Physio-biochemical and metabolomic responses of the woody plant Dalbergia odorifera to salinity and waterlogging.

BACKGROUND: Trees have developed a broad spectrum of molecular mechanisms to counteract oxidative stress. Secondary metabolites via phenolic compounds emblematized the hidden bridge among plant kingdom, human health, and oxidative stress. Although studies have demonstrated that abiotic stresses can increase the production of medicinal compounds in plants, research comparing the efficiency of these stresses still needs to be explored. Thus, the present research paper provided an exhaustive comparative metabolomic study in Dalbergia odorifera under salinity (ST) and waterlogging (WL). RESULTS: High ST reduced D. odorifera's fresh biomass compared to WL. While WL only slightly affected leaf and vein size, ST had a significant negative impact. ST also caused more significant damage to water status and leaflet anatomy than WL. As a result, WL-treated seedlings exhibited better photosynthesis and an up-regulation of nonenzymatic pathways involved in scavenging reactive oxygen species. The metabolomic and physiological responses of D. odorifera under WL and salinity ST stress revealed an accumulation of secondary metabolites by the less aggressive stress (WL) to counterbalance the oxidative stress. Under WL, more metabolites were more regulated compared to ST. ST significantly altered the metabolite profile in D. odorifera leaflets, indicating its sensitivity to salinity. WL synthesized more metabolites involved in phenylpropanoid, flavone, flavonol, flavonoid, and isoflavonoid pathways than ST. Moreover, the down-regulation of L-phenylalanine correlated with increased p-coumarate, caffeate, and ferulate associated with better cell homeostasis and leaf anatomical indexes under WL. CONCLUSIONS: From a pharmacological and medicinal perspective, WL improved larger phenolics with therapeutic values compared to ST. Therefore, the data showed evidence of the crucial role of medical tree species' adaptability on ROS detoxification under environmental stresses that led to a significant accumulation of secondary metabolites with therapeutic value.

Dalbergia odorifera undergoes massive molecular shifts in response to waterlogging combined with salinity.

Field and greenhouse studies attempting to describe the molecular responses of plant species under waterlogging (WL) combined with salinity (ST) are almost nonexistent. We integrated transcriptional, metabolic, and physiological responses involving several crucial transcripts and common differentially expressed genes and metabolites in fragrant rosewood (Dalbergia odorifera) leaflets to dissect plant-specific molecular responses and patterns under WL combined with ST (SWL). We discovered that the synergistic pattern of the transcriptional response of fragrant rosewood under SWL was exclusively characterized by the number of regulated transcripts. The response patterns under SWL based on transcriptome and metabolome regulation statuses revealed different patterns (additive, dominant, neutral, minor, unilateral, and antagonistic) of transcripts or metabolites that were commonly regulated or expressed uniquely under SWL. Under SWL, the synergistic transcriptional response of several functional gene subsets was positively associated with several metabolomic and physiological responses related to the shutdown of the photosynthetic apparatus and the extensive degradation of starch into saccharides through α-amylase, ß-amylase, and α-glucosidase or plastoglobuli accumulation. The dissimilarity between the regulation status and number of transcripts in plants under combined stresses led to nonsynergistic responses in several physiological and phytohormonal traits. As inferred from the impressive synergistic transcriptional response to morpho-physiological changes, combined stresses exhibited a gradually decreasing effect on the changes observed at the molecular level compared to those in the morphological one. Here, by characterizing the molecular responses and patterns of plant species under SWL, our study considerably improves our understanding of the molecular mechanisms underlying combined stress.

Exogenous ABA and IAA modulate physiological and hormonal adaptation strategies in Cleistocalyx operculatus and Syzygium jambos under long-term waterlogging conditions.

BACKGROUND: The mechanisms of abscisic acid (ABA) and auxin (IAA) in inducing adventitious root (AR) formation, biomass accumulation, and plant development under long-term waterlogging (LT-WL) conditions are largely unexplored. This study aimed to determine the roles of exogenous application of ABA and IAA in two woody plants (Cleistocalyx operculatus and Syzygium jambos) under LT-WL conditions. A pot experiment was conducted using a complete randomized design with two factors: (i) LT-WL and (ii) application of exogenous phytohormones (ABA and IAA) for 120 d. RESULTS: Results revealed that exogenous ABA and IAA promoted LT-WL tolerance in both species. In C. operculatus and S. jambos, plant height, the number of blades, leaf area, and fresh shoot weight were increased by exogenous IAA under LT-WL. However, exogenous ABA affected more the adventitious and primary root in C. operculatus compared to S. jambos. LT-WL decreased drastically the photosynthetic activities in both species, but adding moderate amounts of exogenous ABA or IAA protected the photosynthesis apparatus under LT-WL. Exogenous phytohormones at certain levels decreased the superoxide anion level and malondialdehyde accumulation in plants under LT-WL. Also, the increase of the peroxidases and superoxide dismutase activities by exogenous phytohormones was more marked in C. operculatus compared to S. jambos. Meanwhile, the catalase activity was down-regulated in both species by exogenous phytohormones. Exogenous ABA or IAA positively regulated the jasmonic acid content in ARs under LT-WL. Moderate application of exogenous ABA or IAA in plants under LT-WL decreased the ABA content in the leaves. Lower accumulation of IAA and ABA in the leaves of C. operculatus under LT-WL was positively correlated with a decrease in antioxidant activity. CONCLUSIONS: Lastly, C. operculatus which has greater morphology indexes was more tolerant to waterlogging than S. jambos. Moreover, the adaptive strategies via exogenous ABA were more built around the below-ground biomass indexes particularly in C. operculatus, while exogenous IAA backed the above-ground biomass in both species. Overall, the exogenous hormones applied (spraying or watering) influenced differentially the plant's responses to LT-WL. The phytohormonal profile of plants exposed to waterlogging stress varied depending on the species' tolerance level.

Competitive Relationship Between Cleistocalyx operculatus and Syzygium jambos Under Well-Watered Conditions Transforms Into a Mutualistic Relationship Under Waterlogging Stress.

Competition and abiotic stress such as waterlogging (WL) represent main factors limiting plant growth and determining plant resistance and distribution patterns in wetland ecosystems. One of the basic steps for wetland restoration is to plant trees to ensure a quicker recovery and prevent erosion. Plant survival and adaptation are considered criteria of principal priority for the screening of plant species for wetland ecosystem restoration. WL influences plant species in wetlands via the deterioration of the plant root environment which leads to oxygen deficiency that affects plant growth, photosynthesis, respiration, and other metabolic processes. A suitable plant species was determined according to tolerance to WL during wetland vegetation recovery activities. Thus, two tree species (Cleistocalyx operculatus and Syzygium jambos) that showed a certain waterlogging tolerance were chosen to study their behaviors in different planting model and environmental conditions. Given that interspecific relationship should be considered during plant community construction, the eco-physiological adaptable mechanisms between these woody plants under well-watered condition and waterlogging stress were explored. Results showed that both species were waterlogging-tolerant species due to their ability to adapt to submergence conditions for 120 days. Moreover, C. operculatus possessed stronger tolerance to waterlogging stress because of a significant adventitious roots biomass accumulation. A competitive relationship was found between C. operculatus and S. jambos under well-watered condition, and C. operculatus showed better growth performance benefited from morphological responses (plant height, number of blade and leaf area) and endogenous hormone variations. In comparison, S. jambos suffered some negative effects when the well-watered mixed planting was used. However, the competitive relationship under well-watered condition was transformed into mutualistic relationship under waterlogging stress. The mixed planting under waterlogging condition significantly improved the tolerance of C. operculatus and S. jambos to waterlogging stress, compared with the monoculture., Especially, S. jambos showed improvements in root length, root surface area, and redox equilibration between lower levels of relative conductivity, malondialdehyde, and O 2 ⋅ - and had increased levels of non-enzymatic antioxidant components, such as reduced glutathione and soluble proteins. The interspecific relationship between C. operculatus and S. jambos was altered by waterlogging stress, and both showed improved tolerance to waterlogging stress. This study can provide a glimmer of light on suitable plant species selection and plant community construction during the revegetation activities in wetland zones. C. operculatus and S. jambos represent potential candidates in wetland restoration in a mixed planting model.

Glucose Fluctuations Aggravate Myocardial Fibrosis via the Nuclear Factor-κB-Mediated Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Activation.

Background: Glucose fluctuations may be associated with myocardial fibrosis. This study aimed to investigate the underlying mechanisms of glucose fluctuation-related myocardial fibrosis. Methods: Streptozotocin (STZ)-injected type 1 diabetic rats were randomized to five groups: the controlled blood glucose (CBG) group, uncontrolled blood glucose (UBG) group, fluctuated blood glucose (FBG) group, FBG rats injected with 0.9% sodium chloride (NaCl) (FBG + NaCl) group, and FBG rats injected with MCC950 (FBG + MCC950) group. Eight weeks later, left ventricular function was evaluated by echocardiography and myocardial fibrosis was observed by Masson trichrome staining. The primary neonatal rat cardiac fibroblasts were cultured with different concentrations of glucose in vitro. Results: The left ventricular function was impaired and myocardial fibrosis was aggravated most significantly in the FBG group compared with the CBG and UBG groups. The levels of interleukin (IL)-1ß, IL-18, transforming growth factor-ß1 (TGF-ß1), collagen type 1 (collagen I), nuclear factor (NF)-κB, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome were significantly increased in the FBG group. In vitro, the inhibition of NF-κB and inflammasome reversed these effects. In vivo, NLRP3 inhibition with MCC950 reversed left ventricular systolic dysfunction and myocardial fibrosis induced by glucose fluctuations. Conclusion: Glucose fluctuations promote diabetic myocardial fibrosis by the NF-κB-mediated inflammasome activation.

Drought and Nitrogen Application Modulate the Morphological and Physiological Responses of Dalbergia odorifera to Different Niche Neighbors.

Mixed stands can be more productive if growth facilitation via niche segregation occurs. Dalbergia odorifera T. Chen, a tropical tree species endemic to Hainan Island with great economic values, belongs to the family Leguminosae. However, selecting mixed species with suitable ecological niches to efficiently construct mixed forests of D. odorifera in the context of abiotic stress [drought, nitrogen (N) deposition] remained obscure. In the present study, the target plant D. odorifera was planted with the same species D. odorifera, heterogeneous but the same family Delonix regia and non-Leguminous Family Swietenia mahagoni in the root interaction and isolated models under two watering regimes [100% and 30% field capacity (FC)] and two N applications (application, non-application), respectively. Principle component analysis based on the performances of growth, phenotype, and physiology was performed to identify the main factors affected by the treatments and the most discriminatory effects of water, N level, and species interaction models. Both comprehensive evaluation values and comprehensive index values were calculated to evaluate the influences of different niche neighbors on D. odorifera. Results showed that D. odorifera was benefited from S. mahagoni but inhibited from D. odorifera in all treatments under root system interaction. Drought stress aggravated the inhibitory effects on D. odorifera from D. odorifera. N application stimulated the promoted effects on D. odorifera from S. mahagoni but enhanced competition intensity of D. odorifera from D. regia under the 100% FC condition. N application alleviated the inhibitory effect of drought stress on D. odorifera from D. odorifera and S. mahagoni. Furthermore, the responses of D. odorifera to different niche neighbors were dominated by belowground interaction rather than the negligible aboveground one. Therefore, the feasibility of niche segregation as the criterion for selecting neighbors to construct D. odorifera mixed stands was confirmed. In addition, water level and N application could alter responses of D. odorifera to different niche neighbors under the root system interaction. Appropriate N application could alleviate the inhibitory effect of drought stress on D. odorifera in its mixed forests. A mixture with S. mahagoni under appropriate N application could be the optimal planting model.

Neighbors, Drought, and Nitrogen Application Affect the Root Morphological Plasticity of Dalbergia odorifera.

In forest systems, neighbor-induced root morphological plasticity (RMP) is species specific and environment dependent. However, related studies on leguminous woody trees remain sparse. The objectives of this study were to evaluate the root morphological response of the leguminous woody Dalbergia odorifera T. Chen to different N-fixing niche neighbors under models of root system contact and isolation and to evaluate whether such response can be modified by drought or the application of nitrogen (N). The relationship between root morphology and the relative competitiveness of the whole D. odorifera plantlet was also assessed. D. odorifera plantlets from the woody Leguminosae family were used as target species and were grown with either identical N-fixing niche D. odorifera, the heterogeneous but con-leguminous Delonix regia, or the non-leguminous Swietenia mahagoni. All plants were grown under two water conditions (100% and 30% field capacity) and two N treatments (no N application and N application). Two planting models (root system contact in Experiment 1, root system isolation in Experiment 2) were applied to neighboring plantlets. The RMP of D. odorifera was assessed based on root morphology, root system classification, root nodules, and RMP-related indices. The growth of D. odorifera was estimated based on the relative growth ratio, net assimilation rate, and leaf N content. The relative competitiveness of the whole D. odorifera plantlet was evaluated through relative yield. The results of Experiment 1 showed that D. odorifera had different RMP responses to a different N-fixing niche neighbor with root system contact. The RMP of D. odorifera was promoted by a different N-fixing niche neighbor under conditions of drought or N deficiency. Drought improved the RMP of D. odorifera exposed to a different N-fixing niche neighbor. N application converted the promoting effect of D. regia on RMP to an inhibitory effect under well-watered conditions. Experiment 2 showed that belowground interaction with a different N-fixing niche neighbor may be the only way to influence RMP, as effects of aboveground interaction were negligible. Finally, correlation analysis showed that neighbor-induced RMP might predict the relative competitiveness of the whole D. odorifera plantlet under conditions of drought or N deficiency. These findings highlight the influences of neighbors, drought, and N application on the RMP of D. odorifera and contribute to understanding neighbor-induced dynamic changes in the root traits of leguminous woody species in forest systems in the context of climate change.

A method to screen left ventricular dysfunction through ECG based on convolutional neural network.

OBJECTIVE: This study aims to develop an artificial intelligence-based method to screen patients with left ventricular ejection fraction (LVEF) of 50% or lesser using electrocardiogram (ECG) data alone. METHODS: Convolutional neural network (CNN) is a class of deep neural networks, which has been widely used in medical image recognition. We collected standard 12-lead ECG and transthoracic echocardiogram (TTE) data including the LVEF value. Then, we paired the ECG and TTE data from the same individual. For multiple ECG-TTE pairs from a single individual, only the earliest data pair was included. All the ECG-TTE pairs were randomly divided into the training, validation, or testing data set in a ratio of 9:1:1 to create or evaluate the CNN model. Finally, we assessed the screening performance by overall accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: We retrospectively enrolled a total of 26 786 ECG-TTE pairs and randomly divided them into training (n = 21 732), validation (n = 2 530), and testing data set (n = 2 530). In the testing set, the CNN algorithm showed an overall accuracy of 73.9%, sensitivity of 69.2%, specificity of 70.5%, positive predictive value of 70.1%, and negative predictive value of 69.9%. CONCLUSION: Our results demonstrate that a well-trained CNN algorithm may be used as a low-cost and noninvasive method to identify patients with left ventricular dysfunction.

Gly Betaine Surpasses Melatonin to Improve Salt Tolerance in Dalbergia odorifera.

Salinity is one of the most serious factors limiting plant growth which can provoke significant losses in agricultural crop production, particularly in arid and semi-arid areas. This study aimed to investigate whether melatonin (MT; 0.05 and 0.1 mM), which has pleiotropic roles, has a better effect than glycine betaine (GB; 10 and 50 mM) on providing salt tolerance in a woody plant Dalbergia odorifera T. Chen. Also, the alternative oxidase activity (AOX) in plant subjected to MT or GB under salinity (150 and 250 mM) was evaluated given that the effect of exogenous MT or GB on AOX has not been reported yet. The results showed that the exogenous application of GB on the seedlings of D. odorifera increased the plant growth parameters, relative water content, total of chlorophyll content, and carotenoid content compared with well-watered and MT treatments. Under severe salinity, the seedlings subjected to GB showed, a significant enhancement in water use efficiency, transpiration, and net photosynthetic rate regardless to MT-treated seedlings. The levels of proline and soluble sugar in the seedlings treated with MT or GB decreased significantly under mild and severe salinity correlated with those in salt-stressed seedlings. Furthermore, GB-treated plants exhibited a significant inhibition of malondialdehyde content compared with MT-treated plants. The concentration of thiols and phenolic compounds were significantly enhanced in the leaves of seedlings treated with MT compared with those treated with GB. Under salt stress condition, GB scavenged significantly higher levels of hydrogen peroxide than MT; while under severe salinity, plants subjected to MT showed better scavenging ability for hydroxyl radicals compared with GB-treated seedlings. The results demonstrated also an enhancement of the levels of superoxide dismutase (SOD), guaiacol peroxidase, and AOX activities in seedlings treated with GB or MT compared with salt-stressed plants. The catalase activity (CAT) was increased by 0.05 mM MT and 0.1 mM GB under mild salinity. Meanwhile, the AOX activity under severe salinity was enhanced only by GB 50 mM. The findings of this study suggested that GB-treated seedlings possessed a better salt tolerance in comparison with MT-treated seedlings.

Cardiovascular disease-specific mortality in 270,618 patients with non-small cell lung cancer.

BACKGROUND: This study aimed to investigate the trend of cardiovascular disease (CVD)-specific mortality in patients with non-small cell lung cancer (NSCLC) and identify prognostic factors for CVD-specific death in stage NSCLC patients. METHODS: In this study, 270,618 NSCLC patients were collected from the Surveillance, Epidemiology, and End Results database. CVD- and NSCLC-specific cumulative mortality and proportion of death were calculated and graphically displayed to describe the probability of specific endpoints. Prognostic factors for CVD-specific mortality were evaluated by cause-specific hazard ratios (HR) with 95% confidence intervals (CI) using the competing risk model with non-cardiovascular death as competing risks. RESULTS: Among all competing causes of death, lung cancer resulted in the highest cumulative mortality, followed by CVDs and other causes. In the proportion of cause-specific death, heart diseases accounted for approximately 5.3% of the total death, only secondary to primary cancer. In all three stages, higher age, squamous cell carcinoma, and no-or-unknown chemotherapy and/or radiotherapy were associated with a higher risk of CVD-specific death, while surgery treatment seemed to be a protective factor. Female gender was statistically related to CVD-specific death in stage I and III patients with HRs of 0.84 (0.78-0.91) and 0.84 (0.77-0.93), respectively. Interestingly, right-sided laterality was correlated with lower CVD-specific mortality with HR of 0.82 (0.74-0.90) in stage III. CONCLUSIONS: This study illustrated the historical trend of CVD-specific death in NSCLC patients and assesses potential prognostic risk factors, highlighting the involvement of cardio-oncology teams in cancer treatment to provide optimal comprehensive care and long-term surveillance for cancer patients.

Glucose fluctuations promote vascular BK channels dysfunction via PKCα/NF-κB/MuRF1 signaling.

Glucose fluctuations may contribute to large conductance calcium activated potassium (BK) channel dysfunction. However, the underlying mechanisms remain elusive. The aim of this study was to investigate the molecular mechanisms involved in BK channel dysfunction as a result of glucose fluctuations. A rat diabetic model was established through the injection of streptozotocin. Glucose fluctuations in diabetic rats were induced via consumption and starvation. Rat coronary arteries were isolated and coronary vascular tensions were measured after three weeks. Rat coronary artery smooth muscle cells were isolated and whole-cell BK channel currents were recorded using a patch clamp technique. Human coronary artery smooth muscle cells in vitro were used to explore the underlying mechanisms. After incubation with iberiotoxin (IBTX), the Δ tensions (% Max) of rat coronary arteries in the controlled diabetes mellitus (C-DM), the uncontrolled DM (U-DM) and the DM with glucose fluctuation (GF-DM) groups were found to be 84.46 ± 5.75, 61.89 ± 10.20 and 14.77 ± 5.90, respectively (P < .05), while the current densities of the BK channels in the three groups were 43.09 ± 4.35 pA/pF, 34.23 ± 6.07 pA/pF and 17.87 ± 4.33 pA/pF, respectively (P < .05). The Δ tensions (% Max) of rat coronary arteries after applying IBTX in the GF-DM rats injected with 0.9% sodium chloride (NaCl) (GF-DM + NaCl) and the GF-DM rats injected with N-acetyl-L-cysteine (NAC) (GF-DM + NAC) groups were found to be 8.86 ± 1.09 and 48.90 ± 10.85, respectively (P < .05). Excessive oxidative stress and the activation of protein kinase C (PKC) α and nuclear factor (NF)-κB induced by glucose fluctuations promoted the decrease of BK-ß1 expression, while the inhibition of reactive oxygen species (ROS), PKCα, NF-κB and muscle ring finger protein 1 (MuRF1) reversed this effect. Glucose fluctuations aggravate BK channel dysfunction via the ROS overproduction and the PKCα/NF-κB/MuRF1 signaling pathway.

Morphological and physiological responses of Dalbergia odorifera T. Chen seedlings to different culture substances.

Dalbergia odorifera T. Chen seedlings do not grow well in the typical red soils of tropical regions. Eighteen culture substances filled with different substrate combinations and proportions of red soil, coconut coir powder, deciduous leaf powder, and sand were used as to determine their effects on the growth, root system development, dry matter accumulation and allocation, leaf relative electrolyte leakage, chlorophyll content, root superoxide dismutase activity, root malondialdehyde content, and total soluble sugar content of D. odorifera. Results demonstrated that different substrate combinations and proportions had different effects on the performance of D. odorifera. All mixed substrates were better than any single substrate. The suitable substrate combinations and proportions of sand, coconut coir powder, and deciduous leaf powder mixed with red soil improved the growth, root architecture, and physiological characteristics of D. odorifera seedling. For example, groups C1-2 (coconut coir/red soil = 2/2, v/v, the same below) and C3-2 (red soil/sand = 2/2) exerted the best effects on plant growth and biomass accumulation. Groups C1-2, C2-2 (deciduous leaf powder/red soil = 2/2), and C3-2 remarkably enhanced root system development. Group C6 (coconut coir/red soil/sand = 1/1/1) substantially promoted root nodule development. Group C3-1 (red soil/sand = 3/1) exhibited the best effects on physiological characteristics. On the basis of the comprehensive evaluation of Euclid's multidimensional space mathematical model, we found that the suitable substrate combinations followed the order of C1-2 > C3-1 > C2-2. This research provides scientific guidance for the proper seedling culture of D. odorifera and the rational utilization of solid wastes such as coconut coir and deciduous leaves of Ficus elastica.

Correction: Comprehensive Analysis of Human Cytomegalovirus MicroRNA Expression during Lytic and Quiescent Infection.

[This corrects the article DOI: 10.1371/journal.pone.0088531.].

Glucose Fluctuations Promote Aortic Fibrosis through the ROS/p38 MAPK/Runx2 Signaling Pathway.

AIM: Glucose fluctuations may be responsible for, or further the onset of arterial hypertension, but the exact mechanisms remain unclear. The purpose of this study was to investigate the mechanisms behind and related to aortic fibrosis and aortic stiffening induced by glucose fluctuations. METHODS: Sprague-Dawley rats were injected with streptozotocin (STZ) and randomly divided into three treatment groups: controlled STZ-induced diabetes (C-STZ); uncontrolled STZ-induced diabetes (U-STZ); and STZ-induced diabetes with glucose fluctuations (STZ-GF). After 3 weeks, rat blood pressure (BP) was tested, and aortic fibrosis was detected by using the Masson trichrome staining technique. Levels of p38 mitogen-activated protein kinase (p38 MAPK), runt-related transcription factor 2 (Runx2), collagen type 1 (collagen I), and NADPH oxidases were determined by Western blot.Rat vascular smooth muscle cells in vitro were used to explore underlying mechanisms. RESULTS: The systolic BP of diabetic rats in the C-STZ, U-STZ, and STZ-GF groups was 127.67 ± 6.53, 150.03 ± 5.24, and 171.63 ± 3.53 mm Hg, respectively (p< 0.05). The mean BP of diabetic rats in the three groups was 91.20 ± 10.07, 117.29 ± 4.28, and 140.58 ± 2.14 mm Hg, respectively (p< 0.05). The diastolic BP of diabetic rats in the three groups was 73.20 ± 12.63, 101.93 ± 5.79, and 125.37 ± 4.62 mm Hg, respectively (p< 0.05). The ratios of fibrosis areas in the aortas of the three groups were 11.85 ± 1.23, 29.00 ± 0.87, and 48.36 ± 0.55, respectively (p< 0.05). The expressions of p38 MAPK, Runx2, and collagen I were significantly increased in the STZ-GF group. In vitro, applications of inhibitors of reactive oxygen species (ROS) and p38 MAPK successfully reversed glucose fluctuations that would have possibly induced aortic fibrosis. CONCLUSIONS: Blood glucose fluctuations aggravate aortic fibrosis via affecting the ROS/p38 MAPK /Runx2 signaling pathway.

Molecular Mechanisms of Glucose Fluctuations on Diabetic Complications.

Accumulating evidence indicates the occurrence and development of diabetic complications relates to not only constant high plasma glucose, but also glucose fluctuations which affect various kinds of molecular mechanisms in various target cells and tissues. In this review, we detail reactive oxygen species and their potentially damaging effects upon glucose fluctuations and resultant downstream regulation of protein signaling pathways, including protein kinase C, protein kinase B, nuclear factor-κB, and the mitogen-activated protein kinase signaling pathway. A deeper understanding of glucose-fluctuation-related molecular mechanisms in the development of diabetic complications may enable more potential target therapies in future.

Sex-specific responses to winter flooding, spring waterlogging and post-flooding recovery in Populus deltoides.

Winter flooding events are common in some rivers and streams due to dam constructions, and flooding and waterlogging inhibit the growth of trees in riparian zones. This study investigated sex-specific morphological, physiological and ultrastructural responses to various durations of winter flooding and spring waterlogging stresses, and post-flooding recovery characteristics in Populus deltoides. There were no significant differences in the morphological, ultrastructural and the majority of physiological traits in trees subjected to medium and severe winter flooding stresses, suggesting that males and females of P. deltoides were winter flooding tolerant, and insensitive to winter flooding duration. Males were more tolerant to winter flooding stress in terms of photosynthesis and chlorophyll fluorescence than females. Females displayed greater oxidative damage due to flooding stress than males. Males developed more efficient antioxidant enzymatic systems to control reactive oxygen species. Both sexes had similarly strong post-flooding recovery capabilities in terms of plant growth, and physiological and ultrastructural parameters. However, Males had better recovery capabilities in terms of pigment content. These results increase the understanding of poplars's adaptation to winter flooding stress. They also elucidate sex-specific differences in response to flooding stress during the dormant season, and during post-flooding recovery periods.

Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells.

UNLABELLED: Human cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell development in vitro. Similar events in vivo may be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain. IMPORTANCE: Congenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.

MicroRNA miR-21 attenuates human cytomegalovirus replication in neural cells by targeting Cdc25a.

UNLABELLED: Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily manifesting as neurological disorders. HCMV infection alters expression of cellular microRNAs (miRs) and induces cell cycle arrest, which in turn modifies the cellular environment to favor virus replication. Previous observations found that HCMV infection reduces miR-21 expression in neural progenitor/stem cells (NPCs). Here, we show that infection of NPCs and U-251MG cells represses miR-21 while increasing the levels of Cdc25a, a cell cycle regulator and known target of miR-21. These opposing responses to infection prompted an investigation of the relationship between miR-21, Cdc25a, and viral replication. Overexpression of miR-21 in NPCs and U-251MG cells inhibited viral gene expression, genome replication, and production of infectious progeny, while shRNA-knockdown of miR-21 in U-251MG cells increased viral gene expression. In contrast, overexpression of Cdc25a in U-251MG cells increased viral gene expression and production of infectious progeny and overcame the inhibitory effects of miR-21 overexpression. Three viral gene products-IE1, pp71, and UL26-were shown to inhibit miR-21 expression at the transcriptional level. These results suggest that Cdc25a promotes HCMV replication and elevation of Cdc25a levels after HCMV infection are due in part to HCMV-mediated repression of miR-21. Thus, miR-21 is an intrinsic antiviral factor that is modulated by HCMV infection. This suggests a role for miR-21 downregulation in the neuropathogenesis of HCMV infection of the developing CNS. IMPORTANCE: Human cytomegalovirus (HCMV) is a ubiquitous pathogen and has very high prevalence among population, especially in China, and congenital HCMV infection is a major cause for birth defects. Elucidating virus-host interactions that govern HCMV replication in neuronal cells is critical to understanding the neuropathogenesis of birth defects resulting from congenital infection. In this study, we confirm that HCMV infection downregulates miR-21 but upregulates Cdc25a. Further determined the negative effects of cellular miRNA miR-21 on HCMV replication in neural progenitor/stem cells and U-251MG glioblastoma/astrocytoma cells. More importantly, our results provide the first evidence that miR-21 negatively regulates HCMV replication by targeting Cdc25a, a vital cell cycle regulator. We further found that viral gene products of IE1, pp71, and UL26 play roles in inhibiting miR-21 expression, which in turn causes increases in Cdc25a and benefits HCMV replication. Thus, miR-21 appears to be an intrinsic antiviral factor that represents a potential target for therapeutic intervention.

Comprehensive analysis of human cytomegalovirus microRNA expression during lytic and quiescent infection.

BACKGROUND: Human cytomegalovirus (HCMV) encodes microRNAs (miRNAs) that function as post-transcriptional regulators of gene expression during lytic infection in permissive cells. Some miRNAs have been shown to suppress virus replication, which could help HCMV to establish or maintain latent infection. However, HCMV miRNA expression has not been comprehensively examined and compared using cell culture systems representing permissive (lytic) and semi-permissive vs. non-permissive (latent-like) infection. METHODS: Viral miRNAs levels and expression kinetics during HCMV infection were determined by miRNA-specific stem-loop RT-PCR. HCMV infected THP-1 (non-permissive), differentiated THP-1 (d-THP-1, semi-permissive) and human embryo lung fibroblasts (HELs, fully-permissive) were examined. The impact of selected miRNAs on HCMV infection (gene expression, genome replication and virus release) was determined by Western blotting, RT-PCR, qPCR, and plaque assay. RESULTS: Abundant expression of 15 HCMV miRNAs was observed during lytic infection in HELs; highest peak inductions (11- to 1502-fold) occurred at 48 hpi. In d-THP-1s, fourteen mRNAs were detected with moderate induction (3- to 288-fold), but kinetics of expression was generally delayed for 24 h relative to HELs. In contrast, only three miRNAs were induced to low levels (3- to 4-fold) during quiescent infection in THP-1s. Interestingly, miR-UL70-3p was poorly induced in HEL (1.5-fold), moderately in THP-1s (4-fold), and strongly (58-fold) in d-THP-1s, suggesting a potentially specific role for miR-UL70-3p in THP-1s and d-THP-1s. MiR-US33, -UL22A and -UL70 were further evaluated for their impact on HCMV replication in HELs. Ectopic expression of miR-UL22A and miR-UL70 did not affect HCMV replication in HELs, whereas miR-US33 inhibited HCMV replication and reduced levels of HCMV US29 mRNA, confirming that US29 is a target of miR-US33. CONCLUSIONS: Viral miRNA expression kinetics differs between permissive, semi-permissive and quiescent infections, and miR-US33 down-regulates HCMV replication. These results suggest that miR-US33 may function to impair entry into lytic replication and hence promote establishment of latency.