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Biomedical subjects

K Cheng

Publications and source records attributed to K Cheng.

At least 109 records · Page 6Linked to original sources
PubMed1994

A novel 3-substituted benzazepinone growth hormone secretagogue (L-692,429).

The 3-substituted benzazepinone, L-692,429 (compound 1), is the prototype compound of a novel class of compounds that stimulate release of growth hormone (GH). The molecule evolved from efforts to identify a non-peptide mimic of the growth hormone-releasing hexapeptide, GHRP-6. Compound 1 is prepared by sequential attachment of dimethyl-beta-alanine and 2'-biphenylyltetrazole side chains to a chiral 3-aminobenzolactam nucleus. Comparison of the biological activity of 1 with the corresponding six- and eight-membered lactam analogs shows the seven-membered benzazepinone skeleton to be preferred. Molecular modeling of the structurally diverse GH secretagogues, L-692,429 and GHRP-6, was performed.

Amino Acid Sequence↗
PubMed1994

Comparison of neuronal selectivity for stimulus speed, length, and contrast in the prestriate visual cortical areas V4 and MT of the macaque monkey.

1. Prestriate area V4 and the middle temporal area (MT) compose the first stage in which the ventral and dorsal visual cortical pathways are segregated. To better known the functional dichotomy between the two pathways at this level, we recorded cell responses from V4 and MT using anesthetized, immobilized macaque monkeys and compared the selectivity for speed of stimulus motion and stimulus length and the sensitivity to luminance contrast between the two areas. 2. V4 cells were as selective as MT cells for speed. The sharpness of tuning was not different between the two populations. The optimal speed varied widely in both areas, but both of the two distributions showed peaks at 32 degrees/s. 3. V4 and MT cells were similar in that about one-half of the cells (45% in V4 and 48% in MT) showed inhibition by long (16 degrees) bars. However, V4 cells preferred stimuli whose lengths were distributed around the lengths of the receptive field, whereas an overwhelming majority of MT cells preferred stimuli whose lengths were much shorter than the lengths of the receptive field. 4. The cutoff contrast at which one-half the maximum response was elicited was distributed widely in both areas, and the two distributions considerably overlapped. MT cells as a whole, however, were slightly more sensitive to the luminance contrast than V4 cells. 5. There was a tendency toward local clustering for cells with similar speed preferences in MT but not in V4. Pairs of MT cells recorded within 400 microns had smaller difference in the optimal speed than that of cell pairs taken randomly from the whole sample of MT cells.

Animals↗
PubMed1994

Antiproliferative effect of tumor necrosis factor-alpha on human glioblastoma cells linked with cell cycle arrest in G1 phase.

The effects of tumor necrosis factor-alpha (TNF) on proliferation and cell cycle alterations in human malignant glioma cell lines, SF-188 and LN-382, were investigated by flow cytometry with the bromodeoxyuridine-propidium iodide dual staining technique. Low concentrations of TNF (1-100 U/ml) suppressed the growth of SF-188 assessed by cell count, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and thymidine incorporation assay, but not that of LN-382. After TNF treatment, the percentage of SF-188 cells in the G0/G1 phase increased, while the percentage of cells in the S phase decreased. LN-382 cells did not show any marked change in cell kinetics. TNF arrests certain human glioma cells in the G0/G1 phase resulting in reduction of deoxyribonucleic acid synthesis in the subsequent S phase, suppressing the proliferation pathway.

Brain Neoplasms↗
PubMed1993

Pituitary adenylate cyclase activating polypeptide-induced desensitization on growth hormone release from rat primary pituitary cells.

Pituitary adenylate cyclase activating polypeptide (PACAP38) stimulated growth hormone release as well as cAMP accumulation in a static rat primary pituitary cell culture in a dose-dependent manner with EC50 values of 1.9 +/- 0.4 nM (n = 13) and 0.9 +/- 0.3 nM (n = 5), respectively. The maximal GH response was observed between 5 to 15 min. Prolonged incubation (3 to 4 hrs) markedly reduced the stimulatory effect of PACAP38. The effect of PACAP38 on GH release was desensitized by pretreatment of the cells with PACAP38 or GRF, but not with PMA. The PACAP38-induced desensitization appeared to be time- and dose-dependent. Somatostatin (20 nM) inhibited PACAP-stimulated GH release through a cAMP-independent pathway.

Animals↗
PubMed1993

A nonpeptidyl growth hormone secretagogue.

A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6). L-692,429 is an example of a nonpeptidyl specific secretagogue for growth hormone.

Amino Acid Sequence↗
PubMed1993

A novel non-peptidyl growth hormone secretagogue.

Direct screening of preselected compounds in a rat primary pituitary cell culture assay, followed by chemical modification of selected pharmacophores led to the identification of a novel non-peptidyl class of GH secretagogues (substituted benzolactams). The prototype compound of this class, L-692,429, stimulated GH release from rat primary pituitary cells in a time- and dose-dependent manner with an EC50 value of 60 nM. Under the same conditions, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GH-releasing peptide, GHRP-6) and GH-releasing factor (GRF) had EC50 values of 10(-8) and 5 x 10(-10) M, respectively. L-692,428, the S-enantiomer, of L-692,429, was inactive at a concentration as high as 2 microM. GH release induced by L-692,429 was inhibited by somatostatin as well as by GHRP-6 and substance P antagonists but not by GRF or opiate antagonists. L-692,400, which is structurally related to L-692,429 but biologically inactive, inhibited GH response not only to L-692,429 but also GHRP-6. Like GHRP-6, L-692,429 alone had no effect on intracellular cAMP levels; however, it synergized with GRF to further increase both the accumulation of cAMP and the release of GH. Maximal effects of L-692,429 and GHRP-6 on GH release were comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause an additional GH release when compared with either secretagogue alone. L-692,429 had a small effect on prolactin release but not adrenocorticotropin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue.

L-692,429, a benzolactam derivative, stimulated GH release from rat primary pituitary cells in a dose-dependent manner. The concentration of L-692,429 required for half-maximal stimulation were 59.6 +/- 7.3 nM. Under the same conditions, GHRP-6 and GRF had EC50 values of 10.3 +/- 1.9 nM and 0.47 +/- 0.09 nM, respectively. L-692,428, the enantiomer of L-692,429, was inactive at a concentration as high as 2 microM. Like GHRP-6, L-692,429 had no effect on intracellular cAMP level; however, it synergized with GRF to further increase not only the accumulation of cAMP but also the release of GH. The magnitude of GH release stimulated by maximal concentrations of L-692,429 and GHRP-6 was comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause additional GH release when compared with either secretagogue alone. The L-692,429-stimulated GH release was completely inhibited by 20 nM somatostatin. To our knowledge, L-692,429 is the first non-peptidyl GH secretagogue which has a direct effect on the release of growth hormone from rat primary pituitary cells. Its effect is most likely mediated through a mechanism which is similar to that of GHRP-6.

Animals↗
PubMed1993

Asymptomatic large hypothalamic hamartoma associated with polydactyly in an adult.

A hypothalamic hamartoma is a congenital tumor-like neural malformation. It is usually seen in children and is associated with neuroendocrinological symptoms, seizures, or psychological impairments. An asymptomatic hypothalamic hamartoma in an adult is extremely rare. This report describes an asymptomatic adult with a large hypothalamic hamartoma associated with polydactyly in his feet. Both polydactyly and hamartoma are rare lesions; therefore, this may not be a coincidental presentation. It is thought to have occurred in the embryonic period presumably between 37 and 40 gestational days.

Adult↗
PubMed1993

Theoretical study of rectangular pulse electrical stimulation (RPES) onskin cells (in vivo) under conforming electrodes.

Our previous in vivo experimental results have shown RPES can enhance skin wound healing by using conforming electrodes. Based on an equation of polarization transmembrane voltage [Cole, K. S. 1972], two equations were derived to describe the peak RPES intensity on skin cells in vivo: (1) U = 1.5 a J/sigma, (2) Jm = 1.5 a (J/sigma) (Cm/tau). Where U: polarization transmembrane voltage. a: radius (R) for spherical cells or semi-length (L) for long fibers parallel to the electrical field. J: external imposed pulse current density under the electrode. sigma: average conductivity of skin tissue. Jm: transmembrane displacement current density. Cm: membrane capacitance per unit area and tau: time constant. Calculations indicated that the sensory fibers (SF) would receive the strongest stimulation compared to other cells in skin since generally LSF > or = 100 R. The sensitivity of SF to the stimulation could enhance skin wound healing as well as protect normal skin cells from harmful electroporation. From these theoretical calculations. We proposed a theoretical range of the pulse current density as: U1 sigma/(1.5 L) < or = J < or = U2 sigma/(1.5 L), where U1 and U2 are the excitation threshold voltage (about 0.01 V) and polarization electroporation voltage (about 0.1 V) for a SF respectively, for RPES to enhance skin wound healing.

Electric Conductivity↗
PubMed1993

Schrodinger equation, Maxwell-Bolzmann distribution and a single channel current.

The dual nature, wave and particle, of ions in the biological system was considered. A theoretical model, based on the steady state Schrodinger equation and Maxwell-Bolzmann distribution of energy, is proposed to describe passive transport of ions through a biological membrane channel in a time independent field. Constant height (V2) and length(L) of the potential energy barrier and effective mass of ions are used in the model. This model shows that an ion may go through or be reflected from a channel whether its energy is lower or higher than the barrier. This is a departure from classical theory. Based on a published I-Vm (channel current-transmembrane voltage) curve from an activated K+ channel in a human erythrocyte membrane [Palle Christophersen, 1991], calculations with our model show that more than 99% of the channel current is contributed by ions with higher energy than the potential barrier. The current can be amplified 10,000 times while V2 is reduced from 0.45 eV (channel closed) to 0.20 eV (channel opened) at Vm = 0.07 V. In contrast, the current changes only 1.5% while L is narrowed from 90 A to 30 A at Vm = 0.07 V, V2 = 0.20 eV. The energy barrier: V2 = 0.16 + 0.43 Vm (eV), at r = 0.99, for 0.02 V < or = Vm < or = 0.12 V.

Biological Transport↗
PubMed1992

Columns for visual features of objects in monkey inferotemporal cortex.

At early stages of the mammalian visual cortex, neurons with similar stimulus selectivities are vertically arrayed through the thickness of the cortical sheet and clustered in patches or bands across the surface. This organization, referred to as a 'column', has been found with respect to one-dimensional stimulus parameters such as orientation of stimulus contours, eye dominance of visual inputs, and direction of stimulus motion. It is unclear, however, whether information with extremely high dimensions, such as visual shape, is organized in a similar columnar fashion or in a different manner in the brain. Here we report that the anterior inferotemporal area of the monkey cortex, the final station of the visual cortical stream crucial for object recognition, consists of columns, each containing cells responsive to similar visual features of objects.

Animals↗
PubMed1992

PMA-sensitive protein kinase C is not necessary in TRH-stimulated prolactin release from female rat primary pituitary cells.

In GH3 cells and other clonal rat pituitary tumor cells, TRH has been shown to mediate its effects on prolactin release via a rise of cytosolic Ca2+ and activation of protein kinase C. In this study, we examined the role of protein kinase C in TRH-stimulated prolactin release from female rat primary pituitary cell culture. Both TRH and PMA stimulated prolactin release in a dose-dependent manner. When present together at maximal concentrations, TRH and PMA produced an effect which was slightly less than additive. Pretreatment of rat pituitary cells with 10(-6) M PMA for 24 hrs completely down-regulated protein kinase C, since such PMA-pretreated cells did not release prolactin in response to a second dose of PMA. Interestingly, protein kinase C down-regulation had no effect on TRH-induced prolactin release from rat pituitary cells. In contrast, PMA-pretreated GH3 cells did not respond to a subsequent stimulation by either PMA or TRH. Pretreatment of rat pituitary cells with TRH (10(-7) M, 24 hrs) inhibited the subsequent response to TRH, but not PMA. Forskolin, an adenylate cyclase activator, stimulated prolactin release by itself and in a synergistic manner when incubated together with TRH or PMA. The synergistic effects of forskolin on prolactin release was greater in the presence of PMA than TRH. Down-regulation of protein kinase C by PMA pretreatment abolished the synergistic effect produced by PMA and forskolin but had no effect on those generated by TRH and forskolin. sn-1,2-Dioctanylglycerol (DOG) pretreatment attenuated the subsequent response to DOG and PMA but not TRH. The effect of TRH, but not PMA, on prolactin release required the presence of extracellular Ca2+. In conclusion, the mechanism by which TRH causes prolactin release from rat primary pituitary cells is different from that of GH3 cells; the former is a protein kinase C-independent process whereas the latter is at least partially dependent upon the activation of protein kinase C.

Animals↗
PubMed1991

Evidence for a role of protein kinase-C in His-D-Trp-Ala-Trp-D-Phe-Lys-NH2-induced growth hormone release from rat primary pituitary cells.

We have recently reported that His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6) synergizes with GH-releasing factor (GRF) to increase GH release and cAMP accumulation in rat pituitary cells in vitro. This study was undertaken to further investigate the mechanism of action of GHRP-6 on GH release, particularly the involvement of protein kinase-C. Forskolin (10(-5) M), A23187 (10(-6) M), and phorbol 12-myristate 13-acetate (PMA; 10(-7) M) all stimulated GH release. However, only PMA can mimic the synergistic effects of GHRP-6 on GRF-stimulated GH release and intracellular cAMP accumulation. 4 alpha-Phorbol 12,13-didecanoate, an inactive phorbol ester, was unable to stimulate GH release or potentiate the effect of GRF. Extracellularly added phospholipase-C not only stimulated GH release in a dose-dependent manner, but also potentiated GRF-induced GH release. Phloretin, a protein kinase-C inhibitor, in a concentration range of 10-250 microM had very little or no effect on basal and GRF-stimulated GH release, but markedly inhibited the stimulatory effects induced by either PMA or GHRP-6. Incubation of rat pituitary cells with 10(-6) M PMA for 24 h completely down-regulated protein kinase-C, since such PMA-pretreated cells did not release GH in response to a second dose of PMA. The protein kinase-C-depleted cells had an attenuated GHRP-6 response, but they responded normally to GRF. Moreover, the synergistic effects of GHRP-6 and GRF on GH release and cAMP accumulation were also greatly inhibited by protein kinase-C down-regulation. These data suggest that the effects of GHRP-6 on GH release, either alone or together with GRF, are at least partially mediated via the activation of protein kinase-C.

Amino Acid Sequence↗
PubMed1990

Insulin-like effects of ATP on adipocyte pyruvate dehydrogenase and phosphorylase.

Extracellular ATP stimulated adipocyte pyruvate dehydrogenase in a time- and dose-dependent manner with an EC50 of 0.1 mM. The maximal effect was observed at 0.5 mM ATP after a 15-min incubation with a lag period of about 5 min. Depletion of intracellular Ca2+ with ethylene glycol bis(beta-aminoethyl ether) N,N'-tetraacetic acid reduced the effect of ATP by 50% and completely abolished the stimulatory effect of vasopressin on adipocyte pyruvate dehydrogenase but had no effect on the stimulation induced by insulin or adenosine. The effects of insulin and ATP on pyruvate dehydrogenase were glucose-dependent whereas the effect of adenosine was glucose-independent. Furthermore, ATP, like insulin, partially blocked the stimulatory effect of isoproterenol on phosphorylase. Adenosine, at a concentration of 1 mM, did not affect either basal or isoproterenol-stimulated phosphorylase activities. It is concluded that ATP activates adipocyte pyruvate dehydrogenase by at least two separate mechanisms: one is Ca2(+)-dependent and the other is Ca2(+)-independent. However, neither is the result of the formation of adenosine from ATP through hydrolysis.

Adenosine↗