Photoinduced Redox Cascade Reaction of Isatins and Aliphatic Carboxylic Acids to Access 6-Hydroxyindoloquinazolinones.

A visible-light-induced cascade reaction is described for the one-pot synthesis of 6-hydroxyindoloquinazolinones using isatins (or isatins and isatoic anhydrides) and aliphatic carboxylic acids. The method provides 36 desired products in 33-96 % yield, exhibiting broad substrate scope and good functional group tolerance. This approach utilizes inexpensive and commercially available starting materials, enabling the direct construction of high-value complex structures under mild conditions without the need for photocatalyst, showcasing significant applicability and environmental friendliness.

Photoredox-Neutral Radical-Radical Cross-Coupling of Isatins and Benzyl Carboxylic Acids.

A photoredox-neutral radical-radical cross-coupling is described for the synthesis of 3-hydroxy-3-alkyloxindoles using isatins and benzyl carboxylic acids as substrates and 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) as the photocatalyst. The method features a broad substrate scope and good functional group tolerance, providing 30 sterically hindered alcohols with moderate to excellent yields. This approach utilizes inexpensive and commercially available starting materials, avoiding the use of transition metals, extra oxidants/reductants, and harsh reaction conditions, showcasing significant applicability and environmental friendliness.

Visible Light-Induced Hydroacylation of Benzylidenemalononitriles with Aroyl Chlorides Using Silane as a Hydrogen Donor.

A novel photoredox-catalyzed direct hydroacylation of benzylidenemalononitriles is described. In this method, aroyl chlorides are employed as a readily available and affordable source of acyl groups, while commercially available tris(trimethylsilyl)silane acts as both the hydrogen atom donor and electron donor. By eliminating the requirement for complex synthesis of acyl precursors and hydrogen atom-transfer (HAT) reagents, this approach offers a convenient and efficient strategy for the hydroacylation of benzylidenemalononitriles.

Visible-Light Induced Radical Addition-Elimination Reaction for Constructing Allylic Sulfones from Sulfonyl Chlorides and Allyl Bromides.

Allyl sulfones are commonly present in bioactive compounds and organic building blocks. This work introduces a photocatalytic radical addition-elimination reaction involving readily accessible sulfonyl chlorides and allyl bromides. It delivers structurally diverse allylic sulfones in moderate to excellent yields, showcasing a high tolerance to functional groups. Notably, this method operates under mild reaction conditions without the need for oxidants, stoichiometric reducing metals, or additives.

Electrochemical Synthesis of Selenosulfonates from Diselenides and Sulfonyl Hydrazides.

The electrochemical oxidative radical-radical cross-coupling of sulfonyl hydrazides with diselenides for the synthesis of selenosulfonates was successfully accomplished. The method is applicable to a wide range of aromatic/aliphatic sulfonyl hydrazides and diselenides, providing products in good to excellent yields. Notably, this protocol stands out for its green and sustainable nature, as it does not rely on transition metals and oxidizing agents, and the starting materials are cost-effective and readily available.

Bioinformatics analysis identifies potential autophagy key genes and immune infiltration in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a disease that seriously threatens maternal and fetal health. Appropriate autophagy can shield the placenta from oxidative stress, but its role in PE is unclear. OBJECTIVE: To identify potential autophagy-related genes in PE. METHODS: Microarray datasets from the Gene Expression Omnibus database, compassing the test dataset GSE10588, along with validation datasets GSE4707 and GSE60438 GPL10558, were utilized. Differentially expressed genes (DEGs) were identified using the limma R package, intersected with autophagy-related genes. Hub genes were obtained using the Cytoscape software and analyzed via gene set enrichment analysis (GSEA). The diagnostic capability of hub genes was evaluated using receiver operating characteristic (ROC) curve analysis. Analysis of immune cell infiltration was conducted using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT methods. Placental tissues were collected from 10 normal pregnant women and 10 preeclamptic pregnant women, and the expression of hub genes was validated through immunohistochemistry and western blot analysis. RESULTS: Analysis of the microarray data identified 2224 DEGs, among which 26 were autophagy-related DEGs identified through intersection with autophagy genes. Ten hub genes were identified. Immune cell infiltration analysis suggested the potential involvement of T regulatory cells (Tregs), natural killer cells, neutrophils, and T follicular helper cells in the pathogenesis of PE. ROC curve analysis indicated promising diagnostic capabilities for EGFR and TP53. Additionally, levels of EGFR and TP53 were significantly higher in placental tissue from PE pregnancies compared to normal pregnancies. CONCLUSION: EGFR and TP53 may play a role in PE by influencing autophagy.

First Report of Leaf Rot Caused by Apiospora paraphaeosperma on Lily in Wuhan, China.

Lily (Lilium spp.) is a valuable ornamental bulb flower plant in Liliaceae, and its bulbs have high edible and medicinal value. Compared with bulb propagation of other lilies, seed propagation and short growth period are the most significant characteristics of Lilium×formolongi. In 2023, leaf rot disease (LRD) was observed on approximately 70% of the Lilium×formolongi seedlings sown in an experimental greenhouse in Wuhan, Hubei province, China. Irregular brown water-soaked spots were discovered in the early stages of infected seedlings. Then, spots spread throughout the leaves and caused the leaves to brown, soften, and wilted. A pathogen associated with symptoms was isolated by incubating sterilized leaves on potato dextrose agar plates at 25 ℃ for 2-3 days. Then, a pure single colony was isolated through a single hyphal tip isolation method. The fungal colony was white with abundant aerial mycelium and produced a yellow pigment diffusible into the agar. Microscopically, isolated mycelia were reticulate and pale yellow, while conidia were dark brown, smooth, and spherical, 7.31 to 6.98 × 4.03 to 3.87µm (average 5.44×5.41µm; n=30); oval in lateral view, and had a light stripe in the middle. To identify the species of the fungus at the molecular level, ITS and EF-1α genes were amplified and sequenced using primers ITS1/ITS4 (M Gardes et al. 1993) and 758F/986R (Carbone and Kohn 1999). The BLAST results in GenBank showed that the ITS(OR523578) and EF-1α(PP066842) sequences of LRD shared 99.82% and 99.24% identity with the distinct Apiospora paraphaeosperma strains (GenBank accession MT040110, ON806628.1, respectively). Combined with the morphology of the colony and conidium, the fungus was identified as Ap. paraphaeosperma. In the pathogenicity test, six healthy leaves were inoculated with mycelium disc and then kept in an incubator (22 ℃, 90% humidity, 16h light /8h darkness). The inoculated leaves showed necrosis and wilt symptoms similar to those observed in the greenhouse, while the control leaves were asymptomatic. A re-isolation, morphology identification and DNA sequencing of the fungus confirmed its infection with Ap. paraphaeosperma in Lilium spp. At present, rot caused by Ap. paraphaeosperma has only been reported in Thailand and South Korea, both of which are found on bamboo stems (Hyde et al. 2016; Sun Lul Kwon et al. 2022). As far as we know, this is the first report of leaf rot of lily caused by Ap. paraphaeosperma in China. This report can help identify this disease and further develop effective control measures.

Alteration of Lipid Profile Between Subclinical Hypothyroidism and Well-Matched Controls: A Meta-Analysis.

In previous studies, subclinical hypothyroidism (SCH) has been associated with altered lipid profiles. However, since the discrepancy between these study results may reside in the great heterogeneity of the populations studied, this relationship is controversial. This study aimed to explore the changes in total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) between subclinical hypothyroidism (SCH) and well-matched euthyroid (EU) groups. Multiple databases were searched for publications before December 1, 2021, including cross-sectional studies on the association between SCH and lipid profile matched by age, gender, and BMI. Twenty-five articles with 3347 participants were included for meta-analysis. The results showed that the TC, TG, and LDL-c levels of the SCH groups were higher than the EU groups (TC, SMD=0.49, 95% CI 0.27, 0.71, p<0.001) (TG, SMD=0.43, 95% CI 0.21, 0.64, p<0.05 ) (LDL-c, SMD=0.75, 95% CI 0.46, 1.03, p<0.001 ). The HDL-c levels of the SCH group were lower than the control group (SMD=-0.53, 95% CI -0.81, -0.25, p<0.05). SCH has a larger impact on LDL-c than the other three indicators. After subgroup analyses, there was a larger impact on lipid alteration in the subgroup of TSH>10 µIU/ml, especially on LDL-c. This study found that SCH was associated with altered lipid profiles. Appropriate clinical treatment may be needed to prevent dyslipidemia and related diseases.

Photoredox-Catalyzed Radical-Radical Cross-Coupling of Sulfonyl Chlorides with Trifluoroborate Salts.

Sulfones are widely found in natural products and drug molecules. Here, we disclose a strategy for direct synthesis of sulfone compounds with diverse structures by visible-light-catalyzed radical-radical cross-coupling of sulfonyl chlorides and trifluoroborate salts. Allyl, benzyl, vinyl, and aryl trifluoroborates can be successfully cross-coupled with (hetero)aryl and alkyl sulfonyl chlorides, respectively. This strategy features redox neutrality, good substrate generality, simple operation, and benign reaction conditions.

Visible Light-Induced Cross-Dehydrocoupling of 3-Cyanocoumarins with Unactivated Aliphatic Aldehydes Enables Access to 4-Acylated Coumarins.

We report visible light-induced cross-dehydrocoupling of 3-cyanocoumarins with unactivated aliphatic aldehydes for the direct synthesis of 4-acylated coumarins. Inexpensive and readily available (n-Bu)4NBr was used as a precursor of the hydrogen atom transfer (HAT) catalyst and [Ir(ppy)2(dtbbpy)PF6] as a photocatalyst. A variety of aldehydes including linear, branched, cyclic, and α,ß-unsaturated aliphatic aldehydes were suitable for this reaction yielding the desired acylated coumarin derivatives in 41-98% yields. This method provides a mild, atom-economical, and environmentally friendly synthetic route for the direct acylation of 3-cyanocoumarins. This is the first example so far of C-4 aliphatic acylation of coumarins.

Electrochemical Cross-Dehydrogenative Coupling of Isochroman and Unactivated Ketones.

An unprecedented electrochemical cross-dehydrogenative coupling reaction between isochroman and unactivated ketones to directly synthesize α-substituted isochromans has been developed. This strategy provides a facile and efficient procedure to the direct activation of C(sp3)-H bond adjacent to the O atom of isochroman. The method features high atom economy, chemical oxidant-free, and mild conditions, in which methanesulfonic acid (MsOH) acts as both electrolyte and catalyst, making the process more convenient and environmentally friendly. Gram-scale experiment and synthesis of antitumor active compounds demonstrate the great potential of this protocol for practical applications.

Electrochemical Synthesis of ß-Iodoesters by 1,2-Iodoesterization of Unactivated Alkenes with Carboxylic Acids and Tetrabutylammonium Iodide.

We report a novel and highly selective electrochemical method for the synthesis of ß-iodoesters via difunctionalization of alkenes. The reaction is carried out in an undivided cell under constant current conditions without any additives, catalysts, oxidants, and sacrificial reagents. Inexpensive and readily available tetrabutylammonium iodide not only acts as an electrolyte but also serves as an iodine source. The reaction shows high selectivity and good functional group tolerance, providing products in yields of up to 98%. This method is applicable not only to the iodofunctionalization of alkenes but also to the chloro- and bromofunctionalization of alkenes. The successful modification of drugs and natural products demonstrates the potential utility of this approach.

Electroreductive Hydroxymethylation of Imines with Ketones To Access ß-Amino Alcohols.

In this article, an electrochemical method for the direct synthesis of ß-amino alcohols from imines and ketones is described. Mechanistic studies, including a radical trapping experiment, electron paramagnetic resonance, cyclic voltammetry, and divided-cell electrolysis experiment, support the radical-involved reductive cross coupling of imines with ketones at the cathode. The use of abundant and easily prepared starting materials, high atom- and step-economy, and insensitivity to air and moisture make this synthetic strategy more efficient for the construction of various ß-amino alcohol derivatives.

Direct Hydroxylarylation of Benzylic Carbons (sp3/sp2/sp) via Radical-Radical Cross-Coupling Powered by Paired Electrolysis.

Diaryl alcohol moieties are widespread in pharmaceuticals. Existing methods for the synthesis of diaryl alcohols require the use of pre-functionalized benzylic alcohols, aromatic aldehydes, or ketones as starting materials. Herein, the first convergent paired electrochemical approach to the direct hydroxylarylation of unactivated benzylic carbons (sp3/sp2/sp) is proposed. This protocol features direct functionalization of unactivated benzylic C(sp3)-H bonds and benzylic sp2/sp-carbons, mild conditions (open air, room temperature), an environmentally friendly procedure (without any external catalyst/mediator/additive), and direct access to sterically hindered alcohols from inexpensive and readily available alkyl/alkenyl/alkynylbenzenes. Mechanistic studies, including divided-cell experiments, isotope labeling, radical trapping, electron paramagnetic resonance, reaction kinetics, and cyclic voltammetry, strongly support the proposed radical-radical cross-coupling between transient ketyl radicals and persistent radical anions. Gram-scale synthesis and diversification of drug derivatives have visualized the tremendous potential of this protocol for practical applications.

Effects of different iodine levels on the DNA methylation of intrinsic apoptosis-associated genes and analysis of gene-environment interactions in patients with autoimmune thyroiditis.

Iodine is an essential nutrient that may change the occurrence of autoimmune thyroiditis (AIT). Apoptosis and DNA methylation participate in the pathogenesis and destructive mechanism of AIT. We detected the methylation and the expression of mRNA of intrinsic apoptosis-associated genes (YWHAG, ING4, BRSK2 and GJA1) to identify the potential interactions between the levels of methylation in these genes and different levels of iodine. 176 adult patients with AIT in Shandong Province, China, were included. The MethylTargetTM assay was used to verify the levels of methylation. We used PCR to detect the mRNA levels of the candidate genes. Interactions between methylation levels of the candidate genes and iodine levels were evaluated with multiplicative and addictive interaction models and GMDR. In the AIT group, YWHAG_1 and six CpG sites and BRSK2_1 and eight CpG sites were hypermethylated, whereas ING4_1 and one CpG site were hypomethylated. A negative correlation was found between methylation levels of YWHAG and mRNA expression. The combination of iodine fortification, YWHAG_1 hypermethylation and BRSK2_1 hypermethylation was significantly associated with elevated AIT risk. A four-locus model (YWHAG_1 × ING4_1 × BRSK2_1 × iodine level) was found to be the best model of the gene-environment interactions. We identified abnormal changes in the methylation status of YWHAG, ING4 and BRSK2 in patients with AIT in different iodine levels. Iodine fortification not only affected the methylation levels of YWHAG and BRSK2 but also interacted with the methylation levels of these genes and may ultimately increase the risk of AIT.

Electrochemical C(sp2)-H/N-H "formal" cross-dehydrogenative coupling of olefins with benzotriazoles for synthesis of N-vinyl benzotriazoles.

The paper details an electrochemical method that couples olefins with benzotriazoles to form C(sp2)-N bonds, enabling the synthesis of N-vinyl benzotriazoles in moderate to good yields. nBu4NI functions as both an electrolyte and an iodine mediator, and the method does not require oxidants or metals. It is a highly atom-economical and clean reaction, with hydrogen as the sole byproduct.

A study of programmed death-1/programmed death ligand and iodine-induced autoimmune thyroiditis in NOD.H-2h4 mice.

Excess iodine will trigger the occurrence of autoimmune thyroiditis (AIT), and programmed death-1 (PD-1)/programmed death ligand (PD-L) will also contribute to the development of AIT. The purpose of this study was to explore the role that negative regulatory signals mediated by PD-1/PD-L play in the development of spontaneous autoimmune thyroiditis (SAT) in NOD.H-2h4 mice when they are exposed to iodine. Programmed death ligand 1 (PD-L1) antibody was administered intraperitoneally to NOD.H-2h4 mice. The relevant indicators were determined by flow cytometry, real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry, pathological hematoxylin and eosin staining, and arsenic-cerium catalytic spectrophotometry. Results showed that the level of urinary iodine, the level of thyroid lymphocyte infiltration, the level of thyroglobulin antibodies (TgAb) and interferon (IFN-γ)/tumor necrosis factor (TNF-α)/interleukin (IL-2)/IL-17, and the relative expression of PD-1/PD-L1/programmed death-2 (PD-L2) increased with the intervention of excess iodine. After the intervention of the PD-L1 antibody, the expression of PD-1/PD-L1/PD-L2 in different degrees was inhibited, but the level of thyroid lymphocyte infiltration and serum TgAb/IFN-γ/TNF-α/ IL-2/IL-17 did not decrease. Collectively, although PD-1/PD-L participates in the occurrence of SAT and induces inflammation, administration of the PD-L1 antibody does not effectively improve the pathological process of SAT. More research is needed to determine whether PD-1/PD-L intervention can treat autoimmune thyroid disease.

The whole blood DNA methylation of RAB8A and RAP1A in autoimmune thyroiditis: evidence and validation of iodine exposure in a population from different water iodine areas.

Our study aimed to identify and verify G protein-related methylated genes in AIT patients, while also investigate those genes in AIT patients exposed to iodine in different water iodine areas. Different areas were classified by median water iodine (MWI) concentrations: Iodine-Fortified Areas (IFA, MWI<10µg/L), Iodine-Adequate Areas (IAA, 40≤MWI≤100 µg/L), and Iodine-Excessive Areas (IEA, MWI>100 µg/L). We studied 176 AIT cases and 176 controls, with 89, 40, and 47 pairs in IFA, IAA, and IEA, respectively. Using the Illumina Human Methylation 850k BeadChip, we identified candidate methylated genes. MethylTargetTM and QRT-PCR validated DNA methylation and mRNA expression. Results showed hypomethylation and high expression of RAB8A and RAP1A in all 176 AIT cases. RAB8A's CpG sites were mainly hypomethylated in IFA and IEA, while RAP1A's sites were primarily hypomethylated in IEA. This study underscores how water iodine exposure may influence RAB8A and RAP1A methylation in AIT.

Puerarin Alleviates LPS-Induced H9C2 Cell Injury by Inducing Mitochondrial Autophagy.

ABSTRACT: Sepsis leads to the damage of multiple organs, and thereby adversely affects the cardiovascular system. At present, no effective method has been found to treat myocardial injury caused by sepsis. Although Puerarin was reported to attenuate lipopolysaccharide (LPS)-induced mitochondrial injury in H9C2 cells, the effects of Puerarin in sepsis-induced myocardial injury remain unclear. In this study, H9C2 cells were stimulated with LPS, CCK-8 assays were performed to assess cell viability, and flow cytometry and TUNEL staining were used to assess cell apoptosis. Levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and enzyme activity were investigated using commercial kits. Reactive oxygen species (ROS) levels in H9C2 cells were detected by flow cytometry. Autophagosomes in the mitochondria of H9C2 cells were observed by transmission electron microscope, and protein expression was assessed by western blotting. Furthermore, in vivo experiments were applied to test the function of Puerarin in sepsis. We found that Puerarin significantly reversed LPS-induced decreases in H9C2 cell viability by inhibiting apoptosis. The ROS levels in H9C2 cells were significantly upregulated by LPS, but that effect was markedly reduced by Puerarin. In addition, Puerarin attenuated LPS-induced mitochondrial injury in H9C2 cells by regulating dynamin-related protein 1 (Drp1) and mitofusin 1 (MFN1). LPS decreased enzyme activity and reduced the levels of ADP, ALP, and AMP in mitochondria; however, those effects were reversed by Puerarin. Puerarin and Torin1 reversed LPS-induced inhibition of autophagy in the mitochondria of H9C2 cells via mediation of p62, LC3B, Pink1, and Parkin. Puerarin notably inhibited the progression of sepsis in vivo . Puerarin inhibited LPS-induced H9C2 cell injury by inducing mitochondrial autophagy, which acts as a mechanism for preventing myocardial injury caused by sepsis.

Relationships between the serum TPOAb and TGAb antibody distributions and water iodine concentrations, thyroid hormones and thyroid diseases: a cross-sectional study of 2503 adults in China.

The aim of this study was to explore the status of thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) in three areas with differing water iodine concentrations; and to discuss the relationships between these two thyroid antibodies and thyroid diseases in the three areas. We investigated 2503 adults from three areas. Urinary iodine concentrations, thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), TPOAb, TGAb and thyroid volume (TV) were measured, and thyroid ultrasonography was performed. The positivity rates of TGAb(+), TPOAb(+) and TGAb(+) and TPOAb(+) or TGAb(+) were significantly higher in iodine fortification (IF) areas than iodine adequate (IA) areas (all P < 0·05). In IF and iodine excess areas, the positivity rates of TPOAb(+), TGAb(+) and TPOAb(+) or TGAb(+) significantly increased with age (all P for trend < 0·05). The levels of TSH, TV and the prevalence of overt hypothyroidism, subclinical hypothyroidism and goitre were significantly elevated in the thyroid antibody-positive groups in the three areas, but the FT3 was diminished (all P < 0·010). Positivity for TPOAb and TGAb was associated with an increased risk of subclinical hypothyroidism in the three areas. In areas with different median water iodine, positivity for both TPOAb and TGAb was associated with elevated TSH values. Notably, with the increased levels of TPOAb, the frequency of abnormally elevated TSH increased dramatically in the three areas.