Expression of indoleamine 2,3-dioxygenase in nasopharyngeal carcinoma impairs the cytolytic function of peripheral blood lymphocytes

<p>Abstract</p> <p>Background</p> <p>Tumor-specific cytotoxic T cells and infiltrating lymphocytes are frequently found in tumor tissues in patients with nasopharyngeal carcinoma (NPC). Most patients with NPC, however, especially those with advanced stages, have a poor clinical prognosis despite conventional immunotherapy. The aim of this work was to examine the effect of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme, on the lymphocyte function in NPC.</p> <p>Methods</p> <p>The NPC cell line CNE2 was treated by interferon-γ (IFNγ) and the levels of IDO expression was analyzed by Western blotting and reverse phase high-performance liquid chromatography (HPLC). Lymphocytes from health human exposed to the milieu created by IDO-positive CNE2 cells and the lymphocyte cytotoxicity to target tumor cells was analyzed by standard lactate dehydrogenase (LDH) release assay. Additionally, expression of IDO was determined by Immunohistochemical assay in the tumor tissues form clinically evaluated NPC.</p> <p>Results</p> <p>IDO expression was acutely induced in the NPC cell line CNE2 by low dose interferon-γ (IFNγ) or by co-incubation with activated lymphocytes. Exposure to the milieu created by IDO-positive CNE2 cells did not promote lymphocyte death, but lymphocyte cytotoxicity against target tumor cells was impaired. The suppression of lymphocyte cytotoxic function was fully restored when the conditioned medium was replaced by fresh medium for 24 h. In additionally, the IDO-positive cells were found scattered in the tumor tissues from patients with NPC.</p> <p>Conclusion</p> <p>Altogether, these findings suggest that IDO-mediated immunosuppression may be involved in the tumor immune evasion, and that blocking IDO activity in tumor cells may help to re-establish an effective anti-tumor T cell response in NPC.</p

Effective inhibition of foot-and-mouth disease virus (FMDV) replication in vitro by vector-delivered microRNAs targeting the 3D gene

<p>Abstract</p> <p>Background</p> <p>Foot-and-mouth disease virus (FMDV) causes an economically important and highly contagious disease of cloven-hoofed animals. RNAi triggered by small RNA molecules, including siRNAs and miRNAs, offers a new approach for controlling viral infections. There is no report available for FMDV inhibition by vector-delivered miRNA, although miRNA is believed to have more potential than siRNA. In this study, the inhibitory effects of vector-delivered miRNAs targeting the 3D gene on FMDV replication were examined.</p> <p>Results</p> <p>Four pairs of oligonucleotides encoding 3D-specific miRNA of FMDV were designed and selected for construction of miRNA expression plasmids. In the reporter assays, two of four miRNA expression plasmids were able to significantly silence the expression of 3D-GFP fusion proteins from the reporter plasmid, p3D-GFP, which was cotransfected with each miRNA expression plasmid. After detecting the silencing effects of the reporter genes, the inhibitory effects of FMDV replication were determined in the miRNA expression plasmid-transfected and FMDV-infected cells. Virus titration and real-time RT-PCR assays showed that the p3D715-miR and p3D983-miR plasmids were able to potently inhibit the replication of FMDV when BHK-21 cells were infected with FMDV.</p> <p>Conclusion</p> <p>Our results indicated that vector-delivered miRNAs targeting the 3D gene efficiently inhibits FMDV replication <it>in vitro</it>. This finding provides evidence that miRNAs could be used as a potential tool against FMDV infection.</p

Multiple-element exposure and metabolic syndrome in Chinese adults: A case-control study based on the Beijing population health cohort

Background Metabolic syndrome (MetS) patients have a considerably increased risk for noncommunicable diseases, which poses a serious burden on public health. The effects of different elements on MetS have received increasing attention in the field of noncommunicable diseases over the past decade. These elements can exert adverse or favourable effects on human health by synergistic or antagonistic actions. Nevertheless, few studies have explored the relationship between multiple-element exposure and MetS. Method A total of 2095 MetS patients and 2039 controls free of major cardiovascular disease at baseline and follow-up visits were frequency matched for age (±5 years) and sex. The internal exposure levels of 15 elements in serum were investigated. Logistic regression models were employed to estimate odds ratios (ORs) of MetS for element concentrations categorized according to quartiles in the controls. Result Magnesium (Mg), selenium (Se), barium (Ba) and mercury (Hg) were significantly associated with MetS in the multi-element exposure model. The ORs for the extreme quartiles of Mg, Se, Ba, and Hg were 0.29 (95% CI: 0.23–0.37, P-trend < 0.001), 0.52 (95% CI: 0.42–0.65, P-trend < 0.001), 1.86 (95% CI: 1.51–2.28, P-trend < 0.001), and 2.61 (95% CI: 2.11–3.22, P-trend < 0.001), respectively. Ba may be antagonistic to Mg and Se in the human body. Conclusions Our study suggested that MetS was negatively associated with Mg and Se and positively associated with Ba and Hg. There were significant dose-response relationships between Mg, Se, Ba and Hg and the prevalence of MetS, suggesting that multiple elements may be involved in MetS

Asthma prevalence based on the Baidu index and China's Health Statistical Yearbook from 2011 to 2020 in China

BackgroundDue to environmental pollution, changes in lifestyle, and advancements in diagnostic technology, the prevalence of asthma has been increasing over the years. Although China has made early efforts in asthma epidemiology and prevention, there is still a lack of unified and comprehensive epidemiological research within the country. The objective of the study is to determine the nationwide prevalence distribution of asthma using the Baidu Index and China's Health Statistical Yearbook.MethodsBased on China's Health Statistical Yearbook, we analyzed the gender and age distribution of asthma in China from 2011 to 2020, as well as the length of hospitalization and associated costs. By utilizing the Baidu Index and setting the covering all 31 provinces and autonomous regions in China, we obtained the Baidu Index for the keyword 'asthma'. Heatmaps and growth ratios described the prevalence and growth of asthma in mainland China.ResultsThe average expenditure for discharged asthma (standard deviation) patients was ¥5,870 (808). The average length of stay (standard deviation) was 7.9 (0.38) days. During the period of 2011 to 2020, hospitalization expenses for asthma increased while the length of hospital stay decreased. The proportion of discharged patients who were children under the age of 5 were 25.3% (2011), 19.4% (2012), 16% (2013), 17.9% (2014), 13.9% (2015), 11.3% (2016), 10.2% (2017), 9.4% (2018), 8.1% (2019), and 7.2% (2020), respectively. The prevalence of asthma among boys was higher than girls before the age of 14. In contrast, the proportion of women with asthma was larger than men after the age of 14. During the period from 2011 to 2020, the median [The first quartile (Q1)-the third quartile (Q3)] daily asthma Baidu index in Guangdong, Beijing, Jiangsu, Sichuan, and Zhejiang were 419 (279–476), 328 (258–376), 315 (227–365), 272 (166–313), and 312 (233–362) respectively. Coastal regions showed higher levels of attention toward asthma, indicating a higher incidence rate. Since 2014, there has been a rapid increase in the level of attention toward asthma, with the provinces of Qinghai, Sichuan, and Guangdong experiencing the fastest growth.ConclusionThere are regional variations in the prevalence of asthma among different provinces in China, and the overall prevalence of asthma is increasing

The tomato Prf complex is a molecular trap for bacterial effectors based on Pto transphosphorylation

The bacteria Pseudomonas syringae is a pathogen of many crop species and one of the model pathogens for studying plant and bacterial arms race coevolution. In the current model, plants perceive bacteria pathogens via plasma membrane receptors, and recognition leads to the activation of general defenses. In turn, bacteria inject proteins called effectors into the plant cell to prevent the activation of immune responses. AvrPto and AvrPtoB are two such proteins that inhibit multiple plant kinases. The tomato plant has reacted to these effectors by the evolution of a cytoplasmic resistance complex. This complex is compromised of two proteins, Prf and Pto kinase, and is capable of recognizing the effector proteins. How the Pto kinase is able to avoid inhibition by the effector proteins is currently unknown. Our data shows how the tomato plant utilizes dimerization of resistance proteins to gain advantage over the faster evolving bacterial pathogen. Here we illustrate that oligomerisation of Prf brings into proximity two Pto kinases allowing them to avoid inhibition by the effectors by transphosphorylation and to activate immune responses

Senescence marker protein 30 in acute liver failure: validation of a mass spectrometry proteomics assay

<p>Abstract</p> <p>Background</p> <p>Our previous proteomic study showed that the senescence marker protein (SMP30) is selectively present in the plasma of a murine model of acute liver failure (ALF). The aim of this study was to validate this SMP30 expression in the plasma and liver tissues of mice and humans with ALF.</p> <p>Methods</p> <p>After the proteomic analysis of plasma from a murine model of D-galactosamine/lipopolysaccharide (GalN/LPS)-induced ALF by two-dimensional electrophoresis (2-DE) and mass spectrometry, the expression levels of SMP30 in the plasma and liver tissues were validated by western blot and RT-PCR analyses. These results were then confirmed in plasma samples from humans.</p> <p>Results</p> <p>These data validate the results of 2-DE, and western blot showed that SMP30 protein levels were only elevated in the plasma of ALF mice. Further analysis revealed that GalN/LPS induced the downregulation of SMP30 protein levels in liver tissues (by approximately 25% and 16% in the GalN/LPS-treated mice and in the treated mice that survived, respectively; <it>P </it>< 0.01). Hepatic SMP30 mRNA levels decreased by about 90% only in the mice that survived the GalN/LPS treatment. Importantly, plasma obtained from patients with ALF also contained higher levels of SMP30, about (3.65 ± 0.34) times those observed in healthy volunteers.</p> <p>Conclusion</p> <p>This study shows that SMP30 is not only a potential biomarker for the diagnosis and even prognosis of ALF. It also plays a very important role in a self-protective mechanism in survival and participates in the pathophysiological processes of ALF.</p

Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy

Diabetes is a recognized risk factor for cardiovascular diseases and heart failure. Diabetic cardiovascular dysfunction also underscores the development of diabetic retinopathy, nephropathy and neuropathy. Despite the broad availability of antidiabetic therapy, glycaemic control still remains a major challenge in the management of diabetic patients. Hyperglycaemia triggers formation of advanced glycosylation end products(AGEs), activates protein kinase C, enhances polyol pathway, glucose autoxidation, which coupled with elevated levels of free fatty acids, and leptin have been implicated in increased generation of superoxide anion by mitochondria, NADPH oxidases and xanthine oxidoreductase in diabetic vasculature and myocardium. Superoxide anion interacts with nitric oxide forming the potent toxin peroxynitrite via diffusion limited reaction, which in concert with other oxidants triggers activation of stress kinases, endoplasmic reticulum stress, mitochondrial and poly(ADP-ribose) polymerase 1-dependent cell death, dysregulates autophagy/mitophagy, inactivates key proteins involved in myocardial calcium handling/contractility and antioxidant defense, activates matrix metalloproteinases and redox-dependent pro-inflammatory transcription factors (e.g. nuclear factor kappaB) promoting inflammation, AGEs formation, eventually culminating in myocardial dysfunction, remodeling and heart failure. Understanding the complex interplay of oxidative/nitrosative stress with pro-inflammatory, metabolic and cell death pathways is critical to devise novel targeted therapies for diabetic cardiomyopathy, which will be overviewed in this brief synopsis. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases

ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity

B-cell lymphoma 2 (Bcl-2) homology 3 (BH3)-only proteins represent a class of pro-apoptotic factors that neutralize pro-survival Bcl-2 proteins, and, in some cases, directly activate Bax. The mechanisms of control and the role of BH3-only proteins, such as Bcl-2 like protein 11 extra large and Bad are well studied. By contrast, relatively little is known about the regulation and role of Bcl-2 modifying factor (Bmf). The B-RAF oncogene is mutated in ∼8% of human tumors. We have previously shown that Bmf is upregulated at the transcript level and is required for apoptosis induced by targeting B-RAF signaling in tumor cells harboring mutant B-RAF. In this study, we show that Bmf is regulated at the post-translational level by mutant B-RAF-MEK-ERK2 signaling. Extracellular signal-regulated kinase (ERK2) directly phosphorylates Bmf on serine 74 and serine 77 residues with serine 77 being the predominant site. In addition, serine 77 phosphorylation reduces Bmf pro-apoptotic activity likely through a mechanism independent of altering Bmf localization to the mitochondria and/or interactions with dynein light chain 2 and the pro-survival proteins, B-cell lymphoma extra large, Bcl-2 and Mcl-1. These data identify a novel mode of regulation in Bmf that modulates its pro-apoptotic activity in mutant B-RAF tumor cells