Biomedical subjects
Publications and source records attributed to S Jiang.
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The chemical transformation of synthetic combinatorial libraries to increase the diversity of compounds of medicinal interest was reported recently. Chemical modification of natural products represents a complementary approach to accomplish this aim. Modification of lysines by aromatic acid anhydrides, preferentially by 3-hydroxyphthalic and trimellitic anhydrides and trimellitic anhydride chloride, converted commonly available proteins (human and bovine serum albumin and casein) into potent inhibitors of (i) binding between the HIV-1 gp 120 envelope glycoprotein and the CD4 cell receptor, probably owing to their binding to CD4, and (ii) infection by HIV-1. Modified bovine milk proteins are also potent HIV-1 inhibitors and may have potential for anti-HIV-1 prophylaxis.
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Using an Amplatzer membranous eccentric occluder, 186 patients with an average weight of 43.5 kg (range 12.5-77) underwent attempted catheter closure of a perimembranous venricular septal defect (PMVSD). Their age ranged from 3 to 51 years, with the an average age being 15.9 years. The patients were divided into three groups according to morphology of PMVSD: 106 patients with single PMVSD, 63 patients with single PMVSD with aneurysmatic formation, and 17 patients with multiple VSD with aneurysmatic formation. Using angiography, PMVSDs were measured to be between 2.5 and 12 mm, with an average of 5.1 mm. In the third group of patients, we did not measure the size of PMVSD and a device was selected according to the size of entry to the aneurysm. The device was successfully implanted in all patients. The immediate closure rate was 90% in the first group, increasing to 100% at 1 month and remained at that level during follow-up. The immediate closure rate in the second group was 98% and remained the same during follow-up. The immediate closure rate in the third group was 89% and during 1 year of follow-up remained the same. There was no clinical evidence of hemolysis and no incidence of device embolization or bacterial endocarditis after implantation. Before the procedure, all patients showed normal electrocardiogram (ECG) or left ventricle enlargement. After the procedure (at least 3 months later) ECG showed left anterior hemiblock (LAH) in nine patients, complete right bundle branch block in eight patients, and incomplete right bundle branch block in seven patients. A complete heart block (CHB) developed in 2 patients after the procedure (1.07%). The first patient developed LAH immediately after closure and CHB within 24 hours, The heart rate was 28 beats per minute. After treatment with steroids and atropine, CHB changed to sinus rhythm with LAH within 2 months. One year later, the ECG revealed the same findings. The second patient developed CHB immediately after the procedure and was on temporary pacing for 1 week. After 1 month, the patient recovered to sinus rhythm and ECG showed LAH.
The responses of single cells to luminance, color and computer-generated spots, bars, kinematograms, and motion-in-depth stimuli were studied in the nucleus rotundus of pigeons. Systematic electrode penetrations revealed that there are several functionally distinct subdivisions within rotundus where six classes of visual-selective cells cluster. Cells in the dorsal-posterior zone of the nucleus respond selectively to motion in depth (i.e. an expanding or contracting figure in the visual field). Most cells recorded from the dorsal-anterior region responded selectively to the color of the stimulus. The firing rate of the cells in the anterior-central zone, however, is dramatically modulated by changing the level of illumination over the whole visual field. Cells in the ventral subdivision strongly respond to moving occlusion edges and very small moving objects, with either excitatory or inhibitory responses. These results indicate that visual information processing of color, ambient illumination, and motion in depth are segregated into different subdivisions at the level of nucleus rotundus in the avian brain.
OBJECTIVE: C-reactive protein (CRP) is a plasma protein of hepatic origin thought to play an important role in host defences. We used transgenic mice, capable of expressing high levels of rabbit CRP (serum concentration>50 microg/mL) in response to dietary manipulation, to determine whether high levels of this acute-phase reactant can alter the course of experimentally induced monoarticular arthritis. METHOD: Arthritis was induced by a single injection of methylated bovine serum albumin (mBSA) on day 0 followed by injections of interleukin (IL)-1beta. RESULTS: In transgenic animals in which CRP expression had been suppressed (serum concentration<10 microg/mL), inflammatory arthritis began to develop by day 4 and was fully developed by 7 days after the mBSA challenge. This arthritis was characterized by marked inflammatory cell infiltrates in soft tissues, synovitis, pannus, cartilage loss, and bone erosion. By contrast, when CRP expression was induced, resulting in serum concentrations>50 microg/mL on the day of mBSA and IL-1beta injections, the inflammatory response was dramatically reduced at day 7. These mice manifested little to no evidence of joint inflammation. This anti-inflammatory effect of CRP was seen in animals with high CRP levels on days 0-1 following immunization and did not require elevated CRP levels during the period of rapid inflammatory progression, 4-7 days after challenge. CONCLUSION: CRP, expressed at the time of antigenic stimulation, effectively blocked the subsequent development of inflammatory arthritis in this model by altering the immune or inflammatory responses.
Chronic exposure to n-hexane may result in peripheral neuropathy. 2,5-Hexanedione (2,5-HD) has been identified as a toxic metabolite of n-hexane. The CYP2E1, CYP1A1 and GST genes are involved in the formation of 2,5-hexanedione from n-hexane as well as the elimination of 2,5-HD-formed electrophile, and these genes are highly polymorphic in the general population. A nested case-control study in an industrial cohort was conducted to evaluate the associations between polymorphisms in these metabolic genes and n-hexane-induced peripheral nerve damage. The study subjects included 22 cases, who worked in a printing factory with symptoms of peripheral nerve damage, and 163 controls, who came from the same factory of cases. DNA was extracted from blood samples and genotyping was conducted for CYP2E1 Pst, CYP2E1 Dra, CYP2E1 Ins96, CYP1A1 Msp, GSTT1 null, GSTM1 null and GSTP1 105V. Unconditional logistic regression was applied to estimate the odds ratio and 95% confidence intervals. There were no significant differences between the two groups regarding age, sex, smoking and alcohol status. A significant association between Dra polymorphism and peripheral nerve damage was found. The frequency of CYP2E1 Dra homozygous mutation in the case group (18.2%) was higher than that in the control group (3.7%, p=0.015). Individuals with homozygote genotype (CC) of CYP2E1 Dra had a significantly higher risk of peripheral nerve damage compared with those with DD genotype (adjusted OR=?.58, 95% CI=1.32-23.65) after n-hexane exposure duration, sex, age, smoking and alcohol status were adjusted. No significant association was found that CYP2E1 Pst, CYP2E1 Ins96, CYP1A1 Msp, GSTT1, GSTM1, GSTP gene polymorphisms associated with the susceptibility of peripheral nerve damage. These findings suggested that CYP2E1 gene might increase the susceptibility to n-hexane-induced peripheral damage.
Human ovarian cancer cell lines, SKOV3 and its adriamycin-resistant substrain SKOV3/ADR and COC1 and its cisplatin-resistant substrain COC1/DDP, were exposed to nonlethal ultrasound. Ultrastructures in sham-insonated and insonated cells were inspected by transmission electron microscopy, and cytochrome C in cytosol was determined by enzyme-linked immunosorbent assay. Ultrasound exposure led to no significant changes in SKOV3/ADR cells, but tumid mitochondria occurred in SKOV3 cells. Mitochondria changes were also detected in some exposed COC1 and COC1/DDP cells. Apoptotic bodies could be detected in either control or insonated COC1/DDP cells. A few exposed COC1/DDP cells became reticular. Cytochrome C in cytosol in exposed SKOV3/ADR cells was increased but that in exposed COC1/DDP cells was decreased. These findings revealed that the bioeffect of ultrasound on chemosensitive cells was not identical to that of chemoresistant ones, and ultrasound was a potential approach for treatment of drug-resistant ovarian cancers.
Because the efficacy of genetic prodrug activation therapy (GPAT) using herpes simplex virus thymidine kinase (tk)/ganciclovir (GCV) or Escherichia coli cytosine deaminase (cd)/5-fluorocytosine (5-FC) is not satisfied in early clinical trials and the mechanism of both the GPATs have been shown to lead to the activation of cell apoptotic pathway, we hypothesized that coexpression of procaspase-3, a central downstream executioner of apoptotic pathways, with cd-tk gene leads to enhanced cell death in ovarian cancer cells in vitro. Following transfection with the vectors encoding cd and tk, 5-FC and GCV treatments lead to greater cell death in procaspase-3-expressing clones of 3AO (3AO-caspase-3) than control cells (3AO-pcDNA3), as well as more rapid activation of caspase-3 and more rapid cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP). There is a greater degree of cell apoptotic rate in the procaspase-3-expressing clones than in control cells following the treatment with cd-tk/5-FC + GCV, and apoptosis is the main cell death form. None of these effects is seen following transfection with a control vector that does not encode tk and cd (pBTdel-279). The results strongly suggest that coexpression of procaspase-3 may lead to a significant enhancement of the efficacy of cd-tk/5-FC + GCV, and this strategy would be a novel and promising approach for the treatment of ovarian cancer.
Extracellular non-adenine based purines are neuroprotective. Preliminary studies indicate that administration of the synthetic purine 4-[[3-(1,6 dihydro-6-oxo-9-purine-9-yl)-1-oxypropyl] amino] benzoic acid (AIT-082, leteprinim potassium) to rats immediately after acute spinal cord injury (SCI), improves functional outcome. The effects of potential new agents are often compared to methylprednisolone (MPSS). We evaluated the effects of AIT-082 and MPSS, separately and in combination, on the functional and morphological outcome of acute SCI in adult rats. After standardized T11-12 spinal cord compression rats were given intraperitoneally one of the following: vehicle (saline); MPSS (30 mg/kg or 60 mg/kg body weight, first dose 15 min after crush); AIT-082 (60 mg/kg body weight daily, first dose 15 min after crush); or AIT-082 plus MPSS. After 1, 3, or 21 days, the rats were perfused for histological analysis. AIT-082 administrations significantly reduced locomotor impairment from 121 days post-operatively. At 1 and 3 days post injury, AIT-082-treatment reduced tissue swelling, tissue loss and astrogliosis at the injured cords but did not alter the extent of hemorrhage and the number of macrophages and/or microglia. MPSS reduced hemorrhage and the number of macrophages and/or microglia, but did not alter astrogliosis. At 21 days, either AIT-082 or MPSS administration improved function and morphology similarly (less tissue loss and astrogliosis). In contrast, administration of AIT-082 and MPSS together abolished the beneficial effects observed when either drug was given individually. These results suggest that MPSS and AIT-082 may exert their beneficial effects through different and potentially antagonistic pathways.
Among P2 metabotropic ATP receptors, P2Y2 subtype seems to be peculiar as its upregulation triggers important biological events in different cells types. In non-stimulated cells including astrocytes, P2Y2 receptors are usually expressed at levels lower than P2Y1 sites, however the promoter region of the P2Y2 receptors has not yet been studied and little is known about the mechanisms underlying the regulation of the expression of this ATP receptor. We showed that not only UTP and ATP are the most potent and naturally occurring agonist for P2Y2 sites, but also guanosine induced an up-regulation of astrocyte P2Y2 receptor mRNA evaluated by Northern blot analysis. We also focused our attention on this nucleoside since in our previous studies it was reported to be released by cultured astrocytes and to exert different neuroprotective effects. UTP and guanosine-evoked P2Y2 receptor up-regulation in rat brain cultured astrocytes was linked to an increased P2Y2-mediated intracellular calcium response, thus suggesting an increased P2Y2 activity. Actinomycin D, a RNA polymerase inhibitor, abrogated both UTP and guanosine-mediated P2Y2 up-regulation, thus indicating that de novo transcription was required. The effect of UTP and guanosine was also evaluated in astrocytes pretreated with different inhibitors of signal transduction pathways including ERK, PKC and PKA reported to be involved in the regulation of other cell surface receptor mRNAs. The results show that ERK1-2/MAPK pathway play a key role in the P2Y2 receptor up-regulation mediated by either UTP or guanosine. Moreover, our data suggest that PKA is also involved in guanosine-induced transcriptional activation of P2Y2 mRNA and that increased intracellular calcium levels and PKC activation may also mediate P2Y2 receptor up-regulation triggered by UTP. The extracellular release of ATP under physiological and pathological conditions has been widely studied. On the contrary, little is known about the release of pyrimidines and in particular of UTP. Here we show that astrocytes are able to release UTP, either at rest or during and following hypoxia/hypoglycemia obtained by submitting the cells to glucose-oxygen deprivation (OGD). Interestingly, also P2Y2 receptor mRNA increased by about two-fold the control values when the cultures were submitted to OGD. It has been recently reported that P2Y2 receptors can play a protective role in astrocytes, thus either guanosine administration or increased extracellular concentrations of guanosine and UTP reached locally following CNS injury may increase P2Y2-mediated biological events aimed at promoting a protective astrocyte response.
Our previous study demonstrated that the CYP2C9*3 gene variant was significantly associated with elevated plasma irbesartan concentration and blood pressure decline, assessed by a 4-week follow-up and revisit following daily administration of irbesartan. We conducted a further analysis to examine the acute effects of the CYP2C9 polymorphism on plasma concentration and blood pressure through remeasurement 6 h after administration of irbesartan. We used an extreme-sampling approach by selecting individuals from the top and bottom deciles of blood pressure response residuals to irbesartan from the previous study population in Anhui, Taihu, and Dongzhi Counties, in China. A total of 196 subjects were available for the analysis. Pre- and posttreatment systolic and diastolic blood pressures (SBP and DBP), and venous blood samples (0.5, 2, and 6 h following the first treatment) were collected from each individual. Plasma irbesartan concentrations were determined by a standard HPLC/fluorescence method. The observed frequencies were 97.7% for CYP2C9*1 (Ile359) and 2.3% for CYP2C9*3 (Leu359). Subjects with the CYP2C9*1/CYP2C9*3 genotype had significantly higher plasma irbesartan concentrations when compared with those with the CYP2C9*1/CYP2C9*1 genotype (beta +/- SE = 81 +/- 36) and greater DBP response (beta +/- SE = 5.6 +/- 2.5 mmHg) at the 6-h time point after adjusting for important confounders. Our finding suggests that the CYP2C9*3 gene variant significantly alters the plasma concentration and acute DBP response at the 6-h point following irbesartan treatment in Chinese hypertensive patients.
We demonstrated that a synthetic peptide (EWDREINNYTSLIHSLIEESQNQQEKNEQEGGC), designated SJ-2176, corresponding to the HIV-1 IIIB gp41 sequence (637-666), inhibited HIV-1 replication, virus-induced cell-cell fusion and cytopathic effects in both CD4+ T and monocytic cell lines. In this study, we show that lengthening the peptide at either the N- or C-terminus enhanced its activity, while shortening the peptide from either end decreased the antiviral activity. Substitution of conserved residues in SJ-2176 by alanines resulted in a decrease or elimination of antiviral activity. Replacement of arginine and lysine in the peptide by glutamines did not diminish antiviral activity and rendered the peptide resistant to trypsin.
Bcl-2 is a major anti-apoptotic protein expressed in many normal and malignant cells. Recently, low to absent expression was reported in human natural killer (NK) cells cultured in serum-free media which could be induced with stem cell factor. We investigated the expression of bcl-2 protein of NK cells in normal blood donors and compared the bcl-2 expression in CD56+ NK cells with CD3+ T cells. To determine bcl-2 reactivity, a three-color flow-cytometric technique was used. CD56+ CD3- NK cells had an average bcl-2 expression of 83% compared with CD3+ T cells. CD56 and CD3 double positive T cells had an average content of 111% compared with all peripheral CD3+ T lymphocytes. When peripheral mononuclear cells were cultured with interleukin-2 (IL-2), bcl-2 could be upregulated by IL-2 in all cell populations studied. The induction of bcl-2 in these cell populations paralleled the induction in CD56- T lymphocytes cultured under identical conditions. The induction of bcl-2 by IL-2 was confirmed by Western blotting. The maximum induction of bcl-2 by IL-2 was observed at an IL-2 dose of 100-1,000 U/ml. Our data confirm the anti-apoptotic protein bcl-2 as an activation- or proliferation-associated marker of normal NK cells which can be induced by IL-2.