An overview of sphingosine-1-phosphate receptor 2: Structure, biological function, and small-molecule modulators.

Over the past decade, there has been a notable increase in research on sphingosine-1-phosphate receptor 2 (S1PR2), which is a type of G-protein-coupled receptor. Upon activation by S1P or other ligands, S1PR2 initiates downstream signaling pathways such as phosphoinositide 3-kinase (PI3K), Mitogen-activated protein kinase (MAPK), Rho/Rho-associated coiled-coil containing kinases (ROCK), and others, contributing to the diverse biological functions of S1PR2 and playing a pivotal role in various physiological processes and disease progressions, such as multiple sclerosis, fibrosis, inflammation, and tumors. Due to the extensive biological functions of S1PR2, many S1PR2 modulators, including agonists and antagonists, have been developed and discovered by pharmaceutical companies (e.g., Novartis and Galapagos NV) and academic medicinal chemists for disease diagnosis and treatment. However, few reviews have been published that comprehensively overview the functions and regulators of S1PR2. Herein, we provide an in-depth review of the advances in the function of S1PR2 and its modulators. We first summarize the structure and biological function of S1PR2 and its pathological role in human diseases. We then focus on the discovery approach, design strategy, development process, and biomedical application of S1PR2 modulators. Additionally, we outline the major challenges and future directions in this field. Our comprehensive review will aid in the discovery and development of more effective and clinically applicable S1PR2 modulators.

Marine Cytotoxin Santacruzamate A Derivatives as Potent HDAC1-3 Inhibitors and Their Synergistic Anti-Leukemia Effects with Venetoclax.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by infiltration of the blood and bone marrow, exhibiting a low remission rate and high recurrence rate. Current research has demonstrated that class I HDAC inhibitors can downregulate anti-apoptotic proteins, leading to apoptosis of AML cells. In the present investigation, we conducted structural modifications of marine cytotoxin Santacruzamate A (SCA), a compound known for its inhibitory activity towards HDACs, resulting in the development of a novel series of potent class I HDACs hydrazide inhibitors. Representative hydrazide-based compound 25c exhibited concentration-dependent induction of apoptosis in AML cells as a single agent. Moreover, 25c exhibited a synergistic anti-AML effect when combined with Venetoclax, a clinical Bcl-2 inhibitor employed in AML therapy. This combination resulted in a more pronounced downregulation of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with a significant upregulation of the pro-apoptotic protein cleaved-caspase3 and the DNA double-strand break biomarker γ-H2AX compared to monotherapy. These results highlighted the potential of 25c as a promising lead compound for AML treatment, particularly when used in combination with Venetoclax.

Copper Nanowires Modified with Graphene Oxide Nanosheets for Simultaneous Voltammetric Determination of Ascorbic Acid, Dopamine and Acetaminophen.

Copper nanowires (Cu NWs) were modified with graphene oxide (GO) nanosheets to obtain a sensor for simultaneous voltammetric determination of ascorbic acid (AA), dopamine (DA) and acetaminophen (AC). The nanocomposite was obtained via sonication, and its structures were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and energy-dispersive X-ray spectroscopy (EDS). The electrochemical oxidation activity of the materials (placed on a glassy carbon electrode) was studied by cyclic voltammetry and differential pulse voltammetry. Due to the synergistic effect of Cu NWs and GO, the specific surface, electrochemical oxidation performance and conductivity are improved when compared to each individual component. The peaks for AA (-0.08 V), DA (+0.16 V), and AC (+0.38 V) are well separated. The sensor has wide linear ranges which are from 1-60 µM, 1-100 µM, and 1-100 µM for AA, DA, and AC, respectively, when operated in the differential pulse voltammetric mode. The detection limits are 50, 410 and 40 nM, respectively. Potential interferences by uric acid (20 µM), glucose (10 mM), NaCl (1 mM), and KCl (1 mM) were tested for AA (1 µΜ), DA (1 µΜ), and AC (1 µΜ) and were found to be insignificant. The method was successfully applied to the quantification of AA, DA, and AC in spiked serum samples.

Using Dual-source Photon-counting Detector CT to Simultaneously Quantify Fat and Iron Content: A Phantom Study.

RATIONALE AND OBJECTIVES: To evaluate the feasibility of using photon-counting detector computed tomography (PCD CT) to simultaneously quantify fat and iron content MATERIALS AND METHODS: Phantoms with pure fat, pure iron and fat-iron deposition were scanned by two tube voltages (120 and 140 kV) and two image quality (IQ) settings (80 and 145). Using an iron-specific three-material decomposition algorithm, virtual noniron (VNI) and virtual iron content (VIC) images were generated at quantum iterative reconstruction (QIR) strength levels 1-4. RESULTS: Significant linear correlations were observed between known fat content (FC) and VNI for pure fat phantoms (r = 0.981-0.999, p < 0.001) and between known iron content (IC) and VIC for pure iron phantoms (r = 0.897-0.975, p < 0.001). In fat-iron phantoms, the measurement for fat content of 5-30% demonstrated good linearity between FC and VNI (r = 0.919-0.990, p < 0.001), and VNI were not affected by 75, 150, and 225 µmol/g iron overload (p = 0.174-0.519). The measurement for iron demonstrated a linear range of 75-225 µmol/g between IC and VIC (r = 0.961-0.994, p < 0.001) and VIC was not confounded by the coexisting 5%, 20%, and 30% fat deposition (p = 0.943-0.999). The Bland-Altman of fat and iron measurements were not significantly different at varying tube voltages and IQ settings (all p > 0.05). No significant difference in VNI and VIC at QIR 1-4. CONCLUSION: PCD CT can accurately and simultaneously quantify fat and iron, including scan parameters with lower radiation dose.

NOX4-derived ROS Regulates Aerobic Glycolysis of Breast Cancer through YAP Pathway.

Background: NOX4 is highly expressed in breast cancer and is closely associated with cell invasion and metastasis. The involvement of NOX4 in glycolysis in breast cancer remains unclear. The aim of this study was to investigate the role and mechanism of NOX4 in glycolysis in breast cancer. Methods: NOX4 expression in breast cancer cells was detected by qRT-PCR and western blotting. siRNAs and plasmids were used to silence or enhance the expression of NOX4. The mRNA and protein expression of HK2, GLUT1, PKM2, LDHA, and YAP was detected by qRT-PCR and western blotting, and the 18F-FDG uptake rate was detected by γ-radiometer. Detection of reactive oxygen species (ROS) in cells was performed using a commercial ROS kit. After transfection, CCK8, EDU and Transwell experiments were conducted to detect cell proliferation and migration ability. MicroPET imaging was used to detect the effects of NOX4 on tumor metabolism. Immunohistochemistry was used to detect the expression of NOX4, glycolytic enzymes HK2, GLUT1, PKM2, LDHA, the proliferation index KI67, and the activation of YAP pathway molecule. Results: In this study, the expression of NOX4 in MDA-MB-231 and MDA-MB-453 was higher than in MCF10A. qRT-PCR and western blotting experiments showed that NOX4 downregulation decreased the expression of glycolytic enzymes HK2, GLUT1, PKM2, LDHA, and 18F-FDG uptake. Conversely, the overexpression of NOX4 enhanced the expression of HK2, GLUT1, PKM2, LDHA, and 18F-FDG uptake. Proliferation and migration experiments showed that after down-regulation of NOX4, cell proliferation and migration ability decreased, while NOX4 overexpression promoted cell proliferation and migration ability. Additionally, ROS content and YAP expression decreased after NOX4 down-regulation, while ROS content and YAP expression increased following NOX4 overexpression, which was reversed by N-acetyl cysteine (NAC), a ROS inhibitor. Furthermore, exposure to NAC and Peptide17, a YAP inhibitor, blocked the increase in glycolytic enzyme expression, and the enhancement of proliferation and migration caused by NOX4 overexpression. In addition, in animal experiments, the results of the MicroPET imaging showed that the glucose metabolism rate of the NOX4 inhibitor group was significantly lower than that of the control group. ROS levels in the NOX4 inhibitor group was lower than that in the control group. Immunohistochemistry showed that the expression of HK2, GLUT1, PKM2, LDHA, KI67, and YAP in the NOX4 knock-down group were decreased. Conclusions: NOX4 affects breast cancer glycolysis through ROS-induced activation of the YAP pathway, further promoting the proliferation and migration of breast cancer cells.

Discordant Metabolic Response on 18F-FDG PET/CT in Synchronous Primary Gastric Lymphoma and Gastric Adenocarcinoma.

ABSTRACT: An 84-year-old man presented with dysphagia for 20 days. The biopsies of the multiple lesions through gastroscopy revealed gastric diffuse large B-cell lymphoma and gastric adenocarcinoma. Staging 18F-FDG PET/CT showed multiple hypermetabolic lesions in the stomach, abdomen, and pelvis. After 4 courses of chemotherapy, except for the lesion of biopsy-proven gastric adenocarcinoma, other hypermetabolic lesions in stomach and other sites returned to normal on posttherapy 18F-FDG PET/CT. This case indicated that 18F-FDG PET/CT can track differential treatment response of synchronous gastric tumors and guide subsequent therapy.

Loss-of-function mutations in the ERF96 gene enhance iron-deficient tolerance in Arabidopsis.

Iron is an essential micronutrient for plant growth and development. Here we provide evidence for a role of ERF96 in iron-deficiency response in Arabidopsis thaliana. The ERF96-loss-of-function mutants were found to be more tolerant to iron-deficiency stress than wild type (WT) and to have higher iron and chlorophyll content. Further studies showed that the transcriptional levels of iron-uptake related genes IRT1, FRO2, AHA2, FIT and bHLH38 in mutants were significantly higher than in WT under iron deficiency. Comparative transcriptome analysis suggested that the differentially expressed genes (DEGs) between ERF96-loss-of-function mutant and WT under iron deficiency were mainly enriched in iron uptake and chlorophyll degradation. According to the specific analysis of these two kinds of DEGs, the expression of iron uptake and transport related genes in ERF96-loss-of-function mutant was higher and the expression of chlorophyll degradation related genes was lower under iron deficiency. Furthermore, loss-of-function of ERF96 influenced the plant hormone, especially auxin and ethylene signal transduction. Altogether, our results demonstrate that loss-of-function of ERF96 increased Fe uptake and chlorophyll level through ethylene and auxin signal pathway in the regulation of iron-deficiency response in Arabidopsis.

Distinct Brain Dynamic Functional Connectivity Patterns in Schizophrenia Patients With and Without Auditory Verbal Hallucinations.

Schizophrenia patients with auditory verbal hallucinations (AVHs) are diseased groups of serious psychosis with still unknown etiology. The aim of this research was to identify the neurophysiological correlates of auditory verbal hallucinations. Revealing the neural correlates of auditory hallucination is not merely of great clinical significance, but it is also quite essential to study the pathophysiological correlates of schizophrenia. In this study, 25 Schizophrenia patients with AVHs (AVHs group, 23.2 ± 5.35 years), 52 Schizophrenia patients without AVHs (non-AVHs group, 25.79 ± 5.63 years) and 28 healthy subjects (NC group, 26.14 ± 5.45 years) were enrolled. Dynamic functional connectivity was studied with a sliding-window method and functional connectivity states were then obtained with the k-means clustering algorithm in the three groups. We found that schizophrenia patients with AVHs were characterized by significant decreased static functional connectivity and enhanced variability of dynamic functional connectivity (non-parametric permutation test, Bonferroni correction, p < 0.05). In addition, the AVHs group also demonstrated increased number of brain states, suggesting brain dynamics enhanced in these patients compared with the non-AVHs group. Our findings suggested that there were abnormalities in the connection of brain language regions in auditory verbal hallucinations. It appears that the interruption of connectivity from the language region might be critical to the pathological basis of AVHs.