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P Narasimhan

Publications and source records attributed to P Narasimhan.

At least 19 recordsLinked to original sources
PubMed2006

A new approach for the investigation of reperfusion-related brain injury.

Effective stroke therapies require recanalization of occluded cerebral blood vessels; however, early reperfusion can cause BBB (blood-brain barrier) injury, leading to cerebral oedema and/or devastating brain haemorrhage. These complications of early reperfusion, which result from excess production of ROS (reactive oxygen species), significantly limit the benefits of stroke therapies. Here, we summarize some of the findings that lead to the development of a novel animal model that facilitates identification of specific free radical-associated components of the reperfusion injury process and allows therapeutic interventions to be assessed. In this model, KO (knockout) mice containing 50% activity of the mitochondrial antioxidant manganese-SOD (superoxide dismutase) (SOD2-KO) undergo transient focal ischaemia followed by reperfusion. These animals have delayed (>24 h) BBB breakdown associated with activation of matrix metalloproteinase-9, inflammation and a high brain haemorrhage rate. These adverse consequences are absent from wild-type littermates, SOD2 overexpressors and minocycline-treated SOD2-KO animals. In addition, using microvessel isolations following in vivo ischaemia/reperfusion, we were able to show that the tight junction membrane protein, occludin, is an early and specific target in ROS-mediated microvascular injury. This new model is ideal for studying ischaemia/reperfusion-induced vascular injury and secondary brain damage and offers a unique opportunity to evaluate free radical-based neurovascular protective strategies.

Animals↗
PubMed2000

Rapidly progressive fatal cutaneous T cell lymphoma with a trauma-related presentation.

A case of rapidly progressive cutaneous T cell lymphoma with a trauma-related presentation in a 73-year-old man is reported. Clinically, the patient presented with an ulcerated cutaneous mass at the site of trauma-related hematoma of the leg. The histopathology was that of tumor phase cutaneous T cell lymphoma with involvement of the skin and subcutis. The diagnostic challenge of this clinical presentation and the rapidly progressive course are highlighted.

Aged↗
PubMed1999

Copper-zinc superoxide dismutase prevents the early decrease of apurinic/apyrimidinic endonuclease and subsequent DNA fragmentation after transient focal cerebral ischemia in mice.

BACKGROUND AND PURPOSE: DNA damage and its repair mechanism are thought to be involved in ischemia/reperfusion injury in the brain. We have previously shown that apurinic/apyrimidinic endonuclease (APE/Ref-1), a multifunctional protein in the DNA base excision repair pathway, rapidly decreased after transient focal cerebral ischemia (FCI) before the peak of DNA fragmentation. To further investigate the role of reactive oxygen species in APE/Ref-1 expression in vivo, we examined the expression of APE/Ref-1 and DNA damage after FCI in wild-type and transgenic mice overexpressing copper-zinc superoxide dismutase. METHODS: Transgenic mice overexpressing copper-zinc superoxide dismutase and wild-type littermates were subjected to 60 minutes of transient FCI by intraluminal blockade of the middle cerebral artery. APE/Ref-1 protein expression was analyzed by immunohistochemistry and Western blot analysis. DNA damage was evaluated by gel electrophoresis and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL). RESULTS: A similar level of APE/Ref-1 was detected in the control brains from both groups. APE/Ref-1 was significantly reduced 1 hour after transient FCI in both groups, whereas the transgenic mice had less reduction than that seen in wild-type mice 1 and 4 hours after FCI. DNA laddering was detected 24 hours after FCI and was decreased in transgenic mice. Double staining with APE/Ref-1 and TUNEL showed that the neurons that lost APE/Ref-1 immunoreactivity became TUNEL positive. CONCLUSIONS: These results suggest that reactive oxygen species contribute to the early decrease of APE/Ref-1 and thereby exacerbate DNA fragmentation after transient FCI in mice.

Animals↗
PubMed1996

Ten kilobases of 5'-flanking region confers proper regulation of the mouse alcohol dehydrogenase-1 (Adh-1) gene in kidney and adrenal of transgenic mice.

The expression profile of the mouse Adh-1 gene, which encodes class I alcohol dehydrogenase enzyme (ADH), is complex and includes tissue specificity and differential hormone responsiveness. Whereas kidney Adh-1 transcription rate is stimulated six- to sevenfold by testosterone treatment, adrenal gland ADH-1 mRNA is reduced to less than 5% of control level within 18 h following hormone administration. Androgen receptor is required for both responses since neither occurs in Tfm mutant mice lacking receptor. Hormonal and tissue-specific aspects of Adh-1 regulation were studied in transgenic mice harboring either of two constructs containing either -2.5 kb or -10 kb of 5'-flanking sequence attached to an Adh-1 minigene. The minigene transcript was expressed in kidney and adrenal tissues, but not liver, in five independent lines harboring a transgene with -2.5 kb of 5'-flanking sequence. Androgen treatment repressed the level of the minigene transcript in adrenal gland, but did not cause induction in kidney. In four lines of transgenic mice carrying the construct with -10 kb of 5'-flanking sequence, the minigene transcript was both repressed in adrenal and induced in kidney by testosterone. These lines have no detectable transgene expression in liver tissue. The -10 kb region in the mouse Adh-1 gene contains necessary controlling regions for proper tissue expression and hormonal regulation in kidney and adrenal; however, this region does not contain all essential elements necessary for expression in liver.

Adrenal Glands↗
PubMed1996

Methylmalonyl-CoA mutase induction by cerebral ischemia and neurotoxicity of the mitochondrial toxin methylmalonic acid.

Differential screening of gerbil brain hippocampal cDNA libraries was used to search for genes expressed in ischemic, but not normal, brain. The methylmalonyl-CoA mutase (MCM) cDNA was highly expressed after ischemia and showed a 95% similarity to mouse and 91% similarity to the human MCM cDNAs. Transient global ischemia induced a fourfold increase in MCM mRNA on Northern blots from both hippocampus and whole forebrain. MCM protein exhibited a similar induction on Western blots of gerbil cerebral cortex 8 and 24 hr after ischemia. Treatment of primary brain astrocytes with either the branched-chain amino acid (BCAA) isoleucine or the BCAA metabolite, propionate, induced MCM mRNA fourfold. Increased concentrations of BCAAs and odd-chain fatty acids, both of which are metabolized to propionate, may contribute to inducing the MCM gene during ischemia. Methylmalonic acid, which is formed from the MCM substrate methylmalonyl-CoA and which inhibits succinate dehydrogenase (SDH), produced dose-related cell death when injected into the basal ganglia of adult rat brain. This neurotoxicity is similar to that of structurally related mitochondrial SDH inhibitors, malonate and 3-nitropropionic acid. Methylmalonic acid may contribute to neuronal injury in human conditions in which it accumulates, including MCM mutations and B12 deficiency. This study shows that methylmalonyl-CoA mutase is induced by several stresses, including ischemia, and would serve to decrease the accumulation of an endogenous cellular mitochondrial inhibitor and neurotoxin, methylmalonic acid.

Animals↗
PubMed1996

Astrocyte survival and HSP70 heat shock protein induction following heat shock and acidosis.

Although severe acidosis is an important mediator of brain infarction, recent evidence suggests that mild acidosis may protect ischemic cells. The HSP70 heat shock protein is induced by acidosis in cultured cells and in ischemic brain and protects cells against many types of injury. Therefore, this study determined whether induction of heat shock proteins protects cultured astrocytes against acidosis. Brief exposure of cultured cortical astrocytes to acid (pH 5.2 for 40 min) or heat shock (45 degrees C for 40 min) markedly induced hsp70 mRNA and HSP70 protein. HSP70 protein was detected with the C92 monoclonal antibody (Welch and Suhan: J Cell Biol 103:2035, 1986), which has been shown to recognize the protein product of the full-length rat hsp70 cDNA (Longo et al: J Neurosci Res 36:325, 1993). Heat shock of the cultured cortical astrocytes completely protected the astrocytes from an otherwise lethal heat exposure 24 h later (45 degrees C for 4 h). In contrast, heat pretreatment sensitized the astrocytes to injury from acidosis 24 h later. Acid pretreatment, which markedly induced the HSP70 protein without producing astrocytic cell death, similarly sensitized the cells to injury from acidosis 24 h later (60% survival following pH 5.2 for 3 h versus 90% survival in controls; P < 0.0001). Surprisingly, heat shock pretreatment protected astrocytes against exposure to acid 48 h later (P < 0.05, 1.5-3 h), whereas acid pretreatment had no effect on astrocyte survival 48 h later. Since heat shock did not protect against acidosis at 24 h when HSP70 induction was maximal but did protect at 48 h when HSP70 was markedly diminished, the protective effect of heat shock at 48 h may be related to stress proteins present at 48 h. It is concluded that induction of HSP70 and other heat shock proteins by heat shock protects astrocytes against subsequent lethal heat shock. However, heat shock and acid treatment increase the vulnerability of astrocytes to acidosis 24 h later in spite of the induction of HSP70 heat shock proteins. The finding that heat shock protected astrocytes against acidosis 2 days later may suggest that delayed induction of stress proteins partially protects the astrocytes against damage produced by high concentrations of hydrogen ions.

Acidosis↗
PubMed1993

cDNA cloning and expression of stress-inducible rat hsp70 in normal and injured rat brain.

A reverse transcriptase-polymerase chain reaction (RT-PCR) product obtained from ischemic rat brain RNA was used to screen a rat ischemic forebrain cDNA library for a cDNA clone containing the entire open reading frame for the inducible hsp70. The coding sequence for the rat hsp70 cDNA demonstrated significant similarities with the human hsp70 of Hunt and Morimoto (Proc Natl Acad Sci 82:6455-6459, 1985) and the mouse hsp70 of Hunt and Calderwood (Gene 87:199-204, 1990). The rat inducible hsp70 and constitutive hsc73 sequences are distinct. There was a low level of hsp70 mRNA expression in normal rat brain as in found in other tissues. hsp70 mRNA was markedly induced in rat brain 8 hours following global ischemia and kainic acid-induced seizures. Northern blots showed a approximately 2.9kb hsp70 mRNA band from control, kainic acid, and ischemic brains. RT-PCR confirmed the presence of hsp70 mRNA in normal rat brain. Since there are at least five human and six mouse inducible hsp70 genes known, many other rat hsp70 genes probably exist that could function in different cells or organelles or be induced under different circumstances.

Animals↗
PubMed1992

Acute leukostasis pulmonary distress syndrome.

A 75-year-old woman in accelerated-phase chronic myeloid leukemia with hyperleukocytosis presented with acute respiratory distress syndrome. Despite early and aggressive pulmonary support and cytoreductive chemotherapy, the patient died. Autopsy confirmed the presence of the leukostasis syndrome. The clinical, radiologic, pathophysiologic, and therapeutic aspects of this entity are reviewed.

Acute Disease↗
PubMed1988

Displacement of nutritional receptors on cell membrane as an initiation factor in carcinogenesis.

Carcinogenesis is a multi-step process, and initiation is the first step. The cell membrane may hold the key to the entry of carcinogens. According to our hypothesis, the cell membrane may have receptors for nutrients including the essential vitamins, in addition to hormones, immune modulators, prostaglandins and neurotransmitters. In addition, there may be cytoplasmic counter receptors to the above. Carcinogens after prolonged contact with cell membrane may displace nutritional receptors to gain an abnormal foothold on cell membrane before entering the cytoplasm and cell nucleus and activating the oncogenes. If this is proven to be correct, there is a possibility of cancer prevention at the cellular level. A possible experimental approach is also described.

Cell Membrane↗
PubMed1982

Responses of chronic lymphocytic leukemic lymphocytes to increasing concentrations of phytohemagglutinin during short-term culture.

Lymphocytes obtained from CLL patients containing high and low peripheral lymphocyte cell counts were cultured in the absence and presence of increasing concentrations of phytohemagglutinin for periods of up to 2 h. Lymphocytes from patients with low cell counts (less than 50,000/mm3) were stimulated to incorporate 3H-uridine during the 1st h of culture by concentrations of PHA ranging from 1 to 32 microgram/ml. Under identical conditions, lymphocytes from patients with high cell count (greater than 50,000/mm3) were barely affected. During the 2nd h of culture the above concentrations stimulated to a lesser degree the former group of lymphocytes, whereas it inhibited incorporation by the latter group. The results obtained suggest a qualitative difference in the response of CLL lymphocytes to PHA in accordance with the progression of the disease.

Cells, Cultured↗
PubMed1981

The effect of steroids on the synthesis of RNA by isolated T and B lymphocytes of normal donors and patients with chronic lymphocytic leukemia.

T- and B-lymphocyte populations were isolated from peripheral blood of 11 patients who had chronic lymphocytic leukemia (CLL) and four normal healthy donors. The isolated T and B cells were cultured in the absence and presence of cortisol, dexamethasone, beta-estradiol, testosterone, and progesterone, and the effects of these steroids on the synthesis of RNA was investigated. T and B cells of the CLL group were significantly more inhibited in the synthesis of RNA than the respective cells of the normal control group. The individual responses of T and B cells to each of the steroids differed in both the CLL and control groups, as well as between the respective subpopulations of each of the groups. Analysis of th LDH isoenzyme patterns of T and B cells of each group suggested major differences in the distribution of their LDH isoenzymes.

Aged↗