Simultaneous Visualization and Depletion of Peroxynitrite by a Simple Aggregation-Induced Emission Nanoprobe for Preventing Breast Cancer Metastasis after Surgery.

Inflammation has been confirmed to be closely related to the development of tumors, while peroxynitrite (ONOO-) is one of the most powerful oxidative pro-inflammatory factors. Although ONOO- can kill bacteria through oxidation, it will activate matrix metalloproteinases (MMPs), accelerate the degradation of the extracellular matrix (ECM), and subsequently lead to the activation and release of other tumor promotion factors existing in the ECM, promoting tumor metastasis and invasion. Herein, we report a simple aggregation-induced emission (AIE) nanoprobe (NP), TPE-4NMB, that can simultaneously visualize and deplete ONOO-. The probe can light up the endogenous and exogenous ONOO- in cells and selectively inhibit the proliferation and migration of 4T1 cells by inducing an intracellular redox homeostasis imbalance through ONOO- depletion. After being modified with DSPE-PEG2000, the TPE-4NMB NPs can be used to image ONOO- induced by various models in vivo; especially, it can monitor the dynamic changes of ONOO- level in the residual tumor after surgery, which can provide evidence for clarifying the association between surgery, ONOO-, and cancer metastasis. Excitingly, inhibited tumor volume growth and decreased counts of lung metastases were observed in the TPE-4NMB NPs group, which can be attributed to the downregulated expression of MMP-9 and transforming growth factor-ß (TGF-ß), increased cell apoptosis, and inhibited epithelial-mesenchymal transition (EMT) mediated by ONOO-. The results will provide new evidence for clarifying the relationship between surgery, ONOO-, and tumor metastasis and serve as a new intervention strategy for preventing tumor metastasis after tumor resection.

TGF-ß1 mediates tumor immunosuppression aggravating at the late stage post-high-light-dose photodynamic therapy.

Photodynamic therapy (PDT) is an emerging clinical treatment that is expected to become an important adjuvant strategy for the immunotherapeutic cancer treatment. Recently, numerous works have reported combination strategies. However, clinical data showed that the anti-tumor immune response of PDT was not lasting though existing. The immune activation effect will eventually turn to immunosuppressive effect and get aggravated at the late stage post-PDT. So far, the mechanism is still unclear, which limits the design of specific correction strategies and further development of PDT. Several lines of evidence suggest a role for TGF-ß1 in the immunosuppression associated with PDT. Herein, this study systematically illustrated the dynamic changes of immune states post-PDT within the tumor microenvironment. The results clearly demonstrated that high-light-dose PDT, as a therapeutic dose, induced early immune activation followed by late immunosuppression, which was mediated by the activated TGF-ß1 upregulation. Then, the mechanism of PDT-induced TGF-ß1 accumulation and immunosuppression was elucidated, including the ROS/TGF-ß1/MMP-9 positive feedback loop and CD44-mediated local amplification, which was further confirmed by spatial transcriptomics, as well as by the extensive immune inhibitory effect of local high concentration of TGF-ß1. Finally, a TGF-ß blockade treatment strategy was presented as a promising combinational strategy to reverse high-light-dose PDT-associated immunosuppression. The results of this study provide new insights for the biology mechanism and smart improvement approaches to enhance tumor photodynamic immunotherapy.

Single-cell transcriptomic analysis reveals key immune cell phenotypes in the lungs of patients with asthma exacerbation.

BACKGROUND: Asthma exacerbations are associated with heightened asthma symptoms, which can result in hospitalization in severe cases. However, the molecular immunologic processes that determine the course of an exacerbation remain poorly understood, impeding the progression of development of effective therapies. OBJECTIVE: Our aim was to identify candidate genes that are strongly associated with asthma exacerbation at a cellular level. METHODS: Subjects with asthma exacerbation and healthy control subjects were recruited, and bronchoalveolar lavage fluid was isolated from these subjects via bronchoscopy. Cells were isolated through fluorescence-activated cell sorting, and single-cell RNA sequencing was performed on enriched cell populations. RESULTS: We showed that the levels of monocytes, CD8+ T cells, and macrophages are significantly elevated in the bronchoalveolar lavage fluid of patients. A set of cytokines and intracellular transduction regulators are associated with asthma exacerbations and are shared across multiple cell clusters, forming a complicated molecular framework. An additional group of core exacerbation-associated modules is activated, including eukaryotic initiation factor 2 signaling, ephrin receptor signaling, and C-X-C chemokine receptor type 4 signaling in the subpopulations of CD8+ T cells (C1-a) and monocyte clusters (C7 clusters), which are associated with infection. CONCLUSION: Our study identified a significant number of severe asthma-associated genes that are differentially expressed by multiple cell clusters.

FUS-induced circular RNA ZNF609 promotes tumorigenesis and progression via sponging miR-142-3p in lung cancer.

Circular RNAs (circRNAs) have been associated with lung cancer (LC), one of the most common cancers, but the underlying molecular mechanisms of the specific correlation with LC carcinogenesis remain unveiled. Quantitative real-time polymerase chain reaction was applied to examine the level of circZNF609. LC cells were transfected with silenced circZNF609 by siRNAs, and cell proliferation, migration, and apoptosis were evaluated to reflect the influences of circZNF609 knockdown in LC. Biotin-coupled circRNA capture, FISH and luciferase reporter assays were performed to study the relationship between circZNF609 and miR-142-3p. In current work, it was discovered that circZNF609 functioned as an onco-circRNA, which exhibited high expression as well as facilitated the proliferation and migration in LC cells. Next, we discovered that FUS RNA-binding protein, which could bind to the ZNF609 pre-mRNA, induced circZNF609 formation, and increased circZNF609 expression in LC. Furthermore, circZNF609 was verified to sponge and sequester miR-142-3p; circZNF609 enhanced LC cell proliferative and migrative ability via targeting miR-142-3p. Finally, G protein subunit beta 2 (GNB2) was figured out to involve in circZNF609/miR-142-3p axis-induced LC development. Conclusively, the results indicated that FUS-induced circZNF609 exerts promotional effects on LC cell proliferation and migration through modulation of the miR-142-3p/GNB2 axis, which could offer new insight for understanding LC.

lncRNA SNHG11 promotes lung cancer cell proliferation and migration via activation of Wnt/ß-catenin signaling pathway.

Lung cancer ranks topmost among the most frequently diagnosed cancers. Despite increasing research, there are still unresolved mysteries in the molecular mechanism of lung cancer. Long noncoding RNA small nucleolar RNA host gene 11 (SNHG11) was found to be upregulated in lung cancer and facilitated lung cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition progression while suppressed cell apoptosis. Moreover, the high expression of SNHG11 was correlated with poor prognosis of lung cancer patients, TNM stage, and tumor size. Further assays demonstrated that SNHG11 functioned in lung cancer cells via Wnt/ß-catenin signaling pathway. Subsequently, Wnt/ß-catenin pathway was found to be activated through SNHG11/miR-4436a/CTNNB1 ceRNA axis. As inhibiting miR-4436 could only partly rescue the suppression of cell function induced by silencing SNHG11, it was suspected that ß-catenin might enter cell nucleus through other pathways. Mechanism investigation proved that SNHG11 would directly bind with ß-catenin to activate classic Wnt pathway. Subsequently, in vivo tumorigenesis was also demonstrated to be enhanced by SNHG11. Hence, SNHG11 was found to promote lung cancer progression by activating Wnt/ß-catenin pathway in two different patterns, implying that SNHG11 might contribute to lung cancer treatment by acting as a therapeutic target.

Arterial stiffness in adults with steady-state bronchiectasis: association with clinical indices and disease severity.

BACKGROUND: Cardiovascular disease are common co-morbidities in bronchiectasis and contribute substantially to disease burden and mortality. Brachial-ankle pulse wave velocity (baPWV), a measure of arterial stiffness, has a strong predictive value for cardiovascular event. We hypothesized that baPWV would be increased in steady-state bronchiectasis patients, and correlates with the degree of systemic inflammation and disease severity assessed with Bronchiectasis Severity Index and FACED scores. METHODS: Eighty patients with steady-state bronchiectasis and 80 age- and sex-matched controls were enrolled. BaPWV was measured as an indicator of arterial stiffness. Demographic, clinical indices, radiology, spirometry, sputum bacteriology and systemic inflammatory mediators were also assessed. RESULTS: Bronchiectasis patients had significantly increased baPWV [median 1514 cm/s vs. 1352 cm/s, P = 0.0003] compared with control subjects. BaPWV significantly correlated with Bronchiectasis Severity Index (rho = 0.65, P < 0.001) and FACED (rho = 0.49, P < 0.001) scores. In multivariate regression analysis, age, Pseudomonas aeruginosa colonization, systolic blood pressure, body-mass index and exacerbation frequency in the last 12 months, but not systemic inflammatory markers, were independent factors influencing on baPWV in bronchiectasis patient after adjustment for other clinical variables. Reproducibility of baPWV measurement was good. CONCLUSION: Bronchiectasis patients have increased arterial stiffness compared with control subjects, which correlates with disease severity, but not systemic inflammatory markers. Age, Pseudomonas aeruginosa colonization, systolic blood pressure, body-mass index and exacerbation frequency in last 12 months might independently predict the severity of arterial stiffness in bronchiectasis. Therefore, arterial stiffness might have contributed to the increased risks of developing cardiovascular diseases in bronchiectasis.

Aetiology of bronchiectasis in adults: A systematic literature review.

While identifying the underlying aetiology is a key part of bronchiectasis management, the prevalence and impact of identifying the aetiologies on clinical management remain unclear. We aimed to determine the etiological spectrum of bronchiectasis, and how often etiological assessment could lead to the changes in patients' management. A comprehensive search was conducted using MEDLINE (via PubMed) and EMBASE for observational studies published before October 2015 reporting aetiologies in adults with bronchiectasis. Of the 8216 citations identified, 56 studies including 8608 adults with bronchiectasis were relevant for this systematic review. The crude prevalence for the identified aetiologies ranged from 18% to 95%, which possibly resulted from the differences in the geographic regions and diagnostic workup. Post-infective (29.9%), immunodeficiency (5%), chronic obstructive pulmonary disease (3.9%), connective tissue disease (3.8%), ciliary dysfunction (2.5%), allergic bronchopulmonary aspergillosis (2.6%) were the most common aetiologies. In 1577 patients (18.3%), identifying the aetiologies led to changes in patient's management. Aetiologies varied considerably among different geographic regions (P < 0.001). Intensive investigations of these aetiologies might help change patient's management and therefore should be incorporated into routine clinical practice.

Effects of resveratrol on HIF-1α/VEGF pathway and apoptosis in vitrified duck ovary transplantation.

Preservation of ovarian tissues is an effective way to ensure genetic diversity of susceptible natural bird populations that are in danger of extinction. We examined whether the addition of the plant phenol resveratrol to vitrification solutions ameliorates the damaging effects of tissue hypoxia and reperfusion injury when the tissues are transplanted. Duck ovary tissues were frozen in the presence of varying concentrations of resveratrol in cryopreservation solutions and then transplanted under the renal capsules of 2-day-old Shelducks. Samples of the transplanted tissues were examined on days 3- and 9- post transplantation for activation of hypoxia-, antioxidant- and apoptosis-related gene expression and apoptosis. Resveratrol significantly increased expression of VEGF, HIF-1α, Nrf2, CAT and Bcl-2 mRNA and decreased BAX and Caspase-3 mRNA and reduced numbers of TUNEL-positive cells after vitrification and heterotopic ovarian transplantation. Resveratrol improved the antioxidant capacity, reduced apoptosis and activated the HIF-1α/VEGF pathway to promote angiogenesis 3- and 9-days following transplantation. These results indicated that the addition of resveratrol to vitrification solutions intended for long-term cryopreservation of ovary tissues improves survival in storage and the grafts following transplantation. This study provides a theoretical basis for the successful transplantation of avian ovarian tissue after vitrification.

HBO1 induces histone acetylation and is important for non-small cell lung cancer cell growth.

We examined the expression and the potential biological function of HBO1 in non-small cell lung cancer (NSCLC). TCGA and Oncomine databases showed that HBO1 transcripts were elevated in NSCLC. Furthermore, in local NSCLC tumor tissues HBO1 expression was higher than that in matched adjacent lung tissues. In primary and immortalized NSCLC cells, HBO1 shRNA robustly inhibited cell viability, proliferation and migration. Moreover, HBO1 knockout by CRISPR/Cas9 induced significant anti-tumor activity in NSCLC cells. Conversely, ectopic HBO1 overexpression in primary NSCLC cells increased proliferation and migration. H3-H4 histone acetylation and expression of several potential oncogenic genes (CCR2, MYLK, VEGFR2 and OCIAD2) were significantly decreased in NSCLC cells with HBO1 silencing or knockout. They were however increased after HBO1 overexpression. Intratumoral injection of HBO1 shRNA-expressing adeno-associated virus hindered the growth of A549 cell xenografts and primary NSCLC cell xenografts in nude mice. H3-H4 histone acetylation as well as expression of HBO1 and HBO1-dependent genes were decreased in HBO1-silenced NSCLC xenograft tissues. An HBO1 inhibitor WM-3835 potently inhibited NSCLC cell growth. Together, HBO1 overexpression promotes NSCLC cell growth.

Birth Weight and Incidence of Breast Cancer: Dose-Response Meta-analysis of Prospective Studies.

BACKGROUND: Many studies have shown the association between birth weight and breast cancer (BC), but the evidence remains limited and inconsistent, especially in different menopause status. We sought to clarify the relationship and shape of the dose-response relation between birth weight and BC. METHODS: The Web of Science, PubMed, and Embase databases were searched for prospective studies involving the relationship between birth weight and risk of BC published to November 2019. Random effects of generalized least squares regression models were used to estimate the quantitative dose-response association, and restricted cubic splines were used to model the association. RESULTS: We included reports of 16 prospective studies describing 16,000 incident cases among 553,644 participants. We identified a modest-in-magnitude, but significant, association between birth weight and BC risk: risk increased by 2% (risk ratio, 1.02, 95% confidence interval, 1.01-1.03) and 9% (risk ratio, 1.09, 95% confidence interval, 1.04-1.15) with a per-500 g birth weight increment in all ages and premenopausal women, respectively. Our results showed a linear dose-response relationship between birth weight and BC risk (Pnonlinearity = .311) in premenopausal women, with statistical significance when birth weight was above about 3.5 kg. No significant association was found in postmenopausal women. CONCLUSION: Higher birth weight has a relationship with increased risk of BC in premenopausal women, particularly when birth weight is above 3.5 kg.

[Effect of selenium-protein polysaccharide extracted from Se-rich Cordyceps militaris on tumor-bearing mice].

OBJECTIVE: To extract and analysis the active components of Se-protein polysaccharide from Se-rich Cordyceps militaris, and to discuss the anti-tumor effect of Se-protein polysaccharide. METHOD: Protein, polysaccharides and selenium content were determined by the methods of Folin-phenol reagent (lowry), phenol-sulfate and DAN fluorescence, respectively. Tumor-bearing mouse model was established and divided into the model group, cyclophosphamide group, cordyceps high and low dosage group (200, 100 mg x kg(-1)). Then the Se-protein polysaccharide's anti-tumor activity and immune function in vivo were observed by compare with model group in the weight of mice, inhibitory rate, conversion rate of peripheral blood lymphocytes, dissection index K, swallowed factor alpha, liver and spleen factor coefficient, GSH-Px and SOD activity and the content of MDA. RESULT: Se-protein polysaccharides from Se-rich Cordyceps militaris had a significant anti-tumor action with the inhibitory rate 46.92% and could avoid toxic effect of chemotherapy drug like cyclophosphamide. It also could enhance immune function and body antioxidant capacity by inhibiting the decline of tumor-bearing mouse liver coefficient and spleen coefficient in tumor-bearing mice caused by cyclophosphamide. CONCLUSION: Se-protein polysaccharide, the extraction of Se-rich Cordyceps militaris's can inhibit tumor grouth of tumor-bearing mouse.

Subclinical atherosclerosis in adults with steady-state bronchiectasis: A case-control study.

BACKGROUND AND OBJECTIVE: Bronchiectasis has been associated with increased risks of cardiovascular disease, in which early-stage endothelial dysfunction might have played pivotal roles. We aimed to investigate endothelial function in bronchiectasis patients, by measuring flow-mediated dilatation (FMD) and carotid intima-media thickness (CIMT) as compared with control subjects, and to elucidate the impact of different risk factors on subclinical atherosclerosis. METHODS: The study included 80 bronchiectasis patients and 80 age- and sex-matched healthy subjects. Vascular endothelial function was evaluated with FMD in the brachial artery in response to reactive hyperemia, and CIMT was measured with high-resolution ultrasonography. Disease severity was evaluated with Bronchiectasis Severity Index and FACED scores. Demographic, disease duration, radiology, spirometry, sputum bacteriology and systemic inflammatory indices were also assessed. RESULTS: FMD was significantly lower in bronchiectasis patients than in control subjects (8.92 ± 2.70% vs. 11.17 ± 3.44%, P < 0.001). FMD significantly correlated with Bronchiectasis Severity Index (rho = -0.60, P < 0.001) and FACED score (rho = -0.39, P < 0.001). In multivariate regression analysis, age, body-mass index, Pseudomonas aeruginosa colonization and high-resolution computed tomography scores were independent factors influencing on the FMD in bronchiectasis patients, even after adjustment for other clinical variables. No significant difference in CIMT was detected between bronchiectasis patients and healthy subjects (P > 0.05). CONCLUSIONS: Compared with healthy subjects, bronchiectasis patients have greater risks of endothelial dysfunction which is independent of previously well-studied risk factors, calling for the vigilance to screen early for vascular changes to minimize the future risks of cardiovascular events.

Subclinical atherosclerosis risk markers in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular morbidity and mortality. Identifying early changes of cardiovascular system before the occurrence of fatal clinical event is critical for the management of COPD. We performed a meta-analysis to investigate the associations between COPD and subclinical markers of cardiovascular risk. METHODS: We searched PUBMED, EMBASE for studies published before Aug 1st, 2016, on the association between COPD and carotid intima-media thickness (CIMT), prevalence of carotid plaques, flow-mediated dilation (FMD), pulse-wave velocity (PWV) and augmentation index (AIx). RESULTS: Thirty-two studies (3198 patients, 13867 controls) were included. Compared with controls, COPD patients had significantly higher CIMT (MD: 0.10 mm; 95% CI: 0.04, 0.16; p = 0.0007), PWV (SMD: 0.70; 95% CI: 0.52, 0.88; p < 0.0001), AIx (MD: 4.60%; 95% CI: 0.52, 8.68; p = 0.03), AIx@75 (AIx normalized to a heart rate of 75 beats per minute) (MD: 4.59%; 95% CI: 2.80, 6.38; p < 0.0001), prevalence of carotid plaque (OR: 2.54; 95% CI: 2.04, 3.15; p < 0.0001), and significantly lower FMD (MD: -4.21%; 95% CI: -6.71, -1.71; p = 0.001). Sensitivity and subgroups analyses substantially confirmed our results. Meta-regression analysis revealed that spirometry (as expressed by FEV1%predicted) might influence on PWV. CONCLUSIONS: These findings indicate that COPD, even in mild to moderate patients, had greater impaired markers of subclinical atherosclerosis and cardiovascular risk. However, further studies are still needed to address confounders, such as age, smoking, hypertension, diabetes etc, which might affect the associations in COPD patients.

Therapeutic efficiency of succimer used with calcium and ascorbic acid in the treatment of mild lead-poisoning.

The aim of this study was to explore therapeutic efficiency of succimer used with calcium and ascorbic acid in the treatment of mildly lead-poisoned mice and preschool children. Mice were exposed to lead by drinking water, and then treated with saline solution, 50mg/kg body weight (b.w.) succimer, 100mg/kg b.w. succimer, or 50mg/kg b.w. succimer plus calcium and ascorbic acid by gavage. Seventy-two children aged 48-72 months were randomly assigned into combined treatment or nutritional intervention group. Lead levels in blood and bone were analyzed by atomic absorption spectrophotometry. Activities of aminolevulinic acid dehydratase (ALAD) in blood were determined by colorimetric method. Results of animal experiment showed that succimer used alone could reduce lead levels in blood and bone and reverse activities of ALAD in blood, however, a better therapeutic efficiency in mobilizing bone lead could be achieved by succimer used with calcium and ascorbic acid. Findings from the clinical study showed that reduction of blood lead levels (BLLs) between the end and initiation of therapy in the combined treatment group was significantly greater than that in the nutritional intervention group. Percentage of children with BLLs less than 10µg/dL at the end of therapy and the eighth week after therapy in the combined treatment group was significantly higher than that in the nutritional intervention group. In conclusion, combined use of succimer with calcium and ascorbic acid seemed to be a choice in the treatment of mildly lead poisoned children.

Health effects in children aged 3-6 years induced by environmental lead exposure.

OBJECTIVES: To investigate the involvement of oxidative damage in lead-induced toxicity in children aged 3-6 years and to enlighten whether oxidative stress indicators are correlated with the known indices of lead toxicity. METHODS: Blood samples were collected from 408 subjects (217 boys and 191 girls) in the urban kindergartens. The age range of the subjects was 3-6 years. Blood lead levels (BLLs) were analyzed by flameless atomic absorption spectrophotometry. Activities of delta-aminolevulinic acid dehydratase (ALAD), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and contents of glutathione (GSH) in erythrocyte and levels of plasma malondialdehyde (MDA) were analyzed spectrophotometrically in these children. RESULTS: Children with BLLs >or = 100 microg/L had significantly decreased erythrocyte ALAD activities and increased plasma MDA levels compared to the children with BLLs < 100 microg/L. No significant changes were observed in erythrocyte SOD and GSH-Px activities and GSH levels associated with elevated BLLs in these children. CONCLUSION: Present data indicate that oxidative damage could be induced by lead in children with BLLs > or = 100 microg/L, and this may partly be attributed to the inhibited ALAD activities. Statistically significant changes of oxidative stress parameters in preschool children while BLLs were more than 100 microg/L could be implicated that oxidative damage might contribute to lead-induced intellectual impairment.