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Biomedical subjects

S H Zaidi

Publications and source records attributed to S H Zaidi.

At least 19 recordsLinked to original sources
PubMed2000

Gene transfer of the serine elastase inhibitor elafin protects against vein graft degeneration.

BACKGROUND: Leukocyte infiltration and serine elastase activity lead to smooth muscle cell proliferation in association with posttransplant coronary arteriopathy and may also be involved in vein graft neointimal formation. A number of therapies have targeted cellular proliferation, but the inhibition of serine elastase-mediated extracellular matrix remodeling has not been investigated as a potential strategy to prevent neointimal formation and subsequent atherosclerotic degeneration in vein grafts. METHODS AND RESULTS: We studied jugular vein grafts 48 hours after interposition into the carotid arteries of rabbits and demonstrated inflammatory cell infiltration and elevated serine elastase activity, a stimulus for matrix remodeling and deposition of elastin. Therefore, elastolytic activity in vein grafts was targeted through transient expression of the selective serine elastase inhibitor elafin with hemagglutinating virus of Japan liposome-mediated gene transfer. Elafin transfection reduced inflammation by 60% at 48 hours and neointimal formation by approximately 50% at 4 weeks after implantation. At 3 months, a 74% decrease in neointimal elastin deposition correlated with protection against cholesterol-induced macrophage infiltration and lipid accumulation, which were both reduced by approximately 50% in elafin-transfected grafts relative to controls. CONCLUSIONS: Gene transfer of the selective serine elastase inhibitor elafin in vein grafts is effective in reducing the early inflammatory response. Although transient expression of elafin delays neointimal formation, it is also sufficient to cause an alteration in elastin content of the extracellular matrix, making it relatively resistant to atherosclerotic degeneration.

Animals↗
PubMed2000

Cancer incidence in Karachi, Pakistan: first results from Karachi Cancer Registry.

No cancer incidence data from Pakistan have been published in the 5 decades since independence. Incidence data for the period 1995-1997 from the population of the Karachi South district (1.7 million) are presented here. A total of 4,268 new cancer cases were registered during this period: 2,160 cases in males and 2,108 cases in females. Overall, 95.3% of the incident cases were microscopically verified. The incidence rates for all cancers combined were 80.5 per 100,000 (crude) and 136.7 per 100,000 (age- standardised rates [ASR]) for males and 91.8 (crude) and 163.2 per 100,000 (ASR) for females. In males, lung cancer (ASR 20.3) was the most frequently recorded malignancy followed by oral cavity (ASR 13.8) and larynx cancer (ASR 8.6). In females, breast was the most common site of cancer, accounting for one third of female cancers (ASR 51.7), followed by oral cavity (ASR 14.1) and ovarian cancer (ASR 10.2). Karachi reports the highest incidence of breast cancer for any Asian population, except Jews in Israel. Tobacco smoking is estimated to be responsible for 40% of cancers in males and tobacco chewing for a further substantial proportion of head and neck cancers.

Adolescent↗
PubMed2000

Nitric oxide reduces vascular smooth muscle cell elastase activity through cGMP-mediated suppression of ERK phosphorylation and AML1B nuclear partitioning.

Nitric oxide (NO) reduces the severity of pulmonary vascular disease in rats as do elastase inhibitors. We therefore hypothesized that NO inhibits elastase by suppressing mitogen-activated protein kinases that trans-activate AML1B, a transcription factor for elastase. We used cultured pulmonary artery smooth muscle cells in which serum-treated elastin (STE) induces a > threefold increase in elastase activity as evaluated by solubilization of [(3)H]-elastin. NO donors (SNAP and DETA NONOate) inhibited elastase in a dose-dependent manner as did a cGMP mimetic (8-pCPT-cGMP). SNAP inhibition of elastase was reversed by coadministration of a cGMP-PKG inhibitor (Rp-8-pCPT-cGMP). The STE-induced increase in phospho-ERK was suppressed by NO donors and the cGMP mimetic, and reversed by cGMP-PKG inhibitor, as was expression of AML1B and DNA binding in nuclear extracts. A concomitant increase in p38 phosphorylation was also inhibited by SNAP, but whereas MEK inhibitor (PD98059) suppressed elastase and AML1B-DNA binding, a p38 inhibitor (SB202190) did not. Our study uniquely links NO with inhibition of elastase-dependent matrix remodeling in vascular disease by suggesting a cGMP-PKG-related mechanism suppressing ERK-mediated partitioning of AML1B in nuclear extracts.

Animals↗
PubMed2000

Suppressed smooth muscle proliferation and inflammatory cell invasion after arterial injury in elafin-overexpressing mice.

Elastases degrade the extracellular matrix, releasing growth factors and chemotactic peptides, inducing glycoproteins such as tenascin, and thereby promoting vascular cell proliferation and migration. Administration of serine elastase inhibitors reduces experimentally induced vascular disease. The ability to mount an intrinsic anti-elastase response may, therefore, protect against intimal/medial thickening after vascular injury. To investigate this, we showed that wire-induced endothelial denudation of the carotid artery is associated with transient elevation in elastase activity and confirmed that this is abolished in transgenic mice overexpressing the serine elastase inhibitor, elafin, targeted to the cardiovascular system. Ten days after injury, nontransgenic littermates show vessel enlargement, intimal thickening, increased medial area and cellularity, and 2-fold increase in tenascin. Injured vessels in transgenic mice become enlarged but are otherwise similar to sham-operated controls. Injury-induced vessel wall thickening, which is observed only in nontransgenic mice, is related to foci of neutrophils and macrophages, in addition to smooth muscle cells that fail to stain for alpha-actin and are likely dedifferentiated. Our study therefore suggests that a major determinant of the vascular response to injury is the early transient induction of serine elastase activity, which leads to cellular proliferation and inflammatory cell migration.

Animals↗
PubMed1999

Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis.

Serine elastases degrade elastin, stimulate vascular smooth muscle cell migration and proliferation, and are associated with myocardial damage. To evaluate the impact of elastase inhibition on cardiovascular development and disease, transgenic mice were created in which the mouse preproendothelin-1 promoter was used to target elafin overexpression to the cardiovascular system. To distinguish the transgene from endogenous elafin, constructs were made incorporating a FLAG sequence; the COOH-terminus FLAG-tagged elafin construct produced a stable, functionally active gene product and was used to create transgenic mice. Consistent with endothelin expression, abundant elafin mRNA was observed in transgenic F1 embryos (embryonic day 13.5) and in adult transgenic mice heart, trachea, aorta, kidney, lung, and skin, but not in liver, spleen, and intestine. Functional activity of the transgene was confirmed by heightened myocardial elastase inhibitory activity. No tissue abnormalities were detected by light microscopy or elastin content. However, injection of 10 plaque-forming units (PFU) of encephalomyocarditis virus resulted in death within 11 days in 10 out of 12 nontransgenic mice compared with one out of nine transgenic littermates. This reduced mortality was associated with better cardiac function and less myocardial inflammatory damage. Thus, elafin expression may confer a protective advantage in myocarditis and other inflammatory diseases.

Animals↗
PubMed1998

AML1-like transcription factor induces serine elastase activity in ovine pulmonary artery smooth muscle cells.

In previous studies, we showed that induction of pulmonary artery (PA) smooth muscle cell (SMC) elastase activity by serum-treated elastin (STE) requires DNA transcription. We therefore used differential mRNA display to identify transcripts expressed coincident with elastase induction. Twenty-four individual transcripts were differentially expressed from a screen of approximately 2000 mRNA sequences. An mRNA with sequence homology to the human transcription factor AML1 was identified and subsequently cloned from ovine PA SMCs. Since AML1 binds to a consensus sequence in the promoter of neutrophil elastase, we pursued the possibility that AML1 is a candidate transcription factor for SMC elastase. We documented by immunohistochemistry that serum stimulation induces increased expression of AML1 in the nucleus of PA SMCs. We also showed that STE induction of elastase activity is associated with early expression of AML1 mRNA and protein and that AML1 consensus sequence DNA binding activity is increased in nuclear extracts of STE-treated cells. In addition, AML1 antisense oligonucleotides reduced serum induction of elastase activity. Our study thus provides the first functional evidence of AML1 transcriptional activity related to elastase genes and offers novel insights into the broader biological significance of AML1 in nonmyeloid cells.

Animals↗
PubMed1998

A serine elastase inhibitor reduces inflammation and fibrosis and preserves cardiac function after experimentally-induced murine myocarditis.

In viral myocarditis, inflammation and destruction of cardiac myocytes leads to fibrosis, causing progressive impairment in cardiac function. Here we show the etiologic importance of serine elastase activity in the pathophysiology of acute viral myocarditis and the therapeutic efficacy of an elastase inhibitor. In DBA/2 mice inoculated with the encephalomyocarditis virus, a more than 150% increase in myocardial serine elastase activity is observed. This is suppressed by a selective serine elastase inhibitor, ZD0892, which is biologically effective after oral administration. Mice treated with this compound had little evidence of microvascular constriction and obstruction associated with myocarditis-induced ischemia reperfusion injury, much less inflammation and necrosis, only mild fibrosis and myocardial collagen deposition, and normal ventricular function, compared with the infected nontreated group.

Administration, Oral↗
PubMed1995

Nucleolin and heterogeneous nuclear ribonucleoprotein C proteins specifically interact with the 3'-untranslated region of amyloid protein precursor mRNA.

The central nervous system deposition by neurons and glia of beta A4 amyloid protein is an important contributing factor to the development of Alzheimer's disease. Amyloidogenic cells overexpress amyloid precursor protein (APP) mRNAs suggesting a transcriptional or post-transcriptional defect may contribute to this process. We have previously shown that APP mRNAs display regulated stability which is dependent on a 29-base element within the 3'-untranslated region (UTR). This domain specifically interacted with several cytoplasmic RNA-binding proteins. We have purified these APP RNA-binding proteins from a human T-cell leukemia and demonstrate that five cytoplasmic proteins of 70, 48, 47, 39, and 38 kDa form the previously observed APP RNA protein complexes. Amino acid sequence analyses showed that the 70-, 48-, and 47-kDa proteins were fragments of nucleolin and that the 39- and 38-kDa proteins were heterogeneous nuclear ribonucleoprotein (hnRNP) C protein. Northwestern and Western blot analyses of purified material further confirmed these data. Nucleolin protein is known to shuttle between the nucleus and cytoplasm but hnRNP C has not been reported within the cytoplasm. This report of sequence specific, mRNA binding by nucleolin and hnRNP C suggests that these proteins participate in the post-transcriptional regulation of APP mRNA through 3'-UTR, site-specific interactions.

Amino Acid Sequence↗
PubMed1995

Post-transcriptional regulation of the p53 tumor suppressor gene during growth-induction of human peripheral blood mononuclear cells.

Regulation of p53 gene expression at the post-transcriptional level was investigated during growth induction of human peripheral blood mononuclear cells (PBMCs). Freshly isolated PBMCs, which are in the Go phase of the cell cycle, were shown to express low levels of p53 mRNA that was rapidly degraded with a half life of 1 h. The rapid decay of p53 mRNA in quiescent PBMCs was dependent on global protein synthesis as treatment with cycloheximide resulted in stabilization of the p53 message. PBMCs were stimulated to enter the cell cycle by treatment with a combination of the mitogenic lectin phytohemagglutinin (PHA) and phorbol ester (TPA). Progressive stabilization of the p53 message occurred in PBMCs during growth induction. By 24 h of incubation in the presence of PHA and TPA, the half life of p53 mRNA was 6 h and p53 mRNA steady state levels were increased 4.5 to 5.0-fold. p53 protein was not detected in quiescent PBMCs, but was readily detected in PBMCs stimulated for 24 h with PHA and TPA. Stabilization of p53 mRNA was observed in PBMCs treated with either PHA or TPA, but to a lesser degree than when PHA and TPA were used as co-stimulants. These results indicate that differential degradation of p53 messenger RNA occurs in quiescent vs mitogen stimulated PBMCs and suggest that post-transcriptional regulation importantly contributes to increased p53 mRNA steady state levels as PBMCs enter the cell cycle.

Cell Division↗
PubMed1995

Danger to the popliteal artery in high tibial osteotomy.

We report a case in which the popliteal artery was divided during upper tibial osteotomy performed with the knee in 90 degrees of flexion. This position is believed to allow it to fall safely back from the tibia, but we could find no published confirmation. We used duplex ultrasonography in ten healthy volunteers to measure the distance from the popliteal artery to the posterior surface of the tibia at various degrees of flexion of the knee. Our results showed that in 12 of 20 knees the popliteal artery was closer to the tibia in 90 degrees of knee flexion than in full extension. Surgeons performing upper tibial osteotomy should be aware that flexing the knee does not protect the popliteal artery from injury.

Aged↗
PubMed1994

Multiple proteins interact at a unique cis-element in the 3'-untranslated region of amyloid precursor protein mRNA.

Growing evidence suggests that Alzheimer's disease results from dysregulated production and deposition of beta-amyloid in the central nervous system. beta-Amyloid is derived from proteolytic processing of one of multiple amyloid precursor protein (APP) isoforms. The production of APP in many somatic tissues and tumor cell lines provides a more accessible model to study the regulation of APP gene expression. Recent data suggest that APP mRNAs accumulate in activated lymphocytes and neuronal tumor lines. We are interested in defining the contribution of alterations in stability to changes in steady-state APP mRNA levels in these model systems. Herein we demonstrate by mobility shift assay that the 3'-untranslated region of APP RNAs which contain a contiguous 29-base region interacts in vitro with multiple mRNA-binding proteins found in cytosolic lysates prepared from normal and transformed human cells. UV cross-linking of radiolabeled APP RNAs to cytosolic protein extracts followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis identified six distinct RNA-protein complexes of 42, 47, 65, 73, 84, and 104 kDa. Competition assays with APP, AU-rich, or irrelevant RNAs demonstrated that binding was specific and in some cases preferential for AU- or U-rich sequences by which we tentatively place the binding site of the proteins along the 29-base region. APP mRNA-binding proteins were constitutively active in all tumor lines examined as well as at diminished levels in whole human brain cytosolic lysates. The core element is AU-rich and highly conserved between human and some murine APP mRNAs. In the accompanying paper (Zaidi, S. H. E. and Malter, J. S. (1994) J. Biol. Chem. 269, 24007-24013) we show that this 29-base element in the 3'-untranslated region regulates the stability of APP mRNA. Cumulatively these data suggest that steady-state APP mRNA levels are modulated by cytosolic protein-RNA interactions.

Amyloid beta-Protein Precursor↗
PubMed1994

Amyloid precursor protein mRNA stability is controlled by a 29-base element in the 3'-untranslated region.

In the accompanying paper (Zaidi, S. H. E., Denman, R., and Malter, J. S. (1994) J. Biol. Chem. 269, 24000-24006) we demonstrate that in tumor and normal cells, multiple cytosolic proteins interact with a 29-base sequence in the 3'-untranslated region of amyloid precursor protein (APP) mRNA. These data suggested that APP gene expression may be modulated by regulated APP mRNA decay. We have investigated this prediction by measuring the decay rates of APP mRNA in resting and mitogen-treated peripheral blood mononuclear cells and H4 and K562 tumor cell lines. In resting peripheral blood mononuclear cells, APP mRNA decayed with a half-life of 4 h. Under these conditions, the activity of APP mRNA-binding proteins was not detectable. After activation, binding protein activities were induced, and APP mRNA decay was blocked with a half-life of > 12 h. In log phase neuronal or lymphoid tumor cell lines, binding activity was constitutively present and APP mRNA displayed a half-life of > 12 h. Protein synthesis inhibition by cycloheximide had no effect on APP mRNA decay in normal or tumor cells. Transfected wild type or mutant APP mRNAs that lacked the 29-base region were stable (t1/2 > 10 h) in K562 tumor cells. Therefore, we conclude that the 29-base region functions in cis to destabilize APP mRNA in resting, normal cells. Upon activation APP mRNA-binding proteins are induced, interact with the 29-base region, and likely participate in stabilization of the mRNA.

Amyloid beta-Protein Precursor↗
PubMed1992

Pattern of leucocyte acid phosphatase reaction in T-cell lymphoblastic leukaemia.

Acid phosphatase (AP) reaction is a specific cytochemical marker for T-cell lymphoblastic leukaemia (T-ALL). Twenty six cases of ALL were diagnosed as T-ALL employing cytochemical profiles including AP and sheep red blood cell rosettes. Three district patterns of AP reaction were observed. On one end of the spectrum, 100% of the positive blasts showed the classical dot-like reaction while on the other 100% showed a scattered reaction. Between the two a mixed pattern was observed with 30-80% of the positive blasts showing the dot-like reaction while the rest showed scattered pattern. Dot-like pattern showed L1 morphology, high counts and low SRBC rosettes while scattered showed L2 morphology, low counts and high SRBC rosettes. The pattern observed in our series differs from the dot-like reaction observed in T-ALL in the western series. We recommend that this pattern must be borne in mind when employing AP reaction for T-ALL diagnosis (JPMA 42: 151, 1992).

Acid Phosphatase↗
PubMed1991

Unilateral proptosis in E.N.T. practice.

Seventeen cases of unilateral proptosis aged 11-54 years are presented. The proptosis was due to mucormycosis in 7, ethmoid polyposis in 4, malignancy in 4, and one each due to Ringert's tumour and fibrous dysplasia. Surgery was performed in all cases with the aim of total extirpation of disease and orbital repositioning. The surgical approaches included transverse maxillary osteotomy, transantral ethmoidectomy, modified lateral rhinotomy, and orbital decompression. There was one fatality, and two recurrences. Three cases showed satisfactory and eleven excellent results.

Adolescent↗
PubMed1990

A study of H2 receptor antagonists in the treatment of chronic intractable pharyngitis.

In a controlled study of 75 patients suffering from chronic pharyngitis: 30 were treated with H2-receptor antagonist, 30 with H1-receptor antagonist, local decongestants and antiseptic gargles: and 15 treated with alum, salt or Dispirin gargles acted as controls. Best response was obtained with the first mode of treatment, raising the possibility of role of the H2-receptors in causing chronic pharyngitis. The difference was highly significant (P less than 0.001).

Adult↗