Cysteine Radical and Glutamate Collaboratively Enable C-H Bond Activation and C-N Bond Cleavage in a Glycyl Radical Enzyme HplG.

Hydroxyprolines are abundant in nature and widely utilized by many living organisms. Isomerization of trans-4-hydroxy-d-proline (t4D-HP) to generate 2-amino-4-ketopentanoate has been found to need a glycyl radical enzyme HplG, which catalyzes the cleavage of the C-N bond, while dehydration of trans-4-hydroxy-l-proline involves a homologous enzyme of HplG. Herein, molecular dynamics simulations and quantum mechanics/molecular mechanics (QM/MM) calculations are employed to understand the reaction mechanism of HplG. Two possible reaction pathways of HplG have been explored to decipher the origin of its chemoselectivity. The QM/MM calculations reveal that the isomerization proceeds via an initial hydrogen shift from the Cγ site of t4D-HP to a catalytic cysteine radical, followed by cleavage of the Cδ-N bond in t4D-HP to form a radical intermediate that captures a hydrogen atom from the cysteine. Activation of the Cδ-H bond in t4D-HP to bring about dehydration of t4D-HP possesses an extremely high energy barrier, thus rendering the dehydration pathway implausible in HplG. On the basis of the current calculations, conserved residue Glu429 plays a pivotal role in the isomerization pathway: the hydrogen bonding between it and t4D-HP weakens the hydroxyalkyl Cγ-Hγ bond, and it acts as a proton acceptor to trigger the cleavage of the C-N bond in t4D-HP. Our current QM/MM calculations rationalize the origin of the experimentally observed chemoselectivity of HplG and propose an H-bond-assisted bond activation strategy in radical-containing enzymes. These findings have general implications on radical-mediated enzymatic catalysis and expand our understanding of how nature wisely and selectively activates the C-H bond to modulate catalytic selectivity.

Influence of mHealth-Based Lifestyle Interventions on Symptoms of Anxiety and Depression of Women With Gestational Diabetes: A Meta-Analysis.

BACKGROUND: Symptoms of anxiety and depression are common in women with gestational diabetes mellitus (GDM). Mobile health (mHealth)-based lifestyle interventions have been shown to be effective in improving glycemic control of these women. PURPOSE/OBJECTIVE: The aim of the study was to evaluate the influence of mHealth-based lifestyle interventions on symptoms of anxiety and depression in women with GDM. DESIGN: A systematic review and meta-analysis or randomized controlled trials. SETTING: Clinical or community-based settings. SAMPLE: Nine studies involving 1,168 pregnant women with GDM were included. INTERVENTION: mHealth-based lifestyle interventions. MEASURES: Symptoms of anxiety and depression quantitatively analyzed in clinical scales. ANALYSIS: A systematic literature search was performed in electronic databases, including PubMed, Cochrane library, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure to obtain relevant randomized controlled studies. A random-effects model was used to pool the results by incorporating the impact of the potential heterogeneity. RESULTS: Findings revealed that when compared to usual care, women who received mHealth-based lifestyle interventions had significant improvements in symptoms of anxiety (standardized mean difference [SMD]: -0.55, 95% CI [-0.77, -0.33], p < .001; I2 = 67%) and depression (SMD: -0.51, [-0.72, -0.29], p < .001; I2 = 65%). Sensitivity analyses by excluding one study at a time showed consistent results. Subgroup analyses showed similar results in mHealth achieved by phone, websites, and applications, in mHealth targeting diet and exercise with and without psychological support, in mHealth lead by nurse with and without other clinical specialists, and in studies with different evaluating tools for anxiety and depression. CONCLUSIONS: mHealth-based lifestyle interventions could significantly improve the symptoms of anxiety and depression in women with GDM.

Cobalt-Catalyzed Acceptorless Dehydrogenation of Primary Amines to Nitriles.

The direct double dehydrogenation from primary amines to nitriles without an oxidant or hydrogen acceptor is both intriguing and challenging. In this paper, we describe a non-noble metal catalyst capable of realizing such a transformation with high efficiency. A cobalt-centered N,N-bidentate complex was designed and employed as a metal-ligand cooperative dehydrogenation catalyst. Detailed kinetic studies, control experiments, and DFT calculations revealed the crucial hydride transfer, proton transfer, and hydrogen evolution processes. Finally, a tandem outer-sphere/inner-sphere mechanism was proposed for the dehydrogenation of amines to nitriles through an imine intermediate.

Ultrahigh-reflective optical thin films prepared by reactive magnetron sputtering with RF-induced substrate bias.

Optical thin films with high-reflectivity (HR) are essential for applications in quantum precision measurements. In this work, we propose a coating technique based on reactive magnetron sputtering with RF-induced substrate bias to fabricate HR-optical thin films. First, atomically flat SiO2 and Ta2O5 layers have been demonstrated due to the assistance of radio-frequency plasma during the coating process. Second, a distributed Bragg reflector (DBR) mirror with an HR of ∼99.999 328% centered at 1397 nm has been realized. The DBR structure is air-H{LH}19-substrate, in which the L and H denote a single layer of SiO2 with a thickness of 237.8 nm and a single layer of Ta2O5 with a thickness of 171.6 nm, respectively. This novel coating method would facilitate the development of HR reflectors and promote their wide applications in precision measurements.

Exploring the Cooperation of the Redox Non-Innocent Ligand and Di-Cobalt Center for the Water Oxidation Reaction Catalyzed by a Binuclear Complex.

Water oxidation is a crucial reaction in the artificial photosynthesis system. In the present work, density functional calculations were employed to decipher the mechanism of water oxidation catalyzed by a binuclear cobalt complex, which was disclosed to be a homogeneous water oxidation catalyst in pH=7 phosphate buffer. The calculations showed that the catalytic cycle starts from the CoIII,III-OH2 species. Then, a proton-coupled electron transfer followed by a one-electron transfer process leads to the generation of the formal CoIV,IV-OH intermediate. The subsequent PCET produces the active species, namely the formal CoIV,V=O intermediate (4). The oxidation processes mainly occur on the ligand moiety, including the coordinated water moiety, implying a redox non-innocent behavior. Two cobalt centers keep their oxidation states and provide one catalytic center for water activation during the oxidation process. 4 triggers the O-O bond formation via the water nucleophilic attack pathway, in which the phosphate buffer ion functions as the proton acceptor. The O-O bond formation is the rate-limiting step with a calculated total barrier of 17.7 kcal/mol. The last electron oxidation process coupled with an intramolecular electron transfer results in the generation of O2.

Bimetallic H2 Addition and Intramolecular Caryl-H Activation Mediated by an Iron-Zinc Hydride.

Heteronuclear Fe(µ-H)Zn hydride Cp*Fe(1,2-Cy2PC6H4)HZnEt (3) undergoes reversible intramolecular Caryl-H reductive elimination through coupling of the cyclometalated phosphinoaryl ligand and the hydride, giving rise to a formal Fe(0)-Zn(II) species. Addition of CO intercepts this equilibrium, affording Cp*(Cy2PPh)(CO)Fe-ZnEt that features a dative Fe-Zn bond. Significantly, this system achieves bimetallic H2 addition, as demonstrated by the transformation of the monohydride Fe(µ-H)Zn to a deuterated dihydride Fe-(µ-D)2-Zn upon reaction with D2.

A sensitive immunosensing platform based on the high cathodic photoelectrochemical activity of Zr-MOF and dual-signal amplification of peroxidase-mimetic Fe-MOF.

Cathodic photoelectrochemical (PEC) analysis has received special concerns because of its outstanding anti-interference capability toward reductive substances in samples, so it is highly desirable to develop high-performance photocathodic materials for PEC analysis. Herein, a Zr-based metal-organic framework (Zr-MOF), MOF-525, is explored as a photoactive material in aqueous solution for the first time, which shows a narrow band-gap of 1.82 eV, excellent visible-light absorption, and high cathodic PEC activity. A sandwiched-type PEC immunosensor for detecting prostate-specific antigen (PSA) is fabricated by using MIL-101-NH2(Fe) label and MOF-525 photoactive material. MIL-101-NH2(Fe) as a typical Fe-MOF can serve as a peroxidase mimic to catalyze the production of precipitates on the photoelectrode. Both the produced precipitates and the MIL-101-NH2(Fe) labels can quench the photocathodic current, enabling "signal-off" immunosensing of PSA. The detection limit is 3 fg mL-1, and the linear range is between 10 fg mL-1 and 100 ng mL-1 for detecting PSA. The present study not only develops a high-performance Zr-MOF photoactive material for cathodic PEC analysis but also constructs a sensitive PEC immunosensing platform based on the dual-signal amplification of peroxidase-mimetic Fe-MOF.

Accessing ladder-shape azetidine-fused indoline pentacycles through intermolecular regiodivergent aza-Paternò-Büchi reactions.

Small molecules with conformationally rigid, three-dimensional geometry are highly desirable in drug development, toward which a direct, simple-to-complexity synthetic logic is still of considerable challenges. Here, we report intermolecular aza-[2 + 2] photocycloaddition (the aza-Paternò-Büchi reaction) of indole that facilely assembles planar building blocks into ladder-shape azetidine-fused indoline pentacycles with contiguous quaternary carbons, divergent head-to-head/head-to-tail regioselectivity, and absolute exo stereoselectivity. These products exhibit marked three-dimensionality, many of which possess 3D score values distributed in the highest 0.5% region with reference to structures from DrugBank database. Mechanistic studies elucidated the origin of the observed regio- and stereoselectivities, which arise from distortion-controlled C-N coupling scenarios. This study expands the synthetic repertoire of energy transfer catalysis for accessing structurally intriguing architectures with high molecular complexity and underexplored topological chemical space.

Predictive visual field outcomes after optic chiasm decompressive surgery by retinal vessels parameters using optical coherence tomography angiography.

AIM: To evaluate the predictive value of superficial retinal capillary plexus (SRCP) and radial peripapillary capillary (RPC) for visual field recovery after optic cross decompression and compare them with peripapillary nerve fiber layer (pRNFL) and ganglion cell complex (GCC). METHODS: This prospective longitudinal observational study included patients with chiasmal compression due to sellar region mass scheduled for decompressive surgery. Generalized estimating equations were used to compare retinal vessel density and retinal layer thickness pre- and post-operatively and with healthy controls. Logistic regression models were used to assess the relationship between preoperative GCC, pRNFL, SRCP, and RPC parameters and visual field recovery after surgery. RESULTS: The study included 43 eyes of 24 patients and 48 eyes of 24 healthy controls. Preoperative RPC and SRCP vessel density and pRNFL and GCC thickness were lower than healthy controls and higher than postoperative values. The best predictive GCC and pRNFL models were based on the superior GCC [area under the curve (AUC)=0.866] and the tempo-inferior pRNFL (AUC=0.824), and the best predictive SRCP and RPC models were based on the nasal SRCP (AUC=0.718) and tempo-inferior RPC (AUC=0.825). There was no statistical difference in the predictive value of the superior GCC, tempo-inferior pRNFL, and tempo-inferior RPC (all P>0.05). CONCLUSION: Compression of the optic chiasm by tumors in the saddle area can reduce retinal thickness and blood perfusion. This reduction persists despite the recovery of the visual field after decompression surgery. GCC, pRNFL, and RPC can be used as sensitive predictors of visual field recovery after decompression surgery.

Unveiling protein corona composition: predicting with resampling embedding and machine learning.

Biomaterials with surface nanostructures effectively enhance protein secretion and stimulate tissue regeneration. When nanoparticles (NPs) enter the living system, they quickly interact with proteins in the body fluid, forming the protein corona (PC). The accurate prediction of the PC composition is critical for analyzing the osteoinductivity of biomaterials and guiding the reverse design of NPs. However, achieving accurate predictions remains a significant challenge. Although several machine learning (ML) models like Random Forest (RF) have been used for PC prediction, they often fail to consider the extreme values in the abundance region of PC absorption and struggle to improve accuracy due to the imbalanced data distribution. In this study, resampling embedding was introduced to resolve the issue of imbalanced distribution in PC data. Various ML models were evaluated, and RF model was finally used for prediction, and good correlation coefficient (R2) and root-mean-square deviation (RMSE) values were obtained. Our ablation experiments demonstrated that the proposed method achieved an R2 of 0.68, indicating an improvement of approximately 10%, and an RMSE of 0.90, representing a reduction of approximately 10%. Furthermore, through the verification of label-free quantification of four NPs: hydroxyapatite (HA), titanium dioxide (TiO2), silicon dioxide (SiO2) and silver (Ag), and we achieved a prediction performance with an R2 value >0.70 using Random Oversampling. Additionally, the feature analysis revealed that the composition of the PC is most significantly influenced by the incubation plasma concentration, PDI and surface modification.

Pivotal Role of Geometry Regulation on O-O Bond Formation Mechanism of Bimetallic Water Oxidation Catalysts.

In this study, we highlight the impact of catalyst geometry on the formation of O-O bonds in Cu2 and Fe2 catalysts. A series of Cu2 complexes with diverse linkers are designed as electrocatalysts for water oxidation. Interestingly, the catalytic performance of these Cu2 complexes is enhanced as their molecular skeletons become more rigid, which contrasts with the behavior observed in our previous investigation with Fe2 analogs. Moreover, mechanistic studies reveal that the reactivity of the bridging O atom results in distinct pathways for O-O bond formation in Cu2 and Fe2 catalysts. In Cu2 systems, the coupling takes place between a terminal CuIII -OH and a bridging µ-O⋅ radical. Whereas in Fe2 systems, it involves the coupling of two terminal Fe-oxo entities. Furthermore, an in-depth structure-activity analysis uncovers the spatial geometric prerequisites for the coupling of the terminal OH with the bridging µ-O⋅ radical, ultimately leading to the O-O bond formation. Overall, this study emphasizes the critical role of precisely adjusting the spatial geometry of catalysts to align with the O-O bonding pathway.

Regioselective Diels-Alder Reactions of Anthracenes with Olefins via Visible Light Photocatalysis in a Homogeneous Solution.

Diels-Alder cycloaddition of anthracene with olefin is achieved in a homogeneous solution via energy transfer under visible light. A series of substrates including electroneutral styrene derivatives can be successfully converted into the corresponding cycloadducts in a head-to-head orientation with high to excellent yields. The high ortho-regioselectivity, mild condition, and broad substrate scope enable promising advances in organic transformation.

Mechanism of photocatalytic CO2 reduction to HCO2H by a robust multifunctional iridium complex.

The tetradentate PNNP-type IrIII complex Mes-IrPCY2 ([Cl-IrIII-H]+) is reported to be an efficient catalyst for the reduction of CO2 to formate with excellent selectivity under visible light irradiation. Density functional calculations have been carried out to elucidate the mechanism and the origin of selectivity in the present work. Calculations suggest that the double-reduced complex 1-H (1[IrI-H]0) demonstrates higher activity than the single-reduced complex 2-H (2[IrIII(L˙-)-H]+), possibly owing to the higher hydride donor ability of the former compared to the latter; thus 1-H functions as the active species in the overall CO2 reduction reaction. In the HCOO- formation pathway, the hydride of 1-H performs a nucleophilic attack on CO2via an outer-sphere fashion to generate species 1-OCHO (1[IrI-OCHO]0), which then releases HCOO- to produce an IrI intermediate. A subsequent protonation and chloride coordination of the Ir center leads to the regeneration of catalyst 1[Cl-IrIII-H]+. For the CO production, a nucleophilic attack on CO2 takes place by the Ir atom of 1-Hvia an inner-sphere manner to afford complex O2C-3-H (1[O2C-IrIII-H]0), followed by a two-proton-one-electron reduction to furnish the OC-2-H complex (2[OC-IrIII(L˙-)-H]+) after liberating a H2O. Ultimately, CO is released to form 2-H. The stronger nucleophilicity as well as smaller steric hindrance of the hydride than the Ir atom of the active species 1-H (1[IrI-H]0) is found to account for the favoring of formate formation over CO formation. Meanwhile, the CO2 reduction reaction is calculated to be preferred over the hydrogen evolution reaction, and this is consistent with the experimental product distributions.

Dearomatization of [2.2]Paracyclophane-Derived N-Sulfonylimines through Cyclopropanation with Sulfur Ylides.

An unprecedented dearomatization of [2.2]paracyclophane-derived cyclic N-sulfonylimines was conducted through cyclopropanation with sulfur ylides, giving a series of dearomative cyclopropanes with good yields. DFT calculations suggested that the dearomatization was attributed to the relatively weak aromaticity of [2.2]paracyclophane derivatives that resulted from the effect of the unique [2.2]paracyclophane skeleton and the electron-withdrawing N-sulfonyl group. Some downstream elaborations of the products were demonstrated.

Electrocatalytic Interconversions of CO2 and Formate on a Versatile Iron-Thiolate Platform.

Exploring bidirectional CO2/HCO2- catalysis holds significant potential in constructing integrated (photo)electrochemical formate fuel cells for energy storage and applications. Herein, we report selective CO2/HCO2- electrochemical interconversion by exploiting the flexible coordination modes and rich redox properties of a versatile iron-thiolate platform, Cp*Fe(II)L (L = 1,2-Ph2PC6H4S-). Upon oxidation, this iron complex undergoes formate binding to generate a diferric formate complex, [(L-)2Fe(III)(µ-HCO2)Fe(III)]+, which exhibits remarkable electrocatalytic performance for the HCO2--to-CO2 transformation with a maximum turnover frequency (TOFmax) ∼103 s-1 and a Faraday efficiency (FE) ∼92(±4)%. Conversely, this iron system also allows for reduction at -1.85 V (vs Fc+/0) and exhibits an impressive FE ∼93 (±3)% for the CO2-to-HCO2- conversion. Mechanism studies revealed that the HCO2--to-CO2 electrocatalysis passes through dicationic [(L2)-•Fe(III)(µ-HCO2)Fe(III)]2+ generated by unconventional oxidation of the diferric formate species taking place at ligand L, while the CO2-to-HCO2- reduction involves a critical intermediate of [Fe(II)-H]- that was independently synthesized and structurally characterized.

Photocurrent Polarity Switchable Sensing of Hyaluronidase Activity by Regulating Electrostatic Interactions between Two Semiconductors.

Photocurrent polarity switchable photoelectrochemical (PEC) sensing has superior accuracy and anti-interference ability to conventional PEC sensing. The development of a novel strategy for photocurrent polarity switchable sensing is of great interest. Herein, a novel strategy for photocurrent polarity switchable sensing is reported by regulating electrostatic interactions between two semiconductor photoactive materials. Hyaluronic acid (HA)-modified CuO nanosheets show a negatively charged surface, which prevents the attachment of CuO nanosheets to negatively charged CdS nanodendrite-modified photoelectrodes because of the strong electrostatic repulsion. In the presence of hyaluronidase (HAase), the specific hydrolysis of HA on the surface of CuO by HAase can yield a positively charged surface, so CuO can be attached to a CdS-modified photoelectrode via electrostatic attraction, leading to photocurrent polarity switching. The photocurrent polarity switchable detection of HAase activity is achieved with an ultralow detection limit of 2 × 10-3 U mL-1 and a wide linear detection range between 0.01 and 100 U mL-1. This work provides a new and effective photocurrent polarity switching strategy for PEC sensing and a simple and efficient method for detecting HAase activity.

N-3, a novel synthetic derivative of bifendate, inhibits metastasis of triple-negative breast cancer via decreasing p38-regulated FOXC1 protein stability.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high invasiveness, metastatic potential, and poor prognosis. Epithelial-mesenchymal transition (EMT) is pivotal in TNBC progression, becoming a promising target for TNBC treatment. Our study evaluated N-3, a novel synthetic bifendate derivative, which inhibited the EMT-associated migration and invasion of MDA-MB-231 and 4T1 TNBC cells. The results were consistent with the suppression of FOXC1 expression and transcriptional activity. Additional studies indicated that N-3 reduced the protein stability of FOXC1 by enhancing ubiquitination and degradation. Moreover, N-3 downregulated p-p38 expression and FOXC1 interaction, decreasing the stability of p38-regulated FOXC1. Further, N-3 blocked TNBC metastasis with an artificial lung metastasis model in vivo, related to FOXC1 suppression and EMT. These results highlight the potential of N-3 as a TNBC metastasis treatment. Therefore, FOXC1 regulation could be a novel targeted therapeutic strategy for TNBC metastasis.

Mechanistic Insights into Photochemical CO2 Reduction to CH4 by a Molecular Iron-Porphyrin Catalyst.

Iron tetraphenylporphyrin complex modified with four trimethylammonium groups (Fe-p-TMA) is found to be capable of catalyzing the eight-electron eight-proton reduction of CO2 to CH4 photochemically in acetonitrile. In the present work, density functional theory (DFT) calculations have been performed to investigate the reaction mechanism and to rationalize the product selectivity. Our results revealed that the initial catalyst Fe-p-TMA ([Cl-Fe(III)-LR4]4+, where L = tetraphenylporphyrin ligand with a total charge of -2, and R4 = four trimethylammonium groups with a total charge of +4) undergoes three reduction steps, accompanied by the dissociation of the chloride ion to form [Fe(II)-L••2-R4]2+. [Fe(II)-L••2-R4]2+, bearing a Fe(II) center ferromagnetically coupled with a tetraphenylporphyrin diradical, performs a nucleophilic attack on CO2 to produce the 1η-CO2 adduct [CO2•--Fe(II)-L•-R4]2+. Two intermolecular proton transfer steps then take place at the CO2 moiety of [CO2•--Fe(II)-L•-R4]2+, resulting in the cleavage of the C-O bond and the formation of the critical intermediate [Fe(II)-CO]4+ after releasing a water molecule. Subsequently, [Fe(II)-CO]4+ accepts three electrons and one proton to generate [CHO-Fe(II)-L•-R4]2+, which finally undergoes a successive four-electron-five-proton reduction to produce methane without forming formaldehyde, methanol, or formate. Notably, the redox non-innocent tetraphenylporphyrin ligand was found to play an important role in CO2 reduction since it could accept and transfer electron(s) during catalysis, thus keeping the ferrous ion at a relatively high oxidation state. Hydrogen evolution reaction via the formation of Fe-hydride ([Fe(II)-H]3+) turns out to endure a higher total barrier than the CO2 reduction reaction, therefore providing a reasonable explanation for the origin of the product selectivity.

Dingxin recipe â ¢ ameliorates hyperlipidemia injury in SD rats by improving the gut barrier, particularly the SCFAs/GPR43 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Dingxin Recipe Ⅲ (DXR Ⅲ) is a traditional Chinese medicine compound used for hyperlipidemia treatment in clinical practice. However, its curative effects and pharmacological mechanisms in hyperlipidemia have not been clarified to date. AIM OF THE STUDY: Studies have demonstrated that gut barrier was strongly implicated in lipid deposition. Based on gut barrier and lipid metabolism, this study examined the effects and molecular mechanisms of DXR Ⅲ in hyperlipidemia. MATERIALS AND METHODS: The bioactive compounds of DXR Ⅲ were detected by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry, and its effects were evaluated in high-fat diet-fed rats. Specifically, the serum levels of lipids and hepatic enzymes were measured using the appropriate kits; colon and liver sections were obtained for histological analyses; gut microbiota and metabolites were analyzed by 16S rDNA sequencing and liquid chromatography-MS/MS; and the expression of genes and proteins was determined by real-time quantitative polymerase chain reaction and western blotting and immunohistochemistry, respectively. The pharmacological mechanisms of DXR Ⅲ were further explored by fecal microbiota transplantation and short-chain fatty acid (SCFAs)-based interventions. RESULTS: DXR Ⅲ treatment significantly downregulated serum lipid levels, mitigated hepatocyte steatosis and improved lipid metabolism. Moreover, DXR Ⅲ improved the gut barrier, specifically by improving the physical barrier in the colon, causing part composition changes in the gut microbiota, and increasing the serum SCFAs level. DXR Ⅲ also upregulated the expression of colon GPR43/GPR109A. Fecal microbiota transplantation from rats treated with DXR Ⅲ downregulated part hyperlipidemia-related phenotypes, while the SCFAs intervention significantly improved most of the hyperlipidemia-related phenotypes and upregulated the expression of GPR43. Moreover, both DXR Ⅲ and SCFAs upregulated the expression of colon ABCA1. CONCLUSION: DXR Ⅲ protects against hyperlipidemia by improving the gut barrier, particularly the SCFAs/GPR43 pathway.

Ring-closing C-O/C-O metathesis of ethers with primary aliphatic alcohols.

In canonical organic chemistry textbooks, the widely adopted mechanism for the classic transetherifications between ethers and alcohols starts with the activation of the ether in order to weaken the C-O bond, followed by the nucleophilic attack by the alcohol hydroxy group, resulting in a net C-O/O-H σ-bond metathesis. In this manuscript, our experimental and computational investigation of a Re2O7 mediated ring-closing transetherification challenges the fundamental tenets of the traditional transetherification mechanism. Instead of ether activation, the alternative activation of the hydroxy group followed by nucleophilic attack of ether is realized by commercially available Re2O7 through the formation of perrhenate ester intermediate in hexafluoroisopropanol (HFIP), which results in an unusual C-O/C-O σ-bond metathesis. Due to the preference for the activation of alcohol rather than ether, this intramolecular transetherification reaction is therefore suitable for substrates bearing multiple ether moieties, unparalleled by any previous methods.