Diverse Synthesis of Fused Polyheterocyclic Compounds via [3 + 2] Cycloaddition of In Situ-Generated Heteroaromatic N-Ylides and Electron-Deficient Olefins.

[3 + 2] Cycloaddition reactions of heteroaromatic N-ylides with electron-deficient olefins have been developed. The heteroaromatic N-ylides, in situ generated from N-phenacylbenzothiazolium bromides, can smoothly react with maleimides under very mild conditions, affording fused polycyclic octahydropyrrolo[3,4-c]pyrroles in good-to-excellent isolated yields. This reaction concept could also be extended to 3-trifluoroethylidene oxindoles and benzylidenemalononitriles as electron-deficient olefins for accessing highly functionalized polyheterocyclic compounds. A gram-scale experiment was also carried out to verify the practicability of the methodology.

Association between thyroid hormones and skeletal muscle and bone in euthyroid type 2 diabetes patients.

Background: The impact of thyroid hormones within their normal ranges on skeletal muscle and bone in patients with type 2 diabetes mellitus (T2DM) remains unknown. The purpose of this study was to investigate the relationships of thyroid hormones with muscle and bone in euthyroid patients with T2DM. Methods: This cross-sectional study included 344 euthyroid T2DM patients. Muscle mass and bone mineral density were measured by dual-energy X-ray absorptiometry. The levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxin (FT4) were measured by electrochemiluminescence immunoassay. Results: The results revealed that FT3 was positively correlated with body mass index (BMI) in male patients after age correction. In men, FT4 was negatively correlated with body weight, BMI, total muscle mass, appendicular skeletal muscle mass (ASM), and ASM index (ASMI), while FT3/FT4 was positively correlated with body weight, BMI, total muscle mass, ASM, and ASMI after age correction. In women, FT4 was negatively correlated with ASM and ASMI, while FT3/FT4 was positively correlated with ASM and ASMI after age correction. FT3/FT4 was significantly lower in men with low muscle mass than in those with normal muscle mass. The age-adjusted odds for incident low muscle mass comparing the lowest and highest FT3/FT4 increased in men. Conclusions: FT3/FT4 was positively correlated with ASM and ASMI in both men and women. Therefore, FT3/FT4 may be a parameter indicative of low muscle mass in euthyroid men with T2DM.

Access to 4-Trifluoromethyl Quinolines via Cu-Catalyzed Annulation Reaction of Ketone Oxime Acetates with ortho-Trifluoroacetyl Anilines under Redox-Neutral Conditions.

An efficient Cu-catalyzed annulation reaction of ketone oxime acetates with ortho-trifluoroacetyl anilines has been disclosed. With the developed protocol, a series of 4-trifluoromethyl quinolines were obtained in good to excellent yields (58-99%) under redox-neutral conditions. The protocol also could be extended to ferrocene-based ketone oxime acetates for the construction of ferrocene-substituted fluorine-containing quinolines.

Inverse Electron-Demand Aza-Diels-Alder Reaction of α,ß-Unsaturated Thioesters with In Situ-Generated 1,2-Diaza-1,3-dienes for the Synthesis of 1,3,4-Thiadiazines.

A highly regioselective inverse electron-demand aza-Diels-Alder reaction of α,ß-unsaturated thioesters with 1,2-diaza-1,3-dienes generated in situ from α-halogeno hydrazones was developed. With α,ß-unsaturated thioesters as C═S dienophiles, the developed protocol enables the formation of diverse 3,6-dihydro-2H-1,3,4-thiadiazine derivatives in excellent yields. In the presence of lithium aluminum hydride, 3,6-dihydro-2H-1,3,4-thiadiazine derivatives could be further transformed into 5,6-dihydro-4H-1,3,4-thiadiazines in good yields.

α-Nitrosostyrenes as Three-Atom Units for the (3+1) Cyclization Reaction: Facile Access to 2,3-Dihydrodiazete N-Oxides and Their Diversified Synthetic Conversions.

An unprecedented (3+1) cyclization of α-nitrosostyrenes, generated in situ from α-bromooximes, and N-tosyloxycarbamates was developed, which enables the synthesis of a range of structurally unique and hitherto unexplored 2,3-dihydrodiazete N-oxides in moderate to high yields. The products possess a highly strained four-membered ring structure containing two nitrogen atoms. The synthetic applicability of the products was also demonstrated by many important conversions to diverse nitrogen-containing compounds.

Cepharanthine sensitizes human triple negative breast cancer cells to chemotherapeutic agent epirubicin via inducing cofilin oxidation-mediated mitochondrial fission and apoptosis.

Inhibition of autophagy has been accepted as a promising therapeutic strategy in cancer, but its clinical application is hindered by lack of effective and specific autophagy inhibitors. We previously identified cepharanthine (CEP) as a novel autophagy inhibitor, which inhibited autophagy/mitophagy through blockage of autophagosome-lysosome fusion in human breast cancer cells. In this study we investigated whether and how inhibition of autophagy/mitophagy by cepharanthine affected the efficacy of chemotherapeutic agent epirubicin in triple negative breast cancer (TNBC) cells in vitro and in vivo. In human breast cancer MDA-MB-231 and BT549 cells, application of CEP (2 µM) greatly enhanced cepharanthine-induced inhibition on cell viability and colony formation. CEP interacted with epirubicin synergistically to induce apoptosis in TNBC cells via the mitochondrial pathway. We demonstrated that co-administration of CEP and epirubicin induced mitochondrial fission in MDA-MB-231 cells, and the production of mitochondrial superoxide was correlated with mitochondrial fission and apoptosis induced by the combination. Moreover, we revealed that co-administration of CEP and epirubicin markedly increased the generation of mitochondrial superoxide, resulting in oxidation of the actin-remodeling protein cofilin, which promoted formation of an intramolecular disulfide bridge between Cys39 and Cys80 as well as Ser3 dephosphorylation, leading to mitochondria translocation of cofilin, thus causing mitochondrial fission and apoptosis. Finally, in mice bearing MDA-MB-231 cell xenografts, co-administration of CEP (12 mg/kg, ip, once every other day for 36 days) greatly enhanced the therapeutic efficacy of epirubicin (2 mg/kg) as compared with administration of either drug alone. Taken together, our results implicate that a combination of cepharanthine with chemotherapeutic agents could represent a novel therapeutic strategy for the treatment of breast cancer.

Inverse Electron-Demand Aza-Diels-Alder Reaction of Cyclic Enamides with 1,2-Diaza-1,3-dienes in Situ Generated from α-Halogeno Hydrazones: Access to Fused Polycyclic Tetrahydropyridazine Derivatives.

An efficient inverse electron-demand aza-Diels-Alder reaction of cyclic enamides and 1,2-diaza-1,3-dienes, which could be readily formed in situ from α-halogeno hydrazones and a base, has been successfully developed. With the developed approach, a wide range of fused polycyclic tetrahydropyridazines were smoothly obtained in up to 99% yield under benign reaction conditions. This reaction concept was also extended to acyclic enamide substrates for accessing 1,4,5,6-tetrahydropyridazines. A gram-scale experiment and further derivatizations of the polycyclic tetrahydropyridazine products were also conducted to verify the practicability of the methodology.

Protective Effect of Irbesartan by Inhibiting ANGPTL2 Expression in Diabetic Kidney Disease.

Angiopoietin-like protein 2 (ANGPTL2) stimulates inflammation and is important in the pathogenesis of diabetic kidney disease (DKD). Irbesartan is helpful in reducing diabetes-induced renal damage. In this study, the effects of irbesartan on DKD and its renal protective role involving ANGPTL2 in DKD rats were examined. Wistar rats were divided into normal, DKD, and DKD + irbesartan groups. The DKD + irbesartan group was treated once daily for 8 weeks with 50 mg/kg irbesartan via intragastric gavage. The 24-h urinary albumin was determined each week, renal pathological changes were observed, and expression of ANGPTL2 and nuclear factor-kappa B (NF-κB) in rat renal tissue was assessed by immunohistochemistry. Mouse podocytes cultured in a high concentration of glucose were classified into four groups based on the irbesartan concentrations (0, 25, 50, and 75 ºg/mL). Expression of ANGPTL2 and phosphorylated IκB-α was assessed by Western blotting. The mRNA levels of ANGPTL2 and monocyte chemotactic protein 1 (MCP-1) were assessed by real-time polymerase chain reaction. The DKD rats displayed proteinuria, podocyte injury, and increased ANGPTL2 and NF-κB expression. All were relieved by irbesartan treatment. In podocytes cultured in elevated glucose, ANGPTL2 and phosphorylated IκB-α were overexpressed at the protein level, and ANGPTL2 and MCP-1 were highly expressed at the mRNA level. Irbesartan down-regulated ANGPTL2 and phosphorylated IκB-αexpression at the protein level and inhibited ANGPTL2 and MCP-1 expression at the mRNA level. The ameliorative effects of irbesartan against DKD involves podocyte protection and suppression of ANGPTL2.

Inhibition of Influenza A virus propagation by benzoselenoxanthenes stabilizing TMPRSS2 Gene G-quadruplex and hence down-regulating TMPRSS2 expression.

Proteolytic cleavage of influenza A virus (IAV) hemagglutinin by host proteases is crucial for virus infectivity and spread. The transmembrane serine protease TMPRSS2 was previously identified as the essential protease that can cleave hemagglutinin of many subtypes of influenza virus and spike protein of coronavirus. Herein, we found that a guanine rich tract, capable of forming intramolecular G-quadruplex in the presence of potassium ions, in the promoter region of human TMPRSS2 gene was quite important for gene transcriptional activity, hence affecting its function. Furthermore, 7 new synthesized benzoselenoxanthene analogues were found to enable stabilizing such G-quadruplex. More importantly, compounds can down-regulate TMPRSS2 gene expression, especially endogenous TMPRSS2 protein levels, and consequently suppress influenza A virus propagation in vitro. Our results provide a new strategy for anti-influenza A virus infection by small molecules targeting the TMPRSS2 gene G-quadruplex and thus inhibiting TMPRSS2 expression, which is valuable for developing small molecule drugs against influenza A virus and also may be a potential candidate as anti- SARS-CoV-2 (Severe Acute Respiratory Syndrome CoV 2) lead molecules.

Diastereoselective Construction of Cyclopropane-Fused Tetrahydroquinolines via a Sequential [4 + 2]/[2 + 1] Annulation Reaction.

A sequential [4 + 2]/[2 + 1] annulation of α-aryl vinylsulfoniums with 2-aminochalcones and 2-(2-aminobenzylidene)-1H-indene-1,3(2H)-dione is reported that affords a series of cyclopropane-fused tetrahydroquinolines. The salient features of this novel and practical transformation include high efficiency, transition-metal-free nature, operational simplicity, and outstanding functional group tolerance.

Investigating the relationship between 25-hydroxyvitamin D and thyroid function in second-trimester pregnant women.

This study aims to explore the correlation between serum 25-hydroxyvitamin D and thyroid hormones during the second trimester. In total, 277 pregnant women at 13-28 weeks of gestation were enrolled. According to the level of thyrotropic-stimulating hormone, they were divided into a reduced TSH group, a normal TSH group and an elevated TSH group. In this study, we found that the prevalence of vitamin D deficiency was as high as 94.58%. The 25-hydroxyvitamin D level in the reduced TSH group was lower than that in the normal thyroid function group (p = .0005), and the 25-hydroxyvitamin D level in the elevated TSH group was higher than that in normal TSH group (p=.0339). A positive correlation was observed between 25-hydroxyvitamin D and thyrotropic-stimulating hormone (r = 0.3034, p = .0000). Furthermore, 25-hydroxyvitamin D was negatively correlated with the free thyroxine level (r = -0.1286, p = .0323) as well as the free triiodothyronine level (r = 0.1247, p = .0380). These data suggest that the relationships between 25-hydroxyvitamin D and thyroid parameters were characterized during the second trimester. Pregnant women in the second-trimester who are diagnosed with transient hyperthyroidism should be evaluated for the possibility of vitamin D deficiency.

TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections.

Influenza virus and coronavirus epidemics or pandemics have occurred in succession worldwide throughout the early 21st century. These epidemics or pandemics pose a major threat to human health. Here, we outline a critical role of the host cell protease TMPRSS2 in influenza virus and coronavirus infections and highlight an antiviral therapeutic strategy targeting TMPRSS2.

Preliminary success in the characterization and management of a sudden breakout of a novel H7N9 influenza A virus.

Influenza has always been one of the major threats to human health. The Spanish influenza in 1918, the pandemic influenza A/H1N1 in 2009, and the avian influenza A/H5N1 have brought about great disasters or losses to mankind. More recently, a novel avian influenza A/H7N9 broke out in China and until December 2, 2013, it had caused 139 cases of infection, including 45 deaths. Its risk and pandemic potential attract worldwide attention. In this article, we summarize epidemiology, virology characteristics, clinical symptoms, diagnosis methods, clinical treatment and preventive measures about the avian influenza A/H7N9 virus infection to provide a reference for a possible next wave of flu outbreak.

γδ T cells and their potential for immunotherapy.

Vγ9Vδ2 (also termed Vγ2Vδ2) T cells, a major human peripheral blood γδ T cell subset, recognize microbial (E)-4-hydroxy-3-methylbut-2-enyl diphosphate and endogenous isopentenyl diphosphate in a TCR-dependent manner. The recognition does not require specific accessory cells, antigen uptake, antigen processing, or MHC class I, class II, or class Ib expression. This subset of T cells plays important roles in mediating innate immunity against a wide variety of infections and displays potent and broad cytotoxic activity against human tumor cells. Because γδT cells express both natural killer receptors such as NKG2D and γδ T cell receptors, they are considered to represent a link between innate and adaptive immunity. In addition, activated γδ T cells express a high level of antigen-presenting cell-related molecules and can present peptide antigens derived from destructed cells to αß T cells. Utilizing these antimicrobial and anti-tumor properties of γδ T cells, preclinical and clinical trials have been conducted to develop novel immunotherapies for infections and malignancies. Here, we review the immunological properties of γδ T cells including the underlying recognition mechanism of nonpeptitde antigens and summarize the results of γδ T cell-based therapies so far performed. Based on the results of the reported trials, γδ T cells appear to be a promising tool for novel immunotherapies against certain types of diseases.