Search PubMed⌕ Search

Biomedical subjects

C H Hill

Publications and source records attributed to C H Hill.

At least 19 recordsLinked to original sources
PubMed1992

Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity.

A hypothetical mode of inhibition of protein kinase C (PKC) by the natural product staurosporine has been used as a basis for the design of substituted bisindolylmaleimides with improved potency over the parent compound. Structure-activity relationships were consistent with the interaction of a cationic group in the inhibitor with a carboxylate group in the enzyme, and the most potent compound had a Ki of 3 nM. The inhibitors were competitive with ATP but inhibited cAMP-dependent protein kinase (PKA) only at much higher concentrations despite the extensive sequence homology between the ATP-binding regions of PKA and PKC. Three compounds were evaluated further and found to inhibit a human allogeneic mixed lymphocyte reaction pointing to the potential utility of PKC inhibitors in immunosuppressive therapy. One of these compounds was orally absorbed in the rat and represents an attractive lead in the development of PKC inhibitors as drugs.

Animals↗
PubMed1992

Oral, anti-inflammatory activity of a potent, selective, protein kinase C inhibitor.

The protein kinase C family of enzymes is thought to be important in mediating signal transduction. Ro 31-8830 is a novel, potent inhibitor of protein kinase C, derived from the non-selective protein kinase inhibitor staurosporine. In this paper we demonstrate the selectivity of Ro 31-8830 for protein kinase C over other protein kinases and its ability to inhibit protein kinase-C-mediated events in platelets and lymphocytes. In addition, we describe a novel system for the in vivo evaluation of inhibitors of protein kinase C, and we demonstrate the oral anti-inflammatory activity of Ro 31-8830. This finding has implications for the treatment of inflammatory disorders in the clinic.

Administration, Oral↗
PubMed1992

Dietary vanadium and the oxidative state of hepatic and renal pyridine nucleotides.

1. NAD, NADH, NADP and NADPH were measured in the livers and kidneys of chicks receiving 50 mg vanadium/kg diet. 2. There was no effect of dietary vanadium on the oxidative states of the nucleotides, although the growth rate was decreased. 3. The lack of effect of vanadium on the oxidative status of the nucleotides was ascribed to the low tissue concentration of vanadium.

Animals↗
PubMed1992

Heat shock protein response in phosphorus-deficient heat-stressed broiler chickens.

1. During acute in vivo heat stress, a normal heat shock protein (HSP) response was not inducible in chickens deficient in inorganic phosphorus (P(i)-deficient). 2. Small quantities of HSP 70 and HSP 90 were induced, but little or no HSP 23 was induced in P(i)-deficient chickens compared to P(i)-adequate chickens. 3. Increased susceptibility of P(i)-deficient chickens to acute heat stress was attributed to their inability to produce an adequate HSP response.

Animals↗
PubMed1992

Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides.

The design and synthesis of a series of novel inhibitors of protein kinase C (PKC) is described. These 2,3-bisarylmaleimides were derived from the structural lead provided by the indolocarbazoles, staurosporine and K252a. Optimum activity required the imide NH, both carbonyl groups, and the olefinic bond of the maleimide ring. 2,3-Bisindolylmaleimides were the most active, and the potency of these was improved by a chloro substituent at the 5-position of one indole ring (compound 28, IC50 0.11 microM). In a series of (phenylindolyl)maleimides, nitro compound 74 was most active (IC50 0.67 microM). Naphthalene 19 and benzothiophene 21 showed greater than 100-fold selectivity for inhibition of PKC over the closely related cAMP-dependent protein kinase (PKA).

Animals↗
PubMed1991

A novel conformationally restricted protein kinase C inhibitor, Ro 31-8425, inhibits human neutrophil superoxide generation by soluble, particulate and post-receptor stimuli.

A novel, bis-indolylmaleimide, Ro 31-8425, bearing a conformationally restricted side chain, inhibits protein kinase C isolated from rat brain and human neutrophils with a high degree of selectivity over cAMP-dependent kinase and Ca2+/calmodulin-dependent kinase. It also inhibits phorbol ester-induced intracellular events known to be mediated by protein kinase C (p47 phosphorylation in intact platelets, CD3 and CD4 down-regulation in T-cells). Ro 31-8425 inhibited superoxide generation in human neutrophils activated by both receptor stimuli (formyl-methionyl-leucylphenylalanine, opsonized zymosan, IgG and heat aggregated IgG) and post-receptor stimuli (1,2-dioctanoylglycerol and fluoride). The compound also blocked antigen driven, but not IL-2 induced, T-cell proliferation. These results support a central role for protein kinase C in the activation of the respiratory burst and antigen-driven T-cell proliferation.

Animals↗
PubMed1991

Novel, potent and selective inhibitors of protein kinase C show oral anti-inflammatory activity.

Clarification of the precise role of protein kinase C (PKC) in cellular functional responses has been hampered by a lack of potent, selective inhibitors. The structural lead provided by staurosporine, a potent but non-selective protein kinase (PK) inhibitor, was used to derive a series of bis(indolyl)maleimides of which the most potent, Ro 31-8425 (I50: PKC = 8 nM) showed 350-fold selectivity for PKC over cAMP-dependent protein kinase. Ro 31-8425 antagonised cellular processes triggered by phorbol esters (potent, specific PKC activators) and inhibited the allogeneic mixed lymphocyte reaction, suggesting a role for PKC in T-cell activation. Methylation of the primary amine in Ro 31-8425 produced an analogue. Ro 31-8830 which, when administered orally, produced a dose-dependent inhibition of a phorbol ester-induced paw oedema in mice (minimum effective dose = 15 mg/kg). Ro 31-8830 also selectively inhibited the secondary inflammation in a developing adjuvant arthritis model in the rat. The results presented here suggest that these selective inhibitors of PKC may have therapeutic value in the treatment of T-cell-mediated autoimmune diseases.

Administration, Oral↗
PubMed1990

K252a is a potent and selective inhibitor of phosphorylase kinase.

The inhibition of phosphorylase kinase by a number of protein kinase inhibitors was examined. Both K252a and staurosporine are potent inhibitors of phosphorylase kinase with IC50 values of 1.7 nM and 0.5 nM respectively. K252a shows a 300-fold selectivity for this enzyme over protein kinase C whereas staurosporine shows only a 20-fold selectivity for phosphorylase kinase. In contrast, the Roche bis-indolyl maleimides inhibit phosphorylase kinase with IC50 values of approximately 1 microM and are highly selective for protein kinase C.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1990

Synthesis and antiviral activity of metabolites of rimantadine.

The hydroxy metabolites of rimantadine (3-5) were synthesized and compared to amantadine (1) and rimantadine (2) for their ability to inhibit the replication of influenza viruses in vitro. All three metabolites were inhibitory to wild-type influenza A viruses (H3N2 and H1N1). In particular, 2-hydroxyrimantadine (3) showed similar activity to amantadine, but the 3- and 4-hydroxy metabolites (4 and 5, respectively), both of which are found in rimantadine-treated patients, showed only modest inhibitory activity. A rimantadine-resistant isolate of influenza A virus exhibited cross-resistance to amantadine and to each of the metabolites 3-5. None of the compounds were effective against influenza B virus.

Adamantane↗
PubMed1989

Potent selective inhibitors of protein kinase C.

A series of potent, selective inhibitors of protein kinase C has been derived from the structural lead provided by the microbial broth products, staurosporine and K252a. Our inhibitors block PCK in intact cells (platelets and T cells), and prevent the proliferation of mononuclear cells in response to interleukin 2 (IL2).

Alkaloids↗
PubMed1989

Effect of Salmonella gallinarum infection on zinc metabolism in chicks.

The effect of Salmonella gallinarum infection in chicks on serum, liver, and kidney zinc concentrations was studied. Within 48 h after intraperitoneal administration of the organism, serum zinc declined to approximately one-half the control value. In one experiment, the serum zinc concentration remained low for the 12 days of the experiment, whereas in a second experiment, the concentration gradually increased after 6 days postinoculation but never returned to the control value. Feeding as much as 500 ppm supplemental zinc did not prevent the infection-induced decline in the serum zinc concentration. The infection resulted in a sequestering of zinc in the liver; the kidney remained relatively unresponsive in this system. Fractionation of liver homogenates by gel filtration column chromatography revealed that the zinc in the livers of the infected animals eluted in a volume characteristic of metallothionein, whereas that of control animals was associated with high molecular weight proteins. Increasing the zinc content of the serum by repeated subcutaneous injections of zinc had no effect on mortality from this infection. Restricting feed consumption of uninfected chicks to that of infected animals did mimic the influence of infection of serum zinc and hepatic metallothionein concentrations.

Animals↗
PubMed1980

Effect of zinc deficiency on bone collagenase and collagen turnover.

The effect of zinc deficiency on bone collagenase activity and collagen turnover was studied in the chick. Zinc deficiency symptoms, evident after 8 days on the low zinc diet, included tibia deformities and decreased alkaline phosphatase. Bone collagen metabolism was markedly altered, with a significant reduction in collagen synthesis and turnover. Half-turnover time for tibia collagen was 13 days in the control and 35 days in the zinc-deficient chicks. Tibia collagenase activity was reduced by 40-80% in the zinc-deficient as compared to the control chicks. Heparin markedly increased collagenase activity in the zinc-deficient tibias elevating activity to control levels. But commercially available heparin was found high in zinc content which may explain this effect entirely. These data show that zinc deficiency decreases bone collagen turnover and probably accounts for the leg deformities seen in zinc-deficient chicks.

Alkaline Phosphatase↗
PubMed1979

Tongue lesions in children.

A review of tongue lesions in children showed that there is a great variety requiring operative intervention, often in infancy. While the presenting symptoms may be related to dysphagia and dyspnea, the aim of operative intervention should not only be to salvage life by restoration of breathing and swallowing, but also to leave a tongue capable of adequate speech, taste, sensation, and normal orofacial development. Intimate knowledge of lingual anatomy and function is necessary to allow selection of the ideal procedure and appropriate timing of the therapy. While careful observation and nonoperative approach may be indicated in non-neoplastic macroglossia, early intervention is often necessary in diffuse neoplastic lesions such as lymphangioma, fibromatosis, or fibrolipomatous dysplasia. While malignant tumors are rare in childhood, they do occur and have to ruled out.

Adolescent↗
PubMed1979

Studies on the ameliorating effect of ascorbic acid on mineral toxicities in the chick.

The effect of dietary ascorbic acid on the toxicity of high levels of cobalt, selenium, vanadium, cadmium, copper, and mercury was determined in chicks. The vitamin reduced the growth retardation caused by cobalt, selenium, vanadium, and cadmium administration but had no such effect on copper and mercury toxicity at the levels used. The effect of ascorbic acid on growth could not be mimicked by ferrous iron administration. Ascorbic acid did not alleviate the increased susceptibility of chicks to Salmonella gallinarum caused by feeding high levels of these elements.

Animals↗
PubMed1979

The effect of dietary protein levels on mineral toxicity in chicks.

Studies have been conducted to determine the influence of dietary protein levels of 10, 20, and 30% fed as soybean meal on the toxicity of selenium, cadmium, vanadium, cobalt, and nickel to chicks. The toxicity was evaluated in terms of growth retardation and a decrease in resistance to S. gallinarum infection as measured by mortality. The toxicity of selenium or cadmium was unaffected by the protein level of the diet while the toxicity of vanadium, cobalt and nickel was decreased by increased dietary protein as measured by the interactions on growth. The interactions apparent on growth were not as apparent on resistance to infection indicating that the latter parameter is much less sensitive to these dietary manipulations than is growth.

Animals↗
PubMed1979

Dietary influences on resistance to Salmonella infection in chicks.

Studies on the influence of nutritional factors on the resistance of chicks to Salmonella gallinarum have been reviewed. Increased dietary protein decreased the resistance of chicks to this infection although resistance to Escherichia coli infections was not appreciably affected. The administration of high levels of iron, particularly when accompanied by a chelating agent such as EDTA, resulted in increased resistance to this infection. The additional iron resulted in the prevention of the transient hypoferremia and anemia during the course of the disease. Fewer viable S. gallinarum were present in the blood, liver, and spleen in the presence of increased dietary or injected iron. Cadmium added to the diet at a nontoxic level also enhanced resistance to this infection.

Amino Acids↗
PubMed1978

Abnormal cellular copper metabolism in the blotchy mouse.

Defective copper metabolism was demonstrated in male mice bearing the blotchy (Moblo/y) allele at the mottled locus on the X-chromosome. Copper absorption from the gut was only 64% of that found in normal mice and hepatic copper levels were only 56% of the controls. Ceruloplasmin and heart cytochrome c oxidase activities were normal, yet lysyl oxidase activity from cultured fibroblasts was only 45% of control levels. Copper accumulated in fibroblasts cultured from these mutants to values that were five times normal. The accumulation of copper in the fibroblasts was associated with a protein of approximately 12,000 molecular weight.

Alleles↗