High dose lamivudine and hepatitis B.
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Anti-HIV Agents↗
Biomedical subjects
S J Saggi
Publications and source records attributed to S J Saggi.
Evidence for pH sensitivity of tumor necrosis factor-alpha release by alveolar macrophages.
Alveolar macrophages (m phi) participate in inflammatory and immune responses in acidic microenvironments such as the interstitial fluids of tumors and abscesses. Two plasmalemmal H+ extruders interact to control the acid-base status of alveolar m phi, namely a V-type H+ pump (V-ATPase) and a Na+/H+ exchanger. The present study examined the effects of extracellular pH (pHo) and H+ transport inhibitors on tumor necrosis factor-alpha (TNF-alpha) release induced by endotoxin (lipopolysaccharide) in rabbit alveolar m phi. The amount and activity of TNF-alpha in m phi-conditioned media were determined by enzyme-linked immunosorbent assay and L929 fibroblast bioassay, respectively. TNF-alpha release was suppressed progressively at lower pHo values (< or = 7.0). Also, bafilomycin A1 (a specific inhibitor of V-ATPases) significantly reduced the amount and activity of TNF-alpha in m phi-conditioned media (pHo 7.4). However, bafilomycin caused a significant increase in the nonspecific cytotoxicity (i.e. bioactivity insensitive to TNF-alpha antibody) of m phi-conditioned media. The effects of bafilomycin specifically on TNF-alpha release followed a time course similar to that of acidic pHo, suggesting that both treatments acted on similar events in the lipopolysaccharide signal transduction pathway. Amiloride (an inhibitor of Na+ transporters including the Na+/H+ exchanger) also suppressed TNF-alpha release but displayed a time course of action different from the acidic pHo or bafilomycin.
Amiloride↗
Expression of cytokine-like genes JE and KC is increased during renal ischemia.
Both mitogenic and inflammatory phenomena accompany the renal response to ischemic injury. Previous studies have shown that several nuclear-binding members of the immediate early genes are prominently expressed after renal ischemia and may underlie the mitogenic response to such injury. We now report on the expression of JE and KC, other growth-factor-responsive genes that code for small secreted glycoproteins with cytokine-like properties, which may play a role in inflammation. The expression of the immediate early genes JE and KC was determined in rat kidney tissue at varying time points after release of a 50-min period of bilateral renal hilar clamping. Relative levels of mRNA for JE and KC were analyzed by Northern blot analysis of cortical and outer stripe mRNA. KC mRNA rose rapidly to peak values at 1 h and returned toward low baseline levels by 24 h after release of the hilar clamp. By contrast, JE mRNA reached peak levels later and remained elevated for at least 96 h after ischemia. JE antigen was localized immunocytochemically to the apical regions of the cortical and medullary thick ascending limbs as well as in the lumen of the distal nephron in ischemic kidneys. Cells of the glomerulus and proximal tubules were negative for JE antigen. In contrast to the increase in JE and KC mRNA, steady-state levels of uromodulin (Tamm Horsfall) mRNA, a cytokine binding protein also made by the thick ascending limb, declined to virtually undetectable levels by 24 h after ischemia. Thus the increases in JE and KC are not generalized phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Changes in gene expression after temporary renal ischemia.
Temporary renal ischemia is followed by increased DNA synthesis and cell division as the kidney restores the continuity of the renal epithelium. We sought to characterize some of the changes in proto-oncogene and growth factor expression during this proliferative response. Northern analysis of polyadenylated RNAs of kidney cortical and outer stripe of outer medullary tissue from male Sprague-Dawley rats was performed following release of renal hilar clamping of 50 minutes duration. Ischemia produced an increase in c-fos mRNA that reached a peak at one hour and declined rapidly to control levels by four hours after release of the clamp. A similar rapid increase and decrease in early growth response 1 (Egr 1) mRNA was noted. The response of these immediate early genes was typical of their response to mitogens, suggesting that they served a similar role in renal cell regeneration. Levels of c-Ki-ras and glyceraldehyde phosphate dehydrogenase mRNA were unchanged. Renal preproEGF mRNA decreased at two hours, was virtually absent by 24 hours and remained low for at least four days after ischemia. Urinary excretion of EGF fell immediately after release of ischemia and before the decline in preproEGF mRNA or SNGFR, suggesting post-transcriptional affects of ischemia on renal EGF production. EGF excretion returned to only 50% of control by day 21. Specific 125I-EGF binding increased in membrane fractions of cortex, outer medulla and inner medulla as early as 24 hours after release of the clamp. Cortical 125I-EGF binding increased in the proximal tubule but not in the glomerulus.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cloning and sequencing of the rat preproepidermal growth factor cDNA: comparison with mouse and human sequences.
We have cloned and sequenced the cDNA corresponding to the rat preproepidermal growth factor (ppEGF) mRNA. The cDNA contained 4,801 nucleotides, similar to that reported for the mouse (4,749 nucleotides) and the human mRNAs (4,871 nucleotides). The predicted protein sequence would contain 1,133 amino acids, smaller than that reported for the mouse (1,217 amino acids) and the human sequences (1,207 amino acids). The results of the sequencing of several cDNA clones suggested the existence of more than one structural gene for ppEGF. In addition, there was an occurrence of alternative splicing events, resulting in deletions of entire exons from the mature mRNA. These alternative splicing events do not create frameshift mutations but cause a deletion of one or more of the "EGF-like" repeat units from the ppEGF. There is approximately the same homology between the rat and mouse amino acid sequences both in the EGF region and in the other regions of the ppEGF protein. We conclude that, because of this conservation of homology, there may be an important function performed by these other regions of the ppEGF besides their function as a precursor for the EGF protein.
Amino Acid Sequence↗