6,077 research outputs found
Ultrastructural characterisation of Bacillus subtilis TatA complexes suggests they are too small to form homooligomeric translocation pores
No full textTat-dependent protein transport permits the traffic of fully folded proteins across membranes in bacteria and chloroplasts. The mechanism by which this occurs is not understood. Current theories propose that a key step requires the coalescence of a substrate-binding TatC-containing complex with a TatA complex, which forms pores of varying sizes that could accommodate different substrates. We have studied the structure of the TatAd complex from Bacillus subtilis using electron microscopy to generate the first 3D model of a TatA complex from a Gram-positive bacterium. We observe that TatAd does not exhibit the remarkable heterogeneity of Escherichia coli TatA complexes but instead forms ring-shaped complexes of 7.5–9 nm diameter with potential pores of 2.5–3 nm diameter that are occluded at one end. Such structures are consistent with those seen for E. coli TatE complexes. Furthermore, the small diameter of the TatAd pore, and the homogeneous nature of the complexes, suggest that TatAd cannot form the translocation channel by itself. Biochemical data indicate that another B. subtilis TatA complex, TatAc, has similar properties, suggesting a common theme for TatA-type complexes from Bacillus
Pharmacological approaches to targeting muscarinic acetylcholine receptors
No full textThe presence of cholinergic system markers and muscarinic receptor subtypes in several tissues also of non-neuronal type has been largely demonstrated. Acetylcholine, synthesized in and out of the nervous system, can locally contribute to modulate cell proliferation, survival and apoptosis. Considering that the cholinergic system functions are impaired in a number of disorders, the identification of new drugs regulating cholinergic system functions, appears of great clinical relevance.
The possible involvement of muscarinic acetylcholine receptors in different pathologies has been proposed in recent years and is becoming an important area of study. However, the lack of selective muscarinic receptor ligands has for long time limited the therapeutic treatment based on muscarinic receptors as targets. To date some muscarinic ligands such as xanomeline (patent , US5980933) or cevimeline (patents US4855290; US5571918) have been developed for the treatment of several pathologies (Alzheimer’s and Sjogren’s diseases). The present review will be focused on the potential effects produced by muscarinic receptor activation in different pathologies, including tumors. In fact, the potential use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that several muscarinic antagonists, already used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864), have also been demonstrated to arrest the tumor growth in vivo.
Moreover, the contribution of muscarinic receptors to analgesia is also over-viewed.
Finally, some of the most significant achievements in the field of bitopic/dualsteric ligands will be discussed and the molecules patented so far will be presented
Dualsteric activation of M2 muscarinic acetylcholine receptors inhibits cell proliferation in human glioblastoma cell lines
No full textMuscarinic acetylcholine receptors (mAChRs) are expressed in several primary and metastatic tumours. ACh synthesized by the tumour cells can modulate cell proliferation by an autocrine mechanism which involves cholinergic receptors. Although a direct or indirect role of transduction pathways activated by cholinergic receptors has not yet been demonstrated, the inhibition of ACh synthesis as well as the release or use of cholinergic antagonists are able to counteract tumour cell growth and slow down the tumour progression in small cell lung carcinoma [1]. In mammary adenocarcinoma and melanoma cell lines, mAChRs can also modulate cell migration and angiogenesis, suggesting their involvement in the metastases formation [2]. The characterization of mAChR effects on more aggressive brain tumours is still poorly investigated. Glioblastomas are the most common brain tumours in humans. Recently, Tata et al. demonstrated that M2 receptor activation inhibits glioma cell growth and survival, suggesting that this receptor subtype may represent a new putative target for glioblastoma therapy [3,4]. Therefore, the identification of more selective ligands for M2 mAChRs may be of clinical significance. Here we report the results on the effects of the muscarinic orthosteric superagonist Iperoxo [5] and its related dualsteric agonists P-6-Iper and N-8-Iper [6]. Our data demonstrate that cell proliferation as well as cell survival of the U251 and U87 stable cell lines were unaffected by treatment with Iperoxo and P-6-Iper. Conversely, N-8-Iper decreased cell proliferation in a time and dose dependent manner. Similarly, N-8-Iper (100 uM) was also able to counteract cell proliferation in glioblastoma cancer stem cells (GB7) obtained from human biopsy. The antiproliferative effect shown by N-8-Iper was significantly counteracted by the selective M2 antagonist methoctramine (10^-7 M), suggesting an actual contribution of the M2 selective activation.
References:
1) Song P, Sekhon HS, Jia Y, Keller JA, Blusztajn JK, Mark GP, Spindel ER. Cancer Res. 2003, 63(1), 214-221
2) Boss A, Oppitz M, Lippert G, Drews U. Clin Exp Dermatol. 2005, 30(5), 557-564
3) Ferretti M, Fabbiano C, Di Bari M, Ponti D, Calogero A, Tata AM. Life Sci. 2012, 91(21-22), 1134-1137
4) Ferretti M, Fabbiano C, Di Bari M, Conte C, Castigli E, Sciaccaluga M, Ponti D, Ruggieri P, Raco A, Ricordy R, Calogero A, Tata AM. J Cell Mol Med. 2013, 17(4), 552-566
5) Schrage R, Seemann WK, Klöckner J, Dallanoce C, Racké K, Kostenis E, De Amici M, Holzgrabe U, Mohr K. Br J Pharmacol. 2013, 169(2), 357-370
6) Matera C, Flammini L, Quadri M, Vivo V, Ballabeni V, Holzgrabe U, Mohr K, De Amici M, Barocelli E, Bertoni S, Dallanoce C. Eur J Med Chem. 2014, 75, 222-23
New Pharmacological Approaches to the Cholinergic System: An Overview on Muscarinic Receptor Ligands and Cholinesterase Inhibitors.
No full textThe cholinergic system is expressed in neuronal and in non-neuronal tissues. Acetylcholine (ACh), synthesized in and out of the nervous system can locally contribute to modulation of various cell functions (e.g. survival, proliferation). Considering that the cholinergic system and its functions are impaired in a number of disorders, the identification of new pharmacological approaches to regulate cholinergic system components appears of great relevance. The present review focuses on recent pharmacological drugs able to modulate the activity of cholinergic receptors and thereby, cholinergic function, with an emphasis on the muscarinic receptor subtype, and additionally covers the cholinesterases, the main enzymes involved in ACh hydrolysis.
The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells has been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. The possible involvement of ACh in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent, US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer’ and Sjogren’s diseases). The present review focuses on the potential implications of muscarinic receptors in different pathologies, including tumors. Moreover, the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin, patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice.
The involvement of muscarinic receptors in nociception also is over-viewed. In fact, muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects in animal models comparable or more pronounced to those produced by morphine or opiates.
Likewise, the crucial role of cholinesterases (acetylcholinesterase and butirylcholinesterase) in neural transmission is discussed, as large number of drugs inhibiting cholinesterase activity have become of increasing relevance particularly for the treatment of neurodegenerative disorders. Herein we summarize the current knowledge of the cholinesterase inhibitors with particular attention to recent patents for Alzheimer’s disease drugs
Chapter 15 Novel Pharmacological Approaches to Schwann Cells as Neuroprotective Agents for Peripheral Nerve Regeneration
No full textPeripheral neuropathies are common neurologic disorders, but current treatments are limited. Among the different approaches to treat the acquired neuropathies due to traumatic injuries, the pharmacological interventions directed to Schwann cell may represent a useful and challenging opportunity. Following nerve damage the distal axon and the ensheathing Schwann cells degenerate, ensuing a process known as "Wallerian degeneration". Schwann cells then dedifferentiate and proliferate to support neurite outgrowth. In the recent years, several pharmacological agents that may promote the Schwann cell in its role of supporting nerve regeneration have been proposed. However, in view of increased understanding of the cellular mechanisms controlling neuron-glial interactions, a great attention has focused on neurotransmitters, neuroactive steroids, and neurohormones. In this review, we survey the latest findings on these factors and assess their potential as novel promising treatments for peripheral neuropathies caused by injury
Group living homes for older people with dementia: Concept and effects
No full textEefsting, J.A. [Promotor]Pot, A.M. [Promotor]Depla, M.F.I.A. [Copromotor]Lange, J. de [Copromotor
Cementbetonnen plaatbekledingen op oevers en dijken, bundeling van artikelen uit de vakpers 1990-1991
No full textCUR; Proefproject: Open colloidaal beton a/s dijkbekleding; PT civiele techniek, april 1990. Burger, A.M., Eversdijk, P.J. en Hendriksma, A.M.; Open cementbeton toegepast a/s bekleding voor dijken; Zeewering Breskens, proefproject voor colloidaal beton; Land + Water, mei 1990. Burger, A.M., Eversdijk, P.J. en Hendriksma, A.M.; Colloidaal beton weerstaat zware storm en hoge golven; De praktijk van open cementbeton a/s Plaatbekleding; Land + Water, juni 1990. CUR; Cementbetonnen plaatbekledingen op dijken; Proefprojecten CUR; Civiele Techniek, No4, 1990. Vrieze, C.G. de; Betonnen dijken, groen a/s gras; Proeven met colloidaal beton voor begroeide rivierdijken; Land + Water No.6, juni 1991. Eversdijk, P.J. en Fase, A.G.; Breuksteen met colloidaal beton pakt rivierdijken goed in; Proefproject Opijnen in Julianakanaal; Land + Water No. 7/8, augustus 1991. Rijke, W.G. de en Burger, A.M.; Cementbetonnen plaatbekledingen op dijken en oevers; Praktische ontwerpmethode (1); Civiele Techniek, jaargang 46, No.3, 1991. Rijke, W.G. de en Burger, A.M.; Cementbetonnen plaatbekledingen op dijken en oevers theoretisch waterdicht; Praktische ontwerpmethode (2); Civiele Techniek, jaargang 46, No.4, 1991. CUR; oemonstratieproject open colloidaal beton Noordoostpolder; Civiele Techniek, No.3, 1991
IoWoman, March/April 2004, Vol.34, no.2
No full textNewsletter for the Iowa Commission on the Status of Wome
IoWoman, March/April 2004, Vol. 34, no. 2
No full textNewsletter for the Iowa Commission on the Status of Wome
Gauge Fields and Strings
No full textBased on his own work, the author synthesizes the most promising approaches and ideals in field theory today. He presents such subjects as statistical mechanics, quantum field theory and their interrelation, continuous global symmetry, non-Abelian gauge fields, instantons and the quantam theory of loops, and quantum strings and random surfaces. This book is aimed at postgraduate students studying field theory and statistical mechanics, and for research workers in continuous global theory
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