Oxidation of 5,15-Dioxaporphyrin: Its Generality and Novelty as an Oxaporphyrin Analogue.

5,15-Dioxaporphyrin (DOP) is a novel meso-oxaporphyrin analogue and exhibits unique 20π-antiaromaticity, unlike its mother congener of 18π-aromatic 5-oxaporphyrin, commonly known as its cationic iron complex called verdohem, which is a key intermediate of heme catabolism. To reveal its reactivities and properties as an oxaporphyrin analogue, the oxidation of tetra-ß-arylated DOP (DOP-Ar4 ) was explored in this study. Stepwise oxidation from the 20π-electron neutral state was achieved, and the corresponding 19π-electron radical cation and 18π-electron dication were characterized. Further oxidation of the 18π-aromatic dication resulted in the formation of a ring-opened dipyrrindione product by hydrolysis. Considering a similar reaction of verdoheme to ring-opened biliverdin in the heme degradation in nature, the current result consolidates the ring-opening reactivity of oxaporphyrinium cation species.

Er-xian ameliorates myocardial ischemia-reperfusion injury in rats through RISK pathway involving estrogen receptors.

Curculigo orchioides (CUR) and Epimedium (EPI) are traditional Chinese medicines with estrogen-like biological activity, called Xianmao and Xianlingpi (Er-xian) in Chinese. However, whether Er-xian exerts protective effects on myocardial ischemia-reperfusion injury (MIRI) is unknown. This study aimed to investigate the cardioprotective effects of Er-xian preconditioning against MIRI and the underlying mechanisms. CUR or EPI was administered intragastrically to aged female rats as a monotherapy or combination therapy. 2 weeks later, a rat MIRI model was established. Myocardial infarction size, myocardial morphology, cTnT, cell apoptosis rate, intracellular calcium concentration, mitochondrial permeability transition pore (MPTP) opening and reperfusion injury salvage kinase (RISK) signaling pathway molecules were observed after the surgery. To evaluate the mechanisms of Er-xian, estrogen receptors antagonists ICI 182780 and G15 were used. In this study, Er-xian notably alleviated myocardial tissue damage, maintained mitochondrial morphology, reduced infarct size and cardiac markers, and increased sera levels of E2. Moreover, Er-xian inhibited calcium overload and mPTP opening, and decreased cardiomyocyte apoptosis. We found that the dual therapy of CUR and EPI elicited more noticeable results than CUR or EPI monotherapy. The significant protective effects of Er-xian on ischemia-reperfusion myocardium were attributed to the up-regulation of AKT, ERK1/2 and GSK-3ß phosphorylation levels. The cardioprotective effects of Er-xian were significantly reduced after estrogen receptor blockade, especially GPER30. These results indicate that Er-xian attenuates MIRI through RISK signaling pathway and estrogen receptors are the critical mediators.

Spontaneous Assembly and Three-Dimensional Stacking of Antiaromatic 5,15-Dioxaporphyrin on HOPG.

Antiaromatic compounds have recently received considerable attention because of their novel properties such as narrow HOMO-LUMO gaps and facile formation of mutual stacking. Here, the spontaneous assembly of antiaromatic meso-2-thienyl-substituted 5,15-dioxaporphyrin (DOP-1) is scrutinized at the liquid-solid interface by scanning tunneling microscopy (STM). Polymorphism in monolayers characterized by the orthogonal and parallel assemblies is found at the low concentration of 0.05 mM. The parallel assembly is more stable and dominantly formed at higher concentrations. Aggregation was observed at concentrations >0.2 mM, and the STM images of the aggregates implied the formation of stacked layers. The intrinsic electronic structures of the mutually stacked bilayer generated by applying an electric pulse to the monolayer were probed by scanning tunneling spectroscopy to reveal the narrowing of the HOMO-LUMO gap by about 20 % compared with the monolayer, thus suggesting significant molecular orbital interactions.

Peoniflorin Preconditioning Protects Against Myocardial Ischemia/Reperfusion Injury Through Inhibiting Myocardial Apoptosis: RISK Pathway Involved.

Preconditioning with Peoniflorin, a component of traditional Chinese prescriptions, was proposed to be a potential strategy for cardioprotection against ischemia/reperfusion (I/R) injury. However, the cardioprotective effect of Peoniflorin preconditioning has not been thoroughly confirmed, and the underlying mechanism remains unclear. Here, we examined the cardioprotective effect and its mechanism of Peoniflorin preconditioning against myocardial I/R injury. Rats were subjected to 30 min of transient ischemia followed by 2 h of reperfusion with or without Peoniflorin (100 mg/kg) prior to reperfusion. Peoniflorin preconditioning significantly limited myocardial infarct size and reperfusion arrhythmias, as well as obviously attenuated the histomorphological and micromorphological damages induced by I/R injury. The reduced myocardial injury was also associated with the anti-apoptotic effect of Peoniflorin, as evidence by decreased TUNEL-positive cells, upregulation of BCL-2 expression, and downregulation of Bax and caspase-3 expression. In an effort to evaluate the mechanism responsible for the observed cardioprotective and anti-apoptotic effect, Western blot of phosphorylated protein was performed after 20 min of reperfusion. Results showed that Peoniflorin preconditioning activated both the Akt and ERK1/2 arm of the reperfusion injury salvage kinase (RISK) pathway. To further confirm this mechanism, the PI3K signaling inhibitor LY294002 and ERK1/2 signaling inhibitor PD98059 were administered in vivo. The cardioprotective and anti-apoptotic effects of Peoniflorin preconditioning were diminished but not abolished by pretreatment with LY294002 or PD98059. Taken together, these results indicate that Peoniflorin preconditioning protects the myocardial against I/R injury and inhibits myocardial apoptosis via the activation of the RISK pathway, highlighting the potential therapeutic effects of Peoniflorin on reducing myocardial I/R injury.

Correlation between US-FNAC with BRAF V600E Mutation Analysis and Central Neck Lymph Node Metastasis in cN0 Papillary Thyroid Cancer.

The aim of this study was to explore the correlation between ultrasound-guided fine-needle aspiration cytology(US-FNAC) combined with BRAF V600E mutation analysis and central neck lymph node metastasis in cN0 papillary thyroid cancer, so as to provide reliable molecular evidence to use it for preoperative evaluation, operation procedure design, and postoperative follow-up planning in clinic. Specimens were obtained from 250 patients with cN0 thyroid cancer (TI-RADS≥4a, highly suspected of PTC by US-FNAC) after bilateral thyroidectomy and central neck lymph node dissection with accessible postoperative pathologic results of PTC and central neck lymph nodes and used for cytological diagnosis by H&E stain and BRAF V600E mutation detection. Single-factor analysis showed that differences between the central neck lymph node metastasis and nonmetastasis groups were statistically significant in gender, BRAF V600E mutation, and extracapsular extension. Logistic multivariate regression analysis showed significant differences in gender, BRAF V600E mutation, and extracapsular extension. Positive BRAF V600E mutations by US-FNAC, extracapsular extension, and male gender are risk factors of central neck lymph node metastasis in cN0 PTC metastatic PTC to central neck lymph node. Patients with those factors should undergo prophylactic central neck lymph node dissection.

Marine furanocembranoids-inspired macrocycles enabled by Pd-catalyzed unactivated C(sp3)-H olefination mediated by donor/donor carbenes.

Biomimetic modularization and function-oriented synthesis of structurally diversified natural product-like macrocycles in a step-economical fashion is highly desirable. Inspired by marine furanocembranoids, herein, we synthesize diverse alkenes substituted furan-embedded macrolactams via a modular biomimetic assembly strategy. The success of this assembly is the development of crucial Pd-catalyzed carbene coupling between ene-yne-ketones as donor/donor carbene precursors and unactivated Csp3‒H bonds which represents a great challenge in organic synthesis. Notably, this method not only obviates the use of unstable, explosive, and toxic diazo compounds, but also can be amenable to allenyl ketones carbene precursors. DFT calculations demonstrate that a formal 1,4-Pd shift could be involved in the mechanism. Moreover, the collected furanocembranoids-like macrolactams show significant anti-inflammatory activities against TNF-α, IL-6, and IL-1ß and the cytotoxicity is comparable to Dexamethasone.

Pd-Catalyzed Decarboxylative Olefination: Stereoselective Synthesis of Polysubstituted Butadienes and Macrocyclic P-glycoprotein Inhibitors.

The efficient and stereoselective synthesis of polysubstituted butadienes, especially the multifunctional butadienes, represents a great challenge in organic synthesis. Herein, we wish to report a distinctive Pd(0) carbene-initiated decarboxylative olefination approach that enables the direct coupling of diazo esters with vinylethylene carbonates (VECs), vinyl oxazolidinones, or vinyl benzoxazinones to afford alcohol-, amine-, or aniline-containing 1,3-dienes in moderate to high yields and with excellent stereoselectivity. This protocol features operational simplicity, mild reaction conditions, a broad substrate scope, and gram-scalability. Notably, a structurally unique allylic Pd(II) intermediate was isolated and characterized. DFT calculation and control experiments demonstrated that a rare Pd(0) carbene intermediate could be involved in this reaction. Moreover, the polysubstituted butadienes as novel building blocks were unprecedentedly assembled into macrocycles, which efficiently inhibited the P-glycoprotein and dramatically reversed multidrug resistance in cancer cells by 190-fold.

Enantioselective Pallada-Electrocatalyzed C-H Activation by Transient Directing Groups: Expedient Access to Helicenes.

Asymmetric pallada-electrocatalyzed C-H olefinations were achieved through the synergistic cooperation with transient directing groups. The electrochemical, atroposelective C-H activations were realized with high position-, diastereo-, and enantio-control under mild reaction conditions to obtain highly enantiomerically-enriched biaryls and fluorinated N-C axially chiral scaffolds. Our strategy provided expedient access to, among others, novel chiral BINOLs, dicarboxylic acids and helicenes of value to asymmetric catalysis. Mechanistic studies by experiments and computation provided key insights into the catalyst's mode of action.

Pd-Catalyzed Three-Component Domino Reaction of Vinyl Benzoxazinanones for Regioselective and Stereoselective Synthesis of Allylic Sulfone-Containing Amino Acid Derivatives.

A Pd-catalyzed, highly regioselective and stereoselective three-component domino allylic substitution/N-H carbene insertion reaction under mild conditions is described. This reaction demonstrates a wide substrate scope and satisfactory functional group tolerance, providing a broad range of allylic sulfone-containing amino acid derivatives. Moreover, DBU mediates highly diastereoselective cross-dehydrogenative coupling annulation of allylic sulfones without using peroxides or any metal oxidants. This developed protocol affords 7-membered ring heterocyclic compounds incorporating both sulfone-containing amino acid esters and one quaternary carbon center. Mechanistic studies indicate that an unusual umpolung of glycine occurred in this annulation.

Protective effect of the combinations of glycyrrhizic, ferulic and cinnamic acid pretreatment on myocardial ischemia-reperfusion injury in rats.

The aim of this study was to find an effective drug cocktail pretreatment to protect myocardial tissue of the heart from ischemia-reperfusion (I/R) injury. The mechanisms underlying the effects of the drug cocktail were subsequently explored in order to expand the application of Dang-gui-si-ni-tang (DGSN), a Traditional Chinese Medicine. The active components of DGSN in the serum following oral administration were investigated using high-performance liquid chromatography. The activity of superoxide dismutase (SOD) and malondialdehyde (MDA) levels were then analyzed to show the effect of the active components in the treatment of myocardial I/R injury. An L16 (44) orthogonal experiment was utilized to determine the most effective cocktail mix and the mechanism underlying the effect of this mix on myocardial I/R injury was investigated. It was observed that FCG, a mixture of glycyrrhizic (50 mg/kg), cinnamic (200 mg/kg) and ferulic (300 mg/kg) acid, was the optimal drug cocktail present in DGSN. This was absorbed into the blood following oral administration and was shown to decrease MDA levels and increase the activity of SOD. In conclusion, the findings suggest that FCG, a combination of active ingredients in the DGSN decoction, can be absorbed into the blood and protect the myocardium from I/R injury.