Ultrasound-Responsive Nanocarriers Delivering siRNA and Fe3O4 Nanoparticles Reprogram Macrophages and Inhibit M2 Polarization for Enhanced NSCLC Immunotherapy.

Lung cancer has emerged as the second most common type of malignant tumor worldwide, and it has the highest mortality rate. The overall 5-year survival rate stands at less than 20%, which is primarily related to the limited therapeutic options and the complexity of the tumor immune microenvironment. In the tumor microenvironment, M1 macrophages are known for their tumor-killing capabilities. Although they are less numerous, they play an important role in tumor immunity. Therefore, increasing M1 macrophages' presence is considered a strategy to enhance targeted phagocytosis and antitumor efficacy in nonsmall cell lung cancer (NSCLC). This study introduces the development of folic acid (FA)-conjugated liposomal nanobubbles for precise delivery of PFH, STAT3 siRNA, and Fe3O4 to the tumor microenvironment. These encapsulated PFH liposomal nanobubbles exhibit significant visualization potential and underwent phase transition when exposed to low-intensity focused ultrasound (LIFU). The release of Fe3O4 activates the IRF5 signaling pathway, converting M2-like macrophages to M1. In addition, STAT3 siRNA effectively interrupts the JAK-STAT3 pathway, inhibiting the polarization of M2-like macrophages in tumor-associated macrophages (TAMs). This dual-action therapy facilitates T-cell activation and proliferation, thereby enhancing the immune response against NSCLC.

A molecular mechanism underlies grass carp (Ctenopharyngodon idella) TARBP2 regulating PKR-mediated cell apoptosis.

Interferon-inducible double-stranded RNA-dependent protein kinase (PKR) is one of the key antiviral arms in the innate immune system. The activated PKR performs its antiviral function by inhibiting protein translation and inducing apoptosis. In our previous study, we identified grass carp TARBP2 as an inhibitor of PKR activity, thereby suppressing cell apoptosis. This study aimed to explore the effects of grass carp TARBP2 on PKR activity and cell apoptosis. Grass carp TARBP2 comprises two N-terminal dsRBDs and a C-terminal C4 domain. Subcellular localization analysis conducted in CIK cells revealed that TARBP2-FL (full-length TARBP2), TARBP2-Δ1 (lack of the first dsRBD), and TARBP2-Δ2 (lack of the second dsRBD) are predominantly located in the cytoplasm, while TARBP2-Δ3 (lack of the two dsRBDs) is distributed both in the nucleus and cytoplasm. Colocalization and immunoprecipitation assays confirmed the interaction of TARBP2-FL, TARBP2-Δ1, and TARBP2-Δ2 with PKR, while TARBP2-Δ3 showed no binding. Furthermore, our findings suggested that the inhibitory effect of TARBP2-Δ1 or TARBP2-Δ2 on the PKR-eIF2α pathway is depressed compared to TARBP2-FL. In cell apoptosis assays, it was observed that TARBP2-FL inhibits PKR-mediated cell apoptosis. TARBP2-Δ1 or TARBP2-Δ2 exhibits decreased inhibition to PKR-mediated cell apoptosis, whereas TARBP2-Δ3 nearly completely loses this inhibitory effect. These findings highlight the critical importance of two dsRBDs of TARBP2 in interaction with PKR, as well as in the inhibition of PKR activity, resulting in the suppression of cell apoptosis triggered by prolonged PKR activation.

New insights into evodiamine attenuates IPEC-J2 cells pyroptosis induced by T-2 toxin - Activating Keap1-Nrf2/NF-κB signaling pathway through binding with Keap1.

T-2 toxin (T-2) is a highly toxic mycotoxin with a molecular weight of 466.52 g/mol. Evodiamine (EV), an alkaloid component of Evodia, has anti-inflammation and antioxidant properties. As a receptor of oxidative stress, Keap1 with a molecular weight of 70 kDa, is a molecular switch that controls the Nrf2 signaling pathway. In this paper, the effect of EV on Keap1-Nrf2/NF-κB pathway was investigated. Based on our research outcomes, it was observed that T-2 exposure substantially increased IPEC-J2 cells intracellular ROS levels and MDA accumulation, decreased SOD and CAT activities, disrupted intestinal tight junction (ZO-1, occludin, and claudin-1), and up-regulated pyroptosis-related protein (ASC, NLRP3, caspase-1, GSDMD, IL-1ß, and IL-18). Additionally, EV could bind well with Keap1, the separating it from Nrf2, promoting Nrf2 into the nucleus, enhanced antioxidant enzyme activities, reduced the production of ROS, down-regulated NF-κB expression, alleviated T-2-induced pyroptosis, and restored tight junction protein expression. However, after treatment with the Nrf2 inhibitor ML385, ML385 reversed the protective effect of EV on IPEC-J2 cells. Collectively, EV can activate the Keap1-Nrf2/NF-κB signaling pathway via binding to Keap1, exert anti-inflammatory and antioxidant effects, inhibit the pyroptosis of IPEC-J2 cells triggered by T-2, and retore intestinal barrier function.

Metabolic profiles in gestational diabetes mellitus can reveal novel biomarkers for prediction of adverse neonatal outcomes.

Background: Gestational diabetes mellitus (GDM) significantly affects the fetal metabolic environment, elevating risks of neonatal hypoglycemia and macrosomia. Metabolomics offers promising avenues for early prediction and diagnosis of GDM and associated adverse offspring outcomes. Methods: This study analyzed serum samples from pregnant women diagnosed with GDM at 24 to 28 weeks of gestation using untargeted metabolomics. We monitored the health outcomes of their offspring to explore the correlation between initial serum metabolite profiles and subsequent health outcomes, to uncover the predictive markers for hypoglycemia and macrosomia in these offspring. Results: Out of 200 participants, 154 had normal newborns, 33 had offspring with hypoglycemia, and 19 had offspring with macrosomia. From 448 identified metabolites, 66 showed significant differences in cases of hypoglycemia, and 45 in macrosomia. A panel of serum metabolite biomarkers achieved Area Under the Curve (AUC) values of 0.8712 for predicting hypoglycemia and 0.9434 for macrosomia. Conclusion: The study delineated metabolic disruptions in GDM during 24-28 weeks of gestation and pinpointed biomarkers capable of forecasting adverse neonatal outcomes. These findings could inform GDM management strategies and minimize the incidence of such outcomes.

Gut microbiota-NLRP3 inflammasome crosstalk in metabolic dysfunction-associated steatotic liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with metabolic dysfunction, ranging from hepatic steatosis with or without mild inflammation to nonalcoholic steatohepatitis, which can rapidly progress to liver fibrosis and even liver cancer. In 2023, after several rounds of Delphi surveys, a new consensus recommended renaming NAFLD as metabolic dysfunction-associated steatotic liver disease (MASLD). Ninety-nine percent of NAFLD patients meet the new MASLD criteria related to metabolic cardiovascular risk factors under the "multiple parallel hits" of lipotoxicity, insulin resistance (IR), a proinflammatory diet, and an intestinal microbiota disorder, and previous research on NAFLD remains valid. The NLRP3 inflammasome, a well-known member of the pattern recognition receptor (PRR) family, can be activated by danger signals transmitted by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), as well as cytokines involved in immune and inflammatory responses. The activation of the NLRP3 inflammasome pathway by MASLD triggers the production of the inflammatory cytokines IL-1ß and IL-18. In MASLD, while changes in the composition and metabolites of the intestinal microbiota occur, the disrupted intestinal microbiota can also generate the inflammatory cytokines IL-1ß and IL-18 by damaging the intestinal barrier, negatively regulating the liver on the gut-liver axis, and further aggravating MASLD. Therefore, modulating the gut-microbiota-liver axis through the NLRP3 inflammasome may emerge as a novel therapeutic approach for MASLD patients. In this article, we review the evidence regarding the functions of the NLRP3 inflammasome and the intestinal microbiota in MASLD, as well as their interactions in this disease.

Cross-modal integration of bulk RNA-seq and single-cell RNA sequencing data to reveal T-cell exhaustion in colorectal cancer.

Colorectal cancer (CRC) is a relatively common malignancy clinically and the second leading cause of cancer-related deaths. Recent studies have identified T-cell exhaustion as playing a crucial role in the pathogenesis of CRC. A long-standing challenge in the clinical management of CRC is to understand how T cells function during its progression and metastasis, and whether potential therapeutic targets for CRC treatment can be predicted through T cells. Here, we propose DeepTEX, a multi-omics deep learning approach that integrates cross-model data to investigate the heterogeneity of T-cell exhaustion in CRC. DeepTEX uses a domain adaptation model to align the data distributions from two different modalities and applies a cross-modal knowledge distillation model to predict the heterogeneity of T-cell exhaustion across diverse patients, identifying key functional pathways and genes. DeepTEX offers valuable insights into the application of deep learning in multi-omics, providing crucial data for exploring the stages of T-cell exhaustion associated with CRC and relevant therapeutic targets.

High-dimensional variable selection accounting for heterogeneity in regression coefficients across multiple data sources.

When analyzing data combined from multiple sources (e.g., hospitals, studies), the heterogeneity across different sources must be accounted for. In this paper, we consider high-dimensional linear regression models for integrative data analysis. We propose a new adaptive clustering penalty (ACP) method to simultaneously select variables and cluster source-specific regression coefficients with sub-homogeneity. We show that the estimator based on the ACP method enjoys a strong oracle property under certain regularity conditions. We also develop an efficient algorithm based on the alternating direction method of multipliers (ADMM) for parameter estimation. We conduct simulation studies to compare the performance of the proposed method to three existing methods (a fused LASSO with adjacent fusion, a pairwise fused LASSO, and a multi-directional shrinkage penalty method). Finally, we apply the proposed method to the multi-center Childhood Adenotonsillectomy Trial to identify sub-homogeneity in the treatment effects across different study sites.

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SOLID: minimizing tissue distortion for brain-wide profiling of diverse architectures.

Brain-wide profiling of diverse biological components is fundamental for understanding complex brain pathology. Despite the availability in whole-brain imaging, it is still challenging to conduct multiplexed, brain-wide analysis with current tissue clearing techniques. Here, we propose SOLID, a hydrophobic tissue clearing method that can minimize tissue distortion while offering impressive clearing performance. SOLID achieves high-quality imaging of multi-color labeled mouse brain, and the acquired datasets can be effectively registered to the Allen Brain Atlas via commonly-used algorithms. SOLID enables generation of neural and vascular maps within one mouse brain, as well as tracing of specific neural projections labeled with viruses. SOLID also allows cross-channel investigations of ß-amyloid plaques and neurovascular lesions in the reconstructed all-in-one panorama, providing quantitative insights into structural interactions at different stages of Alzheimer's disease. Altogether, SOLID provides a robust pipeline for whole-brain mapping, which may widen the utility of tissue clearing techniques in diverse neuroscience research.

Reliability of self-reported pubertal development scale for girls in early adolescent: a school population-based study.

OBJECTIVES: The study aimed to evaluate the correlation between self-reported pubertal developmental scale (PDS) and physically assessed Tanner staging by an experienced pediatrician among girls. METHODS: In a school population-based study in Zhongshan, China, we recruited 1,722 girls in grades 1-3 by a multistage stratified cluster random sampling method. Participants completed self-reported PDS questionnaire prior to physical examination. Breast development was evaluated by a female pediatrician combined with ultrasound examination for overweight/obese girls; pubic hair development was evaluated. Otherwise, we tested follicle-stimulating hormone (FSH) and luteinizing hormone (LH) for some participants. RESULTS: We observed a weak association between Tanner-derived composite stage (TDCS) and puberty category scores (PCS) (τ=0.288, p<0.001) among all girls. There was correlation (τ=0.314, p=0.001) between ultrasound-derived composite stage (UDCS) and PCS among overweight/obese girls. Moreover, among overweight/obese girls, PCS was positively correlated with LH (r=0.265, p=0.008), but not FSH (r=0.155, p=0.123), and when the basal LH value was greater than 0.3 mIU/mL, the proportion of PCS stage ≥2 (9/18) was higher than the proportion of TDCS ≥2 (5/18). As for the determination of pubertal onset, when UDCS was used as the gold standard, the specificity of PCS was 0.86 and positive predictive value was 90.00 %. CONCLUSIONS: There was a weak correlation between PCS and TDCS among girls early adolescence. Moreover, among overweight/obese girls, combining hormone values, ultrasonographic stage of breast, and the positive predictive value of PCS, we posit that self-reported PDS might be a more reliable method than TDCS to evaluate pubertal development among overweight/obese girls.

CYP8B1 Catalyzes 12alpha-hydroxylation of C27 Bile Acid: In Vitro Conversion of Dihydroxycoprostanic Acid into Trihydroxycoprostanic Acid.

CYP8B1 is the unique P450 enzyme with sterol 12-oxidation activity, playing an exclusive role in 12α-hydroxylating intermediates along the bile acid (BA) synthesis pathway. Despite the long history of BA metabolism studies, it is unclear whether CYP8B1 catalyzes 12α-hydroxylation of C27 BAs, the key intermediates shuttling between mitochondria and peroxisomes. This work provides robust in vitro evidence that both microsomal and recombinant CYP8B1 enzymes catalyze the 12α-hydroxylation of dihydroxycoprostanic acid (DHCA) into trihydroxycoprostanic acid (THCA). On the one hand, DHCA 12α-hydroxylation reactivity is conservatively detected in liver microsomes of both human and preclinical animals. The reactivity of human tissue fractions conforms well with the selectivity of CYP8B1 mRNA expression, while the contribution of P450 enzymes other than CYP8B1 is excluded by reaction phenotyping in commercial recombinant enzymes. On the other hand, we prepared functional recombinant human CYP8B1 proteins according to a recently published protocol. Titration of the purified CYP8B1 proteins with either C4 (7α-hydroxy-4-cholesten-3-one) or DHCA yields expected blue shifts of the heme Soret peak (type I binding). The recombinant CYP8B1 proteins efficiently catalyze 12α-hydroxylation of both DHCA and C4, with Km of 3.0 and 1.9 µM and kcat of 3.2 and 2.6 min-1, respectively. In summary, the confirmed role of CYP8B1 in 12α-hydroxylation of C27 BAs has furnished the forgotten passageway in the BA synthesis pathway. The present finding might have opened a new window to consider the biology of CYP8B1 in glucolipid metabolism and to evaluate CYP8B1 inhibition as a therapeutic approach of crucial interest for metabolic diseases. Significance Statement Academic community has spent about 90 years interpreting the synthesis of bile acids. However, the 12α-hydroxylation of intermediates catalyzed by CYP8B1 is not completely mapped on the classic pathway, particularly for the C27 bile acids, the pivotal intermediates shuttling between mitochondria and peroxisomes. This work discloses the forgotten 12α-hydroxylation pathway from dihydroxycoprostanic acid into trihydroxycoprostanic acid. The present finding may facilitate evaluating CYP8B1 inhibition as a therapeutic approach of crucial interest for metabolic diseases.

Nanofluidic sensing inspired by the anomalous water dynamics in electrical angstrom-scale channels.

Manipulation of confined water dynamics by voltage keeps great importance for diverse applications. However, limitations on the membrane functions, voltage-control range, and unclear dynamics need to be addressed. Herein, we report an anomalous electrically controlled gating phenomenon on cation-intercalated multi-layer Ti3C2 membranes and reveal the confined water dynamics. The water permeation rate was improved rapidly following the application and rise of voltage and finally reached a maximum rate at 0.9 V. The permeation rate starts to decrease from 0.9 V. Below 0.9 V, the electric field affects the charge and polarity of water molecules and then leads to ordered and denser rearrangement in the two-dimensional (2D) channel to accelerate the permeation rate. Above 0.9 V, with the assistance of metal cations, the surge in current induced aggregation of water molecules into clusters, thereby limiting the water mobility. Based on these findings, a high-performance humidity sensor was developed by simultaneously optimizing the response and recovery speeds through electric manipulation. This work provides flexible strategies in intelligent membrane design and nanofluidic sensing.

Biomaterial Scaffolds for Periodontal Tissue Engineering.

Advanced periodontitis poses a significant threat to oral health, causing extensive damage and loss of both hard and soft periodontal tissues. While traditional therapies such as scaling and root planing can effectively halt the disease's progression, they often fail to fully restore the original architecture and function of periodontal tissues due to the limited capacity for spontaneous regeneration. To address this challenge, periodontal tissue engineering has emerged as a promising approach. This technology centers on the utilization of biomaterial scaffolds, which function as three-dimensional (3D) templates or frameworks, supporting and guiding the regeneration of periodontal tissues, including the periodontal ligament, cementum, alveolar bone, and gingival tissue. These scaffolds mimic the extracellular matrix (ECM) of native periodontal tissues, aiming to foster cell attachment, proliferation, differentiation, and, ultimately, the formation of new, functional periodontal structures. Despite the inherent challenges associated with preclinical testing, the intensification of research on biomaterial scaffolds, coupled with the continuous advancement of fabrication technology, leads us to anticipate a significant expansion in their application for periodontal tissue regeneration. This review comprehensively covers the recent advancements in biomaterial scaffolds engineered specifically for periodontal tissue regeneration, aiming to provide insights into the current state of the field and potential directions for future research.

External fistula internalization - Endoscopic ultrasound guided stent implantation between stomach and fistula in the treatment of refractory pancreatic cutaneous fistula.

Pancreatic cutaneous fistula is a complex condition, making it challenging to achieve favorable outcomes with conservative medical treatment. Surgical interventions often entail surgical risks and postoperative complications. Here, we present a case involving endoscopically guided stent placement between the stomach and the fistula. By internalizing the fistula, patients can potentially remove the external drainage tube, offering a novel endoscopic treatment approach for such cases.

PGD 2 /DP1 axis promotes liver regeneration by secreting Wnt2 in KCs in mice.

BACKGROUND AND AIMS: The liver possesses a remarkable regenerative capacity in response to injuries or viral infections. Various growth factors and cytokines are involved in regulating liver regeneration. Prostaglandin D 2 , a pro-resolution lipid mediator, is the most abundant hepatic prostanoid. However, the role of prostaglandin D 2 in the injury-induced liver regeneration remains unclear. APPROACH AND RESULTS: Two-thirds partial hepatectomy (70% PH), massive hepatectomy (85% resection), and carbon tetrachloride-induced chronic injury were performed in mice to study the mechanisms of live regeneration. Hepatic prostaglandin D 2 production was elevated in mice after PH. Global deletion of D prostanoid receptor (DP) 1, but not DP2, slowed PH-induced liver regeneration in mice, as evidenced by lower liver weight to body weight ratio, less Ki67 + hepatocyte proliferation, and G2/M phase hepatocytes. In addition, DP1 deficiency, specifically in resident KCs, and not in endothelial cells or HSCs, retarded liver regeneration in mice after PH. Conversely, the overexpression of exogenous DP1 in KCs accelerated liver regeneration in mice. Mechanistically, DP1 activation promoted Wnt2 transcription in a PKA/CREB-dependent manner in resident KCs and mediated hepatocyte proliferation through Frizzled8/ß-catenin signaling. Adeno-associated virus vector serotype 8-mediated Frizzled8 knockdown in hepatocytes attenuated accelerated liver regeneration in KC-DP1 transgenic mice after PH. Treatment with the DP1 receptor agonist BW245C promotes PH-induced liver regeneration in mice. CONCLUSIONS: DP1 activation mediates crosstalk between KCs and hepatocytes through Wnt2 and facilitates liver regeneration. Hence, DP1 may serve as a novel therapeutic target in acute and chronic liver diseases.

Cepharanthine triggers ferroptosis through inhibition of NRF2 for robust ER stress against lung cancer.

BACKGROUND: Severe endoplasmic reticulum (ER) stress elicits apoptosis to suppress lung cancer. Our previous research identified that Cepharanthine (CEP), a kind of phytomedicine, possessed powerful anti-cancer efficacy, for which the underlying mechanism was still uncovered. Herein, we investigated how CEP induced ER stress and worked against lung cancer. METHODS: The differential expression genes (DEGs) and enrichment were detected by RNA-sequence. The affinity of CEP and NRF2 was analyzed by cellular thermal shift assay (CETSA) and molecular docking. The function assay of lung cancer cells was measured by western blots, flow cytometry, immunofluorescence staining, and ferroptosis inhibitors. RESULTS: CEP treatment enriched DEGs in ferroptosis and ER stress. Further analysis demonstrated the target was NRF2. In vitro and in vivo experiments showed that CEP induced obvious ferroptosis, as characterized by the elevated iron ions, ROS, COX-2 expression, down-regulation of GPX4, and atrophic mitochondria. Moreover, enhanced Grp78, CHOP expression, ß-amyloid mass, and disappearing parallel stacked structures of ER were observed in CEP group, suggesting ER stress was aroused. CEP exhibited excellent anti-lung cancer efficacy, as evidenced by the increased apoptosis, reduced proliferation, diminished cell stemness, and prominent inhibition of tumor grafts in animal models. Furthermore, the addition of ferroptosis inhibitors weakened CEP-induced ER stress and apoptosis. CONCLUSION: In summary, our findings proved CEP drives ferroptosis through inhibition of NRF2 for induction of robust ER stress, thereby leading to apoptosis and attenuated stemness of lung cancer cells. The current work presents a novel mechanism for the anti-tumor efficacy of the natural compound CEP.

Coordination analysis and evaluation of population, water resources, economy, and ecosystem coupling in the Tuha region of China.

The non-coordination between the socio-economic systems and ecosystems of a region is a crucial obstacle to sustainable development. To reveal the relationships between complex urban systems and achieve the goal of sustainable and coordinated urban development, we constructed a coupling coordination degree model (CCDM) and coupling angle model (CAM) and analyzed the degree of coupling coordination and evolution process among the population, water resources, economy, and ecology (PWEE) system of the Tuha region for 2005-2020. The results indicated that: (1) During 2005-2020, the comprehensive development index (CDI) of the population, water resources and economy subsystems was 0.21-0.65, with the three subsystems portraying an overall increase; the average values of the RSEI at five-year intervals were 0.29, 0.28, 0.28, and 0.26, indicating a downward trend in the environmental quality. (2) The coupling coordination effect of the PWEE system portrayed a low level; the coupling coordination degree (CCD) values were 0.28-0.58, portraying a fluctuating upward trend. The level of CCD increased from low disorder to marginal coordination. (3) The PWEE system's scissor difference reflects large evolutionary characteristics. The ecological support capacity was not observed until the late stage. We conclude that the PWEE composite system of the region is in a stage of disordered development. These findings significantly bolster the theoretical underpinnings of sustainable development studies, offering essential scientific theories and methodological frameworks for crafting sustainable development policies tailored to urban systems in the Tuha region.

Drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.

Background: The present study aimed to investigate the drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics. Research design and methods: A total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects. Results: The weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg-1 day-1 were recommended for patients with schizophrenia weighing 40-95 and 95-120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg-1 day-1 was recommended for those weighing 40-120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg-1 day-1 was recommended for patients with schizophrenia weighing 40-120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg-1 day-1 were recommended for those weighing 40-60 and 60-120 kg, respectively. Conclusion: This is the first investigation of the effects of fluoxetine on aripiprazole via drug-drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

RNA demethylase FTO participates in malignant progression of gastric cancer by regulating SP1-AURKB-ATM pathway.

Gastric cancer (GC) is the 5th most prevalent cancer and the 4th primary cancer-associated mortality globally. As the first identified m6A demethylase for removing RNA methylation modification, fat mass and obesity-associated protein (FTO) plays instrumental roles in cancer development. Therefore, we study the biological functions and oncogenic mechanisms of FTO in GC tumorigenesis and progression. In our study, FTO expression is obviously upregulated in GC tissues and cells. The upregulation of FTO is associated with advanced nerve invasion, tumor size, and LNM, as well as the poor prognosis in GC patients, and promoted GC cell viability, colony formation, migration and invasion. Mechanistically, FTO targeted specificity protein 1 and Aurora Kinase B, resulting in the phosphorylation of ataxia telangiectasia mutated and P38 and dephosphorylation of P53. In conclusion, the m6A demethylase FTO promotes GC tumorigenesis and progression by regulating the SP1-AURKB-ATM pathway, which may highlight the potential of FTO as a diagnostic biomarker for GC patients' therapy response and prognosis.

Non-invasive assessment of proarrhythmic risks associated with isoprenaline and the dietary supplement ingredient synephrine using human induced pluripotent stem cell-derived cardiomyocytes.

Background: There have been conflicting reports about the proarrhythmic risk of p-synephrine (SYN). To address this, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with the microelectrode array (MEA) system have been utilized to assess arrhythmia risks, particularly in the context of adrenomimetic drugs. Aim: This study aims to determine whether MEA recordings from hiPSC-CMs could predict the proarrhythmic risk of adrenomimetic drugs and to investigate the cardiovascular effects and mechanisms of SYN. Materials and methods: We employed MEA recordings to assess the electrophysiological properties of hiPSC-CMs and conducted concentration-response analyses to evaluate the effects of SYN and Isoprenaline (ISO) on beating rate and contractility. A risk scoring system for proarrhythmic risks was established based on hiPSC-CMs in this study. ISO, a classic beta-adrenergic drug, was also evaluated. Furthermore, the study evaluated the risk of SYN and recorded the concentration-response of beating rate, contractility and the change in the presence or absence of selective ß1, ß2 and ß3 adrenergic blockers. Results: Our results suggested that ISO carries a high risk of inducing arrhythmias, aligning with existing literature. SYN caused a 30% prolongation of the field potential duration (FPD) at a concentration of 206.326 µM, a change significantly different from baseline measurements and control treatments. The half maximal effective concentration (EC50) of SYN (3.31 µM) to affect hiPSC-CM beating rate is much higher than that of ISO (18.00 nM). The effect of SYN at an EC50 of 3.31 µM is about ten times more potent in hiPSC-CMs compared to neonatal rat cardiomyocytes (34.12 µM). SYN increased the contractility of cardiomyocytes by 29.97 ± 11.65%, compared to ISO's increase of 50.56 ± 24.15%. ß1 receptor blockers almost eliminated the beating rate increase induced by both ISO and SYN, while neither ß2 nor ß3 blockers had a complete inhibitory effect. Conclusion: The MEA and hiPSC-CM system could effectively predict the risk of adrenomimetic drugs. The study concludes that the proarrhythmia risk of SYN at conventional doses is low. SYN is more sensitive in increasing beating rate and contractility in human cardiomyocytes compared to rats, primarily activating ß1 receptor.