Mitochondrial inhibition of uracil-DNA glycosylase is not mutagenic

BACKGROUND: Uracil DNA glycosylase (UDG) plays a major role in repair of uracil formed due to deamination of cytosine. UDG in human cells is present in both the nucleus and mitochondrial compartments. Although, UDG's role in the nucleus is well established its role in mitochondria is less clear. RESULTS: In order to identify UDG's role in the mitochondria we expressed UGI (uracil glycosylase inhibitor) a natural inhibitor of UDG in the mitochondria. Our studies suggest that inhibition of UDG by UGI in the mitochondria does not lead to either spontaneous or induced mutations in mtDNA. Our studies also suggest that UGI expression has no affect on cellular growth or cytochrome c-oxidase activity. CONCLUSIONS: These results suggest that human cell mitochondria contain alternatives glycosylase (s) that may function as back up DNA repair protein (s) that repair uracil in the mitochondria

Effect of different combinations of animal dung, and agro/kitchen wastes ongrowth and development of earthworm Eisenia foetida.

Abstract: The effect of various animal agro and kitchen wastes on the growth and development of an epigeic earthworm Eisenia foetida was studied under identical laboratory condition. There was observed significant growth and development of earthworm among different combination of animal agro and kitchen wastes. Maximum number of earthworm was observed in dung with gram bran even when they were counted after one night. Highest significant growth was observed in gram bran with cattle dung. The maximum significant gain in weight and length attained in combination of gram bran with buffalo dung and highest number of Eisenia foetida were observed in combination of gram bran with horse dung

Evaluation of Cell Types for Assessment of Cytogenetic Damage in Arsenic Exposed Population

Background: Cytogenetic biomarkers are essential for assessing environmental exposure, and reflect adverse human health effects such as cellular damage. Arsenic is a potential clastogen and aneugen. In general, the majority of the studies on clastogenic effects of arsenic are based on frequency of micronuclei (MN) study in peripheral lymphocytes, urothelial and oral epithelial cells. To find out the most suitable cell type, here, we compared cytogenetic damage through MN assay in (a) various populations exposed to arsenic through drinking water retrieved from literature review, as also (b) arsenic-induced Bowen's patients from our own survey. Results: For literature review, we have searched the Pubmed database for English language journal articles using the following keywords: "arsenic", "micronuclei", "drinking water", and "human" in various combinations. We have selected 13 studies consistent with our inclusion criteria that measured micronuclei in either one or more of the above-mentioned three cell types, in human samples. Compared to urothelial and buccal mucosa cells, the median effect sizes measured by the difference between people with exposed and unexposed, lymphocyte based MN counts were found to be stronger. This general pattern pooled from 10 studies was consistent with our own set of three earlier studies. MN counts were also found to be stronger for lymphocytes even in arsenicinduced Bowen's patients (cases) compared to control individuals having arsenic-induced noncancerous skin lesions. Conclusion: Overall, it can be concluded that MN in lymphocytes may be superior to other epithelial cells for studying arsenic-induced cytogenetic damage

The Importance of Mitochondrial DNA in Aging and Cancer

Mitochondrial dysfunction has been implicated in premature aging, age-related diseases, and tumor initiation and progression. Alterations of the mitochondrial genome accumulate both in aging tissue and tumors. This paper describes our contemporary view of mechanisms by which alterations of the mitochondrial genome contributes to the development of age- and tumor-related pathological conditions. The mechanisms described encompass altered production of mitochondrial ROS, altered regulation of the nuclear epigenome, affected initiation of apoptosis, and a limiting effect on the production of ribonucleotides and deoxyribonucleotides

Nuclear genes involved in mitochondria-to-nucleus communication in breast cancer cells

BACKGROUND: The interaction of nuclear and mitochondrial genes is an essential feature in maintenance of normal cellular function. Of 82 structural subunits that make up the oxidative phosphorylation system in the mitochondria, mitochondrial DNA (mtDNA) encodes 13 subunits and rest of the subunits are encoded by nuclear DNA. Mutations in mitochondrial genes encoding the 13 subunits have been reported in a variety of cancers. However, little is known about the nuclear response to impairment of mitochondrial function in human cells. RESULTS: We isolated a Rho(0) (devoid of mtDNA) derivative of a breast cancer cell line. Our study suggests that depletion of mtDNA results in oxidative stress, causing increased lipid peroxidation in breast cancer cells. Using a cDNA microarray we compared differences in the nuclear gene expression profile between a breast cancer cell line (parental Rho(+)) and its Rho(0) derivative impaired in mitochondrial function. Expression of several nuclear genes involved in cell signaling, cell architecture, energy metabolism, cell growth, apoptosis including general transcription factor TFIIH, v-maf, AML1, was induced in Rho(0) cells. Expression of several genes was also down regulated. These include phospholipase C, agouti related protein, PKC gamma, protein tyrosine phosphatase C, phosphodiestarase 1A (cell signaling), PIBF1, cytochrome p450, (metabolism) and cyclin dependent kinase inhibitor p19, and GAP43 (cell growth and differentiation). CONCLUSIONS: Mitochondrial impairment in breast cancer cells results in altered expression of nuclear genes involved in signaling, cellular architecture, metabolism, cell growth and differentiation, and apoptosis. These genes may mediate the cross talk between mitochondria and the nucleus

Metronidazole induced neurotoxicity: a case report

Metronidazole is a well-known antimicrobial agent, used for the treatment of anaerobic bacterial and protozoal infections. It is generally well tolerated with common side effects like nausea, dizziness, headache and metallic taste in the mouth. But prolonged use of metronidazole can cause neurotoxicity like ataxic gait, dysarthria, seizures and encephalopathy. Here, we are reporting a case of a 60 years old male patient who was a chronic alcoholic with liver abscess and he developed acute ataxia and dysarthria after four weeks use of metronidazole. The causality of metronidazole in this case was “probable” with score 7 as per Naranjo scale. The patient was managed by discontinuing the metronidazole and there was considerable improvement in his gait and speech after that. The case was recorded properly in adverse drug reaction reporting form and was sent to nearby adverse drug reaction (ADR) monitoring centre

Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues

BACKGROUND: In prostate cancer, normal citrate-producing glandular secretory epithelial cells undergo a metabolic transformation to malignant citrate-oxidizing cells. m-Aconitase is the critical step involved in this altered citrate metabolism that is essential to prostate malignancy. The limiting m-aconitase activity in prostate epithelial cells could be the result of a decreased level of m-aconitase enzyme and/or the inhibition of existing m-aconitase. Earlier studies identified zinc as an inhibitor of m-aconitase activity in prostate cells; and that the depletion of zinc in malignant cells is an important factor in this metabolic transformation. However, a possibility remains that an altered expression and level of m-aconitase enzyme might also be involved in this metabolic transformation. To address this issue, the in situ level of m-aconitase enzyme was determined by immunohistochemical analysis of prostate cancer tissue sections and malignant prostate cell lines. RESULTS: The immunocytochemical procedure successfully identified the presence of m-aconitase localized in the mitochondrial compartment in PC-3, LNCaP, and DU-145 malignant prostate cell lines. The examination of prostate tissue sections from prostate cancer subjects demonstrated that m-aconitase enzyme is present in the glandular epithelium of normal glands, hyperplastic glands, adenocrcinomatous glands, and prostatic intraepithelial neoplastic foci. Quantitative analysis of the relative level of m-aconitase in the glandular epithelium of citrate-producing adenomatous glands versus the citrate-oxidizing adenocarcinomatous glands revealed no significant difference in m-aconitase enzyme levels. This is in contrast to the down-regulation of ZIP1 zinc transporter in the malignant glands versus hyperplastic glands that exists in the same tissue samples. CONCLUSION: The results demonstrate the existence of m-aconitase enzyme in the citrate-producing glandular epithelial cells; so that deficient m-aconitase enzyme is not associated with the limiting m-aconitase activity that prevents citrate oxidation in these cells. The level of m-aconitase is maintained in the malignant cells; so that an altered enzyme level is not associated with the increased m-aconitase activity. Consequently, the elevated zinc level that inhibits m-aconitase enzyme is responsible for the impaired citrate oxidation in normal and hyperplastic prostate glandular epithelial cells. Moreover, the down-regulation of ZIP1 zinc transporter and corresponding depletion of zinc results in the increase in the activity of the existing m-aconitase activity in the malignant prostate cells. The studies now define the mechanism for the metabolic transformation that characterizes the essential transition of normal citrate-producing epithelial cells to malignant citrate-oxidizing cells

Meeting Report: Mitochondrial DNA and Cancer Epidemiology

n/

Brakes Analysis of BAJA ATV

In the modern day and age where automobiles are an essential part of our day to day life, the requirements of each are different. Some demand for a high-performance machine whereas others require a comfortable ride. The modern engineering helps in achieving all the aspects of a safe, reliable and fast vehicle. With the change in time, the need for an all-terrain vehicle has gradually increased. The research paper includes the optimisation of braking system for minimum stopping distance and locking all four tyres simultaneously. The SolidWorks struct-static analysis and simulation are done to obtain a better braking system which can provide the best in class arrangements for the customer. The research focused on disc, master cylinder position. The designs provide the sturdiness and durability which is the primary requirement for an all-terrain vehicle. The study comprises of braking for BAJA-ATV. The all-terrain conditions require active braking and all wheels locking at the instant time. The research paper includes the parameters for the efficient disc, callipers, master cylinder position for effective braking

Impaired OXPHOS Complex III in Breast Cancer

We measured the mitochondrial oxidative phosphorylation (mtOXPHOS) activities of all five complexes and determined the activity and gene expression in detail of the Complex III subunits in human breast cancer cell lines and primary tumors. Our analysis revealed dramatic differences in activity of complex III between normal and aggressive metastatic breast cancer cell lines. Determination of Complex III subunit gene expression identified over expression and co-regulation of UQCRFS1 (encoding RISP protein) and UQCRH (encoding Hinge protein) in 6 out of 9 human breast tumors. Analyses of UQCRFS1/RISP expression in additional matched normal and breast tumors demonstrated an over expression in 14 out of 40 (35%) breast tumors. UQCRFS1/RISP knockdown in breast tumor cell line led to decreased mitochondrial membrane potential as well as a decrease in matrigel invasion. Furthermore, reduced matrigel invasion was mediated by reduced ROS levels coinciding with decreased expression of NADPH oxidase 2, 3, 4 and 5 involved in ROS production. These studies provide direct evidence for contribution of impaired mtOXPHOS Complex III to breast tumorigenesis