachment regions (MAR/SAR) tethered upstream from the SV40 promoter (pGL3-Xmn I) with matrin 3 appeared to be required for augmentation of luciferase gene transcription. In this study, we investigated the levels of induction in cells overexpressing the wild type and several deletion mutants of matrin 3. It appeared that pGL3-Xmn I augmented luciferase production to 4-times the control level in Ac2F cells, but 23-fold in cells overexpressing matrin 3. Electrophoretic mobility shift assay showed that the Xmn I fragment augmented luciferase gene transcription through interaction with matrin 3. Furthermore, our findings suggest that all of the functional domains tested in matrin 3 were necessary for transcriptional augmentation. We aim not only to describe the transcriptional augmentation of matrin 3 with MAR/SAR, but also to strengthen interest in their use to mediate the expression of therapeutic transgenes.

Forschungsartikel

APC, FBXW7, KRAS, PIK3CA, and TP53 Gene Mutations in Human Colorectal Cancer Tumors Frequently Detected by Next-Generation DNA Sequencing

Zheng Xu Cai, Xu Dong Tang, He Li Gao, Chuanning Tang, Vijayalakshmi Nandakumar, Lindsey Jones, Hua Ye, Feng Lou, Dandan Zhang, Hong Sun, Haichao Dong, Guangchun Zhang, Zhiyuan Liu, Zhishou Dong, Baishuai Guo, He Yan, Chaowei Yan, Lu Wang, Ziyi Su, Feng Yun Wang, Jia Jia Wan, Feng Qi Fang, Hai Long Chen, Dong Shang, Xue F Huang, Si-Yi Chen and and Hui S

Colorectal cancer (CRC) is the fourth leading cause of cancer deaths worldwide. Genetic mutations have been linked to 5-10% of CRCs, with other environmental, genetic, and epigenetic factors influencing development and progression of the cancer. As individual cancers exhibit unique mutation patterns, identification of the distinctive CRC profile is essential to develop more effective target therapies. In this study, we used Ion Torrent Ampliseq Cancer Panel to sequence 737 loci from 45 cancer-related genes to identify genetic mutations in 93 human colorectal cancer samples. Sequencing analysis revealed frequent missense mutations in APC (17.2%), FBXW7 (10.8%), KRAS (50.5%), PIK3CA (10.8%), and TP53 (23.7%) in CRC samples of various histologic types, and additional mutations were also detected in other genes (BRAF, CTNNB1, NRAS, and SMAD4) at lesser frequencies. We also found common combination mutations between KRAS and TP53 (12.9%), KRAS and APC (8.6%), and KRAS and PIK3CA (8.6%). Sequencing individual human cancers may be the key to developing more effective drugs to target individual, cancer-specific mutations. Identifying the complete mutation profile in CRCs for the application of personalized and tailored targeted therapy is critical for developing new cancer treatments. We believe a faster and cost effective genotyping tool such as Ion Torrent sequencing technology will be greatly beneficial for the assignment of such specific therapeutics for CRCs in the near future.

Forschungsartikel

Effect of Vaccination with Different Types and Dosages against a Very Virulent Marek's Disease Virus Strain

Zhenhua Gong, Kang Zhang, Lei Li, Hongwei Wang, Yuan Qiu, Inping Li, Guangyu Hou, Jianmin Yu, Jianlin Wang and Hu Shan

In this study, Marek’s disease(MD) vaccines including herpes virus of turkeys (HVT) vaccine, attenuated serotype 1 Marek’s disease virus (MDV) CVI988/Rispens vaccine and nonpathogenic serotype 2 MDV (SB1 strain) culture were used individually or jointly to immunize 1-day-old specific pathogen free (SPF) chickens at different doses, the immunized chickens were intradermally infected with 2000 plague forming unit (PFU) of duck embryo fibroblast (DEF) passaged SD2012-1, a very virulent Marek's disease virus. All chickens of the experiments and control chickens were observed daily throughout the entire experimental period to assess the vaccines efficacy and immunization dose against MDV SD2012-1 Strain. CVI988, CVI988+HVT and CVI988+SB1+HVT could partially protect immunized chickens against SD2012-1. CVI988+HVT and CVI988+SB1+HVT could provide more efficient protection than CVI988 at normal and high immunization dose. Excessive dilution of these vaccines could result in obvious decrease on protection against SD2012-1. In this study, 450 feather pulp samples collected from the dead or living chickens on Day 150 were detected to be MDV positive by polymerase chain reaction (PCR), and the positive rate of MDV was 100%.

Fallbericht

Berardinelli – Seip Congenital Lipodystrophy

Jagabandhu Ghosh and Joydeep Ghosh

Berardinelli-Seip Congenital lipodystrophy is a rare autosomal recessive disorder characterized by acanthosis nigricans, loss of subcutaneous fat, hepatosplenomegaly, mental retardation, hypertriglyceridemia, insulin resistance. An inability to store energy in adipose tissue is one of the important pathogenetic mechanisms. In congenital lipodystrophy, insulin resistance is present from birth, resulting in hyperlipidaemia, hyperinsulinaemia, insulin resistance diabetes and acanthosis nigricans. We report here a case of congenital lipodystrophy presenting with seizure and acanthosis nigricans in absence of insulin resistance.

Rezensionsartikel

Molecular Methods in Microbiology and their Clinical Application

Malhotra S, Sharma S, Bhatia NJK, Kumar P and Hans C

Conventional microbiology is an inexpensive but protracted diagnostic method and there are certain limitations associated with it. Molecular methods have been increasingly incorporated in laboratories, particularly for the detection and characterization of isolates and for the diagnosis of diseases due to fastidious, slow growing, nonviable or non-cultivable organisms which cannot be detected by conventional culture techniques. The introduction of these techniques and their automation provides new opportunities for the clinical laboratory to affect patient care. These tests provide timely results which are useful for high-quality patient care at a reasonable cost and are associated with improvement in patients care. The use of amplification techniques such as polymerase chain reaction, real-time polymerase chain reaction or nucleic acid sequence-based amplification for micro-organisms detection, genotyping and quantification. Molecular methods are rapid and highly sensitive and specific. This review will focus on various molecular techniques which are performed in clinical microbiology laboratories and their clinical applications and therefore help in management of infectious diseases.

Rezensionsartikel

Glutamate Excitotoxicity and Neurodegeneration

Ezza HSA and Khadrawyb YA

Glutamate plays crucial roles in the physiology of the central nervous system as it can control many functions such as memory, learning, cognitive, emotional, endocrine and other visceral functions. In addition, glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. It has the potential to be involved in the pathogenesis of many CNS diseases either due to excessive release, reduced uptake or alteration of receptor functions. Growing evidence links glutamate excitotoxicity to various neurodegenerative diseases as cerebral ischemia, epilepsy, Alzheimer's disease, Parkinsons' disease and multiple sclerosis. In addition, several environmental pollutants result in excessive glutamatergic neurotransmission and may eventually lead to neurodegenerative diseases.

Forschungsartikel

Immunodetection of Cytoplasmatic Membrane-Bound Thrombomodulin in Formalin-Fixed Paraffin-Embedded Human Tissue Microarrays

Ruddock MW, Reid CN, McReynolds D, Lamont JV, Fitzgerald SP and Williamson KE

Background: Loss of thrombomodulin immunoreactivity denotes a poor prognosis for patients presenting with malignant disease. Objectives: Immunodetection for cytoplasmatic membrane-bound thrombomodulin in formalin-fixed paraffinembedded (FFPE) tissue microarrays. Methods: Thrombomodulin immunoreactivity was assessed in 97 FFPE tissue cores representing bladder, kidney, prostate, testis, penis, ovary, cervix, vulva, endometriosis, and myometrium, from 84 patients arrayed on three TMAs (64 (66%) cancers, 22 (23%) normal controls, and 11 (11%) benign pathologies). Human bladder tissue lysate from matched normal urothelium and TCC biopsies were also examined by western blot analysis for thrombomodulin expression. Results: Thrombomodulin immunoreactivity was strongest in the TCC cores where ≥60% of the tissue sections scored +3, or greater. By contrast, SCCs, adenocarcinomas, CCCs, papillary carcinoma, sarcomas, seminomas, teratoma and all other tissue sections scored ≤ +2. Thrombomodulin expression was also detected by western blot analysis in the human bladder tumour lysate. No signal was detected in adjacent normal control. Conclusion: Cytoplasmatic membrane-bound thrombomodulin immunostaining is strongest in TCC sections with respect to SCC, adenocarcinoma, sarcoma, seminoma, teratoma, papillary carcinoma, CCC, and is independent of both grade and stage. Thrombomodulin immunostaining in tumour tissue sections are predominately membranous.

Kleiner Rückblick

Regeneration and the Plant We have Inside

Cernaro V, Donato V, Romeo A, Lacquaniti A, Buemi M

Regeneration is a process that occurs in simple organisms and allows them to rebuild entire parts of the body following an injury. This process is subject to restrictions as progressive as going from the simplest organisms to more complex ones, such as humans, where regeneration is limited to a few examples and an injury is followed in most cases by fibrosis. The mechanisms underlying the different regeneration entity among the various species are still unclear. An example of regeneration is given by plants, whose development and growth are regulated by a class of phytohormones called “Auxin”. The principal auxin produced by the plants is indole-3-acetic acid. Surprisingly, this substance has also been found in humans, where it is considered one of uremic toxins. Why auxin not associated with regenerative abilities in humans as is occurs in plants? And yet, why should a plant hormone is found in an animal organism? In 2011, the first evidence of symbiosis was assessed between a green alga and a vertebrate, the spotted salamander. Moreover in fishes, cells called “rodlet cells” are present and their nature is still uncertain, since they have a cell wall that is typical of vegetable organisms. As both salamanders and fishes can regenerate parts of their body after injury, we wonder if these different aspects, apparently independent of each other, have not actually common points. Auxin may be the connecting link, both for its functions in plants and because there are examples of symbiosis between the animal and plant kingdoms.

Fallbericht

Relapsing Transient Neonatal Diabetes Mellitus due to ABCC8 Mutation

Poovazhagi V and Thangavelu S

Neonatal diabetes mellitus with onset in the first six months of life is predominantly monogenic. Genetic evaluation of such infants is mandatory irrespective of the diabetic duration. Management of sulphonylurea responsive mutation induced diabetes is rewarding as it improves the metabolic control without exogenous insulin lifelong. Here we present a child with neonatal onset diabetes who remitted at 10 months of age and relapsed at 10 years, 8 months of age and was effectively switched over to oral sulphonylurea following identification of mutation in the ABCC8- SUR1 subunit of the K-ATP channel.

Rezensionsartikel

Molecular Analyses in Families with Hunter Syndrome Indicate Unequal Male and Female Mutation Rates in the Iduronate-2-Sulfatase Gene

Li P

Molecular diagnosis for patients with mucopolysaccharidosis type II (MPS II, Hunter syndrome) has detected a spectrum of mutations including large deletions, intragenic rearrangements, recurrent nucleotide substitutions at CpG sites, and high proportion of novel point mutations in the X-linked iduronate-2-sulfatase (IDS) gene. The mutational heterogeneity and the X-linked inheritance make the IDS gene a good disease model for studying human germline mutations and underlying mechanisms. Pooling data from 135 MPS II families observed that 8% were sporadic cases from de novo maternal germline mutations and 92% were transmitted cases from carrier females. Haplotyping analysis on transmitted cases showed preference of germline mutations from maternal grandfather. Estimation of male-to-female ratio of mutation rates indicated a 3.76-to-10.5-fold higher mutation rate in males for mutations in the IDS gene. However, little is known on gender-specific mutation rate for different type of mutations in the IDS gene. A large-scale population based collaborative study to construct a database of detailed mutational composition and family pedigrees is needed to further characterize the mutation origin and male/female mutation rates in the IDS gene. This information will be helpful in genetic counseling and disease prevention and also gain insight into mutagenesis mechanisms for various types of mutations.

Rezensionsartikel

Methionine Metabolism in Humans: New Perspectives on Epigenetic Inheritance

Venkatachalam KV

Epigenetic control by methylation is directly dependent on SAM/methionine. Free methionine aside from being used for protein synthesis is activated to universal methyl group donor SAM and the methyl group from it can be transferred mainly onto DNA, histones, mRNA and noncoding (Nc) RNA, in the nucleus and onto various cytosolic recipients by specific methyltransferases. The product S-adenosylhomocysteine (SAH) from methyltransferase reaction is cleaved into free homocysteine and adenosine. Homocysteine has two fates, one to enter methionine resynthesis which requires methionine synthase (MetS), the coenzymes N5-methyltetrahydrofolate (vitamin B9) and methylcobalamin (vitamin B12). The second option of homocysteine is to enter cysteine synthesis pathway which requires cystathionine -synthase (CBS), serine, vitamin B6 (pyridoxal phosphate) and cystathionine γ-lyase (CGL). I predict serine and vitamin B6 are the critical diverting factors in a fully developed organism where the methylation is minimal and all other factors such as MetS, B9, B12, ATP, Methionine adenosyltransferase (MAT), are more relevant during normal development or in abnormal deregulated cancer cell metabolism. In a developed organism the demethylation pathway would play a critical role during tissue regeneration and must involve hydroxylation (CH2OH), oxidation (CHO) and decarboxylation (COOH) and the corresponding hydroxylase, oxidase and decarboxylase. The hydroxylation is predicted to involve vitamin C (ascorbate) and decarboxylation would involve (vitamin B6). The control of methylation and equally the demethylation is extremely crucial for epigenetic control mechanisms (gene suppression/expression) and any dysregulation would cause abnormal tissues/cancer.

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