The Inhibitory Effect of Resveratrol from Reynoutria japonica on MNV-1, a Human Norovirus Surrogate.

As a natural nonflavonoid polyphenol compound, resveratrol is the main functional component of Reynoutria japonica and has anti-inflammatory, antioxidant, antiviral, and other physiological activities. In this study, the effect of resveratrol on the viability of RAW264.7 cells was examined, and murine norovirus (MNV-1) was used as a surrogate for human norovirus to evaluate the inhibitory effect of resveratrol. The concentrations of resveratrol resulting in 50% cytotoxicity (CC50) for RAW264.7 cells were 21.32 and 24.97 µg/mL after 24 and 48 h of incubation, respectively, and resveratrol at a concentration lower than the half-effective inhibitory concentration (EC50) could not damage cell DNA. The EC50 of resveratrol on MNV-1 in infected RAW264.7 cells was determined to equal 5.496 µg/mL. After RAW264.7 cells, virus, and a fresh mixture of virus and RAW264.7 cells were treated with resveratrol solution for 1 h (denoted cell pre-treatment, virus pre-treatment, and mixture coprocessing), the RAW264.7 cells obtained after cell pre-treatment exhibited lower virus infection, and MNV-1 obtained after virus pre-treatment and mixture coprocessing showed a decreased infectious capacity. The inhibition ratio of resveratrol on MNV-1 did not significantly differ between the treatments at 4 and 25 °C or among the various pH values except for the lower acidic condition (pH 2). TEM revealed significant changes in the morphology of MNV-1 after treatment with resveratrol, and molecular docking indicated that resveratrol strongly binds to the viral capsid protein of MNV-1. In addition, resveratrol regulated the expression of cytokine that protects against MNV-1 infection. Therefore, at a lower concentration, resveratrol, a natural component from Reynoutria japonica, exerts an inhibitory effect on MNV-1 growth and could be used as a safe additive in food products to improve the nutritional status and control norovirus.

A supramolecular colloidal system based on folate-conjugated ß-cyclodextrin polymer and indocyanine green for enhanced tumor-targeted cell imaging in 2D culture and 3D tumor spheroids.

Indocyanine green (ICG) is an FDA-approved medical diagnostic agent that is widely used as a near-infrared (NIR) fluorescent imaging molecular probe. However, ICG tends to aggregate to form dimers or H-aggregates in water and lacks physical and optical stability, which greatly decreases its absorbance and fluorescence intensity in various applications. Additionally, ICG has no tissue- or tumor-targeting properties, and its structure is not easy to modify, which has further limited its application in cancer diagnosis. In this study, we addressed these challenges by developing a supramolecular colloidal carrier system that targets tumor cells. To this end, we synthesized a water-soluble ß-cyclodextrin (ß-CD) polymer conjugated with folate (FA), denoted PCD-FA, which is capable of forming inclusion complexes with ICG in water through host-guest interactions between the ß-CD moieties and ICG molecules. The inclusion complexes formed by PCD-FA and ICG, called ICG@PCD-FA, dispersed stably in solution as colloidal nanoparticles, greatly improving the physical and optical properties of ICG by preventing ICG dimer formation, where ICG appeared as monomers and even J-aggregates. This resulted in stronger and more stable absorption at a longer wavelength of 900 nm, which may allow for deeper tissue penetration and imaging with reduced interference from biological tissues' autofluorescence. Moreover, ICG@PCD-FA showed a targeting effect on folate receptor-positive (FR+) tumor cells, which specifically highlighted FR+ cells via NIR endoscopic imaging. Notably, ICG@PCD-FA further improved permeation and accumulation in FR+ 3D tumor spheroids. Therefore, this ICG@PCD-FA supramolecular colloidal system may have a great potential for use in tumor NIR imaging and diagnostic applications.

Increased sensitivity for negative emotional images in individuals with problematic pornography use.

Background: Despite the frequent comorbidity of affective and addictive disorders, the significance of affective dysregulation in problematic pornography use (PPU) is commonly disregarded. The objective of this study is to investigate whether individuals with PPU demonstrate increased sensitivity to negative emotional stimuli in comparison to healthy controls (HCs). Methods: Electrophysiological responses were captured via event-related potentials (ERPs) from 27 individuals with PPU and 29 HCs. They completed an oddball task involving the presentation of deviant stimuli in the form of highly negative (HN), moderately negative (MN), and neutral images, with a standard stimulus being a neutral kettle image. To evaluate participants' subjective feelings of valence and arousal, the Self-Assessment Manikin (SAM) was employed. Results: Regarding subjective evaluations, individuals with PPU indicated diminished valence ratings for HN images as opposed to HCs. Concerning electrophysiological assessments, those with PPU manifested elevated N2 amplitudes in response to both HN and MN images when contrasted against neutral images. Additionally, PPU participants displayed an intensified P3 response to HN images in contrast to MN images, a distinction not evident within the HCs. Discussion: These outcomes suggest that individuals with PPU exhibited heightened reactivity toward negative stimuli. This increased sensitivity to negative cues could potentially play a role in the propensity of PPU individuals to resort to pornography as a coping mechanism for managing stress regulation.

Effects of right ventricular remodeling in chronic thromboembolic pulmonary hypertension on the outcomes of balloon pulmonary angioplasty: a 2D-speckle tracking echocardiography study.

BACKGROUND: Balloon pulmonary angioplasty (BPA) improves the prognosis of chronic thromboembolic pulmonary hypertension (CTEPH). Right ventricle (RV) is an important predictor of prognosis in CTEPH patients. 2D-speckle tracking echocardiography (2D-STE) can evaluate RV function. This study aimed to evaluate the effectiveness of BPA in CTEPH patients and to assess the value of 2D-STE in predicting outcomes of BPA. METHODS: A total of 76 patients with CTEPH underwent 354 BPA sessions from January 2017 to October 2022. Responders were defined as those with mean pulmonary artery pressure (mPAP) ≤ 30 mmHg or those showing ≥ 30% decrease in pulmonary vascular resistance (PVR) after the last BPA session, compared to baseline. Logistic regression analysis was performed to identify predictors of BPA efficacy. RESULTS: BPA resulted in a significant decrease in mPAP (from 50.8 ± 10.4 mmHg to 35.5 ± 11.9 mmHg, p < 0.001), PVR (from 888.7 ± 363.5 dyn·s·cm-5 to 545.5 ± 383.8 dyn·s·cm-5, p < 0.001), and eccentricity index (from 1.3 to 1.1, p < 0.001), and a significant increase in RV free wall longitudinal strain (RVFWLS: from 15.7% to 21.0%, p < 0.001). Significant improvement was also observed in the 6-min walking distance (from 385.5 m to 454.5 m, p < 0.001). After adjusting for confounders, multivariate analysis showed that RVFWLS was the only independent predictor of BPA efficacy. The optimal RVFWLS cutoff value for predicting BPA responders was 12%. CONCLUSIONS: BPA was found to reduce pulmonary artery pressure, reverse RV remodeling, and improve exercise capacity. RVFWLS obtained by 2D-STE was an independent predictor of BPA outcomes. Our study may provide a meaningful reference for interventional therapy of CTEPH.

Genome-wide QTL mapping for agronomic traits in the winter wheat cultivar Pindong 34 based on 90K SNP array.

Introduction: Agronomic traits are key components of wheat yield. Exploitation of the major underlying quantitative trait loci (QTLs) can improve the yield potential in wheat breeding. Methods: In this study, we constructed a recombinant inbred line (RIL) population from Mingxian 169 (MX169) and Pindong 34 (PD34) to determine the QTLs for grain length (GL), grain width (GW), grain length-to-width ratio (LWR), plant height (PH), spike length (SL), grain number per spike (GNS), and the thousand grain weight (TGW) across four environments using wheat 90K SNP array. Results: A QTL associated with TGW, i.e., QTGWpd.swust-6BS, was identified on chromosome 6B, which explained approximately 14.1%-16.2% of the phenotypic variation. In addition, eight QTLs associated with GL were detected across six chromosomes in four different test environments. These were QGLpd.swust-1BL, QGLpd.swust-2BL, QGLpd.swust-3BL.1, QGLpd.swust-3BL.2, QGLpd.swust-5DL, QGLpd.swust-6AL, QGLpd.swust-6DL.1, and QGLpd.swust-6DL.2. They accounted for 9.0%-21.3% of the phenotypic variation. Two QTLs, namely, QGWpd.swust-3BS and QGWpd.swust-6DL, were detected for GW on chromosomes 3B and 6D, respectively. These QTLs explained 12.8%-14.6% and 10.8%-15.2% of the phenotypic variation, respectively. In addition, two QTLs, i.e., QLWRpd.swust-7AS.1 and QLWRpd.swust-7AS.2, were detected on chromosome 7A for the grain LWR, which explained 10.9%-11.6% and 11.6%-11.2% of the phenotypic variation, respectively. Another QTL, named QGNSpd-swust-6DS, was discovered on chromosome 6D, which determines the GNS and which accounted for 11.4%-13.8% of the phenotypic variation. Furthermore, five QTLs associated with PH were mapped on chromosomes 2D, 3A, 5A, 6B, and 7B. These QTLs were QPHpd.swust-2DL, QPHpd.swust-3AL, QPHpd.swust-5AL, QPHpd.swust-6BL, and QPHpd.swust-7BS, which accounted for 11.3%-19.3% of the phenotypic variation. Lastly, a QTL named QSLpd.swust-3AL, conferring SL, was detected on chromosome 3A and explained 16.1%-17.6% of the phenotypic variation. All of these QTLs were defined within the physical interval of the Chinese spring reference genome. Discussion: The findings of this study have significant implications for the development of fine genetic maps, for genomic breeding, and for marker-assisted selection to enhance wheat grain yield.

Effect of P. corylifolia on the pharmacokinetic profile of tofacitinib and the underlying mechanism.

This work aimed to explore the mechanisms underlying the interaction of the active furanocoumarins in P. corylifolia on tofacitinib both in vivo and in vitro. The concentration of tofacitinib and its metabolite M8 was determined using UPLC-MS/MS. The peak area ratio of M8 to tofacitinib was calculated to compare the inhibitory ability of furanocoumarin contained in the traditional Chinese medicine P. corylifolia in rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP3A4 (rCYP3A4). We found that bergapten and isopsoralen exhibited more significant inhibitory activity in RLMs than other furanocoumarins. Bergapten and isopsoralen were selected to investigate tofacitinib drug interactions in vitro and in vivo. Thirty rats were randomly allocated into 5 groups (n = 6): control (0.5% CMC-Na), low-dose bergapten (20 mg/kg), high-dose bergapten (50 mg/kg), low-dose isopsoralen (20 mg/kg) and ketoconazole. 10 mg/kg of tofacitinib was orally intervented to each rat and the concentration level of tofacitinib in the rats were determined by UPLC-MS/MS. More imporrantly, the results showed that bergapten and isopsoralen significantly inhibited the metabolism of tofacitinib metabolism. The AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞) and Cmax of tofacitinib increased in varying degrees compared with the control group (all p < 0.05), but CLz/F decreased in varying degrees (p < 0.05) in the different dose bergapten group and isopsoralen group. Bergapten, isopsoralen and tofacitinib exhibit similar binding capacities with CYP3A4 by AutoDock 4.2 software, confirming that they compete for tofacitinib metabolism. P. corylifolia may considerably impact the metabolism of tofacitinib, which can provide essential information for the accurate therapeutic application of tofacitinib.

Nanomaterials in crossroad of autophagy control in human cancers: Amplification of cell death mechanisms.

Cancer is the result of genetic abnormalities that cause normal cells to grow into neoplastic cells. Cancer is characterized by several distinct features, such as uncontrolled cell growth, extensive spreading to other parts of the body, and the ability to resist treatment. The scientists have stressed the development of nanostructures as novel therapeutic options in suppressing cancer, in response to the emergence of resistance to standard medicines. One of the specific mechanisms with dysregulation during cancer is autophagy. Nanomaterials have the ability to specifically carry medications and genes, and they can also enhance the responsiveness of tumor cells to standard therapy while promoting drug sensitivity. The primary mechanism in this process relies on autophagosomes and their fusion with lysosomes to break down the components of the cytoplasm. While autophagy was initially described as a form of cellular demise, it has been demonstrated to play a crucial role in controlling metastasis, proliferation, and treatment resistance in human malignancies. The pharmacokinetic profile of autophagy modulators is poor, despite their development for use in cancer therapy. Consequently, nanoparticles have been developed for the purpose of delivering medications and autophagy modulators selectively and specifically to the cancer process. Furthermore, several categories of nanoparticles have demonstrated the ability to regulate autophagy, which plays a crucial role in defining the biological characteristics and response to therapy of tumor cells.

Cigarette smoking inhibits myoblast regeneration by promoting proteasomal degradation of NPAT protein and hindering cell cycle progression.

Cigarette smoking (CS) causes skeletal muscle dysfunction, leading to sarcopenia and worse prognosis of patients with diverse systemic diseases. Here, we found that CS exposure prevented C2C12 myoblasts proliferation in a dose-dependent manner. Immunoblotting assays verified that CS exposure promoted the expression of cell cycle suppressor protein p21. Furthermore, CS exposure significantly inhibited replication-dependent (RD) histone transcription and caused S phase arrest in the cell cycle during C2C12 proliferation. Mechanistically, CS deregulated the expression levels of Nuclear Protein Ataxia-Telangiectasia Locus (NPAT/p220). Notably, the proteasome inhibitor MG132 was able to reverse the expression of NPAT in myoblasts, implying that the degradation of CS-mediated NPAT is proteasome-dependent. Overexpression of NPAT also rescued the defective proliferation phenotype induced by CS in C2C12 myoblasts. Taken together, we suggest that CS exposure induces NPAT degradation in C2C12 myoblasts and impairs myogenic proliferation through NPAT associated proteasomal-dependent mechanisms. As an application of the proteasome inhibitor MG132 or overexpression of NPAT could reverse the impaired proliferation of myoblasts induced by CS, the recovery of myoblast proliferation may be potential strategies to treat CS-related skeletal muscle dysfunction.

Phosphorylated CPI-17 and MLC2 as Biomarkers of Coronary Artery Spasm-Induced Sudden Cardiac Death.

Coronary artery spasm (CAS) plays an important role in the pathogeneses of various ischemic heart diseases and has gradually become a common cause of life-threatening arrhythmia. The specific molecular mechanism of CAS has not been fully elucidated, nor are there any specific diagnostic markers for the condition. Therefore, this study aimed to examine the specific molecular mechanism underlying CAS, and screen for potential diagnostic markers. To this end, we successfully constructed a rat CAS model and achieved in vitro culture of a human coronary-artery smooth-muscle cell (hCASMC) contraction model. Possible molecular mechanisms by which protein kinase C (PKC) regulated CAS through the C kinase-potentiated protein phosphatase 1 inhibitor of 17 kDa (CPI-17)/myosin II regulatory light chain (MLC2) pathway were studied in vivo and in vitro to screen for potential molecular markers of CAS. We performed hematoxylin and eosin staining, myocardial zymogram, and transmission electron microscopy to determine myocardial and coronary artery injury in CAS rats. Then, using immunohistochemical staining, immunofluorescence staining, and Western blotting, we further demonstrated a potential molecular mechanism by which PKC regulated CAS via the CPI-17/MLC2 pathway. The results showed that membrane translocation of PKCα occurred in the coronary arteries of CAS rats. CPI-17/MLC2 signaling was observably activated in coronary arteries undergoing CAS. In addition, in vitro treatment of hCASMCs with angiotensin II (Ang II) increased PKCα membrane translocation while consistently activating CPI-17/MLC2 signaling. Conversely, GF-109203X and calphostin C, specific inhibitors of PKC, inactivated CPI-17/MLC2 signaling. We also collected the coronary artery tissues from deceased subjects suspected to have died of CAS and measured their levels of phosphorylated CPI-17 (p-CPI-17) and MLC2 (p-MLC2). Immunohistochemical staining was positive for p-CPI-17 and p-MLC2 in the tissues of these subjects. These findings suggest that PKCα induced CAS through the CPI-17/MLC2 pathway; therefore, p-CPI-17 and p-MLC2 could be used as potential markers for CAS. Our data provide novel evidence that therapeutic strategies against PKC or CPI-17/MLC2 signaling might be promising in the treatment of CAS.

Application of benzothiadiazole to Cabernet Gernischt grapes (Vitis vinifera L.) for quality improvement: Effects on aroma metabolism precursors and related genes expression.

Pre-harvest spraying of benzothiadiazole (BTH) can improve the winemaking properties of grapes, especially their aroma compounds and phenolics. Limited research has explored the molecular mechanisms by which BTH influences the accumulation of grape aroma precursors during early grape development. This study investigated the effects and putative molecular mechanisms of applying 0.37 mM BTH through whole-plant spraying on the accumulation of aroma metabolism precursors and gene expression in Cabernet Gernischt grapes during ripening. The results showed that BTH treatment increased the levels of fructose, alanine, aspartate, threonine, myristic acid, myristoleic acid, palmitic acid, ß-cryptoxanthin, norisoprenoids and methoxypyrazines. Contrarily, it decreased the levels of glucose, sucrose, phenylalanine, tyrosine, leucine, valine, glycine, arginine, histidine, total unsaturated fatty acids (particularly linoleic acid), zeaxanthin, lutein, and organic acids. Additionally, BTH upregulated the expression of genes associated with the production and degradation of amino acids, fatty acids, and carotenoids while decreasing the expression of genes involved in the synthesis and degradation of soluble sugars and organic acids. Ten different metabolites, including fumaric acid, were identified as potential biological markers for distinguishing BTH-treated grapes from control grapes. The study demonstrates that BTH treatment had a substantial impact on the concentration and developmental patterns of aroma metabolism precursors. Furthermore, it altered the winemaking characteristics of Cabernet Gernischt grapes by modulating genes associated with the production and breakdown of metabolites.

An unexpected interaction between diabetes and cardiovascular diseases on cognitive function: A cross-sectional study.

OBJECTIVE: Impaired cognitive function in older individuals significantly affects quality of life. The interaction between comorbid diabetes and cardiovascular disease (CVD) and its impact on cognitive impairment remains unclear. METHODS: This study analyzed 2564 subjects from the National Health and Nutrition Examination Survey dataset. Cognitive function was measured using various scores, including CERAD Total Score, CERAD Delayed Recall Score (CDRS), Animal Fluency Total Score, and Digit Symbol Score. Multiple regression models were constructed to explore the relationship between different diseases and cognitive function, considering covariates such as age, sex, education, body mass index, alcohol intake, smoking, physical activity, kidney function, and hypertension. RESULTS: After adjusting for multiple factors, the presence of CVD, diabetes, or both showed a significant negative association with the total cognitive score. The CDRS was associated with both CVD and diabetes. The Digit Symbol score was associated with the presence of CVD, diabetes, or both. No significant differences were found between patients with diabetes and CVD in cognitive test results. An interaction between CVD and diabetes was observed in relation to the CDRS but not in other test scores or the total score. CONCLUSION: The individual impact of each disease on cognitive function was not significant. However, an interaction between CVD and diabetes was found when both diseases coexisted, specifically in relation to delayed learning ability.

Spatiotemporal formation of glands in plants is modulated by MYB-like transcription factors.

About one third of vascular plants develop glandular trichomes, which produce defensive compounds that repel herbivores and act as a natural biofactory for important pharmaceuticals such as artemisinin and cannabinoids. However, only a few regulators of glandular structures have been characterized so far. Here we have identified two closely-related MYB-like genes that redundantly inhibit the formation of glandular cells in tomatoes, and they are named as GLAND CELL REPRESSOR (GCR) 1 and 2. The GCR genes highly express in the apical cells of tomato trichomes, with expression gradually diminishing as the cells transition into glands. The spatiotemporal expression of GCR genes is coordinated by a two-step inhibition process mediated by SlTOE1B and GCRs. Furthermore, we demonstrate that the GCR genes act by suppressing Leafless (LFS), a gene that promotes gland formation. Intriguingly, homologous GCR genes from tobacco and petunia also inhibit gland formation, suggesting that the GCR-mediated repression mechanism likely represents a conserved regulatory pathway for glands across different plant species.

Dysregulation of sphingolipid metabolism in pain.

Pain is a clinical condition that is currently of great concern and is often caused by tissue or nerve damage or occurs as a concomitant symptom of a variety of diseases such as cancer. Severe pain seriously affects the functional status of the body. However, existing pain management programs are not fully satisfactory. Therefore, there is a need to delve deeper into the pathological mechanisms underlying pain generation and to find new targets for drug therapy. Sphingolipids (SLs), as a major component of the bilayer structure of eukaryotic cell membranes, also have powerful signal transduction functions. Sphingolipids are abundant, and their intracellular metabolism constitutes a huge network. Sphingolipids and their various metabolites play significant roles in cell proliferation, differentiation, apoptosis, etc., and have powerful biological activities. The molecules related to sphingolipid metabolism, mainly the core molecule ceramide and the downstream metabolism molecule sphingosine-1-phosphate (S1P), are involved in the specific mechanisms of neurological disorders as well as the onset and progression of various types of pain, and are closely related to a variety of pain-related diseases. Therefore, sphingolipid metabolism can be the focus of research on pain regulation and provide new drug targets and ideas for pain.

Uncoordinated 51-like kinase 1a/b and 2 in fish Megalobrama amblycephala: Molecular cloning, functional characterization, and their potential roles in glucose metabolism.

Uncoordinated (Unc) 51-like kinase (ulk1) and ulk2 are closely involved in autophagy activation, but little is known about their roles in regulating glucose homeostasis. In this study, the genes of ulk1a, ulk1b and ulk2 were cloned and characterized in fish Megalobrama amblycephala. All the three genes shared the approximate N-terminal kinase domain and the C-terminal Atg1-like_tMIT domain structure, while the amino acid sequence identity of them are different between M. amblycephala and other vertebrates. Their transcripts were widely observed in various tissues (brain, muscle, gill, heart, spleen, eye, liver, intestine, abdominal adipose and kidney), but differed in tissue expression patterns. During the glucose tolerance test and the insulin tolerance test, the up-regulated transcriptions of ulk1a, ulk1b and ulk2 were all found despite some differences in the temporal patterns. At the same time, the activities of glycolytic enzymes like hexokinase and phosphofructokinase both showed parallel increases. Furthermore, the feeding of a high-carbohydrate diet decreased the transcriptions of ulk1a, ulk1b and ulk2. Collectively, this study demonstrated that ulk1a, ulk1b and ulk2 in M. amblycephala had similar molecular characterizations, but with different conservation and tissue expression patterns. In addition, ulk1/2 might play important roles in maintaining the glucose homeostasis in fish through regulating the glycolytic pathway.

Association of epicardial fat volume with subclinical myocardial damage in patients with type 2 diabetes mellitus.

Background: In type 2 diabetes mellitus (T2DM) patients, left ventricular systolic dyssynchrony (LVSD) with normal left ventricular ejection fraction (LVEF) and normal myocardial perfusion could referred to as subclinical myocardial damage, which is difficult to diagnose at an early stage. Epicardial adipose tissue, a distinctive heart-specific visceral fat, is closely related to various cardiovascular diseases. The objective of this study was to investigate the correlation between epicardial fat volume (EFV) and subclinical myocardial damage in T2DM patients. Methods: This retrospective cross-sectional study included 117 T2DM patients with normal myocardial perfusion by single photon emission computed tomography-computed tomography (SPECT-CT) and normal LVEF by echocardiography. The study was conducted from January 2018 to December 2022. Patient data were collected through electronic medical records including basic patient information, medical history, laboratory tests, and medication data. The EFV was quantified through a non-contrast CT scan. Quantitative indicators of LVSD including phase standard deviation (PSD) and phase histogram bandwidth (PBW) were obtained through phase analysis of the gated rest myocardial perfusion imaging (MPI). Additionally, 83 healthy individuals at the same time were selected to gain the reference threshold of LVSD indicators (13.1° for PSD and 37.6° for PBW). Univariate and multivariable logistic regression models were performed to analyze factors influencing LVSD. A generalized additive model (GAM) was applied to explore the relationship between EFV and LVSD. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of EFV for LVSD. Results: Among all patients, 32 (27.4%) patients had LVSD. Compared with the non-LVSD group, the body mass index (BMI) and EFV were higher in the LVSD group (25.83±2.66 vs. 23.94±3.13 kg/m2; 142.41±44.17 vs. 108.01±38.24 cm3, respectively, both P<0.05). Multivariate regression analysis revealed that EFV was independently associated with LVSD [odds ratio (OR) =1.19; 95% confidence interval (CI): 1.06-1.34; P=0.003]. Age, BMI, incidence of hypertension, and LVSD were increased with tertiles of EFV (all P<0.05). The GAM indicated a linear association between EFV and LVSD. The ROC curve analysis concluded that the area under the curve (AUC) of EFV for predicting subclinical myocardial damage in T2DM patients was 0.732 (95% CI: 0.633-0.831, P<0.001), with the optimal threshold of 122.26 cm3, sensitivity of 71.9%, and specificity of 69.4%. Conclusions: EFV is an independent risk factor for LVSD in T2DM patients with normal LVEF and normal MPI, which could potentially serve as a novel imaging marker and a potential therapeutic target for subclinical myocardial damage.

Efficacy of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension patients with pulmonary comorbidity.

Background: Balloon pulmonary angioplasty (BPA) is an established treatment for inoperable chronic thromboembolic pulmonary hypertension (CTEPH), but its efficacy in CTEPH patients with a pulmonary comorbidity has not been well-studied. Here, we compared post-BPA outcomes between CTEPH patients with and without chronic pulmonary disease at baseline and analyzed predictors of BPA success. Methods: From August 2017 to October 2022, 62 patients with inoperable CTEPH who underwent BPA were consecutively enrolled and grouped based on the presence of a pulmonary comorbidity at baseline. All patients underwent transthoracic echocardiography, pulmonary function tests, and right heart catheterization. Pre- and post-BPA data were evaluated to identify factors that influence the success of BPA. Results: Among the 62 CTEPH patients, BPA was considered successful in 50 patients and unsuccessful in 12 patients. Responders to BPA had better exercise capacity and right heart function at baseline, but no differences in hemodynamic or respiratory function were detected between the groups. In CTEPH patients with chronic pulmonary disease (n = 14), BPA significantly improved mean pulmonary arterial pressure, pulmonary vascular resistance and right heart function parameters. Only CTEPH patients without chronic pulmonary disease (n = 48) exhibited significant improvement in 6-minute walk distance and respiratory function. Multivariate logistic regression analysis showed that pulmonary comorbidity at baseline was independently associated with the efficacy of BPA. Conclusions: BPA provided significantly improvements in hemodynamics and right heart function in CTEPH patients, independent of pulmonary comorbidity at baseline. However, pulmonary comorbidity can negatively impact post-BPA outcomes.

Low shear stress induces macrophage infiltration and aggravates aneurysm wall inflammation via CCL7/CCR1/TAK1/ NF-κB axis.

BACKGROUND: This study aimed to elucidate the mechanism by which wall shear stress (WSS) influences vascular walls, accounting for the susceptibility of intracranial aneurysms (IAs) to rupture. METHOD: We collected blood samples from the sacs of 24 ruptured and 28 unruptured IAs and analyzed the expression of chemokine CCL7 using enzyme-linked immunosorbent assay (ELISA). Univariate and multivariate logistic regression analyses were employed to assess clinical data, aneurysm morphology, and hemodynamics in both groups. Pearson correlation analysis investigated the relationship between CCL7 expression in aneurysm sac blood and WSS. Additionally, we established a bionic cell parallel plate co-culture shear stress model and a mouse low shear stress (LSS) model. The model was modulated using CCL7 recombinant protein, CCR1 inhibitor, and TAK1 inhibitor. We further evaluated CCL7 expression in endothelial cells and the levels of TAK1, NF-κB, IL-1ß, and TNF-α in macrophages. Subsequently, the intergroup differences in expression were calculated. RESULTS: CCL7 expression was significantly higher in the ruptured group compared to the unruptured group. Hemodynamic analysis indicated that WSS was an independent predictor of the risk of aneurysm rupture. A negative linear correlation was observed between CCL7 expression and WSS. Upon addition of CCL7 recombinant protein, upregulation of CCR1 expression and increased levels of p-TAK1 and p-p65 were observed. Treatment with CCR1 and TAK1 inhibitors reduced inflammatory cytokine expression in macrophages under LSS conditions. Overexpression of TAK1 significantly alleviated the inhibitory effects of CCR1 inhibitors on p-p65 and inflammatory cytokines. CONCLUSION: LSS prompts endothelial cells to secrete CCL7, which, upon binding to the macrophage surface receptor CCR1, stimulates the release of macrophage inflammatory factors via the TAK1/NF-κB signaling pathway. This process exacerbates aneurysm wall inflammation and increases the risk of aneurysm rupture.

3-Monochloropropane-1,2-diol esters induce HepG2 cells necroptosis via CTSB/TFAM/ROS pathway.

3-monochloropropane-1,2-diol esters (3-MCPDE) are toxic substances that form in food thermal processing and have a diverse range of toxicities. In this study, we found that 3-MCPDE triggered necroptosis by RIPK1/RIPK3/MLKL pathway in HepG2 cells. Previous studies have shown that ROS is an important activator of RIPK1 and RIPK3. The data showed that 3-MCPDE induced excessive ROS production through mitochondrial damage. After treatment with ROS inhibitor N-acetylcysteine (NAC), 3-MCPDE-induced necroptosis was relieved. Further, we explored how 3-MCPDE destroys mitochondria. The data suggested that 3-MCPDE induced mitochondrial dysfunction through the CTSB/TFAM pathway. Overall, the results indicated that 3-MCPDE induced necroptosis through CTSB/TFAM/ROS pathway in HepG2 cells. Our study provided a new mechanism for 3-MCPDE hepatotoxicity.

Acceleration Mechanism of Steel Slag Hydration Using THEED.

In this paper, the strength development of a pure steel slag (SS) system with various concentrations of N,N,N',N'-Tetrakis-(2-hydroxyethyl) ethylenediamine (THEED) was investigated. The hydration kinetics, pore structure and microstructure of SS pastes with and without THEED were characterized to underscore the working mechanism of THEED. Results show that THEED additions significantly increase the 3, 7 and 28 days compressive strength of hardened SS pastes. The enhancement effect increases with the dosage of THEED. At a concentration of 2000 ppm, THEED increased the compressive strength by 733%, 665%, and 545% at 3, 7 and 28 days, respectively. It is confirmed that THEED additions improve the hydration degree of SS by accelerating hydration of the aluminum phase (C3A, PDF-38-1429; C12A7, PDF-48-1882) and C2F,( PDF 38-0408) to generate Mc (PDF-41-0219) and Pa (PDF-30-0222) in the presence of CaCO3. Also, the hydration degree of silicates is increased by THEED. In this way, THEED additions refine the pore structure of hardened SS paste by increasing the pore volume with a diameter below 300 nm to achieve enhancement. The chelating effect of THEED results in promoting dissolution of SS, which provides the driving force for accelerating SS hydration.

Sodium sulfite triggered hepatic apoptosis, necroptosis, and pyroptosis by inducing mitochondrial damage in mice and AML-12 cells.

Sodium sulfite (SS) is a biological derivative of the air pollutant sulfur dioxide, and is often used as a food and pharmaceutical additive. Improper or excessive SS exposure in liver cell death. The phenomenon of simultaneous regulation of apoptosis, necroptosis, and pyroptosis is defined as PANoptosis. However, the specific types of programmed cell death (PCD) caused by SS and their interconnections remain unclear. In the present study, C57BL/6 mice were orally administered SS for 30 d, consecutively, to establish an in vivo mouse exposure model. AML-12 cells were treated with SS for 24 h to establish an in vitro exposure model. The results showed that SS-induced mitochondrial reactive oxygen species (mtROS) accumulation activated the BAX/Bcl-2/caspase 3 pathway to trigger apoptosis and RIPK1/RIPK3/p-MLKL to trigger necroptosis. Interestingly, ROS-activated p-MLKL perforated not the cell membrane as well as the lysosomal membrane. We determined that p-MLKL mediates lysosomal membrane permeabilization (LMP), resulting in cathepsin B (CTSB) release. Furthermore, knockdown of MLKL, a CTSB inhibitor (CA074-ME) and an NLRP3 inhibitor (MCC950) alleviated SS-induced pyroptosis. In summary, our study showed that SS induced apoptosis and necroptosis though mtROS accumulation, whereas the activation of p-MLKL mediated NLRP3-dependent pyroptosis by causing CTSB leakage through LMP. This study comprehensively explored the mechanism unerlying SS-induced PCD and provided an experimental basis for p-MLKL as a potential regulatory protein in PANoptosis.