This study aimed to verify whether the decreased vascular endothelial growth factor (VEGF)-to-pigment epithelium-derived factor (PEDF) ratio can serve as an indicator for the protective effect of angiotensin-converting enzyme inhibitors (ACEIs) on diabetic retinopathy (DR) and to investigate the role of mitochondrial reactive oxygen species (ROS) in the downregulated VEGF-to-PEDF ratio.

A key initiator in the development of diabetic retinopathy is considered to be the production of reactive oxygen species (ROS) in the retinal mitochondria, and their scavenging enzyme, manganese superoxide dismutase (MnSOD), is compromised. However, the mechanism by which high glucose regulates MnSOD is unclear. In this study, we found that a high concentration of glucose inhibited the expression of the histone deacetylase SIRT3, which resulted in a reduction in MnSOD activity in bovine retinal capillary endothelial cells and in the retinas of diabetic rats. Conversely, SIRT3 overexpression attenuated hyperglycemic stress through deacetylation and activation of MnSOD. Furthermore, the hyperglycemia-induced downregulation of SIRT3 involved the activation of poly (ADP-ribose) polymerase (PARP). Our study is the first to link the deacetylation of MnSOD by PARP-regulated SIRT3 with the pathogenesis of diabetic retinopathy. Understanding the role of SIRT3 in the pathogenesis of diabetic retinopathy could help elucidate key molecular targets for future pharmacological interventions.

Pyrroquinoline quinone-dependent alcohol dehydrogenase (PQQ-ADH) is a key enzyme in the ethanol oxidase respiratory chain of acetic acid bacteria (AAB). To investigate the effect of PQQ-ADH on acetic acid production by Acetobacter pasteurianus JST-S, subunits I (adhA) and II (adhB) of PQQ-ADH were over-expressed, the fermentation parameters and the metabolic flux analysis were compared in the engineered strain and the original one. The acetic acid production was improved by the engineered strain (61.42 g L-1) while the residual ethanol content (4.18 g L-1) was decreased. Analysis of 2D maps indicated that 19 proteins were differently expressed between the two strains; of these, 17 were identified and analyzed by mass spectrometry and two-dimensional gel electrophoresis. With further investigation of metabolic flux analysis (MFA) of the pathway from ethanol and glucose, the results reveal that over-expression of PQQ-ADH is an effective way to improve the ethanol oxidation respiratory chain pathway and these can offer theoretical references for potential mechanism of metabolic regulation in AAB and researches with its acetic acid resistance.

Metastasis is a major cause of breast cancer-associated mortality. Natural products extracted from herbs provide rich bioactive compounds with anticancer efficacy but may have limited or moderate potency and considerable toxicity. We developed a novel aziridonin, YD0514, by aziridinating oridonin, a natural product of the medicinal herb Rabdosia rubescens. In this study, we found that YD0514 significantly inhibited proliferation, motility, and adhesion of metastatic breast cancer cell lines MDA-MB-231, GI101, GILM2, and GILM3. YD0514 also decreased the protein expression of matrix metalloproteinases 2 and 9 (MMP2 and MMP9), focal adhesion kinase (FAK), and integrin family members. Importantly, YD0514 suppressed the growth of metastatic breast cancer xenograft tumors and significantly inhibited lung metastasis in vivo. Lastly, we showed that YD0514's anti-metastatic effect on highly aggressive breast cancer is mediated via regulating the NRF-2/RHOA/ROCK signaling pathway. These results demonstrate that YD0514, the first active analog based on an oridonin D-ring modification, has the potential to be developed as an anti-metastasis therapy for patients with metastatic cancers.

Oxidative stress induced by long-term glucocorticoid (GC) use weakens the repair capacity of bone tissue. Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase (NOX) is a superoxide-generating enzyme that plays an important role in regulating bone metabolism. To clarify the role of nonphagocytic NOX isoforms in osteoblast reactive oxygen species (ROS) generation and apoptosis, dexamethasone was used to establish a high-dose GC environment in vitro. A dose-dependent increase in intracellular ROS generation was demonstrated, which was accompanied by increased osteoblastic MC3T3-E1 cell apoptosis. Addition of the ROS inhibitor NAC (N-acetyl-L-cysteine) or NOX inhibitor DPI (diphenyleneiodonium) reversed this effect, indicating that NOX-derived ROS can induce osteoblast apoptosis under high-dose dexamethasone stimulation. NOX1, NOX2, and NOX4 are NOX homologs recently identified in bone tissue. To clarify the NOX isoforms that play a role in osteoblast ROS generation, Nox1, Nox2, and Nox4 mRNA expression and NOX2 and NOX4 protein expression were analyzed. Nox1 and Nox4 mRNA expression was elevated in a dose-dependent manner after culture in 100 nM, 250 nM, 500 nM, or 1000 nM dexamethasone, and the increased expression of NOX1 mRNA was more significant compared with NOX4 mRNA. Small interfering RNAs (siRNAs) were used to confirm the role of NOX1 and NOX4 in ROS generation. To clarify the signaling pathway in ROS-induced osteoblast apoptosis, mitogen-activated protein kinase (MAPK) signaling molecules were analyzed. Phosphorylated ASK1 and p38 levels were significantly higher in the 1000 nM dexamethasone group, which NAC or DPI markedly attenuated. However, the total mRNA and protein levels of ASK1 and p38 between the dexamethasone group and control were not significantly different. This is related to ROS regulating the posttranslational modification of ASK1 and p38 in MC3T3-E1 cell apoptosis. Altogether, NOX1- and NOX4-derived ROS plays a pivotal role in high-dose dexamethasone-induced preosteoblast apoptosis by increasing phosphorylated ASK1 and p38 and may be an important mechanism in steroid-induced avascular necrosis of the femoral head (SANFH).

This study aimed to evaluate the mechanisms underlying the effects of 1,25-dihydroxyvitamin D (vitamin D3) on diabetes-induced retinal vascular damage and retinal vascular endothelial cell apoptosis.

High-altitude retinopathy (HAR) is an ocular manifestation of acute oxygen deficiency at high altitudes. Although the pathophysiology of HAR has been revealed by many studies in recent years, the molecular mechanism is not yet clear. Our study aimed to systematically identify the genes and microRNA (miRNA) and explore the potential biomarkers associated with HAR by integrated bioinformatics analysis. The mRNA and miRNA expression profiles were obtained from the Gene Expression Omnibus database. We performed Gene Ontology functional annotations and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Potential target gene analysis and miRNA-mRNA network analysis were also conducted. Quantitative RT-PCR (qRT-PCR) was used to validate the results of the bioinformatics analysis. Through a series of bioinformatics analyses and experiments, we selected 16 differentially expressed miRNAs (DE-miRNAs) and 157 differentially expressed genes related to acute mountain sickness (AMS) and constructed a miRNA-mRNA network containing 240 relationship pairs. The hub genes were filtered from the protein-protein interaction network: IL7R, FOS, IL10, FCGR2A, DDX3X, CDK1, BCL11B and HNRNPH1, which were all down-regulated in the AMS group. Then, nine up-regulated DE-miRNAs and eight hub genes were verified by qRT-PCR in our hypoxia-induced HAR cell model. The expression of miR-3177-3p, miR-369-3p, miR-603, miR-495, miR-4791, miR-424-5p, FOS, IL10 and IL7R was consistent with our bioinformatics results. In conclusion, FOS, IL10, IL-7R and 7 DE-miRNAs may participate in the development of HAR. Our findings will contribute to the identification of biomarkers and promote the effective prevention and treatment of HAR in the future.

Angiogenesis is an important parameter in the development of diabetic retinopathy (DR), and it is indicative of an early stage evolving into a late phase. Therefore, examining the role of angiogenic factors in early DR is crucial to understanding the mechanism of neovascularization.

Metabolic syndrome is a disorder of energy use and storage, which is characterized by central obesity, dyslipidemia, and raised blood pressure and blood sugar levels. Maternal 25-hydroxyvitamin D deficiency is known to cause metabolic changes, chronic disease, and increased adiposity in adulthood. However, the underlying mechanism of induced metabolic syndrome (MetS) in the offspring in vitamin D deficient pregnant mothers remains unclear. We identified that maternal 25-hydroxyvitamin D deficiency enhances oxidative stress, which leads to the development of MetS in the mother and her offspring. Further, immunohistochemical, Western blotting, and qRT-PCR analyses revealed that maternal 25-hydroxyvitamin D deficiency inhibited the activation of the Nrf2/carbonyl reductase 1 (CBR1) pathway in maternal placenta, liver, and pancreas, as well as the offspring's liver and pancreas. Further analyses uncovered that application of 25-hydroxyvitamin D activated the Nrf2/CBR1 pathway, relieving the oxidative stress in BRL cells, suggesting that 25-hydroxyvitamin D regulates oxidative stress in offspring and induces the activation of the Nrf2/CBR1 pathway. Taken together, our study finds that maternal 25-hydroxyvitamin D deficiency is likely to result in offspring's MetS probably via abnormal nutrition transformation across placenta. Depression of the Nrf2/CBR1 pathway in both mothers and their offspring is one of the causes of oxidative stress leading to MetS. This study suggests that 25-hydroxyvitamin D treatment may relieve the offspring's MetS.

The initial colonisation of the human microbiota and the impact of maternal health on neonatal microbiota at birth remain largely unknown. The aim of our study is to investigate the possible dysbiosis of maternal and neonatal microbiota associated with gestational diabetes mellitus (GDM) and to estimate the potential risks of the microbial shift to neonates.

Epigenetic variation may contribute to traits that are important in domestication, but how patterns of genetic and epigenetic variation differ between cultivated and wild plants remains poorly understood. In particular, we know little about how selection may shape epigenetic variation in natural and cultivated populations. In this study, we investigated 11 natural populations and 6 major cultivated populations using amplified fragment length polymorphism (AFLP) and methylation-sensitive AFLP (MS-AFLP or MSAP) markers to identify patterns of genetic and epigenetic diversity among Corydalis yanhusuo populations. We further explored correlations among genetic, epigenetic, alkaloidal, and climatic factors in natural and cultivated C. yanhusuo. We found support for a single origin for all cultivated populations, from a natural population which was differentiated from the other natural populations. The magnitude of F ST based on AFLP was significantly correlated with that for MSAP in pairwise comparisons in both natural and cultivated populations, suggesting a relationship between genetic and epigenetic variation in C. yanhusuo. This relationship was further supported by dbRDA (distance-based redundancy analyses) where some of the epigenetic variation could be explained by genetic variation in natural and cultivated populations. Genetic variation was slightly higher in natural than cultivated populations, and exceeded epigenetic variation in both types of populations. However, epigenetic differentiation exceeded that of genetic differentiation among cultivated populations, while the reverse was observed among natural populations. The differences between wild and cultivated plants may be partly due to processes inherent to cultivation and in particular the differences in mode of reproduction. The importance of epigenetic compared to genetic modifications is thought to vary depending on reproductive strategies, and C. yanhusuo usually reproduces sexually in natural environments, while the cultivated C. yanhusuo are propagated clonally. In addition, alkaloid content of C. yanhusuo varied across cultivated populations, and alkaloid content was significantly correlated to climatic variation, but also to genetic (6.89%) and even more so to epigenetic (14.09%) variation in cultivated populations. Our study demonstrates that epigenetic variation could be important in cultivation of C. yanhusuo and serve as a source of variation for response to environmental conditions.

To investigate the effect of home quarantine during the COVID-19 pandemic on myopia progression in children and its associated factors.

In China, guidelines for the treatment of hiatal hernia (HH) are lacking. Furthermore, efficacy and safety assessments of surgical approaches for HH and for the protection of the vagus nerve and organ function are needed. Therefore, the present clinical trial is being conducted to establish the normative treatment for HH.

Inspired by the biological use of a combination of precision and self-assembly to achieve exquisite control and diversity from 20 natural amino acids, there is considerable scope for the development of synthetic precision materials with complex architecture that can access advanced function for biomedical applications. Single cyclic polymers (SCPs) have been shown to offer different and often better performance compared to their linear analogues. Because multicyclic topology in nature offers enhanced effects relative to single cyclization, we hypothesize that multicyclic polymers (MCPs) would access unique features compared to SCPs. However, there are currently quite limited ways to efficiently synthesize MCPs and to precisely modulate the valency of cyclic units. In this work, we report for the first time a straightforward and robust strategy to synthesize MCPs with controllable valency via facile one-pot statistical reversible addition-fragmentation chain transfer (RAFT) copolymerization. We use this strategy to synthesize biocompatible MCPs based on the most classic and important biocompatible polymers of oligo (ethylene glycol) (OEG) and cyclic poly(ε-caprolactone) (cPCL), which can further self-assemble into well-defined nanostructures. We then apply these MCP-based formulations as drug delivery vehicles and demonstrate greater colloidal stability with a low critical micelle concentration (CMC) of 80.3 nM, larger drug loading capacity, higher cellular uptake efficiency, more tumor accumulation, and increased anti-tumor efficacy in murine tumor models compared to SCP-based analogues. We believe this cumulative work demonstrating facile synthesis of MCPs and demonstration of multicyclic topology-enhanced anti-cancer efficiency in vivo provides key technologies and concepts to the burgeoning field of cyclic topology-derived biomaterials.

Ischemia reperfusion (I/R)‑induced intestinal injury is a pathophysiological process leading to oxidative stress and inflammatory responses, and revealing its underlying mechanisms is essential for developing therapeutic strategies. Cyclooxygenase (COX) has been reported to be involved in I/R injury. Parecoxib sodium, a selective inhibitor for COX‑2, exerts protective effects, such as reducing I/R‑induced injuries in the heart, kidney and brain. However, the potential role of parecoxib sodium in protecting the small intestine against I/R‑induced injury has rarely been investigated. Therefore, the aim of the present study was to elucidate the effects and potential mechanisms of parecoxib sodium in I/R‑induced intestinal injury. In total, 60 Sprague‑Dawley rats were randomly divided into four groups: Control (sham operation) group, intestinal I/R group, 10 mg/kg parecoxib sodium‑pre‑treated I/R (I/R + Pare/10) group and the 20 mg/kg parecoxib sodium‑pre‑treated I/R (I/R + Pare/20) group. A regular I/R model was established to induce the intestinal injury in rats. Parecoxib sodium at 10 or 20 mg/kg was intraperitoneally administered into rats in both I/R + Pare groups once daily for 5 consecutive days prior to ischemia. Blood samples and small intestinal tissues were collected at 2 h after reperfusion. Changes in the levels of malondialdehyde, nitric oxide, interleukin (IL)‑1β, IL‑8, intercellular cell adhesion molecule‑1 and IL‑10, as well as the total antioxidant capacity were determined using ELISA, as were the activities of superoxidase dismutase and myeloperoxidase. Furthermore, the protein expression levels of total caspase‑3, cleaved caspase‑3, Bcl‑2 and Bax were examined via western blot analysis. In addition, the daily survival rate post‑reperfusion was examined for 7 days. It was revealed that parecoxib sodium increased the levels of antioxidants and suppressed the intestinal oxidative injury induced by I/R. Moreover, parecoxib sodium downregulated the expression levels of the proinflammatory factors, but upregulated the expression levels of anti‑inflammatory factors. The results also demonstrated that parecoxib sodium attenuated I/R‑induced apoptosis and increased the survival rate of rats. Thus, administration of parecoxib sodium prior to intestinal I/R attenuated intestinal injury and increased the rat survival rate by inhibiting I/R‑induced inflammation, oxidative stress and apoptosis.

This study reported the identification and validation of novel QTL conferring coleoptile length in barley and predicted candidate genes underlying the largest effect QTL based on orthologous analysis and comparison of the whole genome assemblies for both parental genotypes of the mapping population. Coleoptile length (CL) is one of the most important agronomic traits in cereal crops due to its direct influence on the optimal depth for seed sowing which facilitates better seedling establishment. Varieties with longer coleoptiles are preferred in drought-prone areas where less moisture maintains at the top layer of the soil. Compared to wheat, genetic study on coleoptile length is limited in barley. Here, we reported a study on detecting the genomic regions associated with CL in barley by assessing a population consisting of 201 recombinant inbred lines. Four putative QTL conferring CL were consistently identified on chromosomes 1H, 5H, 6H, and 7H in each of the trials conducted. Of these QTL, the two located on chromosomes 5H and 6H (designated as Qcl.caf-5H and Qcl.caf-6H) are likely novel and Qcl.caf-5H showed the most significant effect explaining up to 30.9% of phenotypic variance with a LOD value of 15.1. To further validate the effect of this putative QTL, five pairs of near isogenic lines (NILs) were then developed and assessed. Analysis of the NILs showed an average difference of 21.0% in CL between the two isolines. Notably, none of the other assessed morphological characteristics showed consistent differences between the two isolines for each pair of the NILs. Candidate genes underlying the Qcl.caf-5H locus were also predicted by employing orthologous analysis and comparing the genome assemblies for both parental genotypes of the mapping population in the present study. Taken together, these findings expand our understanding on genetic basis of CL and will be indicative for further gene cloning and functional analysis underly this locus in barley.

Studies of methylation biomarkers for cervical cancer often involved only few randomly selected CpGs per candidate gene analyzed by methylation-specific PCR-based methods, with often inconsistent results from different laboratories. We evaluated the role of different CpGs from multiple genes as methylation biomarkers for high-grade cervical intraepithelial neoplasia (CIN).

Fusarium crown rot (FCR), caused by various Fusarium species, is a destructive disease of cereal crops in semiarid regions worldwide. As part of our contribution to the development of Fusarium resistant cultivars, we identified several novel sources of resistance by systematically assessing barley genotypes representing different geographical origins and plant types. One of these sources of resistance was investigated in this study by generating and analysing two populations of recombinant inbred lines. A major locus conferring FCR resistance, designated as Qcrs.cpi-4H, was detected in one of the populations (mapping population) and the effects of the QTL was confirmed in the other population. The QTL was mapped to the distal end of chromosome arm 4HL and it is effective against both of the Fusarium isolates tested, one F. pseudograminearum and the other F. graminearum. The QTL explains up to 45.3% of the phenotypic variance. As distinct from an earlier report which demonstrated co-locations of loci conferring FCR resistance and plant height in barley, a correlation between these two traits was not detected in the mapping population. However, as observed in a screen of random genotypes, an association between FCR resistance and plant growth rate was detected and a QTL controlling the latter was detected near the Qcrs.cpi-4H locus in the mapping population. Existing data indicate that, although growth rate may affect FCR resistance, different genes at this locus are likely involved in controlling these two traits.

Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) that is easily introduced to humans via consumption of grilled or smoked meat. BaP causes harmful oxidative effects on cell development, growth and survival through an increase in membrane lipid peroxidation, oxidative DNA damage and mutagenesis. Therefore, the present study was conducted to evaluate the synergistic effects of BaP on oxidative stress in hepatic tumors. In this study, we established a hepatic tumor model by injecting rat hepatoma N1-S1 cells into healthy rats. Changes in the abundance of heat shock proteins (HSPs), antioxidant enzymes and pro-inflammatory cytokines were then investigated by western blot analysis. In addition, we examined changes in oxidative stress levels. Injection of N1-S1 cells or concomitant injection of BaP and N1-S1 cells resulted in the formation of hepatic tumors at the injection site. Evaluation of rat plasma reveals that hepatic tumors induced by BaP and N1-S1 cells expresses higher levels of Hsp27, superoxide dismutase (SOD), and tumor necrosis factor-α (TNF-α) when compared to those induced by N1-S1 cells only. The collective results of this study suggest that BaP exerts synergistic effects on the expression of HSP, cytokines and antioxidant enzymes in hepatic tumors induced by rat hepatoma N1-S1 cells.

Fusarium crown rot (FCR) is one of the most damaging cereal diseases in semi-arid regions worldwide. The genetics of FCR resistance in the bread wheat (Triticum eastivum L.) variety EGA Wylie, the most resistant commercial variety available, was studied by QTL mapping. Three populations of recombinant inbred lines were developed with this elite variety as the resistant parent. Four QTL conferring FCR resistance were detected and resistance alleles of all of them were derived from the resistant parent EGA Wylie. One of these loci was located on the short arm of chromosome 5D (designated as Qcrs.cpi-5D). This QTL explains up to 31.1% of the phenotypic variance with an LOD value of 9.6. The second locus was located on the long arm of chromosome 2D (designated as Qcrs.cpi-2D) and explained up to 20.2% of the phenotypic variance with an LOD value of 4.5. Significant effects of both Qcrs.cpi-5D and Qcrs.cpi-2D were detected in each of the three populations assessed. Another two QTL (designated as Qcrs.cpi-4B.1 and Qcrs.cpi-4B.2, respectively) were located on the short arm of chromosome 4B. These two QTL explained up to 16.9% and 18.8% of phenotypic variance, respectively. However, significant effects of Qcrs.cpi-4B.1 and Qcrs.cpi-4B.2 were not detected when the effects of plant height was accounted for by covariance analysis. The elite characteristics of this commercial variety should facilitate the incorporation of the resistance loci it contains into breeding programs.