Chiral Brønsted Acid-Catalyzed Kinetic Resolution of Sulfoximines for the Synthesis of Benzothiadiazine-1-Oxides.

Benzothiadiazine-1-oxide scaffolds with S-stereogenic centers are prevalent in bioactive and pharmaceutical molecules. Reported works mainly focused on the metal-catalyzed asymmetric C-H amination/cyclization reaction for the synthesis of benzothiadiazine-1-oxides. Here, we reported a chiral phosphoric acid-catalyzed kinetic resolution of sulfoximines, providing chiral benzothiadiazine-1-oxides and recovered chiral sulfoximines with moderate to good enantioselectivities (s factors up to 36.6).

Chiral Phosphoric Acid Catalyzed Asymmetric Hydrolysis of Biaryl Oxazepines for the Synthesis of Axially Chiral Biaryl Amino Phenol Derivatives.

The development of catalytic asymmetric reaction with water as the reactant is challenging due to the reactivity- and stereoselectivity-control issues resulted from the low nucleophilicity and the small size of water. We disclose herein a chiral phosphoric acid (CPA) catalyzed atroposelective ring-opening reaction of biaryl oxazepines with water. A series of biaryl oxazepines undergo the CPA catalyzed asymmetric hydrolysis in a highly enantioselective manner. The key for the success of this reaction is the use of a new SPINOL-derived CPA catalyst and the high reactivity of biaryl oxazepine substrates towards water under acidic conditions. Density functional theory calculations suggest that the reaction proceeds via a dynamic kinetic resolution pathway and the CPA catalyzed addition of water to the imine group is both enantio- and rate-determining.

23,24-Dihydrocucurbitacin B promotes lipid clearance by dual transcriptional regulation of LDLR and PCSK9.

23,24-Dihydrocucurbitacin B (designated as C95 in this article) is a cucurbitane triterpenoid that has been shown to possess a variety of pharmacological activities, such as anti-inflammatory and anti-HIV-1 activities etc. In this study, we investigated the effects of 23,24-dihydrocucurbitacin B on lipid regulation. We showed that 23,24-dihydrocucurbitacin B (1-5 µM) dose-dependently promoted DiI-LDL uptake in HepG2 cells by upregulating low-density lipoprotein receptor (LDLR) protein. In HepG2 cells, 23,24-dihydrocucurbitacin B (1-10 µM) dose-dependently enhanced LDLR promoter activity by elevating the mature form of SREBP2 (sterol regulatory element binding protein 2) protein levels on one hand, and inhibited PCSK9 (proprotein convertase subtilisin/kexin type 9) promoter activity by attenuating HNF1α (hepatocyte nuclear factor-1α) protein levels in nuclei on the other hand. Consequently, the expression of LDLR protein markedly increased, whereas the PCSK9-mediated LDLR protein degradation decreased. In a high-cholesterol LVG golden Syrian Hamster model, administration of 23,24-dihydrocucurbitacin B (30 mg · kg-1⋅ d-1, intragastric, for 3 weeks) significantly decreased the serum LDL-cholesterol (LDL-C) levels. PCSK9 protein levels in the serum and liver tissues were significantly decreased, whereas LDLR protein levels in liver tissues were significantly increased in the treated animals as compared with the control animals. In conclusion, our study demonstrates for the first time that 23,24-dihydrocucurbitacin B exhibits dual transcriptional regulation of LDLR and PCSK9 in HepG2 cells by increasing SREBP2 protein levels and decreasing HNF1α protein levels in the nuclei. These results propose a new strategy to simultaneously manage LDLR and PCSK9 protein expression and provide a promising lead compound for drug development.

Magnesium lithospermate B protects the endothelium from inflammation-induced dysfunction through activation of Nrf2 pathway.

Magnesium lithospermate B (MLB) is an active component of Salvia miltiorrhiza Radix, a traditional Chinese herb used in treating cardiovascular diseases. In this study, we investigated the protective effects of MLB against inflammation-induced endothelial dysfunction in vitro and in vivo, and the underlying mechanisms. Endothelial dysfunction was induced in human dermal microvascular endothelial cells (HMEC-1) in vitro by lipopolysaccharide (LPS, 1 µg/mL). We showed that pretreatment with MLB (10-100 µM) dose-dependently inhibited LPS-induced upregulation of inflammatory cytokines ICAM1, VCAM1, and TNFα, which contributed to reduced leukocytes adhesion and attenuation of endothelial hyperpermeability in HMEC-1 cells. SD rats were injected with LPS (10 mg/kg, ip) to induce endothelial dysfunction in vivo. We showed that pretreatment with MLB (25-100 mg/kg, ip) dose-dependently restored LPS-impaired endothelial-dependent vasodilation in superior mesenteric artery (SMA), attenuated leukocyte adhesion in mesenteric venules and decreased vascular leakage in the lungs. We further elucidated the mechanisms underlying the protective effects of MLB, and revealed that MLB pretreatment inhibited NF-κB activation through inhibition of IκBα degradation and subsequent phosphorylation of NF-κB p65 in vitro and in vivo. In HMEC-1 cells, MLB pretreatment activated the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. Knockdown of Nrf2 with siRNA abolished the inhibitory effects of MLB on IκBα degradation and ICAM1 up-regulation, which were mimicked by PKC inhibition (Gö6983) or PI3K/Akt inhibition (LY294002). In summary, our results demonstrate that MLB inhibits NF-κB activation through PKC- and PI3K/Akt-mediated Nrf2 activation in HMEC-1 cells and protects against LPS-induced endothelial dysfunction in murine model of acute inflammation.

Metabolomic profiling reveals decreased serum cysteine levels during gestational diabetes mellitus progression.

Gestational diabetes mellitus (GDM) is a pregnancy-related metabolic disorder associated with short-term and long-term adverse health outcomes, but its pathogenesis has not been clearly elucidated. Investigations of the dynamic changes in metabolomic markers in different trimesters may reveal the underlying pathophysiology of GDM progression. Therefore, in the present study, we analyzed the metabolic profiles of 75 women with GDM and 75 women with normal glucose tolerance (NGT) throughout the three trimesters. We found that the variation trends of 38 metabolites were significantly different during GDM development. Specifically, longitudinal analyses revealed that cysteine (Cys) levels significantly decreased over the course of GDM progression. Further study showed that Cys alleviated GDM in female mice at gestational day 14.5 possibly by inhibiting phosphoenolpyruvate carboxykinase to suppress hepatic gluconeogenesis. Taken together, these findings suggest that the Cys metabolic pathway might play a crucial role in GDM and that Cys supplementation represents a potential new treatment strategy for GDM patients.

Base-Promoted S-Arylation of Sulfenamides for the Synthesis of Sulfilimines.

Sulfilimines are key intermediates to common motifs in medicines and agrochemicals. Typically, this class of compounds are prepared by imidation of thioethers, transition-metal-catalyzed or base-promoted sulfur alkylation and transition-metal-catalyzed sulfur arylation. Here, we report a practical and efficient base-mediated sulfur arylation reaction for the preparation of sulfilimines. A wide range of N-acyl and N-aryl sulfenamides react with various diaryliodonium salts smoothly to afford the sulfilimines in high yields with excellent chemoselectivities.

Fused-ring α-pyrones from intramolecular C-H activation and their lipids-lowering activity associated with LXR-IDOL-LDLR axis regulation.

Lipids-lowering is considered as the most effective approach to decrease the risk of Atherosclerotic cardiovascular disease (ASCVD), of which atherosclerosis is the most common cause. Natural products containing a unique type of α-pyrone was reported to suppress atherosclerosis in which α-pyrone might be considered as an important pharmacore. In this study, an efficient one-pot intramolecular C-H activation strategy was applied to the synthesis of potentially bioactive α-pyrone derivatives. As the result, three different scaffolds were quickly and conveniently generated, including thiophenes, pyrrole and indole derivatives. Among of them, eight α-pyrone derivatives showed potential effects to promote the uptake of LDL in HepG2 cells. Active unique α-pyrones compounds exhibiting potent in vitro and in vivo lipids-lowering effects, and a novel mechanism associated with the regulation of LXR-IDOL-LDLR axis, the new pathway targeted pharmacologically to control plasma cholesterol levels, were disclosed firstly in this study.

Euphornin L promotes lipid clearance by dual regulation of LDLR and PCSK9.

Our previous study identified euphornin L as an active lipid-lowering compound in high-fat diet-fed Golden Syrian hamsters. The aim of the present study was to investigate the mechanisms underlying the lipid-lowering effects of euphornin L. Euphornin L in HepG2 cells was assessed via DiI-LDL update assays and found to increase LDL-update and LDLR protein levels. RNA interference assays demonstrated that its LDL-update effects were LDLR-dependent. Dual luciferase reporter and mRNA stability assays revealed that euphornin L had little effect on LDLR mRNA transcription but lengthened the half-life of LDLR mRNA by activating ERK protein in cells. Euphornin L decreased the secretion of PCSK9 protein and alleviated PCSK9-mediated LDLR protein degradation. In vivo experiments in hamsters, which were treated with euphornin L (30 mg/kg/day) for 3 weeks, confirmed these findings. LDLR protein levels in liver tissue were upregulated, while PCSK9 protein levels in serum were downregulated. Altogether, the present study demonstrated that euphornin L increased LDLR protein levels by dual regulation of LDLR mRNA and PCSK9 protein, and represented an active compound for lipid-lowering drug development.

A simultaneous identification and quantification strategy for determination of sulfhydryl-containing metabolites in normal- and high-fat diet hamsters using stable isotope labeling combined with LC-MS.

Sulfur-containing metabolites are related to several physiologic disorders and metabolic diseases. In this study, a simultaneous identification and quantification strategy in one batch for determination of sulfhydryl-containing metabolites was developed using stable isotope labeling combined with liquid chromatography-tandem mass spectrometry (SIL-LC-MS). In the proposed method, a pair of isotope labeling reagents, D0/D5-N-ethylmaleimide (D0/D5-NEM), was used to derivatize sulfhydryl-containing metabolites in blood and plasma of normal- and high-fat-diet (NFD and HFD) hamsters for reduced (-SH) and total (-SH, -S-S-, S-glutathionylated proteins) analysis. Quality control (QC) samples and test samples were prepared for LC-MS analysis. First, both QC samples and stable isotope labeled internal standards were used to monitor the status of the instrument and ensure the reliability of the analysis. Subsequently, an inhouse database containing 45 sulfhydryl-containing metabolites was established by MS1 based on QC samples. Then, qualitatively differential sulfhydryl-containing metabolites were found by MS2 between the NFD and HFD hamsters of the test samples, including 3 in reduced and 8 in total analysis of blood samples, and 2 in reduced and 2 in total analysis of plasma samples. Next, in quantitative analysis, satisfied linearities for 6 sulfhydryl-containing metabolites were obtained with the correlation coefficient (R2) > 0.99 and absolute quantification was carried out. The results showed that glutathione and cysteine have different concentrations in blood and plasma of hamsters. Finally, the correlation of sulfhydryl-containing metabolites with blood lipid and oxidative stress levels was determined, which provided insight into the hyperlipidemia-related oxidative stress. Taken together, the developed method of simultaneous identification with the inhouse database and MS2 and quantification with standards in one batch provides a promising strategy for the analysis of sulfhydryl-containing metabolites in biological samples, which may promote the in-depth investigation on sulfhydryl-containing metabolites and related diseases.

The influence of alexithymia on mobile phone addiction: The role of depression, anxiety and stress.

BACKGROUND: Alexithymia is an important predictor of mobile phone addiction. Enhancing and improving college students' mental health can reduce the rate of mobile phone addiction. However, it is not clear about the role of depression, anxiety and stress in the relationship between college students' alexithymia and mobile phone addiction. METHODS: A total of 1105 college students were tested with the Toronto Alexithymia Scale, the Depression Anxiety Stress Scale and the Mobile Phone Addiction Index. RESULTS: An individual's level of alexithymia was significantly correlated with depression, anxiety, stress and mobile phone addiction. Alexithymia had a significantly positive prediction effect on mobile phone addiction, and depression, anxiety, and stress on mobile phone are positive predictors. Depression, anxiety or stress had partially mediating effects between alexithymia and mobile phone addiction. Alexithymia not only directly had a positively impact on mobile phone addiction, but both also had an indirect effect on mobile phone addiction through depression, anxiety or stress. LIMITATIONS: Limitations included sampling method and modest sample size, self-report measures, and unmeasured potential confounders. CONCLUSION: Alexithymia is an important correlate of mobile phone addiction, and depression, anxiety or stress is an important mediator in this relationship.

The Relationship between Impulsivity and Internet Addiction in Chinese College Students: A Moderated Mediation Analysis of Meaning in Life and Self-Esteem.

Internet addiction (IA) has increasingly been recognized as a serious psychological malady among college students. Impulsivity has been shown to be associated to addictive behaviors, also to IA, and that the purpose of the study is to investigate whether or not there are variables modulating the relation between impulsivity and IA. "Meaning in life" is regarded as a desirable attribute, with positive mental health outcomes. "Self-esteem" is often regarded as an important component of psychological health which has relation to IA. Therefore, we examined meaning in life and self-esteem's possible effects in this relationship. A total of 1068 Chinese college students ranging in age from 18 to 25 years were recruited for this cross-sectional survey study. Correlations and multivariate regressions were used to calculate the possible mediation and moderation relationship among the variables of meaning in life, self-esteem, impulsivity, and IA. In the analyses that we conducted, IA was shown to be prevalent among Chinese university students. The relationship between impulsivity and IA was partially mediated by meaning in life, and the relationship between meaning in life and IA was moderated by self-esteem. Our findings demonstrate that meaning in life and self-esteem can be useful buffers to IA for highly impulsive individuals. Further randomized trials to confirm these results are needed.