A phytomedicine extract exerts an anti-inflammatory response in the lungs by reducing STING-mediated type I interferon release.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is an acute respiratory disease characterized by bilateral chest radiolucency and severe hypoxemia. Quzhou Fructus Aurantii ethyl acetate extract (QFAEE), which is prepared from the traditional Chinese respiratory anti-inflammatory natural herb Quzhou Fructus Arantii, has the potential to alleviate ARDS. In this work, we aimed to investigate the potential and mechanism underlying the action of QFAEE on ARDS and how QFAEE modulates the STING pathway to reduce type I interferon release to alleviate the inflammatory response. METHODS: Lipopolysaccharide (LPS), a potential proinflammatory stimulant capable of causing pulmonary inflammation with edema after nasal drops, was employed to model ARDS in vitro and in vivo. Under QFAEE intervention, the mechanism of action of QFAEE to alleviate ARDS was explored in this study. TREX1-/- mice were sued as a research model for the activation of the congenital STING signaling pathway. The effect of QFAEE on TREX1-/- mice could explain the STING-targeted effect of QFAEE on alleviating the inflammatory response. Our explorations covered several techniques, Western blot, histological assays, immunofluorescence staining, transcriptomic assays and qRT-PCR to determine the potential mechanism of action of QFAEE in antagonizing the inflammatory response in the lungs, as well as the mechanism of action of QFAEE in targeting the STING signaling pathway to regulate the release of type I interferon. RESULTS: QFAEE effectively alleviates ARDS symptoms in LPS-induced ARDS. We revealed that the mechanism underlying LPS-induced ARDS is the STING-TBK1 signaling pathway and further elucidated the molecular mechanism of QFAEE in the prevention and treatment of ARDS. QFAEE reduced the release of type I interferons by inhibiting the STING-TBK1-IRF3 axis, thus alleviating LPS-induced pneumonia and lung cell death in mice. Another key finding is that activation of the STING pathway by activators or targeted knockdown of the TREX1 gene can also induce ARDS. As expected, QFAEE was found to be an effective protective agent in alleviating ARDS and the antagonistic effect of QFAEE on ARDS was achieved by inhibiting the STING signaling pathway. CONCLUSIONS: The main anti-inflammatory effect of QFAEE was achieved by inhibiting the STING signaling pathway and reducing the release of type I interferons. According to this mechanism of effect, QFAEE can effectively alleviate ARDS and can be considered a potential therapeutic agent. In addition, the STING pathway plays an essential role in the development and progression of ARDS, and it is a potential target for ARDS therapy.

Short-term effectiveness and potential factors of ustekinumab based on real-world data in Chinese psoriasis patients.

BACKGROUND: As one of the most effective biologic treatments for psoriasis, the short-term effectiveness of ustekinumab has yet to be studied extensively. OBJECTIVE: The purpose of this study was to evaluate the short-term effectiveness and potential factors within four weeks after the first-dose ustekinumab treatment based on real-world data. METHODS: The study enrolled 98 patients with moderate-to-severe psoriasis, given ustekinumab 45 mg at week 0, week 4, and then every 12 weeks. Based on clinical data collected at baseline and week 4, we investigated the short-term effectiveness of ustekinumab after the first dose and potential factors associated with the treatment. For evaluation, we collected demographic information, body data, medical history, laboratory examination results, Psoriasis Area and Severity Index (PASI), body surface area (BSA), and dermatology life quality index (DLQI). Response rates were calculated based on the number of patients that achieved a 75/90/100% reduction in PASI (PASI 75/90/100), and the primary treatment goal was to achieve PASI 75. RESULTS: The response rates for PASI 75/90/100 at week 4 were 30.5%, 18.9%, and 16.8%, respectively. For PASI 75, the response rate was higher in patients without metabolic syndrome (MS) (without MS vs. with MS: 36.9% vs. 5.9%, p = 0.013); the serum triglyceride (TG) level was significantly lower in patients achieving PASI 75 (expressed as mean ± standard deviation, achieved vs. unachieved: 1.82 ± 1.79 vs. 3.59 ± 8.89, p = 0.010). For PASI 100, the response rates were higher in female patients (female vs. male: 26.3% vs. 10.5%, p = 0.044) and patients with a family history of psoriasis (with family history vs. without family history: 44.4% vs. 13.9%, p = 0.042). In addition, the possibility of achieving PASI 75/90/100 went up along with the serum high-density lipoprotein cholesterol (HDL-C) level (expressed as adjusted odds ratio < 95% confidence interval>: PASI 75: 28.484 < 2.035-248.419>, p = 0.011; PASI 90: 28.226 < 2.828-281.729>, p = 0.004; PASI 100: 12.175 < 1.876-79.028>, p = 0.009). CONCLUSION: In this study, nearly one-third of patients achieved PASI 75 after only the first-dose ustekinumab treatment. Sex, family history of psoriasis, MS, serum TG level might affect the short-term effectiveness, and serum HDL-C level may be a potential factor. The possibility of achieving treatment goals (PASI 75/90/100) at week 4 increased along with serum HDL-C levels.

Doxorubicin downregulates autophagy to promote apoptosis-induced dilated cardiomyopathy via regulating the AMPK/mTOR pathway.

The broad-spectrum antineoplastic drug doxorubicin (DOX) has one of the most serious chronic side effects on the heart, dilated cardiomyopathy, but the precise molecular mechanisms underlying disease progression subsequent to long latency periods remain puzzling. Here, we established a model of DOX-induced dilated cardiomyopathy. In a cardiac cytology exploration, we found that differentially expressed genes in the KEGG signaling pathway enrichment provided a novel complex network of mTOR bridging autophagy and oxidative stress. Validation results showed that DOX caused intracellular reactive oxygen species accumulation in cardiomyocytes, disrupted mitochondria, led to imbalanced intracellular energy metabolism, and triggered cardiomyocyte apoptosis. Apoptosis showed a negative correlation with DOX-regulated cardiomyocyte autophagy. To evaluate whether the inhibition of mTOR could upregulate autophagy to protect cardiomyocytes, we used rapamycin to restore autophagy depressed by DOX. Rapamycin increased cardiomyocyte survival by easing the autophagic flux blocked by DOX. In addition, rapamycin reduced oxidative stress, prevented mitochondrial damage, and restored energy metabolic homeostasis in DOX-treated cardiomyocytes. In vivo, we used metformin (Met) which is an AMPK activator to protect cardiac tissue to alleviate DOX-induced dilated cardiomyopathy. In this study, Met significantly attenuated the oxidative stress response of myocardial tissue caused by DOX and activated cardiomyocyte autophagy to maintain cardiomyocyte energy metabolism and reduce cardiomyocyte apoptosis by downregulating mTOR activity. Overall, our study revealed the role of autophagy and apoptosis in DOX-induced dilated cardiomyopathy and demonstrated the potential role of regulation of the AMPK/mTOR axis in the treatment of DOX-induced dilated cardiomyopathy.

Psoriatic Foot Involvement is the Most Significant Contributor to the Inconsistency Between PASI and DLQI: A Retrospective Study from China.

Background: The Psoriasis Area and Severity Index (PASI) and the Dermatology Life Quality Index (DLQI) are important evaluation tools for assessing psoriasis severity and guiding treatment options. However, the scores of PASI and DLQI are often inconsistent. Objective: This study aimed to identify the factors affecting the consistency between PASI and DLQI. Methods: The retrospective study was based on 4125 patients. We collected the PASI, DLQI, demographic and clinical characteristics data. Results: DLQI has a weak correlation with PASI (r=0.37; P<0.001). For the DLQI >10 groups, DLQI has almost no correlation with PASI (r=0.16; P<0.001). There are 43.60% of mild-to-moderate patients (PASI<10) in the DLQI>10 groups. Our adjusted model showed that foot (OR=2.109; 95% CI:1.581-2.815) involvement led to the greatest impairment of QoL except for PASI≥10 (OR=5.547; 95% CI:3.477-8.845). Furthermore, DLQI impairment was associated with female (OR=1.336; 95% CI:1.071-1.667); the age of 20-39 subgroup (OR=1.795; 95% CI:1.100-2.930); psoriatic arthritis (OR=1.718; 95% CI:1.208-2.443); higher income (OR = 1.408; 95% CI: 1.067-1.858); family history of psoriasis (OR=1.460; 95% CI:1.131-1.885). Moreover, the influence of exposed lesions (such as scalp; face; neck; nails; and hands) were positively associated with severely impaired QoL. Conclusion: Dermatologists should recognize the underestimated disease burden of psoriasis patients and actively identify and treat mild-to-moderate patients with high burden. In particular, the foot was a significant contributor to the burden.

Elevated C-Reactive Protein and Erythrocyte Sedimentation Rate Correlates with Depression in Psoriasis: A Chinese Cross-Sectional Study.

Purpose: Psoriasis patients often suffers from anxiety and depression. Inflammation, anxiety, and depression have been associated with each other, but the relationship has not been examined in subjects with psoriasis. The primary objective was to investigate the relationship between the C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) and depression among patients with psoriasis. Methods: In this case-control, cross-sectional study, 239 individuals with psoriasis and 142 with healthy controls (HCs) were recruited. Psychological as well as clinical, and laboratory data were collected. Results: 50.2% of subjects with psoriasis reported depressive symptoms, compared with 26.8% of HCs. 39.7% and 17.6% observed anxiety symptoms in psoriasis patients and HCs. The odds of anxiety (AOR= 3.123; 95% CI = 1.851-5.269) and depression (AOR= 2.698; 95% CI = 1.690-4.306) were higher in psoriasis patients relative to HCs. Furthermore, the elevated CRP (AOR =2.139; 95% CI = 1.249-3.663) and ESR (AOR =1.827; 95% CI = 1.078-3.096) were the risk factors of depression in patients with psoriasis. The threshold for distinguish psoriasis patients in depression was 3.24 (area under the curve [AUC], 0.605; sensitivity, 0.57; specificity, 0.64) for CRP and 26.5 (AUC, 0.632; sensitivity, 0.52; specificity, 0.73) for ESR. Conclusion: A substantial prevalence of anxiety and depression symptoms was observed in Chinese psoriasis subjects, and the odds were much higher in psoriasis patients relative to HCs. The elevated CRP and ESR level was significantly associated with depression in psoriasis patients. Besides, the discrimination capability of CPR and ESR on depression further indicates the extra value of inflammatory biomarkers in the management of psoriasis patients.

Effectiveness and Safety of Guselkumab for the Treatment of Psoriasis in Real-World Settings at 52 weeks: A Retrospective, Observational, Multicenter Study from China.

BACKGROUND: Real-life studies evaluating the long-term efficacy of guselkumab in moderate-to-severe psoriasis in China are limited and not available. METHODS: In this real-life study, we retrospectively examined a total of 27 patients with moderate-to-severe psoriasis treated with guselkumab [100 mg, subcutaneous (s.c.)] with a follow-up period of at least 52 weeks in a real-life setting conducted at the Department of Dermatology, Xiangya Hospital, Central South University and Department of Psoriasis, Dalian Dermatosis Hospital. The primary endpoint of the study was long-term effectiveness [reduction of Psoriasis Area and Severity Index (PASI) score, improvement of Dermatology Life Quality Index (DLQI)], safety, and tolerability of guselkumab. RESULTS: Guselkumab treatment decreased the mean PASI score from 12.46 ± 6.34 at baseline to 4.03 ± 3.25 (P < 0.001) and 0.77 ± 1.25 (P < 0.001) at 12 and 52 weeks. At 12 weeks, PASI 75, 90, and 100 response was achieved in 44.4%, 18.5%, and 11.1% of patients, respectively. At 1 year, PASI 75, 90, and 100 response was achieved in 88%, 72%, and 48% of patients, respectively. At 52 weeks, 96% of patients achieved a PASI score of ≤ 3 and 80% of patients achieved DLQI (0/1). No patients withdrewed from the study due to primary or secondary ineffectiveness or failure to adhere to the medication. During the follow-up period, only two adverse events were reported (tinea capitis and diarrhea). CONCLUSIONS: Our findings confirm that guselkumab is an appropriate therapeutic option in routine clinical practice, particularly when treating sophisticated patients with comorbidities or who failed to previous biologic therapy.

Refined polysaccharide from Dendrobium devonianum resists H1N1 influenza viral infection in mice by activating immunity through the TLR4/MyD88/NF-κB pathway.

Dendrobium polysaccharide exhibits multiple biological activities, such as immune regulation, antioxidation, and antitumor. However, its resistance to viral infection by stimulating immunity is rarely reported. In this study, we explored the effect and mechanism of DVP-1, a novel polysaccharide from Dendrobium devonianum, in the activation of immunity. After being activated by DVP-1, the ability of mice to prevent H1N1 influenza virus infection was investigated. Results of immune regulation showed that DVP-1 significantly improved the immune organ index, lymphocyte proliferation, and mRNA expression level of cytokines, such as IL-1ß, IL-4, IL-6, and TNF-α in the spleen. Immunohistochemical results showed that DVP-1 obviously promoted the mucosal immunity in the jejunum tissue. In addition, the expression levels of TLR4, MyD88, and TRAF6 and the phosphorylation levels of TAK1, Erk, JNK, and NF-κB in the spleen were upregulated by DVP-1. The virus infection results showed that the weight loss of mice slowed down, the survival rate increased, the organ index of the lung reduced, and the virus content in the lung decreased after DVP-1 activated immunity. By activating immunity with DVP-1, the production of inflammatory cells and inflammatory factors in BALF, and alveolar as well as peribronchiolar inflammation could be prevented. The results manifested that DVP-1 could resist H1N1 influenza virus infection by activating immunity through the TLR4/MyD88/NF-κB pathway.

Microbiota differences of skin and pharyngeal microbiota between patients with plaque and guttate psoriasis in China.

Psoriasis can be provoked or exacerbated by environmental exposures such as certain microbiomes. The distinction between plaque psoriasis (PP) and guttate psoriasis (GP) in the skin or pharyngeal microbiota is not yet clear. High-throughput sequencing using Illumina MiSeq was used in this study to characterize skin and pharyngeal microbial composition in patients with PP [large PP (LPP, n = 62), small PP (SPP, n = 41)] and GP (n = 14). The alpha- and beta-diversity of skin microbiota LPP was similar to that of the SPP group, but different from the GP group. There were no differences in pharyngeal microbiota among the groups. According to linear discriminant analysis effect size (LEfSe) analysis, Staphylococcus, Stenotrophomonas, Enhydrobacter, Brevundimonas, and Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium were the dominant genera of skin microbiota in PP. Diversity of skin microbiota correlated with Psoriasis Area and Severity Index (PASI). Moderate-to-severe psoriasis and mild psoriasis have different microbiota compositions. The skin microbiota may be related to the pharyngeal microbiota. Furthermore, two microbiota-based models could distinguish psoriasis subtypes with area under the receiver-operating characteristic curve (AUC-ROC) of 0.935 and 0.836, respectively. In conclusion, the skin microbiota in patients with LPP is similar to that in patients with SPP, but displays variations compared to that of GP, no differences are noted between subtypes in pharyngeal microbiota. Skin microbiota diversity correlated with PASI.

Crosstalk of cholinergic pathway on thyroid disrupting effects of the insecticide chlorpyrifos in zebrafish (Danio rerio).

Chlorpyrifos is a widely used organophosphate insecticide and ubiquitously detected in the environment. However, little attention has been paid to its endocrine disrupting effect to non-target organisms. In the present study, zebrafish was exposed to 13 and 65 µg/L of chlorpyrifos for 7 and 10 days to determine the induced neurotoxicity and the alteration of thyroid metabolism. The 120 h LC50 and LC10 of chlorpyrifos was estimated as 1.35 mg/L and 0.62 mg/L based on the acute embryo toxicity assay, respectively. The acetylcholinesterase (AChE) inhibitory was detected by 13 µg/L chlorpyrifos and could be reversed by the co-exposure of 100 and 1000 µg/L anticholinergic agent atropine. For thyroid hormone level, 13 and 65 µg/L of chlorpyrifos induced increased free T3 levels in 10 dpf (days post-fertilization). The expression of thyroid related genes in 7 and 10 dpf exposed zebrafish were measured by the quantitative Real-Time PCR (qRT-PCR) assay. The mRNA expression of tshba, thrb, crhb, ttr, tpo, ugt1ab and slc5a5 had significant change. However, the alterations of thyroid hormone and mRNA expression could be partly rescued by the addition of atropine. The molecular docking of chlorpyrifos and T3 to the thyroid receptor ß in zebrafish using homology modelling and CDOCKER procedures shown weaker binding ability of chlorpyrifos compared to T3. Therefore, we concluded that the disturbance of thyroid signaling in zebrafish might arise from the developmental neurotoxicity induced by chlorpyrifos.

Macrofungi: A review of cultivation strategies, bioactivity, and application of mushrooms.

The production of macrofungi (mushrooms) as well as their economic value have been steadily increasing globally. The use of functional foods, dietary supplements, and traditional medicines derived from macrofungi is increasing as they have numerous health benefits as well as abundant nutrients. Macrofungi are diverse with complex and highly varied growth conditions and bioactive constituents, most macrofungal resources have not yet been fully explored and applicated, leading to an urgent need for appropriate strategies to address the problem. Increasing attention has been paid to the macrofungal cultivation and application, in particular, potential prebiotics. Herein, the present review comprehensively summarizes recent progress in the cultivation, newly identified bioactive constituents, and their effects on gut microbiota as well as the potential ways in which they affect human health. Moreover, the macrofungal food development is discussed to improve food nutritional value and change the quality characteristics of food. Finally, the review addresses consumer safety concerns and the prospective genetic manipulation of macrofungi. We hope that this review can provide a comprehensive research reference for ensuring the safety and efficacy, along with maximizing the value and profitability of macrofungi production.

Chinese Yellow Rice Wine Processing with Reduced Ethyl Carbamate Formation by Deleting Transcriptional Regulator Dal80p in Saccharomyces cerevisiae.

Ethyl carbamate (EC) is a potential carcinogen that forms spontaneously during Chinese rice wine fermentation. The primary precursor for EC formation is urea, which originates from both external sources and arginine degradation. Urea degradation is suppressed by nitrogen catabolite repression (NCR) in Saccharomyces cerevisiae. The regulation of NCR is mediated by two positive regulators (Gln3p, Gat1p/Nil1p) and two negative regulators (Dal80p/Uga43p, Deh1p/Nil2p/GZF3p). DAL80 revealed higher transcriptional level when yeast cells were cultivated under nitrogen-limited conditions. In this study, when DAL80-deleted yeast cells were compared to wild-type BY4741 cells, less urea was accumulated, and genes involved in urea utilization were up-regulated. Furthermore, Chinese rice wine fermentation was conducted using dal80Δ cells; the concentrations of urea and EC were both reduced when compared to the BY4741 and traditional fermentation starter. The findings of this work indicated Dal80p is involved in EC formation possibly through regulating urea metabolism and may be used as the potential target for EC reduction.

Long noncoding RNAs involvement in Epstein-Barr virus infection and tumorigenesis.

The Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus related to various types of cancers, including epithelial nasopharyngeal carcinoma, gastric carcinoma, and lymphoma. Long noncoding RNAs (lncRNAs) are expressed extensively in mammalian cells and play crucial roles in regulating various cellular processes and multiple cancers. Cellular lncRNAs can be differentially expressed induced by EBV infection. The dysregulated lncRNAs probably modulate the host immune response and other biological functions. At present, lncRNAs have been found to be significantly increased or decreased in EBV-infected cells, exosomes and EBV-associated cancers, suggesting their potential function and clinical application as biomarkers. In addition, EBV-encoded lncRNAs, BART and BHLF1 lncRNAs, may play roles in the viral oncogenesis. Analysis of the specific lncRNAs involved in interactions with the EBV machinery will provide information on their potential mechanism of action during multiple steps of EBV tumorigenesis. Here, we review the current knowledge regarding EBV-related lncRNAs and their possible roles in the pathogenesis of EBV-associated cancers.

Application of bamboo leaves extract to Chinese yellow rice wine brewing for ethyl carbamate regulation and its mitigation mechanism.

Bamboo leaves extract (BLE) contains various effective ingredients, including phenolic compounds. In this study, the effect of BLE on ethyl carbamate (EC) formation was investigated in Chinese yellow rice wine brewing with three different fermentation starters (Saccharomyces cerevisiae, Saccharomyces cerevisiae and Lactobacillus brevis, and Chinese yeast). As a result, BLE showed significant inhibition effect on EC in multi-microbial fermented rice wine, by preventing the reactions between urea/citrulline and ethanol. We found that BLE had influence on arginine transport (GAP1, CAN1, ALP1, and VBA2 gene) in Saccharomyces cerevisiae (S. cerevisiae), which significantly up-regulated arginine uptake gene expression in vacuole (VBA2 gene) so that inhibited arginine metabolism. Besides, the presence of BLE could improve the overall quality of Chinese yellow rice wine. Consequently, it was worthwhile applying BLE to Chinese rice wine fermentation, especially the wine brewing with S. cerevisiae and Lactobacillus brevis starter.

Identification of Down-Regulated Proteome in Saccharomyces cerevisiae with the Deletion of Yeast Cathepsin D in Response to Nitrogen Stress.

Vacuolar proteinase A (Pep4p) is required for the post-translational precursor maturation of vacuolar proteinases in Saccharomyces cerevisiae, and important for protein turnover after oxidative damage. The presence of proteinase A in brewing yeast leads to the decline of beer foam stability, thus the deletion or inhibition of Pep4p is generally used. However, the influence of Pep4p deletion on cell metabolism in Saccharomyces cerevisiae is still unclear. Herein, we report the identification of differentially down-regulated metabolic proteins in the absence of Pep4p by a comparative proteomics approach. 2D-PAGE (two-dimensional polyacrylamide gel electrophoresis) presented that the number of significantly up-regulated spots (the Pep4p-deficient species versus the wild type) was 183, whereas the down-regulated spots numbered 111. Among them, 35 identified proteins were differentially down-regulated more than 10-fold in the Pep4p-deficient compared to the wild-type species. The data revealed that Pep4p was required for the synthesis and maturation of several glycolytic enzymes and stress proteins, including Eno2p, Fba1p, Pdc1p, Tpi1p, Ssa1, Hsp82p, and Trr1p. The transcription and post-translational modifications of glycolytic enzymes like Eno2p and Fba1p were sensitive to the absence of Pep4p; whereas the depletion of the pep4 gene had a negative impact on mitochondrial and other physiological functions. The finding of this study provides a systematic understanding that Pep4p may serve as a regulating factor for cell physiology and metabolic processes in S. cerevisiae under a nitrogen stress environment.

Piezo-driven sample rotation system with ultra-low electron temperature.

Piezo-driven rotator is convenient for tilted magnetic field experiments due to its precise angle control. However, the rotator itself and the sample mounted on it are difficult to be cooled down because of extra heat leaks and presumably bad thermal contacts from the piezo. Here, we report a piezo-driven sample rotation system designed for ultra-low temperature environment. The sample, as well as the rotating sample holder, can be cooled to as low as 25 mK by customized thermal links and thermal contacts. More importantly, the electron temperature in the electrical transport measurements can also be cooled down to 25 mK with the help of home-made filters. To demonstrate the application of our rotation system at ultra-low electron temperature, a measurement revealing tilt-induced localization and delocalization in the second Landau level of two-dimensional electron gas is provided.

Deletion of Atg22 gene contributes to reduce programmed cell death induced by acetic acid stress in Saccharomyces cerevisiae.

BACKGROUND: Programmed cell death (PCD) induced by acetic acid, the main by-product released during cellulosic hydrolysis, cast a cloud over lignocellulosic biofuel fermented by Saccharomyces cerevisiae and became a burning problem. Atg22p, an ignored integral membrane protein located in vacuole belongs to autophagy-related genes family; prior study recently reported that it is required for autophagic degradation and efflux of amino acids from vacuole to cytoplasm. It may alleviate the intracellular starvation of nutrition caused by Ac and increase cell tolerance. Therefore, we investigate the role of atg22 in cell death process induced by Ac in which attempt is made to discover new perspectives for better understanding of the mechanisms behind tolerance and more robust industrial strain construction. RESULTS: In this study, we compared cell growth, physiological changes in the absence and presence of Atg22p under Ac exposure conditions. It is observed that disruption and overexpression of Atg22p delays and enhances acetic acid-induced PCD, respectively. The deletion of Atg22p in S. cerevisiae maintains cell wall integrity, and protects cytomembrane integrity, fluidity and permeability upon Ac stress by changing cytomembrane phospholipids, sterols and fatty acids. More interestingly, atg22 deletion increases intracellular amino acids to aid yeast cells for tackling amino acid starvation and intracellular acidification. Further, atg22 deletion upregulates series of stress response genes expression such as heat shock protein family, cell wall integrity and autophagy. CONCLUSIONS: The findings show that Atg22p possessed the new function related to cell resistance to Ac. This may help us have a deeper understanding of PCD induced by Ac and provide a new strategy to improve Ac resistance in designing industrial yeast strains for bioethanol production during lignocellulosic biofuel fermentation.

Epstein-Barr Virus Nuclear Antigen 1 Recruits Cyclophilin A to Facilitate the Replication of Viral DNA Genome.

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1)-mediated DNA episomal genome replication and persistence are essential for the viral pathogenesis. Cyclophilin A (CYPA) is upregulated in EBV-associated nasopharyngeal carcinoma (NPC) with unknown roles. In the present approach, cytosolic CYPA was found to be bound with EBNA1 into the nucleus. The amino acid 376-459 of the EBNA1 domain was important for the binding. CYPA depletion attenuated and ectopic CYPA expression improved EBNA1 expression in EBV-positive cells. The loss of viral copy number was also accelerated by CYPA consumption in daughter cells during culture passages. Mechanistically, CYPA mediated the connection of EBNA1 with oriP (origin of EBV DNA replication) and subsequent oriP transcription, which is a key step for the initiation of EBV genome replication. Moreover, CYPA overexpression markedly antagonized the connection of EBNA1 to Ubiquitin-specific protease 7 (USP7), which is a strong host barrier with a role of inhibiting EBV genome replication. The PPIase activity of CYPA was required for the promotion of oriP transcription and antagonism with USP7. The results revealed a strategy that EBV recruited a host factor to counteract the host defense, thus facilitating its own latent genome replication. This study provides a new insight into EBV pathogenesis and potential virus-targeted therapeutics in EBV-associated NPC, in which CYPA is upregulated at all stages.

RNA-Seq-based transcriptomic and metabolomic analysis reveal stress responses and programmed cell death induced by acetic acid in Saccharomyces cerevisiae.

As a typical harmful inhibitor in cellulosic hydrolyzates, acetic acid not only hinders bioethanol production, but also induces cell death in Saccharomyces cerevisiae. Herein, we conducted both transcriptomic and metabolomic analyses to investigate the global responses under acetic acid stress at different stages. There were 295 up-regulated and 427 down-regulated genes identified at more than two time points during acetic acid treatment (150 mM, pH 3.0). These differentially expressed genes (DEGs) were mainly involved in intracellular homeostasis, central metabolic pathway, transcription regulation, protein folding and stabilization, ubiquitin-dependent protein catabolic process, vesicle-mediated transport, protein synthesis, MAPK signaling pathways, cell cycle, programmed cell death, etc. The interaction network of all identified DEGs was constructed to speculate the potential regulatory genes and dominant pathways in response to acetic acid. The transcriptional changes were confirmed by metabolic profiles and phenotypic analysis. Acetic acid resulted in severe acidification in both cytosol and mitochondria, which was different from the effect of extracellular pH. Additionally, the imbalance of intracellular acetylation was shown to aggravate cell death under this stress. Overall, this work provides a novel and comprehensive understanding of stress responses and programmed cell death induced by acetic acid in yeast.

Thyroid endocrine disruption of acetochlor on zebrafish (Danio rerio) larvae.

The herbicide acetochlor is widely used and detected in the environment and biota, and has been suspected to disrupt the thyroid endocrine system, but underlying mechanisms have not yet been clarified. In the present study, zebrafish larvae (7 days post-fertilization) were exposed to a series concentration of acetochlor (0, 1, 3, 10, 30, 100 and 300 µg l(-1) ) within a 14-day window until 21 days post-fertilization. Thyroid hormones and mRNA expression profiles of genes involved in the hypothalamic-pituitary-thyroid (HPT) axis were analyzed. Exposure to the positive control, 3,5,3'-triiodothyronine (T3 ), altered the mRNA expression, suggesting that the HPT axis in the critical window of zebrafish responded to chemical exposure and could be used to evaluate the effects of chemicals on the thyroid endocrine system. The mRNA expressions of genes involved in thyroid hormone synthesis (tshß, slc5a5 and tpo) were upregulated significantly with acetochlor treatment, which might be responsible for the increased thyroxine concentrations. The downregulation of genes related to thyroid hormone metabolism (dio1 and ugt1ab) and transport (ttr) in zebrafish larvae exposed to acetochlor might further explain the increased thyroxine levels and decreased T3 levels. The mRNA expression of the thyroid hormone receptor (trα) was also upregulated upon acetochlor exposure. Results suggested that acetochlor altered mRNA expression of the HPT axis-related genes and changed the whole body thyroid hormone levels in zebrafish larvae. It demonstrated that acetochlor could cause endocrine disruption of the thyroid system by simulating the biological activity of T3 . Copyright © 2015 John Wiley & Sons, Ltd.