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Biomedical subjects

W Tang

Publications and source records attributed to W Tang.

At least 325 records · Page 18Linked to original sources
PubMed1991

Agonist/inositol trisphosphate-induced release of calcium from murine keratinocytes: a possible link with keratinocyte differentiation.

Extracellular calcium concentrations markedly affect the pattern of proliferation and differentiation in cultured keratinocytes. When medium contains 0.1 mM calcium or above, the cells lose their proliferative ability, rapidly stratify, and terminally differentiate. Because 1,25(OH)2D3 (a modulator of Ca++ homeostasis) enhances the differentiation of keratinocytes, we investigated whether a link exists between 1,25(OH)2D3-induced release of inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) from PtdIns 4,5-P2 and intracellular calcium [Ca++]i release from keratinocytes. Specifically, primary culture of keratinocytes were loaded with fluorescence dye Fura-2AM (10 microM) and changes in fluorescence intensity were monitored at the excitation wavelengths of 340 and 380 nm and emission wavelength of 505 nm. Additions of two agonists, 1,25(OH)2D3 (1.2 x 10(-9) M) and 13-Cis retinoic acid (0.2 x 10(-9) M), to dye-loaded keratinocytes induced rapid release of [Ca++]i, respectively, followed by gradual return to the prestimulated state. Addition of Ins(1,4,5)P3 (10 microM) to saponin-treated (leaky) keratinocytes also resulted in a rapid release of [Ca++]i. In contrast, the addition of inositol-1,3,4,5-tetrakisphosphate Ins(1,3,4,5)P4 at similar concentrations exerted negligible effect. Taken together, these results support the view that 1,25(OH)2D3-induced [Ca++]i release in keratinocytes may be via the Ins(1,4,5)P3-induced early release of intracellular [Ca++]i. This may explain, at least in part, 1,25(OH)2D3-enhanced keratinocyte differentiation.

Animals↗
PubMed1991

Nanosecond kinetic absorption and calorimetric studies of cyclopentenone: the triplet, self-quenching, and the predimerization biradicals.

The photolysis of 2-cyclopentenone has been studied by a combination of kinetic absorption spectrophotometry and time-resolved photoacoustic calorimetry. The lifetime of the cyclopentenone triplet is strongly concentration dependent and corresponds to a value of 380 +/- 75 ns at infinite dilution in acetonitrile. The biradical intermediate (or pair of isomeric biradicals) immediately preceding formation of photodimer forms with very high efficiency upon quenching of triplet cyclopentenone by a second ground state cyclopentenone molecule and has an energy of 47 kcal/mol relative to two molecules of reactant. Quenching of the cyclopentenone triplet by conjugated dienes is much slower than expected, which is the reason that early estimates of the triplet lifetime were much too short.

Calorimetry↗
PubMed1991

Pulmonary ventilation/perfusion defects induced by epinephrine during cardiopulmonary resuscitation.

BACKGROUND: Epinephrine has been shown to impair pulmonary excretion of CO2 during resuscitation. This phenomenon was investigated in a rodent model of cardiac arrest and conventional resuscitation. METHODS AND RESULTS: The effects of racemic epinephrine were compared with the selective alpha 1-agonist methoxamine and with saline placebo during cardiac resuscitation in 15 Sprague-Dawley rats mechanically ventilated with gas containing 70% oxygen. Epinephrine and methoxamine but not saline placebo significantly increased coronary perfusion pressure from approximately 32 to 55 mm Hg. Following epinephrine, end-tidal PCO2 decreased from approximately 10 to 5 mm Hg. This was associated with a time-coincident decrease in PaO2 from approximately 130 to 74 mm Hg and an increase in PaCO2 from approximately 26 to 40 mm Hg. These changes indicated increases in alveolar dead space ventilation concomitant with increases in pulmonary arteriovenous admixture. No such effects were observed after administration of either methoxamine or saline placebo. Each of the 15 rats was successfully resuscitated. However, a significantly larger number of transthoracic countershocks were required after epinephrine compared with methoxamine or placebo before return of spontaneous circulation. CONCLUSIONS: Epinephrine induced ventilation/perfusion during cardiopulmonary resuscitation as a result of redistribution of pulmonary blood flow.

Animals↗
PubMed1991

[Rational management of cardiac arrest].

When immediate defibrillation fails, successful cardiac resuscitation is contingent on prompt reestablishment of myocardial blood flow. Conventional methods of closed-chest resuscitation generates only critical levels of myocardial blood flow and therefore are of limited value for successful resuscitation. Methods that optimize the site, depth, rate and duration of precordial compression may increase myocardial blood flow, however, the lack of objective measurements of their hemodynamic effects limits the optimal performance of this resuscitation method. With the recognition that elimination of CO2 is flow limited, measurement of end-expired PCO2 has emerged as a practical option for continuous assessment of systemic blood flow and coronary perfusion pressure. With measurement of the end-expired PCO2, operator fatigue may be recognized, the technique of precordial compression may be optimized, and the likelihood of restoring spontaneous circulation may be estimated. When conventional cardiac resuscitation fails or is predicted to fail by measurements of end-tidal PCO2, more effective interventions such as open-chest direct cardiac massage may be instituted. Regarding the vast resuscitation polypharmacy, only agents that act by selectively augmenting coronary perfusion pressure and myocardial blood flow are of proven benefit for successful resuscitation.

Cardiopulmonary Resuscitation↗
PubMed1990

Carcinoma of the cervix with extensive endometrial and myometrial involvement.

Verrucous carcinoma is a rare variant of epidermoid carcinoma with distinct clinical and histopathologic features. To date, 31 cases have been reported in the cervix. They are typically slow-growing, locally invasive tumors with low potential for lymphatic metastasis and appear to be radioresistant. We report a case which is unusual in having endometrial and deep myometrial invasion. Electron microscopy, immunohistochemical stains, and DNA in situ hybridization studies failed to detect human papilloma virus particles but the oncogenic potential of the virus is not excluded.

Aged↗
PubMed1990

Determination of triplet excitation energies of cyclic enones by time-resolved photoacoustic calorimetry.

Energies and lifetimes of triplet states of a series of 2-cyclohexenones have been measured in solution under ambient conditions by time-resolved photoacoustic calorimetry (PAC). The PAC triplet lifetimes are in excellent agreement with lifetimes measured by kinetic absorption spectrophotometry (KAS) using nanosecond flash techniques, indicating that the present data indeed pertain to the enone triplets previously studied using KAS. The data demonstrate that, as previously proposed, the pi pi triplet energies in these systems are indeed correlated with triplet lifetimes, and vary sensibly with the anticipated extent of conformational flexibility of the C = C bond. No evidence supporting formation of metastable trans-cyclohexenones was obtained. The data also demonstrate greater precision and, for lifetimes, greater accuracy than has hitherto been claimed for the PAC technique for study of transients with lifetimes in the 25 ns range.

Calorimetry↗
PubMed1989

Synthesis and characterization of steroid-linked N-(2-chloroethyl)nitrosoureas.

Syntheses of steroid-linked N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-(CNC-) amino acid esters and -amides with potential antineoplastic activity are described. The esters are prepared by reaction of CNC-amino acids with steroids using N,N'-carbonyldiimidazole and N,N'-dicyclohexylcarbodiimide. The corresponding amides are prepared by reaction of 1-(CNC-amino acyloxy)-pyrrolidine-2,5-diones with 17 beta-amino-3-hydroxy-1,3,5(10)-estratriene or 17 beta-O-[4-(6-aminohexylamino)-1,4-dioxo-butyl]-estradiol. Estradiol-17 beta-hemisuccinate is esterified with N-(2-hydroxyethyl)-N'-(2-chloro-ethyl)-N'-nitrosourea (HECNU). Spectroscopic characteristics and relative binding affinities to steroid receptors are given.

Antineoplastic Agents↗
PubMed1989

Regulatory role of retinoic acid on cultured mouse keratinocyte inositol phospholipid metabolism: dose-dependent release of inositol triphosphate.

The incorporation of precursor 14C-myoinositol into the three cellular inositol phospholipids (PtdIns, PtdInsP, and PtdInsP2) of cultured, rapidly proliferating keratinocytes is significantly enhanced by the exogenous addition of a high concentration (1 X 10(-7) M) of all-trans retinoic acid or its analog 13-Cis analog, whereas a similar incubation with a low concentration (1 X 10(-10) M) of the same retinoid resulted in an insignificant incorporation of the radio-precursor into the three inositol phospholipids. Incorporation was most marked into the more phosphorylated PtdIns4P and PtdIns4,5P2. These results indicate that retinoic acid affects the biosynthesis of the inositol phospholipids at high concentrations. In contrast, the hydrolysis of 14C-PtdIns4,5P2 and release of 14C-InsP3 from the prelabeled keratinocytes is markedly enhanced by a low physiologic concentration (1 X 10(-10) M) of retinoic acid or its 13-Cis analog. The hydrolysis is rapid, with an accompanying elevated transient release of 14C-InsP3. High concentration (1 X 10(-5) M), on the other hand, supresses 14C-InsP3 release. These results taken together underscore a bifunctional, dose-dependent effect of both the all-trans-RA and its 13-Cis analog on the synthesis and hydrolysis of keratinocyte PtdIns4,5P2. Furthermore, the results suggest that at low physiologic concentrations, these retinoids may function as agonists to perturb the membrane resulting in induced rapid hydrolysis of cellular PtdIns4,5P2, which is coupled to a "transient" generation of InsP3 (an intracellular second messenger). The rapid formation of this putative "second messenger" may in turn play a role in the cellular proliferative or differentiating biochemical events in the murine keratinocytes.

Animals↗
PubMed1989

Nitrosoureas. Modes of action and perspectives in the use of hormone receptor affinity carrier molecules.

Mechanisms of DNA adduct formation by antineoplastic 2-chloroethyl-N-nitrosoureas (CNUs) and of DNA damage induced by these compounds are discussed. CNUs are alkylating agents that form DNA-DNA cross-links as well as 2-chloroethylated and 2-hydroxyethylated adducts, the N-7-position of guanine being the predominantly alkylated site. A close correlation exists between the potential of a given compound to induce DNA-DNA cross-links and its antineoplastic effectiveness. However, levels of DNA-DNA cross-linking in bone marrow and extent of myelosuppression as measured in rodents are also closely correlated. The design of new cross-linking analogues capable of directing the antineoplastically relevant activity predominantly to the target tumour appears therefore to be of great promise. Cross-linking agents have been attached to a variety of steroid hormone carrier molecules and the conjugates have been tested in structure-activity studies using hormone-receptor containing animal tumours. These studies have revealed that some hormone-linked antineoplastic agents are highly effective in receptor positive experimental tumours and are superior to mixtures of unlinked alkylating agents with hormones. Indications for a relative enrichment of DNA damaging effects in the tumour tissue and for reduced myelotoxicity have been obtained with specific hormone conjugates.

Animals↗
PubMed1988

Reversal of epidermal hyperproliferation in essential fatty acid deficient guinea pigs is accompanied by rapid generation of inositol triphosphate.

This study probes the extent of coupling between the reversal of epidermal hyperproliferation induced by essential fatty acid (EFA) deficiency in guinea pigs, the hydrolysis of epidermal phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P2), and the rapid formation of inositol triphosphate (InsP3). Our data revealed that the incorporation of free [3H]-inositol into phosphatidylinositol 4P and PtdIns4,5P2 of microsomal preparations from hyperproliferative epidermis was markedly elevated when compared with epidermis from normal-fed animals. The reversal of the hyperproliferating epidermis by dietary cross-over supplementations with safflower oil and primrose oil resulted in striking morphological normalization, cellular decrease in epidermal DNA synthesis, decrease in the biosynthesis of 14C-PtdIn4,5P2 from precursor 14C-inositol, and a significant increase in the rapid generation of transient InsP3 by epidermis from the cross-over-fed animals. These findings taken together indicate that the reversal of epidermal hyperproliferation to normal in guinea pig skin and the increased capability of the tissue microsomal preparation to generate InsP3 are linked in this tissue, and raise the possibility that epidermal inositol-phospholipid metabolism may play a role in the pathogenesis of cutaneous hyperproliferative disorders.

Animals↗
PubMed1988

Turnover of inositol phospholipids in cultured murine keratinocytes: possible involvement of inositol triphosphate in cellular differentiation.

The relationship between the turnover of inositol phospholipids (PtdIns) and the growth and differentiation of normal murine keratinocytes in culture was studied. Addition of myo-[U-14C]inositol to freshly plated cells resulted in a linear incorporation of radiolabel into the inositol phospholipids of the proliferating basal cells in culture during the initial 36 h, after which time the rate of radiolabel incorporation into the cells declined. The decrease in the incorporation of the radiolabel into the PtdIns, particularly the more highly phosphorylated PtdIns-4P and PtdIns4,5P2, correlated with the marked hydrolysis of these polyphosphoinositides and the rapid hydrolytic release of the inositol phosphates (InsP2 and InsP3). The transient accumulation of the InsPs correlated with the onset of differentiation of these cells. To ascertain whether the above observations of keratinocytes that were undergoing normal proliferative and differentiating phases in culture are consistent with the more synchronized populations of proliferative and differentiating cells, we investigated the turnover of PtdIns in a Ca2+-regulated system of homogenous populations of proliferating mouse keratinocytes in 0.09 mM Ca2+, and a differentiating population in 1.8 mM Ca2+. Our data from system revealed rapid hydrolysis of the PtdIns in the prelabeled low-Ca2+ proliferating cells immediately after a switch from the low to normal extracellular Ca2+ medium. Associated with this hydrolysis was the rapid and transient accumulation of the InsPs (maximum of 60 sec). The hydrolysis of the PtdIns and the accumulation of the InsP3 were not observed when the prelabeled proliferating cells were switched from a low to a low extracellular Ca2+ medium. These results suggest that the rapid hydrolysis of the PtdIns, particularly PtdIns4,5P2, which was accompanied by the hydrolytic release of InsP3, could be the initiating signal to program proliferating keratinocytes into differentiation.

Animals↗
PubMed1988

Development of more selective anti-cancer nitrosoureas.

2-Chloroethyl-N-nitrosoureas are highly active anti-neoplastic drugs in clinical use for many years. Therapy with these DNA cross-linking agents is limited by their toxic side effects, cumulative and delayed bone marrow toxicity being the main dose-limiting one. Since the intrinsic anti-tumour activity of the nitrosourea group is very high, coupling to appropriate carrier molecules represents a challenge for target-orientated chemotherapy. Many human tumours contain receptors for steroid hormones. Therefore, 2-chloroethyl-N-nitroso-carbamoyl(CNC)-amino acid derivatives have been developed that are linked to steroid hormones. In the series of oestradiol (E2)-linked analogues CNC-L-alanine-E2-17-ester was significantly superior to other E2-linked congeners and to the unlinked equimolar mixture when tested against hormone-dependent N-methyl-N-nitrosourea-induced mammary carcinoma of the rat. Relevance of E2 receptor contents for therapy with E2-linked drugs is evidenced by loss of superiority of this analogue in hormone-independent mammary carcinomas. Some androgen-linked CNC-amino acids showed substantial affinity to the androgen receptor and in part also to the progesterone receptor. A preliminary study in rat leukaemia L5222 revealed the CNC-L-alanine-dihydrotestosterone-17-ester to be highly active. Studies with hormone-dependent tumour models are under way.

Androgens↗
PubMed1987

Novel regulatory actions of 1 alpha,25-dihydroxyvitamin D3 on the metabolism of polyphosphoinositides in murine epidermal keratinocytes.

The in vitro incubation of murine keratinocytes in the presence of 1 alpha,25-dihydroxyvitamin D3 enhanced the rapid hydrolysis of the prelabeled keratinocyte polyphosphoinositides (polyPtdIns) when compared to untreated cells. The rapid hydrolysis of the polyPtdIns and the release of the inositol phosphates (particularly InsP3 and InsP2) precede the onset of differentiation of these cells. These data therefore suggest that 1 alpha,25-dihydroxyvitamin D3 functions in vitro to initiate the rapid generation of InsP3 from cellular polyPtdIns; this in turn may mobilize intracellular Ca2+, thus providing the signal which program the murine keratinocytes from a proliferating mode into a differentiating mode.

Animals↗
PubMed1987

Lysophospholipase activity in rat brain subcellular fractions.

Lysophospholipase activity in brain subcellular fractions was measured by the release of myristic acid from 1-myristoylglycerophosphocholine or through the formation of [32P]glycerophosphocholine from [32P]lysophosphatidylcholine. Although the lysophospholipase activity was highest in microsomes, considerable enzyme activity was also found in other subcellular membrane fractions. The pH optimum for the microsomal enzyme was around 7, whereas the synaptosomes and non-synaptic plasma membranes exhibited a pH maximum around 8. Although the enzyme did not require divalent cations for activity, divalent cations (1 mM) such as Hg2+, Cu2+, and Zn2+ inhibited potently the enzyme activity. Enzyme activity was also partially inhibited by both saturated and polyunsaturated fatty acids (25-200 microM), and the inhibition seemed to be greater in the membrane than in the cytosolic fractions. Ionic detergents such as deoxycholate and taurocholate inhibited the lysophospholipase. On the other hand, the effect of Triton X-100 was biphasic, i.e., stimulation at concentrations below 100 micrograms/mg protein and inhibition at higher concentrations. Addition of cholesterol (50-250 micrograms/ml), but not cholesteryl esters, also potently inhibited enzyme activity. The presence of active lysophospholipase(s) in brain is probably an important mechanism for preventing unnecessary accumulation of lysophospholipids which may exert a deleterious effect on the membranes because of their detergent properties.

Animals↗