Malignant paraganglioma of the prostate invading the bladder and bilateral seminal vesicles: a case report.

Malignant paraganglioma (PGL) of the prostate is extremely rare, with only 3 cases reported in the English literature to date. In this article, we present a case of malignant prostatic PGL invading the bladder and bilateral seminal vesicles, in which the patient had a history of long-term haematuria and normal serum prostate specific antigen (PSA) level, and was misdiagnosed as a bladder tumour invading the prostate preoperatively. As this case belongs to functional tumour, there is a risk of developing hypertensive crisis during diagnostic biopsy or radical resection. The CT manifestations of prostatic PGL are characteristic, but its imaging features are rarely described due to the rarity of the tumour site. Meanwhile, improving the comprehensive understanding of CT, MRI, functional imaging, and clinical features of prostate PGL is conducive to make the correct diagnosis before surgery and ensure the safety of surgical treatment.

Effects of cigarette smoking associated with sarcopenia in persons 60 years and older: a cross-sectional study in Zhejiang province.

PURPOSE: Smoking is a risk factor for sarcopenia. Nevertheless, few studies analyzed the independent effects of various smoking dimensions (duration, intensity, cumulative dose) on sarcopenia risk. This is a cross-sectional study based on an older population in Zhejiang Province to determine which smoking dimensions are mainly important for sarcopenia risk and to explore the dose-response relationship between them. METHODS: Our study included 783 patients with sarcopenia and 4918 non-sarcopenic individuals. Logistic regression and restricted cubic with logistic regression (for nonlinear dose effects) were used to obtain odds ratios (ORs) and 95% confidence intervals as well as restricted cubic splines (RCS) curves. RESULTS: Compared with never-smokers, current smokers had an increased risk of sarcopenia (OR = 1.786; 95% CI 1.387-2.301) after adjusting for confounders such as age, sex, education, alcohol consumption, disease history, etc. There was no significant association between smoking intensity and sarcopenia after more than 20 cigarettes per day (OR = 1.484; 95% CI 0.886-2.487), whereas the risk of sarcopenia increased significantly with increasing duration of smoking after more than 40 years (OR = 1.733; 95% CI 1.214-2.473). Meanwhile, there was a significant non-linear dose-response relationship between smoking duration or intensity and the risk of sarcopenia. However, the risk of sarcopenia increased linearly with the number of pack-years of smoking, which is not a significant nonlinear dose-response relationship. CONCLUSIONS: This study indicated the association between smoking and sarcopenia. Both smoking duration and cumulative dose were significantly and positively associated with sarcopenia. These findings reflect the important role of the number of years of smoking in increasing the risk of sarcopenia and provide scientific evidence that different smoking dimensions may influence the risk of the sarcopenia.

Interactome Analysis of ClpX Reveals Its Regulatory Role in Metabolism and Photosynthesis in Cyanobacteria.

Protein homeostasis is essential for cyanobacteria to maintain proper cellular function under adverse and fluctuating conditions. The AAA+ superfamily of proteolytic complexes in cyanobacteria plays a critical role in this process, including ClpXP, which comprises a hexameric ATPase ClpX and a tetradecameric peptidase ClpP. Despite the physiological effects of ClpX on growth and photosynthesis, its potential substrates and underlying mechanisms in cyanobacteria remain unknown. In this study, we employed a streptavidin-biotin affinity pull-down assay coupled with label-free proteome quantitation to analyze the interactome of ClpX in the model cyanobacterium Synechocystis sp. PCC 6803 (hereafter Synechocystis). We identified 503 proteins as potential ClpX-binding targets, many of which had novel interactions. These ClpX-binding targets were found to be involved in various biological processes, with particular enrichment in metabolic processes and photosynthesis. Using protein-protein docking, GST pull-down, and biolayer interferometry assays, we confirmed the direct association of ClpX with the photosynthetic proteins, ferredoxin-NADP+ oxidoreductase (FNR) and phycocyanin subunit (CpcA). Subsequent functional investigations revealed that ClpX participates in the maintenance of FNR homeostasis and functionality in Synechocystis grown under different light conditions. Overall, our study provides a comprehensive understanding of the extensive functions regulated by ClpX in cyanobacteria to maintain protein homeostasis and adapt to environmental challenges.

The intention of college students to use electronic cigarettes: A study based on the theory of innovation diffusion.

INTRODUCTION: The purpose of this study is to examine the use of electronic cigarettes (e-cigarettes) among college students in Hangzhou, and to analyze the influencing factors of their intention to use e-cigarettes. METHODS: Using a stratified cluster sampling method, 775 students from two universities in Hangzhou were selected for an on-site questionnaire survey from March to April 2022. Adjusted logistic regression analysis was conducted on the influencing factors of use intention, based on innovation diffusion theory. RESULTS: Within our sample of college students, 16.5% of students had tried e-cigarettes; 6.32% had used e-cigarettes in the past month, and 8.0% had the intention to use e-cigarettes. There were significant differences in willingness to use e-cigarettes among different genders, economic status, smoking status of close friends around them, and their own use of tobacco and alcohol (p<0.05). The logistic regression model showed that the observability of e-cigarettes (AOR=1.28; p<0.05), personal factors (AOR=1.39; p<0.05), and social systems (AOR=1.63; p<0.05), were all influencing factors of intention to use e-cigarettes. CONCLUSIONS: College students in Hangzhou have a high intention to use e-cigarettes, and the impacts of the product itself, individual characteristics and the living environment are crucial. It is necessary to strengthen the promotion of tobacco knowledge at the social and family levels to reduce the occurrence of vaping.

Novel CAR-T cells targeting TRKB for the treatment of solid cancer.

Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating blood cancers such as B-cell malignancies, however, its effectiveness as an approach to treat solid tumors remains to be further explored. Here, we focused on the development of CAR-T cell therapies targeting tropomyosin-related kinase receptor B (TRKB), a highly expressed protein that is significantly associated with tumor progression, malignancy, and drug resistance in multiple forms of aggressive solid tumors. To achieve this, we screened brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NTF4) ligand-based CAR-T cells for their efficiency in targeting the TRKB receptor in the context of solid tumors, particularly hepatocellular carcinoma and pancreatic cancer. We demonstrated that TRKB is overexpressed not only in hepatocellular carcinoma and pancreatic carcinoma cell lines but also in cancer stem-like cells (CSCs). Notably, BDNF-CAR T and NTF4-CAR T cells could not only effectively target and kill TRKB-expressing pan-cancer cell lines in a dose-dependent manner but also effectively kill CSCs. We also performed in vivo studies to show that NTF4-CAR T cells have a better potential to inhibit the tumor growth of hepatocellular carcinoma xenografts in mice, compared with BDNF-CAR T cells. Taken together, our findings suggest that CAR-T targeting TRKB may be a promising approach for developing novel therapies to treat solid cancers.

Identification of patients with nonischemic dilated cardiomyopathy at risk of malignant ventricular arrhythmias: insights from cardiac magnetic resonance feature tracking.

BACKGROUND: Patients with nonischemic dilated cardiomyopathy (NIDCM) are prone to arrhythmias, and the cause of mortality in these patients is either end-organ dysfunction due to pump failure or malignant arrhythmia-related death. However, the identification of patients with NIDCM at risk of malignant ventricular arrhythmias (VAs) is challenging in clinical practice. The aim of this study was to evaluate whether cardiovascular magnetic resonance feature tracking (CMR-FT) could help in the identification of patients with NIDCM at risk of malignant VAs. METHODS: A total of 263 NIDCM patients who underwent CMR, 24-hour Holter electrocardiography (ECG) and inpatient ECG were retrospectively evaluated. The patients with NIDCM were allocated to two subgroups: NIDCM with VAs and NIDCM without VAs. From CMR-FT, the global peak radial strain (GPRS), global longitudinal strain (GPLS), and global peak circumferential strain (GPCS) were calculated from the left ventricle (LV) model. We investigated the possible predictors of NIDCM combined with VAs by univariate and multivariate logistic regression analyses. RESULTS: The percent LGE (15.51 ± 3.30 vs. 9.62 ± 2.18, P < 0.001) was higher in NIDCM patients with VAs than in NIDCM patients without VAs. Furthermore, the NIDCM patients complicated with VAs had significantly lower GPCS than the NIDCM patients without VAs (- 5.38 (- 7.50, - 4.22) vs.-9.22 (- 10.73, - 8.19), P < 0.01). Subgroup analysis based on LGE negativity showed that NIDCM patients complicated with VAs had significantly lower GPRS, GPCS, and GPLS than NIDCM patients without VAs (P < 0.05 for all). Multivariate analysis showed that both GPCS and %LGE were independent predictors of NIDCM combined with VAs. CONCLUSIONS: CMR global strain can be used to identify NIDCM patients complicated with VAs early, specifically when LGE is not present. GPCS < - 13.19% and %LGE > 10.37% are independent predictors of NIDCM combined with VAs.

The p53/ZEB1-PLD3 feedback loop regulates cell proliferation in breast cancer.

Breast cancer is the most prevalent cancer globally, endangering women's physical and mental health. Phospholipase D3 (PLD3) belongs to the phosphodiesterase family (PLD). PLD3 is related to insulin-mediated phosphorylation of the AKT pathway, suggesting that it may play a role in the occurrence and development of malignant tumors. This study may further explore the molecular mechanism of PLD3 inhibiting breast cancer cell proliferation. In this study, we demonstrated that PLD3 and miR-6796 are co-expressed in breast cancer. PLD3 can bind with CDK1 and inhibit its expression, leading to mitotic arrest and inhibiting breast cancer proliferation. Wild-type p53 regulates PLD3 and miR-6796 expression by competitively binding to the PLD3 promoter with ZEB1. DNMT3B, as the target gene of miR-6796, is recruited into the PLD3 promoter by combining with ZEB1 to regulate the DNA methylation of the PLD3 promoter and ultimately affect PLD3 and miR-6796 expression. In conclusion, we revealed the role and molecular mechanism of PLD3 and its embedded miR-6796 in breast cancer proliferation, providing clues and a theoretical foundation for future research and development of therapeutic targets and prognostic markers for breast cancer.

PAX5-miR-142 feedback loop promotes breast cancer proliferation by regulating DNMT1 and ZEB1.

BACKGROUND: Breast cancer is one of the most common malignancies occurred in female around the globe. Recent studies have revealed the crucial characters of miRNA and genes, as well as the essential roles of epigenetic regulation in breast cancer initiation and progression. In our previous study, miR-142-3p was identified as a tumor suppressor and led to G2/M arrest through targeting CDC25C. However, the specific mechanism is still uncertain. METHODS: We identified PAX5 as the upstream regulator of miR-142-5p/3p through ALGGEN website and verified by series of assays in vitro and in vivo. The expression of PAX5 in breast cancer was detected by qRT-PCR and western blot. Besides, bioinformatics analysis and BSP sequencing were performed to analyze the methylation of PAX5 promoter region. Finally, the binding sites of miR-142 on DNMT1 and ZEB1 were predicted by JASPAR, and proved by luciferase reporter assay, ChIP analysis and co-IP. RESULTS: PAX5 functioned as a tumor suppressor by positive regulation of miR-142-5p/3p both in vitro and in vivo. The expression of PAX5 was regulated by the methylation of its promoter region induced by DNMT1 and ZEB1. In addition, miR-142-5p/3p could regulate the expression of DNMT1 and ZEB1 through binding with their 3'UTR region, respectively. CONCLUSION: In summary, PAX5-miR-142-DNMT1/ZEB1 constructed a negative feedback loop to regulate the progression of breast cancer, which provided emerging strategies for breast cancer therapy.

HGF-Based CAR-T Cells Target Hepatocellular Carcinoma Cells That Express High Levels of c-Met.

BACKGROUND: CAR-T is emerging as an effective treatment strategy for hematologic malignancies, however its effectiveness for treating solid tumors, such as Hepatocellular Carcinoma (HCC) is limited. Here, we screened a variety of CAR-T cells that target c-Met to investigate their potential to induce HCC cell death in vitro. METHODS: Human T cells were transduced to express CARs by lentiviral vector transfection. c-Met expression in human HCC cell lines and CARs expression were monitored by flow cytometry. Tumor cell killing was evaluated by Luciferase Assay System Kit. The concentrations of cytokine were tested by Enzyme-linked immunosorbent assays. Knock down and overexpression studies targeting c-Met were conducted to assess the targeting specificity of CARs. RESULTS: We found that CAR T cells expressing a minimal amino-terminal polypeptide sequence comprising the first kringle (kringle 1) domain (denoted as NK1 CAR-T cells), efficiently killed HCC cell lines that expressed high levels of the HGF receptor c-Met. Furthermore, we report that while NK1 CAR-T cells were efficient at targeting SMMC7221 cells for destruction, and its potency was significantly attenuated in parallel experiments with cells stably expressing short hairpin RNAs (shRNAs) that suppressed c-Met expression. Correspondingly, overexpression of c-Met in the embryonic kidney cell line HEK293T led to their enhanced killing by NK1 CAR-T cells. CONCLUSION: Our studies demonstrate that a minimal amino-terminal polypeptide sequence comprising the kirngle1 domain of HGF is highly relevant to the design of effective CAR-T cell therapies that kill HCC cells expressing high levels of c-Met.

Effect of air pollution on the prevalence of breast and cervical cancer in China: a panel data regression analysis.

The association between the prevalence of breast and cervical cancer in Chinese women and air pollution is obscure. The study aims to analyze the correlation between air pollution and the prevalence of breast and cervical cancer, and whether the gross domestic product (GDP) has a modifying effect on the impact of air pollution on the prevalence of breast and cervical cancer. Extracting panel data from 31 provinces and cities between 2006 and 2020, we evaluated the association between breast and cervical cancer prevalence and pollutant emissions from 2006 to 2015 with two-way fixed-effect models. We also analyzed the interaction between GDP and pollutant emissions and further check the robustness of the moderating effect results using group regression from 2016 to 2020. Cluster robust standard errors were used to correct for the heteroskedasticity and autocorrelation. The coefficients of models show that the coefficients of logarithmic soot and dust emissions are estimated to be significantly positive, and the coefficients of their square terms are significantly negative. The robust results suggest that the relationship between soot and dust emissions and breast or cervical cancer prevalence is non-linear, from 2006 to 2015. In the analysis of particulate matter (PM) data in 2016-2020, the PM-GDP interaction term was also significantly negative, indicating that GDP growth weakened the effect of PM on the prevalence of breast cancer and cervical cancer. In provinces with higher GDP, the indirect effect of PM emissions concerning breast cancer is -0.396 while in provinces with lower GDP, it is about -0.215. The corresponding coefficient concerning cervical cancer is about -0.209 in provinces with higher GDP but not significant in provinces with lower GDP. Our results suggest that there is an inverted U-shaped relationship between the prevalence of breast cancer and cervical cancer and air pollutants from 2006 to 2015. GDP growth has a significant negative moderating effect on the impact of air pollutants on the prevalence of breast cancer and cervical cancer. PM emissions have a higher effect on the prevalence of breast and cervical cancer in provinces with higher GDP and a lower impact in provinces with lower GDP.

Engineering iron carbide catalyst with aerophilic and electron-rich surface for improved electrochemical CO2 reduction.

Highly efficient electrocatalyst for carbon dioxide reduction (CO2RR) is desirable for converting CO2 into carbon-based chemicals and reducing anthropogenic carbon emission. Regulating catalyst surface to improve the affinity for CO2 and the capability of CO2 activation is the key to high-efficiency CO2RR. In this work, we develop an iron carbide catalyst encapsulated in nitrogenated carbon (SeN-Fe3C) with an aerophilic and electron-rich surface by inducing preferential formation of pyridinic-N species and engineering more negatively charged Fe sites. The SeN-Fe3C exhibits an excellent CO selectivity with a CO Faradaic efficiency (FE) of 92 % at -0.5 V (vs. RHE) and remarkably enhanced CO partial current density as compared to the N-Fe3C catalyst. Our results demonstrate that Se doping reduces the Fe3C particle size and improves the dispersion of Fe3C on nitrogenated carbon. More importantly, the preferential formation of pyridinic-N species induced by Se doping endows the SeN-Fe3C with an aerophilic surface and improves the affinity of the SeN-Fe3C for CO2. Density functional theory (DFT) calculations reveal that the electron-rich surface, which is caused by pyridinic N species and much more negatively charged Fe sites, leads to a high degree of polarization and activation of CO2 molecule, thus conferring a remarkably improved CO2RR activity on the SeN-Fe3C catalyst.

SECTM1-based CAR T cells enriched with CD7-low/negative subsets exhibit efficacy in CD7-positive malignancies.

CD7 has been found to be a promising chimeric antigen receptor (CAR) T cell target in several clinical trials. However, its expression on normal T cells poses additional challenges in CD7-directed CAR therapy, such as complete fratricide, contamination with malignant cells, and immune suppression due to T-cell aplasia. By taking advantage of evolved affinity between ligand and receptor, we constructed a CD7-directed CAR with the extracellular domain of SECTM1, a natural ligand of CD7, as the recognition domain. SECTM1 CAR T cells killed the majority of T cells with high CD7 expression in vitro. However, SECTM1 CAR T cells with low or negative CD7 expression survived, expanded, and showed strong cytotoxicity to CD7+ malignant cell lines and primary leukemic blasts from patients with T-cell acute lymphoblastic leukemia and acute myelogenous leukemia in vitro. It also exhibited efficacy in inhibiting xenograft tumor growth in vivo. More exploration is needed for clinical efficacy potential to patients with CD7+ malignancies.

CMTM7 inhibits breast cancer progression by regulating Wnt/ß-catenin signaling.

BACKGROUND: Breast cancer is the major cause of death in females globally. Chemokine-like factor like MARVEL transmembrane domain containing 7 (CMTM7) is reported as a tumor suppressor and is involved in epidermal growth factor receptor degradation and PI3K/AKT signaling in previous studies. However, other molecular mechanisms of CMTM7 remain unclear. METHODS: The expression level of CMTM7 in breast cancer cells and tissues was detected by qRT-PCR and western blot, and the methylation of CMTM7 promoter was detected by BSP sequencing. The effect of CMTM7 was verified both in vitro and in vivo, including MTT, colony formation, EdU assay, transwell assay and wound healing assay. The interaction between CMTM7 and CTNNA1 was investigated by co-IP assay. The regulation of miR-182-5p on CMTM7 and TCF3 on miR-182-5p was detected by luciferase reporter assay and ChIP analysis. RESULTS: This study detected the hypermethylation levels of the CMTM7 promoter region in breast cancer tissues and cell lines. CMTM7 was performed as a tumor suppressor both in vitro and in vivo. Furthermore, CMTM7 was a direct miR-182-5p target. Besides, we found that CMTM7 could interact with Catenin Alpha 1 (CTNNA1) and regulate Wnt/ß-catenin signaling. Finally, transcription factor 3 (TCF3) can regulate miR-182-5p. We identified a feedback loop with the composition of miR-182-5p, CMTM7, CTNNA1, CTNNB1 (ß-catenin), and TCF3, which play essential roles in breast cancer progression. CONCLUSION: These findings reveal the emerging character of CMTM7 in Wnt/ß-catenin signaling and bring new sights of gene interaction. CMTM7 and other elements in the feedback loop may serve as emerging targets for breast cancer therapy.

A Novel Oxidative Stress-Related lncRNA Signature That Predicts the Prognosis and Tumor Immune Microenvironment of Breast Cancer.

Background: The association between oxidative stress and lncRNAs within the cancer-related researching field has been a controversial subject. At present, the exact function of oxidative stress as well as lncRNAs exert in breast cancer (BC) are still unclear. Therefore, the present study examined the lncRNAs oxidative stress-related in BC. Methods: Transcriptome data of BC obtained from TCGA (The Cancer Genome Atlas) database were used to generate synthetic matrices. Patients with breast cancer were randomly assigned to training, testing, or combined groups. The prognostic signature of oxidative stress was created using the selection operator Cox regression method, and the difference in prognosis between groups was examined using Kaplan-Meier curves, the accuracy of which was calculated using a receiver-operating characteristic-area through the curve (ROC-AUC) analysis with internal validation. Also, the Gene Set Enrichment Analyses (GSEA) was applied for the analysis of the risk groups. To conclude, the half-maximal inhibitory concentration (IC50) of these groups were investigated by immunoassay assay. Results: A model based on 7 lncRNAs related to oxidative stress was proposed, and the calibration plots and projected prognosis matched well. For prognosis at 5, 3, and 1 year, the area under the ROC curve (AUC) values were 0.777, 0.777, and 0.759. The functions of target genes identified by GSEA appear to be mainly expressed in metabolism, signal transduction, tumorigenesis, and also the progression. The remarkable differences in IC50 and gene expression between risk groups in this study provide a deep insight for further systemic treatment. Higher macrophage scores were acquired in the high-risk group, of which patients showed more response to conventional chemotherapy drugs, such as AKT inhibitor VIII and Lapatinib, as well as immunotherapy strategies including anti-CD80, TNF SF4, CD276, and NRP1. Conclusion: The prognosis of breast cancer can be independently predicted by the markers, which sheds light on further research of the specific role of lncRNAs which are oxidative stress-related and clinical treatment of breast cancer.

miR-92a-3p promotes breast cancer proliferation by regulating the KLF2/BIRC5 axis.

BACKGROUND: Breast cancer remains the most common malignancy in females around the world. Recently, a growing number of studies have focused on gene dysregulation. In our previous study, Krüppel-like factors (KLFs) were found to play essential roles in breast cancer development, among which KLF2 could function as a tumor suppressor. Nevertheless, the underlying molecular mechanism remains unclear. METHODS: miR-92a-3p was identified as the upstream regulator of KLF2 by starBase v.3.0. The regulation of KLF2 by miR-92a-3p was verified by a series of in vitro and in vivo assays. Further exploration revealed that Baculoviral IAP Repeat Containing 5 (BIRC5) was the target of KLF2. ChIP assay, dual-luciferase reporter analysis, quantitative real-time PCR, and western blot were performed for verification. RESULTS: miR-92a-3p functioned as a tumor promoter by inhibiting KLF2 by binding to its 3'-untranslated region (3'-UTR). In addition, KLF2 could transcriptionally suppress the expression of BIRC5. CONCLUSION: Collectively, our results uncovered the miR-92a-3p/KLF2/BIRC5 axis in breast cancer and provided a potential mechanism for breast cancer development, which may serve as promising strategies for breast cancer therapy.

Impact of maternal age on neonatal outcomes among very preterm infants admitted to Chinese neonatal intensive care units: a multi-center cohort study.

Background: The percentage of advanced maternal age (aged over 35 years) mothers has been rising across the world, the evidence of maternal age on neonatal outcomes from low- and middle-income countries is scarce. Our objective was to evaluate the effect of maternal age on mortality and major morbidity among very preterm infants admitted to Chinese neonatal intensive care units. Methods: Data from a retrospective multi-center cohort of all complete care very preterm infants admitted to 57 neonatal intensive care units that participated in the Chinese Neonatal Network from January 1st to December 31st, 2019 were analyzed. Neonatal outcomes including mortality or any major morbidity, defined as necrotizing enterocolitis stage 2 or 3, moderate & severe bronchopulmonary dysplasia, severe intraventricular hemorrhage, cystic periventricular leukomalacia, severe retinopathy of prematurity, or sepsis. A multiple logistic regression model was constructed to analyze the independent association between maternal age and neonatal outcome. Results: Among 7,698 eligible newborns, 80.5% of very preterm infants were born to mothers between the ages of 21 and 35 years, with 18.0% born to mothers >35 years and 1.5% born to mothers <21 years. Higher rates of maternal hypertension, maternal diabetes, cesarean deliveries, antenatal steroid usage were noted as maternal age increased. The proportion of prenatal care, cesarean section, antenatal steroid usage and inborn for very preterm infants born to mothers <21 years was lower than those of mothers of other ages. Compared to the ages of 21-35 years group, the odds of severe intraventricular hemorrhage (adjusted odd ratio: 2.00, 95% CI: 1.08-3.71) was significantly higher in the ages of 15-20 years group. Increasing maternal age was associated with higher rates of small for gestational age and lower birth weight of very preterm infants, but no correlation between advanced maternal age and very preterm infants mortality or major morbidity. Conclusions: Among very preterm infants, increasing maternal age was associated with higher rates of small for gestational age but not neonatal mortality or major morbidity. Young maternal age may increase the risk of severe intraventricular hemorrhage of very preterm infants.

The ginger extract could improve diabetic retinopathy by inhibiting the expression of e/iNOS and G6PDH, apoptosis, inflammation, and angiogenesis.

Diabetic retinopathy is a complication of diabetes, caused by high blood sugar levels damaging the retina. It is the result of damage to the small blood vessels and neurons of the retina. Ginger and its phytochemical compounds can improve oxidative damage and inflammation. However, the effects of this plant on ocular expression G6PDH and e/iNOS, eye cell apoptosis, and angiogenesis are not well known in this tissue. Therefore, the aim of this study was to evaluate the therapeutic potential of ginger extract on rats with type 2 diabetic retinopathy. Thirty-two Wistar rats were randomly divided into four controlled and treated groups. The serum level of metabolic factors such as lipid profiles, insulin and glucose, and the level of oxidative biomarkers along with the TNF-α level in eye tissue were measured. The expression of NF-κB, VEGF, BAX, Bcl-2, caspase-3, e/iNOS, and G6PDH in eye tissue was measured. Serum levels of lipid profiles, glucose, and insulin, oxidative and inflammatory markers were significantly increased in the diabetic group compared to control. While, treatment with ginger extract could significantly improve these factors in diabetic rats. Moreover, the ocular expression of e/iNOS, G6PDH, VEGF, NF-κB, and genes involved in apoptosis was changed in diabetic rats. However, treatment with ginger extract could ameliorate these changes in the diabetic-treated group. It can be concluded that ginger extract could improve diabetic retinopathy by inhibiting oxidative damage, inflammation, iNOS, VEGF, apoptosis, and improving eNOS and G6PDH. PRACTICAL APPLICATIONS: Microvascular complications of diabetes such as retinopathy can be one of the main causes of disability in people with diabetes. Chronic hyperglycemia, oxidative stress, inflammation, and apoptosis cause diabetic retinopathy through retinal damage. Ginger, on the other hand, is an available, inexpensive, and uncomplicated medicinal plant that contains more than 20 different phytochemicals, such as gingerol and shogaol, which have anti-inflammatory, antioxidant, antihypertensive, hypoglycemic, and hypolipidemic properties. The results of our study showed well that the ginger extract could improve diabetic retinopathy by inhibiting the expression of e/iNOS and G6PDH and oxidative damage, apoptosis, inflammation, and angiogenesis. Therefore, ginger and its compounds can be a good option to improve the complications of diabetes.

NLRP3 Inflammasome Contributes to Host Defense Against Talaromyces marneffei Infection.

Talaromyce marneffei is an important thermally dimorphic pathogen causing disseminated mycoses in immunocompromised individuals in southeast Asia. Previous studies have suggested that NLRP3 inflammasome plays a critical role in antifungal immunity. However, the mechanism underlying the role of NLRP3 inflammasome activation in host defense against T. marneffei remains unclear. We show that T. marneffei yeasts but not conidia induce potent IL-1ß production. The IL-1ß response to T. marneffei yeasts is differently regulated in different cell types; T. marneffei yeasts alone are able to induce IL-1ß production in human PBMCs and monocytes, whereas LPS priming is essential for IL-1ß response to yeasts. We also find that Dectin-1/Syk signaling pathway mediates pro-IL-1ß production, and NLRP3-ASC-caspase-1 inflammasome is assembled to trigger the processing of pro-IL-1ß into IL-1ß. In vivo, mice deficient in NLRP3 or caspase-1 exhibit higher mortality rate and fungal load compared to wild-type mice after systemic T. marneffei infection, which correlates with the diminished recruitment of CD4 T cells into granulomas in knockout mice. Thus, our study first demonstrates that NLRP3 inflammasome contributes to host defense against T. marneffei infection.

Clinical and imaging predictors of impaired myocardial perfusion in symptomatic patients after percutaneous coronary intervention: insights from dynamic CT myocardial perfusion imaging.

BACKGROUND: We aimed to investigate the relationship between baseline clinical characteristics and postprocedural myocardial perfusion as determined by dynamic computed tomography myocardial perfusion imaging (CT-MPI). METHODS: We retrospectively included consecutive symptomatic post percutaneous coronary intervention (PCI) patients, who underwent dynamic CT-MPI + coronary CT angiography (CCTA) and who were revealed to have patent stents on previously revascularized lesions. Myocardial blood flow (MBF) was measured for stented territories and reference territories. Various baseline clinical and angiographic parameters were tested for the association with reduced MBF of stented territories. RESULTS: A total of 81 patients with 96 stented vessels were included in the analysis. The mean effective doses of radiation for the whole integrated CT protocol (calcium score + dynamic CT-MPI + CCTA) was 4.89±1.14 (2.58-6.93) mSv. Overall, 49 stented vessels had reduced MBF (75.3±17.2 mL/100 mL/min) within related territories, whereas 47 stented vessels had normal MBF (138.6±20.5 mL/100 mL/min). Peak levels of high-sensitivity cardiac troponin I (hs-cTnI), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), high-sensitivity C-reactive protein (hs-CRP), and glucose were significantly higher, while preprocedural thrombolysis in myocardial infarction (TIMI) flow grade was lower in participants with reduced MBF of stented territories. Acute myocardial infarction (AMI) also predominantly presented in participants with decreased MBF after revascularization. According to multivariate analysis, peak hs-cTnI level was the strongest predictor [adjusted hazard ratio (HR): 4.548, P=0.003] for decreased myocardial perfusion, followed by TIMI flow grade, AMI, stenotic extent, and NT-pro-BNP. CONCLUSIONS: The baseline hs-cTnI peak level was the strongest predictor for decreased myocardial perfusion after revascularization, followed by AMI, stenotic extent, and NT-pro-BNP.

Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene.

BACKGROUND: Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. METHODS AND RESULTS: Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6, respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. CONCLUSION: Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.