Suppression of squamous cell carcinoma in hairless mice by dietary nutrient variation.

In experiments involving the induction of squamous cell carcinoma in 1846 hairless mice that were maintained on a wide variety of diets, it was found that those diets with the least optimum balance of nutrients had the greatest inhibitory effect on growth of cancer. Rate of onset and severity of tumors was caused to vary over a 20-fold range by means of dietary balance alone. These experiments suggest that dietary variation in general and intentional malnutrition in particular should be given special attention in the control of existing cancer in humans.

Serotonin binding sites. II. Muramyl dipeptide binds to serotonin binding sites on myelin basic protein, LHRH, and MSH-ACTH 4-10.

Previously, we reported the existence of structurally similar serotonin binding sites on myelin basic protein, LHRH, and MSH-ACTH 4-10. We now report that the adjuvant peptide, muramyl dipeptide (N-acetyl-muramyl-L-Ala-D-isoGln) also binds to these sites. This observation may help to explain previous observations of serotonin-like activity by muramyl peptides, including the promotion of slow-wave sleep and fever induction. The observation may also provide an important link between the immune system and the nervous system that may explain the role of muramyl dipeptide adjuvants in causing autoimmune diseases to serotonin-regulated proteins and their receptors, as well as the alterations in serotonin levels that are often observed in autoimmune diseases. The observation provides concrete evidence for a dual-antigen hypothesis for the induction of autoimmune diseases by an adjuvant-peptide complex. Application of such a mechanism for induction of autoimmunity may be of importance in understanding a number of postinfectious and postvaccinal neuropathies, and suggests a possible etiology for autism, in which many patients have high blood serotonin levels, autoimmune reactions to myelin basic protein, and antibodies to serotonin binding sites. Finally, the observation suggests that glycopeptides may act as neurotransmitters.

Bovine pineal antireproductive tripeptide binds to luteinizing hormone-releasing hormone: a model for peptide modulation by sequence specific peptide interactions?

We report results of chromatographic, pH titration and nuclear magnetic resonance (NMR) spectroscopy studies demonstrating that the bovine pineal antireproductive tripeptide, Thr-Ser-Lys (BPART), binds to luteinizing hormone-releasing hormone (LHRH) at a site comprised of LHRH 2-5 (His-Trp-Ser-Tyr). BPART and LHRH have been shown to be antagonists in vitro. The binding constant is ca. 2 X 10(3)/mole. An NMR study of fifty other peptide pairs demonstrates that the binding is sequence and residue specific. The binding provides evidence of the amino acid pairing hypothesis, and suggests the possibility of modulation of one peptide by directly binding with another peptide.

Clinical suppression of experimental allergic encephalomyelitis by muramyl dipeptide "adjuvant".

Experimental allergic encephalomyelitis (EAE) is a model for several human diseases including multiple sclerosis and post-vaccinal encephalopathies. EAE is generally thought to be an autoimmune response to the antigen myelin basic protein (MBP). Oddly, MBP can also suppress EAE, and many observations suggest that an independent immune response to so-called "adjuvant" material is also necessary to EAE induction. Thus, EAE may be a result of a pair of interactive immune responses, one against MBP, and one against adjuvant. If so, the adjuvant should, like MBP, suppress EAE. We present data from experiments on strain 13 guinea pigs demonstrating EAE suppression by muramyl dipeptide, an active component of complete Freund's adjuvant. These results are striking because classically adjuvants are defined as immunopotentiators, not immunosuppressants. Our results, therefore, suggest that a revaluation of the role of adjuvants in inducing autoimmune diseases may be necessary.

Fibrinopeptide A binds Gly-Pro-Arg-Pro.

The tetrapeptide Gly-Pro-Arg-Pro inhibits fibrinogen aggregation, probably by binding to the same sites used during initiation of fibrin formation. The Gly-Pro-Arg-Pro binding sites have not yet been identified. However, their possible sequence and locations have been predicted on the basis of the amino acid pairing hypothesis. One of these predicted sites is on fibrinopeptide A. We report here that nuclear magnetic resonance studies indicate that Gly-Pro-Arg-Pro binds to fibrinopeptide A with a binding constant, K, of ca. 10(4) per mol. We also report results of 19 related peptide combinations used as controls.

Serotonin binding sites. I. Structures of sites on myelin basic protein, LHRH, MSH, ACTH, interferon, serum albumin, ovalbumin and red pigment concentrating hormone.

We report the results of nuclear magnetic resonance spectroscopy studies of combinations of serotonin (5-hydroxytryptamine) with the tryptophan peptide sequence and similar peptides from myelin basic protein. The binding site appears to consist of the sequence Arg Phe Ser Trp. Similar serotonin binding sites were found to exist on LHRH (Tyr Ser Trp) and MSH-ACTH tetrapeptide (Phe Arg Trp). These binding sites are specific to serotonin as is demonstrated by lack of binding by dopamine, histamine, acetylcholine and a dozen other pharmacologically active amines and indoles. Drugs known to affect serotonin levels, e.g., fenfluramine and L-DOPA, bind weakly to these sites. Structural and functional similarities between the tryptophan peptide, LHRH, and MSH-ACTH with an ACTH-like peptide of human leukocyte interferon, with human and bovine serum albumin, hen ovalbumin, and with red pigment concentrating hormone suggest that the latter peptides may also contain similar serotonin binding sites. The elucidation of serotonin binding sites on these peptides and proteins has implications for understanding various aspects of cancer, autoimmunity, neurological disease, and peptide hormone control.

Fenfluramine binds 5-hydroxytryptophan.

Fenfluramine, an anorexigenic drug, lowers serotonin (5-hydroxytryptamine) and 5-hydroxyindoleacetic acid levels in brain, spinal fluid, and blood, and has been used as a treatment for autism. Fenfluramine's mode of action is unknown. We present evidence from chromatography and nuclear magnetic resonance spectroscopy that fenfluramine selectively binds the serotonin and 5-hydroxyindoleacetic acid precursor, 5-hydroxytryptophan. The mode of binding may have general applications for the understanding of drug activity, receptor binding, and for the design of specific antagonists to aromatic compounds.

Brain-derived fibroblast growth factor: a study of its inactivation.

Brain fibroblast growth factor has been identified as a component of myelin basic protein. Its activity is destroyed when treated with a variety of solvents including dilute acid, organic solvents and solutions of guanidine hydrochloride. These conditions do not alter the encephalitogenic properties of myelin basic protein.

Cancer basic protein: a cellular growth factor in cancer cells?

Cancer basic protein possesses amazingly similar, but not identical, properties to myelin basic protein. Because of these similarities a theory is presented that cancer basic protein is a cellular growth factor and is intricately involved in the abnormal growth processes occurring in cancer cells.

Serum demyelinating factors in multiple sclerosis.

Sera from 21 patients with multiple sclerosis were applied to myelinated spinal cord cultures and evaluated for demyelinating activity. Samples were collected at various times when patients were on or off therapy with myelin basic protein or prednisone or both, and at various stages of disease. Five of 31 serum samples from 17 patients exhibited demyelinating activity when tested in a 40% concentration in tissue culture nutrient medium. Four of the 10 serum samples taken from patients with active or remitting multiple sclerosis (2 samples from the same patient) were demyelinative; 1 of 21 sera collected during stationary periods of disease was positive. There was no correlation between serum demyelinating activity and the presence or absence of treatment. Sera positive for demyelinating activity failed to inhibit myelin formation in initially unmyelinated cerebellar cultures.

An explanation of prevention and suppression of experimental allergic encephalomyelitis.

An explanation of experimental allergic encephalomyelitis prevention and suppression is presented based upon evidence that the active unit in disease induction is an encephalitogen-adjuvant complex. The stereochemical complementarity in structure of the encephalitogen and adjuvant is mirrored in complementarity in the recognition sites of lymphocyte populations activated against encephalitogen and adjuvant. Since two complementary lymphocyte populations are necessary for disease induction, any procedure that prevents the development of one of these populations will prevent disease induction. Any procedure that eliminates one population after induction has occurred will suppress the disease. We argue that all extant data support the hypothesis. Several new experiments are proposed to further test it.

Low percentage of T mu cells in amyotrophic lateral sclerosis.

The percentage of T mu cells in amyotrophic lateral sclerosis patients is markedly reduced. The T gamma population appears normal.

Brain fibroblast growth factors do not stimulate myelination or remyelination in tissue culture.

Myelin basic protein fragments that stimulated proliferation of fibroblasts in vitro did not enchance myelin formation or remyelination in nervous system tissue cultures. Similar fragments are present during demyelination in multiple sclerosis, but the lack of myelin stimulating activity in vitro suggests that they may not play a role in remyelination in vivo.