Transcriptome Analysis of Salvia miltiorrhiza under Drought Stress.

Phenolic acids are one of the major secondary metabolites accumulated in Salvia miltiorrhiza with various pharmacological activities. Moderate drought stress can promote the accumulation of phenolic acids in S. miltiorrhiza, while the mechanism remains unclear. Therefore, we performed transcriptome sequencing of S. miltiorrhiza under drought treatment. A total of 47,169 unigenes were successfully annotated in at least one of the six major databases. Key enzyme genes involved in the phenolic acid biosynthetic pathway, including SmPAL, SmC4H, Sm4CL, SmTAT, SmHPPR, SmRAS and SmCYP98A14, were induced. Unigenes annotated as laccase correlated with SmRAS and SmCYP98A14 were analyzed, and seven candidates that may be involved in the key step of SalB biosynthesis by RA were obtained. A total of 15 transcription factors significantly up-regulated at 2 h and 4 h potentially regulating phenolic acid biosynthesis were screened out. TRINITY_DN14213_c0_g1 (AP2/ERF) significantly transactivated the expression of SmC4H and SmRAS, suggesting its role in the regulation of phenolic acid biosynthesis. GO and KEGG enrichment analysis of differential expression genes showed that phenylpropanoid biosynthesis and plant hormone signal transduction were significantly higher. The ABA-dependent pathway is essential for resistance to drought and phenolic acid accumulation. Expression patterns in drought and ABA databases showed that four PYLs respond to both drought and ABA, and three potential SnRK2 family members were annotated and analyzed. The present study presented a comprehensive transcriptome analysis of S. miltiorrhiza affected by drought, which provides a rich source for understanding the molecular mechanism facing abiotic stress in S. miltiorrhiza.

Algorithm as Recommending Source and Persuasive Health Communication: Effects of Source Cues, Language Intensity, and Perceived Issue Involvement.

Algorithms are now playing significant roles in online health information selection and recommendation. A question arises as to when and why people would be persuaded by the content they recommend. We conducted a 4 (recommending source: algorithm, other users, a friend, the CDC) x 2 (language intensity: high vs. low) experiment to find out. Participants (N = 299) were exposed to a health-related public service announcement embedded in a social media post. The results showed that overall, an algorithm induced a similar level of compliance intention compared with other recommending sources. We also found a significant three-way interaction when comparing the effects of the algorithm and the CDC: for individuals with low issue involvement, the algorithm was less persuasive when paired with a message with high language intensity. In contrast, for high-involvement individuals, the algorithm elicited more fear than the CDC when recommending an assertive message, partially leading to more compliance intention.

Prenatal Diagnosis of Placenta Accreta Spectrum Disorders: Deep Learning Radiomics of Pelvic MRI.

BACKGROUND: Diagnostic performance of placenta accreta spectrum (PAS) by prenatal MRI is unsatisfactory. Deep learning radiomics (DLR) has the potential to quantify the MRI features of PAS. PURPOSE: To explore whether DLR from MRI can be used to identify pregnancies with PAS. STUDY TYPE: Retrospective. POPULATION: 324 pregnant women (mean age, 33.3 years) suspected PAS (170 training and 72 validation from institution 1, 82 external validation from institution 2) with clinicopathologically proved PAS (206 PAS, 118 non-PAS). FIELD STRENGTH/SEQUENCE: 3-T, turbo spin-echo T2-weighted images. ASSESSMENT: The DLR features were extracted using the MedicalNet. An MRI-based DLR model incorporating DLR signature, clinical model (different clinical characteristics between PAS and non-PAS groups), and MRI morphologic model (radiologists' binary assessment for the PAS diagnosis) was developed. These models were constructed in the training dataset and then validated in the validation datasets. STATISTICAL TESTS: The Student t-test or Mann-Whitney U, χ2 or Fisher exact test, Kappa, dice similarity coefficient, intraclass correlation coefficients, least absolute shrinkage and selection operator logistic regression, multivariate logistic regression, receiver operating characteristic (ROC) curve, DeLong test, net reclassification improvement (NRI) and integrated discrimination improvement (IDI), calibration curve with Hosmer-Lemeshow test, decision curve analysis (DCA). P < 0.05 indicated a significant difference. RESULTS: The MRI-based DLR model had a higher area under the curve than the clinical model in three datasets (0.880 vs. 0.741, 0.861 vs. 0.772, 0.852 vs. 0.675, respectively) or MRI morphologic model in training and independent validation datasets (0.880 vs. 0.760, 0.861, vs. 0.781, respectively). The NRI and IDI were 0.123 and 0.104, respectively. The Hosmer-Lemeshow test had nonsignificant statistics (P = 0.296 to 0.590). The DCA offered a net benefit at any threshold probability. DATA CONCLUSION: An MRI-based DLR model may show better performance in diagnosing PAS than a clinical or MRI morphologic model. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Biased Dopamine D2 Receptors Exhibit Distinct Intracellular Trafficking Properties and ERK Activation in Different Subcellular Domains.

Biased signaling or functional selectivity refers to the ability of an agonist or receptor to selectively activate a subset of transducers such as G protein and arrestin in the case of G protein-coupled receptors (GPCRs). Although signaling through arrestin has been reported from various GPCRs, only a few studies have examined side-by-side how it differs from signaling via G protein. In this study, two signaling pathways were compared using dopamine D2 receptor (D2R) mutants engineered via the evolutionary tracer method to selectively transduce signals through G protein or arrestin (D2G and D2Arr, respectively). D2G mediated the inhibition of cAMP production and ERK activation in the cytoplasm. D2Arr, in contrast, mediated receptor endocytosis accompanied by arrestin ubiquitination and ERK activation in the nucleus as well as in the cytoplasm. D2Arr-mediated ERK activation occurred in a manner dependent on arrestin3 but not arrestin2, accompanied by the nuclear translocation of arrestin3 via importin1. D2R-mediated ERK activation, which occurred in both the cytosol and nucleus, was limited to the cytosol when cellular arrestin3 was depleted. This finding supports the results obtained with D2Arr and D2G. Taken together, these observations indicate that biased signal transduction pathways activate distinct downstream mechanisms and that the subcellular regions in which they occur could be different when the same effectors are involved. These findings broaden our understanding on the relation between biased receptors and the corresponding downstream signaling, which is critical for elucidating the functional roles of biased pathways.

Myeloid-derived suppressor cells ameliorate corneal alkali burn through IL-10-dependent anti-inflammatory properties.

This study aims to investigate the efficiency and the underlying mechanism of myeloid-derived suppressor cells (MDSCs) in corneal alkali burns (CAB). In the study, CD11b+ Gr-1+ cells from C57BL/6J mice bone marrow were cultured and induced. Cell activity and immunoregulatory function were assessed by flow cytometry in vitro. The optimal strategy of MDSCs therapy was assessed by slit-lamp microscopy, and flow cytometry in vivo. The therapeutic effects of MDSCs and the critical signaling pathway were investigated by hematoxylin-eosin (HE) staining, slit-lamp microscopy, flow cytometry, and immunofluorescence. The expression level of the NLRP3 inflammasome pathway was examined. The crucial biochemical parameters of MDSCs were examined by RNA-seq and qPCR to screen out the key regulators. The mechanism of MDSCs' therapeutic effects was explored using MDSCs with IL-10 knockout/rescue by slit-lamp microscopy, HE staining, and qPCR evaluation. The cell frequencies of macrophages and neutrophils in the cornea were examined by flow cytometry in vivo. The results demonstrated that the induced MDSCs meet the standard of phenotypic and functional characteristics. The treatment of 5 × 105 MDSCs conjunctival injection on alternate days significantly ameliorated the disease development, downregulated the NLRP3 inflammasome pathway, and decreased the cell frequencies of macrophages and neutrophils in vivo significantly. IL-10 was screened out to be the critical factor for MDSCs therapy. The therapeutic effects of MDSCs were impaired largely by IL-10 knock-out and saved by the IL-10 supplement. In conclusion, MDSCs therapy is a promising therapeutic solution for CAB. MDSCs fulfilled immunoregulatory roles for CAB by IL-10-dependent anti-inflammatory properties.

Toxicokinetics of recombinant human fibroblast growth factor 21 for injection in cynomolgus monkey for 3 months.

Introduction: Recombinant human fibroblast growth factor 21 (FGF-21) is a potential therapeutic agent for multiple metabolic diseases. However, little is known about the toxicokinetic characteristics of FGF-21. Methods: In the present study, we investigated the toxicokinetics of FGF-21 delivered via subcutaneous injection in vivo. Twenty cynomolgus monkeys were injected subcutaneously with different doses of FGF-21 for 86 days. Serum samples were collected at eight different time points (0, 0.5, 1.5, 3, 5, 8, 12, and 24 h) on day 1, 37 and 86 for toxicokinetic analysis. The serum concentrations of FGF-21 were measured using a double sandwich Enzyme-linked immunosorbent assay. Blood samples were collected on day 0, 30, 65, and 87 for blood and blood biochemical tests. Necropsy and pathological analysis were performed on d87 and d116 (after recovery for 29 days). Results: The average AUC(0-24h) values of low-dose FGF-21 on d1, d37, and d86 were 5253, 25268, and 60445 µg h/L, and the average AUC(0-24h) values of high-dose FGF-21 on d1, d37, and d86 were 19964, 78999, and 1952821 µg h/L, respectively. Analysis of the blood and blood biochemical indexes showed that prothrombin time and AST content in the high-dose FGF-21 group increased. However, no significant changes in other blood and blood biochemical indexes were observed. The anatomical and pathological results showed that continuous subcutaneous injection of FGF-21 for 86 days did not affect organ weight, the organ coefficient, and histopathology in cynomolgus monkeys. Discussion: Our results have guiding significance for the preclinical research and clinical use of FGF-21.

IL-6/gp130/STAT3 signaling contributed to the activation of the PERK arm of the unfolded protein response in response to chronic ß-adrenergic stimulation.

Prolonged activation of the PERK branch of the unfolded protein response (UPR) promotes cardiomyocytes apoptosis in response to chronic ß-adrenergic stimulation. STAT3 plays a critical role in ß-adrenergic functions in the heart. However, whether STAT3 contributed to ß-adrenoceptor-mediated PERK activation and how ß-adrenergic signaling activates STAT3 remains unclear. This study aimed to investigate whether STAT3-Y705 phosphorylation contributed to the PERK arm activation in cardiomyocytes and if IL-6/gp130 signaling was involved in the chronic ß-AR-stimulation-induced STAT3 and PERK arm activation. We found that the PERK phosphorylation was positively associated with STAT3 activation. Wild-type STAT3 plasmids transfection activated the PERK/eIF2α/ATF4/CHOP pathway in cardiomyocytes while dominant negative Y705F STAT3 plasmids caused no obvious effect on PERK signaling. Stimulation with isoproterenol produced a significant increase in the level of IL-6 in the cardiomyocyte's supernatants, while IL-6 silence inhibited PERK phosphorylation but failed to attenuate STAT3 activation in response to isoproterenol stimulation. Gp130 silence attenuated isoproterenol-induced STAT3 activation and PERK phosphorylation. Inhibiting IL-6/gp130 pathway by bazedoxifene and inhibiting STAT3 by stattic both reversed isoproterenol-induced STAT3-Y705 phosphorylation, ROS production, PERK activation, IRE1α activation, and cardiomyocytes apoptosis in vitro. Bazedoxifene (5 mg/kg/day by oral gavage once a day) exhibited similar effect as carvedilol (10 mg/kg/day by oral gavage once a day) on attenuating chronic isoproterenol (30 mg/kg by abdominal injection once a day, 7 days) induced cardiac systolic dysfunction, cardiac hypertrophy and fibrosis in C57BL/6 mice. Meanwhile, bazedoxifene attenuates isoproterenol-induced STAT3-Y705 phosphorylation, PERK/eIF2α/ATF4/CHOP activation, IRE1α activation, and cardiomyocytes apoptosis to a similar extend as carvedilol in the cardiac tissue of mice. Our results showed that chronic ß-adrenoceptor-mediated stimulation activated the STAT3 and PERK arm of the UPR at least partially via IL-6/gp130 pathway. Bazedoxifene has great potential to be used as an alternative to conventional ß-blockers to attenuate ß-adrenoceptor-mediated maladaptive UPR.

Systematic analysis of the necroptosis index in pan-cancer and classification in discriminating the prognosis and immunotherapy responses of 1716 glioma patients.

Necroptosis is a programmed form of necrotic cell death that serves as a host gatekeeper for defense against invasion by certain pathogens. Previous studies have uncovered the essential role of necroptosis in tumor progression and implied the potential for novel therapies targeting necroptosis. However, no comprehensive analysis of multi-omics data has been conducted to better understand the relationship between necroptosis and tumor. We developed the necroptosis index (NI) to uncover the effect of necroptosis in most cancers. NI not only correlated with clinical characteristics of multiple tumors, but also could influence drug sensitivity in glioma. Based on necroptosis-related differentially expressed genes, the consensus clustering was used to classify glioma patients into two NI subgroups. Then, we revealed NI subgroup I were more sensitive to immunotherapy, particularly anti-PD1 therapy. This new NI-based classification may have prospective predictive factors for prognosis and guide physicians in prioritizing immunotherapy for potential responders.

Integrative analysis to screen novel pyroptosis-related LncRNAs for predicting clinical outcome of glioma and validation in tumor tissue.

BACKGROUND: Pyroptosis, also known as inflammatory necrosis, is a programmed cell death that manifests itself as a continuous swelling of cells until the cell membrane breaks, leading to the liberation of cellular contents, which triggers an intense inflammatory response. Pyroptosis might be a panacea for a variety of cancers, which include immunotherapy and chemotherapy-insensitive tumors such as glioma. Several findings have observed that long non-coding RNAs (lncRNAs) modulate the bio-behavior of tumor cells by binding to RNA, DNA and protein. Nevertheless, there are few studies reporting the effect of lncRNAs in pyroptosis processes in glioma. METHODS: The principal goal of this study was to identify pyroptosis-related lncRNAs (PRLs) utilizing bioinformatic algorithm and to apply PCR techniques for validation in human glioma tissues. The second goal was to establish a prognostic model for predicting the overall survival patients with glioma. Predict algorithm was used to construct prognosis model with good diagnostic precision for potential clinical translation. RESULTS: Noticeably, molecular subtypes categorized by the PRLs were not distinct from any previously published subtypes of glioma. The immune and mutation landscapes were obviously different from previous subtypes of glioma. Analysis of the sensitivity (IC50) of patients to 30 chemotherapeutic agents identified 22 agents as potential therapeutic agents for patients with low riskscores. CONCLUSIONS: We established an exact prognostic model according to the expression profile of PRLs, which may facilitate the assessment of patient prognosis and treatment patterns and could be further applied to clinical.

STAT3 signaling promotes cardiac injury by upregulating NCOA4-mediated ferritinophagy and ferroptosis in high-fat-diet fed mice.

High-fat diet (HFD) intake provokes obesity and cardiac anomalies. Recent studies have found that ferroptosis plays a role in HFD-induced cardiac injury, but the underlying mechanism is largely unclear. Ferritinophagy is an important part of ferroptosis that is regulated by nuclear receptor coactivator 4 (NCOA4). However, the relationship between ferritinophagy and HFD-induced cardiac damage has not been explored. In this study, we found that oleic acid/palmitic acid (OA/PA) increased the level of ferroptotic events including iron and ROS accumulation, upregulation of PTGS2 mRNA and protein levels, reduced SOD and GSH levels, and significant mitochondrial damage in H9C2 cells, which could be reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Intriguingly, we found that the autophagy inhibitor 3-methyladenine mitigated OA/PA-induced ferritin downregulation, iron overload and ferroptosis. OA/PA increased the protein level of NCOA4. Knockdown of NCOA4 by SiRNA partly reversed the reduction in ferritin, mitigated iron overload and lipid peroxidation, and subsequently alleviated OA/PA-induced cell death, indicating that NCOA4-mediated ferritinophagy was required for OA/PA-induced ferroptosis. Furthermore, we demonstrated that NCOA4 was regulated by IL-6/STAT3 signaling. Inhibition or knockdown of STAT3 effectively reduced NCOA4 levels to protect H9C2 cells from ferritinophagy-mediated ferroptosis, whereas STAT3 overexpression by plasmid appeared to increase NCOA4 expression and contribute to classical ferroptotic events. Consistently, phosphorylated STAT3 upregulation, ferritinophagy activation, and ferroptosis induction also occurred in HFD-fed mice and were responsible for HFD-induced cardiac injury. In addition, we found evidence that piperlongumine, a natural compound, effectively reduced phosphorylated STAT3 levels to protect cardiomyocytes from ferritinophagy-mediated ferroptosis both in vitro and in vivo. Based on these findings, we concluded that ferritinophagy-mediated ferroptosis was one of the critical mechanisms contributing to HFD-induced cardiac injury. The STAT3/NCOA4/FTH1 axis might be a novel therapeutic target for the treatment of HFD-induced cardiac injury.

Efficiency and safety of high-power ablation guided by Lesion size index: An ex vivo porcine heart study.

BACKGROUND: Although Lesion size index (LSI) has been reported to highly predict radiofrequency lesion size in vitro, its accuracy in lesion size and steam pop estimation has not been well investigated for every possible scenario. METHODS: Initially, radiofrequency ablations were performed on porcine myocardial slabs at various power, CF, and time settings with blinded LSI. Subsequently, radiofrequency power at 20, 30, 40, 50, and 60 W was applied at CF values of 5, 10, 20, and 30 g to reach target LSIs of 4, 5, 6, and 7. Lesion size and steam pops were recorded for each ablation. RESULTS: Lesion size was positively correlated with LSI regardless of power settings (p < 0.001). The linear correlation coefficients of lesion size and LSI decreased at higher power settings. At high power combined with high CF settings (50 W/20 g), lesion depth and LSI showed an irrelevant correlation (p = 0.7855). High-power ablation shortened ablation time and increased the effect of resistive heating. LSI could predict the risk of steam pops at high-power settings with the optimal threshold of 5.65 (sensitivity, 94.1%; specificity, 46.1%). The ablation depth of the heavy heart was shallower than that of the light heart under similar ablation settings. CONCLUSIONS: LSI could predict radiofrequency lesion size and steam pops at high power settings in vitro, while synchronous high power and high CF should be avoided. Lighter hearts require relatively lower ablation settings to create appropriate ablation depth.

ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury.

Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl2 or elesclomol-CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe-S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.

Exposure to anti-Black Lives Matter movement and obesity of the Black population.

RATIONALE: Black Lives Matter (BLM) is a social movement against systematic injustice and police violence toward Black people whose goal is to ensure their safety and the expression of their culture. As BLM gained momentum, counter-movements emerged, such as All Lives Matter (ALM), White Lives Matter (WLM), and Blue Lives Matter (BlueLM). Because they undermine support for Black people's safety and culture, exposure to stances against BLM can be a race-related stressor. Although the perception of racial discrimination has been associated with negative health outcomes in Black people, it is not clear whether exposure to negative stances on a race-related social issue is associated with worse health outcomes. OBJECTIVE: We investigated whether living in areas of the United States with a high prevalence of negative stances on BLM is associated with worse health outcomes, such as higher body mass index (BMI) and prevalence of obesity. METHODS: We scraped geo-coded tweets (N = 51,020) that contained #BLM, #ALM, #WLM, and #BlueLM from 2014 to 2016. We determined the stances of the tweets on BLM using machine learning algorithms and aggregated stances at the metropolitan or micropolitan statistical area (MMSA) levels. Participants' BMI and obesity status were derived from the 2017 BRFSS SMART data in 76 MMSAs, as compiled by the Centers for Disease Control and Prevention (N = 20,530). RESULTS: After controlling for individual- and regional-level covariates, regional measures of racism and police brutality rate, and baseline BMI in 2014 aggregated on MMSA level, Black people had a higher BMI and prevalence of obesity in areas that showed higher negative stances on BLM. Stances against BLM were positively associated with implicit racism against Black people and can be an acute race-related stressor associated with negative downstream health outcomes. CONCLUSION: Negative societal sentiments around race-related issues may be detrimental to the health outcomes of minority populations.

Personalized Fair Split Learning for Resource-Constrained Internet of Things.

With the flourishing development of the Internet of Things (IoT), federated learning has garnered significant attention as a distributed learning method aimed at preserving the privacy of participant data. However, certain IoT devices, such as sensors, face challenges in effectively employing conventional federated learning approaches due to limited computational and storage resources, which hinder their ability to train complex local models. Additionally, in IoT environments, devices often face problems of data heterogeneity and uneven benefit distribution between them. To address these challenges, a personalized and fair split learning framework is proposed for resource-constrained clients. This framework first adopts a U-shaped structure, dividing the model to enable resource-constrained clients to offload subsets of the foundational model to a central server while retaining personalized model subsets locally to meet the specific personalized requirements of different clients. Furthermore, to ensure fair benefit distribution, a model-aggregation method with optimized aggregation weights is used. This method reasonably allocates model-aggregation weights based on the contributions of clients, thereby achieving collaborative fairness. Experimental results demonstrate that, in three distinct data heterogeneity scenarios, employing personalized training through this framework exhibits higher accuracy compared to existing baseline methods. Simultaneously, the framework ensures collaborative fairness, fostering a more balanced and sustainable cooperation among IoT devices.

Cirsiliol regulates mitophagy in colon cancer cells via STAT3 signaling.

BACKGROUND: Mitophagy is a type of selective autophagy for dysfunctional mitochondria and plays a key role in tumorigenesis and cancer progression. However, whether mitophagy plays a role in colon cancer remains unclear. Cirsiliol is a natural product and has been found to exert anti-cancer effects in multiple tumors. The effects of cirsiliol in the tumorigenesis and progression of colon cancer remain unknown. METHODS: CCK8 assay, plate cloning assay, and cell scratch assay were performed to determine cell viability, colony formation, and wound healing abilities of HCT116 and SW480 cells. JC-1 staining, H2DCFDA staining, and Mito-Tracker Red staining were carried out to evaluate mitochondrial membrane potential (Δψm), intracellular reactive oxygen species (ROS) level, and mitochondrial morphology. Molecular docking technology was utilized to predict interaction of cirsiliol and signal transducer and activator of transcription 3 (STAT3). Immunofluorescence staining was used to measure nuclear translocation of STAT3. The protein levels of phosphorylated STAT3 (Y705), total STAT3, and mitophagy proteins were detected by western blot. RESULTS: In this study, we first found that cirsiliol inhibited cell viability, colony formation, and wound healing abilities of HCT116 and SW480 colon cancer cells. Moreover, cirsiliol suppressed Δψm, increased ROS production, and disrupted mitochondrial morphology via inhibiting the levels of mitophagy proteins including PINK1, Parkin, BNIP3, and FUNDC1. Application of mitophagy activator improved the levels of mitophagy-related proteins, and ameliorated Δψm and ROS levels. According to the result of molecular docking, we found that cirsiliol potentially bound to the SH2 domain of STAT3, the key domain for the functional activation of STAT3. Moreover, it was found that cirsiliol inhibited constitutive and IL­6­induced STAT3 phosphorylation and nuclear translocation by western blot and immunofluorescence analysis. Comparing with cirsiliol group, we found that overexpression of STAT3 restored the expressions of mitophagy proteins. CONCLUSIONS: Cirsiliol targets STAT3 to inhibit colon cancer cell proliferation by regulating mitophagy.

Myocardial protection of S-nitroso-L-cysteine in diabetic cardiomyopathy mice.

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes mellitus that is characterized by aberrant myocardial structure and function and is the primary cause of heart failure and death in diabetic patients. Endothelial dysfunction plays an essential role in diabetes and is associated with an increased risk of cardiovascular events, but its role in DCM is unclear. Previously, we showed that S-nitroso-L-cysteine(CSNO), an endogenous S-nitrosothiol derived from eNOS, inhibited the activity of protein tyrosine phosphatase 1B (PTP1B), a critical negative modulator of insulin signaling. In this study, we reported that CSNO treatment induced cellular insulin-dependent and insulin-independent glucose uptake. In addition, CSNO activated insulin signaling pathway and promoted GLUT4 membrane translocation. CSNO protected cardiomyocytes against high glucose-induced injury by ameliorating excessive autophagy activation, mitochondrial impairment and oxidative stress. Furthermore, nebulized CSNO improved cardiac function and myocardial fibrosis in diabetic mice. These results suggested a potential site for endothelial modulation of insulin sensitivity and energy metabolism in the development of DCM. Data from these studies will not only help us understand the mechanisms of DCM, but also provide new therapeutic options for treatment.

To Explore the Effect of Preoperative Hemodynamic Factors on The Outcome of Pseudolumen After Stanford Type B Aortic Dissection TEVAR Based on Computer Fluid Dynamics.

OBJECTIVE: The preoperative aortic hemodynamic data of patients with Stanford type B aortic dissection were obtained by computer fluid dynamics (CFD). Then we explored the relationship between hemodynamic data and short-term residual pseudolumen after thoracic endovascular aortic repair (TEVAR) and predict the latter through the former. METHODS: We collected the relevant data of 53 patients who underwent TEVAR in our hospital. They were divided into the A group (residual false lumen group) and B group (closed false lumen group), according to whether there was a residual false cavity around the stent recently after TEVAR. Three-dimensional reconstruction and CFD analysis of the thoracic and abdominal aorta was performed by DSCTA before the operation to obtain the aortic wall shear stress (WSS) and maximum blood flow velocity of the true and false lumen at the entrance, middle point of the long axis, and distal decompression port at the peak time of ventricular systolic velocity. Through the statistical analysis, we further studied the predictive value of hemodynamic data for residual pseudolumen. RESULTS: There was no significant difference in age, male, preoperative and postoperative thoracic and abdominal aorta DSCTA interval, history of hypertension, history of diabetes, smoking, Pt and APTT at admission between the two groups (P > 0.05). The blood flow velocity and shear stress at the entrance of the false lumen and the distal decompression port in the two groups were statistically significant (P < 0.05), while the other hemodynamic indexes were not statistically significant (P > 0.05). Binary logistic regression analysis further showed that the shear stress of the false lumen at the level of the distal decompression port (OR = 1.73, P = 0.01) was an independent risk factor for the residual false lumen around the stent in the early stage after TEVAR. The ROC curve analysis showed that the AUC area of the ROC curve corresponding to the shear stress of the false cavity at the level of the distal decompression port was 0.83, the best cross-sectional value was 9.49pa, and the sensitivity and specificity were 84.60% and 72.50%. CONCLUSIONS: The residual pseudolumen after TEVAR is related to the hemodynamic factors in the aorta before TEVAR. Preoperative hemodynamic data also have good predictive value. When the shear stress of the false lumen at the level of the distal decompression port is greater than 9.49pa, the probability of residual false lumen around the stent during the perioperative period significantly increases.

Developing a new treatment for superficial fungal infection using antifungal Collagen-HSAF dressing.

Fungal pathogens are common causes of superficial clinical infection. Their increasing drug resistance gradually makes existing antifungal drugs ineffective. Heat stable antifungal factor (HSAF) is a novel antifungal natural product with a unique structure. However, the application of HSAF has been hampered by very low yield in the current microbial producers and from extremely poor solubility in water and common solvents. In this study, we developed an effective mode of treatment applying HSAF to superficial fungal infections. The marine-derived Lysobacter enzymogenes YC36 contains the HSAF biosynthetic gene cluster, which we activated by the interspecific signaling molecule indole. An efficient extraction strategy was used to significantly improve the purity to 95.3%. Scanning electron microscopy images revealed that the Type I collagen-based HSAF (Col-HSAF) has a transparent appearance and good physical properties, and the in vitro sustained-release effect of HSAF was maintained for more than 2 weeks. The effective therapeutic concentration of Col-HSAF against superficial fungal infection was explored, and Col-HSAF showed good biocompatibility, lower clinical scores, mild histological changes, and antifungal capabilities in animals with Aspergillus fumigatus keratitis and cutaneous candidiasis. In conclusion, Col-HSAF is an antifungal reagent with significant clinical value in the treatment of superficial fungal infections.

MRI-radiomics-clinical-based nomogram for prenatal prediction of the placenta accreta spectrum disorders.

OBJECTIVES: To investigate whether an MRI-radiomics-clinical-based nomogram can be used to prenatal predict the placenta accreta spectrum (PAS) disorders. METHODS: The pelvic MR images and clinical data of 156 pregnant women with pathologic-proved PAS (PAS group) and 115 pregnant women with no PAS (non-PAS group) identified by clinical and prenatal ultrasonic examination were retrospectively collected from two centers. These pregnancies were divided into a training (n = 133), an independent validation (n = 57), and an external validation (n = 81) cohort. Radiomic features were extracted from images of transverse oblique T2-weighted imaging. A radiomics signature was constructed. A nomogram, composed of MRI morphological findings, radiomic features, and prenatal clinical characteristics, was developed. The discrimination and calibration of the nomogram were conducted to assess its performance. RESULTS: A radiomics signature, including three PAS-related features, was associated with the presence of PAS in the three cohorts (p < 0.001 to p = 0.001). An MRI-radiomics-clinical nomogram incorporating radiomics signature, two prenatal clinical features, and two MRI morphological findings was developed, yielding a higher area under the curve (AUC) than that of the MRI morphological-determined PAS in the training cohort (0.89 vs. 0.78; p < 0.001) and external validation cohort (0.87 vs. 0.75; p = 0.003), while a comparable AUC value in the validation cohort (0.91 vs. 0.81; p = 0.09). The calibration was good. CONCLUSIONS: An MRI-radiomics-clinical nomogram had a robust performance in antenatal predicting the PAS in pregnancies. KEY POINTS: • An MRI-radiomics-clinical-based nomogram might serve as an adjunctive approach for the treatment decision-making in pregnancies suspicious of PAS. • The radiomic score provides a mathematical formula that predicts the possibility of PAS by using the MRI data, and pregnant women with PAS had higher radiomic scores than those without PAS.