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31.
Ram Kandasamy Todd M. Hillhouse Kathryn E. Livingston Kelsey E. Kochan Claire Meurice Shainnel O. Eans Ming-Hua Li Andrew D. White Bernard P. Roques Jay P. McLaughlin Susan L. Ingram Neil T. Burford Andrew Alt John R. Traynor 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(16)
Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.Mu-opioid receptor (MOR) agonists are the most effective treatments for moderate to severe acute and chronic pain, yet their use is limited by serious side effects, including constipation, respiratory depression, and physical and psychological dependence. These side effects are on-target effects (MOR-mediated) and result from the wide distribution of MORs across the central nervous system (CNS) (1, 2). Safer pain therapies are desperately needed. However, because of the efficacy of MOR agonists in blocking pain, this receptor continues to be a primary target for the discovery of novel pain therapies. Unfortunately, most drug discovery programs involve designing compounds that bind to the orthosteric site on MOR—the site that binds endogenous opioid peptides as well as exogenous opioids. Not surprisingly, these newer drugs tend to exhibit qualitatively similar side effect profiles to traditional opioid analgesics.As an alternative, we have discovered small molecule, positive allosteric modulators of MOR [mu-PAMs (3)], including BMS-986122 (SI Appendix, Fig. S1). Such compounds interact with a site on MOR that is spatially distinct from the orthosteric site (3–7). Across a variety of in vitro assays, mu-PAMs increase the affinity and/or potency of orthosteric agonists at MOR, including exogenous MOR agonists as well as the endogenous opioid peptides Leucine- and Methionine-enkephalin, endomorphin-1, and β-endorphin (3, 8).These in vitro studies have led to development of a so-far untested hypothesis that in vivo, mu-PAMs will promote the activity of endogenous opioid peptides released during pain (9–11). If this hypothesis is correct, mu-PAMs could replace traditional opioids by boosting the body’s own natural response to pain to provide clinically meaningful analgesia. In support of this concept, so called “enkephalinase inhibitors” that prolong the lifetime of endogenous opioid peptides are effective in the management of pain in preclinical and clinical studies (12–14), although such compounds are not selective for opioid peptides. Since mu-PAMs do not alter peptide release or metabolism, they should be more selective than enkephalinase inhibitors and also preserve the natural spatial and temporal release of the peptides in vivo following injury and/or during pain. To test this hypothesis, we examined the antinociceptive effects of BMS-986122 in mouse models of acute and inflammatory pain using measures of pain-evoked and pain-depressed behaviors as well as opioid side effects and the potential role of endogenous opioid peptides in these responses. 相似文献
32.
Rebecca E. Conway Camilo Rojas Jesse Alt Zora Nováková Spencer M. Richardson Tori C. Rodrick Julio L. Fuentes Noah H. Richardson Jonathan Attalla Samantha Stewart Beshoy Fahmy Cyril Barinka Mallika Ghosh Linda H. Shapiro Barbara S. Slusher 《Angiogenesis》2016,19(4):487-500
Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies. 相似文献
33.
S. Sathe C. Alt A. Black E. Manolas R. Warren P. Valentine 《Internal medicine journal》1994,24(3):277-281
Background: Coronary angioplasty, although of proven use in partial occlusion, has not been shown to be of similar benefit in chronic total occlusion. Aims: To assess the utility of coronary angioplasty in chronically totally occluded vessels in patients undergoing angioplasty and to determine the success of TIMI-I flow before angioplasty compared to those patients with TIMI-O flow. Methods: A group of 178 consecutive patients (from 1984 to 1992), who underwent angioplasty of a chronic occlusion, were analysed. There were 136 males and 42 females with a mean age of 56.9 years. Results: Initial technical success was achieved in 65%. Patients with TIMI-I flow before angioplasty had a higher chance of success (700%) compared to those with TIMI-O flow (53%), p < 0.04. During hospitalisation six patients suffered myocardial infarction (MI), two required surgery and one patient died. During a mean follow-up of 2.8 years the overall survival rate was 95% for the group as a whole. Freedom from coronary surgery was significantly greater in patients with successful angioplasty (93%) than those without (66%, p < 0.002). The above two populations also showed a significant difference in the incidence of angina (35%vs 56%, p < 0.0003). However, the incidence of MI (6%vs 5%, p > O.5) and cardiac survival (98%vs 94%, p > 0.l) did not differ significantly in the two groups. Restenosis occurred in 63% of the 95 patients (82%) who returned for follow-up angiography. Eighteen of the 59 patients (28%) with restenosis had a reocclusion. Conclusion: The success rate for angioplasty of chronic total occlusions is acceptable. Long-term clinical benefit in patients with successful angioplasty is suggested by the high freedom from angina and the lesser need for coronary surgery. No major impact on either the incidence of MI or cardiac survival was noted when patients who had coronary surgery were included, although it must be emphasised that the sample size in this study was insufficient to detect a difference in these outcome variables. 相似文献
34.
Alt E Haehnel I Beilharz C Prietzel K Preter D Stemberger A Fliedner T Erhardt W Schömig A 《Circulation》2000,101(12):1453-1458
35.
Synthesis of immunoglobulin mu chain gene products precedes synthesis of light chains during B-lymphocyte development. 总被引:14,自引:3,他引:14 下载免费PDF全文
E Siden F W Alt L Shinefeld V Sato D Baltimore 《Proceedings of the National Academy of Sciences of the United States of America》1981,78(3):1823-1827
Immunoglobulin (Ig) gene expression has been followed during the later stages of development of the murine fetal liver. Biosynthetic labeling and immunoprecipitation were used to isolate Ig-related polypeptides from fetal and neonatal livers. By examination of the specific immune precipitates, the earliest detectable Ig was shown to consist only of mu heavy chain. At about the time of birth, when light chain synthesis became evident, separation of surface Ig-positive cells from surface Ig-negative cells by using anti-Ig-coated dishes showed that cells lacking surface Ig (pre-B lymphocytes) synthesized only mu chains. Thus, commencement of light chain synthesis was closely coordinated with the appearance of surface Ig. Ig RNA species were examined by electrophoretic fractionation and hybridization with cloned Ig DNA sequences. The sizes and amounts of Ig mRNA were found to correlate with the pattern of mu and light chain protein biosynthesis. mu chain RNA species appeared earlier in gestation than light chain RNA did, and only after birth did light chain sequences reach levels equivalent to those of mu chain. Cell populations enriched in pre-B lymphocytes also contained an excess of mu over light chain mRNA. 相似文献
36.
Subirà M Sureda A Ancín I Martino R Altés A Brunet S Sierra J 《Bone marrow transplantation》2003,32(9):869-872
Allogeneic stem cell transplantation (allo-SCT) after a reduced-intensity conditioning (RIC) protocol is associated with decreased short-term toxicity. This suggests that the procedure could be performed on an outpatient basis. We analysed the incidence and risk factors of grade >or=2 conditioning-related toxicities (CRTs) as a hallmark for hospital admission, in 41 consecutive patients allografted from an HLA identical sibling after RIC. The RIC regimen consisted of fludarabine plus melphalan for lymphoid malignancies, and fludarabine plus busulphan for myeloid malignancies. In all, 11 patients (27%) did not experience any toxicity. The more frequent CRTs observed were neutropenic fever and gastrointestinal toxicity. The median duration of hospitalisation was 27 (range, 17-50) days. If allo-SCT had been planned as an outpatient procedure and admission indicated only in the case of >or=2 CRTs, the inpatient period would have decreased to 9 (range, 0-33) days (P<0.001). No risk factors for CRTs were identified. Allo-SCT after an RIC regimen is a well-tolerated procedure. Our results warrant a prospective pilot trial of nonmyeloablative allo-SCT performed in the outpatient setting. 相似文献
37.
Borghesani PR Alt FW Bottaro A Davidson L Aksoy S Rathbun GA Roberts TM Swat W Segal RA Gu Y 《Proceedings of the National Academy of Sciences of the United States of America》2000,97(7):3336-3341
Motor incoordination, immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia-telangiectasia (A-T), which is caused by mutations in the ATM gene. Through gene targeting, we have generated a line of Atm mutant mice, Atm(y/y) mice. In contrast to other Atm mutant mice, Atm(y/y) mice show a lower incidence of thymic lymphoma and survive beyond a few months of age. Atm(y/y) mice exhibit deficits in motor learning indicative of cerebellar dysfunction. Even though we found no gross cerebellar degeneration in older Atm(y/y) animals, ectopic and abnormally differentiated Purkinje cells were apparent in mutant mice of all ages. These findings establish that some neuropathological abnormalities seen in A-T patients also are present in Atm mutant mice. In addition, we report a previously unrecognized effect of Atm deficiency on development or maintenance of CD4(+)8(+) thymocytes. We discuss these findings in the context of the hypothesis that abnormal development of Purkinje cells and lymphocytes contributes to the pathogenesis of A-T. 相似文献
38.
Zha S Sekiguchi J Brush JW Bassing CH Alt FW 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(27):9302-9306
Upon DNA damage, histone H2AX is phosphorylated by ataxia-telangiectasia mutated (ATM) and other phosphoinositide 3-kinase-related protein kinases. To elucidate further the potential overlapping and unique functions of ATM and H2AX, we asked whether they have synergistic functions in the development and maintenance of genomic stability by inactivating both genes in mouse germ line. Combined ATM/H2AX deficiency caused embryonic lethality and dramatic cellular genomic instability. Mechanistically, severe genomic instability in the double-deficient cells is associated with a requirement for H2AX to repair oxidative DNA damage resulting from ATM deficiency. We discuss these findings in the context of synergies between ATM and other repair factors. 相似文献
39.
A Ma J C Pena B Chang E Margosian L Davidson F W Alt C B Thompson 《Proceedings of the National Academy of Sciences of the United States of America》1995,92(11):4763-4767
The bclx gene has been shown to regulate programmed cell death in vitro. We now show that Bclx expression increases dramatically when T cells differentiate from CD4- CD8- (double negative) thymocytes to CD4+ CD8+ [double positive (DP)] thymocytes. In contrast single-positive (SP) thymocytes express negligible amounts of Bclx protein. This expression pattern contrasts with that of Bcl2, which is present in double-negative thymocytes, down-regulated in DP thymocytes, and reinduced upon maturation to SP thymocytes. Elimination of Bclx by gene targeting dramatically shortens the survival of DP thymocytes but not the survival of SP thymocytes or peripheral SP T cells. These data suggest that the induction of Bclx during thymic maturation plays a critical role in regulating the length of time DP thymocytes survive in the absence of selection. 相似文献
40.
W Swat Y Shinkai H L Cheng L Davidson F W Alt 《Proceedings of the National Academy of Sciences of the United States of America》1996,93(10):4683-4687
We describe a novel approach to assay the ability of particular gene products to signal transitions in lymphocyte differentiation in vivo. The method involves transfection of test expression constructs into RAG-1-deficient embryonic stem cells, which are subsequently assayed by the RAG-2-deficient blastocyst complementation approach. We have used this method to demonstrate that expression of activated Ras in CD4-8- (double negative, DN) prothymocytes in vivo induces their differentiation into small CD4+8+ (double positive, DP) cortical thymocytes with accompanying expansion to normal thymocyte numbers. However, activated Ras expression in DP cells does not cause proliferation or maturation to CD4+8- or CD4-8+ (single positive) thymocytes. Therefore, signaling through Ras is sufficient for promoting differentiation of DN to DP cells, but further differentiation requires the activity of additional signaling pathways. 相似文献