The Keap1-Nrf2-ARE pathway regulates the constitutive and inducible transcription of various genes that encode detoxification enzymes, antioxidant proteins and anti-inflammatory proteins and has ...pivotal roles in the defence against cellular oxidative stress. In this study, we investigated the therapeutic potential of CPUY192018, a potent small-molecule inhibitor of the Keap1-Nrf2 protein-protein interaction (PPI), in renal inflammation. In human proximal tubular epithelial HK-2 cells, CPUY192018 treatment significantly increased Nrf2 protein level and Nrf2 nuclear translocation, which enhanced Nrf2-ARE transcription capacity and the downstream protein content in a Nrf2 dependent manner. In lipopolysaccharide (LPS)-challenged human HK-2 cells, CPUY192018 exhibited cytoprotective effects by enhancing the Nrf2-ARE regulated antioxidant system and diminished the LPS-induced inflammatory response by hindering the ROS-mediated activation of the NF-κB pathway. In the LPS-induced mouse model of chronic renal inflammation, by activating Nrf2, CPUY192018 treatment balanced renal oxidative stress and suppressed inflammatory responses. Hence, administration of CPUY192018 reduced kidney damage and ameliorated pathological alterations of the glomerulus. Taken together, our study suggested that small-molecule Keap1-Nrf2 PPI inhibitors can activate the Nrf2-based cytoprotective system and protect the kidney from inflammatory injury, raising a potential application of Keap1-Nrf2 PPI inhibitors in the treatment of inflammatory kidney disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of various pulmonary diseases via the activation of the unfolded protein response. However, the role of ER stress in ...pulmonary arterial hypertension (PAH) remains unclear. The well-known chemical chaperone 4-phenylbutyric acid (4-PBA) inhibits ER stress signaling. We hypothesized that known chemical chaperones, including 4-PBA, would inhibit the activation of ER stress and prevent and/or reverse PAH.
Male Wistar rats were randomly divided into four groups: a normal control group (NORMAL group), a PAH group, and two PAH model plus 4-PBA treatment groups. The latter two groups included rats receiving 4-PBA by gavage each day as a preventive measure (the PRE group, with PBA starting on the day of PAH induction and continuing for 4 weeks) or as a reversal measure (the REV group, with PBA starting on the third week of PAH induction and continuing for 2 weeks). The PAH model was induced by intraperitoneally administering monocrotaline. The mean pulmonary artery pressure and mean right ventricular pressure were lower in the REV and PRE groups than in the NORMAL group. Furthermore, 4-PBA improved pulmonary arterial remodeling and suppressed the expression of ER stress indicators.
Our findings indicate that PAH induces ER stress and provokes pulmonary arterial and right ventricular remodeling. Additionally, we show that attenuation of ER stress has the potential to be an effective therapeutic strategy for protecting pulmonary arteries.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
VEGF/VEGFR2 pathway is the central therapeutic target in anti-angiogenic treatment in multiple cancers. However, little work has been carried out concerning the pro-malignancy functions of VEGFR2 ...that are independent of its pro-angiogenesis effects in gastric cancer. Here, we demonstrated that VEGFR2 up-regulation in gastric cancer tissues was a prognostic marker for poor disease-free survival and overall survival of gastric cancer patients.
Immunohistochemistry was used to detect VEGFR2 and VTN expressions in specimens. Kaplan-Meier curves were constructed for survival analysis. Stably knockdown cell lines and overexpression cell lines were constructed by small interfering RNA and plasmids transfection. Real-time PCR and Western blot were used to confirm the expressions of target genes at both RNA and protein levels. Cell proliferation was measured by using Cell Counting Kit-8 and xenograft models. Microarray and bioinformatic analysis were also performed to identify the relationship between Vitronectin (VTN) and VEGFR2.
When overexpressed in gastric cancer cells, VEGFR2 increased cellular proliferation and invasion in vitro and tumor formation in xenograft models. By using integrating microarray and bioinformatic analysis, we identifiedVTN as a downstream of VEGFR2 pathway. In gain- and loss-of function analysis in gastric cancer cells, VTN was further verified in consistent with VEGFR2 in expression levels and in regulating cell growth and motility in vitro and in vivo. Moreover, in gastric cancer samples, VTN was as also revealed as a poor prognostic factor.
Our present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects.
Our present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects, which may provide a new and valuable target for design of therapies for intervention and a new cognitive perspective for the anti-angiogenesis therapies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
High-quality counterfeit stamp impressions made by inkjet printers remain challenging in questioned document examination and forensic analyses. A dataset comprised of various printed stamp ...impressions, using ten options of conditions and materials, and hand stamped impressions was generated. In this paper, we report printed impressions in pure color and high-quality printing mode are very similar to hand stamped impressions in terms of their microscopic characteristics. These similarities may lead to incorrect conclusions via traditional identification methods. Here, we proposed a method for identifying counterfeit stamp impressions via texture features and image quality parameters extracted from impressions. First, the statistical analysis methods were used to verify a significant difference between the printed and hand stamped impressions. Principal component analysis (PCA) was used to show the variation between the impressions, and the differences between printed and hand stamped impressions were obvious in the three-dimensional plot. After filtering the background of the stamp impressions, image processing analysis was introduced to extract features of gray level co-occurrence matrix (GLCM), segmentation-based fractal texture analysis (SFTA), local binary pattern (LBP), and image quality metrics (IQM), which were used to characterize the stamp impressions. Finally, specific cases were simulated by random selection, based on the dataset of stamp impressions, and an evaluation system for stamp evidence was established to calculate the likelihood ratios (LRs) under two alternative hypotheses. The likelihood ratio interprets calibrated evaluations on the strength of stamp impressions as evidence. We can also balance these LRs against the rates of misleading evidence with a reasonable performance (equal error rate = 0.048). This paper provides a system to differentiate high-quality printed and hand stamped impressions with reasonable performance.
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•This paper reported the potential challenge a high-quality stamp impression poses to questioned document examination.•A comprehensive image processing properly demonstrates the difference between genuine and counterfeit stamp impressions.•Evidence evaluation helps to rigorously evaluate the strength of stamp impression evidence with a scientific interpretation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This randomized, open-label, multi-center phase 2 study (NCT03116152) assessed sintilimab, a PD-1 inhibitor, versus chemotherapy in patients with esophageal squamous cell carcinoma after first-line ...chemotherapy. The primary endpoint was overall survival (OS), while exploratory endpoint was the association of biomarkers with efficacy. The median OS in the sintilimab group was significantly improved compared with the chemotherapy group (median OS 7.2 vs.6.2 months; P = 0.032; HR = 0.70; 95% CI, 0.50-0.97). Incidence of treatment-related adverse events of grade 3-5 was lower with sintilimab than with chemotherapy (20.2 vs. 39.1%). Patients with high T-cell receptor (TCR) clonality and low molecular tumor burden index (mTBI) showed the longest median OS (15.0 months). Patients with NLR < 3 at 6 weeks post-treatment had a significantly prolonged median OS (16.6 months) compared with NLR ≥ 3. The results demonstrate a significant improvement in OS of sintilimab compared to chemotherapy as second-line treatment for advanced or metastatic ESCC.
Volatile compounds are considered to be essential for the flavor and aroma quality of grapes. Thidiazuron (TDZ) is a commonly used growth regulator in grape cultivation that stimulates larger berries ...and prevents fruit drop. This study was conducted to investigate the effect of TDZ on the production of aroma volatiles and to identify the key genes involved in the terpene biosynthesis pathways that are affected by this compound. Treatment with TDZ had a negative effect on the concentration of volatile compounds, especially on monoterpenes, which likely impacts the sensory characteristics of the fruit. The expression analysis of genes related to the monoterpenoid biosynthesis pathways confirmed that treatment with TDZ negatively regulated the key genes
,
,
,
,
and
. Specifically, the expression levels of the aforementioned genes were down-regulated in almost all berry development stages in the TDZ-treated samples. The novel results from the present study can be used to aid in the development of food products which maintain the flavor quality and sensory characteristics of grape. Furthermore, these findings can provide the theoretical basis that can help to optimize the utilization of TDZ for the field production of grapes at a commercial scale.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The purpose of this study is to investigate the correlation between glomerular filtration rate (GFR) estimated by different renal function equations and non-vitamin K antagonist oral anticoagulant ...concentration. Atrial fibrillation patients who aged ≥ 20 years and used dabigatran, rivaroxaban, or apixaban for thromboembolism prevention were enrolled to collect blood samples and measure drug concentrations using ultra-high-performance liquid chromatography with tandem mass spectrometry. The GFR was estimated using the Cockroft-Gault formula (abbreviated as creatinine clearance, CrCL), Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) featuring both creatinine and cystatin C, and the Modification of Diet in Renal Disease Study equation (MDRD). Multivariate regression was used to investigate the associations of different renal function estimates with drug concentrations. A total of 511 participants were enrolled, including 146 dabigatran users, 164 rivaroxaban users and 201 apixaban users. Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than the expected range (p < 0.001). CKD-EPI and MDRD estimates classified fewer patients as having GFR < 50 mL/min than CrCL in all 3 groups. Both CrCL and CKD-EPI were associated with higher-than-expected ranges of dabigatran or rivaroxaban concentrations. Nevertheless, none of the renal function equations was associated with higher-than-expected apixaban concentrations. For participants aged ≥ 75 years, CKD-EPI may be associated with higher-than-expected trough concentration of dabigatran. In conclusion, CrCL and CKD-EPI both can be used to identify patients with high trough concentrations of dabigatran or rivaroxaban. Among elderly patients who used dabigatran, CKD-EPI may be associated with increased drug concentration.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Acute type B aortic dissection (ABAD) is a life-threatening cardiovascular disease. A practicable and effective prediction model to predict and evaluate the risk of in-hospital death for ABAD is ...required. The present study aimed to construct a prediction model to predict the risk of in-hospital death in ABAD patients.
A total of 715 patients with ABAD were recruited in the first affiliated hospital of Xinjiang medical university from April 2012 to May 2021. The information on the demographic and clinical characteristics of all subjects was collected. The logistic regression analysis, receiver operating characteristic (ROC) curve analysis, and nomogram were applied to screen the appropriate predictors and to establish a prediction model for the risk of in-hospital mortality in ABAD. The receiver operator characteristic curve and calibration plot were applied to validate the performance of the prediction model.
Of 53 (7.41%) subjects occurred in-hospital death in 715 ABAD patients. The variables including diastolic blood pressure (DBP), platelets, heart rate, neutrophil-lymphocyte ratio, D-dimer, C-reactive protein (CRP), white blood cell (WBC), hemoglobin, lactate dehydrogenase (LDH), procalcitonin, and left ventricular ejection fraction (LVEF) were shown a significant difference between the in-hospital death group and the in-hospital survival group (all P < 0.05). Furthermore, all these factors which existed differences, except CRP, were associated with in-hospital deaths in ABAD patients (all P < 0.05). Then, parameters containing LVEF, WBC, hemoglobin, LDH, and procalcitonin were identified as independent risk factors for in-hospital deaths in ABAD patients by adjusting compound variables (all P < 0.05). In addition, these independent factors were qualified as predictors to build a prediction model (AUC > 0.5, P < 0.05). The prediction model was shown a favorable discriminative ability (C index = 0.745) and demonstrated good consistency.
The novel prediction model combined with WBC, hemoglobin, LDH, procalcitonin, and LVEF, was a practicable and valuable tool to predict in-hospital deaths in ABAD patients.
Background
SSX2IP plays a critical role in tumorigenesis and its overexpression has been found in many types of cancer, such as an associated antigen in acute myeloid leukemia and breast cancer. ...However, the pathophysiological role of SSX2IP in BC has not been evaluated.
Objective
To investigate that SSX2IP gene plays an important role in the development of breast cancer, which can be used as a diagnostic marker for breast cancer.
Results
SSX2IP are detected in BC in this study, the result shown that SSX2IP mRNA and protein were upregulated in both human breast cancer samples and cell lines. With the depletion of SSX2IP, the results demonstrated the BT549 cell activity, proliferation, migratory and invasive, clone formation abilities were inhibited, and the cell apoptosis increased.
Conclusion
These data indicated that SSX2IP promotes tumor progression in BC, include cell activity, proliferation, migratory and invasive, clone formation abilities were inhibited, and the cell apoptosis increased. This work further suggest that SSX2IP could be used to be a potential therapeutic targets in BC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The Fear of Being Single Scale (FOBS) is a widely used measure of the fear of being single, but its applicability to Chinese populations has not been established. This study aimed to translate the ...FOBS into Chinese and examine its psychometric properties among Chinese college students. The study consisted of three phases with three samples (total n = 1768). In the first phase (Sample 1: n = 571), an exploratory factor analysis (EFA) supported a unidimensional structure with 6 items for the Chinese version of the FOBS (C-FOBS). In the second phase (Sample 2: n = 692), a confirmatory factor analysis (CFA) validated the factor structure and indicated good model fit. The C-FOBS also demonstrated good internal consistency, split-half reliability, criterion validity, and cross-gender invariance. In the third phase (Sample 3: n = 505), the C-FOBS showed acceptable test-retest reliability over a two-week interval. The results suggest that the C-FOBS is a reliable and valid instrument for assessing the fear of being single among Chinese college students.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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