Further characterization of the effect of the prototypical antidepressant imipramine on the microstructure of licking for sucrose

We previously reported that treatment with the prototypical antidepressant imipramine induced a dose-dependent reduction of the ingestion of a 10% sucrose solution, due to reduction of the licking burst number, thus suggesting reduced motivation and/or increased satiation. Importantly, the experimental sessions were performed in an alternate order, either 1-h or 24-h after imipramine administration. The observation that imipramine effect was more pronounced in the “1-h after-treatment” sessions, i.e. at the time of the brain drug Cmax, led us to suggest that it was likely related to brain drug levels at testing time. However, such an experimental design does not allow to rule out the alternative possibility that the observed effect might be due to post-session administration, as previously observed with memantine. To determine whether imipramine-induced decrease of sucrose ingestion could be observed even in absence of post-session administration, we examined the effect of a daily 22 day treatment with imipramine (5, 10 and 20 mg/kg). In the first half of the treatment period all behavioural tests were performed 1-h after administration. In the second half of the treatment period, tests were performed alternatively either 1-h or 24-h after imipramine administration. The results confirm that imipramine reduces sucrose ingestion due to a reduction of the licking burst number. Most importantly, these results demonstrate that this effect does not require imipramine post-session administration, since it was present before the beginning of post-session administrations. This supports the interpretation of the reduction of sucrose ingestion as a consequence of reduced motivation and/or increased satiation. Thus, these findings, taken together with the results of our previous study, might be relevant in explaining the effects of imipramine in models of drug-seeking and in body weight gain reduction in rats, but not in accounting for the antidepressant therapeutic effect. At variance with the results of our previous study, an increase in burst size was present in the first half of the treatment period, which might be interpreted as a prohedonic effect and/or as a compensatory effect.

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Enhancement of FSH bioactivity in vivo using site-specific antisera

Journal of Endocrinology ◽

10.1677/joe.0.1520355 ◽

1997 ◽

Vol 152 (3) ◽

pp. 355-363 ◽

Cited By ~ 11

Author(s):

L Ferasin ◽

G Gabai ◽

J Beattie ◽

G Bono ◽

A T Holder

Keyword(s):

Biological Activity ◽

Treatment Period ◽

Ovarian Function ◽

Day Treatment ◽

Site Specific ◽

Dose Dependent Fashion ◽

Snell Dwarf ◽

Fsh Bioactivity ◽

Dose Dependent

The ability of site-specific antipeptide antisera to enhance the biological activity of ovine FSH (oFSH) in vivo was investigated using hypopituitary Snell dwarf mice. These animals were shown to respond to increasing doses of oFSH (3·3–90 μg/day), administered in two daily injections over a 5-day treatment period, in a highly significant dose-dependent fashion. The responses measured were increases in uterine weight, ovarian weight and the index of keratinisation in vaginal smears. The dose-dependent response to oFSH confirmed the suitability of this animal model for these investigations and suggested the suboptimal dose of oFSH (20 μg/day) for use in enhancement studies. Five peptides derived from the β subunit of bovine FSH (bFSH) (A, residues 33–47; B, 40–51; C, 69–80; D, 83–94; E, 27–39) were used to generate polyclonal antipeptide antisera. Of these peptides, only A and B produced an antiserum (raised in sheep) capable of recognising 125I-bFSH in a liquid phase RIA. Antisera prepared against peptide A or peptide B were found to significantly enhance the biological activity of 20 μg oFSH/day over a 5-day treatment period. The response to antipeptide antisera alone did not differ significantly from that observed in PBS-injected control animals, neither did the response to FSH alone differ from that observed in animals treated with FSH plus preimmune serum. Thus the enhanced responses are dependent upon the presence of FSH plus antipeptide antiserum. Peptides A and B are located in a region thought to be involved in receptor recognition, this may have implications for the mechanism underlying this phenomenon and/or the structure/function relationships of FSH. That FSH-enhancing antisera can be generated by immunisation of animals with peptides A and B suggests that it may be possible to develop these peptides as vaccines capable of increasing reproductive performance, such as ovulation rate. The high degree of sequence homology between ovine, bovine and porcine (and to a lesser extent human and equine) FSH in the region covered by peptides A and B suggests that these peptides could also be used to promote and regulate ovarian function in all of these species. Journal of Endocrinology (1997) 152, 355–363

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High-dose Glycerol Monolaurate Up-Regulated Beneficial Indigenous Microbiota without Inducing Metabolic Dysfunction and Systemic Inflammation: New Insights into Its Antimicrobial Potential

Nutrients ◽

10.3390/nu11091981 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1981 ◽

Cited By ~ 9

Author(s):

Qiufen Mo ◽

Aikun Fu ◽

Lingli Deng ◽

Minjie Zhao ◽

Yang Li ◽

...

Keyword(s):

Lipid Metabolism ◽

Systemic Inflammation ◽

Body Weight Gain ◽

High Dose ◽

Dependent Manner ◽

Glucose And Lipid Metabolism ◽

Glycerol Monolaurate ◽

Indigenous Microbiota ◽

Anti Inflammatory ◽

Dose Dependent

Glycerol monolaurate (GML) has potent antimicrobial and anti-inflammatory activities. The present study aimed to assess the dose-dependent antimicrobial-effects of GML on the gut microbiota, glucose and lipid metabolism and inflammatory response in C57BL/6 mice. Mice were fed on diets supplemented with GML at dose of 400, 800 and 1600 mg kg−1 for 4 months, respectively. Results showed that supplementation of GML, regardless of the dosages, induced modest body weight gain without affecting epididymal/brown fat pad, lipid profiles and glycemic markers. A high dose of GML (1600 mg kg−1) showed positive impacts on the anti-inflammatory TGF-β1 and IL-22. GML modulated the indigenous microbiota in a dose-dependent manner. It was found that 400 and 800 mg kg−1 GML improved the richness of Barnesiella, whereas a high dosage of GML (1600 mg kg−1) significantly increased the relative abundances of Clostridium XIVa, Oscillibacter and Parasutterella. The present work indicated that GML could upregulate the favorable microbial taxa without inducing systemic inflammation and dysfunction of glucose and lipid metabolism.

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An engineered IL-2 reprogrammed for anti-tumor therapy using a semi-synthetic organism

Nature Communications ◽

10.1038/s41467-021-24987-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jerod L. Ptacin ◽

Carolina E. Caffaro ◽

Lina Ma ◽

Kristine M. San Jose Gall ◽

Hans R. Aerni ◽

...

Keyword(s):

Nk Cells ◽

Large Scale ◽

Tumor Therapy ◽

Covalent Modification ◽

Synthetic Dna ◽

Expansion Characteristic ◽

Synthetic Organisms ◽

Dose Dependent ◽

Receptor Beta

AbstractThe implementation of applied engineering principles to create synthetic biological systems promises to revolutionize medicine, but application of fundamentally redesigned organisms has thus far not impacted practical drug development. Here we utilize an engineered microbial organism with a six-letter semi-synthetic DNA code to generate a library of site-specific, click chemistry compatible amino acid substitutions in the human cytokine IL-2. Targeted covalent modification of IL-2 variants with PEG polymers and screening identifies compounds with distinct IL-2 receptor specificities and improved pharmacological properties. One variant, termed THOR-707, selectively engages the IL-2 receptor beta/gamma complex without engagement of the IL-2 receptor alpha. In mice, administration of THOR-707 results in large-scale activation and amplification of CD8+ T cells and NK cells, without Treg expansion characteristic of IL-2. In syngeneic B16-F10 tumor-bearing mice, THOR-707 enhances drug accumulation in the tumor tissue, stimulates tumor-infiltrating CD8+ T and NK cells, and leads to a dose-dependent reduction of tumor growth. These results support further characterization of the immune modulatory, anti-tumor properties of THOR-707 and represent a fundamental advance in the application of synthetic biology to medicine, leveraging engineered semi-synthetic organisms as cellular factories to facilitate discovery and production of differentiated classes of chemically modified biologics.

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Influence de la température et de la durée d'un traitement cryoprotecteur sur la résistance au froid de plantules de blé. Étude ultrastructurale des ébauches foliaires

Canadian Journal of Botany ◽

10.1139/b83-110 ◽

1983 ◽

Vol 61 (4) ◽

pp. 1025-1039 ◽

Cited By ~ 5

Author(s):

C. M. Gazeau

Keyword(s):

Endoplasmic Reticulum ◽

Treatment Period ◽

Day Treatment ◽

Leaf Primordia ◽

Ultrastructural Changes ◽

Distilled Water ◽

Wheat Seedlings ◽

Starch Grains ◽

Different Temperatures ◽

Protective Treatment

Wheat seedlings were treated at different temperatures and for various periods of time with a cold-protective substance, composed of a mixture of glycerol, dimethylsulfoxide, and saccharose. When the treatment was done at 20 °C, slight ultrastructural changes appeared in leaf primordia as soon as day 1. Thus numbers of lipid globules increased significantly. When the treatment period was increased to 4 days, numbers of starch grains increased, and there was a marked enlargement of mitochondria and plasts. When the treatment was done at 2 °C, cytoplasmic alterations occurred later than at 20 °C. After a 4-day treatment, they were similar to changes induced at 20 °C. When the treatment period was increased to 12 days, dictyosomes were markedly altered. They clustered close to the nucleus in two or three groups and gave rise to numerous pale vesicles with various shapes and sizes. Around each cluster of such vesicles, there gathered many endoplasmic reticulum vesicles and other organelles (mitochondria, plasts, microbodies, vacuoles). A further cooling of 1 °C/min, down to −15 or −30 °C, enhanced these phenomena. After the seedlings were warmed up to 20 °C in distilled water, the changes induced by the frost-protective treatment and then by freezing were shown to be reversible. [Journal translation]

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Postnatal development and testosterone dependence of a rat epididymal protein identified by neonatal tolerization

Reproduction ◽

10.1530/rep.0.1250495 ◽

2003 ◽

pp. 495-507 ◽

Cited By ~ 6

Author(s):

SA Joshi ◽

S Shaikh ◽

S Ranpura ◽

VV Khole

Keyword(s):

Western Blot ◽

Postnatal Development ◽

Blot Analysis ◽

Western Blot Analysis ◽

Polyclonal Antiserum ◽

Cognate Gene ◽

Specific Proteins ◽

Androgen Regulation ◽

Dose Dependent

A rat epididymal protein of 27 kDa was identified using neonatal tolerization. This study reports the production and characterization of a polyclonal antiserum to this protein. ELISA was used to demonstrate that this antiserum reacts strongly with epididymal sperm proteins, but has little or no reactivity with testicular proteins. Western blot analysis revealed that this polyclonal antiserum recognized a 27 kDa protein extracted from the corpus epididymidis as well as from spermatozoa from the corpus and cauda epididymides, and immunostaining revealed the presence of the protein in the corpus to cauda epididymides. Stronger reactivity was observed in the supranuclear region and stereocilla of principal cells of the corpus epididymidis and in the luminal content of the corpus and cauda epididymides. The testicular section showed no reactivity. Treatment with the antiserum resulted in time- and dose-dependent agglutination of rat spermatozoa. By indirect immunofluorescence, the antiserum localized proteins in the mid-piece region of rat spermatozoa. Studies were carried out to determine the age at which the protein first became apparent during postnatal development. The protein was expressed from day 40 onwards, as demonstrated by western blot analysis. The androgen regulation of this protein was ascertained by castration and supplementation studies. Expression of this protein showed a decline starting at day 14 after castration and by day 21 the protein was absent; however, androgen replacement resulted in the reappearance of the protein. The results of these studies indicate that the protein identified is specific to the epididymis, and is regulated by development and androgens. The importance of epididymis-specific proteins that are regulated by androgens in sperm maturation is discussed, and the need to ascertain the sequence of the protein and clone the cognate gene is indicated.

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Evaluation of the Efficacy of a Bacteriophage in the Treatment of Pneumonia Induced by Multidrug ResistanceKlebsiella pneumoniaein Mice

BioMed Research International ◽

10.1155/2015/752930 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 41

Author(s):

Fang Cao ◽

Xitao Wang ◽

Linhui Wang ◽

Zhen Li ◽

Jian Che ◽

...

Keyword(s):

Bacterial Infections ◽

Burst Size ◽

Multidrug Resistant ◽

Lung Lesion ◽

Lytic Bacteriophage ◽

Short Latent Period ◽

Dose Dependent ◽

Antibiotic Control

Multidrug-resistantKlebsiella pneumoniae(MRKP) has steadily grown beyond antibiotic control. However, a bacteriophage is considered to be a potential antibiotic alternative for treating bacterial infections. In this study, a lytic bacteriophage, phage 1513, was isolated using a clinical MRKP isolate KP 1513 as the host and was characterized. It produced a clear plaque with a halo and was classified as Siphoviridae. It had a short latent period of 30 min, a burst size of 264 and could inhibit KP 1513 growthin vitrowith a dose-dependent pattern. Intranasal administration of a single dose of 2 × 109 PFU/mouse 2 h after KP 1513 inoculation was able to protect mice against lethal pneumonia. In a sublethal pneumonia model, phage-treated mice exhibited a lower level ofK. pneumoniaeburden in the lungs as compared to the untreated control. These mice lost less body weight and exhibited lower levels of inflammatory cytokines in their lungs. Lung lesion conditions were obviously improved by phage therapy. Therefore, phage 1513 has a great effectin vitroandin vivo, which has potential to be used as an alternative to an antibiotic treatment of pneumonia that is caused by the multidrug-resistantK. pneumoniae.

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Behavioural evidence for self-medication in bumblebees?

F1000Research ◽

10.12688/f1000research.6262.3 ◽

2015 ◽

Vol 4 ◽

pp. 73 ◽

Cited By ~ 32

Author(s):

David Baracchi ◽

Mark J. F. Brown ◽

Lars Chittka

Keyword(s):

Secondary Metabolites ◽

Sucrose Solution ◽

Parasite Load ◽

Foraging Activity ◽

Self Medication ◽

Crithidia Bombi ◽

Nicotine Consumption ◽

Behavioural Experiments ◽

Behavioural Tests ◽

Behavioural Evidence

The presence of antimicrobial secondary metabolites in nectar suggests that pollinators, which are threatened globally by emergent disease, may benefit from the consumption of nectars rich in these metabolites. We tested whether nicotine, a nectar secondary metabolite common in Solanaceae and Tilia species, is used by parasitized bumblebees as a source of self-medication, using a series of toxicological, microbiological and behavioural experiments. Caged bees infected with Crithidia bombi had a slight preference for sucrose solution laced with the alkaloid and behavioural tests showed that the parasite infection induced an increased consumption of nicotine during foraging activity, though nicotine had an appetite-reducing effect overall. When ingested, nicotine delayed the progression of a gut infection in bumblebees by a few days, but dietary nicotine did not clear the infection, and after 10 days the parasite load approached that of control bees. Moreover, when pathogens were exposed to the alkaloid prior to host ingestion, the protozoan’s viability was not directly affected, suggesting that anti-parasite effects were relatively weak. Nicotine consumption in a single dose did not impose any cost even in starved bees but the alkaloid had detrimental effects on healthy bees if consistently consumed for weeks. These toxic effects disappeared in infected bees, suggesting that detoxification costs might have been counterbalanced by the advantages in slowing the progression of the infection. Nicotine consumption did not affect bee lifespan but the reduction in the parasite load may have other likely unexplored subtle benefits both for individual bees and their colony. Potential evidence for self-medication is discussed. The contention that secondary metabolites in nectar may be under selection from pollinators, or used by plants to enhance their own reproductive success, remains to be confirmed.

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Production and utilization of monoclonal antibodies to human/rat corticotrophin-releasing factor-41

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0050159 ◽

1990 ◽

Vol 5 (2) ◽

pp. 159-166 ◽

Cited By ~ 6

Author(s):

N. G. N. Milton ◽

E. W. Hillhouse ◽

S. A. Nicholson ◽

C. H. Self ◽

A. M. McGregor

Keyword(s):

Monoclonal Antibodies ◽

Enzyme Linked Immunosorbent Assay ◽

Dependent Manner ◽

Corticotrophin Releasing Factor ◽

Tissue Extracts ◽

Rat Pituitary ◽

Hypothalamic Tissue ◽

Dose Dependent

ABSTRACT Murine monoclonal antibodies against human/rat corticotrophin-releasing factor-41 (CRF-41) were produced and characterized for use in the immunological and biological characterization of CRF-41. Spleen cells from BALB/c mice immunized with CRF-41 conjugated to bovine γ-globulin were fused with a BALB/c-derived non-secretor X-63 myeloma line. Hybridomas were selected for CRF antibody production by enzyme-linked immunosorbent assay, and positive hybridomas cloned twice. Three monoclonal antibodies were obtained (KCHMB001, KCHMB002 and KCHMB003) and characterized as IgG1, IgG1 and IgG2a isotypes respectively, with affinity constants for rat CRF-41 of 30, 53 and 34 nmol/l respectively. All three monoclonal antibodies recognize an epitope contained between residues 34 and 41 of the human/rat sequence. The antibodies were able to neutralize the ACTH-releasing activity of rat CRF-41, applied to rat pituitary fragments in vitro, in a dose-dependent manner. Isoelectric focusing showed that KCHMB 003 detected bands of synthetic rat CRF-41 and rat [Met(O)21,38]-CRF-41 at pH 7·1 and 6·8 respectively. Use of KCHMB003 in a two-site enzyme-amplified immunoassay showed that this antibody recognizes both synthetic rat CRF-41 and immunoreactive CRF-41 in rat hypothalamic tissue extracts.

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Identification and biological activity of ovine and caprine calcitonin receptor-stimulating peptides 1 and 2

Journal of Endocrinology ◽

10.1677/joe-08-0106 ◽

2008 ◽

Vol 198 (2) ◽

pp. 429-437 ◽

Cited By ~ 2

Author(s):

Christopher J Charles ◽

Takeshi Katafuchi ◽

Timothy G Yandle ◽

Naoto Minamino

Keyword(s):

Plasma Renin ◽

New Members ◽

Amino Terminal ◽

Peptide Family ◽

Plasma Camp ◽

Receptor Activity Modifying Proteins ◽

Conscious Sheep ◽

Dose Dependent

We have recently reported the isolation of three new members of the calcitonin (CT) gene-related peptide family of peptides, the CT receptor (CT-R)-stimulating peptides (CRSPs). We now report the sequencing and characterization of ovine/caprine CRSP-1 and caprine CRSP-2. Mature ovine and caprine CRSP-1 are identical and have strong structural homology to CRSP-1s identified to date from other species. As with other CRSP-1s, ovine/caprine CRSP-1 binds to and activates the CT-R but not the CT-like receptor (CL-R) in combination with the receptor activity-modifying proteins (RAMPs). By contrast, caprine CRSP-2 does not activate any of these receptor-RAMP complexes. Intravenous infusions of ovine CRSP-1 to normal conscious sheep induced dose-dependent reduction in plasma total Ca levels (P=0.02) and corrected Ca levels (P=0.017) associated with increases in plasma cAMP (P=0.002). CRSP-1 reduced both plasma amino-terminal pro-C-type natriuretic peptide levels (P=0.006) and plasma renin activity (P=0.028). There were no significant effects observed on hemodynamic or renal indices measured. In conclusion, we have sequenced ovine/caprine CRSP-1 and caprine CRSP-2 precursors. This newly identified CRSP-1 has been shown to share the structural and biological features of CRSP-1s known to date. In vivo studies confirm that ovine CRSP-1 reduces plasma Ca levels in sheep, presumably via a cAMP-mediated mechanism. By contrast, caprine CRSP-2 did not stimulate any combination of CT-R, CL-R, and RAMPs. Accession numbers of cDNA determined in this study are caprine CRSP-1, AB364646; caprine CRSP-2, AB364647; and ovine CRSP-1, AB364648.

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Long-latency growth-promoting activity of EGF when administered to mice at the neonatal stage

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1987.253.3.e251 ◽

1987 ◽

Vol 253 (3) ◽

pp. E251-E254

Author(s):

O. Imada ◽

N. Hayashi ◽

K. Masamoto ◽

S. Kasuga ◽

T. Fuwa ◽

...

Keyword(s):

Body Weight ◽

Body Weight Gain ◽

Daily Administration ◽

Long Latency ◽

Neonatal Stage ◽

Epidermal Growth ◽

Males And Females ◽

Accelerated Growth ◽

Dose Dependent Increase ◽

Dose Dependent

The effect of biosynthetic human epidermal growth factor (Bh-EGF) as well as mouse EGF on postnatal development of mice of ICR strain was examined. Daily administration of Bh-EGF (0.01, 0.1, and 1.0 microgram X g body wt-1 X day-1) for 30 consecutive days postpartum caused a clearly dose-dependent increase in their body weight. Furthermore, in addition to the well-known premature eyelid opening and early tooth eruption, we have also observed precocious opening of the vagina among treated females. As far as the accelerated growth rate as reflected in their body weight gain was concerned, daily administration for only five consecutive days postpartum was just as effective as the above noted 30 consecutive daily injections. As to the precocious vaginal opening, however, the susceptible 5-day-period was found to be 14-18 days after the parturition. Some of those treated females also entered the estrous cycle precociously, a few days after the precocious opening of their vagina. The microscopic examination of various organs from treated males and females revealed no apparent pathological changes. As far as the above noted effects of EGF were concerned, Bh-EGF, which is xenogenic to mice, was as potent as mouse EGF.

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