Journal articles: 'Targeted antagonist'

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Akbar, Mohammad J., Pâmela C. Lukasewicz Ferreira, Melania Giorgetti, Leanne Stokes, and Christopher J. Morris. "Bombesin receptor-targeted liposomes for enhanced delivery to lung cancer cells." Beilstein Journal of Nanotechnology 10 (December 19, 2019): 2553–62. http://dx.doi.org/10.3762/bjnano.10.246.

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Background: Gastrin-releasing peptide is a member of the bombesin family of peptides. Its cognate receptor, gastrin releasing peptide receptor (GRPR), is widely expressed in cancers of the lung, pancreas and ovaries. Gastrin releasing peptide (GRP) is an autocrine growth factor in small cell lung cancer, which has very poor patient outcomes. High affinity antagonist peptides have been developed for in vivo cancer imaging. In this report we decorated pegylated liposomes with a GRPR antagonist peptide and studied its interaction with, and accumulation within, lung cancer cells. Results: An N-terminally cysteine modified GRPR antagonist (termed cystabn) was synthesised and shown to inhibit cell growth in vitro. Cystabn was used to prepare a targeted 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) lipid conjugate that was formulated into liposomes. The liposomes displayed desirable colloidal properties and good stability under storage conditions. Flow cytometric and microscopic studies showed that fluorescently labelled cystabn-decorated liposomes accumulated more extensively in GRPR over-expressing cells than matched liposomes that contained no cystabn targeting motif. Conclusion: The use of GRPR antagonistic peptides for nanoparticle targeting has potential for enhancing drug accumulation in resistant cancer cells.

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Marceau, François, and Hélène Bachelard. "A Robust Bioassay of the Human Bradykinin B2 Receptor That Extends Molecular and Cellular Studies: The Isolated Umbilical Vein." Pharmaceuticals 14, no. 3 (February 24, 2021): 177. http://dx.doi.org/10.3390/ph14030177.

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Bradykinin (BK) has various physiological and pathological roles. Medicinal chemistry efforts targeted toward the widely expressed BK B2 receptor (B2R), a G-protein-coupled receptor, were primarily aimed at developing antagonists. The only B2R antagonist in clinical use is the peptide icatibant, approved to abort attacks of hereditary angioedema. However, the anti-inflammatory applications of B2R antagonists are potentially wider. Furthermore, the B2R antagonists notoriously exhibit species-specific pharmacological profiles. Classical smooth muscle contractility assays are exploited over a time scale of several hours and support determining potency, competitiveness, residual agonist activity, specificity, and reversibility of pharmacological agents. The contractility assay based on the isolated human umbilical vein, expressing B2R at physiological density, was introduced when investigating the first non-peptide B2R antagonist (WIN 64338). Small ligand molecules characterized using the assay include the exquisitely potent competitive antagonist, Pharvaris Compound 3 or the partial agonist Fujisawa Compound 47a. The umbilical vein assay is also useful to verify pharmacologic properties of special peptide B2R ligands, such as the carboxypeptidase-activated latent agonists and fluorescent probes. Furthermore, the proposed agonist effect of tissue kallikrein on the B2R has been disproved using the vein. This assay stands in between cellular and molecular pharmacology and in vivo studies.

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Baghdadi, Neazar E., Benjamin P. Burke, Tahani Alresheedi, Shubhanchi Nigam, Abdu Saeed, Farooq Almutairi, Juozas Domarkas, Abid Khan, and Stephen J. Archibald. "Multivalency in CXCR4 chemokine receptor targeted iron oxide nanoparticles." Dalton Transactions 50, no. 5 (2021): 1599–603. http://dx.doi.org/10.1039/d0dt02626c.

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Tao, Haiyan, Emily Eastwood, Raymond G. Fox, Neil Raheja, Paul D. Crowe, and Scott M. Thacher. "Abstract LB144: Antagonism of SF-1 as a potential targeted therapy for malignant Leydig cell tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB144. http://dx.doi.org/10.1158/1538-7445.am2022-lb144.

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Abstract Leydig cell tumors (LCT), originating from androgen-producing interstitial Leydig cells of the testis, represent about 3% of all testicular cancers. LCT belong to the family of sex cord stromal tumors (SCST), a collection of tumors formed in the supporting tissue within the ovaries or testes. Although 90% of LCT are considered benign and can be cured by orchiectomy, in adult patients about 10% of LCT are malignant and metastasis is common. Non-resectable metastatic disease is poorly responsive to radiation and chemotherapy and patients are advised to seek clinical trials. Steroidogenic Factor 1 (SF-1, or NR5A1) is a transcription factor that is essential for the development of the adrenal gland and gonads. SF-1 mutations result in disorders of sexual development, ovarian failure, and adrenal insufficiency. SF-1 is necessary for development of fetal and adult Leydig cells and is strongly expressed in LCT. Significant data support the role of SF-1 in adrenocortical cancer (ACC). To address the need for a targeted therapy in ACC and other SF-1-dependent malignancies, Orphagen has identified potent small molecule antagonists to SF-1*. Here, using R2C, a rat Leydig tumor cell line, we demonstrate that small molecule antagonists of SF-1 inhibit Leydig tumor cell proliferation in vitro and in vivo. OR-449, an orally available inhibitor of SF-1 transcriptional activity (SF-1 Luc IC50 = 16 nM) and OR-907S, a probe SF-1 antagonist (SF-1 Luc IC50 = 22 nM), exhibit striking anti-proliferative activity in R2C cell cultures, inhibiting DNA synthesis by >90% at 1 μM with estimated IC50’s of 0.068 μM and 0.074 μM, respectively. OR-907R, the ~100-fold less active stereoisomer of OR-907S (SF-1 Luc IC50 = 2 μM) was significantly less active in the R2C proliferation assay (estimated IC50 >10 μM). Moreover, in cell lines lacking SF-1 expression, such as HEK293, SF-1 antagonists have no anti-proliferative activity up to 20 μM, suggesting that the anti-proliferative effect on R2C is SF-1-mediated and not due to cytotoxicity. Furthermore, OR-449 completely blocks R2C xenograft tumor growth in immunocompromised mice at an oral dose of 30 mg/kg/day. OR-449 also dose-dependently regulates expression of SF-1 responsive genes, a mRNA signature first identified in R2C culture by comparison of the activity of OR-907S and OR-907R at 1 μM. OR-449 has excellent pharmacokinetic properties and is well-tolerated in repeat dosing toxicity studies in rodents and non-rodents*. These results highlight SF-1 antagonism as a novel targeted therapeutic approach with potential utility in the treatment of LCT and other SCST. OR-449 is currently in IND-enabling studies in order to enter the clinic by the end of 2022. * P. Crowe, et al. A novel steroidogenic factor-1 antagonist, OR-449, as a targeted therapy for adrenocortical cancer. ENDO 2021: J Endocr Soc, Vol5, Supplement_1, A1010 Citation Format: Haiyan Tao, Emily Eastwood, Raymond G. Fox, Neil Raheja, Paul D. Crowe, Scott M. Thacher. Antagonism of SF-1 as a potential targeted therapy for malignant Leydig cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB144.

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Bryant, Kelly G., Young Chan Chae, Rogelio L. Martinez, John C. Gordon, Khaled M. Elokely, Andrew V. Kossenkov, Steven Grant, Wayne E. Childers, Magid Abou-Gharbia, and Dario C. Altieri. "A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy." Oncotarget 8, no. 68 (December 11, 2017): 112184–98. http://dx.doi.org/10.18632/oncotarget.23097.

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Abouzayed, Ayman, Alisa Gorislav, Panagiotis Kanellopoulos, Vladimir Tolmachev, Theodosia Maina-Nock, Berthold A. Nock, and Anna Orlova. "Development of a stabilized GRPR antagonist for targeted cancer theranostics." Nuclear Medicine and Biology 114-115 (November 2022): S24. http://dx.doi.org/10.1016/s0969-8051(22)02142-4.

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Kwan, Byron H., Eric F. Zhu, Alice Tzeng, Harun R. Sugito, Ahmed A. Eltahir, Botong Ma, Mary K. Delaney, et al. "Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses." Journal of Experimental Medicine 214, no. 6 (May 4, 2017): 1679–90. http://dx.doi.org/10.1084/jem.20160831.

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Certain RGD-binding integrins are required for cell adhesion, migration, and proliferation and are overexpressed in most tumors, making them attractive therapeutic targets. However, multiple integrin antagonist drug candidates have failed to show efficacy in cancer clinical trials. In this work, we instead exploit these integrins as a target for antibody Fc effector functions in the context of cancer immunotherapy. By combining administration of an engineered mouse serum albumin/IL-2 fusion with an Fc fusion to an integrin-binding peptide (2.5F-Fc), significant survival improvements are achieved in three syngeneic mouse tumor models, including complete responses with protective immunity. Functional integrin antagonism does not contribute significantly to efficacy; rather, this therapy recruits both an innate and adaptive immune response, as deficiencies in either arm result in reduced tumor control. Administration of this integrin-targeted immunotherapy together with an anti–PD-1 antibody further improves responses and predominantly results in cures. Overall, this well-tolerated therapy achieves tumor specificity by redirecting inflammation to a functional target fundamental to tumorigenic processes but expressed at significantly lower levels in healthy tissues, and it shows promise for translation.

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Pere, Helene, Yves Montier, Jagadeesh Bayry, Francoise Quintin-Colonna, Nathalie Merillon, Estelle Dransart, Cecile Badoual, et al. "A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens." Blood 118, no. 18 (November 3, 2011): 4853–62. http://dx.doi.org/10.1182/blood-2011-01-329656.

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Abstract Regulatory T cells (Tregs) may impede cancer vaccine efficacy in hematologic malignancies and cancer. CCR4 antagonists, an emergent class of Treg inhibitor, have been shown to block recruitment of Tregs mediated by CCL22 and CCL17. Our aim was to demonstrate the ability of a CCR4 antagonist (a small chemical molecule identified in silico) when combined with vaccines to break peripheral tolerance controlled by Tregs, a prerequisite for the induction of CD8+ T cells against self Ags. Immunization of transgenic or normal mice expressing tumor-associated self Ags (Her2/neu, OVA, gp100) with a CCR4 antagonist combined with various vaccines led to the induction of effector CD8+ T cells and partial inhibition of tumor growth expressing self Ags in both prophylactic and therapeutic settings. The CCR4 antagonist was more efficient than cyclophosphamide to elicit anti-self CD8+ T cells. We also showed that the population of Tregs expressing CCR4 corresponded to memory (CD44high) and activated (ICOS+) Tregs, an important population to be targeted to modulate Treg activity. CCR4 antagonist represents a competitive class of Treg inhibitor able to induce functional anti-self CD8+ T cells and tumor growth inhibition when combined with vaccines. High expression of CCR4 on human Tregs also supports the clinical development of this strategy.

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Bishayee, K., and A. R. Khuda-Bukhsh. "5-Lipoxygenase Antagonist therapy: a new approach towards targeted cancer chemotherapy." Acta Biochimica et Biophysica Sinica 45, no. 9 (June 9, 2013): 709–19. http://dx.doi.org/10.1093/abbs/gmt064.

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Roblek, Marko, Manuela Calin, Martin Schlesinger, Daniela Stan, Reiner Zeisig, Maya Simionescu, Gerd Bendas, and Lubor Borsig. "Targeted delivery of CCR2 antagonist to activated pulmonary endothelium prevents metastasis." Journal of Controlled Release 220 (December 2015): 341–47. http://dx.doi.org/10.1016/j.jconrel.2015.10.055.

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Deviani, Jennisa Mayang, and Jenny Mochtar. "The Ideal Masculinity of Male Ninjas in Naruto and Naruto Shippuden Anime Series." K@ta Kita 9, no. 3 (January 6, 2022): 340–47. http://dx.doi.org/10.9744/katakita.9.3.340-347.

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Shounen is one of the most popular genres of anime. Although Shounen is usually targeted at younger boys, it is often consumed by audiences of all ages, such as Naruto and its sequel, Naruto Shippuden. In this study, I will focus on identifying the masculinity within the male ninjas in the series and analyzing the motivations behind the exercise of masculinity to find the ideal masculinity. I will combine the masculinity theory with the Japanese’s manhood, to analyze the ideal masculinity in the text. Through my analysis, I find that the male ninjas of these anime series show different kinds of masculinity, which divides them into two roles, protagonist and antagonist. The protagonists are the ones who thrive to fight for others while the antagonists fight only to benefit themselves. As a result, the protagonists are able to possess the ideal masculinity as they can exercise their masculinity positively.Keywords: anime, masculinity, male ninjas, protagonist, antagonist.

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Yun, So-Yeon, Hyun Ji Kim, Hyo Jin Park, Seong Kyu Yang, Byeongcheon Lee, Moon-Ku Han, and Han-Gil Jeong. "Neuroleptic Malignant Syndrome Applied with Targeted Temperature Management." Journal of the Korean Neurological Association 39, no. 3 (August 1, 2021): 192–96. http://dx.doi.org/10.17340/jkna.2021.3.14.

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Neuroleptic malignant syndrome (NMS) is a life-threatening neurologic emergency associated with the use of dopamine receptor-antagonist properties or the rapid withdrawal of dopaminergic medications. NMS is characterized by refractory hyperpyrexia, altered mental state, dysautonomia, and rigor. If hyperpyrexia persists, it can result in multiorgan failure. Herein, we report a case of NMS occurring after metoclopramide administration in a patient with pontine hemorrhage, which was successfully treated with targeted temperature management using a surface cooling device.

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Nock, Berthold A., Aikaterini Kaloudi, Panagiotis Kanellopoulos, Barbara Janota, Barbara Bromińska, Dariusz Iżycki, Renata Mikołajczak, Rafał Czepczynski, and Theodosia Maina. "[99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes." Cancers 13, no. 20 (October 12, 2021): 5093. http://dx.doi.org/10.3390/cancers13205093.

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Diagnostic imaging and radionuclide therapy of prostate (PC) and breast cancer (BC) using radiolabeled gastrin-releasing peptide receptor (GRPR)-antagonists represents a promising approach. We herein propose the GRPR-antagonist based radiotracer [99mTc]Tc-DB15 ([99mTc]Tc-N4-AMA-DGA-DPhe6,Sar11,LeuNHEt13]BBN(6-13); N4: 6-carboxy-1,4,8,11-tetraazaundecane, AMA: aminomethyl-aniline, DGA: diglycolic acid) as a new diagnostic tool for GRPR-positive tumors applying SPECT/CT. The uptake of [99mTc]Tc-DB15 was tested in vitro in mammary (T-47D) and prostate cancer (PC-3) cells and in vivo in T-47D or PC-3 xenograft-bearing mice as well as in BC patients. DB15 showed high GRPR-affinity (IC50 = 0.37 ± 0.03 nM) and [99mTc]Tc-DB15 strongly bound to the cell-membrane of T-47D and PC-3 cells, according to a radiolabeled antagonist profile. In mice, the radiotracer showed high and prolonged GRPR-specific uptake in PC-3 (e.g., 25.56 ± 2.78 %IA/g vs. 0.72 ± 0.12 %IA/g in block; 4 h pi) and T-47D (e.g., 15.82 ± 3.20 %IA/g vs. 3.82 ± 0.30 %IA/g in block; 4 h pi) tumors, while rapidly clearing from background. In patients with advanced BC, the tracer could reveal several bone and soft tissue metastases on SPECT/CT. The attractive pharmacokinetic profile of [99mTc]DB15 in mice and its capability to target GRPR-positive BC lesions in patients highlight its prospects for a broader clinical use, an option currently being explored by ongoing clinical studies.

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Xu, Jian, Mindi Yin, Jian Zhao, Chao Xu, and Zihan Mao. "Mechanism of miR-21 Antagonist Packaged with Arsenic Trioxide (As₂O₃) Nanoparticles in Restraining Invasion and Metastasis of Intestinal Cancer by Targeted C-C Motif Chemokine Receptor 7 (CCR7) Protein Through Induction of PI3K/Akt Signal Pathway." Science of Advanced Materials 13, no. 11 (November 1, 2021): 2075–81. http://dx.doi.org/10.1166/sam.2021.4095.

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Our study assessed mechanism of miR-21 antagonist packaged with arsenic trioxide nanoparticles (As2O3) in restraining invasion and metastasis of intestinal cancer by targeted CCR7 protein through induction of PI3K/Akt signal pathway. SW480 cell strains were adopted and divided into blank group, group with empty carrier, group with miR-21 agonist and group with miR-21 antagonist packaged with nanoparticles. Cell invasion and metastasis was observed after they were interfered with miR-21 agonist. Expressions of N-cadherin, Vimentin, MMP-9, MMP-2, PI3K and Akt were detected and targeted correlation between miR-21 and CCR7 was studied. The quantity of cells cross matrix membrane in group with carrier and miR-21 antagonist was lowest, while the quantity in the agonist group was highest. The expressions of N-cadherin, Vimentin, MMP-9, MMP-2, PI3K and Akt in group with carrier and antagonist were lower than in the other three groups, and expression of-cadherin and CCR-7 was reversed. The expression of CCR7 was up-regulated by the miR-21 antagonist packaged with nanoparticles, while activated degree of PI3K/Akt was restrained. The level of pathway factor was reduced abnormally so as to regulate the EMT procession, and expression of E-cadherin was increased. Moreover, the expression of MMP-9 and MMP-2 was reduced, and cell invasion and metastasis were controlled. The molecular mechanism was related with PI3K/AKt signal pathway.

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Galbán, Stefanie, Clara Hwang, Julie M. Rumble, Karolyn A. Oetjen, Casey W. Wright, Alain Boudreault, Jon Durkin, et al. "Cytoprotective effects of IAPs revealed by a small molecule antagonist." Biochemical Journal 417, no. 3 (January 16, 2009): 765–71. http://dx.doi.org/10.1042/bj20081677.

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Deregulated expression of members of the IAP (inhibitor of apoptosis) family has been identified in a wide variety of neoplastic cells, and synthetic IAP antagonists represent a promising novel class of chemotherapeutic agents. Early work focused on the ability of these compounds to block the caspase-inhibitory function of XIAP (X-linked IAP). However, recent studies have shown that IAP antagonists, although primarily designed to target XIAP, trigger ubiquitin-mediated degradation of two related proteins, c-IAP (cellular IAP) 1 and c-IAP2, and through this process potentiates the death of tumour cells via autocrine cellular-signalling pathways. In this context, the relative contribution of XIAP as a target of this class of compounds is unclear. In the present study, we examine the involvement of XIAP using a recently described synthetic IAP antagonist, AEG40730, and through comparison of a human XIAP-depleted tumour cell line with its isogenic wild-type control line. Treatment with nanomolar concentrations of AEG40730 resulted in the loss of both XIAP and c-IAP1 proteins, albeit with different kinetics. Although XIAP-deficient HCT116 cells retained some sensitivity to external apoptotic stimuli, the results suggest that IAP antagonists, such as AEG40730, exert their apoptosis-enhancing effects through XIAP in addition to the c-IAPs. These results indicate that IAP antagonists can target multiple IAPs to augment distinct pro-apoptotic signalling pathways, thereby revealing the potential for these compounds in cancer therapy and underscoring the promise of IAP-targeted therapies.

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Crowe, Paul, Ray Fox, Haiyan Tao, Emily Eastwood, Neil Raheja, Raul Ribeiro, and Scott Thacher. "A Novel Steroidogenic Factor-1 Antagonist, OR-449, as a Targeted Therapy for Adrenocortical Cancer." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A1010. http://dx.doi.org/10.1210/jendso/bvab048.2066.

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Abstract Adrenocortical carcinoma (ACC) is a rare cancer with an annual incidence of 0.7-2.0 cases per million in the US and EU. Surgical resection combined with adjuvant chemotherapy remains the primary treatment for patients with advanced disease. Although surgery is an option for most patients, oftentimes cases presenting with locally advanced or metastatic disease are not candidates for surgical resection. Furthermore, the non-specific adrenolytic and highly toxic FDA-approved chemotherapy drug, mitotane, is only marginally effective in adult and pediatric ACC. Steroidogenic factor-1 (SF-1 or NR5A1), an orphan nuclear receptor that is essential for the growth and development of the adrenal gland, is highly expressed in adult and pediatric ACC. Moreover, SF- is the major, active transcription factor in ACC (1,2). To address the unmet need for a targeted therapy in ACC, we identified potent small molecule SF-1 antagonists that block SF-1 transcriptional activity through the SF-1 ligand-binding domain (IC50 = 15-20 nM in a CHO cell reporter assay). In short-term dissociated cell cultures established from SJ-ACC3 (3), a pediatric ACC patient-derived tumor xenograft (PDX), OR-449 and a related SF-1 antagonist, OR-907S, blocked DNA synthesis as measured by inhibition of EdU incorporation in SF-1+ cells (IC50 = 500-600 nM, >80% efficacy at 10 μM) whereas OR-907R, the 100-fold less potent enantiomer of OR-907S, is nearly inactive. OR-449, which has >20% oral bioavailability and a long plasma half-life (> 9 h) in mouse, rat and dog, inhibited growth of SJ-ACC3 tumors grown in immunocompromised mice following daily oral dosing (30 mg/kg) for 4 weeks. SF-1-responsive genes, both down- and up-regulated, identified by RNAseq (by comparison of OR-907S and OR-907R in SJ-ACC3 dissociated cell culture), also responded to OR-449 in SJ-ACC3 xenografts following 7 days of dosing, indicating transcriptional regulation of SF-1 by OR-449. Importantly, in an exploratory 2-week mouse safety study, OR-449 showed no adverse effects when dosed up to 100 mg/kg. Taken together, these findings suggest that SF-1 antagonists could provide a safe and effective targeted therapy for ACC. References: (1) Mohan, et al., Curr. Opin. Endocrinol. Metab. Res., 2019; 8:72; (2) Corces, et al., Science, 2018; 362:eaav1898; (3) Pinto, et al., Clin. Cancer. Res., 2013; 19:1740.

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Hortobágyi, Tibor, Paul DeVita, Robert Brady, and Patrick Rider. "Training History-Dependent Functional Role of EMG Model-Predicted Antagonist Moments in Knee Extensor Moment Generation in Healthy Young Adults." Biomechanics 2, no. 1 (January 6, 2022): 7–19. http://dx.doi.org/10.3390/biomechanics2010002.

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Resistance training (RT) improves the skeletal muscle’s ability to generate maximal voluntary force and is accompanied by changes in the activation of the antagonist muscle which is not targeted primarily by RT. However, the nature and role of neural adaptation to RT in the antagonist muscle is paradoxical and not well understood. We compared moments, agonist muscle activation, antagonist activation, agonist-antagonist coactivation, and electromyographic (EMG) model-predicted moments generated by antagonist hamstring muscle coactivation during isokinetic knee extension in leg strength-trained (n = 10) and untrained (n = 11) healthy, younger adults. Trained vs. untrained adults were up to 58% stronger. During knee extension, hamstring activation was 1.6-fold greater in trained vs. untrained adults (p = 0.022). This hamstring activation produced 2.6-fold greater model-predicted antagonist moments during knee extension in the trained (42.7 ± 19.55 Nm) vs. untrained group (16.4 ± 12.18 Nm; p = 0.004), which counteracted (reduced) quadriceps knee extensor moments ~43 Nm (0.54 Nm·kg−1) and by ~16 Nm (0.25 Nm·kg−1) in trained vs. untrained. Antagonist hamstring coactivation correlated with decreases and increases, respectively, in quadriceps moments in trained and untrained. The EMG model-predicted antagonist moments revealed training history-dependent functional roles in knee extensor moment generation.

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Matheny, M., K. Y. E. Strehler, M. King, N. Tümer, and P. J. Scarpace. "Targeted leptin receptor blockade: role of ventral tegmental area and nucleus of the solitary tract leptin receptors in body weight homeostasis." Journal of Endocrinology 222, no. 1 (July 2014): 27–41. http://dx.doi.org/10.1530/joe-13-0455.

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The present investigation examined whether leptin stimulation of ventral tegmental area (VTA) or nucleus of the solitary tract (NTS) has a role in body weight homeostasis independent of the medial basal hypothalamus (MBH). To this end, recombinant adeno-associated viral techniques were employed to target leptin overexpression or overexpression of a dominant negative leptin mutant (leptin antagonist). Leptin antagonist overexpression in MBH or VTA increased food intake and body weight to similar extents over 14 days in rats. Simultaneous overexpression of leptin in VTA with antagonist in MBH resulted in food intake and body weight gain that were less than with control treatment but greater than with leptin alone in VTA. Notably, leptin overexpression in VTA increased P-STAT3 in MBH along with VTA, and leptin antagonist overexpression in the VTA partially attenuated P-STAT3 levels in MBH. Interestingly, leptin antagonist overexpression elevated body weight gain, but leptin overexpression in the NTS failed to modulate either food intake or body weight despite increased P-STAT3. These data suggest that leptin function in the VTA participates in the chronic regulation of food consumption and body weight in response to stimulation or blockade of VTA leptin receptors. Moreover, one component of VTA-leptin action appears to be independent of the MBH, and another component appears to be related to leptin receptor-mediated P-STAT3 activation in the MBH. Finally, leptin receptors in the NTS are necessary for normal energy homeostasis, but mostly they appear to have a permissive role. Direct leptin activation of NTS slightly increases UCP1 levels, but has little effect on food consumption or body weight.

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Schalk, Felix, Janis Fricke, Soohyun Um, Benjamin H. Conlon, Hannah Maus, Nils Jäger, Thorsten Heinzel, Tanja Schirmeister, Michael Poulsen, and Christine Beemelmanns. "GNPS-guided discovery of xylacremolide C and D, evaluation of their putative biosynthetic origin and bioactivity studies of xylacremolide A and B." RSC Advances 11, no. 31 (2021): 18748–56. http://dx.doi.org/10.1039/d1ra00997d.

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Targeted HRMS²-GNPS-based metabolomic and genomic analysis of the fungal garden antagonist Pseudoxylaria sp. X187 resulted in the identification of xylacremolide C and D and the identification of their putative PKS-NRPS-based biosynthesis.

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Motta, Jean-Paul, Celine Deraison, Sylvie Le Grand, Bruno Le Grand, and Nathalie Vergnolle. "PAR-1 Antagonism to Promote Gut Mucosa Healing in Crohn’s Disease Patients: A New Avenue for CVT120165." Inflammatory Bowel Diseases 27, Supplement_2 (November 15, 2021): S33—S37. http://dx.doi.org/10.1093/ibd/izab244.

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Abstract A new paradigm has been added for the treatment of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. In addition to resolving symptoms and inflammatory cell activation, the objective of tissue repair and mucosal healing is also now considered a primary goal. In the search of mediators that would be responsible for delayed mucosal healing, protease-activated receptor-1 (PAR-1) has emerged as a most interesting target. Indeed, in Crohn’s disease, the endogenous PAR-1 agonist thrombin is drastically activated. Activation of PAR-1 is known to be associated with epithelial dysfunctions that hamper mucosal homeostasis. This review gathers the scientific evidences of a potential role for PAR-1 in mucosal damage and mucosal dysfunctions associated with chronic intestinal inflammation. The potential clinical benefits of PAR-1 antagonism to promote mucosal repair in CD patients are discussed. Targeted local delivery of a PAR-1 antagonist molecule such as CVT120165, a formulated version of the FDA-approved PAR-1 antagonist vorapaxar, at the mucosa of Crohn’s disease patients could be proposed as a new indication for IBD that could be rapidly tested in clinical trials.

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Hukriede, N. A., Y. Gu, and R. J. Fleming. "A dominant-negative form of Serrate acts as a general antagonist of Notch activation." Development 124, no. 17 (September 1, 1997): 3427–37. http://dx.doi.org/10.1242/dev.124.17.3427.

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Specification of the dorsal-ventral compartment boundary in the developing Drosophila wing disc requires activation of NOTCH from its dorsal ligand SERRATE and its ventral ligand DELTA. Both NOTCH ligands are required in this process and one cannot be substituted for the other. In the wing disc, expression of a dominant-negative, truncated form of SERRATE called BD(G), is capable of inhibiting NOTCH activation in the ventral but not the dorsal compartments. We demonstrate that BD(G) can act as a general antagonist of both SERRATE and DELTA mediated NOTCH interactions, however, BD(G) retains the SERRATE protein domain targeted by FRINGE, hence its antagonistic effects are restricted in the dorsal wing disc. Our findings suggest a model in which ligand binding to NOTCH is a necessary but insufficient step toward NOTCH activation.

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Kwon, Daniel, Jerome Lozada, Zhengxing Zhang, Jutta Zeisler, Richel Poon, Chengcheng Zhang, Áron Roxin, Kuo-Shyan Lin, David Perrin, and Francois Benard. "High-Contrast CXCR4-Targeted 18F-PET Imaging Using a Potent and Selective Antagonist." Molecular Pharmaceutics 18, no. 1 (November 30, 2020): 187–97. http://dx.doi.org/10.1021/acs.molpharmaceut.0c00785.

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Zhang, Hanzhe, Jiajun Wen, G. Caleb Alexander, and Jeffrey R. Curtis. "Comparative effectiveness of biologics and targeted therapies for psoriatic arthritis." RMD Open 7, no. 1 (April 2021): e001399. http://dx.doi.org/10.1136/rmdopen-2020-001399.

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ObjectiveTo quantify comparative effectiveness of interleukin (IL)−12/23 antagonist (ustekinumab), IL-17A antagonists (secukinumab and ixekizumab), PDE4 inhibitor (apremilast) and tumour necrosis factor-alpha (TNF-α) inhibitors (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab) for psoriatic arthritis (PsA).MethodsWe adapted a deidentified claims-based algorithm validated for inflammatory arthritis treatments to compare treatments among a retrospective cohort of commercially insured and Medicare Advantage beneficiaries with PsA from October 2013 to April 2019 in the OptumLabs Data Warehouse. Main outcomes include (1) treatment effectiveness, based on: adherence, adding or switching biologic or PDE4, addition of new non-biologic disease-modifying antirheumatic drug, increase in biologic or PDE4 dose or frequency and glucocorticoid use and (2) percentage of each group fulfilling the effectiveness algorithm. We used Poisson regression with robust variance stratified by prior PsA biologic exposure and adjusted for potential confounders.ResultsOf 2730 individuals with PsA, 327 received IL-12/23, 138 IL-17A’s, 624 PDE4 and 1641 TNF-α’s. Effectiveness criteria were fulfilled among 63 (19.3%) IL-12/23 recipients, 40 (29.0%) IL-17A recipients, 160 (25.6%) PDE4 recipients and 530 (32.3%) TNF-α recipients. Among biologic-naïve individuals, IL-12/23 was less effective than TNF-α’s with fully adjusted relative risk (aRR) compared with TNF-α’s of 0.63 (95% CI 0.45 to 0.89). Among biologic-experienced individuals, PDE4 recipients were less effective than TNF-α’s (aRR 0.67, 95% CI 0.46 to 0.96).ConclusionsTNF-α’s appeared more effective than IL-12/23’s for biologic-naïve individuals, and PDE4’s for biologic-experienced individuals. These results may help inform treatment choice for individuals with PsA.

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Lewicky, Jordan D., Nya L. Fraleigh, Alexandrine L. Martel, Thi M. D. Nguyen, Peter W. Schiller, Leila Mousavifar, René Roy, Anh Dzung Le, Douglas Funk, and Hoang-Thanh Le. "Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes." International Journal of Molecular Sciences 22, no. 15 (July 27, 2021): 7996. http://dx.doi.org/10.3390/ijms22157996.

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Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3–3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30–40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS.

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Chen, Chu-Ling, Shu-Yi Wang, Ta-Cheng Chen, and Chieh-Sen Chuang. "Association between β2-Adrenoreceptor Medications and Risk of Parkinson’s Disease: A Meta-Analysis." Medicina 57, no. 10 (September 24, 2021): 1006. http://dx.doi.org/10.3390/medicina57101006.

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Background and Objective: Parkinson’s disease (PD) is a progressive neurological disorder characterized by an accumulation of Lewy bodies and degeneration of dopaminergic neurons in the substantia nigra. The treatment options currently available are only partly effective and fail to restore the lost dopaminergic neurons or slow the progression. β2-adrenoceptors (β2AR) are widely expressed in various human tissues and organs, regulate many important metabolic functions, and are targeted for treatment of various diseases. Studies have reported a link between chronic use of the β2AR antagonist propranolol and an increased risk of PD, and chronic use of β2AR agonists has been associated with a decreased risk of PD. We conducted a meta-analysis on the association between both β2AR agonist level and β2AR antagonist level and the risk of PD. Materials and Methods: A comprehensive electronic search was conducted on the databases of PubMed, ScienceDirect, ProQuest, Cochrane Library, and ClinicalKey from the start of each database until 30 June 2021. The objective was to identify prospective cohort and case–control studies that have reported on the association between β-adrenoceptor agonist level, antagonist level, and PD risk. Results: A meta-analysis of the data extracted from eight studies revealed that β2AR agonist use was associated with reduced PD risk (RR = 0.859, 95% confidence interval [CI] 0.741–0.995. p = 0.043). Compared with the control group, β2AR antagonist use was associated with an increased risk of PD (RR = 1.490, 95% CI, 1.195 to 1.857. p < 0.005). Propranolol, a type of β2AR antagonist, was related to an increased risk of PD (RR = 2.820, 95% CI, 2.618 to 3.036. p < 0.005). Conclusions: In this meta-analysis, β2AR agonists were associated with a decreased risk of PD, and β2AR antagonists were related with an increased risk of PD. However, further studies with larger sample sizes and an evaluation of the long-term effects of varying dosages of medications are needed.

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Zhong, Beihua, and Donna H. Wang. "N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 2 (August 2008): H728—H735. http://dx.doi.org/10.1152/ajpheart.00022.2008.

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N-oleoyldopamine (OLDA), a bioactive lipid originally found in the mammalian brain, is an endovanilloid that selectively activates the transient receptor potential vanilloid type 1 (TRPV1) channel. This study tests the hypothesis that OLDA protects the heart against ischemia and reperfusion (I/R) injury via activation of the TRPV1 in wild-type (WT) but not in gene-targeted TRPV1-null mutant (TRPV1−/−) mice. Hearts of WT or TRPV1−/− mice were Langendorffly perfused with OLDA (2 × 10−9 M) in the presence or absence of CGRP8–37 (1 × 10−6 M), a selective calcitonin gene-related peptide (CGRP) receptor antagonist; RP-67580 (1 × 10−6 M), a selective neurokinin-1 receptor antagonist; chelerythrine (5 × 10−6 M), a selective protein kinase C (PKC) antagonist; or tetrabutylammonium (TBA, 5 × 10−4 M), a nonselective K+ channel antagonist, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), coronary flow (CF), and left ventricular peak positive dP/d t (+dP/d t) were evaluated after I/R. OLDA improved recovery of cardiac function after I/R in WT but not TRPV1−/− hearts by increasing LVDP, CF, and +dP/d t and by decreasing LVEDP. CGRP8–37, RP-67580, chelerythrine, or TBA abolished the protective effect of OLDA in WT hearts. Radioimmunoassay showed that the release of substance P (SP) and CGRP after OLDA treatment was higher in WT than in TRPV1−/− hearts, which was blocked by chelerythrine or TBA. Thus OLDA exerts a cardiac protective effect during I/R injury in WT hearts via CGRP and SP release, which is abolished by PKC or K+ channel antagonists. The protective effect of OLDA is void in TRPV1−/− hearts, supporting the notion that TRPV1 mediates OLDA-induced protection against cardiac I/R injury.

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Bothwell, Steven W., Daniel Omileke, Adjanie Patabendige, and Neil J. Spratt. "CSF Secretion Is Not Altered by NKCC1 Nor TRPV4 Antagonism in Healthy Rats." Brain Sciences 11, no. 9 (August 24, 2021): 1117. http://dx.doi.org/10.3390/brainsci11091117.

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Background: Cerebrospinal fluid (CSF) secretion can be targeted to reduce elevated intracranial pressure (ICP). Sodium-potassium-chloride cotransporter 1 (NKCC1) antagonism is used clinically. However, supporting evidence is limited. The transient receptor potential vanilloid-4 (TRPV4) channel may also regulate CSF secretion and ICP elevation. We investigated whether antagonism of these proteins reduces CSF secretion. Methods: We quantified CSF secretion rates in male Wistar rats. The cerebral aqueduct was blocked with viscous mineral oil, and a lateral ventricle was cannulated. Secretion rate was measured at baseline and after antagonist administration. Acetazolamide was administered as a positive control to confirm changes in CSF secretion rates. Results: Neither NKCC1, nor TRPV4 antagonism altered CSF secretion rate from baseline, n = 3, t(2) = 1.14, p = 0.37, and n = 4, t(3) = 0.58, p = 0.6, respectively. Acetazolamide reduced CSF secretion by ~50% across all groups, n = 7, t(6) = 4.294, p = 0.005. Conclusions: Acute antagonism of NKCC1 and TRPV4 proteins at the choroid plexus does not reduce CSF secretion in healthy rats. Further investigation of protein changes and antagonism should be explored in neurological disease where increased CSF secretion and ICP are observed before discounting the therapeutic potential of protein antagonism at these sites.

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Peled, Tony, Ela Glukhman, Sophie Adi, Efrat Landau, Nira Hasson, Chana Lador, Julie Mandel, and Eitan Fibach. "Antagonists to Retinoid Receptors Down-Regulate CD38 Expression and Inhibit In Vitro Differentiation of Cord Blood Derived CD34+ Cells." Blood 108, no. 11 (November 16, 2006): 3652. http://dx.doi.org/10.1182/blood.v108.11.3652.3652.

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Abstract CD38, originally described as a differentiation marker, has emerged as an important multifunctional protein. Its most well-characterized function is the ability to catalyze the synthesis of cyclic ADP-ribose (cADPR) from NAD. However, its major enzymatic activity is the hydrolysis of NAD (NADase) implicating it as the major regulator of cellular NAD levels. CD38 expression increases with commitment and differentiation. It is not clear, however, whether such changes in CD38 are merely phenotypic, or reflect an active role for CD38 in the regulation of cell differentiation. The regulation of CD38 gene expression is under the direct control of retinoid receptors (RAR). Antagonists to RAR abolish up-regulation of CD38 gene expression as well as RA induction of granulocytic differentiation down-stream of the myeloid compartment. In the present study we evaluated the involvement of CD38 in the regulation of HPC differentiation by treatment of ex-vivo cultures with LMW antagonists, targeted to either CD38 expression or to its biological activities. CB derived CD34+ cells were cultured with cytokines (S,T,F,6). Treatment of these cultures with an RAR-antagonist (AGN194310) abolished the expression of surface CD38. After 3 weeks in culture, the content of CFC was 3 ±1.1-fold higher, the content of CD34+ cells was 2.4 ± 0.24-fold higher and percentage CD34+ cells displaying CD34+Lin− phenotype was by 35 ± 10-fold higher (p<0.05, n= 14) in RAR-antagonist (10−6M) compared to cytokines-only treated cultures. Colonies derived from RAR-antagonist treated cultures sustained high re-plating capacity, a property that was lost during the first 3-weeks of expansion with cytokines only. In long-term cultures, the peak of CFUc and CD34+ cell expansion of RAR-antagonist treated cultures was 6–10 weeks later than control cultures. At the peak of expansion, cumulative numbers of CD34+ and CFUc were by 130- and 512-fold higher (p<0.05, n=4), respectively, in treated than in control cultures. CFU-MIX colonies were exclusively observed in RAR-antagonist treated cultures (between weeks 7–10). Interestingly, limited (1 week) exposure to the RAR-antagonist was sufficient for this long-term effect. Similarly, we tested the effect of an RXR antagonist (LGN 100754) (10−9 – 10−5 M) on short- and long-term cultures. Treatment with the RXR-antagonist did not down-regulate CD38 expression and only slightly improved ex-vivo expansion parameters over cytokines-only treated cultures. We next evaluated whether inhibition of CD38 enzymatic activities will also modulate in-vitro differentiation of cultured cells. To this end, CD34+ cell cultures were treated with nicotinamide (NA), a non-competitive inhibitor of CD38 NADase, previously demonstrated to abolish its enzymatic activities. 3-week treatment with NA (5mM) resulted in a marked decrease in CD38 expression and a marked increase in the fraction of CD34+Lin− cells as compared to cytokines-only treated cultures (48.0 ± 3.7% vs. 2.8 ± 0.7% and 18.6 ± 3% vs. 0.7 ± 0.06%, n=6, p<0.05, respectively). As with the RAR-antagonist, long-term expansion potential, as determined by CFC and CD34+ cell content, was significantly higher in cultures treated with NA relative to cytokines-only treated cultures. These results demonstrate that both a pan-RAR antagonist and NA inhibit differentiation and promote ex-vivo expansion of progenitor cells, suggesting the possible involvement of CD38 protein in these processes.

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Chauhan, Shreepa J., Anita Thyagarajan, Yanfang Chen, Jeffrey B. Travers, and Ravi P. Sahu. "Platelet-Activating Factor-Receptor Signaling Mediates Targeted Therapies-Induced Microvesicle Particles Release in Lung Cancer Cells." International Journal of Molecular Sciences 21, no. 22 (November 12, 2020): 8517. http://dx.doi.org/10.3390/ijms21228517.

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Microvesicle particles (MVP) secreted by a variety of cell types in response to reactive oxygen species (ROS)-generating pro-oxidative stressors have been implicated in modifying the cellular responses including the sensitivity to therapeutic agents. Our previous studies have shown that expression of a G-protein coupled, platelet-activating factor-receptor (PAFR) pathway plays critical roles in pro-oxidative stressors-mediated cancer growth and MVP release. As most therapeutic agents act as pro-oxidative stressors, the current studies were designed to determine the role of the PAFR signaling in targeted therapies (i.e., gefitinib and erlotinib)-mediated MVP release and underlying mechanisms using PAFR-expressing human A549 and H1299 non-small cell lung cancer (NSCLC) cell lines. Our studies demonstrate that both gefitinib and erlotinib generate ROS in a dose-dependent manner in a process blocked by antioxidant and PAFR antagonist, verifying their pro-oxidative stressor’s ability, and the role of the PAFR in this effect. We observed that these targeted therapies induce MVP release in a dose- and time-dependent manner, similar to a PAFR-agonist, carbamoyl-PAF (CPAF), and PAFR-independent agonist, phorbol myristate acetate (PMA), used as positive controls. To confirm the PAFR dependency, we demonstrate that siRNA-mediated PAFR knockdown or PAFR antagonist significantly blocked only targeted therapies- and CPAF-mediated but not PMA-induced MVP release. The use of pharmacologic inhibitor strategy suggested the involvement of the lipid ceramide-generating enzyme, acid sphingomyelinase (aSMase) in MVP biogenesis, and observed that regardless of the stimuli used, aSMase inhibition significantly blocked MVP release. As mitogen-activated protein kinase (MAPK; ERK1/2 and p38) pathways crosstalk with PAFR, their inhibition also significantly attenuated targeted therapies-mediated MVP release. These findings indicate that PAFR signaling could be targeted to modify cellular responses of targeted therapies in lung cancer cells.

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Secchi, Massimiliano, and Luca Vangelista. "Rational Engineering of a Sub-Picomolar HIV-1 Blocker." Viruses 14, no. 11 (October 31, 2022): 2415. http://dx.doi.org/10.3390/v14112415.

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With the aim of rationally devising a refined and potent HIV-1 blocker, the cDNA of CCL5 5p12 5m, an extremely potent CCR5 antagonist, was fused to that of C37, a gp41-targeted fusion inhibitor. The resulting CCL5 5p12 5m-C37 fusion protein was expressed in E. coli and proved to be capable of inhibiting R5 HIV-1 strains with low to sub-picomolar IC50, maintaining its antagonism toward CCR5. In addition, CCL5 5p12 5m-C37 inhibits R5/X4 and X4 HIV-1 strains in the picomolar concentration range. The combination of CCL5 5p12 5m-C37 with tenofovir (TDF) exhibited a synergic effect, promoting this antiviral cocktail. Interestingly, a CCR5-targeted combination of maraviroc (MVC) with CCL5 5p12 5m-C37 led to a synergic effect that could be explained by an extensive engagement of different CCR5 conformational populations. Within the mechanism of HIV-1 entry, the CCL5 5p12 5m-C37 chimera may fit as a powerful blocker in several instances. In its possible consideration for systemic therapy or pre-exposure prophylaxis, this protein design represents an interesting lead in the combat of HIV-1 infection.

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Dow, Robert L., Philip A. Carpino, Denise Gautreau, John R. Hadcock, Philip A. Iredale, Dawn Kelly-Sullivan, Jeffrey S. Lizano, et al. "Design of a Potent CB1 Receptor Antagonist Series: Potential Scaffold for Peripherally-Targeted Agents." ACS Medicinal Chemistry Letters 3, no. 5 (March 23, 2012): 397–401. http://dx.doi.org/10.1021/ml3000325.

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Endre, Zoltán H., and Jonathan H. Erlich. "Targeted protection of proximal tubular cells by nanoparticle-enhanced delivery of a TLR9-antagonist." Kidney International 98, no. 1 (July 2020): 48–50. http://dx.doi.org/10.1016/j.kint.2020.04.024.

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Foley, K. P. "Targeted disruption of the MYC antagonist MAD1 inhibits cell cycle exit during granulocyte differentiation." EMBO Journal 17, no. 3 (February 1, 1998): 774–85. http://dx.doi.org/10.1093/emboj/17.3.774.

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Kim, Hyun Jung, Jinhong Wie, Insuk So, Myeong Ho Jung, Ki-Tae Ha, and Byung Joo Kim. "Menthol Modulates Pacemaker Potentials through TRPA1 Channels in Cultured Interstitial Cells of Cajal from Murine Small Intestine." Cellular Physiology and Biochemistry 38, no. 5 (2016): 1869–82. http://dx.doi.org/10.1159/000445549.

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Background/Aims: ICCs are the pacemaker cells responsible for slow waves in gastrointestinal (GI) smooth muscle, and generate periodic pacemaker potentials in current-clamp mode. Methods: The effects of menthol on the pacemaker potentials of cultured interstitial cells of Cajal (ICCs) from mouse small intestine were studied using the whole cell patch clamp technique. Results: Menthol (1 - 10 μM) was found to induce membrane potential depolarization in a concentration-dependent manner. The effects of various TRP channel antagonists were examined to investigate the receptors involved. The addition of the TRPM8 antagonist, AMTB, did not block menthol-induced membrane potential depolarizations, but TRPA1 antagonists (A967079 or HC-030031) blocked the effects of menthol, as did intracellular GDPβS. Furthermore, external and internal Ca2+ levels were found to depolarize menthol-induced membrane potentials, whereas external Na+ was not. Y-27632 (a Rho kinase inhibitor), SC-560 (a selective COX 1 inhibitor), NS-398 (a selective COX 2 inhibitor), ozagrel (a thromboxane A2 synthase inhibitor) and SQ-29548 (highly selective thromboxane receptor antagonist) were used to investigate the involvements of Rho-kinase, cyclooxygenase (COX), and the thromboxane pathway in menthol-induced membrane potential depolarizations, and all inhibitors were found to block the effect of menthol. Conclusions: These results suggest that menthol-induced membrane potential depolarizations occur in a G-protein-, Ca2+-, Rho-kinase-, COX-, and thromboxane A2-dependent manner via TRPA1 receptor in cultured ICCs in murine small intestine. The study shows ICCs are targeted by menthol and that this interaction can affect intestinal motility.

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Arendt, Josephine, and Shantha M. W. Rajaratnam. "Melatonin and its agonists: an update." British Journal of Psychiatry 193, no. 4 (October 2008): 267–69. http://dx.doi.org/10.1192/bjp.bp.108.050955.

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SummaryThe pineal hormone melatonin is able to shift the timing of circadian rhythms, including the sleep–wake cycle, and to promote sleep. Melatonin agonists with similar properties have therapeutic potential for the treatment of circadian rhythm sleep disorders. Depression is specifically targeted by agomelatine, which is also a serotonin-2C (5-HT2C) antagonist.

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Liu, Yali, Changpeng Hu, Min Zhou, Qian Zhang, Qin Tang, Wenjing Lai, and Jingbin Huang. "AMD3100-tagged nano-gold as a targeting nanocarrier for delivery of doxorubicin into lung cancer cells." Materials Express 11, no. 5 (May 1, 2021): 618–26. http://dx.doi.org/10.1166/mex.2021.1960.

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Doxorubicin (DOX) is widely used as a traditional chemotherapy drug in tumor treatment, but its dose-dependent side effects make it susceptible to acquired resistance. CXCR4 is a chemokine receptor that has high expression in many cancers, including lung cancer. In this work, we studied the possibility of using CXCR4 antagonist, AMD3100, as a targeting molecule to targeted delivery of DOX to CXCR4 expressing lung cancer cells through conjugated gold nanoparticles (Au NPs). DOX was intercalated inside the pH-responsive doublestrand DNA (dsDNA) and then conveniently loaded onto the Au NPs. The CXCR4 antagonist, AMD3100, was bonded with LA-PEG, and then conjugated to the surface of Au-S bond. The doxorubicin release from AuNPs@DOX@AMD3100 NPs was in a pH-dependent model, and specificity of AuNPs@DOX@AMD3100 nanoparticle was verified by using free DOX and Au@DOX NPs as control. Results in this work not only confirmed the possibility of using AMD3100 as a targeting ligand for tumor-targeted treatment, but also suggested that the non-toxic Au NPs is a prospect nanocarrier for target design of cancer therapy.

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Shinohara, Motoko, Mitsuru Shinohara, Jing Zhao, Yuan Fu, Chia-Chen Liu, Takahisa Kanekiyo, and Guojun Bu. "5-HT3 Antagonist Ondansetron Increases apoE Secretion by Modulating the LXR-ABCA1 Pathway." International Journal of Molecular Sciences 20, no. 6 (March 25, 2019): 1488. http://dx.doi.org/10.3390/ijms20061488.

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Apolipoprotein E (apoE) is linked to the risk for Alzheimer’s disease (AD) and thus has been suggested to be an important therapeutic target. In our drug screening effort, we identified Ondansetron (OS), an FDA-approved 5-HT3 antagonist, as an apoE-modulating drug. OS at low micromolar concentrations significantly increased apoE secretion from immortalized astrocytes and primary astrocytes derived from apoE3 and apoE4-targeted replacement mice without generating cellular toxicity. Other 5-HT3 antagonists also had similar effects as OS, though their effects were milder and required higher concentrations. Antagonists for other 5-HT receptors did not increase apoE secretion. OS also increased mRNA and protein levels of the ATB-binding cassette protein A1 (ABCA1), which is involved in lipidation and secretion of apoE. Accordingly, OS increased high molecular weight apoE. Moreover, the liver X receptor (LXR) and ABCA1 antagonists blocked the OS-induced increase of apoE secretion, indicating that the LXR-ABCA1 pathway is involved in the OS-mediated facilitation of apoE secretion from astrocytes. The effects of OS on apoE and ABCA1 were also observed in human astrocytes derived from induced pluripotent stem cells (iPSC) carrying the APOE ε3/ε3 and APOE ε4/ε4 genotypes. Oral administration of OS at clinically-relevant doses affected apoE levels in the liver, though the effects in the brain were not observed. Collectively, though further studies are needed to probe its effects in vivo, OS could be a potential therapeutic drug for AD by modulating poE metabolism through the LXR-ABCA1 pathway.

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Abouzayed, Ayman, Hanna Tano, Ábel Nagy, Sara S. Rinne, Fadya Wadeea, Sharmishtaa Kumar, Kristina Westerlund, Vladimir Tolmachev, Amelie Eriksson Karlström, and Anna Orlova. "Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer." Pharmaceutics 12, no. 10 (October 16, 2020): 977. http://dx.doi.org/10.3390/pharmaceutics12100977.

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The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC50) of natIn-DOTA-ABD-RM26 in the presence of human serum albumin was 49 ± 5 nM. [111In]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate.

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Cai, Chenguang, Xiang Li, Shin-Chen Hou, Guoqian Sun, Ying Li, Ting Yang, Fengzhi Zhang, et al. "Abstract 5552: Novel set of OX40 targeted antibodies and VHHs include agonists and antagonists for future development." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5552. http://dx.doi.org/10.1158/1538-7445.am2022-5552.

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Abstract Immunotherapy is one of the most effective modern treatments for cancer. While immunotherapy operates through a broad class of mechanisms, modulating immune checkpoints have provided some of the most effective approaches, including inhibition of PD-1/PD-L1 pathway, CTLA-4, LAG-3, OX40, Tim-3, KIR and TIGIT to reverse tumor immune escape.OX40, also known as CD134 or TNFRSF4, is a membrane protein expressed in CD4+ and CD8+ T cells, neutrophils and NK cells. In the process of T cell activation, OX40 plays a synergistic stimulating function by binding with ligand OX40L. OX40 agonist immunotherapy has been previously shown to improve the survival rate of glioblastoma in mice, prevent tumor growth in ovarian cancer, increase the prognostic significance of CD8+ cell infiltration in colorectal cancer, and eliminate the inhibitory function of Foxp3+ Treg cells that constitutively Express OX40. On the contrary, blocking OX40 axis is a promising strategy to treat T cell hyperactivation in autoimmune diseases. As recently reported in the literature, a two-armed, random, double blinded phase 2b clinical trial demonstrated that telazorlimab, an antagonist OX40 antibody developed by Ichnos Sciences, met primary efficacy endpoints in treating atopic dermatitis.In this research, we developed a set of novel antibodies to OX40 using a hybridoma and VHH synthetic library; the set of antibodies includes both agonists and antagonists.We developed one hybridoma origin mAb into a human framework. Agonist activity was equal to MOXR0916 in NF- κB reporter-Jurkat assay, dependent on coupling by proteinA/cell-bound CD32b, non-competing with OX40L, and epitope mapped to domain 2+3.We identified dozens of binders from our synthetic single domain VH library. After construction into a IgG1Fc fusion form, 4 VHHs were obtained with significant agonistic activity, dependent on coupling by proteinA/cell bound CD32b. Another 5 VHHs were also obtained with significant antagonistic activity without coupling by proteinA/cell-bound CD32b. The 4 agonistic VHHs were confirmed with binding to domain 1+2, competitive to OX40L’s binding.These VHHs constructs represent a promising set of novel biologics to modulate OX40—as agonists or antagonists—and serve as the basis for development of potential new therapies in the clinic. Citation Format: Chenguang Cai, Xiang Li, Shin-Chen Hou, Guoqian Sun, Ying Li, Ting Yang, Fengzhi Zhang, Qi Sun, Shiying Fu, Shuang Zhao, You'you Lin, Feizheng Xue. Novel set of OX40 targeted antibodies and VHHs include agonists and antagonists for future development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5552.

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Zhu, Hanxiao, Xiaoli Lai, Jinhong Wu, Chenan Guan, and Junhui Yu. "Meta-Study of the Clinical Effect of Conservative Treatment in Uterine Fibroids." Journal of Oncology 2022 (July 31, 2022): 1–9. http://dx.doi.org/10.1155/2022/6114287.

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Heavy menstrual bleeding (HMB), distress in the pelvis, infertile, and stressed feelings are all indications of fibroids in the uterus, the most prevalent type of benign uterine tumor. Nearly one-third of women with fibroid in the uterus seek medical help. The goal of this analysis is for a better understanding of the mechanisms that relate fibroids to these symptoms and to assess several treatment options, including the application of the gonadotropin-releasing hormone (GnRH) antagonist. We compiled the commonest as well as appropriate studies on the most common symptom of fibroids, as well as medicinal and surgical treatment options. Those who said they used GnRH antagonists orally were probed further. The underlying mechanisms myoma-caused menorrhagia as well as sterility were examined since those have been critical to understand the detailed mechanism as well as the targeted treatment modality. New treatments are determined by the amount, dimension cum localization of fibroids, and the women’s age and also her choice on future childbirth. Myomas have considerable economic consequences with respect to direct expenditure, wage losses, as well as difficulties. In this context, medical, surgical, and nonsurgical techniques were examined. The novelty applied in this research article is the implementation of the GnRH antagonist-based methodology for the removal of fibroids in the uterine layer. The methodology is superior to the existing techniques for the treatment of fibroids in the uterine membrane. Novel medical techniques including GnRH antagonists were investigated and proved to be a viable new option. Alternatives to surgical-surgical modalities are desperately needed, specifically for those who are looking forward for future childbirth. GnRH antagonists have been shown to effectively alleviate the symptoms of fibroids and welcome new techniques for myoma treatment.

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Toader, Despina-Manuela, Ileana Neaca, Alina Paraschiv, and Rodica Musetescu. "The safety of new oral anticoagulants for ischemic stroke and systemic embolism prevention in females with atrial fibrillation." Romanian Journal of Neurology 20, no. 1 (March 31, 2021): 5–14. http://dx.doi.org/10.37897/rjn.2021.1.1.

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The prevalence of atrial fibrillation is lower in females than in men, but the risk of stroke and systemic thromboembolism is comparable or even higher. Administration of anticoagulant therapy does not modify this difference. Two classes of non-vitamin K antagonist oral anticoagulants were studied in atrial fibrillation: direct thrombin inhibitors, like Dabigatran, and activated factor X inhibitors, like Rivaroxaban, Apixaban and Edoxaban. Response to oral anticoagulants could differ between the gender. This medication was evaluated in phase III randomized controlled trials. Non-vitamin K antagonist oral anticoagulants have been proved more efficacious than Warfarin for stroke and systemic embolism prevention in women, but conclusions regarding the safety and the bleeding are heterogeneous. As in men, before prescribing a NOAC to a female with AF, the stroke and the bleeding risk have to be carefully estimated. It is important that future studies to be targeted on comparison between of non-vitamin K antagonist oral anticoagulants versus Warfarin in females with non-valvular atrial fibrillation.

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Morrison, R. Ray, Xing Lin Tan, Catherine Ledent, S. Jamal Mustafa, and Polly A. Hofmann. "Targeted deletion of A2A adenosine receptors attenuates the protective effects of myocardial postconditioning." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 4 (October 2007): H2523—H2529. http://dx.doi.org/10.1152/ajpheart.00612.2007.

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Endogenous adenosine is an important ligand trigger for the cardioprotective effects of postconditioning (POC), yet it is unclear which adenosine receptor subtype is primarily responsible. To evaluate the role of A2A adenosine receptors in POC-induced protection, global ischemia-reperfusion was performed with and without POC in isolated wild-type (WT) and A2A adenosine receptor knockout (A2AKO) mouse hearts. Injury was measured in terms of postischemic functional recovery and release of cardiac troponin I (cTnI). Activation of protective signaling with POC was assessed by Akt and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. In WT hearts, POC improved recovery of postischemic developed pressure in early (81.6 ± 6.4% of preischemic baseline vs. 37.5 ± 5.6% for non-POC WT at 1 min) and late (62.2 ± 4.2% of baseline vs. 45.5 ± 5.3% for non-POC WT at 30 min) reperfusion, reduced cTnI release by 37%, and doubled the phosphorylation of both Akt and ERK1/2. These beneficial effects of POC were blocked by treatment with the selective A2A adenosine receptor antagonist ZM-241385 during reperfusion. Postischemic functional recovery, cTnI release, and phosphorylation of Akt and ERK1/2 were not different between non-POC WT and A2AKO hearts. In A2AKO hearts, POC did not improve functional recovery, reduce cTnI release, nor increase phosphorylation of Akt or ERK1/2. Thus the protective effects of POC are attenuated by both selective A2A receptor antagonism and targeted deletion of the gene encoding A2A adenosine receptors. These observations support the conclusion that endogenous activation of A2A adenosine receptors is an essential trigger leading to the protective effects of POC in isolated murine hearts.

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Zarei, Mehrdad, Rupesh Shrestha, Sneha Johnson, Zuhua Yu, Keshav Karki, Ali Vaziri-Gohar, Jessica Epps, et al. "Nuclear Receptor 4A2 (NR4A2/NURR1) Regulates Autophagy and Chemoresistance in Pancreatic Ductal Adenocarcinoma." Cancer Research Communications 1, no. 2 (November 2021): 65–78. http://dx.doi.org/10.1158/2767-9764.crc-21-0073.

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and chemotherapy with gemcitabine has limited effects and is associated with development of drug resistance. Treatment of Panc1 and MiaPaca2 pancreatic cancer cells with gemcitabine induced expression of the orphan nuclear receptor 4A2 (NURR1) and analysis of The Cancer Genome Atlas indicated the NURR1 is overexpressed in pancreatic tumors and is a negative prognostic factor for patient survival. Results of NURR1 knockdown or treatment with the NURR1 antagonist 1,1-bis(3΄-indolyl)-1-(p-chlorophenyl)methane (C-DIM 12) demonstrated that NURR1 was prooncogenic in pancreatic cancer cells and regulated cancer cell and tumor growth and survival. NURR1 is induced by gemcitabine and serves as a key drug resistance factor and is also required for gemcitabine-induced cytoprotective autophagy. NURR1-regulated genes were determined by RNA sequencing of mRNAs expressed in MiaPaCa2 cells expressing NURR1 and in CRISPR/Cas9 gene–edited cells for NURR1 knockdown and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of the differentially expressed genes showed that autophagy was the major pathway regulated by NURR1. Moreover, NURR1 regulated expression of two major autophagic genes, ATG7 and ATG12, which are also overexpressed in pancreatic tumors and like NURR1 are negative prognostic factors for patient survival. Thus, gemcitabine-induced cytoprotective autophagy is due to the NURR1–ATG7/ATG12 axis and this can be targeted and disrupted by NURR1 antagonist C-DIM12 demonstrating the potential clinical applications for combination therapies with gemcitabine and NURR1 antagonists. Significance: Gemcitabine induces NURR1-dependent ATG7 and ATG12 cytoprotective autophagy in PDA cells that can be reversed by NURR1 antagonists.

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Abe, Toshiharu, Kavita B. Hosur, Evlambia Hajishengallis, Edimara S. Reis, Daniel Ricklin, John D. Lambris, and George Hajishengallis. "Local Complement-Targeted Intervention in Periodontitis: Proof-of-Concept Using a C5a Receptor (CD88) Antagonist." Journal of Immunology 189, no. 11 (October 22, 2012): 5442–48. http://dx.doi.org/10.4049/jimmunol.1202339.

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Kairemo, Kalevi, and Aki Kangasmäki. "Bombesin antagonist based radiotherapy of prostate cancer combined with WST-11 vascular targeted photodynamic therapy." AME Medical Journal 2 (October 2017): 149. http://dx.doi.org/10.21037/amj.2017.09.01.

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Carvalheiro, Manuela, Margarida Ferreira-Silva, Denys Holovanchuk, H. Susana Marinho, João Nuno Moreira, Helena Soares, M. Luisa Corvo, and Maria Eugénia M. Cruz. "Antagonist G-targeted liposomes for improved delivery of anticancer drugs in small cell lung carcinoma." International Journal of Pharmaceutics 612 (January 2022): 121380. http://dx.doi.org/10.1016/j.ijpharm.2021.121380.

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Nucera, Carmelo. "A novel combined targeted therapy with bromodomain antagonist and MEK inhibitor in anaplastic thyroid cancer." Oncotarget 10, no. 7 (January 22, 2019): 686–87. http://dx.doi.org/10.18632/oncotarget.26591.

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Goda, Amira, Abu Siddique, Mohamed Mohyeldin, Nehad Ayoub, and Khalid El Sayed. "The Maxi-K (BK) Channel Antagonist Penitrem A as a Novel Breast Cancer-Targeted Therapeutic." Marine Drugs 16, no. 5 (May 11, 2018): 157. http://dx.doi.org/10.3390/md16050157.

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Kim, Kwanghee, Hanwen Zhang, Stephen La Rosa, Sylvia Jebiwott, Pooja Desai, Simon Kimm, Avigdor Scherz, Joseph A. O'Donoghue, Wolfgang A. Weber, and Jonathan A. Coleman. "Bombesin Antagonist-Based Radiotherapy of Prostate Cancer Combined with WST-11 Vascular Targeted Photodynamic Therapy." Clinical Cancer Research 23, no. 13 (January 20, 2017): 3343–51. http://dx.doi.org/10.1158/1078-0432.ccr-16-2745.

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Chittasupho, Chuda, Kriengsak Lirdprapamongkol, Prartana Kewsuwan, and Narong Sarisuta. "Targeted delivery of doxorubicin to A549 lung cancer cells by CXCR4 antagonist conjugated PLGA nanoparticles." European Journal of Pharmaceutics and Biopharmaceutics 88, no. 2 (October 2014): 529–38. http://dx.doi.org/10.1016/j.ejpb.2014.06.020.

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Journal articles on the topic 'Targeted antagonist'

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