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T Papoian

Publications and source records attributed to T Papoian.

10 recordsLinked to original sources
PubMed1992

Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria.

Zidovudine (AZT) inhibits HIV-1 replication in AIDS. A limiting side effect is AZT-induced toxic myopathy. Molecular changes in a rat model of AZT-induced toxic myopathy in vivo helped define pathogenetic molecular, biochemical, and ultrastructural toxic events in skeletal muscle and supported clinical and in vitro findings. After 35 d of AZT treatment, selective changes in rat striated muscle were localized ultrastructurally to mitochondria, and included swelling, cristae disruption, and myelin figures. Decreased muscle mitochondrial (mt) DNA, mtRNA, and decreased mitochondrial polypeptide synthesis in vitro were found in parallel. Mitochondrial molecular changes occurred in absence of altered abundance of cytosolic glyceraldehyde-3-phosphate dehydrogenase, or sarcomeric mitochondrial creatine kinase mRNAs. Quadriceps mitochondrial DNA polymerase gamma activity was similar in both AZT-treated and control rats. In vivo findings with rats support the hypothesis that AZT-induced inhibition of mtDNA replication has an effect of depressing the abundance of striated muscle mtDNA, mtRNA, and mitochondrial polypeptide synthesis. This experimental approach may be useful to examine mitochondrial or toxic myopathies.

Animals↗
PubMed1992

Anthracyclines selectively decrease alpha cardiac actin mRNA abundance in the rat heart.

Anthracyclines are widely used antineoplastic agents, but possess a major side effect of congestive cardiomyopathy. Previously we showed a selective effect of the most commonly used anthracycline, doxorubicin, on decreasing alpha-cardiac (alpha c) actin mRNA abundance in the rat heart. The current studies examined the effects of several anthracyclines (doxorubicin, daunorubicin, and epirubicin) to determine if doxorubicin's previously reported effect on alpha c actin mRNA abundance is: 1) a property shared by other cardiotoxic anthracyclines; 2) selective when compared with a wider spectrum of contractile protein and muscle-specific mRNAs; and 3) related to the characteristic ultrastructural alterations, such as loss of myofilaments, seen in anthracycline-induced cardiomyopathy. Results showed a major selective effect of doxorubicin, daunorubicin, and epirubicin on decreasing alpha c actin mRNA abundance when compared with other contractile protein and muscle-specific mRNAs. In addition, ultrastructural examination of myocardium showed contractile alterations, including loss of myofilaments. These results suggest that decreased expression of selected cardiac genes may relate to the molecular mechanism of clinical anthracycline-induced cardiomyopathy.

Actin Cytoskeleton↗
PubMed1991

Selective alterations in rat cardiac mRNA induced by doxorubicin: possible subcellular mechanisms.

Doxorubicin (Adriamycin, ADR) is an effective antineoplastic agent with a major side effect of dilated cardiomyopathy. Previously we showed ADR selectively decreased alpha cardiac (alpha c) actin mRNA in the rat heart when compared to other mRNAs examined in heart and skeletal muscle. The present study determined if this effect was selective for mRNAs within the thin filament, related to inhibitory effects on mitochondrial transcription, and modified by pretreatment with the cardioprotective chelating agent ICRF-187. Adult Sprague-Dawley rats received ADR at 8 mg/kg intraperitoneally (ip) with or without pretreatment with ICRF-187 given at 80 mg/kg ip. After 3 days, rats were killed and myocardial RNA was extracted, electrophoresed, transferred to nitrocellulose, and hybridized with the [32]cDNA probes alpha c actin, troponin C (TnC), BamHI fragment of mouse mitochondria (MM), and glyceraldehyde-3-phosphate dehydrogenase (G3PD). Results showed a major depressive effect of ADR on rat myocardial alpha c actin mRNA. No depression of the other mRNAs examined (TnC, MM, or G3PD) was seen. ICRF-187 did not modify the effect. We conclude that the ADR-induced decrease in alpha c actin mRNA was: (1) selective within the thin filament; (2) not related to inhibitory effects on mitochondrial transcription; and (3) not related to free radical formation. Possible subcellular mechanisms are discussed.

Actins↗
PubMed1991

Early in vitro detection of interleukin-2-like activities by pretreatment with allogeneic blood lymphocytes in miniature swine.

In order to determine the means of monitoring the immunological status of allograft recipients in miniature swine, an assay was developed to measure interleukin (IL)-2 production in vitro by pretreatment of donor peripheral blood lymphocytes (PBL). Miniature swine were given 0 to 4 weekly intravenous transfusions of 5-10 X 10(7) donor PBL incompatible at major histocompatibility complex (MHC) and assayed in vitro for donor specific immune IL-2-like activities. The results are summarized as follows: (1) IL-2-like activity in 24 hr and 48 hr supernatants from mixed lymphocyte cultures (MLC) with MHC-incompatible PBL was detected without pretreatment. The 48 hr MLC supernatant exhibited a high IL-2-like activity compared with the 24 hr; (2) IL-2-like activity after only one transfusion with MHC-incompatible PBL was higher than that without pretreatment; (3) IL-2-like activity in 4 weekly transfusions was detectable slightly earlier than that without pretreatment or three transfusions with MHC-incompatible PBL.

Animals↗
PubMed1991

Mitochondrial ultrastructural and molecular changes induced by zidovudine in rat hearts.

Zidovudine (azidothymidine (AZT)) inhibits human immunodeficiency virus replication, prolongs survival, and delays progression of acquired immune deficiency syndrome. We determined AZT-induced molecular and ultrastructural changes in the rat heart. Rats (3 per group) were given drinking water with or without AZT (0.2 to 1.0 mg/ml; 29 to 102 mg/kg/day). After 21, 35, or 49 days, hearts were glutaraldehyde-fixed by abdominal aortic perfusion, processed, and examined by transmission electron microscopy. In parallel, myocardial RNA was extracted from hearts (AZT dose: 1 mg/ml; 35 days) and subjected to Northern analysis using cDNA probes for: alpha c-actin, troponin C, mitochondrial creatine kinase and malate dehydrogenase, a portion of the mitochondrial genome containing cytochrome b coding region (pMM26), and glyceraldehyde-3-phosphate dehydrogenase. Results showed marked and widespread cardiac mitochondrial swelling with fractured and disrupted cristae after 35 days of 1 mg/ml AZT. After a 14-day recovery, these ultrastructural defects did not reverse. Changes were not present in myocardium after 21 days of AZT nor after 35 days of lower dose AZT (0.2 mg/ml). Mitochondrial cytochrome b mRNA expression was depressed in AZT-treated rat hearts (35 days; 1 mg/ml AZT). mRNAs encoding glyceraldehyde-3-phosphate dehydrogenase, alpha c-actin, troponin C, mitochondrial creatine kinase, malate dehydrogenase, and mitochondrial ribosomal RNAs remained unchanged. AZT disrupts cardiac mitochondrial ultrastructure and expression of mitochondrial cytochrome b mRNA in a dose- and time-dependent fashion. The mechanism of AZT cardiotoxicity may relate to inhibition of mitochondrial DNA replication (at the level of DNA polymerase gamma) as postulated by others.

Animals↗
PubMed1990

Adriamycin cardiotoxicity in vivo. Selective alterations in rat cardiac mRNAs.

Adriamycin (ADR) is an antineoplastic agent with a side-effect of dilated cardiomyopathy. The present study examined ADR-induced changes in cardiac mRNA in vivo. Sprague-Dawley female rats (300 to 400 g) received from 2 to 8 mg/kg of ADR intraperitoneally. After 1 to 6 days, rats were killed and RNA was extracted from heart or gastrocnemius muscle by acid guanidinium-phenol-chloroform extraction. RNA underwent agarose electrophoresis, transfer to nitrocellulose, and hybridization with [32P]-cDNA probes specific to mRNA coding for alpha cardiac (alpha c) actin, alpha skeletal (alpha sk) actin, beta (beta) actin, and glyceraldehyde-3-phosphate dehydrogenase (G3PD). Results showed that alpha c actin mRNA levels in heart extracts were lowest at day 3 after injection, with a 60% decrease at 8 mg/kg ADR. beta actin and G3PD mRNAs decreased 28% and 21%, respectively. In gastrocnemius muscle extracts, both alpha sk actin and G3PD mRNAs decreased 30%. Results suggest a selective effect of ADR on depressing alpha c actin mRNA in the rat heart. Such changes may relate to clinical ADR-induced heart muscle disease.

Actins↗
PubMed1987

Insulin-like activity of chromium-binding fractions from brewer's yeast.

51CrCl3 was added to the incubation medium of Saccharomyces cerevisiae for up to 48 hr. After repeated freezing and thawing, lysing in 9 M urea with 1% NP-40 detergent, and dialysis against water, the lower molecular weight (Mr less than 3500) dialysate was retained on a SE53 cationic exchange column, eluted with 0.25 M NH4OH and fractionated on a Bio-gel P-2 column. The insulin-like biological activity of the fractions was measured by the 14C-glucose oxidation in isolated rat adipocytes. The biological activity that was found in two of nine fractions did not correspond to their chromium content. Moreover, identical findings were obtained when chromium was added not to the live yeast but to the yeast extract, which showed that its binding was a chemical process not requiring cellular activity. No fraction demonstrated insulin-potentiating activity on rat adipocytes.

Adipose Tissue↗
PubMed1985

Absence of down-regulation of insulin receptors in human breast cancer cells (MCF-7) cultured in serum-free medium: comparison with epidermal growth factor.

MCF-7 cells were cultured either in RPMI-1640 medium containing 10% fetal calf serum (FCS) or in a serum-free (SF) medium supplemented with insulin, epidermal growth factor (EGF) and transferrin. Binding studies were performed with 125I-insulin or 125I-EGF. In the FCS containing culture, down-regulation was seen for insulin receptors (47%), and for the EGF receptors (75%). Using cells grown in the serum-free medium we could not demonstrate down-regulation of the insulin receptors, while the EGF receptors were down-regulated to the same extent (74%). The number of binding sites per cell was about twice as much in cells cultured in FCS as that in SF medium. No significant differences were observed for receptor affinity of insulin or EGF in cells grown in both media. The rate of internalization of insulin or EGF into cells was similar in both culture conditions. The mechanism in which only EGF but not insulin demonstrated receptor down-regulation in SF medium remains unknown.

Cell Division↗