Dietary factors and patterns in relation to risk of later-onset ulcerative colitis in Chinese: A prospective study of 0.5 million people.

BACKGROUND: There is limited evidence on the associations of dietary factors and patterns with risk of later-onset ulcerative colitis (UC) in Chinese adults. AIMS: To investigate the associations of dietary factors and patterns with risk of later-onset UC in Chinese. METHODS: The prospective China Kadoorie Biobank cohort study recruited 512,726 participants aged 30-79. Dietary habits were assessed using food frequency questionnaires. Dietary patterns were derived by factor analysis with a principal component method. Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 12.1 years, 312 cases of newly diagnosed UC were documented (median age of diagnosis 60.1 years). Egg consumption was associated with higher risk of UC (HR for daily vs. never or rarely: 2.29 [95% CI: 1.26-4.16]), while spicy food consumption was inversely associated with risk of UC (HR: 0.63 [0.45-0.88]). The traditional northern dietary pattern, characterised by high intake of wheat and low intake of rice, was associated with higher risk of UC (HR for highest vs. lowest quartile of score: 2.79 [1.93-4.05]). The modern dietary pattern, characterised by high intake of animal-origin foods and fruits, was associated with higher risk of UC (HR: 2.48 [1.63-3.78]). Population attributable fraction was 13.04% (7.71%-19.11%) for daily/almost daily consumption of eggs and 9.87% (1.94%-18.22%) for never/rarely consumption of spicy food. CONCLUSIONS: The findings highlight the importance of evaluating dietary factors and patterns in the primary prevention of later-onset UC in Chinese adults.

Target-site and non-target-site resistance mechanisms confer mesosulfuron-methyl resistance in Alopecurus aequalis.

BACKGROUND: Shortawn foxtail (Alopecurus aequalis Sobol.) is a noxious weed in China. The resistance of A. aequalis developed rapidly due to the long-term application of acetolactate synthase (ALS)-inhibiting herbicides. Here, a suspected mesosulfuron-methyl-resistant A. aequalis population, Aa-R, was collected from a wheat field in China. RESULTS: A dose‒response test showed that the Aa-R population has evolved a high level of resistance to mesosulfuron-methyl, and its growth was suppressed by imazamox, pyroxsulam and bispyribac-sodium. ALS gene sequence analysis revealed that a known resistance-related mutation (Pro-197-Thr) was present in the Aa-R population. Moreover, ALS gene overexpression was detected in the Aa-R population. The mesosulfuron-methyl resistance could be reversed by cytochrome P450 monooxygenase (CYP450) and glutathione S-transferase (GST) inhibitors. In addition, enhanced metabolism of mesosulfuron-methyl was detected in the Aa-R population compared with the susceptible population. NADPH-cytochrome P450 reductase and GST activities were strongly inducible in the Aa-R population. One CYP450 gene, CYP74A2, and one GST gene, GST4, were constitutively upregulated in the Aa-R population. Molecular docking results showed the binding affinity of CYP74A2 and GST4 for the tested ALS-inhibiting herbicides, respectively. CONCLUSION: This study confirmed that target-site resistance and non-target-site resistance involving CYP450 and GST were the main mechanisms involved in resistance in the mesosulfuron-methyl-resistant A. aequalis population.

The Pro-197-Thr mutation in the ALS gene confers novel resistance patterns to ALS-inhibiting herbicides in Bromus japonicus in China.

Introduction: Bromus japonicus is one of the most notorious agricultural weeds in China. The long-term use of ALS-inhibiting herbicides has led to rapid evolution of herbicide resistance in B. japonicus. B. japonicus population (BJ-R) surviving mesosulfuron-methyl treatment was collected from wheatland. Here, we aimed to confirm the resistance mechanisms in this putative resistant population. Methods: The dose-reponse tests were used to test the resistance level of the B. japonicus to ALS-inhibiting herbicides. Pretreatment with P450 and GST inhibitors and GST activity assays were used to determine whether P450 or GST was involved in the resistance of the BJ-R population. Sanger sequencing was used to analyse the ALS mutation of the BJ-R population. RT-qPCR was used to confirm the the expression levels of the ALS gene in mesosulfuron-methyl -resistant (BJ-R) and-susceptible (BJ-S) B. japonicus. An in vitro ALS activity assay was used to determine the ALS activity of the BJ-R and BJ-S populations. Homology modelling and docking were used to determine the binding energy of the BJ-R and BJ-S populations with ALS-inhibiting herbicides. Results: B. japonicus population (BJ-R) was confirmed to be 454- and 2.7-fold resistant to the SU herbicides mesosulfuron-methyl and nicosulfuron, and 7.3-, 2.3-, 1.1- and 10.8-fold resistant to the IMI herbicide imazamox, the TP herbicide penoxsulam, the PTB herbicide pyribenzoxim and the SCT herbicide flucarbazone-sodium, respectively, compared with its susceptible counterpart (BJ-S). Neither a P450 inhibitor nor a GST inhibitor could reverse the level of resistance to mesosulfuron-methyl in BJ-R. In addition, no significant differences in GST activity were found between the BJ-R and BJ-S. ALS gene sequencing revealed a Pro-197-Thr mutation in BJ-R, and the gene expression had no significant differences between the BJ-R and BJ-S. The ALS activity of BJ-R was 106-fold more tolerant to mesosulfuron-methyl than that of BJ-S. Molecular docking showed that the binding energy of the ALS active site and mesosulfuron-methyl was changed from -6.67 to -4.57 kcal mol-1 due to the mutation at position 197. Discussion: These results suggested that the Pro-197-Thr mutation was the main reason for the high resistance level of BJ-R to mesosulfuron-methyl. Unlike previous reports of the cross-resistance pattern conferred by this mutation, we firstly documented that the Pro-197-Thr mutation confers broad cross-resistance spectrums to ALS-inhibiting herbicides in B. japonicus.

The potential for OGG1 inhibition to be a therapeutic strategy for pulmonary diseases.

INTRODUCTION: Pulmonary diseases impose a daunting burden on healthcare systems and societies. Current treatment approaches primarily address symptoms, underscoring the urgency for the development of innovative pharmaceutical solutions. A noteworthy focus lies in targeting enzymes recognizing oxidatively modified DNA bases within gene regulatory elements, given their pivotal role in governing gene expression. AREAS COVERED: This review delves into the intricate interplay between the substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) and epigenetic regulation, with a focal point on elucidating the molecular underpinnings and their biological implications. The absence of OGG1 distinctly attenuates the binding of transcription factors to cis elements, thereby modulating pro-inflammatory or pro-fibrotic transcriptional activity. Through a synergy of experimental insights gained from cell culture studies and murine models, utilizing prototype OGG1 inhibitors (O8, TH5487, and SU0268), a promising panorama emerges. These investigations underscore the absence of cytotoxicity and the establishment of a favorable tolerance profile for these OGG1 inhibitors. EXPERT OPINION: Thus, the strategic targeting of the active site pocket of OGG1 through the application of small molecules introduces an innovative trajectory for advancing redox medicine. This approach holds particular significance in the context of pulmonary diseases, offering a refined avenue for their management.

Identification of major QTLs for drought tolerance in soybean, together with a novel candidate gene, GmUAA6.

Drought tolerance is a complex trait in soybean that is controlled by polygenetic quantitative trait loci (QTLs). In this study, wilting score, days-to-wilting, leaf relative water content, and leaf relative conductivity were used to identify QTLs associated with drought tolerance in recombinant inbred lines derived from a cross between a drought-sensitive variety, Lin, and a drought-tolerant variety, Meng. A total of 33 drought-tolerance QTLs were detected. Of these 17 were major QTLs. In addition, 15 were novel drought-tolerance QTLs. The most predominant QTL was on chromosome 11. This was detected in at least three environments. The overlapped mapping interval of the four measured traits was 0.2 cM in genetic distance (about 220 kb in physical length). Glyma.11g143500 (designated as GmUAA6), which encodes a UDP-N-acetylglucosamine transporter, was identified as the most likely candidate gene. The allele of GmUAA6 from Lin (GmUAA6Lin) was associated with improved soybean drought tolerance. Overexpression of GmUAA6Lin in Arabidopsis and soybean hairy roots enhanced drought tolerance. Furthermore, a 3-bp insertion/deletion (InDel) in the coding sequence of GmUAA6 explained up to 49.9% of the phenotypic variation in drought tolerance-related traits, suggesting that this InDel might be used in future marker-assisted selection of drought-tolerant lines in soybean breeding programs.

Site-specific acetylation of polynucleotide kinase 3'-phosphatase regulates its distinct role in DNA repair pathways.

Mammalian polynucleotide kinase 3'-phosphatase (PNKP), a DNA end-processing enzyme with 3'-phosphatase and 5'-kinase activities, is involved in multiple DNA repair pathways, including base excision (BER), single-strand break (SSBR), and double-strand break repair (DSBR). However, little is known as to how PNKP functions in such diverse repair processes. Here we report that PNKP is acetylated at K142 (AcK142) by p300 constitutively but at K226 (AcK226) by CBP, only after DSB induction. Co-immunoprecipitation analysis using AcK142 or AcK226 PNKP-specific antibodies showed that AcK142-PNKP associates only with BER/SSBR, and AcK226 PNKP with DSBR proteins. Despite the modest effect of acetylation on PNKP's enzymatic activity in vitro, cells expressing non-acetylable PNKP (K142R or K226R) accumulated DNA damage in transcribed genes. Intriguingly, in striatal neuronal cells of a Huntington's Disease (HD)-based mouse model, K142, but not K226, was acetylated. This is consistent with the reported degradation of CBP, but not p300, in HD cells. Moreover, transcribed genomes of HD cells progressively accumulated DSBs. Chromatin-immunoprecipitation analysis demonstrated the association of Ac-PNKP with the transcribed genes, consistent with PNKP's role in transcription-coupled repair. Thus, our findings demonstrate that acetylation at two lysine residues, located in different domains of PNKP, regulates its distinct role in BER/SSBR versus DSBR.

Epigenetic and "redoxogenetic" adaptation to physical exercise.

Exercise-induced adaptation is achieved by altering the epigenetic landscape of the entire genome leading to the expression of genes involved in various processes including regulatory, metabolic, adaptive, immune, and myogenic functions. Clinical and experimental data suggest that the methylation pattern/levels of promoter/enhancer is not linearly correlated with gene expression and proteome levels during physical activity implying a level of complexity and interplay with other regulatory modulators. It has been shown that a higher level of physical fitness is associated with a slower DNA methylation-based aging clock. There is strong evidence supporting exercise-induced ROS being a key regulatory mediator through overlapping events, both as signaling entities and through oxidative modifications to various protein mediators and DNA molecules. ROS generated by physical activity shapes epigenome both directly and indirectly, a complexity we are beginning to unravel within the epigenetic arrangement. Oxidative modification of guanine to 8-oxoguanine is a non-genotoxic alteration, does not distort DNA helix and serves as an epigenetic-like mark. The reader and eraser of oxidized guanine is the 8-oxoguanine DNA glycosylase 1, contributing to changes in gene expression. In fact, it can modulate methylation patterns of promoters/enhancers consequently leading to multiple phenotypic changes. Here, we provide evidence and discuss the potential roles of exercise-induced ROS in altering cytosine methylation patterns during muscle adaptation processes.

The DNA glycosylase NEIL2 is protective during SARS-CoV-2 infection.

SARS-CoV-2 infection-induced aggravation of host innate immune response not only causes tissue damage and multiorgan failure in COVID-19 patients but also induces host genome damage and activates DNA damage response pathways. To test whether the compromised DNA repair capacity of individuals modulates the severity of COVID-19 infection, we analyze DNA repair gene expression in publicly available patient datasets and observe a lower level of the DNA glycosylase NEIL2 in the lungs of severely infected COVID-19 patients. This observation of lower NEIL2 levels is further validated in infected patients, hamsters and ACE2 receptor-expressing human A549 (A549-ACE2) cells. Furthermore, delivery of recombinant NEIL2 in A549-ACE2 cells shows decreased expression of proinflammatory genes and viral E-gene, as well as lowers the yield of viral progeny compared to mock-treated cells. Mechanistically, NEIL2 cooperatively binds to the 5'-UTR of SARS-CoV-2 genomic RNA to block viral protein synthesis. Collectively, these data strongly suggest that the maintenance of basal NEIL2 levels is critical for the protective response of hosts to viral infection and disease.

A glutathione S-transferase and a cytochrome P450 may confer cyhalofop-butyl resistance in Leptochloa chinensis (L.) Nees.

BACKGROUND: Leptochloa chinensis (L.) Nees is a troublesome weed across China in rice fields, and a suspected L. chinensis resistant population (R) that has survived the recommended field dose of cyhalofop-butyl was collected in a rice field of Hunan Province, China. In this study, we aimed to determine the acetyl-CoA carboxylase-inhibiting herbicide resistance profile of this R population and to investigate its mechanisms of resistance to cyhalofop-butyl. RESULTS: Compared with the susceptible population (S), the R population was confirmed to be 18.9-, 3.2-, 4.1-, 3.6- and 5.8- fold resistant to the APP herbicides cyhalofop-butyl, haloxyfop-P-methyl, clodinafop-propargyl, metamifop and fenoxaprop-P-ethyl, respectively. ACCase gene sequencing analysis revealed no known resistance mutations for TSR in the R population. Pretreatment with the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) and cytochrome P450 (CYP450) inhibitor malathion reversed resistance to cyhalofop-butyl. The GST gene GSTU1 and CYP450 gene CYP707A5 were constitutively upregulated in the R population according to RNA-seq analysis and RT-qPCR verification. The molecular docking results indicated a good affinity of the active site for five APP herbicides with GSTU1 and CYP707A5. CONCLUSION: This study shows that the GSTU1 and CYP707A5 genes expressed highly in the R population may be responsible for cyhalofop-butyl resistance in L. chinensis.

Device-measured movement behaviours in over 20,000 China Kadoorie Biobank participants.

BACKGROUND: Movement behaviours, including physical activity, sedentary behaviour, and sleep have been shown to be associated with several chronic diseases. However, they have not been objectively measured in large-scale prospective cohort studies in low-and middle-income countries. We aim to describe the patterns of device-measured movement behaviours collected in the China Kadoorie Biobank (CKB) study. METHODS: During 2020 and 2021, a random subset of 25,087 surviving CKB individuals participated in the 3rd resurvey of the CKB. Among them, 22,511 (89.7%) agreed to wear an Axivity AX3 wrist-worn triaxial accelerometer for seven consecutive days to assess their habitual movement behaviours. We developed a machine-learning model to infer time spent in four movement behaviours [i.e. sleep, sedentary behaviour, light intensity physical activity (LIPA), and moderate-to-vigorous physical activity (MVPA)]. Descriptive analyses were performed for wear-time compliance and patterns of movement behaviours by different participant characteristics. RESULTS: Data from 21,897 participants (aged 65.4 ± 9.1 years; 35.4% men) were received for demographic and wear-time analysis, with a median wear-time of 6.9 days (IQR: 6.1-7.0). Among them, 20,370 eligible participants were included in movement behavior analyses. On average, they had 31.1 mg/day (total acceleration) overall activity level, accumulated 7.7 h/day (32.3%) of sleep time, 8.8 h/day (36.6%) sedentary, 5.7 h/day (23.9%) in light physical activity, and 104.4 min/day (7.2%) in moderate-to-vigorous physical activity. There was an inverse relationship between age and overall acceleration with an observed decline of 5.4 mg/day (17.4%) per additional decade. Women showed a higher activity level than men (32.3 vs 28.8 mg/day) and there was a marked geographical disparity in the overall activity level and time allocation. CONCLUSIONS: This is the first large-scale accelerometer data collected among Chinese adults, which provides rich and comprehensive information about device-measured movement behaviour patterns. This resource will enhance our knowledge about the potential relevance of different movement behaviours for chronic disease in Chinese adults.

8-Oxoguanine DNA glycosylase 1 selectively modulates ROS-responsive NF-κB targets through recruitment of MSK1 and phosphorylation of RelA/p65 at Ser276.

Nuclear factor kappa B (NF-κB) activity is regulated by various posttranslational modifications, of which Ser276 phosphorylation of RelA/p65 is particularly impacted by reactive oxygen species (ROS). This modification is responsible for selective upregulation of a subset of NF-κB targets; however, the precise mechanism remains elusive. ROS have the ability to modify cellular molecules including DNA. One of the most common oxidation products is 8-oxo-7,8-dihydroguanine (8-oxoGua), which is repaired by the 8-oxoguanine DNA glycosylase1 (OGG1)-initiated base excision repair pathway. Recently, a new function of OGG1 has been uncovered. OGG1 binds to 8-oxoGua, facilitating the occupancy of NF-κB at promoters and enhancing transcription of pro-inflammatory cytokines and chemokines. In the present study, we demonstrated that an interaction between DNA-bound OGG1 and mitogen-and stress-activated kinase 1 is crucial for RelA/p65 Ser276 phosphorylation. ROS scavenging or OGG1 depletion/inhibition hindered the interaction between mitogen-and stress-activated kinase 1 and RelA/p65, thereby decreasing the level of phospho-Ser276 and leading to significantly lowered expression of ROS-responsive cytokine/chemokine genes, but not that of Nfkbis. Blockade of OGG1 binding to DNA also prevented promoter recruitment of RelA/p65, Pol II, and p-RNAP II in a gene-specific manner. Collectively, the data presented offer new insights into how ROS signaling dictates NF-κB phosphorylation codes and how the promoter-situated substrate-bound OGG1 is exploited by aerobic mammalian cells for timely transcriptional activation of ROS-responsive genes.

First Report on Resistance to HPPD Herbicides Mediated by Nontarget-Site Mechanisms in the Grass Leptochloa chinensis.

The emergence of 4-hydroxyphenylpyruvate dioxygenase (HPPD) herbicides as efficacious target-site herbicides has been noteworthy. In recent years, only four species of broadleaf weeds have developed resistance due to the long-term widespread use of HPPD herbicides. This study represents the first reported instance of a grass weed exhibiting resistance to HPPD inhibitors. We identified a new HPPD-resistant Chinese sprangletop [Leptochloa chinensis (L.) Nees] population (R population). At the recommended dose of tripyrasulfone, the inhibition rate of the R population was only half that of the sensitive population (S). The mechanism underlying resistance does not involve target-site resistance triggered by amino acid mutations or depend on disparities within the HPPD INHIBITOR SENSITIVE 1 (HIS1) gene. The impetus for resistance appears to be interlinked with the metabolic activities of cytochrome P450 monooxygenase (P450) and glutathione S-transferase (GST) family genes. Following RNA sequencing (RNA-seq) and quantitative real-time PCR (qRT-PCR) validation, the study suggests that five P450 genes, CYP71C1, CYP74A2, CYP72A1, CYP84A1, and CYP714C2, alongside a single GST gene GSTF1, may be implicated in the process of metabolic detoxification.

Eleusine indica Cytochrome P450 and Glutathione S-Transferase Are Linked to High-Level Resistance to Glufosinate.

Eleusine indica has become a global nuisance weed and has evolved resistance to glufosinate. The involvement of target-site resistance (TSR) in glufosinate resistance in E. indica has been elucidated, while the role of nontarget-site resistance (NTSR) remains unclear. Here, we identified a glufosinate-resistant (R) population that is highly resistant to glufosinate, with a resistance index of 13.5-fold. Molecular analysis indicated that the resistance mechanism of this R population does not involve TSR. In addition, pretreatment with two known metabolic enzyme inhibitors, the cytochrome P450 (CYP450) inhibitor malathion and the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl), increased the sensitivity of the R population to glufosinate. The results of subsequent RNA sequencing (RNA-seq) and quantitative real-time PCR (RT-qPCR) suggested that the constitutive overexpression of a GST gene (GSTU3) and three CYP450 genes (CYP94s and CYP71) may play an important role in glufosinate resistance. This study provides new insights into the resistance mechanism of E. indica.

Knockout of the BRAP homolog in mice leads to abnormal tracheal cilia.

Both bombesin receptor-activated protein (BRAP) and its mouse homolog have been found to be expressed in bronchial epithelia but with unclear functions. Using electron microscopy combined with histological assays, we found that BRAP homolog deficiency in mice led to abnormal tracheal cilia. Rab-3A-interacting protein (Rabin8), a protein that might play a role in cilia development, was screened by yeast two-hybrid and further verified to have interaction with human BRAP by co-immunoprecipitation and pulldown assays. The expression levels of Rabin8, together with acetylated α-tubulin, a marker of cilia, were either downregulated by knockdown of BRAP or upregulated by overexpression of BRAP in cultured immortalized human bronchial epithelial cells. These results reveal a role for BRAP in airway cilia formation.

Epigenetic control of type III interferon expression by 8-oxoguanine and its reader 8-oxoguanine DNA glycosylase1.

Interferons (IFNs) are secreted cytokines with the ability to activate expression of IFN stimulated genes that increase resistance of cells to virus infections. Activated transcription factors in conjunction with chromatin remodelers induce epigenetic changes that reprogram IFN responses. Unexpectedly, 8-oxoguanine DNA glycosylase1 (Ogg1) knockout mice show enhanced stimuli-driven IFN expression that confers increased resistance to viral and bacterial infections and allergen challenges. Here, we tested the hypothesis that the DNA repair protein OGG1 recognizes 8-oxoguanine (8-oxoGua) in promoters modulating IFN expression. We found that functional inhibition, genetic ablation, and inactivation by post-translational modification of OGG1 significantly augment IFN-λ expression in epithelial cells infected by human respiratory syncytial virus (RSV). Mechanistically, OGG1 bound to 8-oxoGua in proximity to interferon response elements, which inhibits the IRF3/IRF7 and NF-κB/RelA DNA occupancy, while promoting the suppressor NF-κB1/p50-p50 homodimer binding to the IFN-λ2/3 promoter. In a mouse model of bronchiolitis induced by RSV infection, functional ablation of OGG1 by a small molecule inhibitor (TH5487) enhances IFN-λ production, decreases immunopathology, neutrophilia, and confers antiviral protection. These findings suggest that the ROS-generated epigenetic mark 8-oxoGua via its reader OGG1 serves as a homeostatic thresholding factor in IFN-λ expression. Pharmaceutical targeting of OGG1 activity may have clinical utility in modulating antiviral response.

Detection of Oxidatively Modified Base Lesion(s) in Defined DNA Sequences by FLARE Quantitative PCR.

Assessment of DNA base and strand damage can be determined using a quantitative PCR assay that is based on the concept that damage blocks the progression of a thermostable polymerase thus resulting in decreased amplification. However, some of the mutagenic DNA base lesions cause little or no distortion in Watson-Crick base pairing. One of the most abundant such lesion is 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo(d)Gua), although it affects the thermodynamic stability of the DNA, duplex 8-oxo(d)Gua does not inhibit DNA synthesis or arrest most of DNA or RNA polymerases during replication and transcription. When unrepaired, it is a pre-mutagenic base as it pairs with adenine in anti-syn conformation. Recent studies considered 8-oxo(d)Gua as an epigenetic-like mark and along with 8-oxoguanine DNA glycosylase1 (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1) has roles in gene expression via nucleating transcription factor's promoter occupancy. Here, we introduce its identification through fragment length analysis with repair enzyme (FLARE)-coupled quantitative (q)-PCR. One of the strengths of the assay is that 8-oxo(d)Gua can be identified within short stretches of nuclear and mitochondrial DNA in ng quantities. Bellow we describe the benefits and limits of using FLARE qPCR to assess DNA damage in mammalian cells and provide a detailed protocol of the assay.

Substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) reprograms mucosal adaptations to chronic airway injury.

Recent advances have uncovered the non-random distribution of 7, 8-dihydro-8-oxoguanine (8-oxoGua) induced by reactive oxygen species, which is believed to have epigenetic effects. Its cognate repair protein, 8-oxoguanine DNA glycosylase 1 (OGG1), reads oxidative substrates and participates in transcriptional initiation. When redox signaling is activated in small airway epithelial cells, the DNA repair function of OGG1 is repurposed to transmit acute inflammatory signals accompanied by cell state transitions and modification of the extracellular matrix. Epithelial-mesenchymal and epithelial-immune interactions act cooperatively to establish a local niche that instructs the mucosal immune landscape. If the transitional cell state governed by OGG1 remains responsive to inflammatory mediators instead of differentiation, the collateral damage provides positive feedback to inflammation, ascribing inflammatory remodeling to one of the drivers in chronic pathologies. In this review, we discuss the substrate-specific read through OGG1 has evolved in regulating the innate immune response, controlling adaptations of the airway to environmental and inflammatory injury, with a focus on the reader function of OGG1 in initiation and progression of epithelial to mesenchymal transitions in chronic pulmonary disease.

Nei-like DNA glycosylase 2 selectively antagonizes interferon-ß expression upon respiratory syncytial virus infection.

As part of the antiviral response, cells activate the expressions of type I interferons (IFNs) and proinflammatory mediators to control viral spreading. Viral infections can impact DNA integrity; however, how DNA damage repair coordinates antiviral response remains elusive. Here we report Nei-like DNA glycosylase 2 (NEIL2), a transcription-coupled DNA repair protein, actively recognizes the oxidative DNA substrates induced by respiratory syncytial virus (RSV) infection to set the threshold of IFN-ß expression. Our results show that NEIL2 antagonizes nuclear factor κB (NF-κB) acting on the IFN-ß promoter early after infection, thus limiting gene expression amplified by type I IFNs. Mice lacking Neil2 are far more susceptible to RSV-induced illness with an exuberant expression of proinflammatory genes and tissue damage, and the administration of NEIL2 protein into the airway corrected these defects. These results suggest a safeguarding function of NEIL2 in controlling IFN-ß levels against RSV infection. Due to the short- and long-term side effects of type I IFNs applied in antiviral therapy, NEIL2 may provide an alternative not only for ensuring genome fidelity but also for controlling immune responses.

Detoxification mechanism of herbicide in Polypogon fugax and its influence on rhizosphere enzyme activities.

The excessive use of chemical herbicides has resulted in evolution of herbicide-resistant weeds. Cytochrome P450 monooxygenases (P450s) are vital detoxification enzymes for herbicide-resistant weeds. Herein, we confirmed a resistant (R) Polypogon fugax population showing resistance to quizalofop-p-ethyl, acetolactate synthase (ALS)-inhibiting herbicide pyroxsulam, and several other ACCase (acetyl-CoA carboxylase)-inhibiting herbicides. Molecular analysis revealed no target-site gene mutations in the R population. Foliar spraying with malathion clearly reversed the quizalofop-p-ethyl phytotoxicity. Higher level of quizalofop-p-ethyl degradation was confirmed in the R population using HPLC analysis. Subsequently, RNA-Seq transcriptome analysis indicated that the overexpression of CYP89A2 gene appeared to be responsible for reducing quizalofop-p-ethyl phytotoxicity. The molecular docking results supported a metabolic effect of CYP89A2 protein on most herbicides tested. Furthermore, we found that low doses of herbicides stimulated the rhizosphere enzyme activities in P. fugax and the increase of rhizosphere dehydrogenase of R population may be related to its resistance mechanism. In summary, our research has shown that metabolic herbicide resistance mediated by CYP89A2, contributes to quizalofop-p-ethyl resistance in P. fugax.