GPR52 is a Gs-coupled G protein-coupled receptor that is predominantly expressed in the striatum and nucleus accumbens (NAc) and was recently proposed as a potential therapeutic target for ...schizophrenia. In the current study, we investigated the in vitro and in vivo pharmacologic activities of a novel GPR52 agonist, 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1
-1,2,4-triazol-1-yl)-2-methylbenzamide (FTBMT). FTBMT functioned as a selective GPR52 agonist in vitro and in vivo, as demonstrated by the activation of Camp signaling in striatal neurons. FTBMT inhibited MK-801-induced hyperactivity, an animal model for acute psychosis, without causing catalepsy in mice. The c-fos expression also revealed that FTBMT preferentially induced neuronal activation in the shell of the Nac compared with the striatum, thereby supporting its antipsychotic-like activity with less catalepsy. Furthermore, FTBMT improved recognition memory in a novel object-recognition test and attenuated MK-801-induced working memory deficits in a radial arm maze test in rats. These recognitive effects were supported by the results of FTBMT-induced c-fos expression in the brain regions related to cognition, including the medial prefrontal cortex, entorhinal cortex, and hippocampus. Taken together, these findings suggest that FTBMT shows antipsychotic and recognitive properties without causing catalepsy in rodents. Given its unique pharmacologic profile, which differs from that of current antipsychotics, FTBMT may provide a new therapeutic option for the treatment of positive and cognitive symptoms of schizophrenia.
Background Transplantation of differentiated cells from human-induced pluripotent stem cells (hiPSCs) holds great promise for clinical treatments. Eliminating the risk factor of malignant cell ...transformation is essential for ensuring the safety of such cells. This study was aimed at assessing and mitigating mutagenicity that may arise during the cell culture process in the protocol of pancreatic islet cell (iPIC) differentiation from hiPSCs. Methods We evaluated the mutagenicity of differentiation factors used for hiPSC-derived pancreatic islet-like cells (iPICs). We employed Ames mutagenicity assay, flow cytometry analysis, immunostaining, time-resolved fluorescence resonance energy transfer-based (TR-FRET) cell-free dose-response assays, single-cell RNA-sequencing and in vivo efficacy study. Results We observed a mutagenic effect of activin receptor-like kinase 5 inhibitor II (ALK5iII). ALK5iII is a widely used beta-cell inducer but no other tested ALK5 inhibitors induced beta-cells. We obtained kinase inhibition profiles and found that only ALK5iII inhibited cyclin-dependent kinases 8 and 19 (CDK8/19) among all ALK5 inhibitors tested. Consistently, CDK8/19 inhibitors efficiently induced beta-cells in the absence of ALK5iII. A combination treatment with non-mutagenic ALK5 inhibitor SB431542 and CDK8/19 inhibitor senexin B afforded generation of iPICs with in vitro cellular composition and in vivo efficacy comparable to those observed with ALK5iII. Conclusion Our findings suggest a new risk mitigation approach for cell therapy and advance our understanding of the beta-cell differentiation mechanism. Keywords: Human-induced pluripotent stem cells, Mutagenicity, Pancreatic islet cell, Activin receptor-like kinase 5 inhibitor II, CDK8/19 inhibitors
Fasiglifam (TAK‐875) is a free fatty acid receptor 1 (FFAR1)/G‐protein–coupled receptor 40 (GPR40) agonist that improves glycemic control in type 2 diabetes with minimum risk of hypoglycemia. ...Fasiglifam potentiates glucose‐stimulated insulin secretion (GSIS) from pancreatic β‐cells glucose dependently, although the precise mechanism underlying the glucose dependency still remains unknown. Here, we investigated key cross‐talk between the GSIS pathway and FFAR1 signaling, and Ca2+ dynamics using mouse insulinoma MIN6 cells. We demonstrated that the glucose‐dependent insulinotropic effect of fasiglifam required membrane depolarization and that fasiglifam induced a glucose‐dependent increase in intracellular Ca2+ level and amplification of Ca2+ oscillations. This differed from the sulfonylurea glimepiride that induced changes in Ca2+ dynamics glucose independently. Stimulation with cell‐permeable analogs of IP3 or diacylglycerol (DAG), downstream second messengers of Gαq‐FFAR1, augmented GSIS similar to fasiglifam, indicating their individual roles in the potentiation of GSIS pathway. Intriguingly, the IP3 analog triggered similar Ca2+ dynamics to fasiglifam, whereas the DAG analog had no effect. Despite the lack of an effect on Ca2+ dynamics, the DAG analog elicited synergistic effects on insulin secretion with Ca2+ influx evoked by an L‐type voltage‐dependent calcium channel opener that mimics glucose‐dependent Ca2+ dynamics. These results indicate that the Gαq signaling activated by fasiglifam enhances GSIS pathway via dual potentiating mechanisms in which IP3 amplifies glucose‐induced Ca2+ oscillations and DAG/protein kinase C (PKC) augments downstream secretory mechanisms independent of Ca2+ oscillations.
Selective free fatty acid receptor 1 (FFAR1)/GPR40 agonist fasiglifam (TAK-875), an antidiabetic drug under phase 3 development, potentiates insulin secretion in a glucose-dependent manner by ...activating FFAR1 expressed in pancreatic beta cells. Although fasiglifam significantly improved glycemic control in type 2 diabetes patients with a minimum risk of hypoglycemia in a phase 2 study, the precise mechanisms of its potent pharmacological effects are not fully understood. Here we demonstrate that fasiglifam acts as an ago-allosteric modulator with a partial agonistic activity for FFAR1. In both Ca2+ influx and insulin secretion assays using cell lines and mouse islets, fasiglifam showed positive cooperativity with the FFAR1 ligand gamma -linolenic acid ( gamma -LA). Augmentation of glucose-induced insulin secretion by fasiglifam, gamma -LA, or their combination was completely abolished in pancreatic islets of FFAR1-knockout mice. In diabetic rats, the insulinotropic effect of fasiglifam was suppressed by pharmacological reduction of plasma free fatty acid (FFA) levels using a lipolysis inhibitor, suggesting that fasiglifam potentiates insulin release in conjunction with plasma FFAs in vivo. Point mutations of FFAR1 differentially affected Ca2+ influx activities of fasiglifam and gamma -LA, further indicating that these agonists may bind to distinct binding sites. Our results strongly suggest that fasiglifam is an ago-allosteric modulator of FFAR1 that exerts its effects by acting cooperatively with endogenous plasma FFAs in human patients as well as diabetic animals. These findings contribute to our understanding of fasiglifam as an attractive antidiabetic drug with a novel mechanism of action.
Objectives
To evaluate the usefulness of deep learning image reconstruction (DLIR) to improve the image quality of dual-energy computed tomography (DECT) of the abdomen, compared to hybrid iterative ...reconstruction (IR).
Methods
This study included 40 patients who underwent contrast-enhanced DECT of the abdomen. Virtual monochromatic 40-, 50-, and 70-keV and iodine density images were reconstructed using three reconstruction algorithms, including hybrid IR (ASiR-V50%) and DLIR (TrueFidelity) at medium- and high-strength level (DLIR-M and DLIR-H, respectively). The standard deviation of attenuation in liver parenchyma was measured as image noise. The contrast-to-noise ratio (CNR) for the portal vein on portal venous phase CT was calculated. The vessel conspicuity and overall image quality were graded on a 5-point scale ranging from 1 (poor) to 5 (excellent). The comparative scale of lesion conspicuity in 47 abdominal solid lesions was evaluated on a 5-point scale ranging from 0 (best) to −4 (markedly inferior).
Results
The image noise of virtual monochromatic 40-, 50 -, and 70-keV and iodine density images was significantly decreased by DLIR compared to hybrid IR (
p
< 0.0001). The CNR was significantly higher in DLIR-H and DLIR-M than in hybrid IR (
p
< 0.0001). The vessel conspicuity and overall image quality scores were also significantly greater in DLIR-H and DLIR-M than in hybrid IR (
p
< 0.05). The lesion conspicuity scores for DLIR-M and DLIR-H were significantly higher than those for hybrid IR in the virtual monochromatic image of all energy levels (
p
≤ 0.001).
Conclusions
DLIR improves vessel conspicuity, CNR, and lesion conspicuity of virtual monochromatic and iodine density images in abdominal contrast-enhanced DECT, compared to hybrid IR.
Key Points
• Deep learning image reconstruction (DLIR) is useful for reducing image noise and improving the CNR of visual monochromatic 40-, 50-, and 70-keV images in dual-energy CT.
• DLIR can improve lesion conspicuity of abdominal solid lesions on virtual monochromatic images compared to hybrid iterative reconstruction.
• DLIR can also be applied to iodine density maps and significantly improves their image quality.
Combined computed tomography–derived myocardial blood flow (CTP-MBF) and computed tomography angiography (CTA) has shown good diagnostic performance for detection of coronary artery disease (CAD). ...However, fractal analysis might provide additional insight into ischemia pathophysiology by characterizing multiscale perfusion patterns and, therefore, may be useful in diagnosing hemodynamically significant CAD.
The purpose of this study was to investigate, in a multicenter setting, whether fractal analysis of perfusion improves detection of hemodynamically relevant CAD over myocardial blood flow quantification (CTP-MBF) using dynamic, 4-dimensional, dynamic stress myocardial computed tomography perfusion (CTP) imaging.
In total, 7 centers participating in the prospective AMPLIFiED (Assessment of Myocardial Perfusion Linked to Infarction and Fibrosis Explored with Dual-source CT) study acquired CTP and CTA data in patients with suspected or known CAD. Hemodynamically relevant CAD was defined as ≥90% stenosis on invasive coronary angiography or fractional flow reserve <0.80. Both fractal analysis and CTP-MBF quantification were performed on CTP images and were combined with CTA results.
This study population included 127 participants, among them 61 patients, or 79 vessels, with CAD as per invasive reference standard. Compared with the combination of CTP-MBF and CTA, combined fractal analysis and CTA improved sensitivity on the per-patient level from 84% (95% CI: 72%-92%) to 95% (95% CI: 86%-99%; P = 0.01) and specificity from 70% (95% CI: 57%-82%) to 89% (95% CI: 78%-96%; P = 0.02). The area under the receiver-operating characteristic curve improved from 0.83 (95% CI: 0.75-0.90) to 0.92 (95% CI: 0.86-0.98; P = 0.01).
Fractal analysis constitutes a quantitative and pathophysiologically meaningful approach to myocardial perfusion analysis using dynamic stress CTP, which improved diagnostic performance over CTP-MBF when combined with anatomical information from CTA.
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Purpose: Pulmonary emphysema may associate with ischemic heart disease through systemic microvascular abnormality as a common pathway. Stress cardiovascular MR (CMR) allows for the assessment of ...global coronary flow reserve (CFR). The purpose of this study was to evaluate the association between the emphysema severity and the multiple MRI parameters in the emphysema patients with known or suspected coronary artery disease (CAD).Methods: A total of 210 patients with known or suspected CAD who underwent both 3.0T CMR including cine CMR, stress and rest perfusion CMR, stress and rest phase-contrast (PC) cine CMR of coronary sinus, and late gadolinium enhancement (LGE) CMR, and lung CT within 6 months were studied. Global CFR, volumes and functions of both ventricles and atria, and presence or absence of myocardial ischemia and infarction were evaluated. Emphysema severity was visually determined on lung CT by Goddard method.Result: Seventy nine (71.0 ± 7.9 years, 75 male) of 210 patients with known or suspected CAD had emphysema on lung CT. Goddard score was significantly correlated with CFR (r = –0.246, P = 0.029), left ventricular end-diastolic volume index (LV EDVI) (r = –0.230, P = 0.041), right ventricular systolic volume index (RV SVI) (r = –0.280, P = 0.012), left atrial (LA) total emptying volume index (r = –0.269, P = 0.017), LA passive emptying volume index (r = –0.309, P = 0.006), LA systolic strain (Es) (r = –0.244, P = 0.030), and LA conduit strain (Ee) (r = –0.285, P = 0.011) in the patients with emphysema. Multiple linear regression analysis revealed LA conduit function was independently associated with emphysema severity as determined by Goddard method (beta = –0.361, P = 0.006).Conclusion: LA conduit function independently associates with emphysema severity in the emphysema patients with known or suspected CAD after adjusting age, sex, smoking, and the CMR indexes including CFR. These findings suggest that impairment of LA function predominantly occurs prior to the reduction of the CFR in the emphysema patients with known or suspected CAD.
PURPOSEThe purposes of this study were to compare global coronary flow reserve (CFR) between patients with idiopathic dilated cardiomyopathy (DCM) and risk-matched controls using cardiac MRI (CMR), ...and to evaluate the relationship between global CFR and CMR left ventricular (LV) parameters. METHODSTwenty-six patients with DCM and 26 risk-matched controls who underwent comprehensive CMR examination, including stress-rest coronary sinus flow measurement by phase contrast (PC) cine CMR were retrospectively studied. LV peak global longitudinal, radial, and circumferential strains (GLS, GRS, and GCS) were determined by feature tracking. RESULTSPatients with DCM had significantly lower global CFR compared with the risk-matched controls (2.87 ± 0.86 vs. 4.03 ± 1.47, P = 0.001). Among the parameters, univariate linear regression analyses revealed significant correlation of global CFR with LV end-diastolic volume index (r = -0.396, P = 0.045), LV mass index (r = -0.461, P = 0.018), GLS (r = -0.558, P = 0.003), and GRS (r = 0.392, P = 0.047). Multiple linear regression analysis revealed GLS as the only independent predictor of global CFR (standardized β = -0.558, P = 0.003). CONCLUSIONGlobal CFR was significantly impaired in patients with idiopathic DCM and independently associated with LV GLS, suggesting that microvascular dysfunction may contribute to deterioration of LV function in patients with idiopathic DCM.
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