Regulatory Peptides最新文献

Pseudhymenochirin-1Pb (Ps-1Pb) and pseudhymenochirin-2Pa (Ps-2Pa) are host-defense peptides, first isolated from skin secretions of the frog Pseudhymenochirus merlini (Pipidae). Ps-1Pb and Ps-2Pa are highly cytotoxic (LC₅₀ < 12 μM) against non-small cell lung adenocarcinoma A549 cells, breast adenocarcinoma MDA-MB-231 cells, and colorectal adenocarcinoma HT-29 cells but are also hemolytic against human erythrocytes (LC₅₀ = 28 ± 2 μM for Ps-1Pb and LC₅₀ = 6 ± 1 μM for Ps-2Pa). Ps-2Pa shows selective cytotoxicity for tumor cells (LC₅₀ against non-neoplastic human umbilical vein (HUVEC) cells = 68 ± 2 μM). Ps-1Pb and Ps-2Pa (5 μg/mL) significantly inhibit production of the anti-inflammatory cytokine IL-10 and the multifunctional cytokine IL-6 from lipopolysaccharide (LPS)-stimulated peritoneal macrophages from C57BL/6 mice and enhance the production of the pro-inflammatory cytokine IL-23 from both unstimulated and LPS-stimulated macrophages. Ps-1Pb potently (MIC ≤ 10 μM) inhibits growth of multidrug-resistant clinical isolates of the Gram-positive bacteria methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, and the Gram-negative bacteria Acinetobacter baumannii and Stenotrophomonas maltophilia.

Ps-2Pa shows the same high potency (MIC ≤ 10 μM) against the Gram-positive bacteria but is 2–4 fold less potent against the Gram-negative isolates. Ps-1Pb at 4 × MIC kills 99.9% of Escherichia coli within 30 min and 99.9% of S. aureus within 180 min. In conclusion, cytotoxicity against tumor cells, cytokine-mediated immunomodulatory properties, and broad-spectrum antimicrobial activity suggest that the Ps-1Pb and Ps-2Pa represent templates for design of non-hemolytic analogs for tumor therapy and for treatment of infections in cancer patients produced by multidrug-resistant pathogens.

Cellular apoptosis and colonic dysmotility are involved in diabetes mellitus (DM) complications. Insulin-like growth factor-1 (IGF-1) is known to affect apoptosis and proliferation. Here, we demonstrated that the treatment of 1500 ng/kg IGF-1 partly recovers the decrease of the muscle thickness, body weight and gastrointestinal transit rate in DM rats. The gastrointestinal transit rate is positively correlated with the IGF-I level, but negatively correlated with the level of colonic cellular apoptosis. The DM-induced colonic apoptosis is also attenuated by the IGF-1 stimulation. Moreover, IGF-1 inhibits the apoptosis of the isolated colonic SMCs in vitro via the activation of PI3K/Akt and ERK1/2 signaling pathways. Taken together, our data indicated that IGF-1 inhibits the DM-induced colonic SMC apoptosis and might be involved in the alleviation of colonic dysmotility in diabetic rats.

Galanin is a neuropeptide expressed in the central and peripheral nervous systems. Galanin is known to be biosynthesized in neural and endocrine cells, but little evidence exists for its synthesis in other cells. In this study, we explored galanin-releasing nonneural cells using radioimmunoassay, finding that some fibroblasts produced and released the galanin-like immunoreactive component (galanin-LI). The molecular weight of the galanin-LI obtained from the fibroblasts, as measured by gel filtration chromatography and Western blotting, was 14 kDa and suggested that the compound was progalanin. Peptide mass fingerprinting analysis identified the large form of galanin-LI as progalanin without its signal sequence. In addition, galanin-LI was located in the Golgi bodies and vesicle-like structures of the fibroblasts. Furthermore, the addition of brefeldin A, an inhibitor of transport from the ER, decreased the release of galanin-LI. In this study, we showed that the fibroblast, a nonneural and nonendocrine cell type, produced and released a galanin precursor, progalanin, without processing via Golgi bodies or secretory vesicles.

Neuromedin U (NmU), first was isolated from the porcine spinal cord, has subsequently been demonstrated in a number of species, in which it is present in the periphery and also the brain. Two receptors have been identified: NmU1R is mainly present in peripheral tissues, and Nmu2R in the central nervous system. NmU, a potent endogenous anorectic, serves as a catabolic signaling molecule in the brain; it inhibits food uptake, increases locomotion, activates stress mechanism, having cardiovasscular effects and, causes hyperthermia. The mechanism of this hyperthermia is unknown. In the present experiments, the effects of NmU on the colon temperature following i.c.v administration were studied in rats. For an investigation of the possible role of receptors in mediating hyperthermia, the animals were treated simultaneously with CRF 9–41 and antalarmin, a CRH1 receptor inhibitors, astressin 2B, a CRH2 receptor antagonist, haloperidol a dopamine receptor antagonist, atropine a muscarinic cholinergic receptor antagonist, noraminophenazone a cyclooxygenase inhibitor or isatin, a prostaglandin receptor antagonist.

NmU increased the colon temperature, maximal action being observed at 2–3 h. CRF 9–41, antalarmin, astressin 2B haloperidol, atropine, noraminophenazone and isatin prevented the NmU-induced increase in colon temperature.

The results demonstrated that, when injected into the lateral brain ventricle NmU increased the body temperature, mediated by CRHR1 and CRHR2, dopamine and muscarinic cholinergic receptors. The final pathway involves prostaglandin.

Natriuretic peptides have emerged as important diagnostic and prognostic tools for cardiovascular disease. Plasma measurement of the bioactive peptides as well as precursor-derived fragments is a sensitive tool in assessing heart failure. In heart failure, the peptides are used as treatment in decompensated disease. In contrast, their biological effects on the cerebral hemodynamics are poorly understood. In this mini-review, we summarize the hemodynamic effects of the natriuretic peptides with a focus on the cerebral hemodynamics. In addition, we will discuss its potential implications in diseases where alteration of the cerebral hemodynamics plays a role such as migraine and acute brain injury including stroke. We conclude that a possible role of the peptides is feasible as evaluated from animal and in vitro studies, but more research is needed in humans to determine the precise response on cerebral vessels.

Islet neogenesis-associated protein (INGAP) is a peptide found in pancreatic exocrine-, duct- and islet- non-β-cells from normal hamsters. Its increase induced by either its exogenous administration or by the overexpression of its gene enhances β-cell secretory function and increases β-cell mass by a combination of stimulation of cell replication and islet neogenesis and reduction of β-cell apoptosis. We studied the potential modulatory role of endogenous INGAP in insulin secretion using two different experimental approaches. Hamster islets transfected with INGAP-small interfering RNA (INGAP-siRNA) were used to study glucose-stimulated insulin secretion (GSIS). In parallel, freshly isolated islets were incubated with high glucose and the same concentration of either a specific anti-INGAP rabbit serum or normal rabbit serum. INGAP-siRNA transfected islets reduced their INGAP mRNA and protein content by 35.1% and 47.2%, respectively whereas GSIS decreased by 25.8%. GSIS by transfected islets attained levels comparable to those recorded in control islets when INGAP pentadecapeptide (INGAP-PP) was added to the culture medium. INGAP antibody in the medium decreased significantly GSIS in a dose-dependent manner. These results indicate that endogenous INGAP plays a “physiological” positive modulatory role in insulin secretion, supporting its possible use in the treatment of prediabetes and Type 2 diabetes.