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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 381-388, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812403

RESUMO

OBJECTIVE: The present study was to evaluate the anti-tumor effects of acidic RNA protein complex (FA-2-b-ß) extracted from the wild edible Qinba mushroom in inducing of apoptosis and immunoregulation of tumor cell. METHODS: Cell proliferation inducing rate of FA-2-b-ß to K562 cell was measured using CCK-8. Apoptosis rate was detected by using flow cytometry. Chronic myeloid leukemia model was developed by tail vein injection/subcutaneous inoculation of K562 cells in NCG mice. The tumor burden of mice was observed. The general condition of the mice was monitored twice daily. The peripherivcal full blood counts of mice was tested daily. RT-qPCR and Western blot was FA-2-b-ß performed to determine involvement of apoptotic-related gene and protenin, Immunofluorescence and immunohistochemistry was used to detected the expression of CD3, CD4 and CD8. RESULTS: The proliferation and apoptosis of K562 cell could be inhibitied and induced by FA-2-b-ß, there was 100% successful in the tumor formation in vivo, after treated by drug for 21 days there were significantly increased peripheral leucocytes, but decreased hemoglobin of mice treated by FA-2-b-ß as compared with those in control group. The CD3, CD4 and CD8 showed positive in mice, and the propotation was imbalance, but it showed reserved after treated by FA-2-b-ß. CONCLUSION: FA-2-b-ß is strong anti-leukemia effect in vitro and in vivo, suggesting the traditional Chinese medicine maybe contribute to the anti-cancer and immunoregulation research.


Assuntos
Agaricales , Leucemia Mielogênica Crônica BCR-ABL Positiva , Animais , Apoptose , Proliferação de Células , Humanos , Células K562 , Camundongos
2.
J Proteomics ; : 104224, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33845180

RESUMO

"Iron prawn" is a condition of severe growth retardation that fishers call. The giant river prawn (Macrobrachium rosenbergii) is a commercially important species contains high protein content and functional nutrients. However, no proteomic information is available for this species. We performed the shotgun 2DLC-MS/MS proteomic analysis of the total protein from "iron prawn". Total 19,758 peptides corresponding to 2613 high-confidence proteins were identified. These proteins range in size from 40 to 70 kDa. KEGG analysis revealed that the largest group consisting total 102 KEGG pathway proteins comparing the "iron prawn" with the normal prawn. Additionally, 7, 11, 1, 6, and 5 commercially important enzymes were found in the eyestalk, liver, muscle, ovary, and testis, respectively. The functions of these differently expressed enzymes include immune system action against pathogens, muscle contraction, digestive system metabolism, cell differentiation, migration, and apoptosis in the severe growth retardation of "iron prawn". Our work provides insight into the understanding of the formation mechanism of "iron prawn".

3.
Anal Chem ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33826298

RESUMO

Enantiomers of various drug molecules have a specific effect on living organisms. Accordingly, developing a sample method for the efficient and rapid recognition of chiral drug enantiomers is of great industrial value and physiological significance. Here, inspired by the structure of ion channels in living organisms, we developed a chiral nanosensor based on an artificial tip-modified nanochannel system that allows efficient selective recognition of chiral drugs. In this system, l-alanine-pillar[5]arenes as selective receptors were introduced on the tip side of conical nanochannels to form an enantioselective "gate". The selective coefficient of our system toward R-propranolol is 4.96, which is higher than the traditional fully modified nanochannels in this work.

4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(4): 351-354, 2021 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-33834463

RESUMO

OBJECTIVE: To detect fusion gene with pathological significance in a patient with refractory and relapsed acute B cell lymphoblastic leukemia (B-ALL) and to explore its laboratory and clinical characteristics. METHODS: Transcriptome sequencing was used to detect potential fusion transcripts. Other laboratory results and clinical data of the patient were also analyzed. RESULTS: The patient was found to harbor TCF3 exon 17-ZNF384 exon 7 in-frame fusion transcript. The minimal residual disease (MRD) has remained positive after multiple chemotherapy protocols including CD19-, CD22- targeted chimeric antigen receptor T cells immunotherapy. The patient eventually achieved complete remission and sustained MRD negativity after allogeneic hemopoietic stem cell transplantation (allo-HSCT). CONCLUSION: Transcriptome sequencing can effectively detect potential fusion genes with clinical significance in leukemia. TCF3-ZNF384 positive B-ALL has unique laboratory and clinical characteristics, may not well respond to chemotherapy and immunotherapy, and is more likely to relapse. Timely allo-HSCT treatment may help such patients to achieve long-term disease-free survival. TCF3-ZNF384 positive B-ALL is not uncommon in pediatric patients but has not been effectively identified.

5.
Langmuir ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849275

RESUMO

The oxygen vacancy caused by ultrathin structures would be introduced into the semiconductor photocatalyst to boost its photocatalytic activity. Herein, ultrathin Bi2O3-Bi2WO6 nanosheet composites have been successfully synthesized via a facile hydrothermal method. Compared to pure Bi2WO6 nanosheets, the Bi2O3-Bi2WO6 nanosheet composites possess abundant oxygen vacancies, which was confirmed by the positron annihilation spectra. The ultrathin Bi2O3-Bi2WO6 nanosheet composites exhibited remarkable photocatalytic degradation performance for oxytetracycline compared with that of pure Bi2WO6 nanosheets. The excellent photocatalytic activities of Bi2O3-Bi2WO6 composites could be attributed to the heterojunction structure and the oxygen vacancies caused by ultrathin structures.

6.
Front Endocrinol (Lausanne) ; 12: 652363, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796080

RESUMO

Somatostatin (SST) and somatostatin receptors (SSTRs) play an important role in the brain and gastrointestinal (GI) system. SST is produced in various organs and cells, and the inhibitory function of somatostatin-containing cells is involved in a range of physiological functions and pathological modifications. The GI system is the largest endocrine organ for digestion and absorption, SST-endocrine cells and neurons in the GI system are a critical effecter to maintain homeostasis via SSTRs 1-5 and co-receptors, while SST-SSTRs are involved in chemo-sensory, mucus, and hormone secretion, motility, inflammation response, itch, and pain via the autocrine, paracrine, endocrine, and exoendocrine pathways. It is also a power inhibitor for tumor cell proliferation, severe inflammation, and post-operation complications, and is a first-line anti-cancer drug in clinical practice. This mini review focuses on the current function of producing SST endocrine cells and local neurons SST-SSTRs in the GI system, discusses new development prognostic markers, phosphate-specific antibodies, and molecular imaging emerging in diagnostics and therapy, and summarizes the mechanism of the SST family in basic research and clinical practice. Understanding of endocrines and neuroendocrines in SST-SSTRs in GI will provide an insight into advanced medicine in basic and clinical research.

7.
Org Lett ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33792341

RESUMO

A base-promoted unprecedented strategy for the regioselective and chemoselective divergent synthesis of highly functionalized aposafranones and their N-oxides has been developed from the [3 + 3] annulation of enaminones with o-fluoronitrobenzenenes. This novel synthetic strategy offers an alternative method for the construction of aposafranones and their N-oxides are meaningful in the fields of both biology and organic synthesis. The established protocol explores the annulation scope of enaminones, and it expands the application of nitro-based cyclization.

8.
CNS Neurosci Ther ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794069

RESUMO

AIMS: At the beginning of spinal cord injury (SCI), the expression of EphB2 on fibroblasts and ephrin-B2 on astrocytes increased simultaneously and their binding triggers the formation of astroglial-fibrotic scars, which represent a barrier to axonal regeneration. In the present study, we sought to suppress scar formation and to promote recovery from SCI by targeting EphB2 in vivo. METHODS: The female rats SCI models were used in vivo experiments by subsequently injecting with EphB2 shRNA lentiviruses. The effect on EphB2 knockdown was evaluated at 14 days after injury. The repair outcomes were evaluated at 3 months by electrophysiological and morphological assessments to regenerated nerve tissue. The EphB2 expression and TGF-ß1 secretion were detected in vitro using a lipopolysaccharides (LPS)-induced astrocyte injury model. RESULTS: RNAi decreased the expression of EphB2 after SCI, which effectively inhibited fibroblasts and astrocytes from aggregating at 14 days. The expression of EphB2 in activated astrocytes, in addition to fibroblasts, was significantly increased after SCI in vivo, in line with upregulated expression of EphB2 and increased secretion of TGF-ß1 in astrocyte culture treated with LPS. Compared to the scramble control, RNAi targeting with EphB2 could promote more nerve regeneration and better myelination. CONCLUSIONS: EphB2 knockdown may effectively inhibit the formation of astroglial-fibrotic scars at the beginning of SCI. It is beneficial to eliminate the barrier of nerve regeneration.

9.
J Ethnopharmacol ; 274: 114046, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33753146

RESUMO

Ethnopharmacological relevance Paeonia lactiflora is a famous Traditional Chinese medicine widely used for immunological regulation. Paeoniflorin, the main component of Paeonia lactiflora, exerts neuroprotective and antidepressant-like effects in rodents. AIM OF THE STUDY: Fibroblast growth factor 2 (FGF-2) is essentially required in the central nervous system as it acts as both a neurotrophic factor and an anti-inflammatory factor participating in the regulation of proliferation, differentiation and apoptosis of neurons in the brain. However, it is unclear whether paeoniflorin could exert antidepressant effects via regulating FGF-2. MATERIALS AND METHODS: In the present study, the effects of paeoniflorin were evaluated in depressive mice induced by the endotoxin lipopolysaccharide (LPS) injection. RESULTS: The results showed that paeoniflorin markedly increased sucrose preference and reduced immobility time in LPS mice, indicating antidepressant effects. Consistent with the results from molecular docking showing paeoniflorin antagonizes TLR4, NF-κB and NLRP3, the biochemical analysis also indicated paeoniflorin inhibited TLR4/NF-κB/NLRP3 signaling, decreased proinflammatory cytokine levels and microglial activation in the hippocampus of LPS induced mice. In addition, the levels of neuronal FGF-2 and the density of dendritic spine were improved by paeoniflorin. More importantly, the FGFR1 inhibitor SU5402 prevented the antidepressant effects of paeoniflorin and blocked the neuroinflammatory and neurogenic regulatory effects of paeoniflorin, indicating that FGF-2/FGFR1 activation was required for the effects of paeoniflorin. CONCLUSION: Taken together, the results demonstrate that paeoniflorin exhibits neuroprotective and antidepressant effects in mice, which may be mediated by activating neuronal FGF-2/FGFR1 signaling via the inhibition of microglial activation in the hippocampus.

10.
Redox Biol ; : 101928, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33722571

RESUMO

Pharmacologic inhibition of PARP is the primary therapeutic strategy for BRCA mutant ovarian cancer. However, most of patients carry wild-type BRCA1/2 with no significant clinical benefits from PARP inhibitors, calling for the needs to further understanding and developing new strategy when employing PARP inhibitors to treat ovarian cancer. Here, we show that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, is partly responsible for the efficacy of PARP inhibitor olaparib. Mechanistically, pharmacological inhibition or genetic deletion of PARP downregulates the expression of cystine transporter SLC7A11 in a p53-dependent manner. Consequently, decreased glutathione biosynthesis caused by SLC7A11 repression promotes lipid peroxidation and ferroptosis. Furthermore, ferroptosis perturbation results in significant resistance to olaparib without affecting DNA damage response, while boosting ferroptosis by ferroptosis inducers (FINs) synergistically sensitizes BRCA-proficient ovarian cancer cells and xenografts to PARP inhibitor. Together, our results reveal a previously unappreciated mechanism coupling ferroptosis to PARP inhibition and suggest the combination of PARP inhibitor and FINs in the treatment of BRCA-proficient ovarian cancer.

11.
mBio ; 12(2)2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758088

RESUMO

In filamentous fungi, 1,8-dihydroxynaphthalene (DHN) melanin is a major component of the extracellular matrix, endowing fungi with environmental tolerance and some pathogenic species with pathogenicity. However, the subcellular location of the melanin biosynthesis pathway components remains obscure. Using the gray mold pathogen Botrytis cinerea, the DHN melanin intermediate scytalone was characterized via phenotypic and chemical analysis of mutants, and the key enzymes participating in melanin synthesis were fused with fluorescent proteins to observe their subcellular localizations. The Δbcscd1 mutant accumulated scytalone in the culture filtrate rather than in mycelium. Excessive scytalone appears to be self-inhibitory to the fungus, leading to repressed sclerotial germination and sporulation in the Δbcscd1 mutant. The BcBRN1/2 enzymes responsible for synthesizing scytalone were localized in endosomes and found to be trafficked to the cell surface, accompanied by the accumulation of BcSCD1 proteins in the cell wall. In contrast, the early-stage melanin synthesis enzymes BcPKS12/13 and BcYGH1 were localized in peroxisomes. Taken together, the results of this study revealed the subcellular distribution of melanin biosynthetic enzymes in B. cinerea, indicating that the encapsulation and externalization of the melanin synthetic enzymes need to be delicately orchestrated to ensure enzymatic efficiency and protect itself from the adverse effect of the toxic intermediate metabolite.IMPORTANCE The devastating gray mold pathogen Botrytis cinerea propagates via melanized conidia and sclerotia. This study reveals that the sclerotial germination of B. cinerea is differentially affected by different enzymes in the melanin synthesis pathway. Using gene knockout mutants and chemical analysis, we found that excessive accumulation of the melanin intermediate scytalone is inhibitory to B. cinerea. Subcellular localization analysis of the melanin synthesis enzymes of B. cinerea suggested two-stage partitioning of the melanogenesis pathway: the intracellular stage involves the steps until the intermediate scytalone was translocated to the cell surface, whereas the extracellular stage comprises all the steps occurring in the wall from scytalone to final melanin formation. These strategies make the fungus avert self-poisoning during melanin production. This study opens avenues for better understanding the mechanisms of secondary metabolite production in filamentous fungi.

12.
Eur J Pharm Sci ; 162: 105815, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33771716

RESUMO

Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor for the treatment of lung cancer patients with T790M-resistant mutations. It is metabolized mainly by the CYP3A4 enzyme. At the same time, it has the potential to induce CYP3A4. In this study, we aimed to estimate the effect of itraconazole (a strong inhibitor of CYP3A4) on the pharmacokinetics of alflutinib. For this aim, a single-center, open-label, single-sequence, two-period trial was designed. The pharmacokinetic parameters of AST2818 and its active metabolite AST5902 were established from blood concentration measurements, and adverse events (AEs) of two periods of treatment were documented. For AST2818, the Cmax, AUC0-t, and AUC0-∞ in period II (coadministration of itraconazole) increased by 6.5 ng/mL, 1263.0 h*ng/mL, and 1067.0 h*ng/mL, respectively. And the corresponding 90% CIs were 1.23 (1.14-1.32), 2.41 (2.29-2.54), and 2.22 (2.11-2.34), respectively. The Cmax, AUC0-t, and AUC0-∞ of AST5902 in period II decreased by 4.849 ng/mL, 415.60 h*ng/mL, and 391.4 h*ng/mL, respectively. Moreover, the corresponding 90% CIs were 0.09 (0.08-0.10), 0.18 (0.17-0.19), and 0.14 (0.13-0.15), respectively. Nonetheless, in period II, plasma concentrations of total active components (AST2818 and AST5902) changed marginally. The AUC0-∞ of total active components increased 60%, and the corresponding Cmax increased 8%. Possible treatment-related AEs assessed by investigators were fewer in period II (23.3% vs 36.7%). In conclusion, the total exposure of AST2818 and active metabolite AST5902 increased following the coadministration of itraconazole, but it was still safe and well-tolerated.

13.
J Med Chem ; 64(6): 3086-3099, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33689340

RESUMO

Apelin-13 is an endogenous peptidic agonist of the apelin receptor (APJ) receptor with the potential for improving cardiac function in heart failure patients. However, the low plasma stability of apelin-13 necessitates continuous intravenous infusion for therapeutic use. There are several approaches to increase the stability of apelin-13 including attachment of pharmacokinetic enhancing groups, stabilized peptides, and Fc-fusion approaches. We sought a small-molecule APJ receptor agonist approach to target a compound with a pharmacokinetic profile amenable for chronic oral administration. This manuscript describes sequential optimization of the pyrimidinone series, leading to pyridinone 14, with in vitro potency equivalent to the endogenous ligand apelin-13 and with an excellent oral bioavailability and PK profile in multiple preclinical species. Compound 14 exhibited robust pharmacodynamic effects similar to apelin-13 in an acute rat pressure-volume loop model and was advanced as a clinical candidate.

14.
J Med Chem ; 64(6): 3131-3152, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33715360

RESUMO

Uveal melanoma is the ocular malignancy and mainly driven by oncogenic mutations of Gαq/11 proteins. Previous targeted therapy for melanoma treatment was limited to specific downstream signaling pathway, and inhibiting the "molecular switches" G proteins for melanoma treatment therapy was rarely described. We herein report the discovery of imidazopiperazine derivatives as Gαq/11 protein inhibitors. The most promising compound GQ127 showed good efficacy and safety in inositol monophosphate (IP1) assay by directly inhibiting Gαq/11 proteins. GQ127 induced uveal melanoma cells apoptosis and displayed potent antitumor activities in uveal melanoma cells viability, migration, and invasion. The effects of GQ127 on Gαq/11 signaling pathway were confirmed by analyzing the downstream effectors yes-associated protein (YAP) and extracellular signal-regulated kinase (ERK). More importantly, GQ127 significantly suppressed UM xenograft growth in mouse model without severe toxicity at the testing dose. These findings provide a lead compound that directly targets the Gαq/11 proteins for uveal melanoma treatment.

15.
J Hazard Mater ; 415: 125605, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33735765

RESUMO

Nickel selenide nanomaterials (NiSe2 NMs) with different vacancies demonstrated high catalytic activity as electrocatalyst in oxygen evolution reaction. As the growing needs of the industrial applications in electrocatalyst, the increased occupational exposure and environmental releasing of NMs would be unavoidable. While, much efforts have been made to evaluate the ecological safety of such engineered NMs at unrealistically high concentrations, failed to provide the comprehensively guideline for exposure thresholds. To supplement the current knowledge gap, we testified the cytotoxicity of NiSe2/rGO nanocomposites with different surface defects under more realistic exposure mode. Compared with the short-term exposure and repetitive exposure, rat lung macrophages exhibited the augmented oxidative stress, dysfunction of mitochondria, damage of DNA and disorder of calcium homeostasis under the long-term NiSe2/rGO exposure. Noteworthily, no significant differences could be found between the NiSe2/rGO with different surface defects, indicated that the defect type of NMs were not the accurate predictor for real risk assessment. Collectively, the study provided the real potential toxic effects and exposure thresholds of NMs that might be highly possible industrial produced, and appealed the new insight for risk assessments of engineered NMs under the long-term exposure, which exhibited difference from the traditional evaluation of short-term and repetitive exposure.

16.
Mol Neurobiol ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723766

RESUMO

Functional and genetic studies have identified association between several Zinc finger (ZNF) proteins and Parkinson's disease (PD). However, most of them were still awaiting further replications, especially in the Asian population. Here, we systematically selected PD-relevant ZNF genes and analyzed the genetic associations between these ZNFs and PD in a large Chinese PD cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated patients with early-onset PD (EOPD, age at onset < 50 years) using whole exome sequencing and evaluated the association between rare variants and EOPD at both allele and gene levels. Totally 91 rare variants were identified in ZNF746, ZNF646, ZNF184, ZNF165, ZND219, and GLIS1. One variant p.R373H in ZNF219 and two variants p.G161D and p.R158H in ZNF746 were significantly associated with EOPD, and gene-based burden analysis showed enrichment of rare variants of ZNF746 in EOPD. Our findings build up the connection between ZNF746 and PD from a genetic perspective for the first time, supplement current understanding for the genetic role of ZNFs in EOPD, and broaden the mutation spectrum in PD.

17.
J Natl Cancer Inst ; 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33705549

RESUMO

BACKGROUND: Accumulated evidence supports the existence of sex-associated differences in immune systems. Understanding the role of sex in immune-related adverse events (irAEs) is important for management of irAE in patients receiving immunotherapy. METHODS: We performed meta-analysis on published clinical study data and multivariable logistic regression on pharmacovigilance data and applied a propensity algorithm to The Cancer Genome Atlas (TCGA) omics data. We further validated our observations in two independent in-house cohorts of 179 and 767 cancer patients treated with immune checkpoint inhibitors. RESULTS: A meta-analysis using 13 clinical studies that reported on 1,096 female patients (36.8%, 95% confidence interval [CI] = 35.0%-38.5%) and 1,886 male patients (63.2%, 95% CI = 61.5%-65.0%) demonstrated no statistically significant irAE risk difference between the sexes (odds ratio [OR] = 1.19; 95% CI = 0.91-1.54; 2-sided P = 0.21). Multivariable logistic regression analysis of 12,225 patients from FAERS and 10,979 patients from VigiBase showed no statistically significant difference in irAEs by sex. A propensity score algorithm used on multi-omics data for 6,019 patients from TCGA found no statistically significant difference by sex for irAE-related factors/pathways. The retrospective analysis of two in-house patient cohorts validated these results (OR = 1.55, 95% CI = 0.98-2.47; FDR = 0.13, for cohort 1; OR = 1.16, 95%CI = 0.86-1.57; FDR = 0.39, for cohort 2). CONCLUSION: We observed minimal sex-associated differences in irAEs among cancer patients who received immune checkpoint inhibitor therapy. It may be unnecessary to consider gender effects for irAE management in clinical practice.

18.
Sci Total Environ ; 777: 145794, 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33676210

RESUMO

Cobalt oxide and porous carbon materials are desirable catalysts for peroxymonosulfate (PMS) advanced oxidation reaction in the degradation of organic pollutants. Herein, carbon-coated Co3O4 (Co3O4/C) mounted biochar (BC) composites (Co3O4/C-BC) with a three-dimensional spongy-like network were constructed by driving a dual-precursors of zeolitic imidazolate framework (ZIF-67) and Eichhornia crassipes. Considering the unique structures and compositions, the Co3O4/C-BC composites enhanced the dispersion of Co3O4/C nanoparticles, minimized the Co leaching, mediated the size of Co3O4/C nanoparticles, and enhanced the overall catalytic activity. Co3O4/C-BC effectively activated PMS for bisphenol A (BPA) degradation along with satisfactory reusability in advanced oxidation reaction. Electron paramagnetic resonance and radical quenching tests revealed that the generation and effect of sulfate and hydroxyl radicals in reaction process. This work not only provided a promising catalyst for the degradation of organic pollutants but also expanded BPA degradation pathway and PMS activation mechanism.

20.
Circ Heart Fail ; 14(3): e007351, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33663236

RESUMO

BACKGROUND: New heart failure therapies that safely augment cardiac contractility and output are needed. Previous apelin peptide studies have highlighted the potential for APJ (apelin receptor) agonism to enhance cardiac function in heart failure. However, apelin's short half-life limits its therapeutic utility. Here, we describe the preclinical characterization of a novel, orally bioavailable APJ agonist, BMS-986224. METHODS: BMS-986224 pharmacology was compared with (Pyr1) apelin-13 using radio ligand binding and signaling pathway assays downstream of APJ (cAMP, phosphorylated ERK [extracellular signal-regulated kinase], bioluminescence resonance energy transfer-based G-protein assays, ß-arrestin recruitment, and receptor internalization). Acute effects on cardiac function were studied in anesthetized instrumented rats. Chronic effects of BMS-986224 were assessed echocardiographically in the RHR (renal hypertensive rat) model of cardiac hypertrophy and decreased cardiac output. RESULTS: BMS-986224 was a potent (Kd=0.3 nmol/L) and selective APJ agonist, exhibiting similar receptor binding and signaling profile to (Pyr1) apelin-13. G-protein signaling assays in human embryonic kidney 293 cells and human cardiomyocytes confirmed this and demonstrated a lack of signaling bias relative to (Pyr1) apelin-13. In anesthetized instrumented rats, short-term BMS-986224 infusion increased cardiac output (10%-15%) without affecting heart rate, which was similar to (Pyr1) apelin-13 but differentiated from dobutamine. Subcutaneous and oral BMS-986224 administration in the RHR model increased stroke volume and cardiac output to levels seen in healthy animals but without preventing cardiac hypertrophy and fibrosis, effects differentiated from enalapril. CONCLUSIONS: We identify a novel, potent, and orally bioavailable nonpeptidic APJ agonist that closely recapitulates the signaling properties of (Pyr1) apelin-13. We show that oral APJ agonist administration induces a sustained increase in cardiac output in the cardiac disease setting and exhibits a differentiated profile from the renin-angiotensin system inhibitor enalapril, supporting further clinical evaluation of BMS-986224 in heart failure.

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