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A metal-free method is developed to perform the synthesis of urea derivatives utilizing CO2as the C1 building block at atmospheric pressure and room temperature. In addition to diverse symmetric and dissymmetric ureas, benzimidazolones and quinazolinone can also be easily prepared using this protocol. Most importantly, the gram-scale preparation of fungicide pencycuron and antipsychotic drug pimavanserin proceeded smoothly under the mild conditions.

The selective double hydroboration of CO2into bis(boryl)acetal (BBA) is a challenging yet appealing reduction process since BBA can be used as a versatile C1and Cnsources for the synthesis of value-added products. In the present study, we demonstrate that simple borohydride compounds are efficient and selective catalysts for the synthesis of BBA when using 9-borabicyclo(3.3.1)nonane (9-BBN) as a reductant. The experimental and theoretical investigations show that while the borohydride species catalyzes the first reduction step of CO2into formoxyborane (2e–reduction intermediate), the observed 4e–reduction selectivity is mostly due to the ability of 9-BBN to reduce the formoxyborane into BBA without a catalyst. Notably, 0.2 mol % of LiH2BBN catalyzed the hydroboration of CO2with 9-BBN as a reductant into the corresponding BBA in 77% yield with TON and TOF of 385 and 196 h–1, respectively. The simplicity of borohydride contrasts with the more elaborate catalytic systems used so far for the 4e–reduction of CO2.

Trained immunity enhances the responsiveness of immune cells to subsequent infections or vaccinations. Here we demonstrate that pre-vaccination with bacteria-derived outer-membrane vesicles, which contain large amounts of pathogen-associated molecular patterns, can be used to potentiate, and enhance, tumour vaccination by trained immunity. Intraperitoneal administration of these outer-membrane vesicles to mice activates inflammasome signalling pathways and induces interleukin-1β secretion. The elevated interleukin-1β increases the generation of antigen-presenting cell progenitors. This results in increased immune response when tumour antigens are delivered, and increases tumour-antigen-specific T-cell activation. This trained immunity increased protection from tumour challenge in two distinct cancer models.

Oxidative stress is tightly associated with liver dysfunction and injury in dairy cows. Previous studies have shown that cis-9, trans-11 conjugated linoleic acid (CLA) possesses anti-inflammatory and antioxidative abilities. In this study, the bovine hepatocytes were pretreated with CLA for 6 h, followed by treatment with hydrogen peroxide (H2O2) for another 6 h to investigate the antioxidative effect of CLA and uncover the underlying mechanisms. The results demonstrated that H2O2treatment elevated the level of mitophagy, promoted mitochondrial DNA (mtDNA) leakage into the cytosol, and activated the stimulator of interferon genes (STING)/nuclear factor kappa B (NF-κB) signaling pathway to trigger an inflammatory response in bovine hepatocytes. In addition, the dynamin-related protein 1(DRP1)-mtDNA-STING-NF-κB axis contributed to the H2O2-induced oxidative injury of bovine hepatocytes. CLA could reduce mitophagy and the inflammatory response to attenuate oxidative damage via the DRP1/mtDNA/STING pathway in bovine hepatocytes. These findings offer a theoretical foundation for the hepatoprotective effect of CLA against oxidative injury in dairy cows.

Biothiols including cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) are crucial in maintaining the redox balance in the body, and the metabolism and transportation of biothiols rely on the coreaction of diverse proteins and enzymes. The abnormal concentrations and metabolism of biothiols are closely associated with many diseases. However, due to the same active reaction site of the sulfydryl group in biothiols, it is inevitable to bear a confused signal of mutual influence on both nonselective detection and discriminate detection, which presents a serious challenge of accurately sensing or imaging the three biothiols. By assigning an α,β-unsaturated ketone moiety as a Michael acceptor to trigger thiols to complete the irreversible equivalent domino response processes of nucleophilic addition, olefinic bond migration, and self-immolation, a targeted strategy was rationally pointed out, and herein, a hemicyanine-based probe CyOCywas prepared as a proof of strategy demonstration. The new probe could be equivalently lit up by Cys, Hcy, GSH, and even biothiol combinations (Cys/Hcy, Cys/GSH, Hcy/GSH, or Cys/Hcy/GSH) with unified linear ranges, detection limits, and response times. The probe CyOCyhas been successfully used for the accurate quantification of total biothiols in the serum samples of healthy persons and coronary heart disease patients. In addition, the probe has been applied for cell screening, exogenous biothiol imaging, and monitoring drug-induced biothiol fluctuations. The purposive thinking of this work may provide an effective avenue for the accurate sensing of multicomponent samples.

Cycloheptenones are widespread in natural products and bioactive molecules. An efficient and convenient NaH-mediated Cope Rearrangement of doubly activated vinylcyclopropanes is reported for the synthesis of cyclohepten-4-ones. These flexible intramolecular reactions were applicable to a wide range of substrates and could be performed on gram scale. The derivatization of the product leads to short and highly efficient synthesis of some useful functional molecules.

Iridium(III) porphycene complex was synthesized and structurally characterized for the first time. The introduction of the posttransition iridium(III) ion not only significantly enhances the absorption intensity at the end of visible region, but also displays efficient singlet oxygen quantum yield (76%), which is applicable for photodynamic therapy in living cells.

The extensive product and application of cadmium-quantum dots (Cd-QDs), one kind of semiconductor nanomaterials, lead to prolonged exposure to the environment. Cd-QDs have shown good properties in biomedical and imaging-related fields; the safety of Cd-QDs limits the application of these materials and technologies, however. The systematic distribution of CdTe QDs in organisms has been ascertained in previous studies. Nevertheless, it is relatively less reported about the toxicity of CdTe QDs to immune macromolecules and organs. Based on this, immunocytes (including lymphocyte subsets-CD4+T and CD8+T cells, splenocytes) and selenoprotein P (SelP) were chosen as targets for CdTe QDs immunotoxicity studies. Results indicate that CdTe QDs induced cytotoxicity to CD4+T cells, CD8+T cells and splenocytes by reducing cell viability and causing apoptosis as CdTe QDs and Cd2+enter cells. At the molecular level, the direct interaction between CdTe QDs and SelP is proved by multispectral measurements, which demonstrated the alteration of protein structure. The combined results show that CdTe QDs induced adverse effects on the immune system at the cellular and molecular levels. This research contributes to a better understanding of CdTe QDs cause harmful damage to the immune system and provides new strategies for the inhibition and treatment of health damages caused by CdTe QDs.Graphical Abstract

Intrauterine adhesions (IUA) are a common gynecological problem. Stem cell therapy has been widely used in the treatment of IUA. However, due to the complex and harsh microenvironment of the uterine cavity, the effectiveness of such therapy is greatly inhibited. This study aimed to investigate whether melatonin pretreatment enhances the efficacy of human umbilical cord mesenchymal stem cells (HucMSCs) in IUA treatment in rats. First, we explored the effect of melatonin on the biological activity of HucMSCs in vitro through a macrophage co-culture system, Cell Counting Kit 8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU), flow cytometry, immunofluorescence staining, and qRT-PCR. Subsequently, we established the IUA rat model and tracked the distribution of HucMSCs in this model. In addition, we observed the number of M1 and M2 macrophages through immunofluorescence staining and detected the levels of inflammatory cytokines. Four weeks after cell transplantation, HE, Masson, and immunohistochemical staining were performed. In vitro experiments showed that melatonin pretreatment of HucMSCs promoted proliferation, reduced apoptosis, up-regulated the stemness gene, and regulated macrophage polarization. In vivo, melatonin pretreatment caused more HucMSCs to remain in the uterine cavity. Melatonin-pretreated HucMSCs recruited more macrophages, regulated macrophage polarization, and reduced inflammation. Melatonin-pretreated HucMSCs relieved fibrosis, increased endometrium thickness, and up-regulated CD34, vimentin, proliferating cell nuclear antigen (PCNA), and alpha small muscle antigen (α-SMA) expression. Fertility tests showed that melatonin-pretreated HucMSCs increased the number of embryos. In summary, pretreatment with melatonin was beneficial for HucMSC treatment because it enhanced the cell’s ability to recruit macrophages and regulate macrophage polarization, which led to the regeneration of the endometrium and improved pregnancy outcomes.Melatonin-pretreated HucMSCs improve endometrium regeneration and fertility recovery through macrophage immunomodulation in rats with intrauterine adhesions.Graphical Abstract

Aberrantly upregulated expression of AQP9 in villus of recurrent spontaneous abortion patients hindered cellular epithelial-mesenchymal transformation and invasion ability by targeting the PI3K/AKT signaling pathway, thus influencing embryo implantation.Graphical Abstract

The present study was conducted to evaluate the regulatory actions and underlying mechanisms of butyrate on the inflammatory response and tight junction (TJ) disruption in bovine mammary epithelial cells (BMECs). Results showed that butyrate declined histone deacetylase 3 (HDAC3) expression, blocked NF-κB activation, and thus suppressed inflammatory cytokine production in γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP)-triggered BMECs. Butyrate also depressed the protein abundance of myosin light chain kinase (MLCK), elevated the expression of TJ proteins, and restored the cellular distribution of TJ proteins and the barrier function of epithelial cells. HDAC3 overexpression abolished the protective effects of butyrate. In conclusion, butyrate alleviated the iE-DAP-induced inflammatory response and TJ injury by blocking NF-κB activation and decreasing inflammatory cytokine production and MLCK expression in a HDAC3-dependent manner. Our finding provides a mechanistic basis for further exploring the regulatory effects of butyrate on the mammary inflammatory response.

The unprecedented metal-free synthesis of both N-unsubstituted and N3-substituted quinazoline-2,4(1H,3H)-diones from o-aminobenzamides and CO2under atmospheric pressure at room temperature is developed. This protocol easily allows for variations of functional groups (including alkyl, aryl, and heterocycle groups) at the N3-position to accommodate the construction of many important drugs and bioactive compounds. The reaction features eco-friendliness, substrate scope tolerance, and versatility and can be implemented even at the gram scale.

In tumor nanovaccines, nanocarriers enhance the delivery of tumor antigens to antigen-presenting cells (APCs), thereby ensuring the robust activation of tumor antigen-specific effector T-cells to kill tumor cells. Through employment of their high immunogenicity and nanosize, we have developed a “Plug-and-Display” delivery platform on the basis of bacterial outer membrane vesicles (OMVs) for tumor nanovaccines (NanoVac), which can rapidly display different tumor antigens and efficiently eliminate lung metastases of melanoma. In this study, we first upgraded the NanoVac to increase their antigen display efficiency. However, we found that the presence of a subcutaneous xenograft seriously hampered the efficiency of NanoVac to eliminate lung metastases, with the subcutaneous xenograft mimicking the primary tumor burden in clinical practice. The primary tumor secreted significant amounts of granulocyte colony-stimulating factor (G-CSF) and altered the epigenetic features of granulocyte monocyte precursor cells (GMPs) in the bone marrow, thus disrupting systemic immunity, particularly the function of APCs, and ultimately resulting in NanoVac failure to affect metastases. These changes in the systemic immune macroenvironment were plastic, and debulking surgery of primary tumor resection reversed the dysfunction of APCs and failure of NanoVac. These results demonstrate that, in addition to the formulation design of the tumor nanovaccines themselves, the systemic immune macroenvironment incapacitated by tumor development is another key factor that cannot be ignored to affect the efficiency of tumor nanovaccines, and the combination of primary tumor resection with NanoVac is a promising radical treatment for widely metastatic tumors.

Objective: To estimate and compare sex-specific differences between metabolically healthy overweight/obesity (MHOO) and the risk of hypertension among Dong, Bouyei, and Miao adults in southwest China. Methods: MHOO was diagnosed when the patient had a body mass index ≥24 kg/m2and the presence of ≤1 component of metabolic syndrome. The main outcome was the occurrence of hypertension after the diagnosis or measurement by a physician at the baseline survey. Multivariate logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between MHOO and the risk of hypertension. Results: We enrolled 16,433 Chinese Dong, Bouyei, and Miao adults. Using the metabolically healthy normal weight (MHNW) as a reference and after adjusting for confounders, the association between MHOO and the risk of hypertension was stronger in Dong (OR = 1.46, 95% CI: 1.07–2.00) and Miao (OR = 2.05, 95% CI: 1.48–2.85) men and did not exist in Bouyei men (OR = 1.14, 95% CI: 0.81–1.60). After adjusting for the age, the association between MHOO and the risk of hypertension was stronger in men than in women among Dong adults aged 30–59 years (OR = 1.64, 95% CI: 1.12–2.40) and did not differ between men and women among Dong adults aged 60–79 years or among Miao or Bouyei adults. Conclusion: The results of this study demonstrated sex-specific differences in the association between MHOO and the risk of hypertension and that sex-specific differences further differed among Dong, Bouyei, and Miao adults.

The asymmetric hydrogenation of α-halogenated ketones with iridium catalyst was developed, utilizing easily accessed cinchona-alkaloid-based NNP ligands. Various α-chloroacetophenones, heterocyclic thienyl and furanyl substrates, and even bromoketones were completely converted to the desired chiral halohydrins by this protocol. Both (R)- and (S)-chiral halohydrins can be prepared by changing the configurations of the chiral ligand NNP with up to 99.6% ee (enantiomeric excess) and 98.8% ee, respectively. Also, a gram-scale experiment was carried out efficiently.

Thermoresponsive aggregation-induced emission (AIE) luminogens, especially in the solid state, have attracted extensive attention due to their potential applications as smart materials. Herein, we report an AIE-active tetraphenylethene (TPE)-based Schiff base derivative (TPENOMe-I) that exhibits rapid and reversible thermochromism along with luminescence in the solid state. The excited-state intramolecular proton transfer-induced AIE and efficient thermochromism (rather than photochromism) are facilitated by the relatively compact crystal packing and polymorphism of TPENOMe-I, which effectively suppress cis-to-transisomerization. Theoretical calculations demonstrated that the two-step isomerization process between the enol isomer and the cis- and twisted cis-keto isomers is responsible for the thermochromic behavior of solid-state TPENOMe-I. The chromic transitions may result from the reversible interconversion between various twisted cis-keto forms during the thermal isomerization process. Three composites containing TPENOMe-I that were simply prepared with low cost excited reversible thermochromism and were successfully demonstrated in thermochromic patterns. The findings suggest that these TPENOMe-I composites have promising applications for use in warning labels, thermochromic textiles, and thermal printing.

AbstractBackgroundSerum YKL-40 is a promising non-invasive biomarker for the early diagnosis of endometrial cancer (EC), but its value is disputed.ObjectiveTo investigate the serum YKL-40 in the early diagnostic value of EC.MethodsDatabases were systematically searched again before April 2021 and 14 studies were finally included in this meta-analysis. Pooled sensitivity, specificity, negative likelihood ratio (NLR), positive likelihood ratio (PLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve analyses were assessed. This meta-analysis investigated the source of heterogeneity using sensitivity analysis, subgroup analysis, and meta-regression.ResultsDatabases were systematically searched again before April 2021 and 14 studies were finally included in this meta-analysis. First, the SROC curve presented an area under the curve (AUC) of 0.853 (SE = 0.0213) for YKL-40 alone and an AUC of 0.946 (SE = 0.0268) for YKL-40 combined with other biomarkers. Second, diagnostic types might be related to the diagnostic accuracy and is a significant source of heterogeneity (P = 0.035).ConclusionSerum YKL-40 helped diagnose EC, and its combination with other biomarkers was better than itself alone.

Herein, an unprecedented transformation of [60]fullerene with ferrocene compounds giving access to various [60]fullerene-fused bicyclo[2.2.1]hept-5-enes is presented. In the presence of an acid, ferrocene compounds undergo an unusual dissociation process and serve as Diels–Alder diene equivalents to react with [60]fullerene for the selective construction of a class of novel fullerene-fused bridged carbocyclic derivatives. The reaction is easy to perform and has a wide substrate scope as well as excellent functional group compatibility, representing a new application of ferrocene compounds in synthetic chemistry.

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Described here is a Cu-catalyzed [2 + 2 + 1] modular synthesis of full-substituted β-pyrrolinones from simple amines, alkynes, and α-diazo-β-ketoesters. This approach involving the regioselective C-nucleophilic attack of enamines, uncommon C-nucleophilic addition to ketenes, and umpolung of imines enables the direct synthesis of full-substituted β-pyrrolinones, which were hardly constructed by traditional synthetic strategies.

Circular RNAs (circRNAs) are a kind of non-coding RNA molecule with highly stable circular structures. CircRNAs are primarily composed of exons and/or introns. Recently, a lot of exciting studies showed that circRNA played an essential role in the development of nervous system diseases. Here, classification, characteristics, biogenesis, and the association of circRNA dysregulation with nervous system diseases, such as Alzheimer’s disease, are summarized. The review not only contributes to a better understanding of circRNAs, but also provides new research directions toward the diagnosis, treatment, and prevention of nervous system diseases.

The first example of Cu(0)-catalyzed decarbonylative cleavage of readily available isatins possessing a five-membered ring diketone structural moiety provides a rapid, atom- and step economical synthetic approach to construct various functionally important acridone molecules.

Several simple single- and double-mutants of cytochrome P450BM3 enzymes enabled a highly regioselective O-demethylation of aromatic ethers with H2O2with the assistance of a dual-functional small molecule (DFSM). The DFSM-facilitated P450BM3 peroxygenase system provides an alternative, simple approach for a key step in the bioconversion of lignin compared with reported NADPH-dependent P450 monooxygenases.

Reported herein is a new copper-catalyzed N–H/C–H sequential relay oxidative radical carboannulation of [60]fullerene with C2-functionalized free indoles for the direct construction of novel [60]fullerene-fused tetrahydrocyclopenta[b]indoles. The transformation shows high regioselectivity and atom economy, broad substrate scope, and good functional group tolerance, providing an efficient and practical approach to access diversely substituted fullerene-fused polycyclic derivatives from simple hydrocarbons.

Rh(III)-catalyzed site-selective oxidative spirocyclization reactions of isoquinolones with α-diazo-1,3-indandiones leading to three kinds of spiro compounds by employing isoquinolones with different structural features or tuning the reaction parameters are presented. In addition, a plausible catalytic cycle is proposed on the basis of control experimental results and density functional theory calculations. Finally, the diverse transformations of the spiro products into other complex skeletons demonstrate the synthetic utility of this protocol.

Cu(II)/Mn(III)-mediated synergistic radical N-heteroannulation reaction of [60]fullerene with N-sulfonylated o-amino-arylmalonates has been developed for the direct and efficient construction of [60]fullerene-fused tetrahydroquinoline derivatives. A plausible mechanism for the formation of fullerotetrahydroquinolines is proposed, and the electrochemical properties of the obtained fullerene adducts are investigated.

Ketosis in dairy cows is often accompanied by the dysregulation of lipid homeostasis in the liver. Acetyl-coenzyme A acetyltransferase 2 (ACAT2) is specifically expressed in the liver and is important for regulating lipid homeostasis in ketotic cows. Lentinan (LNT) has a wide range of pharmacological activities, and this study investigates the protective effects of LNT on β-hydroxybutyrate (BHBA)-induced lipid metabolism disorder in bovine hepatocytes (BHECs) and elucidates the underlying mechanisms. BHECs were first pretreated with LNT to investigate the effect of LNT on BHBA-induced lipid metabolism disorder in BHECs. ACAT2 was then silenced or overexpressed to investigate whether this mediated the protective action of LNT against BHBA-induced lipid metabolism disorder in BHECs. Finally, BHECs were treated with LNT after silencing ACAT2 to investigate the interaction between LNT and ACAT2. LNT pretreatment effectively enhanced the synthesis and absorption of cholesterol, inhibited the synthesis of triglycerides, increased the expression of ACAT2, and elevated the contents of very low-density lipoprotein and low-density lipoprotein cholesterol, thereby ameliorating BHBA-induced lipid metabolism disorder in BHECs. The overexpression of ACAT2 achieved a comparable effect to LNT pretreatment, whereas the silencing of ACAT2 aggravated the effect of BHBA on inducing disorder in lipid metabolism in BHECs. Moreover, the protective effect of LNT against lipid metabolism disorder in BHBA-induced BHECs was abrogated upon silencing of ACAT2. Thus, LNT, as a natural protective agent, can enhance the regulatory capacity of BHECs in maintaining lipid homeostasis by upregulating ACAT2 expression, thereby ameliorating the BHBA-induced lipid metabolism disorder.