5-Hydroxymethylcytosine in circulating cell-free DNA as a potential diagnostic biomarker for SLE.

BACKGROUND: SLE is a complex autoimmune disease with heterogeneous manifestations and unpredictable outcomes. Early diagnosis is challenging due to non-specific symptoms, and current treatments only manage symptoms. Epigenetic alternations, including 5-Hydroxymethylome (5hmC) modifications, are important contributors to SLE pathogenesis. However, the 5hmC modification status in circulating cell-free DNA (cfDNA) of patients with SLE remains largely unexplored. We investigated the distribution of 5hmC in cfDNA of patients with SLE and healthy controls (HCs), and explored its potential as an SLE diagnosis marker. METHODS: We used 5hmC-Seal to generate genome-wide 5hmC profiles of plasma cfDNA and bioinformatics analysis to screen differentially hydroxymethylated regions (DhMRs). In vitro mechanistic exploration was conducted to investigate the regulatory effect of CCCTC-binding factor (CTCF) in 5hmC candidate biomarkers. RESULTS: We found distinct differences in genomic regions and 5hmC modification motif patterns between patients with SLE and HCs, varying with disease progression. Increased 5hmC modification enrichment was detected in SLE. Additionally, we screened 151 genes with hyper-5hmC, which are significantly involved in SLE-related processes, and 5hmC-modified BCL2, CD83, ETS1 and GZMB as SLE biomarkers. Our findings suggest that CTCF regulates 5hmC modification of these genes by recruiting TET (ten-eleven translocation) protein, and CTCF knockdown affected the protein expression of these genes in vitro. CONCLUSIONS: Our findings demonstrate the increased 5hmC distribution in plasma cfDNA in different disease activity in patients with SLE compared with HCs and relating DhMRs involved in SLE-associated pathways. Furthermore, we identified a panel of SLE relevant biomarkers, and these viewpoints could provide insight into the pathogenesis of SLE.

Chiral Brønsted Acid-Catalyzed Asymmetric Reaction via Vinylidene Ortho-Quinone Methides.

Vinylidene ortho-quinone methides (VQMs) have been proven to be versatile and crucial intermediates in the catalytic asymmetric reaction in last decade, and thus have drawn considerable concentrations on account of the practical application in the construction of enantiomerically pure functional organic molecules. However, in comparison to the well established chiral Brønsted base-catalyzed asymmetric reaction via VQMs, chiral Brønsted acid-catalyzed reaction is rarely studied and there is no systematic summary to date. In this review, we summarize the recent advances in the chiral Brønsted acid-catalyzed asymmetric reaction via VQMs according to three types of reactions: a) intermolecular asymmetric nucleophilic addition to VQMs; b) intermolecular asymmetric cycloaddition of VQMs; c) intramolecular asymmetric cyclization of VQMs. Finally, we put forward the remained challenges and opportunities for potential breakthroughs in this area.

The Effect of Different Substances Embedded in Fullerene Cavity on Surfactant Self-Assembly Behavior through Molecular Dynamics Simulation.

Fullerene-based amphiphiles are new types of monomers that form self-assemblies with profound applications. The conical fullerene amphiphiles (CFAs) have attracted attention for their uniquely self-assembled structures and have opened up a new field for amphiphile research. The CFAs and CFAs with different substances embedded in cavities are designed and their self-assembly behaviors are investigated using molecular dynamics (MD) simulations. The surface and internal structures of the micelles are analyzed from various perspectives, including micelle size, shape, and solvent-accessible surface area (SASA). The systems studied are all oblate micelles. In comparison, embedding Cl- or embedding Na+ in the cavities results in larger micelles and a larger deviation from the spherical shape. Two typical configurations of fullerene surfactant micelles, quadrilateral plane and tetrahedral structure, are presented. The dipole moments of the fullerene molecules are also calculated, and the results show that the embedded negatively charged Cl- leads to a decrease in the polarity of the pure fullerene molecules, while the embedded positively charged Na+ leads to an increase.

Emerging roles of the epitranscriptome in parasitic protozoan biology and pathogenesis.

RNA modifications (epitranscriptome) - such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine (Ψ) - modulate RNA processing, stability, interaction, and translation, thereby playing critical roles in the development, replication, virulence, metabolism, and life cycle adaptations of parasitic protozoa. Here, we summarize potential homologs of the major human RNA modification regulatory factors in parasites, outline current knowledge on how RNA modifications affect parasitic protozoa, highlight the regulation of RNA modifications and their crosstalk, and discuss current progress in exploring RNA modifications as potential drug targets. This review contributes to our understanding of epitranscriptomic regulation of parasitic protozoa biology and pathogenesis and provides new perspectives for the treatment of parasitic diseases.

Vegetarian diets and the risk of gastrointestinal cancers: a meta-analysis of observational studies.

The systematic review aimed to assess the association between vegetarian diet and the risk of gastrointestinal tumorigenesis. PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to August 2022 for observational studies on vegetarian diets and the risk of gastrointestinal tumorigenesis. The primary outcome was morbidity due to gastrointestinal cancer. The Newcastle-Ottawa Scale was used to assess the quality of included studies. Pooled effects were analyzed using a random-effects model. The study protocol was registered in PROSPERO (no. CRD42022310187). Eight original studies (seven cohorts and one case-control), involving 686 691 participants, were included. Meta-analysis showed a negative correlation between vegetarian diets and gastrointestinal tumorigenesis risk [relative risk (RR) equals 0.77, 95% confidence interval (CI) is (0.65-0.90)], compared with non-vegetarian diets. Subgroup analysis indicated that vegetarian diets were negatively correlated with the risks of gastric cancer [RR = 0.41, 95% CI (0.28-0.61)] and colorectal cancer [RR = 0.85, 95% CI (0.76-0.95)], but not with that of upper gastrointestinal cancer (excluding stomach) [RR = 0.93, 95% CI (0.61-1.42)]. Vegetarian diets were negatively correlated with the risk of gastrointestinal tumorigenesis in men [RR = 0.57, 95% CI (0.36-0.91)], but were uncorrelated in women [RR = 0.89, 95% CI (0.71-1.11)]. Vegetarian diets were negatively correlated with the risk of gastrointestinal tumorigenesis in North American [RR = 0.76, 95% CI (0.61-0.95)] and Asian populations [RR = 0.43, 95% CI (0.26-0.72)] and were uncorrelated in the European population [RR = 0.83, 95% CI (0.68-1.01)]. Adhering to vegetarian diets reduces the risk of gastrointestinal tumorigenesis. More data from well-conducted cohort and other studies are needed.

Rapamycin antagonizes angiogenesis and lymphangiogenesis through myeloid-derived suppressor cells in corneal transplantation.

Rapamycin is an immunosuppressive drug that is widely used in the postsurgery management of transplantation. To date, the mechanism by which rapamycin reduces posttransplant neovascularization has not been fully understood. Given the original avascularity and immune privilege of the cornea, corneal transplantation is considered as an ideal model to investigate neovascularization and its effects on allograft rejection. Previously, we found that myeloid-derived suppressor cells (MDSC) prolong corneal allograft survival through suppression of angiogenesis and lymphangiogenesis. Here, we show that depletion of MDSC abolished rapamycin-mediated suppression of neovascularization and elongation of corneal allograft survival. RNA-sequencing analysis revealed that rapamycin dramatically enhanced the expression of arginase 1 (Arg1). Furthermore, an Arg1 inhibitor also completely abolished the rapamycin-mediated beneficial effects after corneal transplantation. Taken together, these findings indicate that MDSC and elevated Arg1 activity are essential for the immunosuppressive and antiangiogenic functions of rapamycin.

Enhanced Cycling and Structure Stability of an Electron Transfer-Accelerating Polymer Poly(3,4-ethylenedioxythiophene):Poly(styrenesulfonate)-Covered Mn-Based Layered Cathode with Ga3+ Doping for a Li-Ion Battery.

Mn-based cathode material Li1.20Mn0.52Ni0.20Co0.08O2 was proposed and ameliorated by surface-coating poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and doping Ga3+. X-ray diffraction and high-resolution transmission electron microscopy studies revealed that part of Ga3+ replacing the Ni site could reduce the Li+/Ni2+ mixing by forming a well-ordered layered structure and a homogeneous coating layer of PEDOT:PSS is covered on the surface of Li1.20Mn0.52Ni0.19Co0.08Ga0.01O2. The results of the electrochemical studies demonstrated the higher initial charging-discharging Coulombic efficiency, and outstanding rate capabilities and cyclic performance were obtained for the PEDOT:PSS-covered and Ga3+-doped samples. Especially, 2 wt % PEDOT:PSS-coated Li1.20Mn0.52Ni0.19Co0.08Ga0.01O2 delivered 38.3 mAh g-1, which is larger than the pristine cathode at a 5C high rate. Meanwhile, it could retain 189.6 mAh g-1 (90.3% of its initial discharge capacity at 45 °C) after 300 cycles with a 1C rate, while the pristine cathode only delivered 149.7 mAh g-1 with 80.7% cycling retention left. The results strongly suggested that such PEDOT:PSS-coated and Ga3+-doped Mn-based layered structure materials demonstrated high potential as a cathode candidate especially for high-energy applications.

Organocatalytic Enantioselective Diels-Alder Reaction of 2-Trifluoroacetamido-1,3-dienes with α,ß-Unsaturated Ketones.

We report herein the first examples of chiral phosphoric acid-catalyzed enantioselective Diels-Alder reactions between 2-trifluoroacetamido-1,3-dienes 1 and α,ß-unsaturated carbonyl compounds 2. Polysubstituted 1-acetamido cyclohexenes 3 were formed in high yields with excellent diastereo- and enantioselectivities. The reaction proceeds through a stepwise process as shown by deuterium labelling experiments. A catalytic enantioselective three-component reaction of 1, 2 and ortho-hydroxybenzhydryl alcohols 4 was subsequently developed furnishing the densely functionalized hexahydroxanthenes 5 in a highly stereoselective manner. This multicomponent reaction generates four chemical bonds with concurrent creation of five contiguous stereocenters.

Enantioselective Copper-Catalyzed Formal [2+1] and [4+1] Annulations of Diynes with Ketones via Carbonyl Ylides.

Carbonyl ylides have proven to be powerful synthons for the efficient construction of various valuable O-heterocycles, and the formation of carbonyl ylides by the reaction of metal carbenes with carbonyls has attracted increasing attention over the past decades. However, a catalyst-controlled highly enantioselective reaction of carbonyl ylides from metal carbenes is extremely challenging. Herein, we report a novel copper-catalyzed asymmetric formal [2+1] and [4+1] annulations of diynes with ketones via carbonyl ylides. Importantly, this protocol not only represents the first example of successful asymmetric epoxidation via carbonyl ylides, but also constitutes the first reaction of vinyl cations with carbonyl compounds. This method leads to the divergent, practical and atom-economical synthesis of a range of chiral oxiranes and dihydrofurans in moderate to excellent yields with generally excellent enantioselectivities and diastereoselectivities via remote-stereocontrol strategy.

Establishment and Molecular Modeling Study of Cyclodextrin-Based Synergistic Enantioseparation Systems with Three New Amino Acid Chiral Ionic Liquids as Additives in Capillary Electrophoresis.

Chiral ionic liquids (CILs) have attracted more and more attention due to their superior performance as chiral additives in capillary electrophoresis. In this work, based on the cyclodextrin (CD) derivatives and three new amino acid CILs (trifluoroacetate-L-Hydroxyproline, nitric acid-L-Hydroxyproline and trifluoroacetate-L-threonine), the new synergistic systems were established for chiral drug separation. In contrast to the traditional single glucosyl-ß-CD (Glu-ß-CD) separation system, the CIL/Glu-ß-CD synergistic systems achieved improved resolution of three model drug racemates. Some experimental variables, such as CIL concentration, Glu-ß-CD concentration, buffer pH, applied voltage, and the type and proportion of organic modifier, were optimized in the trifluoroacetate-L-Hydroxyproline/Glu-ß-CD synergistic system. In addition, the recognition process in the synergistic system was studied through the molecular modeling method.

Catalyst-Dependent Stereospecific [3,3]-Sigmatropic Rearrangement of Sulfoxide-Ynamides: Divergent Synthesis of Chiral Medium-Sized N,S-Heterocycles.

Medium-sized N,S-heterocycles have received tremendous interest due to their biological activities and potential medical applications. However, asymmetric synthesis of these compounds are extremely rare. Described herein is a catalyst-dependent [3,3]-sigmatropic rearrangement of sulfoxide-ynamides, enabling divergent and atom-economic synthesis of a series of valuable medium-sized N,S-heterocycles in moderate to good yields with broad substrate scope. Importantly, excellent enantioselectivities have been achieved via an unprecedented chirality-transfer. Moreover, theoretical calculations are employed to elucidate the origins of the catalyst-dependent stereospecific [3,3]-rearrangement.

Copper-Catalyzed Asymmetric Diyne Cyclization via [1,2]-Stevens-Type Rearrangement for the Synthesis of Chiral Chromeno[3,4-c]pyrroles.

Here, we report a copper-catalyzed asymmetric cascade cyclization/[1,2]-Stevens-type rearrangement via a non-diazo approach, leading to the practical and atom-economic assembly of various valuable chiral chromeno[3,4-c]pyrroles bearing a quaternary carbon stereocenter in generally moderate to good yields with wide substrate scope and excellent enantioselectivities (up to 99 % ee). Importantly, this protocol not only represents the first example of catalytic asymmetric [1,2]-Stevens-type rearrangement based on alkynes but also constitutes the first asymmetric formal carbene insertion into the Si-O bond.

Copper-Catalyzed Si-H Bond Insertion Reaction of N-Propargyl Ynamides with Hydrosilanes.

Transition-metal-catalyzed Si-H bond insertion reactions are generally limited to stabilized diazo compounds. An efficient copper-catalyzed Si-H bond insertion reaction of N-propargyl ynamides with hydrosilanes is described, allowing practical and atom-economic construction of valuable organosilanes in generally moderate to excellent yields under mild reaction conditions. Notably, this reaction constitutes a new method of Si-H bond insertion reaction involving vinyl cations as key intermediates.

Copper-Catalyzed Cyclization of N-Propargyl Ynamides with Borane Adducts through B-H Bond Insertion.

An efficient copper-catalyzed cyclization of N-propargyl ynamides with borane adducts through B-H bond insertion has been developed. A series of valuable organoboron compounds are constructed in generally good yields with a wide substrate scope and good functional group tolerance under mild reaction conditions. Importantly, this protocol via vinyl cation intermediates constitutes a novel way of B-H bond insertion.

Copper-catalyzed asymmetric cyclization of alkenyl diynes: method development and new mechanistic insights.

Metal carbenes have proven to be one of the most important and useful intermediates in organic synthesis, but catalytic asymmetric reactions involving metal carbenes are still scarce and remain a challenge. Particularly, the mechanistic pathway and chiral induction model in these asymmetric transformations are far from clear. Described herein is a copper-catalyzed asymmetric cyclization of alkenyl diynes involving a vinylic C(sp2)-H functionalization, which constitutes the first asymmetric vinylic C(sp2)-H functionalization through cyclopentannulation. Significantly, based on extensive mechanistic studies including control experiments and theoretical calculations, a revised mechanism involving a novel type of endocyclic copper carbene via remote-stereocontrol is proposed, thus providing new mechanistic insight into the copper-catalyzed asymmetric diyne cyclization and representing a new chiral control pattern in asymmetric catalysis based on remote-stereocontrol and vinyl cations. This method enables the practical and atom-economical construction of an array of valuable chiral polycyclic-pyrroles in high yields and enantioselectivities.

A porous layer open-tubular capillary column supported with pepsin and zeolitic imidazolate framework for enantioseparation of four basic drugs in capillary electrochromatography.

New material zeolitic imidazolate framework-4, 5-imidazoledicarboxylic acid (ZIF-IMD) located on the pore surface of porous layer open-tubular (PLOT) column previously functionalized with N-(3-aminopropyl)-imidazole have been prepared via a layer-by-layer self-assembly strategy. This new ZIF-IMD coating hybrids are used as solid-phase carriers for chiral selector pepsin immobilization. The ZIF-IMD material was characterized by scanning electron microscopy, energy-dispersive spectroscopy, transmission electron microscope and X-ray diffraction. The synthesized pepsin@ZIF-IMD@POLT column achieved the baseline separation of hydroxychloroquine (HCQ), chloroquine (CHQ) and hydroxyzine (HXY) (the resolution of HCQ: 2.19; CHQ: 1.84; HXY: 1.53). Compared with the pepsin@PLOT column (without ZIF-IMD material), the chiral separation capability of the pepsin@ZIF-IMD@POLT column can be remarkably improved. Several key parameters including concentration of chiral selector, buffer pH, applied voltage and buffer concentration were systematically evaluated to provide the optimal enantioseparation condition. The relative standard deviations (RSDs) of intra-day, inter-day, column-to-column and inter-batch of migration time and Rs of the HCQ were evaluated in detail, respectively (RSD < 7.21%). Additionally, the potential mechanism of increased resolution was discussed in the article.

Nitrene Transfer and Carbene Transfer in Gold Catalysis.

Catalytic transformations involving metal carbenes are considered one of the most important aspects of homogeneous transition metal catalysis. Recently, gold-catalyzed generation of gold carbenes from readily available alkynes represents a significant advance in metal carbene chemistry. This Review summarizes the advances in the gold-catalyzed nitrene-transfer reactions of alkynes with nitrogen-transfer reagents, such as azides, nitrogen ylides, isoxazoles, and anthranils, and gold-catalyzed carbene-transfer reactions, involving oxygen atom-transfer reactions of alkynes with nitro compounds, nitrones, sulfoxides, and pyridine N-oxides, through the presumable α-imino gold carbene and α-oxo gold carbene intermediates, respectively. Gold-catalyzed processes are reviewed by highlighting their product diversity, selectivity, and applicability, and the mechanistic rationale is presented where possible.

Visual chiral recognition of aromatic amino acids with (S)-mandelic acid-based ionic liquids via complexation.

Recently, chiral ionic liquids have attracted increasing attention in analytical chemistry. However, only a few papers focus on the application of them in visual chiral recognition. Herein, two functionalized chiral ionic liquids derived from (S)-mandelic acid (1-butyl-3-methylimidazolium mandelate, CIL1 and N-butyl-N-methylpyrrolidinium mandelate, CIL2) were prepared for visual chiral recognition of aromatic amino acids for the first time. In the presence of Cu(II) and appropriate solvents, visual enantiomeric responses of phenylalanine, tryptophane, tyrosine and phenylglycine were observed. Relying on solubility or color differences, all chiral recognition could be finished within 5 min. The potential mechanism was investigated by means of infrared spectroscopy, ultraviolet spectroscopy, thermal gravity analysis, elemental analysis and scanning electron microscope. Results revealed that CuSO4 interacted with CIL1 and D-tryptophane in the ratio of 1:1.96:0.43 in relevant precipitate, and the different stability of complex was responsible for the chiral recognition. In addition, resolution of racemic tryptophane was performed, which offered excellent enantiomeric excess values (94.2% for CIL1 and 95.1% for CIL2 in solid phase). The proposed ionic liquids had strong enantioselectivity for aromatic amino acids and great potential in visual chiral recognition.

Copper-Catalyzed Asymmetric Reaction of Alkenyl Diynes with Styrenes by Formal [3 + 2] Cycloaddition via Cu-Containing All-Carbon 1,3-Dipoles: Access to Chiral Pyrrole-Fused Bridged [2.2.1] Skeletons.

The generation of metal-containing 1,3-dipoles from metal carbenes represents a significant advance in 1,3-dipolar cycloaddition reactions. However, these transformations have so far been limited to reactions based on diazo compounds or triazoles as precursors. Herein, we disclose a copper-catalyzed enantioselective reaction of alkenyl N-propargyl ynamides with styrene derivatives by formal [3 + 2] cycloaddition via Cu-containing all-carbon 1,3-dipoles, which constitutes a novel way for the generation of metal-containing 1,3-dipoles via metal carbenes. This protocol allows the practical and atom-economical synthesis of valuable chiral pyrrole-fused bridged [2.2.1] skeletons in moderate to good yields (up to 90% yield) with excellent diastereoselectivities (dr > 50/1) and generally excellent enantioselectivities (up to >99% ee).

Zinc-Catalyzed Asymmetric Formal [4+3] Annulation of Isoxazoles with Enynol Ethers by 6π Electrocyclization: Stereoselective Access to 2H-Azepines.

6π electrocyclization has attracted interest in organic synthesis because of its high stereospecificity and atom economy in the construction of versatile 5-7-membered cycles. However, examples of asymmetric 6π electrocyclization are quite scarce, and have to rely on the use of chiral organocatalysts, and been limited to pentadienyl-anion- and triene-type 6π electrocyclizations. Described herein is a zinc-catalyzed formal [4+3] annulation of isoxazoles with 3-en-1-ynol ethers via 6π electrocyclization, leading to the site-selective synthesis of functionalized 2H-azepines and 4H-azepines in good to excellent yields with broad substrate scope. Moreover, this strategy has also been used to produce chiral 2H-azepines with high enantioselectivities (up to 97:3 e.r.). This protocol not only is the first asymmetric heptatrienyl-cation-type 6π electrocyclization, but also is the first asymmetric reaction of isoxazoles with alkynes and the first asymmetric catalysis based on ynol ethers.