Biomedical subjects

K Krishnamurthi

Publications and source records attributed to K Krishnamurthi.

12 recordsLinked to original sources

PubMed2006

ErbB-3 predicts survival in ovarian cancer.

BACKGROUND: HER3 (erbB-3) is a member of the epidermal growth factor receptor (EGFR) family. After dimerization with other members of the EGFR family several signal transduction cascades can be activated, including phosphoinosite 3'-kinase (PI3-K)/Akt and extracellular signal-regulated kinase (ERK1/2). Here, we studied a possible association between HER3 expression and prognosis in patients with ovarian cancer. METHODS: Tumor tissue of 116 consecutive patients diagnosed with primary epithelial ovarian cancer between 1986 and 1995 was analyzed immunohistochemically for HER3 expression. A possible influence of HER3 expression on survival was studied by multivariate Cox regression adjusting for established clinical prognostic factors. RESULTS: A positive HER3 expression was observed in 53.4% of the patients. HER3 expression was associated with decreased survival in proportional hazard modeling, including the International Federation of Gynecology and Obstetrics (FIGO) stage, histologic grade and type, residual disease, and age. After likelihood ratio forward as well as backward selection, only HER3 expression (hazard ratio, 1.71; 95% CI, 1.10 to 2.67; P = .018), FIGO stage (hazard ratio, 4.78; 95% CI, 1.89 to 12.08; P = .001), residual tumor (hazard ratio, 2.69; 95% CI, 1.40 to 5.17; P = .003), and age (hazard ratio, 2.06; 95% CI, 1.17 to 3.65; P = .013) were found to be significant. Kaplan-Meier plots demonstrated a clear influence of HER3 expression on survival time. Median survival time was 3.31 years (95% CI, 1.93 to 4.68) for patients with low HER3 expression, compared with only 1.80 years (95% CI, 0.83 to 2.78) for patients with HER3 overexpression (log-rank test P = .0034). CONCLUSION: HER3 may represent a new prognostic factor in primary epithelial ovarian cancer. Pending validation, exploration of therapeutic strategies to block HER3 could be warranted.

Biomarkers, Tumor↗

PubMed2006

Oncogene-blocking therapies: new insights from conditional mouse tumor models.

Identification of oncogene dependent signaling pathways controlling aggressive tumor growth has led to the emergence of a new era of oncogene-blocking therapies, including Herceptin and Gleevec. In the recent years conditional mouse tumor models have been established that allow switching-off the expression of specific oncogenes controlling tumor growth. The results may have two important implications for oncogene-blocking therapies: (i) downregulation of oncogenes, for instance HER2, MYC, RAS, RAF, BCR-ABL or WNT1, usually leads to a rapid tumor remission. However, it was observed that the initial remission was followed by recurrent tumor growth in most studies. Interestingly, different oncogenes controlled tumor growth in the recurrent than in the primary tumors. This could explain the astonishing clinical observation that inhibitors of a broader spectrum of protein kinases (so-called: "dirty inhibitors") may be superior over highly specific substances. Due to their additional "unspecific" inhibition of a broader spectrum of kinases, they may hamper the escape mechanisms by antagonizing also the pathways controlling recurrent tumor growth. (ii) Experiments with cell systems that allow switching-on oncogene expression point to a so far possibly underestimated cancer drug target: the dormant tumor cell. Oncogene expression (for instance: NeuT or RAS) led to a phenomenon named oncogene-induced senescence or dormancy. Dormant cells are unresponsive to mitogenic stimuli. Importantly, such cells are not at all ready to die, but can remain viable for extended periods of time. Recently, dormant tumor cells have been shown to be more resistant to stresses such as hypoxia or exposure to cytostatic drugs. It still is a matter of debate if and under which conditions dormant tumor cells can be "kissed to life". If these cells contribute to carcinogenesis, it will be important to identify substances specifically killing senescent cells. This review will focus on the possible relevance of senescence both as a pre-oncogenic condition and also for therapy.

Animals↗

PubMed2005

Decolorisation, biodegradation and detoxification of benzidine based azo dye.

The present study deals with the decolorisation, biodegradation and detoxification of Direct Black-38, a benzidine based azo dye, by a mixed microbial culture isolated from an aerobic bioreactor treating textile wastewater. The studies revealed a biotransformation of Direct Black-38 into benzidine and 4-aminobiphenyl followed by complete decolorisation and biodegradation of these toxic intermediates. From cytotoxicity studies, it was concluded that detoxification of the dye took place after degradation of the toxic intermediates by the culture.

Adsorption↗

PubMed2004

Protective effect of distillate and redistillate of cow's urine in human polymorphonuclear leukocytes challenged with established genotoxic chemicals.

OBJECTIVE: From the ancient period cow's urine has been used as a medicine. In Veda, cow's urine was compared to the nectar. In Susrut, several medicinal properties of cow's urine have been mentioned and are known to cause weight loss, reversal of certain cardiac and kidney problems, indigestion, stomach ache, edema, etc. However, the literature and scripture did not mention the antigenotoxic properties of cow's urine. METHODS: In the present investigation, the antigenotoxic/antioxidant properties of cow's urine distillate and redistillate were studied in vitro. The antioxidant status and volatile fatty acid levels were determined. Actinomycin-D (0.1 micromol/L) and hydrogen peroxide (150 micromol/L) were used for inducing DNA strand break with 0.1% DMSO as negative control. Dose for the antigenotoxic effect of cow's urine was chosen from the dose response study carried out earlier. RESULTS: Both actinomycin-D and H202 caused statistically significant DNA unwinding of 80% & 75% respectively (P < 0.001) as revealed by fluorimetric analysis of DNA unwinding (FADU), and the damage could be protected with the redistilled cow's urine distillate (1, 50 & 100 microL) in simultaneous treatment with genotoxic chemicals. CONCLUSION: The redistillate of cow's urine was found to possess total antioxidant status of around 2.6 mmol, contributed mainly by volatile fatty acids (1500 mg/L) as revealed by the GC-MS studies. These fatty acids and other antioxidants might cause the observed protective effects.

Ammonia↗

PubMed2004

Genotoxicity of pesticide waste contaminated soil and its leachate.

OBJECTIVE: Improper land disposal of hazardous waste can result in leaching of hazardous constituents which may contaminate ground and surface water leading to adverse impact on human health and environment consequences. The present study utilized mammalian cell culture for the genotoxicity assessment of waste and its leachate. METHODS: Genotoxic potential and chemical analysis of pesticide derived tarry waste contaminated soil extract and its leachate was assessed using in vitro human lymphocyte cultures and GC-MS. RESULTS: The investigation revealed that the soil extract could cause significant to highly significant genotoxicity in the form of DNA strand break at 25 microL (P < 0.01), 50 microL, 100 microL and 200 microL (P < 0.001) and chromosomal aberration at 25 microL (P < 0.01) and 50 microL and 100 microL (P < 0.001). The leachate could cause significant DNA strand break and chromosomal aberration only at 100 microL and 200 microL (P < 0.01) dose levels. CONCLUSION: The genotoxicity observed is attributed to carbaril and tetra methyl naphthyl carbamate, the major ingredients of the extracts, as revealed by GC-MS.

Adult↗

PubMed2003

Genotoxic effects of PAH containing sludge extracts in Chinese hamster ovary cell cultures.

OBJECTIVE: Many studies have been conducted in order to evaluate the genotoxicity of chemicals and waste materials, which utilized in vivo test protocols. The use of animals for routine toxicity testing is now questioned by a growing segment of society. METHODS: Keeping the above fact in mind, we have conducted in the present study the genotoxicity evaluation of oily sludge samples generated from a petroleum refinery and petrochemical industry and ETP sludge from petroleum refinery using DNA damage, chromosomal aberration, p53 protein induction and apoptosis in short term in vitro mammalian Chinese Hamster Ovary cell cultures. RESULTS: It is evident from the results that the oily sludge compounds derived from petroleum refinery and petrochemical industry could cause DNA damage, chromosomal aberration, p53 protein accumulation and apoptotic cell death on exposure to oily sludge extracts in the presence of metabolic activation system (S-9 mix), however, ETP sludge extract could not cause significant genotoxicity in comparison to oily sludge extract and negative control. CONCLUSION: The effect may be attributed to polycyclic aromatic hydrocarbons present in the samples as evidenced from GC-MS.

Animals↗

PubMed1999

Estrogen regulates angiotensin AT1 receptor expression via cytosolic proteins that bind to the 5' leader sequence of the receptor mRNA.

Two of the most highly recognized factors implicated in the pathogenesis of hypertension, atherosclerosis, congestive heart failure and associated cardiovascular disease are the renin angiotensin system (RAS) and estrogen. A major effect of estrogen results from its influence on the RAS. Beta-estradiol (E2) replacement in ovariectomized (OVX) rats significantly decreased type 1 angiotensin (AT1) receptor expression in the pituitary and adrenal, whereas it significantly increased receptor expression in the uterus when compared to OVX controls. Additional evidence demonstrated an important influence of estrogen on a recently discovered post-transcriptional mechanism for regulating expression of the AT1 receptor. This mechanism consists of cytosolic RNA binding proteins (BPs) that recognize the 5' leader sequence (5'LS) of the receptor mRNA. The activities of these 5'LS BPs were modulated by estrogen in an inverse manner to AT1 receptor regulation. Moreover, in vitro translation assays in wheat germ lysates suggested that the 5'LS BPs inhibited AT1 receptor translation. Our data therefore indicate that hormonal regulation of AT1 receptors involves modulation of 5'LS BPs by estrogen. These findings may in part account for the observed protective effects of estrogen on cardiovascular disease.

Adrenal Glands↗

PubMed1998

Regulation of cytosolic proteins binding cis elements in the 5' leader sequence of the angiotensin AT1 receptor mRNA.

RNA binding proteins (BPs) have been identified which bind within a -271 to -174 nt domain in the 5' leader sequence (5'LS) of the rat type 1 angiotensin (AT1) receptor mRNA and which encompass RNA cis elements upstream of -239. A 100 kDa RNA-protein complex is observed by UV-crosslinking in several tissues including brain, lung, and spleen. 5'LS RNA transcripts of the 1a and 1b AT receptor subtypes are strong competitors of 5'LS-protein complex formation. In contrast, antisense 5'LS AT1a transcripts, plasmid transcripts, poly U and poly A RNAs, or 5'LS AT1a cDNA are poor competitors. Deoxycorticosterone acetate (DOCA) decreased 5'LS-BP activities in the forebrain and hypothalamus under conditions known to significantly increase AT1 receptor expression. DOCA had no effect on 5'LS-BP activities in the pituitary which correlates with its lack of effect on pituitary AT1 receptor expression. These results indicate that DOCA differentially regulates 5'LS-BP activities in a tissue-specific manner and suggest that physiologically mediated changes in AT1 receptor expression are mediated by alterations in 5'LS-BP activities, which represents a previously unrecognized level of regulation for the renin angiotensin system.

Animals↗

PubMed1996

Identification of nonconserved amino acids in the AT1 receptor which comprise a general binding site for biphenylimidazole antagonists.

Mutational analysis based on pharmacological differences between mammalian and amphibian angiotensin II receptors (AT receptors) previously led to construction of a mutant receptor that gained > 25000-fold affinity for the biphenylimidazole, Losartan. This variant frog receptor also bound with high affinity other nonpeptides in the biphenylimidazole chemical class according to the following rank order of potency (expressed in Fmut values=mutant IC50/rAT1b IC50): Losartan, 0.91; L-162,389, 1.0; L-163,491, 1.9; L-158,809, 3.5; L-163,017, 3.9; SC-51,316, 3.9. In contrast, the imidazoleacrylic acids, SKF-108,566 (Fmut= 160) and SB-203,220 (Fmut = 170), bound with markedly less affinity. Thus, nonconserved residues determining the molecular requirements for biphenylimidazole recognition are conserved in general, but are not identical to nonconserved residues necessary for high affinity binding of imidazoleacrylic acids.

Amino Acid Sequence↗

PubMed1995

Augmentation of chrysotile-induced oxidative stress by BHA in mice lungs.

Asbestos is known to induce oxidative stress in the lung. The consumption of butylated hydroxyanisole (BHA) in preserved food and soft drinks is increasing in the general population, which includes workers in asbestos factories. Because there is no information on the effect of co-exposure to chrysotile and BHA, the time-dependent effects of a single intratracheal dose of chrysotile (1 mg per mouse) and a single ip dose of BHA (350 mg/kg body weight) on various indices of oxidative stress such as lipid peroxidation, hydrogen peroxide generation, glutathione peroxidase (GPX), glutathione reductase (GR), catalase, glucose-6-phosphate dehydrogenase (G6PDH) and glutathione (GSH) were followed for up to 14 days. Microsomal lipid peroxidation (as well as that induced by NADPH) was significantly enhanced by BHA in the chrysotile-exposed group. GPX and GR activities in the same group were gradually decreased by BHA. Non-significant modulation of catalase activity by BHA was also noted. BHA induces GSH to a significant extent in lungs exposed with chrysotile. An increase in the G6PDH activity was maximal (19%; P < 0.05) at day 3. The results clearly demonstrate that BHA enhances chrysotile-induced oxidative stress in the lung.

Animals↗

PubMed1993

Growth hormone (GH) stimulates insulin-like growth factor-I (IGF-I) and IGF-I-binding protein-3, but not GH receptor gene expression in livers of juvenile rats.

In the adult rat, expression of the liver GH receptor, insulin-like growth factor-I (IGF-I), and IGF-I-binding protein-3 (IGFBP-3) genes has been shown to be under GH control. Additionally, hypophysectomy and GH treatment have a differential effect on the relative abundance of liver IGF-I mRNA variants in adult rats. To further elucidate the time of appearance and the extent of GH control of liver GH receptor, IGF-I, and IGFBP-3 gene expression, we studied the effect of hypophysectomy and GH and IGF-I treatment in juvenile rats. Male Wistar rats were hypophysectomized (Hx) on postnatal day 26 and received twice daily sc injections of saline, recombinant human GH (2.5 U/kg.day), or recombinant human IGF-I (500 micrograms/kg.day) for 7 days. Sham-operated rats received the same treatment. Hx animals also received T4 (20 micrograms/kg.day). In Hx animals, there was a significant reduction in body weight (69.8 +/- 6.6 vs. 100.4 +/- 5.4 g; P < 0.001). GH, but not IGF-I, treatment increased body weight (79.6 +/- 9.6 g after GH vs. 69.8 +/- 6.6 g before GH; P < 0.05). GH treatment partially maintained liver, kidney, and lung weights in Hx animals and increased them in intact animals, whereas IGF-I treatment did so only in the lungs of intact and Hx animals. Serum GH and IGF-I levels were markedly reduced in Hx animals compared with those in intact controls, and GH treatment maintained, albeit partially, circulating IGF-I levels compared with those in saline-treated Hx animals. IGF-I mRNA levels were markedly reduced in Hx liver (25.0 +/- 5.4%; P < 0.001 compared with intact controls). GH treatment for 7 days increased IGF-I mRNA levels by 4.8-fold over the levels in 9-day Hx animals and increased IGF-I mRNA levels by 2.2-fold in control rats. Hypophysectomy decreased exon 2-containing transcripts by 7.0-fold and exon 1-containing transcripts by 4.1-fold. GH treatment, however, affected both exon 1- and exon 2-containing transcripts similarly. Hepatic IGFBP-3 mRNA levels were reduced in Hx (53.2 +/- 1.8%; P < 0.01 compared with intact controls) and IGF-treated Hx animals, but were not decreased in Hx GH-treated animals (100.6 +/- 9.5). No changes in GH receptor or GH-binding protein mRNA levels were caused by Hx, GH, or IGF-I treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMedDate not supplied

Bioremediation of soil contaminated with organic compounds with special reference to acrylonitrile.

Enrichment of acrylonitrile (AN) degrading bacterial culture from contaminated soil resulted in the isolation of two cultures which were identified as gram negative small rods (C1) and gram positive cocci (C2). One of the cultures (C1) was identified as Citrobacter fruendii on the basis of biochemical and physiological tests. Both the cultures (C1 and C2) were able to utilize acrylonitrile up to a concentration of 2000 mg/l as the sole source of carbon and nitrogen. The studies also confirmed that the acrylonitrile contaminated soil when ploughed with well mixed AN degrading culture, diammonium phosphate and farmyard manure, could be completely remediated within two months from the date of soil amendment.

Acrylonitrile↗