High urea induces anxiety disorders associated with chronic kidney disease by promoting abnormal proliferation of OPC in amygdala.

Chronic kidney disease (CKD) with anxiety disorder is of a great concern due to its high morbidity and mortality. Urea, as an important toxin in CKD, is not only a pathological factor for complications in patients with CKD, but also is accumulated in the brain of aging and neurodegenerative diseases. However, the pathological role and underlying regulatory mechanism of urea in CKD related mood disorders have not been well established. We previously reported a depression phenotype in mice with abnormal urea metabolism. Since patients with depression are more likely to suffer from anxiety, we speculate that high urea may be an important factor causing anxiety in CKD patients. In adenine-induced CKD mouse model and UT-B-/- mouse model, multiple behavioral studies confirmed that high urea induces anxiety-like behavior. Single-cell transcriptome revealed that down-regulation of Egr1 induced compensatory proliferation of oligodendrocyte progenitor cells (OPC). Myelin-related signaling pathways of oligodendrocytes (OL) were change significant in the urea accumulation amygdala. The study showed that high urea downregulated Egr1 with subsequent upregulation of ERK pathways in OPCs. These data indicate that the pathological role and molecular mechanism of high urea in CKD-related anxiety, and provide objective serological indicator and a potential new drug target for the prevention and treatment of anxiety in CKD patients.

Oridonin Delays Aging Through the AKT Signaling Pathway.

Aging is a major risk factor for chronic diseases and disability in humans. Nowadays, no effective anti-aging treatment is available clinically. In this study, oridonin was selected based on the drug screening strategy similar to Connectivity MAP (CMAP) but upon transcriptomes of 102 traditional Chinese medicines treated cell lines. Oridonin is a diterpenoid isolated from Rabdosia rubescens. As reported, Oridonin exhibits a variety of pharmacological activities, including antitumor, antibacterial and anti-inflammatory activities. Here, we found that oridonin inhibited cellular senescence in human diploid fibroblasts (2BS and WI-38), manifested by decreased senescence-associated ß-galactosidase (SA-ß-gal) staining. Compared with the elderly control group, the positive cell rate in the oridonin intervention group was reduced to 48.5%. Notably, oridonin prolonged the lifespan of yeast by 48.9%, and extended the average life span of naturally aged mice by 21.6%. Our mice behavior experiments exhibited that oridonin significantly improved the health status of naturally aged mice. In addition, oridonin also delayed doxorubicin-induced cellular senescence and mouse senescence. Compared with the model group, the percentage of SA-ß-gal positive cells in the oridonin treatment group was reduced to 59.8%. It extended the average lifespan of mice by 53.8% and improved healthspan. Mechanistically, we showed that oridonin delayed aging through the AKT signaling pathway and reversed the genetic changes caused by doxorubicin-induced cell senescence. Therefore, oridonin is a potential candidate for the development of anti-aging drugs.

Ganoderic acid improves 5-fluorouracil-induced cognitive dysfunction in mice.

5-Fluorouracil (5-FU) is a chemotherapeutic drug with a good anti-cancer effect on various types of cancers, such as colorectal cancer and breast cancer. However, previous studies have found that 5-FU could induce cognitive deficit in clinics. As ganoderic acid, isolated from Ganoderma lucidum, has a protective effect on neurons, this study investigated the effects of ganoderic acid (GA) against 5-FU-induced cognitive dysfunction with a series of behavioral tests and related indicators. Experimental results showed that GA significantly prevented the reduction of spatial and non-spatial memory in 5-FU-treated mice. In addition, GA not only ameliorated the damage to hippocampal neurons and mitochondrial structure, but also significantly improved abnormal protein expression of mitochondrial biogenesis related marker PGC-1α, and mitochondrial dynamics related markers MFN2, DRP1 and FIS1 in the hippocampi of 5-FU-treated mice. Moreover, GA could up-regulate the expression of neuronal survival and growth-related proteins, such as BDNF, p-ERK, p-CREB, p-Akt, p-GSK3ß, Nrf2, p-mTOR, and p-S6, in the hippocampi of 5-FU-treated mice. These results suggest that GA could prevent cognitive dysfunction in mice treated with 5-FU via preventing mitochondrial impairment and enhancing neuronal survival and growth, which provide evidence for GA as a promising adjunctive therapy for chemotherapy related cognitive impairment in clinics.

An organophosphorus-mediated cross-Rauhut-Currier/Wittig domino reaction for the efficient synthesis of trisubstituted cyclopentenes.

An efficient organophosphorus-mediated cross-Rauhut-Currier/Wittig domino reaction of vinyl ketones with chalcones has been developed for the synthesis of trisubstituted cyclopentenes. The new synthetic method has the advantages of mild reaction conditions, high efficiency, environmental friendliness and satisfactory yields.

Cleavage factor Im 25 as a potential biomarker for prognosis of colorectal cancer.

BACKGROUND: Cleavage factor Im 25 (CFIm25) affects the prognosis and progression of cancer by regulating alternative polyadenylation; however, its role in colorectal cancer remains unclear. METHODS: A standard EnVision tissue microarray was used to evaluate the expression of CFIm25 by immunohistochemistry in 363 patients with colorectal cancer. The correlation between CFIm25 expression and clinicopathological characteristics was analyzed using the χ2 test. Univariate analysis was used to study the relationship between clinicopathological characteristics and patient prognosis. Multivariate analysis was performed using the Cox regression model to identify independent prognostic factors for patients with colorectal cancer. RESULTS: Statistical analysis revealed that CFIm25 expression was significantly associated with vascular invasion (P=0.000), serous invasion (P=0.007), pT stage (P=0.016), and clinical stage (P=0.007). Age, vascular invasion, nerve invasion, serosal invasion, differentiation, clinical stage, recurrence, and CFIm25 expression were significantly correlated with the survival time of colorectal cancer patients (P<0.05). The mean overall survival rate in colorectal cancer patients with decreased CFIm25 expression was only 88.53 months, compared with 110.69 months in the high expression group (P=0.000). Decreased CFIm25 expression indicated a worse prognosis in patients with colorectal cancer. Further analysis by the Cox multivariate model showed that CFIm25 (HR, 0.543; 95% CI: 0.372-0.792; P=0.002) and serosa invasion (HR, 1.470; 95% CI: 1.032-2.094; P=0.033) are independent prognostic factors for colorectal cancer. CONCLUSIONS: Decreased CFIm25 expression indicates a worse prognosis of colorectal cancer patients and could be a novel target for the treatment of colorectal cancer in the future. KEYWORDS: Polyadenylation; survival analysis; colorectal cancer (CRC); CFIm25.

The BRD4 inhibitor JQ1 protects against chronic obstructive pulmonary disease in mice by suppressing NF-κB activation.

OBJECTIVE: To examine the effect of the BRD4 inhibitor JQ1 on mice with chronic obstructive pulmonary disease (COPD) via NF-κB. METHODS: COPD models constructed by exposure to cigarette smoke and intratracheal instillation of lipopolysaccharides (LPS) in mice were treated with JQ1 (15, 25 or 50 mg/kg). HE staining was performed to observe histopathological changes in the lung tissues. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the levels of IL-10, IFN-γ, IL-17, IL-1ß, IL-6, TNF-α, MMP-2, MMP-9, MDA, SOD, T-AOC and HO-1, and gelatin zymography assays were used to examine MMP-2 and MMP-9 activity. A TransAMTM NF-κB p65 detection kit was used to test NF-κB p65/DNA binding activity. Western blotting was conducted to analyze NF-κB p65 in the nucleus and its acetylation. RESULTS: JQ1 dose-dependently improved the histopathological changes in the lung tissues and decreased the mean linear intercept (MLI), destructive index and inflammatory score of the mice with COPD. The mice with COPD showed increased levels of MMP-2, MMP-9, IFN-γ, IL-17, IL-1ß, IL-6 and TNF-α with decreased IL-10 level; these changes were reversed by JQ1 in a dose-dependent manner. In addition, JQ1 reduced the MDA level and increased the SOD, HO-1 and T-AOC levels in mice with COPD, with suppression of NF-κB p65 expression in the nucleus, NF-κB/p65 (Lys310) acetylation and NF-κB p65/DNA binding activity in the lung tissues. CONCLUSION: The BRD4 inhibitor JQ1 can downregulate MMP-2 and MMP-9 expression, reduce inflammatory responses, and alleviate oxidative stress in mice with COPD, and this mechanism might be related to the inhibition of NF-κB.

Association between Interleukin-10 Gene Polymorphisms and Behcet's Disease Susceptibility: Evidence from a Meta-Analysis.

Epidemiological studies have demonstrated that interleukin-10 (IL-10) polymorphisms may be associated with the development of Behcet's disease (BD). However, the published results were inconsistent. Therefore, this meta-analysis was conducted to derive a more precise relationship between IL-10 polymorphisms and BD susceptibility. Online databases (PubMed, Embase, Science Citation Index (SCI), CNKI, and WanFang) were searched to identify eligible studies. Odds ratio (OR) and a 95% confidence interval (CI) were applied to assess the relationship strength between IL-10 -1082A>G (rs1800896), -819T>C (rs1800871), and -592A>C (rs1800872) polymorphisms and BD susceptibility. Publication bias, sensitivity, and cumulative analyses were conducted to measure the robustness of our findings. Finally, fifteen articles (36 independent case-control studies) involving 5,971 patients and 8,913 controls were included. Overall, significant associations between -819T>C polymorphisms and BD risk were observed in the total population (C vs. T: OR = 0.72, 95%CI = 0.67-0.77, P < 0.01, I 2 = 36.6%; TC vs. TT: OR = 0.73, 95%CI = 0.66-0.80, P < 0.01, I 2 = 23.0%; CC vs. TT: OR = 0.52, 95%CI = 0.39-0.70, P < 0.01, I 2 = 53.7%; TC+CC vs. TT: OR = 0.67, 95%CI = 0.61-0.71, P < 0.01, I 2 = 22.1%; and CC vs. TT+TC: OR = 0.66, 95%CI = 0.53-0.82, P < 0.01, I 2 = 57.8%). Moreover, the IL-10 -592 A>C polymorphism and the ACC haplotype exhibited a significant, protective effect against BD susceptibility. In summary, our meta-analysis suggested that IL-10 gene polymorphisms may play a salient role for BD development.

Chemical synthesis and functional characterization of a new class of ceramide analogues as anti-cancer agents.

Deregulation of ceramide metabolism is a hallmark of human cancer. Ceramide analogues thereby represent a new class of anti-cancer agents. We aimed at developing effective and low toxic ceramide analogues and synthesized a new class of ceramide analogues starting from l-threonine. Several analogues exhibit potent cytotoxicity against human cancer cells in vitro with IC50 as low as 4.8 µM. These ceramide analogues decreased xIAP and Bcl-xL level and exhibited significant sensitization activity to overcome human cancer cell resistance to TRAIL, a cancer-selective agent that are being tested in human clinical trials. Furthermore, we determined that these ceramide analogues effectively suppress human cancer xenograft growth in vivo with no significant toxicity at the efficacious dose. Therefore, we have developed a simple and effective method to synthesize functional ceramide analogues using l-threonine as starting material and these analogues have the great potential to be further developed as anti-cancer agents in human cancer therapy.

Band-to-Band Tunneling-Dominated Thermo-Enhanced Field Electron Emission from p-Si/ZnO Nanoemitters.

Thermo-enhancement is an effective way to achieve high performance field electron emitters, and enables the individually tuning on the emission current by temperature and the electron energy by voltage. The field emission current from metal or n-doped semiconductor emitter at a relatively lower temperature (i.e., < 1000 K) is less temperature sensitive due to the weak dependence of free electron density on temperature, while that from p-doped semiconductor emitter is restricted by its limited free electron density. Here, we developed full array of uniform individual p-Si/ZnO nanoemitters and demonstrated the strong thermo-enhanced field emission. The mechanism of forming uniform nanoemitters with well Si/ZnO mechanical joint in the nanotemplates was elucidated. No current saturation was observed in the thermo-enhanced field emission measurements. The emission current density showed about ten-time enhancement (from 1.31 to 12.11 mA/cm2 at 60.6 MV/m) by increasing the temperature from 323 to 623 K. The distinctive performance did not agree with the interband excitation mechanism but well-fit to the band-to-band tunneling model. The strong thermo-enhancement was proposed to be benefit from the increase of band-to-band tunneling probability at the surface portion of the p-Si/ZnO nanojunction. This work provides promising cathode for portable X-ray tubes/panel, ionization vacuum gauges and low energy electron beam lithography, in where electron-dose control at a fixed energy is needed.

A Cascade Dehydrogenative Cross-Coupling/Annulation Reaction of Benzamides with ß-Keto Esters for the Synthesis of Isoquinolinone Derivatives.

A novel cascade DCC/annulation reaction of N-alkoxybenzamides with ß-keto esters has been developed for the synthesis of isoquinolinone derivatives under palladium catalysis. A plausible mechanism involving α-C(sp2)-H activation and a Pd(II)/Pd(IV) catalytic cycle is also proposed.

A cascade C-H functionalization/cyclization reaction of N-arylpyridin-2-amines with α,ß-unsaturated aldehydes for the synthesis of dihydroquinolinone derivatives under rhodium catalysis.

A novel cascade C-H functionalization/cyclization reaction of N-arylpyridin-2-amines with α,ß-unsaturated aldehydes has been developed under rhodium catalysis, affording dihydroquinolinone derivatives in moderate to excellent yields. A plausible mechanism of dual catalytic cycles by rhodium(iii) catalysis is also proposed.

A Four-Component Cascade C-H Functionalization/Cyclization/Nucleophilic Substitution Reaction To Construct α-Functionalized Tetrahydroquinolines by the Strategy of in Situ Directing Group Formation.

A four-component cascade C-H functionalization/cyclization/nucleophilic substitution reactions of anilines, carboxylic anhydrides, propenol, and alkohols have been developed by a strategy of in situ directing group formation, affording an efficient and convenient synthesis of α-alkoxyl tetrahydroquinolines from basic starting materials. A plausible mechanism involving rhodium(III) catalytic C-H functionalization and double nucleophilic attacks is proposed. The nucleophilicity order of some alcohols is also obtained for the cascade reaction.

Cascade C-H Functionalization/Amidation Reaction for Synthesis of Azepinone Derivatives.

A cascade C-H functionalization/amidation reaction of aminobiaryls with diazomalonates has been developed under rhodium catalysis, affording new azepinone derivatives in moderate to excellent yields.

Morita-Baylis-Hillman Reaction of α,ß-Unsaturated Ketones with Allylic Acetates by the Combination of Transition-Metal Catalysis and Organomediation.

An intermolecular Morita-Baylis-Hillman (MBH) reaction of α,ß-unsaturated ketones with allylic acetates under the catalysis of 10 mol % of tetrakis(triphenylphosphine)palladium(0) and mediation of tributylphosphine has been developed in the presence of acetic acid, affording the desired α-coupling products. The MBH reaction has the advantages of good tolerance to many functional groups, excellent regioselectivity and E-stereoselectivity, and moderate to good yields.

Dehydrogenative Cross-Coupling Reaction between N-Aryl α-Amino Acid Esters and Phenols or Phenol Derivative for Synthesis of α-Aryl α-Amino Acid Esters.

A novel dehydrogenative cross-coupling (DCC) reaction between N-arylglycine esters and phenols or 1,3,5-trimethoxybenzene was developed by copper catalysis using di-tert-butyl peroxide (DTBP) as an oxidant. Under optimized conditions, a range of N-arylglycine esters 1 underwent the DCC reaction smoothly with various phenols 2 or 1,3,5-trimethoxybenzene 4 to give desired α-aryl α -amino acid esters 3 or 5, respectively, with high ortho regioselectivities in a moderate to excellent yield. A possible mechanism involving aromatic electrophilic substitution is proposed.

Domino Reactions Containing Different Types of Heck Reactions for Selective 3,3- and 1,3-Diarylations of Propenol with Aryl Halides by Triple Catalysis.

A new domino Heck-isomerization/Saegusa/Heck reaction of propenol with aryl iodides has been developed for the synthesis of 3,3-diaryl propenals by triple transition-metal catalysis. Moreover, we also developed the domino Heck-isomerization/Heck-type reaction of propenol with aryl iodides for the synthesis of 1,3-diaryl propanones by double transition-metal catalysis and the mediation of secondary amine or triple transition metal catalysis and aminocatalysis.

A dehydrogenative cross-coupling reaction between aromatic aldehydes or ketones and dialkyl H-phosphonates for formyl or acylphenylphosphonates.

A novel DCC reaction between aromatic aldehydes or ketones and H-phosphonates has been developed for the synthesis of p-formyl or p-acylphenylphosphonates. The synthetic method has excellent para regioselectivities, good yields, and broad substrate scopes and is more benign to the environment. The DCC reaction also tolerates many functional groups, and results in a series of new p-formyl and p-acylphenylphosphonates, which should be important building blocks for the synthesis of versatile arylphosphonate derivatives.

Dehydrogenative cross-coupling reaction by cooperative transition-metal and Brønsted acid catalysis for the synthesis of ß-quinolinyl α-amino acid esters.

A novel dehydrogenative cross-coupling (DCC) reaction between methylquinoline derivatives and N-aryl glycine esters was developed by a cooperative catalysis of copper salt and Brønsted acid, affording an efficient synthesis of ß-quinolinyl α-amino acid esters. A plausible mechanism using a proton to activate the methylquinoline derivative and copper(II) to activate N-aryl glycine ester has been proposed.

A cascade alkylarylation reaction of 2-isocyanobiphenyls with simple alkanes for 6-alkyl phenanthridines via dual C(sp3)-H/C(sp2)-H functionalizations.

A cascade alkylarylation reaction of 2-isocyanobiphenyls with simple alkanes for 6-alkyl phenanthridines has been developed through dual C(sp(3))-H/C(sp(2))-H functionalizations. The synthetic method has the advantages of high yields, good compatibility of functional groups and mild reaction conditions, although very unreactive alkanes were involved in the reaction. A plausible mechanism through both copper-catalyzed and DTBP mediated pathways has also been proposed.

Copper-catalyzed dehydrogenative cross-coupling reaction between allylic C-H bonds and α-C-H bonds of ketones or aldehydes.

A dehydrogenative cross-coupling reaction between allylic C-H bonds and the α-C-H bond of ketones or aldehydes was developed using Cu(OTf)2 as a catalyst and DDQ as an oxidant. This synthetic approach to γ,δ-unsaturated ketones and aldehydes has the advantages of broad scope for both ketones and aldehydes as reactants, mild reaction conditions, good yields and atom economy. A plausible mechanism using Cu(OTf)2 as a Lewis acid catalyst was also proposed (DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone; Tf=trifluoromethanesulfonate).