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Biomedical subjects

R M Schultz

Publications and source records attributed to R M Schultz.

At least 199 records · Page 11Linked to original sources
PubMed1983

Expression of creatine kinase isoenzyme during oogenesis and embryogenesis in the mouse.

Creatine kinase activity was discovered in the growing mouse oocyte and in the preimplantation embryo. Changes in the enzyme activity during the growth and maturation of the egg and during the development of the embryo up to the blastocyst stage were determined. Close similarity of the protein to the brain-type isoenzyme of creatine kinase was established immunochemically. The kinetic parameters of the brain-type isoenzyme (M. R. Iyengar, C. E. Fluellen, and C. W. L. Iyengar, 1982, J. Muscle Cell Motil. 3, 231-246) and the pattern of development-associated changes in activity suggest a possible role for creatine kinase in maintaining the reported high ATP/ADP ratio (L. Ginsberg and N. Hillman, 1975, J. Reprod. Fertil. 43, 83-90), which is essential for the biosynthetic activities of the embryo.

Animals↗
PubMed1983

Potentiation of nonspecific immunotherapy of experimental lung metastases by indomethacin.

Intraperitoneal treatment with the interferon inducer, maleic anhydride-divinyl ether copolymer (MVE), has previously been demonstrated to effectively reduce metastatic growth in the lungs and prolong survival times of BALB/c mice bearing the syngeneic Madison lung (M109) carcinoma. Resistance to lung metastasis formation induced by MVE appears to result from an activation of alveolar macrophage function. Since E-type prostaglandins (PGE) suppress the cytotoxic activity of activated macrophages, we sought to determine the effect of indomethacin, a prostaglandin synthetase inhibitor, on the antimetastatic activity of MVE. An artificial metastasis model was developed in which single-cell suspensions of the M109 tumor were injected i.v. into BALB/c mice. A 52,600 molecular weight fraction of MVE (MVE-5) was administered i.p. at 20 mg/kg two days prior to tumor inoculation. MVE-5 treatment produced greater than 80 percent reduction in macroscopic lung lesion formation at Day 15 and Day 19 after tumor inoculation and a resultant 45 percent increase in lifespan. Chronic administration of indomethacin in the drinking water at 10 micrograms/ml potentiated the MVE-5 antitumor induced macrophage activation in vivo. In the absence of any evidence for an interaction between indomethacin and circulating M109 cells, it was felt that the potentiating effect could be best explained in terms of interference with PGE-mediated feedback inhibition of macrophage functional activity.

Animals↗
PubMed1983

Macrophage activation: synergism between hybridoma MAF and poly(I). Poly(C) delivered by liposomes.

High concentrations of a murine T cell hybridoma culture supernatant containing macrophage-activating factor (MAF) rendered resident mouse peritoneal macrophages cytotoxic for P815 mastocytoma cells. The capacity of the hybridoma-derived MAF (MAFH) to induce tumoricidal activity increased 10(3) to 10(4)-fold when the lymphokine was encapsulated into liposomes. Combinations of MAFH and poly(I) X poly(C) acted synergistically to render macrophages potently cytotoxic. Subthreshold (nonactivating) concentrations of free or liposome-encapsulated MAFH increased the potency of free poly(I) X poly(C) and liposome encapsulated poly(I) X poly(C). Either as free agent or encapsulated in liposomes, single-stranded poly(I) or poly(C) did not activate macrophages in the presence or absence of MAFH. Double-stranded poly(I) X poly(C) was thus required for macrophage activation and synergism with MAFH.

Animals↗
PubMed1982

Biochemical studies of mammalian oogenesis: possible existence of a ribosomal and poly(A)-containing RNA-protein supramolecular complex in mouse oocytes.

Mouse follicles were labeled with [3H]uridine and then cultured in vitro for 3 days. When oocytes were disrupted, about 40% of the total radiolabeled RNA could be sedimented at 9,000g. Fractionation of this RNA on poly(U)-Sepharose revealed that about 30% and 60% of the total amount of radiolabeled poly(A)- and poly(A)+ RNA, respectively, were in the pellet fraction. Treatments that disrupt protein structure reduced the amount of 9,000g sedimentable RNA and affected to the same extent the distribution of Poly(A)- and poly(A)+ RNA in the pellet and supernatant fractions. CsCl centrifugation of formaldehyde-fixed pellets revealed that virtually all of the radiolabeled RNA had a density significantly lower than that of ribosomes. The sedimentable RNA appeared not to be polysomal, membrane bound or associated wih a cytoskeleton. Agarose gel electrophoresis after poly(U)-Sepharose fractionation of either the pellet or supernatant revealed the presence of 28S, 18S, 5S + 4S, and heterodisperse poly(A)+ RNA. The size of distribution of poly(A)+ RNA in the pellet and supernatant fractions was fairly similar. Pulse-chase experiments revealed that the stability of poly(A)- RNA in the pellet and supernatant fractions was the same within the experimental error and a similar situation was found for poly(A)+ RNA. RNA in pellet translated in vitro coded for discrete size classes of protein. Since the relative band intensities were similar for both total and pellet RNA translated in vitro there seemed to be no major partitioning of specific size classes of mRNA into the pellet fraction. These results are discussed in terms of a possible composition of the lattice structures that accumulate during mouse oocyte growth and have been postulated to be a storage form for ribosome (Burkholder et al., '71).

Animals↗
PubMed1982

Similarities of murine gamma interferon and the lymphokine that renders macrophages cytotoxic.

Murine spleen lymphoid cells treated with insoluble (Sepharose bound) concanavalin A elaborate Gamma (immune) interferon (IFN-gamma) and macrophage activation factor (MAF) into the culture medium. Similarly, MAF is produced by T cells with other IFN-gamma inducers. MAF induces resting (noncytotoxic) macrophages to become tumoricidal. We have compared various physicochemical properties of MAF and INF-gamma, their neutralization by antibody to IFN-gamma, and their induction period. In these parameters, induction of antiviral activity was compared to induction of macrophage tumoricidal activity. All of the parameters studied have given results that demonstrate close similarity in the physical properties, molecular characteristics, and biological reactivities of the two lymphokines, and this similarity suggests that these two lymphokines reside in the same molecule. This conclusion would include that IFN-gamma, like IFN-alpha and IFN-beta, is capable of activating macrophages to become cytotoxic toward tumor cells.

Animals↗
PubMed1982

Interferon induction and macrophage activation by a mycovirus double-stranded RNA/tobramycin complex following treatment with human serum.

Double-stranded RNA (dsRNA) molecules, generally effective inducers of interferon (IFN), have a weak potency in man apparently because of the presence of a serum RNAase which quickly inactivates extracellular dsRNA. We have discovered that tobramycin, an aminoglycoside, protects Penicillium chrysogenum mycovirus dsRNA (PCMdsRNA) from the degradative action of the nuclease. Exposure of the dsRNA/tobramycin complex to human serum results in some degradation, but still permits the production of significantly high titers of IFN upon injection into mice. Intraperitoneal (i.p.) treatment of CFI mice with both dsRNA and dsRNA/tobramycin complex activated macrophages to inhibit the growth of P815 mastocytoma target cells. Following in vitro treatment with human serum, free dsRNA failed to activate peritoneal macrophages in vivo under conditions where this activity of dsRNA/tobramycin complex was retained. By varying the ratio of moles of tobramycin (as free base) to the moles of RNA phosphorous, toxicity can be minimized, while retaining the biologic activities of dsRNA.

Animals↗
PubMed1982

Synthesis and conformational properties of a synthetic cyclic peptide for the active site of alpha-chymotrypsin.

A nonapeptide Ac-His-Phe-Gly-Cys-D-Phe-Ser-Gly-Glu-Cys-NH2 (XI) cyclized through the cysteines at positions 4 and 9 is synthesized as a model active site for the enzyme alpha-chymotrypsin. A CPK model of XI indicates that the peptide will have a high probability of folding into a conformation in which the two beta-phenyls interact to form a hydrophobic site to one side of the cyclohexyl structure, and the Ser-His-Glu side chains form a hydrogen bonded triad over the plane of cyclopeptidyl structure. Substrates can then bind at the hydrophobic pocket formed by the beta-phenyls and be acted upon by the Ser-His-Glu catalytic triad, as in the enzyme. 1H. n.m.r. shows: (i) multiplet peaks for the phenyl protons in D2O that condense to a singlet in DMSO-d6, (ii) a perturbation of the phenyl protons chemical shift on proflavin association to XI, and (iii) perturbation of the His pKa to a higher value on association of proflavin to XI. These data support the existence of a hydrophobic site and a Glu-His interaction in the peptide. Furthermore, the greater than 10(2) better affinity of proflavin to XI than to AcTrp supports the existence of a hydrophobic site. However, no acceleration of p-nitrophenyl acetate or trans-cinnamoyl imidazole hydrolysis over that of imidazole is observed. The possible reasons for a lack of esterase activity in XI and other peptidyl models of serine protease active sites are discussed.

Binding Sites↗
PubMed1982

Dose-dependent pharmacokinetics of mezlocillin in relation to renal impairment.

The dose dependence of mezlocillin pharmacokinetics was examined in relation to renal function after intravenous doses of 1 and 5 g in 16 subjects with various degrees of renal impairment. Dose and time-average model-independent physiological parameters were calculated from plasma concentration and urinary excretion data. Lack of superimposition of plasma concentration profiles occurred between dosage levels with a twofold exaggeration of areas under the curve produced between doses of 1 and 5 g. Decreased plasma clearances at the higher dose were caused partly by nonlinear renal clearance, but more markedly by dose dependence in nonrenal clearances. At each dosage level, these parameters were examined in relation to creatinine clearances. Plasma and renal clearances exhibited a typical linear correlation with creatinine clearance for each dose level. However, nonrenal clearances demonstrated a linear relationship with creatinine clearance at the 1-g dose, but apparent saturation of this pathway produced lower and relatively constant nonrenal clearance values at the 5-g dose. Mezlocillin pharmacokinetics are thus influenced by both dose and renal function over the dosage range of 1 to 5 g. Saturation in renal clearance and probably in biliary clearance explains the unusual disposition characteristics of mezlocillin observed in this and previously reported studies.

Adult↗
PubMed1981

Biochemical studies of mammalian oogenesis: kinetics of accumulation of total and poly(A)-containing RNA during growth of the mouse oocyte.

Kinetics of accumulation of total and poly(A)-containing RNA have been measured during growth of the mouse oocyte. Total RNA from oocytes isolated at discrete stages of growth was determined by two independent microassays. The full-grown oocyte contained about 0.60 ng of RNA. Kinetics of accumulation of total RNA with respect to oocyte volume were biphasic. Small, growing oocytes (about 30 pl) contained about 0.20 ng of RNA/oocyte. The amount of RNA increased in a quasi-linear fashion until oocyte volume was about 160 pl, at which point there was about 0.57 ng of RNA/oocyte. Thus oocytes about 65% of their final volume had accumulated about 95% of the total amount of RNA present in the fully-grown oocyte. The relative amount of poly (A)-containing RNA in oocytes of various size was determined by in situ hybridization of [3H] poly (U) to ovarian sections from juvenile mice of known age, followed by autoradiography. The kinetics of accumulation of poly (A)-containing RNA were similar to those of total RNA; oocytes about 70% of their final volume had accumulated about 95% of the amount of poly (A)-containing RNA present in the fully-grown oocyte. The poly(A)-containing RNA resided predominantly in the cytoplasm and no obvious cytoplasmic localization was observed. Kinetics of accumulation of total RNA, which is mainly ribosomal, and poly (A)-containing RNA were consistent with levels of RNA polymerases I and II measured by others during oocyte growth (Moore and Lintern-Moore, '78). The number of ribosomes that could be made from the amount of rRNA present at various stages of growth was compared to the actual number of ribosomes calculated from a published morphometric study (Garcia et al., '79). Kinetic differences in accumulation between the theoretical and actual number of ribosomes suggested oocyte ribosomes are recruited into cytoplasmic lattice structures. These structures accumulate during oocyte growth and have been postulated to be a ribosomal storage form. In addition, the results from this study are compared to results derived from lower species.

Animals↗