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We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of N-amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of N-amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of N-acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.

We examine the theoretical underpinnings of the seminal discoveries by Reiner Sustmann about the ambiphilic nature of Huisgen's phenyl azide cycloadditions. Density functional calculations with ωB97X-D and B2PLYP-D3 reproduce the experimental data and provide insights into ambiphilic control of reactivity. Distortion/interaction-activation strain and energy decomposition analyses show why Sustmann's use of dipolarophile ionization potential is such a powerful predictor of reactivity. We add to Sustmann's data set several modern distortion-accelerated dipolarophiles used in bioorthogonal chemistry to show how these fit into the orbital energy criteria that are often used to understand cycloaddition reactivity. We show why such a simple indicator of reactivity is a powerful predictor of reaction rates that are actually controlled by a combination of distortion energies, charge transfer, closed-shell repulsion, polarization, and electrostatic effects.

Whether intra-myocardial delivery of hydrogel can prevent post-infarct heart failure (HF) in a long follow-up period, especially after it is degraded, remains unclear. In this study, Dex-PCL-HEMA/PNIPAAm (DPHP) hydrogel was delivered into peri-infarct myocardium of rat when coronary artery was ligated, while PBS was employed as control. Twelve weeks later, compared with control, left ventricle remodeling was attenuated and cardiac function was preserved; serum brain natriuretic peptide, cardiac aldosterone, and pulmonary congestion were suppressed in hydrogel group. Pro-fibrogenic mRNA increased in infarct area while decreased in remote zone, as well as hypertrophic mRNA. These data proves DPHP hydrogel suppresses ventricular remodeling and HF by promoting fibrotic healing in infarct area and inhibiting reactive fibrosis and hypertrophy in remote zone. Timely intra-myocardial hydrogel implantation is an effective strategy to inhibit post-infarct cardiac remodeling and have a long-term beneficial effect even after it has been biodegraded.

Background: Bisphenol A (BPA) can cause detrimental effects on fetal growth. However, the effects of BPA alternatives, such as bisphenol F (BPF) and bisphenol S (BPS), on fetal growth are less known. Objective: To investigate the relationships of prenatal BPA, BPF, and BPS exposures with fetal growth parameters and gestational age. Methods: Urinary BPA, BPF, and BPS were measured in 1,197 pregnant women before delivery in a Chinese cohort. The associations of prenatal exposure to BPA, BPF, and BPS with fetal growth parameters and gestational age were examined, and associations stratified by fetal sex were also conducted. We used a restricted cubic splines (RCS) model to examine the dose–response associations between exposures and outcomes. Results: Maternal urinary BPA and BPF were negatively related to birth length (-0.30 cm, 95% CI: −0.44, −0.15 and −0.21 cm, 95% CI: −0.36, −0.07 comparing the extreme exposure groups, respectively, both p for trends

Studies indicate that phthalates can disrupt spermatogenesis and lead to the reduction of semen quality. However, the underlying mechanisms remain unclear. This study aimed to examine the associations of phthalate exposures as individual chemicals and mixtures with spermatogenesis-related miRNA106a. We detected eight phthalate metabolites in repeated urine samples and a single seminal plasma specimen among 111 men from an infertility clinic in Wuhan, China. Spermatogenesis-related miRNA106a was measured in seminal plasma. We used multivariable linear regression and Bayesian kernel machine regression (BKMR) models to separately evaluate the associations of phthalate metabolites as individual chemicals and mixtures with spermatogenesis-related miRNA106a. Elevated tertiles of urinary mono (2-ethylhexyl) phthalate (MEHP) was associated with decreased miRNA106a (−61.71%; 95%CI: 81.92, −18.93% for the highest vs. lowest tertile; P for trend = 0.01). Similarly, an inverse exposure-response relationship between seminal plasma MEHP concentrations and miRNA106a was also observed (−59.44%; 95%CI: 79.19, −20.95% for the highest vs. lowest tertile; P for trend = 0.01). The BKMR models showed that the mixtures of seminal plasma phthalate metabolites were associated with decreased miRNA106a when the chemical mixtures were ≥35th percentile compared to their medians. Nonlinear associations with miRNA106a were estimated for urinary and seminal plasma MEHP while fixing other phthalate metabolites at their medians. Our findings suggest that mixtures of phthalate metabolites in seminal plasma were negatively associated with spermatogenesis-related miRNA106a, and individual MEHP was the major contributor to the adverse effects.

Rolf Huisgen explored the Diels-Alder reactions of 1,3,5-cycloheptatriene (CHT) and cyclooctatetraene (COT) with the dienophiles maleic anhydride and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) to determine the kinetics and mechanisms of various electrocyclizations and Diels-Alder reactions. These reactions have been examined with density functional theory. Modern computational chemistry has provided information not previously available by experiment. Transition states for all the reactions have been identified, and their Gibbs energies are used to explain the experimental reactivities. Zwitterionic intermediates were not found in the [4+2] cycloadditions of both CHT or COT with PTAD and are thus not involved in these reactions. [2+2+2] cycloadditions, as an alternative path to the Diels-Alder products, are highly disfavored. Rapid double nitrogen inversion was found for the cycloaddition products with PTAD.

The application of amine derivatives as coupling partners is rare due to the inherent strength of the C-N bond. Herein, we report the first cross-electrophile coupling reaction of unstrained benzylic sulfonamides. Nickel-catalyzed intramolecular cross-electrophile coupling reactions of acyclic and cyclic benzylic sulfonamides with pendant alkyl chlorides generate cyclopropane products. Mechanistic experiments and DFT calculations are consistent with initiation of the reaction by magnesium iodide accelerated oxidative addition of the benzylic sulfonamide. This work establishes neutral and unstrained amine derivatives as XEC partners, furnishes structural rearrangement of benzylic sulfonamides, and provides valuable information regarding catalyst design for the development of new cross-electrophile coupling reactions of carbon-heteroatom bonds.

The palladium/isocyanide catalyst is able to facilitate the intermolecular σ-bond exchange between benzocyclobutenones and silacyclobutanes. This reaction cleaves the C–C bond of the benzocyclobutenones and the C–Si bond of the silacyclobutanes, providing a unprecedented access to the eight-membered silacycles with remarkable chemo- and regioselectivities. We studied the mechanism and origins of the chemo- and regioselectivities with density functional theory (DFT) calculations. The reaction proceeds via two sequential oxidative additions (first with benzocyclobutenone and second with silacyclobutane) and two subsequent reductive eliminations (first, C–Si bond formation; second, C–C bond formation). The oxidative addition abilities of the substrates and the trans effect of silyl group synergistically control the chemoselectivity toward the heteroexchange. The homoexchange of benzocyclobutenones is unfavorable because the oxidative addition ability of benzocyclobutenone is not strong enough to facilely gen...

Background Exposure to bisphenol A (BPA) has been associated with various adverse health outcomes. Recently, an increasing concern on its alternatives such as bisphenol S (BPS) and bisphenol F (BPF) has been aroused due to the restriction use of BPA. Few studies have identified predictors of exposure to BPA alternatives and assessed their health risks. Objective The aim of this study was to identify predictors of BPA and its alternatives and to assess their health risks among pregnant women. Methods We detected first morning urinary concentrations of BPA and its alternatives (BPS and BPF) among 1097 pregnant women from an established Chinese cohort. A questionnaire was conducted to obtain demographic characteristics, dietary habits, and lifestyles. We examined the predictors of creatinine-adjusted urinary BPA and its alternatives concentrations using multivariable linear regression. Risk assessment of exposure to BPA and its alternatives was calculated based on the estimated of daily intake (EDI). Results Geometric means of creatinine-adjusted urinary BPA, BPF, and BPS were 0.92, 0.12, and 0.08 μg/g creatinine, respectively. Pregnant women from Wuhan had lower concentrations of BPA, BPF, and ∑BPs (sum of BPA, BPF, and BPS) than those from Xiaogan. Intake of fried food was related to higher concentrations of BPA, and intake of pickled food was associated with higher concentrations of BPF and ∑BPs. The maximum EDI values for exposure to BPA, BPF, BPS, and ∑BPs ranged from 5.6428 to 13.3356 nmol/kg body weight/day, which were below the tolerable daily intake (TDI) for BPA defined by the European Food Safety Authority (EFSA) (18 nmol/kg body weight/day). The maximum hazard index (HI) value was 0.7409. Conclusion Several predictors identified in this study may inform public recommendations to reduce exposure to BPA and its alternatives.

Pulmonary fibrosis is the final outcome of a variety of diffuse pulmonary interstitial diseases, and it has an unclear pathogenesis. There is no effective drug treatment, so the clinical prognosis is poor. As an effective component of ginseng, total ginsenoside (TG) inhibits acute lung injury. This study determined whether TG has protective effects on pulmonary fibrosis and investigated its protective mechanisms. A pulmonary fibrosis model in BALB/c mice was established by injecting the bleomycin chemotherapeutic agent into the trachea. TG (40, 80, and 160 mg/kg/d) was given continuously for 28 days from the second day after development of the model. Pulmonary fibrosis was determined by measuring the lung coefficient, haematoxylin and eosin, and Masson’s trichrome staining of lung samples, and detection of alpha smooth muscle actin expression in lung tissues. To investigate the mechanisms of anti-pulmonary fibrosis by TG, we detected the genes and proteins of the transforming growth factor-β1 (TGF-β1)/Smad signalling pathway and matrix metalloproteinase (MMP) system. Treatment with TG (40, 80, and 160 mg/kg/d) ameliorated pulmonary fibrosis induced by bleomycin in mice, downregulated the expression of TGF-β1, Smad2, Smad3, MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1, and upregulated the protein expression of Smad7. These results suggest that the protective effects of TG on pulmonary fibrosis induced by bleomycin are related to regulation of the TGF-β1/Smad signalling pathway and MMP system.

Sodium ferulate (SF) is the sodium salt of ferulic acid which is an active ingredient of Radix Angelica Sinensis and Ligusticum chuanxiong hort. Here, we investigated SF inhibition in a rat model of myocardial hypertrophy induced by coarctation of the abdominal aorta. Following coarctation, rats were given SF (20, 40, and 80 mg/kg/day) for 25 consecutive days. We characterized myocardial hypertrophy using myocardial hypertrophic parameters, histopathology, and gene expression of atrial natriuretic factor (ANF) ―a gene related to myocardial hypertrophy. We detected the levels of angiotensin II (Ang II) and endothelin-1 (ET-1), protein kinase C beta (PKC-β), Raf-1, extracellular regulated protein kinase 1/2 (ERK1/2), and mitogen-activated protein kinase phosphatase-1 (MKP-1) in myocardium. Notably, coarctation of the abdominal aorta increases myocardial hypertrophic parameters, cardiac myocyte diameter, the concentration of Ang II and ET-1 in myocardium, and gene expression of ANF. SF significantly ameliorates myocardial hypertrophy caused by coarctation of the abdominal aorta; reduces concentrations of Ang II and ET-1; suppresses the overexpression of ANF, PKC-β, Raf-1, and ERK1/2; and increases the expression of MKP-1. These results indicate that SF alleviates myocardial hypertrophy induced by coarctation of the abdominal aorta, and these protective effects could be related to the inhibition of PKC and mitogen-activated protein kinase (MAPK) signaling pathways.

In order to develop a new process for concentrating and separating sodium sulfate (Na 2 SO 4 ) and magnesium sulfate (MgSO 4 ) of the bloedite by gas hydrate, the equilibrium of the ternary system H 2 O–Na 2 SO 4 –C 3 H 8 , H 2 O–MgSO 4 –C 3 H 8 and the quaternary system H 2 O–Na 2 SO 4 –MgSO 4 –C 3 H 8 with tetrahydrofuran (THF) additive were studied at 0 °C. It showed that the mass percentage of Na 2 SO 4 (MgSO 4 ) in equilibrium liquid was higher than in feed. It proved that gas hydrate could be used to the concentration and separation of Na 2 SO 4 and MgSO 4 . The solubility of the propane was calculated based on the Krichevsky–Kasarnovsky equation. The extended Pitzer model of electrolyte–electrolyte–nonelectrolyte–water system was derived and applied into H 2 O–Na 2 SO 4 –MgSO 4 –C 3 H 8 system and its sub-systems. The necessary thermodynamic parameters had been derived from a least-squares optimization program. The model calculation value was in good agreement with experimental solubility for ternary and quaternary mixtures, which indicated that the Pitzer model could be successfully used to predict the phase equilibrium of the electrolyte–electrolyte–nonelectrolyte–water systems containing gas hydrate.

In order to develop a new process for concentrating and separating sodium sulfate (Na2SO4) and magnesium sulfate (MgSO4) of the bloedite based on tetrahydrofuran (THF) hydrate method, the equilibrium of the ternary systems THF–Na2SO4–H2O and THF–MgSO4–H2O and the quaternary system THF–Na2SO4–MgSO4–H2O were measured at 5 °C, and the phase digrams of these three systems were investigated. It showed that the mass percentage of Na2SO4 (MgSO4) in equilibrium liquid was higher than in feed and we could obtain Na2SO4·10H2O and MgSO4·7H2O in turn. It proved that THF hydrate could be used to the concentration and separation of Na2SO4 and MgSO4. The extended Pitzer model of the electrolyte–electrolyte–nonelectrolyte–water system was derived and applied into THF–Na2SO4–MgSO4–H2O system and its subsystems. The necessary thermodynamic parameters had been derived from a least-squares optimization program. The model calculation value was in good agreement with experimental solubility for ternary and quaternary mixtures,...

In order to develop a new technology for separating the bloedite by the method of gas hydrate formation, the phase equilibrium of the H2O-Na2SO4-MgSO4-C3H8 system and its subsystems was studied at 0°C and pressure.The equilibrium pressure and the composition of solid and liquid above system were investigated.It was found that equilibrium pressure of gas hydrate formation was increasing with the increase of the Na2SO4( or MgSO4) concentration. The addition of anionic surfactant SDS helped to lower the equilibrium pressure of gas hydrate formation. The mother liquor amount entrained in the gas hydrate after liquid separation by sinking was very high when surfactants was not added. But the equilibrium pressure of gas hydrate formation and the mother liquor amount entrained in gas hydrate were decreased when surfactant was added to the system.

The phase equilibrium of the quaternary system H2O-H2O2-CO(NH2)2-C3H8 with gas hydrate formation had been studied at high pressure and low temperature. The temperature and pressure of gas hydrate formed from different hydrogen peroxide concentration aqueous were determined at adding surfactants and no surfactants separately. It was concluded that the equilibrium pressure of gas hydrate formation was increasing with the increase of the hydrogen peroxide concentration, the urea concentration and the temperature, the mother liquor amount entrained in the gas hydrate after liquid separation by sinking was very high when surfactants was not added, but the equilibrium pressure of gas hydrate formation was decreased and the mother liquor amount entrained in gas hydrate was also decreased when surfactants was added to the system. In addition, the equilibrium pressure of gas hydrate formation in the quaternary system H2O-H2O2-CO(NH2)2-C3H8 was calculated according to Chen-Guo thermodynamic model, improved UNIFAC mathematical equation and Aasberg-Peterson fugacity coefficient model. The calculated data was in agreement with the experiment data.

It is widely accepted that the pharmacological activities of anthracyclines antitumor agents express when the quinone-containing chromophore intercalates into base pairs of the duplex DNA. We have successfully synthesized and investigated the DNA-interactions of hybrids composed with quinone chromophore and cationic porphyrin. Herein, a clinic anticancer drug, daunomycin, is introduced to the porphyrin hybrids through different lengths of amide alkyl linkages, and their interactions and cleavage to DNA were studied compared with the previous porphyrin-quinone hybrids. Spectral results and the determined binding affinity constants (Kb) show that the attachment of daunomycin to porphyrin could improve the DNA-binding and photocleaving abilities. The porphyrin-daunomycin hybrids may find useful employment in investigating the ligand-DNA interaction.

Encouraged by the enormous importance attributed to the structure and function of human telomeric DNA, herein we focused our attention on the interaction of a serious of newly prepared porphyrin–daunomycin (Por–DNR) hybrids with the guanine-rich single-strand oligomer (G4) and the complementary cytosine-rich strand (i-motif). Various spectral methods such as absorption and fluorescence titration, surface-enhanced Raman and circular dichroism spectrum were integrated in the experiment and it was found that these Por–DNR hybrids could serve as prominent molecules to recognize G4 and i-motif. What is more, interesting results were obtained that the hybrids with longer flexible links are more favorable in binding with both G4 and i-motif than the hybrid with shorter linkage. These Por–DNR hybrids may help to develop new ideas in the research of human telomeric DNA with small molecules.