Activation of Kir2.1 improves myocardial fibrosis by inhibiting Ca 2+ overload and the TGF-ß1/Smad signaling pathway.

The inwardly rectifying potassium channel Kir2.1 is closely associated with many cardiovascular diseases. However, the effect and mechanism of Kir2.1 in diabetic cardiomyopathy remain unclear. In vivo, we use STZ to establish the model, and ventricular structural changes, myocardial inflammatory infiltration, and myocardial fibrosis severity are detected by echocardiography, histological staining, immunohistochemistry, and western blot analysis, respectively. In vitro, a myocardial fibrosis model is established with high glucose. The Kir2.1 current amplitude, intracellular calcium concentration, fibrosis-related proteins, and TGF-ß1/Smad pathway proteins are detected by whole-cell patch clamp, calcium probes, western blot analysis, and immunofluorescence, respectively. The in vivo results show that compared to diabetic cardiomyopathy, zacopride (a Kir2.1 selective agonist) significantly reduces the left ventricular systolic diameter and diastolic diameter, increases the left ventricular ejection fraction and left ventricular short-axis shortening, improves the degree of cell necrosis, and reduces the expression of myocardial interstitial fibrosis protein and collagen fibre deposition area. The in vitro results show that the current amplitude and protein expression of Kir2.1 are both decreased in the high glucose-induced myocardial fibrosis model. Additionally, zacopride significantly upregulates the expression of Kir2.1 and inhibits the expressions of the fibrosis-related proteins α-SMA, collagen I, and collagen III. Activation of Kir2.1 reduces the intracellular calcium concentration and inhibits the protein expressions of TGF-ß1 and p-Smad 2/3. Activation of Kir2.1 can improve myocardial fibrosis induced by diabetic cardiomyopathy, and the possible mechanism may be related to inhibiting Ca 2+ overload and the TGF-ß1/Smad signaling pathway.

Period 2 Suppresses the Malignant Cellular Behaviors of Colorectal Cancer Through the Epithelial-Mesenchymal Transformation Process.

INTRODUCTION: The PER2 (Period circadian regulator 2) gene is related to the circadian clock, and it has been deemed as a suppressor gene in osteosarcoma and lung carcinoma. However, the part of PER2 in CRC (colorectal cancer) needs to be further determined. METHODS: First, we collected clinical samples to detect PER2 expression in CRC. Then, we used cell transfection to knock down PER2 expression in CRC cell lines and performed a series of functional experiments to elucidate the effects of PER2 on CRC cells. We next verified whether PER2 affects the epithelial-mesenchymal transformation (EMT) process in CRC by conducting quantitative real-time PCR and western blotting. RESULTS: In the research, we revealed that the expression of PER2 decreased in CRC clinical samples. In addition, knocking down PER2 expression caused CRC cells to acquire malignant biological features. Finally, we found that PER2 knockdown may activate the Snail/Slug axis through inhibiting p53, therefore promote the activation of the EMT pathway. CONCLUSION: In conclusion, low PER2 expression reinforces migration and activates EMT in CRC, suggesting that PER2 is closely related to CRC development and could be used as a potential treatment site in the clinic.

Three-dimensional speckle tracking echocardiography to evaluate left ventricular function in patients with acute ST-segment elevation myocardial infarction after percutaneous coronary intervention following Tongxinluo treatment.

OBJECTIVE: Bying comparing the correlation between three-dimensional speckle tracking echocardiography (3D-STE) and troponin I (cTn I), three-dimensional left ventricular ejection fraction (3D-LVEF), to explore the 3D-STE to evaluate the left ventricle of patients with acute ST-segment elevation myocardial infarction (AMI) after percutaneous coronary intervention (PCI) following routine treatment with Tongxinluo drugs. METHODS: Altogether, 61 patients with AMI and 30 healthy adults were selected, and the patients were divided into the routine group and the Tongxinluo group. The serum creatine kinase isoenzyme (CK-MB) and troponin I (cTn I) levels were detected in all patients after admission. All patients underwent PCI, and routine echocardiography and 3D-STE assessments were performed for each group 72 h after PCI and 12 months after PCI to obtain the following left ventricular-related functional parameters: left ventricular end-diastolic diameter (LVEDD), end-ventricular septal end-diastolic thickness (IVSD), left ventricular posterior wall end-diastolic thickness (LVPWD), left ventricular short axis shortening fraction (LVFS), Simpson's left ventricular ejection fraction (Simpson's LVEF), three-dimensional left ventricular ejection fraction (3D-LVEF), global longitudinal strain (GLS), global circumferential strain (GCS), left ventricular twist angle (LVtw), Torsion (Tor), peak strain dispersion (PSD), and myocardial comprehensive index (MCI). The same parameters were collected in the control group, the results were compared. The correlation analysis between 3D-STE parameters and 3D-LVE, cTn I was performed. A total of 10 individuals were selected for repeatability testing. RESULTS: Compared with the control group, the LVFS, LVEF (Simpson), 3D-LVEF, GLS, GCS, LVtw, Tor, and MCI significantly decreased in patients with STEMI after PCI, while the PSD significantly increased (p < 0.05). Compared with the values 72 h after PCI, the LVEDD, LVFS, LVEF (Simpson), 3D-LVEF, GLS, GCS, LVtw, Tor, and MCI significantly increased at 12 m after PCI, while PSD significantly decreased (p < 0.05). No significant difference was observed between the two groups at 72 h after PCI (p > 0.05). At 12 months after PCI, the LVEF, GLS, GCS, LVtw, Tor, and MCI of the Tongxinluo group were higher than those of the routine group. The PSD was significantly lower in the Tongxinluo group (p < 0.05). MCI and 3D-LVEF, cTn I have the strongest correlation and the highest consistency, which can best reflect the changes in the left ventricular function in patients with AMI after PCI. CONCLUSION: 3D-STE can be used to evaluate the protective effect of Tongxinluo on the left ventricular function in patients with AMI after PCI.

Associations of parental depression during adolescence with cognitive development in later life in China: A population-based cohort study.

BACKGROUND: Prior research has underscored negative impacts of perinatal parental depression on offspring cognitive performance in early childhood. However, little is known about the effects of parental depression during adolescence on offspring cognitive development. METHODS AND FINDINGS: This study used longitudinal data from the nationally representative China Family Panel Studies (CFPS). The sample included 2,281 adolescents aged 10-15 years (the median age was 13 years with an interquartile range between 11 and 14 years) in 2012 when their parents were surveyed for depression symptoms with the 20-item Center for Epidemiologic Studies Depression Scale (CES-D). The sample was approximately balanced by sex, with 1,088 females (47.7%). We examined the associations of parental depression in 2012 with offspring cognitive performance (measured by mathematics, vocabulary, immediate word recall, delayed word recall, and number series tests) in subsequent years (i.e., 2014, 2016, and 2018) using linear regression models, adjusting for various offspring (i.e., age, sex, and birth order), parent (i.e., parents' education level, age, whether living with the offspring, and employment status), and household characteristics (i.e., place of residence, household income, and the number of offspring). We found parental depression during adolescence to be significantly associated with worse cognitive performance in subsequent years, in both crude and adjusted models. For example, in the crude models, adolescents whose mothers had depression symptoms in 2012 scored 1.0 point lower (95% confidence interval [CI]: -1.2 to -0.8, p < 0.001) in mathematics in 2014 compared to those whose mothers did not have depression symptoms; after covariate adjustment, this difference marginally reduced to 0.8 points (95% CI: -1.0 to -0.5, p < 0.001); the associations remained robust after further adjusting for offspring earlier cognitive ability in toddlerhood (-1.2, 95% CI: -1.6, -0.9, p < 0.001), offspring cognitive ability in 2012 (-0.6, 95% CI: -0.8, -0.3, p < 0.001), offspring depression status (-0.7, 95% CI: -1.0, -0.5, p < 0.001), and parents' cognitive ability (-0.8, 95% CI: -1.2, -0.3, p < 0.001). In line with the neuroplasticity theory, we observed stronger associations between maternal depression and mathematical/vocabulary scores among the younger adolescents (i.e., 10-11 years) than the older ones (i.e., 12-15 years). For example, the association between maternal depression and 2014 vocabulary scores was estimated to be -2.1 (95% CI: -2.6, -1.6, p < 0.001) in those aged 10-11 years, compared to -1.2 (95% CI: -1.6, -0.8, p < 0.001) in those aged 12-15 years with a difference of 0.9 (95% CI: 0.2, 1.6, p = 0.010). We also observed a stronger association of greater depression severity with worse mathematical scores. The primary limitations of this study were the relatively high attrition rate and residual confounding. CONCLUSIONS: In this study, we observed that parental depression during adolescence was associated with adverse offspring cognitive development assessed up to 6 years later. These findings highlight the intergenerational association between depression in parents and cognitive development across the early life course into adolescence.

Speckle tracking imaging combined with myocardial comprehensive index to evaluate left ventricular function changes in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate early changes in left ventricular systolic function in patients with systemic lupus erythematosus (SLE) using three-dimensional speckle tracking imaging (3D-STI). METHODS: A total of 30 SLE patients and 30 healthy people (control group) were selected, the patients were further divided into subgroups according to their Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) score: ≤ 12: mild-to-moderate group; > 12: severe group. All participants were examined using 3D-STI, the 3D-STI parameters were obtained. Receiver operating curves (ROC) were prepared for above parameters and analyzed to identify correlations among 3D-STI parameters and high sensitivity-TropT (hs-TropT). RESULTS: Compared with the control group, the absolute values of left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), global circumferential strain (GCS), left ventricular twist angle (LVtw), torsion (Tor) and myocardial comprehensive index (MCI) decreased, left ventricular end diastolic mass (LV EDmass), left ventricular end systolic mass (LV ESmass) and peak strain dispersion (PSD) increased in the mild-to-moderate and the severe groups (P2  < 0.05, P3  < 0.05). There was statistically significant difference in terms of 3D-STI parameters between the mild-to-moderate group and the severe group (P1  < 0.05). The highest area under the ROC for MCI was 0.909, the highest sensitivity for MCI was 90.00%, and the highest specificity for Tor was 86.67%. Correlation analysis showed that there was a good correlation between the MCI and hs-TropT (r = - 0.677). CONCLUSION: 3D-STI technology may help detect early changes in left ventricular systolic function in patients with SLE.

Changes in left ventricular function induced by carboplatin combined with paclitaxel in patients with ovarian cancer identified using three-dimensional spot tracking imaging technology.

OBJECTIVE: To investigate the clinical value of three-dimensional speckle tracking imaging (3D-STI) in evaluating left ventricular (LV) systolic function in patients with ovarian cancer (OC) treated with paclitaxel and carboplatin. METHOD: We studied 30 patients with OC treated with paclitaxel combined with carboplatin chemotherapy. Two-dimensional echocardiography and 3D-STI were performed in the patients before they underwent 2- and 6-cycle chemotherapies, and in 30 normal control subjects. Were measured LV end-diastolic volume (EDV), end-systolic volume (ESV), three-dimensional LV ejection fraction (3D-LVEF), stroke volume (SV), spherical index (SPI), LV end-diastolic mass (LV EDmass), LV end-systolic mass (LV ESmass), LV global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), global area strain (GAS) and cardiac troponin T(cTnT). At the end of chemotherapy, magnetic resonance imaging (MRI) was also performed. RESULT: The 3D conventional strain values (3D-LVEF, SV, LV EDV) after the 2- and 6-cycle chemotherapy were lower than before chemotherapy. LV Edmass, LV ESmass and cTnT were higher while LV GLS, GCS, GRS, GAS were lower after 2- and after 6-cycle chemotherapy than before chemotherapy. There was no significant difference in ESV and EDV between the 3D-STI and MRI parameters. GAS showed a significant negative correlation with cTnT. MRI and 3D-STI variables were significantly correlated, and the receiver operating characteristic curves showed the greater area under the curve for GAS after 2- and after 6-cycle chemotherapy. After 2-cycle chemotherapy, the highest specificity for GAS was 93.3%, and the highest sensitivity for GLS was 70.0%. After 6-cycle chemotherapy, the highest specificity for GAS was 96.7%, and the highest sensitivity for GLS was 96.7%. CONCLUSION: The LV systolic function decreased in OC patients treated with paclitaxel and carboplatin, showing that 3D-STI may detect early LV systolic dysfunction.

N-Primary-amine tetrapeptide-catalyzed highly asymmetric Michael addition of aliphatic aldehydes to maleimides.

The highly asymmetric Michael addition reaction between maleimides and aliphatic aldehydes catalyzed by low-loading ß-turn tetrapeptides with excellent yields and enantioselectivities at room temperature was reported. α-Branched and α-unbranched aldehydes both are suitable nucleophiles. N-Aryl, alkyl and hydrogen maleimides all are well tolerated and led to high yields and enantioselectivities. The transformation can be enlarged to the gram scale without decrease in the yield and enantioselectivity. Furthermore, the succinimides were converted into γ-lactams and γ-lactones, showing good practicality of this work. Some reaction intermediates in the proposed reaction mechanism can be captured with the HR-MS method.

Correction: N-Primary-amine tetrapeptide-catalyzed highly asymmetric Michael addition of aliphatic aldehydes to maleimides.

Correction for 'N-Primary-amine tetrapeptide-catalyzed highly asymmetric Michael addition of aliphatic aldehydes to maleimides' by Zhi-Hong Du et al., Org. Biomol. Chem., 2020, 18, 6899-6904, DOI: 10.1039/D0OB01457E.

Dihydroartemisinin induces ER stress-dependent apoptosis of Echinococcus protoscoleces in vitro.

In this study, we investigated the effect of dihydroartemisinin on Echinococcus protoscoleces and explored the role of endoplasmic reticulum stress in this process. Echinococcus protoscoleces were collected and cultured in RPMI 1640 medium. Changes in the expressions of glucose-regulated protein 78 (GRP-78), caspase-12, and C/EBP homologous protein (CHOP) were assessed through confocal immunofluorescence and western blot analysis. Cell viability and morphological changes were observed under a light microscope. The ultrastructure of protoscoleces was observed by scanning electron microscopy and transmission electron microscopy. Caspase-3 activity was detected using an enzyme assay kit. After dihydroartemisinin treatment, the protoscoleces showed loss of viability, and morphological changes including soma contraction, blebs formation, hooks loss, microtrichia destruction, and development of lipid droplets was observed. The levels of caspase-12 and CHOP were increased within 2 days of dihydroartemisinin treatment. However, the levels of GRP-78, caspase-12, and CHOP were decreased in 4 days. Furthermore, caspase-3 activity was increased after treatment with different concentrations of dihydroartemisinin. Dihydroartemisinin can induce apoptosis in protoscoleces via the ER stress-caspase-3 apoptotic pathway in vitro. These results indicate that dihydroartemisinin is a potentially valuable therapeutic agent against echinococcosis.

Sensitive Hyaluronidase Biosensor Based on Target-Responsive Hydrogel Using Electronic Balance as Readout.

The development of simple but sensitive methods for hyaluronidase (HAase) detection has been paid a great deal of attention because HAase is a potential cancer marker. In this work, a novel system coupled with a controlled release system has been designed for HAase determination without complex analytical instruments and skilled technicians. Pt@SiO2 nanoparticles (NPs), which can catalyze the breakdown of H2O2 into O2 and H2O, was embedded in the hydrogel constructed by polyethylenimine (PEI) and hyaluronic acid (HA). In the presence of HAase, the hydrogel was broken down as HAase can catalyze the degradation of HA and hence the Pt@SiO2 NPs in the hydrogel was released. The released Pt@SiO2 NPs mixed with H2O2 solution in a drainage device, and then O2 was generated due to the decomposition of H2O2, resulting in an enhancement of pressure in the drainage device because of the low solubility of O2. A certain amount of H2O overflowed from the drainage device because the difference of the pressure between the inner and outer of the drainage device. The overflowed H2O was collected by a tube, and its amount was easily measured by an electronic balance. The weight of the H2O has a linear relationship with the HAase concentration in the range of 1-60 U/mL (120 min enzymatic hydrolysis time) and 0.2-10 U/mL (240 min enzymatic hydrolysis time). The developed system has been applied to detect the activity of HAase in urine samples with satisfied results.

Changes of CD103-expressing pulmonary CD4+ and CD8+ T cells in S. japonicum infected C57BL/6 mice.

BACKGROUND: Recent studies have shown that CD103 is an important marker for tissue-resident memory T cells (TRM) which plays an important role in anti-infection. However, the role of CD103+ TRM was not elucidated in the progress of S. japonicum infection induced disease. METHODS: 6-8 weeks old C57BL/6 mice were infected by S. japonicum. Mice were sacrificed and the lungs were removed 5-6 weeks after infection. Immunofluorescent staining and Q-PCR were performed to identify the expression of CD103 molecule. Single cellular populations were made, percentages of CD103 on both CD4+ and CD8+ T lymphocytes were dynamical observed by flow cytometry (FCM). Moreover, the expression of memory T cells related molecules CD69 and CD62L, T cell function associated molecules CD107a, IFN-γ, IL-4, IL-9, and IL-10 were compared between CD103+ CD4+ and CD8+ T cells by FCM. RESULTS: CD103+ cells were emerged in the lung of both naive and S. japonicum infected mice. Both the percentage and the absolute numbers of pulmonary CD4+ and CD8+ cells were increased after S. japonicum infection (P < 0.05). The percentage of CD103+ cells in CD8+ T cells decreased significantly at the early stage of S. japonicum infection (P < 0.05). Increased CD69, decreased CD62L and CD107a expressions were detected on both CD4+ and CD8+ CD103+ T cells in the lungs of infected mice (P < 0.05). Compared to CD8+ CD103+ T cells, CD4+ CD103+ T cells from infected mice expressed higher level of CD69 and lower level CD62L molecules (P < 0.05). Moreover, higher percentage of IL-4+, IL-9+ and IL-10+ cells on CD4+ CD103+ pulmonary T cells was found in infected mice (P < 0.05). Significantly increased IL-4 and IL-9, and decreased IFN-γ expressing cells were detected in CD8+CD103+ cells of infected mice (P < 0.05). CONCLUSIONS: CD103-expressing pulmonary CD4+ and CD8+ T cells play important roles in mediating S. japonicum infection induced granulomatous inflammation in the lung.

Toxic effects of arsenic trioxide on Echinococcus granulosus protoscoleces through ROS production, and Ca2+-ER stress-dependent apoptosis.

Cystic echinococcosis is a severe parasitic disease that commonly affects the liver and causes abscesses or rupture into the surrounding tissues, leading to multiple complications, such as shock, severe abdominal pain, and post-treatment abscess recurrence. Currently, there are no efficient measures to prevent these complications. We previously confirmed that arsenic trioxide (As2O3) exhibited in vitro cytotoxicity against Echinococcus granulosus protoscoleces. In the present study, we aimed to explore the mechanism of As2O3-induced E. granulosus protoscoleces apoptosis. After exposing E. granulosus protoscoleces to 0, 4, 6, and 8 µM As2O3, reactive oxygen species (ROS) level was detected by fluorescence microscopy; superoxide dismutase (SOD), and caspase-3 activities were measured; intracellular Ca2+ was detected by flow cytometry; GRP-78 and caspase-12 protein levels were measured by western blot analysis. Our results showed that the expression of caspase-3 was gradually increased and the expression of SOD was gradually decreased in As2O3-treated groups of protoscoleces. Simultaneously, fluorescence microscopy and flow cytometry showed that the ROS level and the intracellular Ca2+ level were increased in a time- and dose-dependent manner. Western blot analysis showed that the expressions of GRP-78 and caspase-12 were higher in As2O3-treated groups than in the control group. These results suggest that As2O3-induced apoptosis in E. granulosus protoscoleces is related to elevation of ROS level, disruption of intracellular Ca2+ homeostasis, and endoplasmic reticulum stress. These mechanisms can be targeted in the future by safer and more effective drugs to prevent recurrence of cystic echinococcosis.

Effects of trigonelline inhibition of the Nrf2 transcription factor in vitro on Echinococcus granulosus.

The aim of this study was to investigate the impact of trigonelline (TRG) on Echinococcus granulosus, and to explore the inhibition impact of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway on E. granulosus protoscoleces. Echinococcus granulosus protoscoleces were incubated with various concentrations of TRG, and then Nrf2 protein expression and its localization in protoscoleces were detected by western blot analysis and immunofluorescence assay, respectively. Reactive oxygen species (ROS) level in protoscoleces was measured using ROS detection kit. Caspase-3 activity was measured using a caspase-3 activity assay kit, and NAD(P)H quinone oxidoreductase (NQO)-1 and heme oxygenase (HO)-1 activities in protoscoleces were measured by ELISA. The effect of TRG on protoscoleces viability was investigated using 0.1% eosin staining, and ultrastructural alterations in protoscoleces were examined by scanning electron microscopy (SEM). Immunolocalization experiment clearly showed that Nrf2 protein was predominantly present in cells of protoscoleces. TRG treatment reduced NQO-1 and HO-1 activities in protoscoleces, but could increase ROS level at early time. Protoscoleces could not survive when treated with 250 µM TRG for 12 days. SEM results showed that TRG-treated protoscoleces presented damage in the protoscoleces region, including hook deformation, lesions, and digitiform protuberance. Nrf2 protein expression was significantly decreased and caspase-3 activity was clearly increased in protoscoleces treated with TRG for 24 and 48 h, respectively, when compared with that in controls (P < 0.05). Our results demonstrated that TRG had scolicidal activity against E. granulosus protoscoleces. Nrf2 protein was mainly expressed in the cells and TRG could efficiently inhibit the Nrf2 signaling pathway in E. granulosus.

Differential pulmonic NK and NKT cell responses in Schistosoma japonicum-infected mice.

Natural killer cells (NK cells) and natural killer T cells (NKT cells) play a role in anti-infection, anti-tumor, transplantation immunity, and autoimmune regulation. However, the role of NK and NKT cells during Schistosoma japonicum (S. japonicum) infection has not been widely reported, especially regarding lung infections. The aim of this study was to research the NK and NKT cell response to S. japonicum infection in the lungs of mice. Using immunofluorescent histological analysis, NK and NKT cells were found near pulmonary granulomas. Moreover, flow cytometry revealed that the percentage and number of pulmonic NK cells in S. japonicum-infected mice were significantly increased (P < 0.05). However, the percentage and cell number of NKT cells were decreased compared to those of normal mice (P < 0.05). The expression of CD69 on pulmonic NK and NKT cells was increased after infection (P < 0.05), and CD25 expression increased only on NKT cells (P < 0.05). Intracellular cytokine staining showed a higher percentage of IFN-γ+ and lower percentage of IL-5+ pulmonic NK cells (P < 0.05) compared to controls. However, the percentage of IL-17+, IL-10+, and IL-5+ pulmonic NKT cells significantly increased (P < 0.05). Additionally, there was a significant decrease in NKG2A/C/E (CD94) expression and an increase of NKG2D (CD314) expression on pulmonic NKT cells (P < 0.05), which might serve as a mechanism for NKT cell activation during S. japonicum infection.

Histogram analysis of ultrasonographic images in the differentiation of benign and malignant parotid gland tumors.

OBJECTIVE: We evaluated the diagnostic value of histogram analysis (HA) using ultrasonographic (US) images for differentiation among pleomorphic adenoma (PA), adenolymphoma (AL), and malignant tumors (MT) of the parotid gland. STUDY DESIGN: Preoperative US images of 48 patients with PA, 39 patients with AL, and 17 patients with MT were retrospectively analyzed for gray-scale histograms. Nine first-order texture features derived from histograms of the tumors were compared. Area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic performance of texture features. The Youden index maximum exponent was used to calculate sensitivity and specificity. RESULTS: Statistically significant differences were discovered in Mean and Skewness HA values between PA and AL (P<0.001), and in Mean values between AL and MT (P<0.001). However, comparison of PA and MT showed no statistically significant differences (P>0.01). Excellent discrimination was detected between PA and AL (AUC=0.802), and between AL and MT (AUC=0.822). The combination of Mean plus Skewness improved discrimination between PA and AL (AUC=0.823) with sensitivity values reaching 1.00. However, Mean plus Skewness applied to differentiate PA from AL and Mean values applied to distinguish AL and MT resulted in low specificity, indicating many false positive interpretations. CONCLUSIONS: Histogram analysis is useful for differentiating PA from AL and AL from MT but not PA from MT.