Iron-catalyzed stereoselective C-H alkylation for simultaneous construction of C-N axial and C-central chirality.

The assembly of chiral molecules with multiple stereogenic elements is challenging, and, despite of indisputable advances, largely limited to toxic, cost-intensive and precious metal catalysts. In sharp contrast, we herein disclose a versatile C-H alkylation using a non-toxic, low-cost iron catalyst for the synthesis of substituted indoles with two chiral elements. The key for achieving excellent diastereo- and enantioselectivity was substitution on a chiral N-heterocyclic carbene ligand providing steric hindrance and extra represented by noncovalent interaction for the concomitant generation of C-N axial chirality and C-stereogenic center. Experimental and computational mechanistic studies have unraveled the origin of the catalytic efficacy and stereoselectivity.

Nickel-Catalyzed Atroposelective C-H Alkylation Enabled by Bimetallic Catalysis with Air-Stable Heteroatom-Substituted Secondary Phosphine Oxide Preligands.

The catalytic asymmetric construction of axially chiral C-N atropisomers remains a formidable challenge due to their low rotational barriers and is largely reliant on toxic, cost-intensive, and precious metal catalysts. In sharp contrast, we herein describe the first nickel-catalyzed atroposelective C-H alkylation for the construction of C-N axially chiral compounds with the aid of a chiral heteroatom-substituted secondary phosphine oxide (HASPO)-ligated Ni-Al bimetallic catalyst. A wide range of alkenes, including terminal and internal alkenes, were well compatible with the reaction, providing a variety of benzimidazole derivatives in high yields and enantioselectivities (up to 97:3 e.r.). The key to success was the identification of novel HASPOs as highly effective chiral preligands. Mechanistic studies revealed the catalyst mode of action, and in-depth data science analysis elucidated the key features of the responsible chiral preligands in controlling the enantioselectivity.

Interaction of Cyclooxygenase-2 with Helicobacter pylori Induces Gastric Chronic Nonresolving Inflammation and the Formation of Syndrome of Internal Block of Static Blood in Helicobacter pylori-Related Gastric Diseases.

Cyclooxygenase-2 (COX-2) is an inducible enzyme stimulated by various inflammatory factors (IFs). Chronic gastritis is a classic model of "inflammation-cancer transformation" and Helicobacter pylori-related gastric diseases (HPGD) are specific ones of this model. Traditional Chinese Medicine (TCM) syndromes could play a predictive role in gastric histopathological evolution. To search for early warning evidence about "inflammation-cancer transformation," this study is about to explore interaction of COX-2 with Helicobacter pylori (Hp) in HPGD with different TCM syndromes. All included subjects underwent endoscopy and biopsy. Hp infection was detected by rapid urease test and methylene blue staining. Histopathological characteristics and COX-2 expression in gastric mucosa (GM) were, respectively, observed by hematoxylin-eosin and Elivision™ plus. SPSS 18.0 and Stata 11.0 statistical software packages were used for statistical analysis. Results of immunohistochemical staining in this study showed COX-2 expression in Hp-positive patients was stronger than that in Hp-negative ones. Spearman' analysis indicated that degrees of both Hp infection and COX-2 expression were positively correlated with those of gastric inflammation and inflammatory activity. Compared with the relative normal group, both severe dysplasia group and gastric carcinoma group had more severe Hp infection and COX-2 expression. Compared with the nonsyndrome, syndrome of internal block of static blood (IBSB) had higher scores in semiquantitative analysis of COX-2 protein expression among TCM groups. Moreover, multivariate logistics regression analysis suggested that patients with Hp infection could increase the risk of IBSB. These results indicated that COX-2 interacting with Hp could play an important role in transforming gastric chronic nonresolving inflammation into carcinoma in subjects with HPGD, as well as inducing the formation of IBSB. HPGD together with IBSB could be an early warning evidence for GM with histopathological evolution from benign to malignant.

[Influence of warming needling technique on gastrointestinal reaction after hyperthermic intrape-ritoneal chemotherapy in patients with postoperation of colon cancer].

OBJECTIVE: To observe the effect of warming needling therapy on gastrointestinal reaction after hyperthermic intraperitoneal chemotherapy (HIPEC) in patients of spleen and stomach deficiency syndrome after colon cancer surgery. METHODS: A total of 120 cases of HIPEC were randomized into observation group and control group, 60 cases in each. The patients of the two groups all received HIPEC. In the observation group, 1 h before HIPEC, warming needling technique was applied to Zusanli (ST36), Sanyinjiao (SP6) and Yinlingquan (SP9) and the even-needing technique of acupuncture was applied to Neiguan (PC6) for 30 min, and then the intravenous injection with Ondansetron was given 30 min before HIPEC. In the control group, The intravenous injection with Ondansetron was given 30 min before HIPEC. In the two groups, the changes in nausea, vomiting, abdominal distention, diarrhea, total bilirubin (TB), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and KPS score, as well as the average hospitalization length of stay were observed. RESULTS: The total effective rates in the treatment of nausea, vomiting, abdominal distention and diarrhea were 91.67%(55/60), 93.33%(56/60), 80.00%(48/60) and 88.33%(53/60) in the observation group and were 78.33%(47/60), 78.33%(47/60), 63.33%(38/60) and 70.00%(42/60) in the control group respectively, and the total effective rate in the treatment of gastrointestinal reaction of HIPEC in the observation group was obviously higher than that in the control group(P<0.05). The KPS score and curative effect in the observation group was obviously higher than those of the control group(P<0.05), and the average hospitalization length of stay in the observation group was obviously reduced as compared with the control group (P<0.05). There were no significant differences in serum TB, ALT and ALP contents between the two groups after treatment (P>0.05). CONCLUSION: The warming needling technique of acupuncture and moxibustion alleviates the gastrointestinal reaction, improves KPS score and reduces the hospitalization length of stay in HIPEC patients after the surgery of colon cancer and differentiated as the spleen and stomach deficiency in traditional Chinese medicine.

Update on urine as a biomarker in cancer: a necessary review of an old story.

Introduction: Cancer causes thousands of deaths worldwide each year. Therefore, monitoring of health status and the early diagnosis of cancer using noninvasive assays, such as the analysis of molecular biomarkers in urine, is essential. However, effective biomarkers for early diagnosis of cancer have not been established in many types of cancer.Areas covered: In this review, we discuss recent findings with regard to the use of urine composition as a biomarker in eleven types of cancer. We also highlight the use of urine biomarkers for improving early diagnosis.Expert opinion: Urinary biomarkers have been applied for clinical application of early diagnosis. The main limitation is a lack of integrated approaches for identification of new biomarkers in most cancer. The utilization of urinary biomarker detection will be promoted by improved detection methods and new data from different types of cancers. With the development of precision medicine, urinary biomarkers will play an increasingly important clinical role. Future early diagnosis would benefit from changes in the utilization of urinary biomarkers.

Grape Seed Procyanidin B2 Protects Porcine Ovarian Granulosa Cells against Oxidative Stress-Induced Apoptosis by Upregulating let-7a Expression.

Oxidative stress is a causal factor and key promoter of all kinds of reproductive disorders related to granulosa cell (GC) apoptosis that acts by dysregulating the expression of related genes. Various studies have suggested that grape seed procyanidin B2 (GSPB2) may protect GCs from oxidative injury, though the underlying mechanisms are not fully understood. Therefore, whether the beneficial effects of GSPB2 are associated with microRNAs, which have been suggested to play a critical role in GC apoptosis by regulating the expression of protein-coding genes, was investigated in this study. The results showed that GSPB2 treatment protected GCs from a H2O2-induced apoptosis, as detected by an MTT assay and TUNEL staining, and increased let-7a expression in GCs. Furthermore, let-7a overexpression markedly increased cell viability and inhibited H2O2-induced GC apoptosis. Furthermore, the overexpression of let-7a reduced the upregulation of Fas expression in H2O2-treated GCs at the mRNA and protein levels. Dual-luciferase reporter assay results indicated that let-7a directly targets the Fas 3'-UTR. Furthermore, the overexpression of let-7a enhanced the protective effects of GSPB2 against GC apoptosis induced by H2O2. These results indicate that GSPB2 inhibits H2O2-induced apoptosis of GCs, possibly through the upregulation of let-7a.

Effects of genetic variants of the bovine WNT8A gene on nine important growth traits in beef cattle.

WNT-ß-catenin-TCF pathway is involved in carcinogenesis and foetal development. As a member of the WNT gene family, Wnt8A encodes secreted signalling proteins and responds to many biological processes.However, similar research on the effects of genetic variations of Wnt8A gene on growth traits is lacking. Therefore, in this study, polymorphisms of Wnt8A were detected in 396 animals from Chinese Qinchuan cattle using DNA pool sequencing and PCR-RFLP methods. Four novel single-nucleotide polymorphisms (SNPs) of Wnt8A gene were identified, including three mutations in introns (g.T-445C, g.G244C and g.G910A) and one in exon (g.T4922C). Additionally, we examined the associations of four SNPs with growth traits. The results revealed that SNP2 (g.G244C) was significantly associated with shoulder height, hip height, body length, hip width, and body weight (P < 0.05). SNP3 (g.G910A) also displayed notable effects on hip width (P < 0.05). Meanwhile, the haplotype combination CC-GC-GA-CC was strongly associated with heavier, taller and longer animals (P < 0.05). These results show that the Wnt8A gene may be a potential candidate gene, and the SNPs could be used as molecular markers in early marker-assisted selection in beef cattle breeding programmes.

Critical Role of FoxO1 in Granulosa Cell Apoptosis Caused by Oxidative Stress and Protective Effects of Grape Seed Procyanidin B2.

Reactive oxygen species (ROS) are closely related to the follicular granulosa cell apoptosis. Grape seed procyanidin B2 (GSPB2) has been reported to possess potent antioxidant activity. However, the GSPB2-mediated protective effects and the underlying molecular mechanisms in granulosa cell apoptosis process remain unknown. In this study, we showed for the first time that GSPB2 treatment decreased FoxO1 protein level, improved granulosa cell viability, upregulated LC3-II protein level, and reduced granulosa cell apoptosis rate. Under a condition of oxidative stress, GSPB2 reversed FoxO1 nuclear localization and increased its level in cytoplasm. In addition, FoxO1 knockdown inhibited the protective effects of GSPB2 induced. Our findings suggest that FoxO1 plays a pivotal role in regulating autophagy in granulosa cells, GSPB2 exerts a potent and beneficial role in reducing granulosa cell apoptosis and inducing autophagy process, and targeting FoxO1 could be significant in fighting against oxidative stress-reduced female reproductive system diseases.

CA IX is upregulated in CoCl2-induced hypoxia and associated with cell invasive potential and a poor prognosis of breast cancer.

Hypoxia, a common phenomenon during the development of malignant solid tumors including breast cancer, serves to propagate a cascade of molecular pathways triggered by hypoxia-inducible factor-1α (HIF-1α). Carbonic anhydrase IX (CA IX), one of the target genes of HIF-1α, has been reported to be involved in progression of malignant tumors. The objective of this study was to investigate the expression of HIF-1α and CA IX in hypoxia, involvement of CA IX in the regulation of migration and invasion/metastasis and its prognostic significance in breast cancer. We used cobalt chloride (CoCl2) as a hypoxia-mimetic agent and found that the expression of HIF-1α protein, CA IX mRNA and protein, is effectively upregulated, except for HIF-1α mRNA. Data showed that the elevated CA IX expression is closely related to in vitro cell migration and invasion, and the underlying mechanism of this process may be associated with epithelial-mesenchymal transition (EMT). The study of clinical tissue samples also demonstrated that CA IX is an independent prognostic marker that may serve as a useful clinical biomarker for predicting tumor progression and the invasion/metastasis of breast cancer. These results provide further insight into the role of CA IX in tumor progression and put forward further strong evidence as well as new consideration for CA IX target therapy.