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ஐ.எஸ்.எஸ்.என்: 1747-0862

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தொகுதி 10, பிரச்சினை 4 (2016)

மினி விமர்சனம்

Carnitine Palmitoyltransferase Inhibitor in Diabetes

Chen Z*, Cui F, Meng L, Chen G, Li Z, Xu Y, Ma Z and Woldegiorgis G

This review addresses progress of carnitine palmitoyltransferase targeted pharmaceuticals in diabetes and the challenges ahead. Since the discovery of carnitine palmitoyltransferase (CPT), there are lots of publications on its role in disease. The wide tissue expression, functional and biological roles have documented the physiological importance of these enzymes both in health and disease. Thus, over the years, studies have revealed essential importance of CPT1 in mammalian pathophysiology revealing CPT1 as potential drug targets. Starting from a brief description of the main functional features of CPTs, their roles in physiology and pathophysiology of different human diseases, this review describes the main classes of small molecules which are able to regulate CPT1 for diagnostic and therapeutic applications.

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Functional Analysis of the C.3705+5G>C Mutation in the SCN1A Gene: Cryptic Splicing Site Activation and Partial Exon Skipping

Ben Mahmoud A, Mansour RB, Driss F, Gargouri SB, Tabebi M, Rhouma BB, Tlili A, Siala O and Fakhfakh F

Several substitutions in Voltage-gated sodium channels (SCN1A) gene have been reported to cause aberrant splicing. Accordingly, this study aimed to investigate the potential effects of a transition in the fifth nucleotide at the donor splice site of intron 18 of the SCN1A gene previously described leading to SIGEI phenotype. Functional analyses using PCR mutagenesis, followed by an ex-vivo splicing assays, revealed that the c.3705+5G>C mutation leads to the activation of a cryptic site into exon 18 leading to a partial exon skipping followed by a premature stop codon at position 1253 in the SCN1A protein. Bioinformatic tools showed an homology between cryptic and normal splicing consensus especially at position - 3, -2, -1, +1, +2 and +5; confirming the crucial role of these positions in the exon definition and explains the strength of the novel donor consensus. This analysis revealed also the enrichment of regions close to the new splice site in ESEs elements with high scores underlining the importance of ESEmediated SR protein function for accurate new splice site recognition. Our results demonstrate that splicing analysis of mRNA may help to understand both the functional consequences of mutations affected splicing consensus and the correlation between genotype and phenotype.

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Fas Role in Ischemic Stroke: Not Only in Apoptosis

Sergeeva SP, Gorbacheva LR, Breslavich ID and Cherdak MA

The receptors, whose ligand interaction activation was previously considered to be associated with initiation of apoptosis only, can have a range of biological effects: apoptosis, inflammation, proliferation, and differentiation. Therefore, interaction between death receptor and its ligand does not always mean the initiation of programmed cell death and blocking of this ligand-receptor interaction can affect the initiation of recovery and neuroplasticity mechanisms. Fas is one of these death receptors. The following review represents data on the conditions of Fasdependent signal pathways induction in ischemic stroke. There is a possibility for the development of new target neuroprotective drugs with selective effects on different separated signal pathways, activated by ligand-receptor interactions in Fas-FasL (Fas ligand) system.

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The Isoquinoline Alkaloid Berberine Augments Radiation Effect by Enhancing the DNA Damage at Molecular Level in HeLa Cells Irradiated with Various Doses of γ-Radiation: Correlation Between DNA Damage and Clonogenicity

Jagetia GC and Rao SK

The passage of ionizing radiations through aqueous medium of biological material leads into the generation of a burst of free radicals owing to radiolysis of water. These free radicals are extremely reactive and interact with important macromolecules of cells resulting in the cytotoxicity. It is well known that ionizing radiation induce damage to the DNA triggering a cascade of events that result in eventual cell kill. Earlier we found that berberine chloride an isoquinoline alkaloid present in certain plants inflicts damage to the molecular DNA. Therefore we wanted to know whether berberine chloride will increase the effects of radiation in HeLa cells exposed to various doses of γ- radiation. HeLa cells were treated or not with 0, 1, 2, 4, 6 or 8 μg/ml of berberine chloride prior to 0, 0.5, 1, 2, 3 or 4 Gy γ-irrradiation and the molecular DNA damage was assessed immediately after irradiation (within 15 minute of irradiation) by single cell gel electrophoresis. The migration of fragmented DNA into comet tails was considered as a measure of molecular damage to DNA and has been expressed as Olive tail moment. Irradiation of HeLa cells to 0, 0.5, 1, 2, 3 or 4 Gy γ-irradiation caused a radiation dose-dependent rise in the Olive tail moment indicating an elevation in the DNA damage in HeLa cells. Treatment of HeLa cells with different concentrations of berberine chloride for 2 or 4 h before irradiation further raised the DNA damage denoted by a rise in the amount of tail DNA of the comets and Olive tail moment immediately after irradiation. The clonogenic assay revealed that clonogenic potential of HeLa cells alleviated with an increase in irradiation dose and treatment of HeLa cells with 1, 2 or 4 μg/ml berberine chloride further reduced the clonognenicity of cells. Our study indicates that berberine is a potent DNA damaging agent and could enhance radiation damage during cancer treatment in clinical conditions and clonogenicity of cells is directly related to the ability of berberine to inflict damage to DNA.

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Oxaliplatin Pharmacokinetics and Pharmacodynamics in Three Metastatic Colorectal Cancer Patients with Hemodialysis

Osawa H

Aim: We investigated the safety and feasibility of L-OHP with chronic renal failure (CRF) on hemodialysis (HD) patients by examining the influence of pharmacokinetics and pharmacodynamics of oxaliplatin (L-OHP). Furthermore, we investigated.

Methods: We present the results of three patients who were treated with modified FOLFOX6 (mFOLFOX6) chemotherapy for a mCRC with chronic renal failure on HD. We measured their plasma concentration of total platinum and free platinum. We evaluated whether L-OHP dose could be safely used for these patients. Different starting dose of L-OHP and 5-fluorouracil (50% and 75%) were used in these patients. Pharmacokinetics monitoring of platinum in plasma, plasma ultrafiltrates were measured these time schedule follow as: pre-chemotherapy infusion and 4 hours (pre-HD), 6 hours (half of HD), 8 hours (post HD), 48 hours after.

Results: The 50% of peak concentrations (Cmax) was 0.27 μg・hr/mL ± 0.02 μg/mL and 75% Cmax was 0.41 μg・hr/mL ± 0.02 μg/mL. 50% of the area under the concentration versus time curve (AUC) was 14.8 μg・hr/mL ± 1.22 μg・hr/mL and 75% AUC was 22.43 μg・hr/mL ± 0.85 μg・hr/mL.

Conclusion: We recognized these free plasma concentration which 50% dose of L-OHP was similar AUC between healthy and CRF patients. L-OHP pharmacokinetics and pharmacodynamics are altered in patients with CRF, but corresponding increase in L-OHP related hematological and non-hematological toxicities is not observed. It is important for cancer patients with CRF that the feasibility and efficacy of L-OHP combined chemotherapy should be determined.

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Multi-Omics Data Integration: A Modular Approach

Gajula MNVP

The concept of data integration is critical to the advancement of agricultural and biomedical research in India, particularly due to un uniformity in the practices that depended upon on multi-disciplinary and multi-technological aspects. So far, no successful attempts were reported in this aspect especially at national level. This concept note briefly outlines one of the modules that were proposed to develop under mutli-omics approach.

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Association Between the Angiotensinogen Gene Polymorphism and The Pro-Oxidant Effect in Tunisian Patients with Coronary Heart Disease

Dandana A, Khelifa SB, Bouzidi N, Addad F and Ferchichi S

Background: Evaluation and investigation of the pro-oxidant role of the angiotensinogen (AGT) among Tunisian coronary.

Materials and methods: The current study evaluated the frequency of AGT (M235T and A(-6)G) polymorphism in relation to coronary artery disease in a group of Tunisian population. AGT polymorphism was determined by Real Time PCR. These subjects (150 patients and 120 controls) beneficed also by an enzymatic determination of superoxide dismutase (SOD), glutathione peroxidase (GPX), total antioxidant status (TAS), catalase (CAT) activity was determined spectrophotometrically and serum lipid peroxides were measured by the fluorimetric method reaction to reveal the atherogenic effects of these radical species and investigate their interactions with AGT polymorphisms.

Results: The results revealed that there was a positive risk of developing coronary artery disease when having the T allele whether in homozygous or heterozygous state. Statistical tests of the baseline correlation between oxidative stress parameters and M235T genotype groups showed a negative correlation between MM genotype group and oxidant parameters (SOD, GPX and TAS). The same result was found in TT and MT genotype groups.

Conclusion: This study shows that the AGT polymorphisms were associated with the presence of coronary artery disease. In addition to its vasoconstrictor role, AGT can be considered as a pro-oxidant, these two effects combine in the genesis and the complications of cardiovascular diseases.

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Role of Oxidative and Nitrosative Stress in Dengue Pathogenesis: A Mini-Review

Raimundo Castro-Orozco and Nelson Rafael Alvis-Guzmán

Dengue is a mosquito–borne acute viral disease with ubiquitous distribution in tropical and subtropical areas of the world. Dengue virus (DENV) infection is transmitted by the bite of a female Aedes aegypti mosquito (the most important vector) infected with DENV. Clinical presentation of this typical arboviral disease varies along a wide spectrum of clinical symptoms. During the course of DENV infection, some individuals develop severe manifestations relates to plasma leakage into tissues caused by increased vascular permeability. The severity of dengue disease may vary considerably according to age, ethnicity, genetic factors, immune status and underlying disease. It may also depend on the co-circulation of DENV serotypes and sequential (secondary) infections with different DENV serotypes. While the exact mechanism of pathogenesis of dengue remains elusive, several lines of evidence demonstrating that DENV infection-derived oxidative stress may trigger the release of proinflammatory cytokines, including TNF-alpha, participating in collective action in dengue disease pathogenesis. In conclusion, we review these findings and discuss about the recent advances that propose a major role of oxidative-nitrosative stress on dengue pathogenesis.

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The Software Development and Design Based Approach in Assessing the Probability of Essential Hypertension Disease

Nagay AV, Khamidullayeva GA, Srojidinova NZ, Hafizova LS, Moon OR and Nagaev SD

Background and objectives: Software design and development for cardiovascular genetics laboratories.

Materials and methods: Integrated development environment-Delphi 7.0, Pascal language. In this program were laid down results of a retrospective analysis of hypertensive patients hospitalized in the Department of Arterial Hypertension (AH) of the Republican Specialized Center of Cardiology (RSCC) for the period from 2011 to 2013 y., passed the clinical and genetic testing according to the plan of Research Project ADCC-15.13.1. The study included 100 healthy volunteers and 800 patients with I-II grade of essential hypertension EH, all of them were Uzbek males in the mean age of 48.3 ± 8.1 yrs. The study was approved by the medical ethical committee of the center of cardiology, Tashkent Uzbekistan. Informed consent was obtained from each individual recruited.

Results: We have attempted to develop «CDS» application for the genetics cardiology department. For support parameters, we took the results of SNP-genotyping cardiovascular markers, biochemical, clinical parameters, as well as nutritional status. We have developed «GeneSecure» platform with «CDS» for IBM Pentium, Windows OS.

Conclusion: The polygenic nature of EH and incomplete update patient records significantly reduce diagnostic effect of the CDS. However, in some cases, the CDS are not always able to clearly determine the synergistic and intergenomic effect of analyzed genes. These issues occur when the volume of new data exceeds the amount of filer memory, leading to the appearance of these areas, which are very difficult to manage.

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Tissue-Specific Size and Methylation Analysis in Two Fragile X Families: Contribution to the Clinical Phenotype

Edith RQM, Silvia J, Inmaculada R, Alicia G, Raquel M, Pablo M and Elizabeth P

Methylation at critical CpG sites on the expanded FMR1 gene is crucial for pathological manifestation of fragile X syndrome and fragile X-related disorders. Methylation status from blood, oral mucosa and root hair was analyzed with the FMR1 mPCR kit (Asuragen). Differential allele expression was studied by TP-PCR. Psychological and neurological explorations were performed in the probands. Patient II-1 of family 1 showed an extremely skewed X-chromosome inactivation of the normal allele in blood, oral mucosa cells and root hair. Analysis of differential expression of both alleles in blood showed the preferential expression of the expanded allele. Similarly, patient II-3 of family 2 showed an extremely skewed X-chromosome inactivation of the normal allele in blood, oral mucosa and root hair. Both females presented clinical features compatible with their skewed methylation toward the normal allele. Methylation analysis at critical CpG sites in the first FMR1 exon may predict clinical manifestations in carriers of premutation or full mutation. Analysis of differential expression of both alleles in women using TP-PCR could contribute to clarify the real impact of skewed methylation on the phenotype.

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