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The hexanucleotide GGGGCC repeat expansion in the intronic region of C9orf72 is the most common cause of Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion-generated toxic RNAs and dipeptide repeats (DPRs) including poly-GR, have been extensively studied in neurodegeneration. Moreover, haploinsufficiency has been implicated as a disease mechanism but how C9orf72 deficiency contributes to neurodegeneration remains unclear. Here, we show that C9orf72 deficiency exacerbates poly-GR-induced neurodegeneration by attenuating non-homologous end joining (NHEJ) repair. We demonstrate that C9orf72 localizes to the nucleus and is rapidly recruited to sites of DNA damage. C9orf72 deficiency resulted in impaired NHEJ repair through attenuated DNA-PK complex assembly and DNA damage response (DDR) signaling. In mouse models, we found that C9orf72 deficiency exacerbated poly-GR-induced neuronal loss, glial activation, and neuromuscular deficits. Furthermore, DNA damage accumulated in C9orf72-deficient neurons that expressed poly-GR, resulting in excessive activation of PARP-1. PARP-1 inhibition rescued neuronal death in cultured neurons treated with poly-GR peptides. Together, our results support a pathological mechanism where C9orf72 haploinsufficiency synergizes with poly-GR-induced DNA double-strand breaks to exacerbate the accumulation of DNA damage and PARP-1 overactivation in C9orf72 ALS/FTD patients.

Kai Bao,1,* Jijun Chen,2,* Ruifang Liu,1,3 Yuanyuan Xiang,1 Wenlong Gao1 1Institution of Epidemiology and Health Statistics, School of Public Health, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 2STD and AIDS Prevention and Control Institute, Lanzhou Municipal Center for Disease Control and Prevention, Lanzhou, Gansu, People’s Republic of China; 3Department of Science and Education, Xi’an No. 5 Hospital, Xi’an, Shanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenlong Gao, Lanzhou University, No. 222 South Tianshui Road, Lanzhou, Gansu, People’s Republic of China, Tel +8613919026975, Email gaowl2019@sina.comObjective: To investigate the prevalence of hepatitis C virus (HCV) infection among hemodialysis (HD) patients in Lanzhou of Northwestern China, we interviewed 565 patients from five randomly sampled HD centers in Lanzhou with a structured questionnaire including sociodemographic characteristics, past medical history and HD-related factors.Methods: The testing results of anti-HCV and HCV-RNA in a recent HD from clinical information system were collected. A generalized estimated equation (GEE) logistic regression model was used to identify the determinants of HCV infection among HD patients.Results: The prevalence of anti-HCV or HCV-RNA infection among HD patients was 1.77% or 1.42% respectively. GEE model showed that history of kidney transplantation (HCV-RNA: OR=19.79, 95%CI: 12.69– 30.85) could dramatically increase the risk of current HCV infection in dialysis patients. Compared with never using of blood products, using of blood products (anti-HCV: OR=2.38, 95%CI: 1.22– 4.64; HCV-RNA: OR=15.23, 95%CI: 1.79– 129.49) could increase the risk of HCV infection in dialysis patients. Moreover, with the increase of HD duration, the risk increased one time or so (anti-HCV: OR=1.83, 95%CI: 1.22– 2.72; HCV-RNA: OR=2.00, 95%CI: 1.11– 3.61). Furthermore, dialysis in multiple hospitals possessed more than three times risk of HCV infection (anti-HCV: OR=3.56, 95%CI: 3.11– 4.08; HCV-RNA: OR=3.35, 95%CI: 1.88– 5.96). Besides, HD patients having the history of acupuncture (HCV-RNA: OR=5.56; 95%CI: 1.16– 26.67) or surgery (HCV-RNA: OR=6.39; 95%CI: 2.86– 14.29) caused an about-six-times risk of current infections.Conclusion: It could be concluded that the prevalence of HCV infection was mild and using of blood products or kidney transplantation, long dialysis duration, dialysis in multiple hospitals, surgery or acupuncture treatment were some risk factors of HCV infection among HD patients in Lanzhou of Northwestern China.Keywords: hemodialysis, hepatitis C virus, generalized estimating equation introduction

Background. Currently, how to successfully control refractory and metastatic diseases remains a fundamental goal for clinicians to improve therapeutic effects for patients with non-small cell lung cancer (NSCLC). Several studies have discovered that TRIM58, a member of tripartite motif protein family, shows antitumor effect in multiple types of cancer. In this study, we aimed to further clarify the molecular regulatory network of TRIM58 and corresponding targets for NSCLC patients. Methods. TRIM58 expression in clinical tumor tissue samples and cancer cell lines was examined. Functional experiments including cellular invasion, cell metastasis, chemoresistance assay, and ubiquitination evaluation experiments were conducted to investigate the interaction between TRIM58 and ZEB1, which is a prime element of transcription factor network that controls epithelial-to-mesenchymal transition. Results. TRIM58 expression was characteristically decreased in NSCLC tumor tissues and cancer cell lines. Functional experiments demonstrated that TRIM58 suppression enhanced malignant biological behaviors including cellular survivability, migration, and invasion, as well as stem-like cellular phenotype of tumor cells. TRIM58 silencing also significantly enhanced the chemoresistance of NSCLC cells to chemoagents. TRIM58-ZEB1 interaction accelerated degradation of ZEB1 protein, thus further leading to the augment of tumor behaviors. Further detailed molecular experiments revealed that the interaction between TRIM58 and ZEB1 was mediated via ubiquitin-proteasome pathway (UPP). Conclusion. TRIM58 suppressed NSCLC through interacting with ZEB1 and promoting ZEB1 protein degradation via UPP. The present research sheds light on the interaction between TRIM58 and ZEB1, and TRIM58/ZEB1 axis might be the potential therapeutic targets of NSCLC.

Objective To investigate the role and mechanism of long noncoding RNA (lncRNA) LOC102640791 in sepsis inflammatory response. Methods The mice model of sepsis was established by intraperitoneal injection of lipopolysaccharide (LPS). The cell model of sepsis was established by treating of RAW264.7 macrophages with LPS. Mice or cells were randomly divided into the control group and the LPS group. The levels of lncRNA and miRNA in serum were detected by microarrays. The levels of LOC102640791 and miR-320-3p were tested by the real time quantitative PCR. The levels of TNF-α, IL-6, IL-8, IL-4 and IL-10 in serum and cell culture supernatant of RAW264.7 were detected by the ELISA. Luciferase reporter gene technology was used to verify the relationship between LOC102640791 and miR-320-3p. Results Compared with the control group, the LPS group had lower expression of LOC102640791 and higher expression of miR-320-3p. Compared with the LPS group, the LPS group with high expression of LOC102640791 and the LPS group with low expression of miR-320-3p had higher expression of pro-inflammatory factors (TNF-α, IL-6 and IL-8) and lower expression of anti-inflammatory factors (IL-4 and IL-10). Wild type LOC102640791 can inhibit the luciferase activity of miR-320-3p. Conclusion LOC102640791 alleviates sepsis inflammatory response by sponging miR-320-5p.

Background: Acute lung injury (ALI) is a clinical syndrome characterized by hyperosmotic pulmonary edema and increased alveolar fluid. Phospholipase C epsilon-1 (PLCE1), identified as a member of phospholipase family, and the relationship between PLCE1 and lung injury is not clear. Objective: To assess the possible role of Phospholipase C Epsilon 1 (PLCE1) in Acute lung injury (ALI) progression and related mechanisms. Materials and methods: The effects of LPS and PLCE1 on cell viability and apoptosis were examined by MTT and flow cytometry. Also, the level of PLCE1 was controlled by transfection of its plasmid and shRNA. The inflammatory response in response to PLCE1 overexpression or ablation was analyzed by quantitative PCR and ELISA assay. And the involvement of PKC and NF-κB signal pathway were detected by Immunoblot. Results: In this study, we developed a LPS-induced ALI cell model. We found PLCE1 was upregulated in LPS-induced pneumonia cells and affected cell viability. Also, knockdown of PLCE1 reduced LPS-induced apoptosis of pneumonia cells. In addition, depletion of PLCE1 suppressed LPS-induced secretion of proinflammatory cytokines in pneumonia cells. Mechanically, we found depletion of PLCE1 inhibited PKC and NF-κB signal pathway, and therefore alleviated LPS-induced ALI. Conclusion: We therefore thought PLCE1 could serve as a promising drug for ALI.

Background. Holmium laser enucleation of the prostate (HoLEP) is considered the standard endoscopic treatment of benign prostatic hyperplasia (BPH), but traditional HoLEP surgery will cause some postoperative complications. This study was attempted to evaluate the safety and efficacy of modified two-lobe technique versus traditional three-lobe technique of HoLEP focusing mainly on incidences of retrograde ejaculation (RE) and urinary incontinence (UI). Methods. From March 2014 to February 2017, 191 men with BPH were randomly assigned to two groups: 97 underwent modified two-lobe technique; 94 underwent traditional three-lobe technique. All patients were followed up for 12 months. Primary outcomes were incidences of RE and UI, and secondary outcomes were international prostate symptom score (IPSS), quality of life (QOL), maximal urine flowing rate (MFR), and residual urine among the studied patients. Results. Compared with the traditional technique, patients in the modified group had a statistically significant decrease in frequency of UI (1.03% vs 8.51%, p=0.036) and RE in the 6th month (33.33% vs 63.64%, p=0.030) and 12th month (13.33% vs 50%, p=0.034) and a significant increase in ejaculatory volume in the 6th month (p=0.050) and 12th month (p=0.003). Besides, the modified HoLEP was more beneficial to patients according to the change of QoL score at 1 month (p=0.002), 3 months (p=0.004), 6 months (p=0.026), and 12 months (p=0.015). Conclusions. The modified two-lobe technology of HoLEP reduced the incidence of RE and UI, which improved the quality of life of the patients after surgery compared to the traditional three-lobe technology. This trial is registered with ChiCTR1800018553.

It is still illusive that the origination and contribution of different primary tumor sites in Colorectal Cancer (CRC). A total 1039 consecutive CRC patient’s profiles were collected and investigated the prediction role of multiple biomarkers during survival period. The correlation and survival analysis were applied to explore the prognostic value of clinical traits (primary tumor sites, and tumor subtypes, the incidence rate) and multiple biomarkers. The sigmoid and rectum (73%) demonstrated the highest incidence rate among other primary tumor sites (27%). Tubular adenocarcinoma, mainly rise from the terminal bowel tumor sites, has significantly worse clinical outcome, lower 5-year survival rate and shorter overall survival time. Serum level of CA19-9 was significantly positive correlated with sigmoid and rectum originated-CRC (Cor =0.88, p=2.2e-16). Higher serum level of CA19-9 (>37 U/mL) was significantly associated with terminal tumor sites, tubular adenocarcinoma and tumor with non-infiltrating. It could be applied for the precise diagnosis of CRC and terminal bowel cancer, especially in the tubular adenocarcinoma. Therefore, terminal tumor sites (sigmoid and rectum) demonstrated potential prognostic value in early screening for CRC patients. CA19-9 could be a promising biomarker for the diagnosis of terminal colorectal cancer, especially for the Tubular adenocarcinomas originated from sigmoid and rectum, and improve the clinical outcome.

Background: It is still illusive that the origination and contribution of different primary tumor sites in Colorectal Cancer (CRC). Methods: A total 1039 consecutive CRC patient’s profiles were collected to discover the prediction role of multiple biomarkers in this cohort study. Multiple serum biomarkers were tested and tracked during survival period. The correlation and survival analysis were applied to explore the prognostic value of clinical traits (primary tumor sites, and tumor subtypes, the incidence rate) and multiple biomarkers for forecasting patient’s overall clinical.Results: The sigmoid and rectum (73%) demonstrated the highest incidence rate among primary tumor sites (27%). Tubular adenocarcinoma, mainly rise from the terminal bowel tumor sites, has significantly worse clinical outcome, lower 5-year survival rate and shorter overall survival time. Serum level of CA19-9 was significantly positive correlated with sigmoid and rectum originated-CRC (Cor =0.88, p=2.2e-16). Higher serum level of CA19-9 (>37 U/mL) was significantly associated with terminal tumor sites, tubular adenocarcinoma and tumor with non-infiltrating. It could be applied for the precise diagnosis of CRC and terminal bowel cancer, especially in the tubular adenocarcinoma. Results: The sigmoid and rectum (73%) demonstrated the highest incidence rate among primary tumor sites (27%). Tubular adenocarcinoma, mainly rise from the terminal bowel tumor sites, has significantly worse clinical outcome, lower 5-year survival rate and shorter overall survival time. Serum level of CA19-9 was significantly positive correlated with sigmoid and rectum originated-CRC (Cor =0.88, p=2.2e-16). Higher serum level of CA19-9 (>37 U/mL) was significantly associated with terminal tumor sites, tubular adenocarcinoma and tumor with non-infiltrating. It could be applied for the precise diagnosis of CRC and terminal bowel cancer, especially in the tubular adenocarcinoma. Conclusions: Therefore, terminal tumor sites (sigmoid and rectum) demonstrated potential prognostic value in early screening for CRC patients. CA19-9 could be a promising biomarker for the diagnosis of terminal colorectal cancer, especially for the Tubular adenocarcinomas originated from sigmoid and rectum, and improve the clinical outcome.

The congenital intellectual disability (ID)-causing gene mutations remain largely unclear, although many genetic variations might relate to ID. We screened gene mutations in Chinese Han children suffering from severe ID and found a single-nucleotide polymorphism (SNP) in the 5′-untranslated region (5′-UTR) of fibroblast growth factor 13 (FGF13) mRNA (NM_001139500.1:c.-32c>G) shared by three male children. In both HEK293 cells and patient-derived induced pluripotent stem cells, this SNP reduced the translation of FGF13, which stabilizes microtubules in developing neurons. Mice carrying the homologous point mutation in 5′-UTR of Fgf13 showed delayed neuronal migration during cortical development, and weakened learning and memory. Furthermore, this SNP reduced the interaction between FGF13 5′-UTR and polypyrimidine-tract-binding protein 2 (PTBP2), which was required for FGF13 translation in cortical neurons. Thus, this 5′-UTR SNP of FGF13 interferes with the translational process of FGF13 and causes deficits in brain development and cognitive functions.

To evaluate the phylogenetic patterns of the distribution and evolution of plant secondary metabolites (PSMs), we selected 8 classes of PSMs and mapped them onto an updated phylogenetic tree including 437 families of seed plants. A significant phylogenetic signal was detected in 17 of the 18 tested seed-plant clades for at least 1 of the 8 PSM classes using the D statistic. The phylogenetic signal, nevertheless, indicated weak clustering of PSMs compared to a random distribution across all seed plants. The observed signal suggests strong diversifying selection during seed-plant evolution and/or relatively weak evolutionary constraints on the evolution of PSMs. In the survey of the current phylogenetic distributions of PSMs, we found that multiple origins of PSM biosynthesis due to external selective forces for diverse genetic pathways may have played important roles. In contrast, a single origin of PSMs seems rather uncommon. The distribution patterns for PSMs observed in this study may also be useful in the search for natural compounds for medicinal purposes.

A novel, secondary amide activation strategy has been developed through the in situ generation of ylides from amides and diazoacetates. Under the developed reaction conditions, Mn-catalyzed ylide formation and interception reaction by sulfonamide delivered a variety of N-sulfonylamidines. Notably, when highly active Zn(OTf)2 was used as the catalyst, further N–H insertion products were obtained. In contrast with traditional methods, our amide activation strategy is distinguished by accessible starting material, inexpensive catalyst, and broad substrate scope.

In this account, we describe our recent progress on transition-metal-free-catalyzed cross-coupling reactions using tetrabutylammonium iodide (TBAI) as the catalyst and tert-butyl hydroperoxide (TBHP) as the oxidant. A rich variety of important organic compounds including α-acyloxy ethers, tert-butyl peresters, allylic esters, amides, α-amino nitriles, fully substituted pyrazoles, N-sulfonyl formamidines, α-amino acid esters, cyanomethyl esters, N-nitrosamines, and 3-acyloxy-2,3-dihydrobenzofurans have been successfully achieved in high chemoselectivity. Mechanistic studies suggested that TBAI could decompose TBHP to t BuO. and t BuOO. or be oxdized to (hypo)iodite by TBHP.

AIMS: Elevation of arginase activity has been linked to vascular dysfunction in diabetes and hypertension by a mechanism involving decreased nitric oxide (NO) bioavailability due to L-arginine depletion. Excessive arginase activity also can drive L-arginine metabolism towards the production of ornithine, polyamines, and proline, promoting proliferation of vascular smooth muscle cells and collagen formation, leading to perivascular fibrosis. We hypothesized that there is a specific involvement of arginase 1 expression within the vascular endothelial cells in this pathology. METHODS AND RESULTS: To test this proposition, we used models of type 2 diabetes and metabolic syndrome. Studies were performed using wild type (WT), endothelial-specific arginase 1 knockout (EC-A1(−)(/)(−)) and littermate controls(A1(con)) mice fed high fat-high sucrose (HFHS) or normal diet (ND) for 6 months and isolated vessels exposed to palmitate-high glucose (PA/HG) media. Some WT mice or isolated vessels were treated with an arginase inhibitor, ABH [2-(S)-amino-6-boronohexanoic acid. In WT mice, the HFHS diet promoted increases in body weight, fasting blood glucose, and post-prandial insulin levels along with arterial stiffening and fibrosis, elevated blood pressure, decreased plasma levels of L-arginine, and elevated L-ornithine. The HFHS diet or PA/HG treatment also induced increases in vascular arginase activity along with oxidative stress, reduced vascular NO levels, and impaired endothelial-dependent vasorelaxation. All of these effects except obesity and hypercholesterolemia were prevented or significantly reduced by endothelial-specific deletion of arginase 1 or ABH treatment. CONCLUSION: Vascular dysfunctions in diet-induced obesity are prevented by deletion of arginase 1 in vascular endothelial cells or arginase inhibition. These findings indicate that upregulation of arginase 1 expression/activity in vascular endothelial cells has an integral role in diet-induced cardiovascular dysfunction and metabolic syndrome.

The mammalian Sirtuins are a family of highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase. The mammalian Sirtuins family has identified seven different types of sirtuin. Sirtuins 3(SirT3) is localized to mitochondria, and is a multiple functional protein deacylase through deacetylating a variety of substrates. Cellular senescence represents a permanent withdraw from cell cycle in response to diverse stress; it is controlled by the p53 and retinoblastoma protein (RB) tumor suppressors, and constitutes a potent anticancer mechanisms. p53 can be deacetylated by a protein complex containing histone deacetylases (HDAC1). There is possibility that SirT3 may also deacetylate p53. We introduce the recent research on the SirT3-p53 interplay directly and indirectly, and discuss the significance of p53 deacetylation by SirT3 in the aging and cancer. J. Cell. Physiol. 232: 2308-2311, 2017. © 2016 Wiley Periodicals, Inc.

Objective To determine whether regulatory T cells (Tregs) are involved in sevoflurane preconditioning-induced brain protection against cerebral ischemia/reperfusion injury. Methods C57BL/6 mice were preconditioned with sevoflurane and then subjected to the middle cerebral artery occlusion modeling. The brain infarct volume and neurological score were assessed at 48 hours after cerebral reperfusion. Meanwhile, the proportion of Tregs in the spleen was analyzed by flow cytometry. Then, CD25 neutralizing antibody was administrated by intraperitoneal injection, following with the analysis of cerebral ischemia/reperfusion injury and the proportion of Tregs in the spleen after sevoflurane preconditioning. Results Compared with a control group, sevoflurane preconditioning markedly mitigated the cerebral ischemia/reperfusion injury in the mice including the infarct volume and neurological score. In the meantime, sevoflurane preconditioning significantly increased the proportion of Tregs in the spleen at 48 hours after cerebral reperfusion. Compared with the isotype antibody group, the CD25 neutralizing antibody reversed the increase of Tregs induced by sevoflurane preconditioning at 48 hours after reperfusion, which was also associated with the reversal of sevoflurane preconditioning-induced protectetion against cerebral ischemia/reperfusion injury. Conclusion Tregs are involved in sevoflurane preconditioning-induced cerebral protection against ischemia/reperfusion injury.

Pedicularis kansuensis is a poisonous grass and a semi-parasitic plant that has spread rapidly in alpine grasslands in recent years and caused great harm to animal husbandry and the ecological environment. However, little is known about the habitat of P. kansuensis and the key environmental factors that influence its expansion. We assessed the potential impact of climate change on the distribution of P. kansuensis in China under representative concentration pathway (RCP) 2.6 and RCP 8.5 using maximum entropy (MaxEnt) and MigClim for the years 2050 and 2070 and examined key environmental factors affecting P. kansuensis distribution. In total, 118 occurrence points and fourteen selected variables were used for the modeling. The models developed for P. kansuensis showed excellent performance (AUC > 0.9 and TSS > 0.90). The results were as follows. 1) The occupied habitats for P. kansuensis in the four climate scenarios were generally offset in the northward direction. 2) The most important environmental variables influencing the spread of P. kansuensis were altitude, annual precipitation, annual temperature range, precipitation in the warmest quarter and ultraviolet-B radiation seasonality (UVB-2). 3) Under RCP 2.6, the occupied habitat would be increased 0.04% by 2050 and would be increased to 0.51% by 2070. Under RCP 8.5, the average occupied habitat was predicted to increase 0.07% by 2050 and increase to 0.53% by 2070. The increase was relatively higher in the occupied habitats located in the southwestern regions (Sichuan, Xizang and Yunnan) than those in the northwestern regions (Gansu and Xinjiang).

Through the interception of amide ylides with sulfonamides, we herein report the first general example of an intermolecular condensation reaction between sulfonamides and amides. Beyond formamides, this approach was successfully applied to a variety of lactams and linear amides, giving rise to a broad array of (E)-N-sulfonyl amidines.

The aim of the present study was to characterize the roles of two microRNAs (miRNAs), miR-122 and miR-199, in oral lichen planus (OLP). miRNA microarray analysis was performed to detect potential miRNAs involved in OLP, while in-silicon analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemistry (IHC) analyses were utilized to explore the molecular mechanisms underlying the roles of miR-199 and miR-122 in OLP. The results from the microarray and RT-qPCR analyses demonstrated that the expression levels of miR-122 and miR-199 were significantly decreased in the peripheral blood mononuclear cells (PBMCs) collected from the OLP group compared with the control group. In addition, miR-122 and miR-199 directly targeted AKT serine/threonine kinase 1 (AKT1) and mammalian target of rapamycin (mTOR), respectively, by binding to their 3′ UTRs. AKT1 and mTOR were highly expressed in PBMCs derived from OLP patients. In fact, a negative regulatory relationship was observed between miR-122 and AKT1, and between miR-199 and mTOR, with negative correlation coefficients of −0.41 and −0.51, respectively. Furthermore, the protein levels of AKT1, mTOR and microtubule associated protein 1 light chain 3β (LC3B) were upregulated in the OLP group compared with the control group. Finally, overexpression of miR-122 inhibited the expression of AKT1 and LC3B, while overexpression of miR-199 reduced the levels of mTOR and LC3B. In conclusion, the present study demonstrated that miR-199 and miR-122 are implicated in the pathogenesis of OLP by regulating the expression of mTOR and AKT1.

The lack of effective therapies to limit neurovascular injury in ischemic retinopathy is a major clinical problem. This study aimed to examine the role of ureohydrolase enzyme, arginase 1 (A1), in retinal ischemia-reperfusion (IR) injury. A1 competes with nitric oxide synthase (NOS) for their common substrate l-arginine. A1-mediated l-arginine depletion reduces nitric oxide (NO) formation by NOS leading to vascular dysfunction when endothelial NOS is involved but prevents inflammatory injury when inducible NOS is involved. Studies were performed using wild-type (WT) mice, global A1+/− knockout (KO), endothelial-specific A1 KO, and myeloid-specific A1 KO mice subjected to retinal IR injury. Global as well as myeloid-specific A1 KO mice showed worsened IR-induced neuronal loss and retinal thinning. Deletion of A1 in endothelial cells had no effect, while treatment with PEGylated (PEG) A1 improved neuronal survival in WT mice. In addition, A1+/− KO mice showed worsened vascular injury manifested by increased acellular capillaries. Western blotting analysis of retinal tissue showed increased inflammatory and necroptotic markers with A1 deletion. In vitro experiments showed that macrophages lacking A1 exhibit increased inflammatory response upon LPS stimulation. PEG-A1 treatment dampened this inflammatory response and decreased the LPS-induced metabolic reprogramming. Moreover, intravitreal injection of A1 KO macrophages or systemic macrophage depletion with clodronate liposomes increased neuronal loss after IR injury. These results demonstrate that A1 reduces IR injury-induced retinal neurovascular degeneration via dampening macrophage inflammatory responses. Increasing A1 offers a novel strategy for limiting neurovascular injury and promoting macrophage-mediated repair.

Cloves (Syzygium aromaticum), a traditional Chinese medicinal herb, displays broad biological activity. In the present study, the aqueous extract of clove (AEC) was prepared, and its anticancer affects were studied. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetra-zolium (MTS) analysis revealed that AEC was able to inhibit cancer cell growth in vitro on several cancer cell lines; the IC50 is around 150 μg/ml for human pancreatic ASPC-1 and human colon HT-29 cancer cells. Treatment of the cancer cells with AEC also diminished the colony formation significantly in both human pancreatic ASPC-1 cancer cells and human colon HT-29 cancer cells. In vivo study revealed that AEC inhibited the tumor growth significantly in HT-29 xenograft mice model. Transmission electron microscope, flow cytometry assay, and fluorescence microscope analysis confirmed that AEC is capable of inducing cell autophagy. Further study showed that AMPK/ULK pathway plays an important role in AEC-induced autophagy in cancer cells. Analysis of AEC components was performed by liquid chromatograph mass spectrometer approach, and more than nine constitutes were identified in AEC fraction. The study provides evidence that AEC has potential to be developed as a novel anticancer agent or as an adjuvant in cancer chemotherapy.

BACKGROUND A wide range of microRNAs (miRNAs) have been shown to play a significant role in disease regulation. The objective of this study was to explore the role of miR-155 and miR-19a in the regulation of oral lichen planus (OLP). MATERIAL AND METHODS Microarray assay, real-time PCR, Western blot assay, computational analysis, luciferase assay, ELISA, and immunohistochemistry analysis were carried out to investigate the role of miR-155 and miR-19a in OLP. RESULTS According to microarray assay and real-time PCR results, the expression of miR-155 was most significantly decreased among the 16 candidate miRNAs in the OLP group, whereas the expression of miR-19a was most significantly increased. MiR-155 and miR-19a directly targeted endothelial nitric oxide synthase (eNOS) and TLR2, respectively, since only the cells co-transfected with miR-155/wild-type eNOS 3'UTR or cells co-transfected with miR-19a/wild-type TLR2 3'UTR exhibited decreased luciferase activity. In addition, the expression of TLR2 was highly upregulated in OLP, whereas the expression of eNOS was significantly downregulated. A negative correlation was found between miR-19a and TLR2 mRNA, with a coefficient value of -0.40. Similarly, a negative correlation was found between miR-155 and eNOS mRNA, with a coefficient value of -0.54. A lower level of NO, IL-4, IL-5, and IL-10 was observed in OLP, which was also accompanied by a higher level of TNF-α and IFN-γ. Finally, the upregulation in miR-155 directly decreased the expression of eNOS and further inhibited the production of NO. Downregulation of miR-19a directly increased the expression of TLR2. The inhibition of NO production and the enhancement in TLR2 expression synergistically increased the production of TNF-α and IFN-γ, while decreasing the levels of IL-4, IL-5, and IL-10. CONCLUSIONS In this study, the peripheral blood mononuclear cells (PBMCs) from subjects with or without OLP were collected and their gene expression profiles were compared. It was found that OLP changed the expression profile of miR-155 and miR-19a, which in turn directly affected the production of eNOS and TLR2, respectively. In addition, by synergistically inducing an imbalance between Th1 and Th2, the simultaneous deregulation of miR-155/eNOS and miR-19a/TLR2 was responsible for an elevated risk of OLP.

Current treatment strategies for Alzheimer’s disease are mainly symptomatic, development of disease-modifying therapies is urgent needed. Polygonum Multiflorum has been used in Traditional Chinese Medicine for long history in the treatment of dementia. Pharmacological studies suggested Polygonum Multiflorum could improve learning and memory ability in the Alzheimer’s disease models, and inhibit β-amyloid production. 2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside(TSG) is one main bioactive stillbene glycoside of Polygonum Multiflorum . The role of TSG in the Alzheimer’s disease treatment has been investigated. TSG might antagonize acetylcholine deficiency and cognitive performance impairment in the animal models of Alzheimer’s disease. By using β-amyloid precursor protein transgenic mice, TSG ameliorated learning and memory functions associated with reduced formation of senile plaques and β-amyloid deposition, and inhibition of γ- secretase and α-synuclein. In β-amyloid injection rat models, TSG increased cognitive behavior performance, and prevented β-amyloid deposition and synaptic degeneration. In the D-galactose induced aging model, TSG improved ability of learning and memory in the mice, inhibited β-amyloid precursor protein and β-amyloid expressions. Learning and memory deterioration in aged animals was reformed by TSG intervention; its effects might be exerted through β-amyloid precursor protein pathway. TSG was also shown to display antioxidant activity in vitro and in vivo. In conclusion, TSG has been demonstrated to improve cognitive performance of Alzheimer’s disease models through multiple targets strategies, and may be a future perspective in the development of Alzheimer’s disease therapy.

A new coupling reaction between 2-vinylphenols and carboxylic acids was developed to synthesize 3-acyloxy-2,3-dihydrobenzofurans using Bu4NI as a catalyst and t-BuOOH as an oxidant. This simple and practical methodology is notable due to the ability to complete it under metal-free conditions, with easily available precursors, resulting in a product with high atom economy and high functional group tolerance. Upon the basis of experimental observations and literature, a plausible mechanism is proposed.

The Ufm1 conjugation system is a novel ubiquitin-like modification system, consisting of Ufm1, Uba5 (E1), Ufc1 (E2) and poorly characterized E3 ligase(s). RCAD/Ufl1 (also known as KIAA0776, NLBP and Maxer) was reported to function as a Ufm1 E3 ligase in ufmylation (Ufm1-mediated conjugation) of DDRGK1 and ASC1 proteins. It has also been implicated in estrogen receptor signaling, unfolded protein response (UPR) and neurodegeneration, yet its physiological function remains completely unknown. In this study, we report that RCAD/Ufl1 is essential for embryonic development, hematopoietic stem cell (HSC) survival and erythroid differentiation. Both germ-line and somatic deletion of RCAD/Ufl1 impaired hematopoietic development, resulting in severe anemia, cytopenia and ultimately animal death. Depletion of RCAD/Ufl1 caused elevated endoplasmic reticulum stress and evoked UPR in bone marrow cells. In addition, loss of RCAD/Ufl1 blocked autophagic degradation, increased mitochondrial mass and reactive oxygen species, and led to DNA damage response, p53 activation and enhanced cell death of HSCs. Collectively, our study provides the first genetic evidence for the indispensable role of RCAD/Ufl1 in murine hematopoiesis and development. The finding of RCAD/Ufl1 as a key regulator of cellular stress response sheds a light into the role of a novel protein network including RCAD/Ufl1 and its associated proteins in regulating cellular homeostasis.

A novel strategy has been developed for the highly chemo- and stereo-selective synthesis of (Z)-β-perfluoroalkyl enaminones from readily available starting materials via a multicomponent radical reaction involving sequential fluoroalkylation and Kornblum-DeLaMare reaction. Notably, this methodology involves the concurrent cleavage of at least three chemical bonds, including two C-F bonds and one C-X (X = Br or I) bond, as well as the formation of three new bonds, including one C=O bond, one C=C bond and one C-N bond, in one pot.

Through the interception of amide ylides with sulfonamides, we herein report the first general example of an intermolecular condensation reaction between sulfonamides and amides. Beyond formamides, this approach was successfully applied to a variety of lactams and linear amides, giving rise to a broad array of (E)-N-sulfonyl amidines.

Introduction: Obesity is a major contributor to cardiovascular disorders, for which endothelial cell (EC) dysfunction is a hallmark. Obesity-induced EC dysfunction has been linked to dysregulation of the visceral adipose tissue (VAT) resulting in increased secretion of the pro-inflammatory cytokine resistin and alterations in endothelial nitric oxide (NO) producing capacity. However, mechanisms underlying this pathology are not well understood. Hypothesis: Resistin impairs vascular EC function via upregulation of endothelial arginase1 (ARG1) expression and activity, thus limiting L-arginine availability for NO synthesis. Methods: To determine the effect of obesity on EC function, conditioned media prepared from VAT (VAT CM) of high fat diet-induced obese mice, VAT CM from lean mice or resistin (100 ηg/ml) were used to treat mouse aortic endothelial cells (MAEC) and aortic rings for 24 hr. Results: VAT CM from obese mice increased endothelial ARG1 mRNA by 34% and decreased NO level by 32% (p Conclusions: VAT factors and particularly resistin induce vascular endothelial dysfunction via elevated arginase expression/activity. Support : NIH EY11766 & HL70215 & AHA fellowship

Four new C

Glucocorticoid receptor (GR) is identified as a member of nuclear receptor family. To exert its biological action, the ligand bound GR is translocated from the cytoplasm into the nucleus by regulating transcriptional signals of related genes. In clinical practice, the effects of glucocorticoid are often mediated by GR signaling pathways. An increasing number of studies have indicated that GR signaling pathways play an essential role in the proliferation, invasion and prognosis of bladder cancer. Meanwhile, the new-generation selective GR activator improves its anti-tumor effects, and at the same time reduces the adverse reactions of hormones, which probably raises the prospect for the treatment of bladder cancer.