DISSOCIATION,AGGREGATION OF SESAME α-GLOBULIN IN NONIONIC DETERGENT SOLUTION

Nonionic detergents Triton X-100 and Brij 36T induce dissociation and aggregation of the protein sesame α-globulin above the critical micelle concentrations (cmc) of the detergents. Spectrophotometric titration in Triton shows no change in the pK_Int value of the tyrosyl groups at 1 × 10^-3M detergent where both dissociation and aggregation of the protein are observed. Fluorescence measurement does not indicate any change in the environment of the tryptophan groups of the protein in Brij. Viscosity measurements show no major conformational change of the protein in the detergent solution. Binding measurements suggest that perhaps micelles of the detergent predominantly bind to the protein. The detergent micelles preferentially bind to the exposed hydrophobic surfaces of the protein subunits. The association of the protein detergent complex through electrostatic interaction is probably responsible for the formation of the aggregates.     

Prion disease: a deadly disease for protein misfolding

An infectious particle, termed prion, composed largely and perhaps solely of a single protein, is the likely causative agent of prion disease. It produces lethal decline of cognitive and motor function. The responsible protein arrives at a pathogenic state by misfolding from a normal form that has ubiquitous tissue distribution. Prion diseases are often called spongiform encephalopathies. Probably most mammalian species develop these diseases. Specific examples in various animals are -Scrapie, Transmissible Mink Encephalopathy (TME ), Chronic Wasting Disease(CWD) and bovine spongiform encephalopathy (BSE). Humans are also susceptible to several prion diseases: Creutzfeld-Jacob Disease (CJD), Gerstmann-Straussler-Scheinker Syndrome (GSS), Fatal Familial Insomnia (FFI), Kuru and Alpers Syndrome. This paper reviews transmission of this diseases, protein involvement, nature of protein, the conversion process from PrP(c) to PrP(Sc), conversion of prion protein in vitro, the different proposed models for the conversion of PrP(c) to PrP(Sc), prion and other amyloid diseases, prion strains, structure of PrP(c) the particular process that may induce prion disease, and immunization against these diseases.     

Effect of 5-hydroxytryptamine on protein synthesis in gastrointestinal and other tissues and on serum gastrin concentrations in rats.

1 The effect of 5-hydroxytryptamine (5-HT) on protein synthesis in the gastrointestinal tissues as well as in the liver, heart and brain was studied by measuring [3H]-leucine incorporation into total tissue protein in vivo in rats. 2 A single injection of 5-HT (10 mg/kg) produced a marked inhibition (45 to 65%) in protein synthesis in the stomach (oxyntic gland area), intestine (jejunum + ileum), colon and brain, but not in the liver and heart. 3 Dose- and time-dependent studies of 5-HT-induced changes in protein synthesis in the stomach of fed rats revealed that the maximal inhibition of about 65% occurred 1 h after a dose of 12.5 mg/kg. 4 Animals deprived of food for 24 h differed from their fed counterparts only in the degree of responsiveness, in that a greater inhibition (75%) of [3H]-leucine incorporation into total protein of the stomach was observed 30 min after 5-HT injection. 5 Pretreatment of animals with methysergide (0.25 mg/kg) essentially abolished the 5-HT-mediated inhibition of protein synthesis in the stomach. 6 Serum gastrin concentration in fasted animals remained slightly elevated during the initial period of 5-HT treatment (up to 1 h). 7 The results demonstrate that in certain tissues, 5-HT markedly inhibits protein synthesis. The inhibition in protein synthesis in the gastrointestinal tract cannot be attributed to changes in the concentration of gastrin.     

Single lesion borderline lepromatous leprosy

A patient is reported who presented with a single lesion on the face which, on histopathological examination, was found to be borderline lepromatous leprosy. The importance of doing skin smears as a routine in all patients to differentiate Multibacillary from Paucibacillary disease is emphasized.     

Synergistic effect of methanol extract of Abies webbiana leaves on sleeping time induced by standard sedatives in mice and anti-inflammatory activity of extracts in rats

During the determination of LD50 values of extracts of Abies webbiana, it was observed that the methanol extract (MEAW) produces sedation of animals. This led to investigation of the effect of MEAW on sleeping time in mice. When various doses of the methanol extract (100, 150, and 200 mg/kg body weight) were administered alone, no hypnotic activity was observed. However, these exhibited significant synergistic effects (P < 0.001) at those dose levels in mice when administered prior to the administration of standard sedatives (pentobarbitone sodium: 50 mg/kg and diazepam: 6 mg/kg, respectively). In addition anti-inflammatory effects of methanol, chloroform, and petroleum ether extracts of Abies webbiana leaves in rats were performed to assess scientific validity of the medicinal claim of Indian folk medicine. The effects of leaf extracts (methanol, chloroform, and petroleum ether) against inflammation were studied by carrageenan-induced paw edema model in rats. The methanol extract (400 mg/kg p.o.) of leaves of Abies webbiana showed the best significant anti-inflammatory activity as compared to that of diclofenac sodium (150 mg/kg p.o.). The LD50 values of methanol, chloroform, and petroleum ether extracts were found to be 986, 1387, and > 3200 mg/kg, respectively. Thus, the therapeutic index of methanol extract may be favorable to open a new vista on combination therapy of hypnotics and may also against inflammation.     

Mammary tumorigenesis in growth hormone deficient spontaneous dwarf rats; effects of hormonal treatments

This study was carried out to investigate mammary tumorigenesis in growth hormone (GH) deficient spontaneous dwarf rats (SDR). At 50–60 days of age, the rats were divided into five groups. Group 1 received bovine (b) GH (prolonged release formulation) administered at a dose of 40–50 mg/kg body wt. in 50 l weekly injections; group 2 received recombinant human insulin-like growth factor-I (IGF-I) at a dose of 1 mg/kg body wt./day administered via osmotic pumps; animals in group 3 were fitted with subcutaneous silastic capsule containing 30 g 17-estradiol (E2) plus 30 mg progesterone (P4), replaced every 2 months; group 4 received both bGH and E2 plus P4 treatments at the same doses as above, and control animals (group 5) received sham treatments (vegetable oil injection, silastic capsules containing cellulose). After 1week of treatment, all animals were injected intraperitoneally with the carcinogen N-methyl-N-nitrosourea (MNU) at a dose of 50 mg/kg body wt. Other groups of animals, receiving identical hormonal treatment to those exposed to MNU, were treated for 10 days only and then sacrificed for assessment of circulating concentrations of hormones and mammary gland characteristics at the time of carcinogen exposure. The hormonal treatments of the animals exposed to the MNU were continued for an additional 20 weeks and mammary tumor development monitored by weekly palpation and tumors collected as necessary. The rats were weighed weekly. At the end of the treatment period, all animals were sacrificed and remaining tumors were collected. Rats in all groups continued to gain weight throughout the experimental period, but the largest weight gain was see in animals receiving GH either alone or with E2 and P4. Animals treated with IGF-I also gained weight compared to controls, but this weight gain was less than that seen in GH-treated rats. GH treatment alone increased mammary tumor incidence from 4.8% in controls to 100%. Average tumor load and latency in the GH-treated rats were 7.0 ± 0.8 tumors/tumor-bearing rat (mean±SEM) and 57.3 ± 2.7 days (mean±SEM), respectively. As in intact Sprague–Dawley rats, approximately 90% of the tumors that developed in the GH-treated rats were ovarian dependent for growth. IGF-I treatment also increased mammary tumor development to 62.5%. Average tumor load and latency in the IGF-I-treated rats were 1.6 ± 0.4 tumors/tumor-bearing rat (mean±SEM) and 96.2 ± 14.5 days (mean±SEM), respectively. However E2+P4 treatments did not significantly alter tumorigenesis and, surprisingly, simultaneous treatment with E2+P4 and GH obliterated the GH-stimulated increase in tumor development. Prolactin (PRL) did not appear to influence mammary tumorigenesis in the SDRs, as untreated SDRs had significantly elevated serum concentration of PRL as compared with normal Sprague–Dawley (SD) rats, whereas GH-treated SDRs had PRL levels similar to that of normal SD rats. No obvious structural characteristics were associated with high or low susceptibility to mammary tumorigenesis, as assessed by mammary gland whole mounts from the different animal groups sacrificed at the time of carcinogen administration.Enhanced expression of the extracellular signal-regulated kinase 1/2 (ERK1/2), and activation (phosphorylation) of ERK1/2 were associated with an increase in mammary tumorigenesis. Similarly, the expression of the estrogen receptor- (ER) was significantly elevated in animal groups with the highest susceptibility to tumorigenesis, whereas the levels of cyclin D1 expression were not related to mammary tumorigenesis.     

Identification and characterization of a novel allosteric modulator (SoRI-6238) of the serotonin transporter

In the present study we describe a novel agent, SoRI-6238 (ethyl 5-amino-3-(3,4-dichlorophenyl)-1,2-dihydropyrido[3,4-b]pyrazin-7-ylcarbamate) that partially inhibits 5-HT transporter (SERT) binding and allosterically modulates SERT function. Membranes were prepared from rat brain. SoRI-6238 partially inhibited SERT binding to brain membranes with a plateau at about 40% of control. SoRI-6238 fully inhibited norepinephrine transporter (NET) and dopamine transporter (DAT) binding with IC(50) values of 12.1 microM and 5.8 microM, respectively. The apparent K(d) of [(125)I]RTI-55 binding to SERT increased, then reached a plateau with increasing concentrations of SoRI-6238. SoRI-6238 fully inhibited [(3)H]5-HT uptake, acting to decrease the V(max) (noncompetitive inhibition). In kinetic experiments, SoRI-6238 slowed the dissociation of [(125)I]RTI-55 from SERT and slowed the initial association rate. We conclude that SoRI-6238 partially inhibits SERT binding and function, most likely via an allosteric mechanism.