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Biomedical subjects

Y Qiao

Publications and source records attributed to Y Qiao.

At least 19 recordsLinked to original sources
PubMed2000

Design and synthesis of potent thiol-based inhibitors of endothelin converting enzyme-1.

Through directed screening of compounds prepared as metalloprotease inhibitors a compound, CGS 30084, that had potent endothelin converting enzyme-1 (ECE-1) in vitro inhibitory activity (IC50 = 77 nM) was identified. Herein we report the synthesis and optimization of ECE-1 inhibitory activity of additional analogues from this lead. Compound 3c, the thioacetate methyl ester derivative of compound 4c, was found to be a long acting inhibitor of ECE-1 activity in rats after oral administration.

Animals↗
PubMed2000

Differentiation of monocytes to macrophages switches the Mycobacterium tuberculosis effect on HIV-1 replication from stimulation to inhibition: modulation of interferon response and CCAAT/enhancer binding protein beta expression.

HIV-1 replication is inhibited in uninflamed lung macrophages and is stimulated during tuberculosis. Attempts to recapitulate activation of HIV-1 replication in primary monocytes and macrophages ex vivo and in the untreated and PMA-treated THP-1 cell line model in vitro have produced opposite results depending on the state of differentiation of the cells. After infection with Mycobacterium tuberculosis, monocytes enhanced HIV-1 replication and produced a stimulatory 37-kDa CCAAT/enhancer binding protein beta (C/EBPbeta) transcription factor, whereas macrophages suppressed HIV-1 replication and produced an inhibitory 16-kDa C/EBPbeta transcription factor. IFN-beta induced inhibitory 16-kDa C/EBPbeta in macrophages, but had no effect on C/EBPbeta expression in monocytes. Macrophages, but not monocytes, were able to activate IFN-stimulated gene factor-3 (ISGF-3), a transcription factor composed of STAT-1, STAT-2, and IFN regulatory factor (IRF)-9, after infection with M. tuberculosis or stimulation with type I IFN. Macrophages expressed IRF-9 DNA-binding activity, but monocytes did not, and addition of the IRF-9 component reconstituted ISGF-3 in extracts of IFN-treated monocytes. Modulation of IFN responsiveness upon differentiation occurred at least in part through a post-transcriptionally regulated increase in IRF-9 expression. Both monocytes and macrophages maintained IFN responsiveness, activating STAT-1 homodimer formation and transcription of the STAT-1 gene after IFN stimulation. In addition, both monocytes and macrophages were able to activate NF-kappaB upon infection with M. tuberculosis. These results show that induction of ISGF-3, expression of the inhibitory 16-kDa C/EBPbeta, and suppression of HIV-1 replication via a transcriptional mechanism are macrophage-specific responses to infection with M. tuberculosis.

CCAAT-Enhancer-Binding Proteins↗
PubMed1999

Design and synthesis of thiol containing inhibitors of matrix metalloproteinases.

A series of thiol containing derivatives was prepared. Several of these compounds were found to inhibit matrix metalloproteinases 1, 3, and 9 with selectivity towards 3 and 9. Compounds 15, 20, and 22 were administered to rats orally at 75 mumol/kg. Drug levels of compounds 20 and 22 in the plasma were found to exceed the IC50 values for MMP 3 and 9 four hours after administration.

Animals↗
PubMed1996

Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase.

Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I-converting enzyme (ACE, EC 2.4.15.1), have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. We have previously reported that compound 2 (N-[[1-[(2(S)-mercapto-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]-carbonyl]-L-tyrosine) was a potent dual inhibitor in vitro (IC50 (ACE) = 7.0 nM, IC50 (NEP) = 1.5 nM) (Fink et al. J. Med. Chem. 1995, 38, 5023-5030). This compound was found to have oral activity; however, its duration of effect was short. A series of thioacetate carboxylic acid ester analogs of compound 2 was prepared. Modifications were also made to the tyrosine phenol. These compounds were evaluated for their ability to inhibit plasma ACE activity when administered orally to conscious normotensive rats. Most of the compounds prepared were found to be orally active with longer durations of effect than compound 2. Compound 38 (N-[[1-[(2(S)-(acetylthio)-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosine ethyl ester), administered at 11.7 mg/kg po, was found to be more efficacious than captopril at 10 mg/kg po. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. Compound 38 was found to lower blood pressure in the aorta-ligated rat and the spontaneously hypertensive rat when administered orally. The synthesis and biological activity of these dual inhibitors are discussed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

New alpha-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11.

Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

dinP, a new gene in Escherichia coli, whose product shows similarities to UmuC and its homologues.

A new gene, designated dinP, was found during E. coli genomic sequencing around the 5.5 min region. Its coding region is preceded by a sequence similar to the consensus binding sequence for LexA, the so-called SOS box sequence. The amino acid sequence of DinP (351 amino acid residues) has a strong similarity to the C. elegans hypothetical protein F22B7.6 and weaker similarities to the UmuC homologues in E. coli and Salmonella typhimurium and also to REV1 of Saccharomyces cerevisiae. Another SOS operon (dinJ1 and dinJ2 genes) found in this region is also described.

Amino Acid Sequence↗
PubMed1995

[Two autopsy cases of malignant mixed müllerian tumor of the uterus with metastasis to alimentary tract and liver].

Two autopsy cases (69 and 87-year-old women) of malignant mixed müllerian tumor (MMMT) following radiation therapy for uterine cervical cancer sixteen and twenty years ago respectively were reported. They were admitted due to abdominal pain and diagnosed as ileus. In the first case, CT examination revealed a tumor measuring about 8 x 10 cm in size in the uterine posterior wall. Recurrence of the uterine cancer was suspected and hysterooophorectomy combined with sigmoidectomy was performed. In the second case, artificial anus formation was performed because of sigmoid stricture by the invasion of the tumor. Histologically, tumors in both cases were composed of carcinomatous and sarcomatous components including heterologous elements such as cartilage. The patients died of extensive spreads and metastasis in the liver and alimentary tract.

Aged↗
PubMed1995

Cell damage and liberation of nitric oxide synthase in rat heart induced by endotoxin administration.

To evaluate the relationship between cardiovascular injury and the pathological aspect of the liberation of the nitric oxide synthase in endotoxin shock, Wistar rats were injected intraperitoneally with 10 mg/kg E. coli endotoxin and the cardiovascular changes were observed chronologically by immunohistochemical and electron microscopic techniques at 2, 4, 8 and 12 h respectively after endotoxin administration. Light microscopically, irregular contraction of cardiomyocytes was observed in the early stage. After 8 h of endotoxin administration, occasional disintegration of the myocytes as well as lysis of myofibrils became prominent, and diminished stainings of myoglobin and actin were seen in these myocytes. Ultrastructurally, increased pinocytotic vesicles were observed in endothelial cells associated with widened intercellular spaces, and vacuolization of endothelial and medial cells of the vasculature. In cardiomyocytes, swelling of mitochondria and interstitial edema were noted at 12 h after endotoxin administration. Immunohistochemically, an increased permeability of albumin was noted in the myocytes and vasculature and nitric oxide synthase was localized on the cytomembrane of the endothelium of the coronary arteries in control rats. After endotoxin administration, the reaction products of nitric oxide synthase increased in the endothelial and medial cells, and cardiomyocytes. These results suggest that the increased activity of nitric oxide synthase is an important factor in the excessive production of nitric oxide and in promoting the pathologic changes in the cardiovascular system after endotoxin administration.

Animals↗
PubMed1994

Increased susceptibility to staphylococcal enterotoxin B intoxication in mice primed with actinomycin D.

Mice (BALB/cJ, C3H/HeN, and C3H/HeJ) primed with actinomycin D became highly susceptible to lethal intoxication with staphylococcal enterotoxin B (SEB). The mice underwent toxicosis and toxic shock and died. Actinomycin D-primed C3H/HeN and C3H/HeJ mice showed equal sensitivity to SEB, suggesting that bacterial lipopolysaccharide derived from gram-negative bacteria in the gut may not be an important cofactor in intoxication. In a time course study of the illness, prominent pathological changes characterized by blood congestion and thickening of alveolar septa were seen in the lung, while blood congestion, inflammation, epithelial cell flattening, and villous blunting were seen in the small intestine. In lymphoid tissues, such as the spleen, congestion, inflammation, and lymphoid cell depletion were the major reactions. The pathological features of the mice had many similarities to those of rhesus monkeys intoxicated with intravenous SEB. The actinomycin D-primed C3H/HeJ mice are thus an ideal mouse model for studying SEB toxicosis and toxic shock.

Animals↗
PubMed1994

[Functional and morphological changes in the cochlea of cholesterol fed guinea pigs].

Although sensory neural hearing loss stemming from hypercholesterolemia has received attention in recent years, no information is available about inner ear injuries resulting from this condition. In this study, we prepared guinea pig models at hypercholesterolemia and observed the inner ear with a transmission electron microscope, and also investigated the effect of vitamin E (Vit. E) on these injuries. One hundred and thirty-nine white male Hartley guinea pigs weighing a mean of 250 g each were divided into three groups. Group A consisted of the control animals, which were fed by a stock diet. Group B animals were fed by a hyperlipid diet (2.5% cholesterol, 0.25% cholic acid, and 7.5% cattle fat). Group C animals were fed by a Vit. E-added (50 units/100 g) hyperlipid diet. All the animals were sacrificed either one, two or three months after treatment and the cochlea duct vasculature, cochleal nerve fiber under spiral limbus, stria vascularis and inner hair cell and outer hair cell of Corti's organ was observed with a transmission electron microscope. Cholesterol, triglyceride, and TBARS values were concurrently measured in the serum. Auditory threshold was measured by auditory brain stem response (ABR). In groups B and C, cholesterol and triglyceride levels remained high,. The TBARS level elevated in group B but remained unchanged in groups A and C. In groups B and C, the threshold of ABR increased mildly. The cholesterol load led to injuries in the endothelium of the vasculature dominating the cochlea.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

An influenza virus temperature-sensitive mutant defective in the nuclear-cytoplasmic transport of the negative-sense viral RNAs.

An influenza A virus mutant ts-51, which contains a temperature-sensitive (ts) defect in the genome encoding the M1 and M2 proteins, was characterized. Nucleotide sequencing of the M segment revealed a predicted single amino acid change of phenylalanine to serine at amino acid position 79 in the M1 protein. The nuclear-cytoplasmic transport of the negative-sense viral RNAs (vRNAs) was then investigated using an in situ hybridization technique. At 6 hr after the ts-51 virus infection, approximately 95% of the vRNAs were accumulated in the nucleus at a non-permissive temperature, when approximately 50% of the vRNAs were transported into the cytoplasm in the wild-type virus-infected cells. The M1 protein of the ts-51 virus was also accumulated in the nucleus under the same conditions. Therefore, the M1 protein of the ts-51 virus may be associated with the vRNPs, but the possible M1-vRNP complex thus formed was defective in the nuclear-cytoplasmic transport and the single amino acid change in the M1 protein was responsible for this defect.

Base Sequence↗
PubMed1993

Effect of vitamin E on vascular integrity in cholesterol-fed guinea pigs.

This study was designed to clarify the effects of vitamin E on the alterations in proteoglycan distribution and vascular permeability, which were examined by immunohistochemical and ultrastructural techniques in the aortas of cholesterol-fed guinea pigs. The animals were divided into three groups: a control group, a cholesterol group, and a vitamin E group. Serum levels of cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, and thiobarbituric acid-reactive substances were measured. An increase in thiobarbituric acid-reactive substances was observed in the cholesterol group compared with control and vitamin E groups. Intimal atheromatous lesions of the aorta were significantly decreased in the vitamin E group compared with the cholesterol group. Histochemically, an increased distribution of proteoglycans such as chondroitin, dermatan, and heparan sulfates and ruthenium red reaction products in the intima; decreased glycocalyx on the endothelial surface; and increased permeability to horseradish peroxidase were revealed in the cholesterol group compared with the vitamin E group. Hypercholesterolemia, resulting in superoxide production, may have contributed to the endothelial damage and increased permeability to plasma proteins and lipids in the vascular wall of the cholesterol group. However, vitamin E administration inhibited lipid deposition and development of this abnormal permeability associated with an irregular distribution of proteoglycan. These results suggest that vitamin E preserves the morphological and functional integrity of the vascular wall and may contribute to the inhibition of atherogenesis in cholesterol-fed guinea pigs.

Animals↗
PubMed1992

The value of adrenal autotransplantation with attached blood vessels for the treatment of Cushing's disease: a preliminary report.

We treated 5 patients with Cushing's disease by total adrenalectomy and left adrenal autotransplantation with attached blood vessels. An end-to-end vascular anastomosis was made between the adrenal central vein and the inferior epigastric artery, and the saphenous vein and adrenal middle artery were anastomosed by intussuscepting the artery into the vein in 4 patients. Steroid replacement was withdrawn 7 to 90 days after bilateral total adrenalectomy. The patients were followed for 1 to 4 years. Repeated measurement of plasma cortisol, 24-hour urinary 17-hydroxycorticosteroid and 17-ketosteroid levels in all cases was normal. As soon as the adrenal central vein and inferior epigastric artery were anastomosed part of the adrenal gland was then excised. Oozing of blood from the cut surface was retained and the adrenal gland was then embedded into the inguinal muscle in 1 patient. Small doses of steroid replacement (12.5 mg. cortisone per day) were still necessary 1 year postoperatively. The result thus indicates that this procedure is feasible and valuable for the treatment of patients with Cushing's disease and no evidence of pituitary adenoma on magnetic resonance imaging or computerized tomography.

Adrenal Glands↗