Magnetite nanoparticle coating chemistry regulates root uptake pathways and iron chlorosis in plants.

Understanding the fundamental interaction of nanoparticles at plant interfaces is critical for reaching field-scale applications of nanotechnology-enabled plant agriculture, as the processes between nanoparticles and root interfaces such as root compartments and root exudates remain largely unclear. Here, using iron deficiency-induced plant chlorosis as an indicator phenotype, we evaluated the iron transport capacity of Fe3O4 nanoparticles coated with citrate (CA) or polyacrylic acid (PAA) in the plant rhizosphere. Both nanoparticles can be used as a regulator of plant hormones to promote root elongation, but they regulate iron deficiency in plant in distinctive ways. In acidic root exudates secreted by iron-deficient Arabidopsis thaliana, CA-coated particles released fivefold more soluble iron by binding to acidic exudates mainly through hydrogen bonds and van der Waals forces and thus, prevented iron chlorosis more effectively than PAA-coated particles. We demonstrate through roots of mutants and visualization of pH changes that acidification of root exudates primarily originates from root tips and the synergistic mode of nanoparticle uptake and transformation in different root compartments. The nanoparticles entered the roots mainly through the epidermis but were not affected by lateral roots or root hairs. Our results show that magnetic nanoparticles can be a sustainable source of iron for preventing leaf chlorosis and that nanoparticle surface coating regulates this process in distinctive ways. This information also serves as an urgently needed theoretical basis for guiding the application of nanomaterials in agriculture.

l-norleucine on high glucose-induced insulin sensitivity and mitochondrial function in skeletal muscle cells.

l-norleucine, an isomer of leucine, stimulates the anabolic process of insulin. However, it is not known if and how it improves insulin sensitivity and insulin resistance. This experiment describes the generation of an insulin resistance model using high glucose-induced cells and the administration of 1.0 mmol/L l-norleucine for 48 h, to observe the effects on metabolism and gene expression in skeletal muscle cells. The results showed that l-norleucine significantly increased mitochondrial ATP content, decreased the amount of reactive oxygen species (ROS) and promoted the expression of mitochondrial generation-related genes TFAM, AMPK, PGC-1α in cells under high glucose treatment; at the same time, l-norleucine also increased glucose uptake, suggesting that l-norleucine increased insulin sensitivity and improved insulin resistance. This study suggesting that l-norleucine improves insulin resistance by ameliorating oxidative stress damage of mitochondria, improving mitochondrial function, and improving insulin sensitivity in skeletal muscle cell caused by high glucose, rather than by altering mitochondrial efficiency.

RhoGDIß inhibition via miR-200c/AUF1/SOX2/miR-137 axis contributed to lncRNA MEG3 downregulation-mediated malignant transformation of human bronchial epithelial cells.

Nickel pollution is a recognized factor contributing to lung cancer. Understanding the molecular mechanisms of its carcinogenic effects is crucial for lung cancer prevention and treatment. Our previous research identified the downregulation of a long noncoding RNA, maternally expressed gene 3 (MEG3), as a key factor in transforming human bronchial epithelial cells (HBECs) into malignant cells following nickel exposure. In our study, we found that deletion of MEG3 also reduced the expression of RhoGDIß. Notably, artificially increasing RhoGDIß levels counteracted the malignant transformation caused by MEG3 deletion in HBECs. This indicates that the reduction in RhoGDIß contributes to the transformation of HBECs due to MEG3 deletion. Further exploration revealed that MEG3 downregulation led to enhanced c-Jun activity, which in turn promoted miR-200c transcription. High levels of miR-200c subsequently increased the translation of AUF1 protein, stabilizing SOX2 messenger RNA (mRNA). This stabilization affected the regulation of miR-137, SP-1 protein translation, and the suppression of RhoGDIß mRNA transcription and protein expression, leading to cell transformation. Our study underscores the co-regulation of RhoGDIß expression by long noncoding RNA MEG3, multiple microRNAs (miR-200c and miR-137), and RNA-regulated transcription factors (c-Jun, SOX2, and SP1). This intricate network of molecular events sheds light on the nature of lung tumorigenesis. These novel findings pave the way for developing targeted strategies for the prevention and treatment of human lung cancer based on the MEG3/RhoGDIß pathway.

Isorhapontigenin inhibition of basal muscle-invasive bladder cancer attributed to its downregulation of SNHG1 and DNMT3b.

BACKGROUND: Bladder cancer (BC) is among the most prevalent malignant urothelial tumors globally, yet the prognosis for patients with muscle-invasive bladder cancer (MIBC) remains dismal, with a very poor 5-year survival rate. Consequently, identifying more effective and less toxic chemotherapeutic alternatives is critical for enhancing clinical outcomes for BC patients. Isorhapontigenin (ISO), a novel stilbene isolated from a Gnetum found in certain provinces of China, has shown potential as an anticancer agent due to its diverse anticancer activities. Despite its promising profile, the specific anticancer effects of ISO on BC and the underlying mechanisms are still largely unexplored. METHODS: The anchorage-independent growth, migration and invasion of BC cells were assessed by soft agar and transwell invasion assays, respectively. The RNA levels of SOX2, miR-129 and SNHG1 were quantified by qRT-PCR, while the protein expression levels were validated through Western blotting. Furthermore, methylation-specific PCR was employed to assess the methylation status of the miR-129 promoter. Functional assays utilized siRNA knockdown, plasmid-mediated overexpression, and chemical inhibition approaches. RESULTS: Our study demonstrated that ISO treatment significantly reduced SNHG1 expression in a dose- and time-dependent manner in BC cells, leading to the inhibition of anchorage-independent growth and invasion in human basal MIBC cells. This effect was accompanied by the downregulation of MMP-2 and MMP-9 and the upregulation of the tumor suppressor PTEN. Further mechanistic investigations revealed that SOX2, a key upstream regulator of SNHG1, played a crucial role in mediating the ISO-induced transcriptional suppression of SNHG1. Additionally, we found that ISO treatment led to a decrease in DNMT3b protein levels, which in turn mediated the hypomethylation of the miR-129 promoter and the subsequent suppression of SOX2 mRNA 3'-UTR activity, highlighting a novel pathway through which ISO exerts its anticancer effects. CONCLUSIONS: Collectively, our study highlights the critical role of SNHG1 downregulation as well as its upstream DNMT3b/miR-129/SOX2 axis in mediating ISO anticancer activity. These findings not only elucidate the mechanism of action of ISO but also suggest novel targets for BC therapy.

Label-free cell phenotypic profiling of histamine H4R receptor and discovery of non-competitive H4R antagonist from natural products.

Histamine 4 receptor (H4R), the most recently identified subtype of histamine receptor, primarily induces inflammatory reactions upon activation. Several H4R antagonists have been developed for the treatment of inflammatory bowel disease (IBD) and atopic dermatitis (AD), but their use has been limited by adverse side effects, such as a short half-life and toxicity. Natural products, as an important source of anti-inflammatory agents, offer minimal side effects and reduced toxicity. This work aimed to identify novel H4R antagonists from natural products. An H4R target-pathway model deconvoluted downstream Gi and MAPK signaling pathways was established utilizing cellular label-free integrative pharmacology (CLIP), on which 148 natural products were screened. Cryptotanshinone was identified as selective H4R antagonist, with an IC50 value of 11.68 ± 1.30 µM, which was verified with Fluorescence Imaging Plate Reader (FLIPR) and Cellular Thermal Shift (CTS) assays. The kinetic binding profile revealed the noncompetitive antagonistic property of cryptotanshinone. Two allosteric binding sites of H4R were predicted using SiteMap, Fpocket and CavityPlus. Subsequent molecular docking and dynamics simulation indicated that cryptotanshinone interacts with H4R at a pocket formed by the outward interfaces between TM3/4/5, potentially representing a new allosteric binding site for H4R. Overall, this study introduced cryptotanshinone as a novel H4R antagonist, offering promise as a new hit for drug design of H4R antagonist. Additionally, this study provided a novel screening model for the discovery of H4R antagonists.

The Lipophilic Extract from Ginkgo biloba L. Leaves Promotes Glucose Uptake and Alleviates Palmitate-Induced Insulin Resistance in C2C12 Myotubes.

Ginkgo biloba L. (ginkgo) is a widely used medicinal plant around the world. Its leaves, which have been used as a traditional Chinese medicine, are rich in various bioactive components. However, most of the research and applications of ginkgo leaves have focused on terpene trilactones and flavonol glycosides, thereby overlooking the other active components. In this study, a lipophilic extract (GL) was isolated from ginkgo leaves. This extract is abundant in lipids and lipid-like molecules. Then, its effect and potential mechanism on glucose uptake and insulin resistance in C2C12 myotubes were investigated. The results showed that GL significantly enhanced the translocation of GLUT4 to the plasma membrane, which subsequently promoted glucose uptake. Meanwhile, it increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream targets. Both knockdown of AMPK with siRNA and inhibition with AMPK inhibitor compound C reversed these effects. Additionally, GL ameliorated palmitate-induced insulin resistance by enhancing insulin-stimulated glucose uptake, increasing the phosphorylation of protein kinase B (PKB/AKT), and restoring the translocation of GLUT4 from the cytoplasm to the membrane. However, pretreatment with compound C abolished these beneficial effects of GL. In conclusion, GL enhances basal glucose uptake in C2C12 myotubes and improves insulin sensitivity in palmitate-induced insulin resistant myotubes through the AMPK pathway.

Analysis of protein expression changes in patients with prediabetes using proteomics approaches.

RATIONALE: Proteomics and metabolomics are widely used in the study of diabetes, but rarely in prediabetes research. This study aimed to explore the mechanisms of early-onset type 2 diabetes mellitus (T2DM) by analyzing proteomic changes at different stages of glucose metabolism. METHODS: A total of 40 individuals undergoing routine physical health examinations between December 2016 and April 2017 were enrolled. Subjects were divided into four groups based on fasting blood glucose (FPG) levels: FPG < 5.6 mmol/L (group A); FPG ≥ 5.6 mmol/L and <6.1 mmol/L (group B); FPG ≥ 6.1 mmol/L and <7.0 mmol/L (group C); and FPG ≥ 7.0 mmol/L (group D). Each group had 10 cases. Sera from these 40 subjects were analyzed by label-free quantitative liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). LC/MS/MS with selected reaction monitoring mode was also performed for qualitative and quantitative metabolomics analysis. Differentially expressed proteins were identified. Partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to analyze the differentially expressed metabolites. RESULTS: A total of 202 differentially expressed proteins were screened and were identified as mainly secreted proteins. Comparing group A with group B, 32 proteins were up-regulated and 18 proteins were down-regulated. Comparing group A with group C, 24 proteins were up-regulated and 24 proteins were down-regulated. Comparing group A with group D, 19 proteins were up-regulated and 17 proteins were down-regulated. The fold change for up-regulated proteins was >1.2, p < 0.05, while the fold change for down-regulated proteins was <-1.2, p < 0.05. PLS-DA and OPLS-DA revealed 113 differentially expressed metabolites. Correlation analysis of differentially expressed metabolites of group A versus group B revealed that among the down-regulated differential proteins, transforming growth factor ß-induced protein ig-h3 correlated negatively with metabolite L-saccharin, while among the up-regulated differential proteins, apolipoprotein C-IV correlated negatively with metabolite 3-methyloxindole. Among all differentially expressed proteins, 19 proteins were associated with early initiation of chronic inflammation, including CD14 and CSF-1R, which were newly identified in the early onset of T2DM. CONCLUSIONS: Many proteins are differentially expressed between prediabetes and after T2DM diagnosis, although the specific mechanism remains unclear. The expression level of CD14 was significantly up-regulated and that of CSF-1R was significantly down-regulated when FPG was ≥5.6 mmol/L, suggesting that CD14 and CSF-1R may be important markers for early-onset T2DM and may serve as new targets for T2DM treatment.

Sequential KOtBu/FeCl3-catalyzed reductive phosphonylation of tertiary amides for the synthesis of α-amino phosphonates and phosphines.

A simple, mild and efficient sequential KOtBu/FeCl3-catalyzed reductive phosphonylation of tertiary amides is herein described. This process first involved the KOtBu-catalyzed selective semi-reduction of tertiary amides to hemiaminal intermediates by TMDS (1,1,3,3-tetramethyldisiloxane) and then the FeCl3-catalyzed nucleophilic addition of the hemiaminal intermediates to phosphonates, which allowed the straightforward synthesis of α-amino phosphonates in moderate to good yields. This method applied well to amides and lactams that bear no strong acidic α-hydrogens, and various functional groups, including methoxy, methylthio, cyano, halogen, and heterocycles, could be tolerated.

Combined coagulation and membrane treatment for anaerobically digested manure centrate: Contaminant residuals and membrane fouling.

To realize water and resource recovery from anaerobically digested manure centrate, the effect of combined coagulation and membrane treatment on contaminant residuals and membrane fouling was investigated. Two combined treatments were used to explore the properties of the retention of nutrients and the removal of risk pollutants. Behaviors and reversibility of membrane fouling after combined treatment were also examined. The result showed that the combined treatment significantly improved the water recovery rate by more than 60% and achieved better nutrient enrichment. Meanwhile, the combined treatment had certain removal effects on heavy metals and antibiotics, which promoted the safety of farmland utilization of anaerobically digested manure centrate. Moreover, the combined treatment reduced the membrane fouling by removing most suspended solids in the digested centrate. Combined coagulation and membrane treatment show great potential for practical applications in the treatment of anaerobically digested manure centrate due to the easy operation and excellent effect. This work provides a technical reference for the harmless and resource recovery of anaerobically digested manure centrate.

Chlorogenic Acid Inhibited Epithelial-Mesenchymal Transition to Treat Pulmonary Fibrosis through Modulating Autophagy.

Chlorogenic acid (CGA), derived from dicotyledons and ferns, has been demonstrated with anti-inflammatory, anti-bacterial, and free radical-scavenging effects and can be used to treat pulmonary fibrosis (PF). However, the specific mechanism by which CGA treats PF needs to be further investigated. In this study, in vivo experiment was firstly performed to evaluate the effects of CGA on epithelial-mesenchymal transition (EMT) and autophagy in bleomycin (BLM)-induced PF mice. Then, the effects of CGA on EMT and autophagy was assessed using transforming growth factor beta (TGF-ß) 1-induced EMT model in vitro. Furthermore, autophagy inhibitor (3-methyladenine) was used to verify that the inhibitory mechanism of CGA on EMT was associated with activating autophagy. Our results found that 60 mg/kg of CGA treatment significantly ameliorated lung inflammation and fibrosis in mice with BLM-induced PF. Besides, CGA inhibited EMT and promoted autophagy in mice with PF. In vitro studies also demonstrated that 50 µM of CGA treatment inhibited EMT and induced autophagy related factors in TGF-ß1-induced EMT cell model. Moreover, the inhibitory effect of CGA on autophagy and EMT in vitro was abolished after using autophagy inhibitor. In conclusion, CGA could inhibit EMT to treat BLM-induced PF in mice through, activating autophagy.

Discovery of Flavonoids as Novel Inhibitors of ATP Citrate Lyase: Structure-Activity Relationship and Inhibition Profiles.

ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism and its aberrantly high expression is closely associated with various cancers, hyperlipemia and atherosclerotic cardiovascular diseases. Prospects of ACLY inhibitors as treatments of these diseases are excellent. To date, flavonoids have not been extensively reported as ACLY inhibitors. In our study, 138 flavonoids were screened and 21 of them were subjected to concentration-response curves. A remarkable structure-activity relationship (SAR) trend was found: ortho-dihydroxyphenyl and a conjugated system maintained by a pyrone ring were critical for inhibitory activity. Among these flavonoids, herbacetin had a typical structure and showed a non-aggregated state in solution and a high inhibition potency (IC50 = 0.50 ± 0.08 µM), and therefore was selected as a representative for the ligand-protein interaction study. In thermal shift assays, herbacetin improved the thermal stability of ACLY, suggesting a direct interaction with ACLY. Kinetic studies determined that herbacetin was a noncompetitive inhibitor of ACLY, as illustrated by molecular docking and dynamics simulation. Together, this work demonstrated flavonoids as novel and potent ACLY inhibitors with a remarkable SAR trend, which may help design high-potency ACLY inhibitors. In-depth studies of herbacetin deepened our understanding of the interactions between flavonoids and ACLY.

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OBJECTIVES: To study the clinical efficacy of ultrasound-guided endoscopic retrograde appendicitis therapy in children with appendix-related chronic abdominal pain. METHODS: A retrospective analysis was performed on the medical data of 30 children with the chief complaint of chronic abdominal pain who were admitted from August 2019 to May 2021. All the children were found to have inflammation of the appendix or intracavitary stool and fecalith by ultrasound and underwent ultrasound-guided endoscopic retrograde appendicitis therapy. The medical data for analysis included clinical manifestations, endoscopic findings, white blood cell count, neutrophil percentage, length of hospital stay, and cure rate. RESULTS: Among the 30 children with chronic abdominal pain, there were 13 boys (43%) and 17 girls (57%), with a mean age of (9±3) years (range 3-15 years) at diagnosis. The median duration of the disease was 12 months, and the median length of hospital stay was 3 days. The children had a median white blood cell count of 6.7×109/L and a neutrophil percentage of 50%±13%. Fecalith and a large amount of feces were flushed out of the appendix cavity for 21 children (70%) during surgery. The follow-up rate was 97% (29/30), and the median follow-up time was 11 months (range 5-26 months). Of the 29 children, abdominal pain completely disappeared in 27 children (93%). CONCLUSIONS: Ultrasound-guided endoscopic retrograde appendicitis therapy is effective in children with chronic abdominal pain caused by feces or fecalith in the appendix cavity.

Photocatalytic Radical Ortho-Dearomative Cyclization: Access to Spiro[4.5]deca-1,7,9-trien-6-ones.

A highly efficient ortho-dearomative cyclization reaction between alkynes and 2-bromo-2-(2-methoxybenzyl)malonate via visible light-induced photoredox catalysis has been reported. In the presence of 1 mol % fac-Ir(ppy)3, a variety of spiro[4.5]deca-1,7,9-trien-6-ones were obtained in moderate to excellent yields under mild conditions. Under the optimized reaction conditions, a sample reaction of 3 mmol scale proceeded smoothly to give the desired products in 84% yield with a low catalyst loading of 0.1 mol %.

Stereoselective Synthesis of cis-2-Ene-1,4-diones via Aerobic Oxidation of Substituted Furans Catalyzed by ABNO/HNO3.

We report a highly efficient and selective catalytic system, ABNO (9-azabicyclo-[3.3.1]nonane N-oxyl)/HNO3, for the aerobic oxidation of substituted furans to cis-2-ene-1,4-diones under mild reaction conditions using oxygen as the oxidant. The catalyst system is amenable to various substituted (mon-, di-, and tri-) furans and tolerates diverse functional groups, including cyano, nitro, naphthyl, ketone, ester, heterocycle, and even formyl groups. Based on the control and 18O-labeling experiments, the possible mechanism of the oxidation is proposed.

Discovery of novel pyrimidine molecules containing boronic acid as VCP/p97 Inhibitors.

Valine-containing protein (VCP) is a member of the adenosine triphosphate family involved in a variety of cellular activities. VCP/p97 is capable of maintaining protein homeostasis and mediating the degradation of misfolded polypeptides by the ubiquitin-proteasome system (UPS). In this manuscript, a series of novel p97 inhibitors with pyrimidine as core structure were designed, synthesized and biologically evaluated. Based on the enzymatic results, a detailed structure-activity relationship discussion of the synthesized compounds was carried out. Furthermore, cellular activities of the compounds with enzymatic potency of less than 200 nM were investigated by using A549 and RPMI8226 cell lines. Among the screened inhibitors, compound 17 (IC50, 54.7 nM) showed good enzymatic activity. Investigation of cellular activities with non-small cell lung cancer A549 and multiple myeloma (MM) RPMI8226 further confirmed the potency of 17 with the IC50 values of 2.80 µM and 0.86 µM, respectively. Compound 17 is now being developed as a candidate. Finally, docking studies were carried out to explore the possible binding mode between the active inhibitor 17 and p97.

The modified endoscopic retrograde appendicitis therapy versus antibiotic therapy alone for acute uncomplicated appendicitis in children.

BACKGROUND: Endoscopic retrograde appendicitis therapy (ERAT) is an emerging endoscopic treatment modality for acute uncomplicated appendicitis (AUA) supported by several case series. However, to date, systematic studies have not been conducted in children and the prospective comparative data are lacking. Moreover, due to a concern for future malignancy risk in children from ionizing radiation, we used contrast-enhanced ultrasound (CEUS) instead of endoscopic retrograde appendiceal radiography (ERAR). Therefore, we conducted a prospective, randomized control clinical trial to compare the modified ERAT (mERAT) to antibiotic therapy in children with AUA. The aim of this study was to evaluate the safety and feasibility and of mERAT in the treatment of hospitalized children with AUA. METHODS: Children with AUA, confirmed by ultrasonography and or abdominal computed tomography, were consecutively enrolled from October 2018 to February, 2020. They were randomly assigned to receive mERAT or routine antibiotic treatment. Patients were followed until May, 2020. Th primary outcome variable was the duration of relief of the abdominal pain after treatment. We collected patient's demographics, ultrasonic imaging findings, colonoscopy findings, and treatment outcomes of the mERAT and adverse even associated with mERAT. RESULTS: A total of 83 children were enrolled. 36 were randomized to mERAT and 47 to antibiotics treatment. All children in the mERAT group had endoscopic confirmed acute uncomplicated appendicitis, and there were no significant complications. However, 9 of patients in antibiotic group were poor responsive to treatment and switched to mERAT. The overall success rate of treatment with mERAT (100%) was significantly higher than that of antibiotics (80.9%) (P = 0.004). The median time to discharge was significantly shorter in mERAT group than in antibiotics treatment group [6.0 ± 1.76 days] (P = 0.004). CONCLUSIONS: mERAT provide a new alternative therapeutic option for childhood with AUA, especially for families who are reluctant to undergo an appendectomy.

Visible-light-induced intramolecular radical cascade of α-bromo-N-benzyl-alkylamides: a new strategy to synthesize tetracyclic N-fused indolo[2,1-a]isoquinolin-6(5H)-ones.

Polycyclic indole scaffolds are ubiquitous in pharmaceuticals and natural products and in materials science. Here, we present a visible-light-initiated intramolecular aryl migration/desulfonylation/cyclization cascade reaction for the synthesis of tetracyclic indolo[2,1-a]isoquinolin-6(5H)-ones. This protocol not only exhibited a wide substrate scope but also provided a mild route to access a variety of tetracyclic N-fused indoles.

Ru-Catalyzed Chemo- and Enantioselective Hydrogenation of 2,4-Pentadien-1-ones: Synthesis of Chiral 2,4-Pentadien-1-ols.

The asymmetric hydrogenation of 2,4-pentadien-1-ones has been achieved by using trans-RuCl2[(R)-XylylSunPhos][(R)-Daipen] as a catalyst under basic conditions. This hydrogenation demonstrated exclusive C1-carbonyl selectivity, and thus the conjugated 2,4-diene motifs remained untouched, which provides a synthetically useful method for various chiral 2,4-pentadien-1-ols.

Highly Diastereo- and Enantioselective Access to syn-α-Amido ß-Hydroxy Esters via Ruthenium-Catalyzed Dynamic Kinetic Resolution-Asymmetric Hydrogenation.

Dynamic kinetic resolution (DKR) of racemic aryl α-amino ß-ketoesters via Ru-diphosphine-catalyzed asymmetric hydrogenation was realized at 70 °C under 50 atm of hydrogen, affording syn α-amido ß-hydroxy esters in high yields (up to 96%) with high reactivity (TON up to 940) and diastereo- and enantioselectivities (up to 99:1 dr, 98% ee). These hydrogenation products provide valuable chiral synthons in many natural products and pharmaceuticals. Gram-scale DKR asymmetric hydrogenation (DKR-AH) was also performed with retained reactivity and stereoselectivity, revealing the synthetic utility of this method.

Visible-Light-Induced Intermolecular Dearomative Cyclization of Furans: Synthesis of 1-Oxaspiro[4.4]nona-3,6-dien-2-one.

A fac-Ir(ppy)3-catalyzed intermolecular dearomative cyclization of 2-bromo-2-((5-bromofuran-2-yl)methyl)malonate and alkynes affording substituted spirolactones in yields of 19-91% via a 5- exo-dig radical cyclization under visible light is presented. This method provides a new access to the synthesis of spirocycle skeletons applying water as an external oxygen source under mild reaction conditions.