Direct Arylation of Unactivated Alkanes with Heteroarenes by Visible-Light Catalysis.

The functionalization of aliphatic C-H bonds is both a major challenge and a desirable goal in organic synthesis. Here, we describe the successful arylation of unactivated alkanes with heteroarenes by using iridium polypyridyl complexes as the photocatalyst and persulfate as the HAT catalyst precursor under visible-light irradiation. This reaction features good functional group tolerance and broad scope with regard to both alkane and heteroarene substrates (37 examples), which allows direct access to alkyl-substituted N-heteroarenes, a key structural motif in natural products and bioactive molecules.

The human epididymis protein 4 acts as a prognostic factor and promotes progression of gastric cancer.

Human epididymis protein 4 (HE4), represented as an epididymis-specific gene and designated a WAP four-disulfide core domain protein 2 (WFDC2), is amplified in many tumors. However, little is known about its clinical significance and biological function in gastric carcinomas. We found that HE4 was more commonly observed in gastric carcinoma tissues than in normal tissues and was significantly correlated with Lauren classification, TNM stage, and tumor size by immunohistochemistry. The overall survival rate of patients with HE4 low expression was significantly higher than that of the patients with HE4 high expression. In addition, silencing of HE4 expression inhibits cell proliferation and migration and enhances cell apoptosis. Subsequent studies reveal that the Src, Akt, and Erk1/2 signaling may be involved with pro-survival and anti-apoptotic effects of the HE4 on gastric cancer cells. Taken together, this study provides new evidence on promotive effects of the HE4 on gastric cancer progression and indicates that HE4 might be a promising prognostic factor for gastric cancer diagnosis.

Undescribed matrine-type alkaloids from Sophora alopecuroides with anti-inflammatory activity.

A phytochemical investigation on the alkaloid fractions of Sophora alopecuroides L. led to the production of 11 undescribed matrine-type alkaloids, sophaloseedlines I-S (1-11), 12 known analogs (12-23), and an unexpected artificial matrine-derived Al(III) complex (24). The corresponding structures were elucidated by the interpretation of spectroscopic analyses, quantum chemical calculation, and six instances (1-4, 18, and 24), verified by X-ray crystallography. The biological activities screening demonstrated that none of the isolates exhibited cytotoxicity against four human cancer cell lines (HepG2, A549, THP-1, and MCF-7) and respiratory syncytial virus (RSV) at 50 µM, while moderate anti-inflammatory activity with IC50 value from 15.6 to 47.8 µM was observed. The key structure-activity relationships of those matrine-type alkaloids for anti-inflammatory effects have been summarized. In addition, the most potent 7-epi-sophoramine (19) and aluminum sophaloseedline T (24) could effectively inhibit the release of pro-inflammatory factors (TNF-α, IL-6, and IL-1ß), as well as the expression of iNOS and COX-2 proteins.

Undescribed phloroglucinol derivatives with antiviral activities from Dryopteris atrata (Wall. Ex Kunze) Ching.

Nine undescribed phloroglucinol derivatives (dryatraols A-I) with five different backbones and three known dimeric acylphloroglucinols were isolated from the rhizome of Dryopteris atrata (Wall. Ex Kunze) Ching (Dryopteridaceae). Dryatraol A contains an unprecedented carbon skeleton-a butyrylphloroglucinol and a rulepidanol-type sesquiterpene are linked via a furan ring to form a 6/5/6/6 ring system. Dryatraols B and C are the first examples of monomeric phloroglucinols coupled with the aristolane-type sesquiterpene through the C-C bond. Dryatraol D features a rare spiro [benzofuran-2',5″-furan] backbone. Dryatraols E-I are five undescribed adducts with a butyrylphloroglucinol or filicinic acid incorporated into the germacrene-type sesquiterpene via a pyran ring. These undescribed structures were determined by comprehensively analysing the spectroscopic data, X-ray diffraction results, and electronic circular dichroism calculations. The result of in vitro antiviral activity evaluation indicated that dryatraol C displayed the strongest antiviral effect against both respiratory syncytial virus and influenza A virus (H1N1), with IC50 values of 11.9 µM and 5.5 µM, respectively. Dryatraols F-H exhibited considerable inhibitory activity against herpes simplex virus type 1 (HSV-1), with IC50 values ranging from 2.6 to 6.3 µM. Analysis of the inhibitory mechanism using a time-of-addition assay revealed that dryatraol G may inhibit the replication of HSV-1 by interfering with the late stage of the viral life cycle.

Direct C-H Thiolation for Selective Cross-Coupling of Arenes with Thiophenols via Aerobic Visible-Light Catalysis.

An aerobic metal-free, visible-light-induced regioselective thiolation of phenols with thiophenols is reported. The cross-coupling protocol exhibits great functional group tolerance and high regioselectivity. Mechanistic studies reveal that the disulfide radical cation plays a crucial role in the visible-light catalysis of aerobic thiolation. Simply controlling the equivalent ratio of substrates enables the selective formation of sulfide or sulfoxide products with high activity in a one-pot reaction.

Thiol Activation toward Selective Thiolation of Aromatic C-H Bond.

Direct C-S bond coupling is an attractive way to construct aryl sulfur ether, a building block for a variety of biological active molecules. Herein, we disclose an effective model for regioselective thiolation of the aromatic C-H bond by thiol activation instead of arene activation. Strikingly, this method has been applied into anisole derivatives that are not available in the arene activation approach to forge a single thioether isomer with high reactivity.

Regioselective Ortho Amination of an Aromatic C-H Bond by Trifluoroacetic Acid via Electrochemistry.

A trifluoroacetic acid-facilitated ortho amination of alkoxyl arene has been established via anodic oxidation in an undivided cell. In the absence of any additional metal or oxidant reagents, a series of aromatic and heteroaromatic amine derivatives have been synthesized in good to excellent yields. Our findings reveal the possibility of achieving complete ortho-selective amination of a simple arene, which emerges as an efficient route for facile and large-scale organic synthesis.

Photoelectrochemical cell for P-H/C-H cross-coupling with hydrogen evolution.

Photoelectrochemistry enables the formation of a variety of active intermediates for organic synthesis in an environmentally friendly manner. Herein, a photoelectrochemical cell is fabricated to realize activation of P-H/C-H bonds for cross-coupling hydrogen evolution. As compared with an electrochemical cell, nearly 90% external bias input is saved to drive the C-P bond construction with good to excellent yields.

The transformation of triclosan by laccase: Effect of humic acid on the reaction kinetics, products and pathway.

This study systematically explored the effect of humic acid (HA) (as model of natural organic matter) on the kinetics, products and transformation pathway of triclosan (TCS) by laccase-catalyzed oxidation. It was found that TCS could be effectively transformed by laccase-catalysis, with the apparent second-order rate constant being 0.056 U-1 mL min-1. HA inhibited the removal rate of TCS. HA-induced inhibition was negatively correlated with HA concentration in the range of 0-10 mg L-1 and pH-dependent from 3.5 to 9.5. FT-IR and 13C NMR spectra showed a decrease of aromatic hydroxyl (phenolic) groups and an increase of aromatic ether groups, indicating the cross-linking of HA via C-O-C and C-N-C bonds during enzyme-catalyzed oxidation. Ten principle oxidative products, including two quinone-like products (2-chlorohydroquinone, 2-chloro-5-(2,4-dichlodichlorophenoxy)-(1,4)benzoquinone), one chlorinated phenol (2,4-dichlorophenol (2,4-DCP)), three dimers, two trimmers and two tetramers, were detected by gas chromatograghy/mass spectrometry (GC-MS) and high performance liquid chromatography/quadrupole time-of-flight/mass spectrometry (HPLC/Q-TOF/MS). The presence of HA induced significantly lesser generation of self-polymers and enhanced cross-coupling between HA and self-polymers via C-O-C, C-N-C and C-C coupling pathways. A plausible transformation pathway was proposed as follows: TCS was initially oxidized to form reactive phenoxyl radicals, which self-coupled to each other subsequently by C-C and C-O pathway, yielding self-polymers. In addition, the scission of ether bond was also observed. The presence of HA can promote scission of ether bond and further oxidation of phenoxyl radicals, forming hydroxylated or quinone-like TCS. This study shed light on the behavior of TCS in natural environment and engineered processes, as well provided a perspective for the water/wastewater treatment using enzyme-catalyzed oxidation techniques.

Upregulation of microRNA-143 reverses drug resistance in human breast cancer cells via inhibition of cytokine-induced apoptosis inhibitor 1.

Cytokine-induced apoptosis inhibitor 1 (CIAPIN1), originally termed anamorsin, is an anti-apoptotic molecule that acts as a downstream effector of the receptor tyrosine kinase-Ras signaling pathway. Overexpression of CIAPIN1 contributes to multidrug resistance (MDR) and microRNA (miR)-143 is typically considered a tumor suppressor in breast cancer. The present study aimed to evaluate the therapeutic potential of miR-143 as a treatment for drug-resistant breast cancer via the downregulation of CIAPIN1 in vitro. The expression levels of miR-143 were measured using quantitative polymerase chain reaction and the expression levels of CIAPIN1 were detected via western blot analysis. Bioinformatic analyses was additionally conducted to search for miR-143, which may potentially target CIAPIN1. Luciferase reporter plasmids were created and used to verify direct targeting. In addition, Taxol-induced drug-resistant (TDR) breast cancer cell proliferation was evaluated using the Cell Counting Kit-8 assay in vitro. The present study identified an inverse association between miR-143 and CIAPIN1 protein expression levels in breast cancer MCF-7, MDA-MB-231 and MDA-MB-453 TDR cells. Specific targeting sites for miR-143 in the 3'-untranslated region of the CIAPIN1 gene were identified, which exhibit the ability to regulate CIAPIN1 expression. It was revealed that the repression of CIAPIN1 via miR-143 suppressed the proliferation of breast cancer TDR cells. The findings of the present study verified the role of miR-143 as a tumor suppressor in breast cancer MDR via inhibition of CIAPIN1 translation.

Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFß1 and miR-29 pathways.

Interleukin 6 (IL-6) has been shown to be an important regulator of cardiac interstitial fibrosis. In this study, we explored the role of interleukin-6 in the development of diabetic cardiomyopathy and the underlying mechanisms. Cardiac function of IL-6 knockout mice was significantly improved and interstitial fibrosis was apparently alleviated in comparison with wildtype (WT) diabetic mice induced by streptozotocin (STZ). Treatment with IL-6 significantly promoted the proliferation and collagen production of cultured cardiac fibroblasts (CFs). High glucose treatment increased collagen production, which were mitigated in CFs from IL-6 KO mice. Moreover, IL-6 knockout alleviated the up-regulation of TGFß1 in diabetic hearts of mice and cultured CFs treated with high glucose or IL-6. Furthermore, the expression of miR-29 reduced upon IL-6 treatment, while increased in IL-6 KO hearts. Overexpression of miR-29 blocked the pro-fibrotic effects of IL-6 on cultured CFs. In summary, deletion of IL-6 is able to mitigate myocardial fibrosis and improve cardiac function of diabetic mice. The mechanism involves the regulation of IL-6 on TGFß1 and miR-29 pathway. This study indicates the therapeutic potential of IL-6 suppression on diabetic cardiomyopathy disease associated with fibrosis.

Silencing of MICAL-L2 suppresses malignancy of ovarian cancer by inducing mesenchymal-epithelial transition.

Ovarian cancer remains the disease with the highest associated mortality rate of gynecologic malignancy due to cancer metastasis. Rearrangement of actin cytoskeleton by cytoskeleton protein plays a critical role in tumor cell metastasis. MICAL-L2, a member of MICAL family, can interact with actin-binding proteins, regulate actin cross-linking and coordinate the assembly of adherens junctions and tight junctions. However, the roles of MICAL-L2 in tumors and diseases have not been explored. In this study, we found that MICAL-L2 protein is significantly up-regulated in ovarian cancer tissues along with FIGO stage and associated with histologic subgroups of ovarian cancer. Silencing of MICAL-L2 suppressed ovarian cancer cell proliferation, migration and invasion ability. Moreover, silencing of MICAL-L2 prevented nuclear translocation of ß-catenin, inhibited canonical wnt/ß-catenin signaling and induced the mesenchymal-epithelial transition (MET). Taken together, our data indicated that MICAL-L2 may be an important regulator of epithelial-mesenchymal transition (EMT) in ovarian cancer cells and a new therapeutic target for interventions against ovarian cancer invasion and metastasis.

SERPINA3 promotes endometrial cancer cells growth by regulating G2/M cell cycle checkpoint and apoptosis.

Endometrial carcinoma (EC) is the most common gynecologic cancer worldwide and is one of the leading causes of death in women. Therefore, it is urgent to elucidate the pathological mechanisms of EC. SERPINA3 is a member of the serpin super-family of protease inhibitors. Its aberrant expression has been observed in various tumor cells. However, its clinical significance and biological function in endometrial cancer remains unknown. In the present study, we demonstrated that SERPINA3 expression was significantly up-regulated in EC samples and was closely correlated with lower differentiation, higher stage, positive lymph node or vascular thrombosis and negative estrogen receptor (ER), indicating a poor prognosis. We then demonstrated that SERPINA3 promoted EC cells proliferation by regulating G2/M checkpoint in cell cycle and inhibited cells apoptosis, and we further uncovered that the pro-proliferative effect of SERPINA3 on EC was likely ascribed to the activation of MAPK/ERK1/2 and PI3K/AKT signaling. The results of our study may provide insight into the application of SERPINA3 as a novel predictor of clinical outcomes and a potential therapeutic target of EC.

Scutellarin exerts its anti-hypertrophic effects via suppressing the Ca2+-mediated calcineurin and CaMKII signaling pathways.

Scutellarin is a flavonoid extracted from a traditional Chinese herb, Erigeron breviscapus Hand Mazz, which has been broadly used in treating various cardiovascular diseases. In this study, we investigated its effect on cardiac hypertrophy and the underlying mechanism. Both in vitro and in vivo cardiac hypertrophy models were employed to explore the anti-hypertrophic action of scutellarin. We found that scutellarin significantly suppressed the hypertrophic growth of neonatal cardiac myocytes exposed to phenylephrine (PE) and mouse heart subjected to pressure overload induced by aortic banding, accompanied with the decreased expression of hypertrophic markers beta-myosin heavy chain and atrial natriuretic peptide. We then measured the change of free intracellular calcium using laser scanning confocal microscope. We found that scutellarin alleviated the increment of free intracellular calcium during cardiac hypertrophy either induced by PE or aortic banding. The expression of calcium downstream effectors calcineurin and phosphorylated calmodulin kinase II (CaMKII) were significantly suppressed by scutellarin. Our study indicated that scutellarin exerts its anti-hypertrophic activity via suppressing the Ca(2+)-mediated calcineurin and CaMKII pathways, which supports the observation that clinical application of scutellarin is beneficial for cardiovascular disease patients.

Effects of Tai Chi exercise on patients with type 2 diabetes.

This study investigated the effects of Tai Chi exercise on the levels of blood glucose, insulin and insulin receptors of patients with type 2 diabetes. Twelve subjects aged 58-75 years old (66.5 +/- 8.5 years) with type 2 diabetes participated in the study. They were trained with the protocol of Tai Chi exercise for 8 weeks. Blood glucose, serum insulin, and insulin receptor activity were measured before and after the 8-week intervention and immediately after a single bout exercise of Tai Chi after the protocol. The results showed that by 8 weeks of Tai Chi exercise, the blood glucose decreased (p < 0.05), while high- and low-affinity insulin receptor numbers (r1, r2) and low-affinity insulin receptor binding capacity (R2) increased. Serum insulin increased (p < 0.05) but was still within the normal range. After the single bout Tai Chi exercise, blood glucose, high- and low-affinity insulin receptor numbers (r1, r2), and their binding capacity (R1, R2) increased (p < 0.05), while serum insulin did not change. The 8-week Tai Chi intervention therefore showed benefits on health status of patients with type 2 diabetes.