Interleukin-6 classic and trans-signaling utilize glucose metabolism reprogramming to achieve anti- or pro-inflammatory effects.

Interleukin (IL)-6 has anti- and pro-inflammatory functions, controlled by IL-6 classic and trans-signaling, respectively. Differences in the downstream signaling mechanism between IL-6 classic and trans-signaling have not been identified. Here, we report that IL-6 activates glycolysis to regulate the inflammatory response. IL-6 regulates glucose metabolism by forming a complex containing signal-transducing activators of transcription 3 (STAT3), hexokinase 2 (HK2), and voltage-dependent anion channel 1 (VDAC1). The IL-6 classic signaling directs glucose flux to oxidative phosphorylation (OxPhos), while IL-6 trans-signaling directs glucose flux to anaerobic glycolysis. Classic IL-6 signaling promotes STAT3 translocation into mitochondria to interact with pyruvate dehydrogenase kinase-1 (PDK1), leading to pyruvate dehydrogenase α (PDHA) dissociation from PDK1. As a result, PDHA is dephosphorylated, and STAT3 is phosphorylated at Ser727. By contrast, IL-6 trans-signaling promotes the interaction of sirtuin 2 (SIRT2) and lactate dehydrogenase A (LDHA), leading to the dissociation of STAT3 from SIRT2. As a result, LDHA is deacetylated, and STAT3 is acetylated and phosphorylated at Tyr705. IL-6 classic signaling promotes the differentiation of regulatory T cells via the PDK1/STAT3/PDHA axis, whereas IL-6 trans-signaling promotes the differentiation of Th17 cells via the SIRT2/STAT3/LDHA axis. Conclusion: IL-6 classic signaling generates anti-inflammatory functions by shifting energy metabolism to OxPhos, while IL-6 trans-signaling generates pro-inflammatory functions by shifting energy metabolism to anaerobic glycolysis.

Kynurenic acid inhibits macrophage pyroptosis by suppressing ROS production via activation of the NRF2 pathway.

Macrophage pyroptosis and related inflammatory responses play an important role in periodontitis. Kynurenic acid (KA) is hypothesized to have anti­inflammatory potential, but whether KA can inhibit macrophage pyroptosis and the underlying mechanisms remain unclear. Lipopolysaccharide (LPS) was used to induce pyroptosis in THP­1­derived macrophages. KA or ML385 was used to pretreat macrophages, after which, cell viability, NOD­like receptor protein 3 (NLRP3) inflammasome­related protein expression, oxidative stress levels and nuclear factor erythroid 2­related factor 2 (NRF2) expression were measured. The results showed that KA improved the LPS­induced decrease in macrophage viability and lactate dehydrogenase release. KA prevented THP­1 macrophage pyroptosis induced by LPS by reducing the expression of NLRP3, Gasdermin­D, and Caspase1, and decreased the expression of inflammatory factors. KA suppressed NLRP3 inflammasome activation by inhibiting ROS overproduction and increasing Heme Oxygenase 1 and glutathione levels. Moreover, KA promoted NRF2 translocation from the cytoplasm to the nucleus. In addition, the anti­pyroptotic and antioxidant effects of KA were reversed by ML385 inhibition of NRF2. In the present study, it was found that KA significantly suppressed macrophage pyroptosis induced by LPS. It was further demonstrated that the anti­pyroptotic effects of KA were mediated by activation of the NRF2 pathway.

Purification Effect of PES-C Ultrafiltration Membrane Incorporated with Emodin on Acanthopanax Senticosus Injection.

A new PES-C/emodin ultrafiltration membrane was prepared by blending natural emodin with phenolphthalein polyethersulfone (PES-C) and was used to purify an acanthopanax senticosus injection in this study. Regarding the purified acanthopanax senticosus injection, its color became lighter, and its clarity increased. On the contrary, for an acanthopanax senticosus injection containing macromolecules, its color deepened, and its turbidity increased. Thermal stability of the purified acanthopanax senticosus injection was the best, followed by the original solution of the acanthopanax senticosus injection, and the acanthopanax senticosus injection containing macromolecules was the worst. The fingerprint spectrum of the purified acanthopanax senticosus injection was similar to the original solution of the acanthopanax senticosus injection, the relative peak area of each single peak was greater than 0.95, and the relative peak area of the total peak was greater than 0.96. Compared with the original solution of the acanthopanax senticosus injection, the histamine release amount and cell degranulation rate of the acanthopanax senticosus injection containing macromolecules increased, while those of the purified acanthopanax senticosus injection decreased, which reduced the risk of allergic reaction to a certain extent. "Inverse proof" confirmed that the acanthopanax senticosus injection containing macromolecules had certain liver and kidney toxicity, which indirectly proved that the liver and kidney toxicity of the purified acanthopanax senticosus injection was effectively reduced.

Effect of flumetsulam alone and coexistence with polyethylene microplastics on soil microbial carbon and nitrogen cycles: Elucidation of bacterial community structure, functional gene expression, and enzyme activity.

Flumetsulam (FLU) is a new class of broad-spectrum herbicides. With the widespread use of plastic products, polyethylene (PE) microplastics (MPs) may remain in the soil. It is possible for these two novel contaminants to co-exist in the soil environment. In the present study, we used brown soil as the test soil and determined the toxicity of FLU at 0.05, 0.5 and 2.5 mg kg-1 alone and in combination with PE MPs (1%) on soil microorganisms. The obtained results demonstrated that the exposure of FLU and FLU+MPs had an inhibitory effect on the numbers of bacteria and fungi. In addition, FLU and FLU+MPs caused changes in the relevant functional bacterial genera, favored nitrogen fixation and denitrification, and promoted soil carbon fixation, but inhibited nitrification. Compared to FLU exposure alone, exposure to FLU+MPs gave rise to significant differences in soil bacterial community composition, but did not affect carbon and nitrogen cycling. The integrated biomarker response results indicated that the toxicity of FLU and FLU+MPs to soil microorganisms increased with increasing concentrations of FLU. The present experiment clarified the toxicological effects of co-exposure of FLU and MPs on microorganisms and filled the toxicological data gap of FLU.

Serum IL-38 Level Was Associated with Incidence of MACE in the STEMI Patients.

Background: The relationship between serum IL-38 and major adverse cardiovascular events (MACE) in patients with ST elevation myocardial infarction (STEMI) remains unclear. Methods: In the present study, 589 STEMI patients were included, the serum level of IL-38 was measured. The median follow-up time was 720 days, the STEMI patients were divided into high IL-38 (IL-38>6.49ng/mL) and low IL-38 groups (IL-38≤6.49ng/mL) to compare the probability of MACE. Results: Plasma IL-38 levels were significantly lower in STEMI patients than in SAP patients (4.0±2.2 vs 6.9±3.2 ng/mL, P < 0.001). Ninety-three STEMI patients met the defined MACE study endpoint. The incidence of MACE was significantly lower in patients with high IL-38 group than in patients with low IL-38 group (7.8% vs 23.7%, P < 0.001). Low plasma IL-38 levels were independently associated with the occurrence of MACE (OR = 0.90, P < 0.001). Conclusion: We get a conclusion that low plasma levels of IL-38 are independently associated with the occurrence of MACE.

The effect of TiO2NPs on cloransulam-methyl toxicity to earthworm (Eisenia fetida).

Cloransulam-methyl is a new herbicide and has broad application prospect. However, the effect of cloransulam-methyl on earthworm have yet to be clarified. As more and more titanium dioxide nanoparticles (TiO2NPs) enter the soil, cloransulam-methyl and TiO2NPs have a risk of co-exposure, but the effect of TiO2NPs on cloransulam-methyl toxicity is unknown. In the study, the ecotoxicity of cloransulam-methyl (0.1, 1 mg kg-1) on earthworm and the effect of TiO2NPs (10 mg kg-1) on cloransulam-methyl toxicity was investigated after exposure for 28 and 56 d. Exposure tests showed cloransulam-methyl and cloransulam-methyl + TiO2NPs promoted the accumulation of reactive oxygen species, malondialdehyde and 8-hydroxydeoxyguanosine, increased the activities of superoxide dismutase and catalase, resulted in lipid peroxidation and DNA damage. Besides, the results at the genetic level showed cloransulam-methyl and cloransulam-methyl + TiO2NPs altered the expression of physiologically-related genes, which demonstrated that cloransulam-methyl and cloransulam-methyl + TiO2NPs induced oxidative stress and cell apoptosis, and disturbed the normal reproduction in earthworm. The results of comprehensive toxicity comparison indicated cloransulam-methyl and TiO2NPs co-exposure has higher toxicity compared to cloransulam single exposure. Our results suggest that TiO2NPs can enhance the toxicity of cloransulam-methyl on Eisenia fetida in terms of oxidative stress, cell apoptosis and reproduction aspects. Based on above studies, it is of great importance for evaluating the risk of cloransulam-methyl co-exposure with TiO2NPs in soil.

Development toxicity and cytotoxicity of pyroxsulam on embryos and adults of zebrafish (Danio rerio).

Pyroxsulam is a typical triazolopyrimidine sulfonamide herbicide, which plays a vital role in weed control for wheat production. Previous studies on pyroxsulam have mainly focused on weed resistance, control effects, and soil microorganisms, however, research on aquatic ecotoxicity is lacking. This study evaluated the toxicity of pyroxsulam in zebrafish embryos (120 h) and adults (14 and 28 d). Chronic exposure to pyroxsulam (0.2, 2, and 10 µg L-1) reduced reactive oxygen species (ROS) content in embryos but increased ROS content in adults. Pyroxsulam caused lipid peroxidation and DNA damage in embryos and adults. The expression of p53, bcl-2/bax, and caspase 3/8/9 indicated that pyroxsulam inhibited apoptosis in embryos but induced apoptosis in adults. By calculating integrated biomarker response, apoptosis was more readily affected than oxidative damage in embryos and adults. The toxicity of pyroxsulam increased with increasing concentration, however, with increasing exposure time, the toxicity of pyroxsulam to adults decreased. Pyroxsulam exerted toxic effects on zebrafish at different life stages (embryos and adults), and different stages had different toxicity. These results indicate that in future studies on the toxicity of pyroxsulam to zebrafish, different life stages (embryos and adults) need to be studied. The present study evaluated the toxicity of environmentally relevant concentrations of pyroxsulam to zebrafish embryos and adults, providing worthy data for assessing its effects on aquatic ecosystems.

Characterization of the responses of soil micro-organisms to azoxystrobin and the residue dynamics of azoxystrobin in wheat-corn rotation fields over two years.

Azoxystrobin, a high-efficiency and broad-spectrum strobilurin fungicide, has been widely used in global agricultural production. However, the effects of azoxystrobin on soil micro-organisms have scarcely been studied, and relevant experiments are usually conducted under laboratory conditions using active ingredient. Therefore, the effects of azoxystrobin on soil micro-organisms when applied to actual farmland are unknown. We sought to address this knowledge gap in this study, where we studied the effects of azoxystrobin on soil micro-organisms in a wheat-corn rotation field over two years. The results indicate that after two years of azoxystrobin application the activities of soil enzymes were inhibited, and the abundance of functional genes related to the nitrogen and carbon cycle were inhibited, which change the abundance of soil microbial bacteria of genera. As a consequence, the soil nitrogen and carbon cycles were disturbed. In addition, azoxystrobin inhibited the abundance of functional bacteria related to organic pollutant degradation and soil metabolism, where the rate of azoxystrobin degradation diminished over time. Moreover, azoxystrobin significantly inhibited the soil-culturable microbial population. The integrated biomarker response (IBR) indicated that the soil-culturable microbial population can be used as a sensitive indicator of the effect of azoxystrobin on soil micro-organisms. The final levels of azoxystrobin residues measured in grains were less than 0.004 mg/kg, lower than the maximum residue limits in European Union and China. The results of this study provide a basis for suggestions regarding the appropriate use of azoxystrobin in addition to support for elucidating the interaction between biological macromolecules and pollutants.

Effect of florasulam on oxidative damage and apoptosis in larvae and adult zebrafish (Danio rerio).

Florasulam is widely used for weed control in wheat fields due to its high activity and low dosage. Previous studies on florasulam have focused on soil microbial and residue determination, however, its ecotoxicity to aquatic organisms is unclear. The toxicity of florasulam was evaluated in larvae (120 h) and adult (14 and 28 d) zebrafish. After florasulam (0.1 and 1 µg L-1) exposure, reactive oxygen species levels in larvae and adult zebrafish significantly increased and antioxidant system was activated. Florasulam induced lipid peroxidation in larvae and adult zebrafish. Florasulam did not cause DNA damage to larvae but caused DNA damage to adult zebrafish. Changes in caspase 3/8/9 genes indicated that apoptosis was induced in larvae but inhibited in adult zebrafish. By calculating integrated biomarker response, caspase 3 and malondialdehyde could be used as early warning indicators of florasulam effect on larvae and adult zebrafish, respectively. The higher the exposure concentration, the greater the toxicity of florasulam to larvae and adult zebrafish. Increasing exposure time resulted in higher toxicity to adult zebrafish. Florasulam has different toxicity at larvae and adult zebrafish. In future studies to investigate florasulam toxicity to zebrafish, different zebrafish life stages (larvae and adult) need to be studied.

Toxicity evaluation of pyraclostrobin exposure in farmland soils and co-exposure with nZnO to Eisenia fetida.

Although the toxicity of pyraclostrobin (PYRA) to earthworms in artificial soil is well known, the toxicity of PYRA in farmland soils is yet to be explored in detail. Additionally, with more zinc oxide nanoparticles (nZnO) entering the soil environment, the risk of PYRA co-exposure with nZnO is increasing alarmingly. However, toxicity caused by this co-exposure of PYRA and nZnO is still unknown. Therefore, we assessed the biomarkers responses to reveal the toxicity of PYRA (0.1, 1, 2.5 mg/kg) on earthworms in farmland soils (black soil, fluvo-aquic soil, and red clay) and evaluated the biomarkers responses of Eisenia fetida exposed to PYRA (0.5 mg/kg)/PYRA+nZnO (10 mg/kg). Moreover, transcriptomic analysis was performed on E. fetida exposed to PYRA/PYRA+nZnO for 28 days to reveal the mechanism of genotoxicity. The Integrated Biomarker Responses (IBR) showed PYRA induced more severe oxidative stress and damage to E. fetida in farmland soils than that in artificial soil. The oxidative stress and damage induced by PYRA+nZnO were greater than that induced by PYRA. Transcriptomic analysis showed that PYRA and PYRA+nZnO significantly altered gene expression of both biological processes and molecular functions. These results provided toxicological data for PYRA exposure in three typical farmland soils and co-exposure with nZnO.

Comparison of the toxic effects of non-task-specific and task-specific ionic liquids on zebrafish.

Ionic liquids (ILs) are composed of only anions and cations and are liquid solvents at room temperature. Different functional groups were introduced into the ILs, conferring them with specific functions or purposes and thus forming special ILs, namely task-specific ILs (TSILs). Imidazolium-based ILs are the most widely used ILs in industrial production. To date, there have been some studies on the toxic effects of ILs on different organisms. However, the effect of functionalized groups on the toxicity of ILs is still unclear. In the present study, zebrafish were used as model organisms to study the toxic effects of 1-ethyl-3-methylimidazolium nitrate ([C2mim]NO3) and 1-hydroxyethyl-3-methylimidazolium nitrate ([HOC2mim]NO3). The results showed that both promoted an increase in reactive oxygen species (ROS) contents, leading to lipid peroxidation and DNA damage. Furthermore, integrated biological response analysis showed that [HOC2mim]NO3 was less toxic to zebrafish than [C2mim]NO3, which indicated that adding functional groups decreased the toxicity of ILs to organisms. The influence of chemical structure on IL toxicity was also reported. These results could provide a scientific basis for better synthesis and utilization of ILs in the future.

New Residue Analysis Method for Four Task-Specific Ionic Liquids in Water, Soil and Plants.

With the extensive application of task-specific ionic liquids (TSILs), their environmental impact has attracted increasing attention. However, no studies involving residue analyses of TSILs have been reported in the literature thus far. In the present study, residues of four TSILs ([C2NH2MIm]BF4, [HOEMIm]BF4, [HOEMIm]NO3, [MOEMIm]BF4) were analyzed by high-performance liquid chromatography-tandem mass spectrometry. The limit of detection of instrument was approximately 10-15 g. Residual TSILs were extracted from soil and plant samples by the accelerated solvent extraction method. In water, soil and plants, the coefficient of variation was 0.38%-4.43%, and the method detection limits of the four TSILs were lower than 1.40 ng g-1. These results meet the standards of residue analysis. The present study can provide an analysis method for studying TSIL residues and toxicity in the environment.

The Nrf2 Signaling in Retinal Ganglion Cells under Oxidative Stress in Ocular Neurodegenerative Diseases.

Retinal ganglion cells (RGCs) are one of the important cell types affected in many ocular neurodegenerative diseases. Oxidative stress is considered to be involved in retinal RGCs death in ocular neurodegenerative diseases. More and more attention has been focused on studying the agents that may have neuroprotective effects. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key nuclear transcription factor for the systemic antioxidant defense system. This review elucidates the underlying mechanism of the Nrf2-mediated neuroprotective effects on RGCs in ocular neurodegenerative diseases, such as diabetic retinopathy and retinal ischemia-reperfusion injury. Several Nrf2 inducers that shield RGCs from oxidative stress-induced neurodegeneration via regulating Nrf2 signaling are discussed.

HOXA11 antisense long noncoding RNA (HOXA11-AS): A promising lncRNA in human cancers.

The cancers are the leading cause of disease-related deaths worldwide with a high risk of morbidity and mortality. Long noncoding RNAs (lncRNAs) play a critical role in a wide range of biological processes, including tumorigenesis. HOXA11-AS (NCRNA00076), the antisense strands of HOXA11 gene, was initially revealed in a mouse embryonic cDNA library in 2009 and it was a fairly novel lncRNA. This review summarized the advanced research progression concerning the expression and role of HOXA11-AS in different human malignancies. The expression of HOXA11-AS is aberrantly altered in many cancers, either as a tumor suppressor or as a tumor accelerator. The different underlying mechanism of HOXA11-AS in different cancers (including, nonsmall cell lung cancers, osteosarcoma, uveal melanoma, glioma, hepatocellular carcinoma, gastric cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, ovarian cancer, and glioblastoma) was also detailed. These findings lead us to conclude that HOXA11-AS participate in the complex network of cancers and plays an important role in the tumorigenesis and progression. Functional HOXA11-AS could be a promising biomarker for early detection as well as prognosis evaluation in cancer patients. Future HOXA11-AS-targeted intervention may become a valuable novel therapeutic tool, improving the clinical management of cancers.

The Cross-Entropy Based Multi-Filter Ensemble Method for Gene Selection.

The gene expression profile has the characteristics of a high dimension, low sample, and continuous type, and it is a great challenge to use gene expression profile data for the classification of tumor samples. This paper proposes a cross-entropy based multi-filter ensemble (CEMFE) method for microarray data classification. Firstly, multiple filters are used to select the microarray data in order to obtain a plurality of the pre-selected feature subsets with a different classification ability. The top N genes with the highest rank of each subset are integrated so as to form a new data set. Secondly, the cross-entropy algorithm is used to remove the redundant data in the data set. Finally, the wrapper method, which is based on forward feature selection, is used to select the best feature subset. The experimental results show that the proposed method is more efficient than other gene selection methods and that it can achieve a higher classification accuracy under fewer characteristic genes.

The BRAF activated non-coding RNA: A pivotal long non-coding RNA in human malignancies.

Long non-coding RNAs (lncRNAs) participate in the complex network of cancer and play an important role in tumourigenesis and progression. BRAF activated non-coding RNA (BANCR), a 4-exon transcript of 693-bp, was first discovered as an oncogenic long non-coding RNA in BRAFV600E melanomas cells in 2012 and was related to melanoma cell migration. Besides melanoma, increasing evidence has explored the potential role of BANCR in the development and progression of multiple other human malignancies, such as retinoblastoma, lung cancer, gastric cancer etc. since its discovery. The expression pattern of BANCR varies in different types of cancers, either as a tumour suppressor or as an accelerator. Functional BANCR may serve as a promising biomarker for cancer diagnosis as well as prognosis evaluation. BANCR-targeted intervention may also become a valuable novel therapeutic tool against human malignancies. This review summarized the advanced research progresses concerning the expression and role of BANCR in different human malignancies.

Nrf2, a Potential Therapeutic Target against Oxidative Stress in Corneal Diseases.

Corneal diseases are one of the major causes of blindness worldwide. Conservative medical agents, which may prevent sight-threatening corneal disease progression, are urgently desired. Numerous evidences have revealed the involvement of oxidative stress in various corneal diseases, such as corneal wound healing and Fuchs endothelial corneal dystrophy (FECD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like erythroid-cell-derived protein with CNC homology- (ECH-) associated protein 1 (Keap1)/antioxidant response element (ARE) signaling is well known as one of the main antioxidative defense systems. To the best of our knowledge, this is the first review to elucidate the different expression profiles of Nrf2 signaling as well as the underlying mechanisms in corneal diseases, implicating that Nrf2 may serve as a potentially promising therapeutic target for corneal diseases.

Nrf2 as a target for prevention of age-related and diabetic cataracts by against oxidative stress.

Cataract is one of the most important causes of blindness worldwide, with age-related cataract being the most common one. Agents preventing cataract formation are urgently required. Substantial evidences point out aggravated oxidative stress as a vital factor for cataract formation. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like erythroid-cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) system is considered as one of the main cellular defense mechanisms against oxidative stresses. This review discusses the role of Nrf2 pathway in the prevention of cataracts and highlights that Nrf2 suppressors may augment oxidative stress of the lens, and Nrf2 inducers may decrease the oxidative stress and prevent the cataract formation. Thus, Nrf2 may serve as a promising therapeutic target for cataract treatment.

A case report of the orbit, ocular association and the lung in granulomatosis with polyangiitis: A diagnostic challenge.

Granulomatosis with polyangiitis (GPA) is a systemic form of vasculitis that involves small to medium sized vessels and is associated with high morbidity and mortality. GPA presents a continuous and difficult clinical diagnostic concern, due to the rarity of the disease and the diversity of the manifestations. This case report discusses the unusual symptoms presented by a particular patient, discusses these manifestations and explains how the final diagnosis was identified as GPA. A 40-year old Chinese woman was initially referred to the present institution for a progressive worsening pain, redness and gradual decrease in visual acuity in the eyes over the past 7-year period. Previous therapeutic interventions included noncompliant topical and intravenous dexamethasone for 6 years. A pre-operative examination conducted in a differing hospital to search for the presence of an orbital mass, resulted in the identification of an asymptomatic space-occupying lesion in the right middle lung, which was surgically removed in March 2015. A total of four weeks later, surgery was then applied to remove a left orbital mass, in the same hospital. A total of three months later, the patient was diagnosed with peripheral ulcerative keratitis associated with GPA, at the present institution. The corneal lesions were then treated bilaterally with cryotherapy and oral prednisone and cyclophosphamide were administered. Following surgery, the condition of the eyes appeared to be stable. A total of seven months later, the redness and pain of the right eye recurred, followed by a deep lamellar keratoplasty for the treatment of necrotizing scleritis. The condition of the two eyes was subsequently observed to be stable during the nine month follow-up. The present case study reviews various points to consider in a rare, complicated and potentially blinding case of GPA. GPA must therefore be considered in the differential diagnosis of further inflammatory conditions and tumors. Early diagnosis and an appropriate interdisciplinary approach to management, are required to decrease recurrence and morbidity in patients with GPA-mediated inflammatory ocular disease.