Drug resistance is a major obstacle to the treatment of most human tumors. In this study, we find that dual-specificity phosphatase 16 (DUSP16) regulates resistance to chemotherapy in nasopharyngeal ...carcinoma, colorectal cancer, gastric and breast cancer. Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression. Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment. In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment. Mechanistically, DUSP16 inhibits JNK and p38 activation, thereby reducing BAX accumulation in mitochondria to reduce apoptosis. Analysis of patient survival in head & neck cancer and breast cancer patient cohorts supports DUSP16 as a marker for sensitivity to chemotherapy and therapeutic outcome. This study therefore identifies DUSP16 as a prognostic marker for the efficacy of chemotherapy, and as a therapeutic target for overcoming chemoresistance in cancer.
IntroductionHigh myopia is a pressing public health concern due to its increasing prevalence, younger trend and the high risk of blindness, particularly in East Asian countries, including China. The ...China Alliance of Research in High Myopia (CHARM) is a newly established consortium that includes more than 100 hospitals and institutions participating across the nation, aiming to promote collaboration and data sharing in the field of high myopia screening, classification, diagnosis and therapeutic development.Methods and analysisThe CHARM project is an ongoing study, and its initiation is distinguished by its unprecedented scale, encompassing plans to involve over 100 000 Chinese patients. This initiative stands out not only for its extensive scope but also for its innovative application of artificial intelligence (AI) to assist in diagnosis and treatment decisions. The CHARM project has been carried out using a ‘three-step’ strategy. The first step involves the collection of basic information, refraction, axial length and fundus photographs from participants with high myopia. In the second step, we will collect multimodal imaging data to expand the scope of clinical information, for example, optical coherence tomography and ultra-widefield fundus images. In the final step, genetic testing will be conducted by incorporating patient family histories and blood samples. The majority of data collected by CHARM is in the form of images that will be used to detect and predict the progression of high myopia through the identification and quantification of biomarkers such as fundus tessellation, optic nerve head and vascular parameters.Ethics and disseminationThe study has received approval from the Ethics Committee of Beijing Tongren Hospital (TREC2022-KY045). The establishment of CHARM represents an opportunity to create a collaborative platform for myopia experts and facilitate the dissemination of research findings to the global community through peer-reviewed publications and conference presentations. These insights can inform clinical decision-making and contribute to the development of new treatment modalities that may benefit patients worldwide.Trial registration numberChiCTR2300071219.
The Calcium-sensing receptor (CaSR) participates in the regulation of gastrointestinal (GI) motility under normal conditions and might be involved in the regulation of GI dysmotility in patients with ...Parkinson's disease (PD).
CaSR antagonist-NPS-2143 was applied in in vivo and ex vivo experiments to study the effect and underlying mechanisms of CaSR inhibition on GI dysmotility in the MPTP-induced PD mouse model.
Oral intake of NPS-2143 promoted GI motility in PD mice as shown by the increased gastric emptying rate and shortened whole gut transit time together with improved weight and water content in the feces of PD mice, and the lack of influence on normal mice. Meanwhile, the number of cholinergic neurons, the proportion of serotonergic neurons, as well as the levels of acetylcholine and serotonin increased, but the numbers of nitrergic and tyrosine hydroxylase immunoreactive neurons, and the levels of nitric oxide synthase and dopamine decreased in the myenteric plexus in the gastric antrum and colon of PD mice in response to NPS-2143 treatment. Furthermore, the numbers of c-fos positive neurons in the nucleus tractus solitarius (NTS) and cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) increased in NPS-2143 treated PD mice, suggesting the involvement of both the enteric (ENS) and central (CNS) nervous systems. However, ex vivo results showed that NPS-2143 directly inhibited the contractility of antral and colonic strips in PD mice via a non-ENS mediated mechanism. Further studies revealed that NPS-2143 directly inhibited the voltage gated Ca2+ channels, which might, at least in part, explain its direct inhibitory effects on the GI muscle strips.
CaSR inhibition by its antagonist ameliorated GI dysmotility in PD mice via coordinated neuronal regulation by both ENS and CNS in vivo, although the direct effects of CaSR inhibition on GI muscle strips were suppressive.
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•Oral intake of NPS-2143 promoted gastrointestinal motility.•ENS and CNS are involved in the effects of NPS-2143 in vivo.•Direct effects of NPS-2143 on gastrointestinal strips is suppressive via VGCC.
Background Asthma is related to airway inflammation and oxidative stress. High levels of reactive oxygen and nitrogen species can induce cytotoxic DNA damage. Nevertheless, little is known about the ...possible role of allergen-induced DNA damage and DNA repair as modulators of asthma-associated pathology. Objective We sought to study DNA damage and DNA damage responses induced by house dust mite (HDM) in vivo and in vitro. Methods We measured DNA double-strand breaks (DSBs), DNA repair proteins, and apoptosis in an HDM-induced allergic asthma model and in lung samples from asthmatic patients. To study DNA repair, we treated mice with the DSB repair inhibitor NU7441. To study the direct DNA-damaging effect of HDM on human bronchial epithelial cells, we exposed BEAS-2B cells to HDM and measured DNA damage and reactive oxygen species levels. Results HDM challenge increased lung levels of oxidative damage to proteins (3-nitrotyrosine), lipids (8-isoprostane), and nucleic acid (8-oxoguanine). Immunohistochemical evidence for HDM-induced DNA DSBs was revealed by increased levels of the DSB marker γ Histone 2AX (H2AX) foci in bronchial epithelium. BEAS-2B cells exposed to HDM showed enhanced DNA damage, as measured by using the comet assay and γH2AX staining. In lung tissue from human patients with asthma, we observed increased levels of DNA repair proteins and apoptosis, as shown by caspase-3 cleavage, caspase-activated DNase levels, and terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling staining. Notably, NU7441 augmented DNA damage and cytokine production in the bronchial epithelium and apoptosis in the allergic airway, implicating DSBs as an underlying driver of asthma pathophysiology. Conclusion This work calls attention to reactive oxygen and nitrogen species and HDM-induced cytotoxicity and to a potential role for DNA repair as a modulator of asthma-associated pathophysiology.
Glutathione (GSH) is a useful biomarker in the development, diagnosis and treatment of cancer. However, most of the reported GSH biosensors are expensive, time-consuming and often require complex ...sample treatment, which limit its biological applications. Herein, a nanobiosensor for the detection of GSH using folic acid-functionalized reduced graphene oxide-modified BSA gold nanoclusters (FA-rGO-BSA/AuNCs) based on the fluorescence quenching interactions is presented. Firstly, a facile and optimized protocol for the fabrication of BSA/AuNCs is developed. Functionalization of rGO with folic acid is performed using EDC/NHS cross-linking reagents, and their interaction after loading with BSA/AuNCs is demonstrated. The formation of FA-rGO, BSA/AuNCs and FA-rGO-BSA/AuNCs are confirmed by the state-of-art characterization techniques. Finally, a fluorescence turn-off sensing strategy is developed using the as-synthesized FA-rGO-BSA/AuNCs for the detection of GSH. The nanobiosensor revealed an excellent sensing performance for the detection of GSH with high sensitivity and desirable selectivity over other potential interfering species. The fluorescence quenching is linearly proportional to the concentration of GSH between 0 and 1.75 µM, with a limit of detection of 0.1 µM under the physiological pH conditions (pH 7.4). Such a sensitive nanobiosensor paves the way to fabricate a "turn-on" or "turn-off" fluorescent sensor for important biomarkers in cancer cells, presenting potential nanotheranostic applications in biological detection and clinical diagnosis.
Atherosclerosis is the major cause of coronary artery disease (CAD) which includes unstable angina, myocardial infarction, and heart failure. The onset of atherogenesis, a process of atherosclerotic ...lesion formation in the intima of arteries, is driven by lipid accumulation, a vicious cycle of reactive oxygen species (ROS)-induced oxidative stress and inflammatory reactions leading to endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) activation, and foam cell formation which further fuel plaque formation and destabilization. In recent years, there is a surge in the number of publications reporting the involvement of circular RNAs (circRNAs) in the pathogenesis of cardiovascular diseases, cancers, and metabolic syndromes. These studies have advanced our understanding on the biological functions of circRNAs. One of the most common mechanism of action of circRNAs reported is the sponging of microRNAs (miRNAs) by binding to the miRNAs response element (MRE), thereby indirectly increases the transcription of their target messenger RNAs (mRNAs). Individual networks of circRNA–miRNA–mRNA associated with atherogenesis have been extensively reported, however, there is a need to connect these findings for a complete overview. This review aims to provide an update on atherogenesis-related circRNAs and analyze the circRNA–miRNA–mRNA interactions in atherogenesis. The atherogenic mechanisms and clinical relevance of each atherogenesis-related circRNA were systematically discussed for better understanding of the knowledge gap in this area.
Comprehensive Summary
A novel polyurethane polymer containing perylene diimide (PDI) unit and aniline segment, denoted as PU‐PDI, was designed and synthesized. Their tensile property and ...photophysical characteristic were investigated using various experimental and theoretical techniques. It is found that the elongation of PU‐PDIs can reach more than 1000%, indicating good tensile performance. Moreover, based on the photoinduced electron transfer mechanism, the aniline segments in polyurethane can quench the auto‐fluorescence of PDI unit to a negligible value, which overcomes the intractable fluorescence drawbacks of conventional colour filters. The non‐emissive characteristic, in combination with the good thermal stability and tensile property of PU‐PDI, provides a feasible design strategy to fabricate optical filters with high display quality.
A series of perylene diimide (PDI) functionalized polyurethane polymers (PU‐PDI) were designed and synthesized. The non‐emissive characteristic, in combination with the good tensile property and thermal stability of PU‐PDI, makes it a promising material for fabrication of optical filters.
Contactin-1 has been shown to promote cancer metastasis. However, the underlying mechanisms remain unclear. We report here that knockdown of contactin-1 in A549 lung cancer cells reduced A549 cell ...invasion and the cell's ability to grow in soft agar without affecting cell proliferation. Reduction of contactin-1 resulted in upregulation of E-cadherin, consistent with E-cadherin being inhibitive of cancer cell invasion. In an effort to investigate the mechanisms whereby contactin-1 reduces E-cadherin expression, we observed that contactin-1 plays a role in AKT activation, as knockdown of contactin-1 attenuated AKT activation. Additionally, inhibition of AKT activation significantly enhanced E-cadherin expression, an observation that mimics the situation observed in contactin-1 knockdown, suggesting that activation of AKT plays a role in contactin-1-mediated downregulation of E-cadherin. In addition, we were able to show that knockdown of contactin-1 did not further reduce A549 cell's invasion ability, when AKT activation was inhibited by an AKT inhibitor. To further support our findings, we overexpressed CNTN-1 in two CNTN-1 null breast cancer cell lines expressing E-cadherin. Upon overexpression, CNTN-1 reduced E-cadherin levels in one cell line and increased AKT activation in the other. Furthermore, in our study of 63 primary lung cancers, we observed 65% of primary lung cancers being contactin-1 positive and in these carcinomas, 61% were E-cadherin negative. Collectively, we provide evidence that contactin-1 plays a role in the downregulation of E-cadherin in lung cancer and that AKT activation contributes to this process. In a study of mechanisms responsible for contactin-1 to activate AKT, we demonstrated that knockdown of CNTN-1 in A549 cells did not enhance PTEN expression but upregulated PHLPP2, a phosphatase that dephosphorylates AKT. These observations thus suggest that contactin-1 enhances AKT activation in part by preventing PHLPP2-mediated AKT dephosphrorylation.
Aims
To assess the overall relative risk of diabetes in individuals with prediabetes based on updated diagnostic criteria, as compared with individuals with normoglycaemia; and to identify the study ...characteristics associated with the heterogeneity between studies.
Design
Meta‐analysis, meta‐regression.
Data sources
PubMed, CINAHL, British Nursing Index. Search time frame: December 1998–December 2018.
Review Methods
The pooled relative risk of developing diabetes among individuals with prediabetes compared with those with normoglycaemia was calculated under a random effects model. Studies reported the natural progression from prediabetes to diabetes were included in this review. Sources of study heterogeneity were examined by a meta‐regression.
Results
Fifty‐nine eligible studies were systematically identified. The pooled relative risk for diabetes among individuals with prediabetes as compared with normoglycaemia was 5.88 (95% CI: 5.02‐6.89). The annualized incidence rate (per 1,000 person‐year) for diabetes among individuals with prediabetes defined by different criteria varied from 2.20–212.15, with high heterogeneity between studies (I2 = 96.64%, Q test: p < .001). In the multivariable meta‐regression analysis, Asian population significantly increased RR compare to Caucasians. Besides, people with ‘elevated glycated haemoglobin A1c or impaired fasting glucose’ had highest relative risk compare to people with other types of prediabetes.
Conclusion
Individuals with prediabetes had higher risk of developing diabetes than those with normoglycaemia. Races and diagnostic criteria of prediabetes were associated with the magnitude of the estimated risk.
Impact
Prediabetes is a precursor of diabetes. To screen people with prediabetes as early as possible, practitioners could consider haemoglobin A1c test as an alternative to fasting plasma glucose test. Nurses should educate people especially Asians with prediabetes for the prevention of progression to diabetes.
摘要
目的
根据更新的诊断标准,与正常血糖的个体相比,评估糖尿病前期个体患糖尿病的总体相对风险;并确定与研究间异质性相关的研究特征。
设计
荟萃分析、荟萃回归。
数据来源
PubMed、CINAHL、英国护理学索引。搜索时间范围:1998年12月至2018年12月。
审查方法
在随机效应模型下,计算了与正常血糖个体相比,糖尿病前期个体患糖尿病的合并相对风险度。研究报告指出,从糖尿病前期发展为糖尿病的自然发展被纳入本审查中。通过荟萃回归检查了研究的异质性来源。
结果
系统化地确定了59项符合条件的研究。与正常血糖个体相比,糖尿病前期个体患糖尿病的合并相对风险度为5.88(95%置信区间:5.02‐6.89)。按不同标准定义的糖尿病前期个体的糖尿病年发病率(每1000人‐年)在2.20‐212.15不等,研究间异质性较高(I2=96.64%,Q检验:P<.001)。在多变量荟萃回归分析中,与白种人相比,亚洲人的相对风险度显著增加。此外,‘糖化血红蛋白A1c升高或空腹血糖受损’的人群与其他类型的糖尿病前期人群相比,相对风险度最高。
结论
糖尿病前期个体患糖尿病的风险血糖正常个体。糖尿病前期的个体类别和诊断标准与估计的风险量级有关。
影响
糖尿病前期是糖尿病的前兆。为了尽早筛查糖尿病前期人群,医生可以考虑用血红蛋白A1c测试来代替空腹血糖检测。护士应提醒人们,尤其是糖尿病前期的亚洲人,以防止发展成糖尿病。
Variants (pathogenic) of the LMNA gene are a common cause of familial dilated cardiomyopathy (DCM), which is characterised by early-onset atrioventricular (AV) block, atrial fibrillation and ...ventricular tachyarrhythmias (VTs), and progressive heart failure. The unstable internal nuclear lamina observed in LMNA-related DCM is a consequence of the disassembly of lamins A and C. This suggests that LMNA variants produce truncated or alternative forms of protein that alter the nuclear structure and the signalling pathway related to cardiac muscle diseases. To date, the pathogenic mechanisms and phenotypes of LMNA-related DCM have been studied using different platforms, such as patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) and transgenic mice. In this review, point variants in the LMNA gene that cause autosomal dominantly inherited forms of LMNA-related DCM are summarised. In addition, potential therapeutic targets based on preclinical studies of LMNA variants using transgenic mice and human iPSC-CMs are discussed. They include mitochondria deficiency, variants in nuclear deformation, chromatin remodelling, altered platelet-derived growth factor and ERK1/2-related pathways, and abnormal calcium handling.
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