Substance P recovers beta -amyloid-induced cognitive deficits in rats

Systemic Administration of Substance P Recovers Beta Amyloid-Induced Cognitive Deficits in Rat: Involvement of Kv Potassium Channels

P Campolongo, P Ratano, MT Ciotti, F Florenzano, SL Nori, R Marolda, M Palmery, AM Rinaldi, C Zona, R Possenti, P Calissano, C Severini, PLos One, 2013, 8(11), e78036.

Reduced levels of Substance P (SP), an endogenous neuropeptide endowed with neuroprotective and anti-apoptotic properties, have been found in brain and spinal fluid of Alzheimer’s disease (AD) patients. Potassium (K+) channel dysfunction is implicated in AD development and the amyloid-β (Aβ)-induced up-regulation of voltage-gated potassium channel subunits could be considered a significant step in Aβ brain toxicity. The aim of this study was to evaluate whether SP could reduce, in vivo, Aβ-induced overexpression of Kv subunits. Rats were intracerebroventricularly infused with amyloid-β 25–35 (Aβ25–35, 20 µg) peptide. SP (50 µg/Kg, i.p.) was daily administered, for 7 days starting from the day of the surgery. Here we demonstrate that the Aβ infused rats showed impairment in cognitive performances in the Morris water maze task 4 weeks after Aβ25–35 infusion and that this impairing effect was prevented by SP administration.

Kv1.4, Kv2.1 and Kv4.2 subunit levels were quantified in hippocampus and in cerebral cortex by Western blot analysis and immunofluorescence. Interestingly, SP reduced Kv1.4 levels overexpressed by Aβ, both in hippocampus and cerebral cortex.

Our findings provide in vivo evidence for a neuroprotective activity of systemic administration of SP in a rat model of AD and suggest a possible mechanism underlying this effect.

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Adrenomedullin and Alzheimer’s Disease

Adrenomedullin Expression in Alzheimer’s Brain

AP Fernandez, JS Masa, MA Guedan, HS Futch, R Martínez-Murillo, Curr. Alzheimer Res., 201613, 428-38.

Adrenomedullin (AM) is a potent vasodilator peptide highly expressed throughout the brain and originally isolated from pheochromocytoma cells. In addition to its vasoactive properties, AM is considered a neuromodulator that possesses antiapoptotic and antioxidant properties that suggest that this peptide can protect the brain from damage. In a previous study, we found that AM exerts a neuroprotective action in the brain and that this effect may be mediated by regulation of nitric oxide synthases, matrix metalloproteases, and inflammatory mediators. AM upregulation contributes to neuroprotection, but understanding the precise roles played by AM and its receptor (RAMP2) in neurodegenerative diseases including Alzheimer´s disease (AD), awaits further research. In search of Alzheimer´s biomarkers, the expression levels of peptides with endothelial vasodilatory action, including AM, were found to be significantly altered in mild AD or during pre-dementia stage of mild cognitive impairment. These studies concluded that ratio of AM or its precursor fragment mid-regional proAM in blood hold promise as diagnostic marker for AD. We are now presenting a study regarding the hypothesis that the AMRAMP2 system might be implicated in the pathophysiology of AD.

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The effect of adrenomedullin and proadrenomedullin N- terminal 20 peptide on angiotensin II induced vascular smooth muscle cell proliferation

The effect of adrenomedullin and proadrenomedullin N- terminal 20 peptide on angiotensin II induced vascular smooth muscle cell proliferation

Thoracic aorta was obtained from Wistar rats and VSMCs were isolated from
aorta tissues and then cultured. In vitro cultured VSMCs were stimulated with Ang II (10‐8 mol/l) followed by various doses of PAMP or ADM (10‐9, 10‐8, or 10‐7 mol/l). Cell proliferation as assessed by 3H‐TdR incorporation. Protein kinase C (PKC) activity was measured by counting γ‐32P radioactivity with liquid scintillation. In a separate cohort, in vitro cultured rat aortic vessels were treated with different doses of Ang II or PAMP (10‐9, 10‐8, or 10‐7 mol/l). Cellular and secreted levels of PAMP, ADM and Ang II were measured using radioimmunoassay in the tissues and intubation mediums, respectively.

Ang II (10‐8 mol/l) treatment significantly increased both 3H‐TdR incorporation and PKC activity in VSMCs (by 2.68 and 1.02‐fold, respectively; both P<0.01 vs. the control). However, Ang II‐ induced elevation of 3H‐TdR incorporation, and PKC activity was significantly inhibited by various doses of ADM and PAMP (all P<0.01 vs. the Ang II group). In rat aortic vascular tissues or intubation media, Ang II treatments stimulated the expression and secretion of PAMP and ADM in a dose‐ dependent manner, while PAMP treatments had no significant effects on Ang II levels. Conclusion: ADM and PAMP inhibit Ang II‐induced VSMCs proliferation. The interaction of Ang II, ADM and PAMP may regulate VSMCs and cardiovascular function.

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Effects of Adrenomedullin on Doxorubicin-induced Cardiac Damage in Mice

Effects of Adrenomedullin on Doxorubicin-induced Cardiac Damage in Mice

T Yoshizawa, S Takizawa, S Shimada, T Tokudome, T Shindo, K Matsumoto, Biol. Pharm. Bull., 2016, Advance publication Feb. 22.

Doxorubicin (DOX) is one of the best known anticancer drugs, and is used in the treatment of lymphoma, lung cancer, stomach cancer, and a number of other cancers. However, DOX has some serious side effects, the worst being lethal heart failure. Occasionally, its side effects result in the cessation of the anticancer treatment, thus having a serious adverse influence on prognosis. Agents that can be administered as alternative prophylactics or to ameliorate the side effects of DOX will be useful in increasing the safety and efficacy of anticancer therapy.Adrenomedullin (AM) is a peptide hormone secreted by many organs, including the heart; it has an organ-protective effect, including antiapoptotic, anti-inflammatory, and antioxidative stress. Blood AM levels increase with heart failure; endogenic AM has been suggested in order to protect the heart. Furthermore, exogenous AM administration has shown therapeutic effects for heart failure in patients. However, it is unclear whether AM can protect the heart against drug-induced cardiac injury in vivo.The present study was performed in order to investigate the effects of AM on DOX-induced cardiac damage. Male BALB/c mice were treated with DOX and/or AM. Exogenous AM improved the survival ratio of DOX-treated mice. In addition, AM reduced serum lactate dehydrogenase (LDH) levels following DOX treatment. On pathological examination, AM was shown to inhibit DOX-induced cardiac tissue damage, mitochondrial abnormality, and cell death. These findings suggest that AM has a protective effect against DOX-induced cardiac damage.

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Endothelin 1 and Anxiety-Like Behaviors

Infralimbic Endothelin1 Is Critical for the Modulation of Anxiety-Like Behaviors. Bi LL, Chen M, Pei L, Shu S, Jin HJ, Yan HL, Wei N, Wang S, Yang X, Yan HH, Xu MM, Yao CY, Li N, Tang N, Wu JH, Zhu HZ, Li H, viagra for sale glasgow Cai Y, Guo Y, Shi Y, Tian Q, Zhu LQ, Lu YM, Mol Neurobiol. 2015 Apr 22. [Epub ahead of print] Endothelin1 (ET1) is a potent vasoconstrictor that is also known to be a neuropeptide that is involved in neural who manufactures viagra circuits. We examined the role of ET1 that has been implicated in the anxiogenic process. We found that infusing ET1 into the IL cortex increased anxiety-like behaviors. cialis pharmacy price The ETA receptor (ETAR) antagonist (BQ123) but not the ETB receptor (ETBR) antagonist (BQ788) alleviated ET1-induced anxiety. ET1 had no effect on GABAergic neurotransmission or NMDA receptor (NMDAR)-mediated neurotransmission, but increased does viagra make you bigger AMPA receptor (AMPAR)-mediated excitatory viagra side effects list synaptic transmission. The changes in AMPAR-mediated excitatory postsynaptic currents were due to presynaptic mechanisms. Finally, we found that the AMPAR antagonists (CNQX) and BQ123 reversed ET1’s anxiogenic effect, with parallel and corresponding electrophysiological changes. Moreover, infusing CNQX + BQ123 into the IL had no additional anxiolytic effect compared to CNQX treatment alone. Altogether, our findings establish a previously unknown anxiogenic action of ET1 in the IL cortex. AMPAR-mediated glutamatergic neurotransmission may underlie the mechanism of ET1-ETAR signaling pathway in the regulation of anxiety.

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Design and Synthesis of Aphicidal Peptides

Eco-friendly Insecticide Discovery via Peptidomimetics: Design, Synthesis and Aphicidal Activity of Novel Insect Kinin Analogs

Chuan-liang Zhang, Yanyan Qv, Xiaoqing Wu, Dunlun Song, Yun Ling, and Xinling Yang, J. Agric. Food Chem., Just Accepted Manuscript  Publication Date (Web): April 26, 2015  Copyright © 2015 American Chemical Society

The insect kinin neuropeptides are pleiotropic peptides that are involved in the regulation of hindgut contraction, diuresis and digestive enzyme release. They share a common C-terminal pentapeptide sequence Phe1-Xaa2-Yaa3-Trp4-Gly5-NH2 (where Xaa2 = His, Asn, Phe, Ser or Tyr; Yaa3 = Pro, Ser or Ala). Recently, the aphicidal activity of insect kinin analogs attracted the attention of researchers. Our previous work demonstrated that the sequence-simplified insect kinin pentapeptide analogue Phe-Phe-[Aib]-Trp-Gly-NH2 could retain good aphicidal activity and be the lead compound for the further discovery of eco-friendly insecticides which encompassed a broad array of biochemicals derived from micro-organisms and other natural sources. Using the peptidomimetics strategy, we chose Phe-Phe-[Aib]-Trp-Gly-NH2 as the lead compound, designed and synthesized three series, including 31 novel insect kinin analogues. The aphicidal activity of the new analogs against soybean aphid was determined. The results showed that all the analogs exhibited aphicidal activity. Of particular interest was the analogue II-1 which exhibited improved aphicidal activity with an LC50 of 0.019mmol/L compared with the lead compound (LC50=0.045mmol/L) or the commercial insecticide pymetrozine (LC50=0.034mmol/L). This suggests that the analogue II-1 could be used as a new lead for the discovery of potential eco-friendly insecticides.

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Stereocontrolled Construction of (E)-2-Amino-2-butenamide

Solid-Phase Total Synthesis of Bogorol A: Stereocontrolled Construction of Thermodynamically Unfavored (E)-2-Amino-2-butenamide

Tomoya Yamashita, Takefumi Kuranaga, and Masayuki Inoue, Org. Lett., Article ASAP Publication Date (Web): April 13, 2015 Copyright © 2015 American Chemical Society

Bogorol A [(E)-1], a potent antibiotic against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp., possesses a thermodynamically unfavored (E)-2-amino-2-butenamide within its linear dodecapeptide sequence. The highly efficient totalsynthesis of natural (E)-isomer (E)-1 and its artificial (Z)-isomer (Z)-1 by employing a full solid-phase strategy is reported. The (E)- and (Z)-2-amino-2-butenamide moieties were stereoselectively constructed by applying traceless Staudinger ligation on the resin. Interestingly, (E)- and (Z)-1 showed comparable antimicrobial activity (MIC = 4 μg/mL).

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Expanded Application of Native Chemical Ligation Using beta-Thio Phenylalanine and Desulfurization

Synthesis of β-Thiol Phenylalanine for Applications in One-Pot Ligation–Desulfurization Chemistry

Lara R. Malins, Andrew M. Giltrap, Luke J. Dowman, and Richard J. Payne, Org. Lett., Article ASAP   Publication Date (Web): April 10, 2015   Copyright © 2015 American Chemical Society

The efficient synthesis of a β-thiol phenylalanine derivative is described starting from Garner’s aldehyde. The utility of this amino acid in peptide ligation–desulfurization chemistry is described, including the trifluoroethanethiol (TFET)-promoted one-pot assembly of the 62 residue peptide hormone augurin.

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Macrocyclic peptide with an unusual Lys-Trp crosslink

Structure and biosynthesis of a macrocyclic peptide containing an unprecedented lysine-to-tryptophan crosslink

Kelsey R. Schramma, Leah B. Bushin & Mohammad R. Seyedsayamdost, Nature Chemistry, 2015, 7, 431–437.

Streptococcal bacteria use peptide signals as a means of intraspecies communication. These peptides can contain unusual post-translational modifications, providing opportunities for expanding our understanding of nature’s chemical and biosynthetic repertoires. Here, we have combined tools from natural products discovery and mechanistic enzymology to elucidate the structure and biosynthesis of streptide, a streptococcal macrocyclic peptide. We show that streptide bears an unprecedented post-translational modification involving a covalent linkage between two unactivated carbons within the side chains of lysine and tryptophan. The biosynthesis of streptide was addressed by genetic and biochemical studies. The former implicated a new SPASM-domain-containing radical SAM enzyme StrB, while the latter revealed that StrB contains two [4Fe–4S] clusters and installs the unusual lysine-to-tryptophan crosslink in a single step. By intramolecularly stitching together the side chains of lysine and tryptophan, StrB provides a new route for biosynthesizing macrocyclic peptides.

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A potent peptide inhibitor of α-synuclein aggregation.

Intracellular screening of a peptide library to derive a potent peptide inhibitor of α-synuclein aggregation.

Cheruvara H, Allen-Baume VL, Kad NM, Mason JM., J. Biol. Chem.2015, First published on-line: January 23, 2015.  DOI: 10.1074/jbc.M114.620484

Aggregation of α-synuclein (α-syn) into toxic fibrils is a pathogenic hallmark of Parkinson’s disease (PD). Studies have largely focused on residues 71-82, yet most early onset mutations are located between residues 46-53. A semi-rationally designed 209,952 member library library based entirely on this region was constructed, containing all wild-type residues and changes associated with early onset PD. Intracellular cell-survival screening and growth competition isolated a 10-residue peptide antagonist that potently inhibits α-syn aggregation and associated toxicity at 1:1 stoichiometry. This was verified using continuous growth measurements, and MTT cytotoxicity studies. Atomic force microscopy, and circular dichroism on the same samples showed a random-coil structure and no oligomers. A new region of α-syn for inhibitor targeting has been highlighted, together with the approach of using semi-rational design and intracellular screening. These peptides are candidates for modification into drugs capable of slowing or even preventing the onset of PD.

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