2,4,6-Trihydroxybenzoic Acid-Catalyzed Oxidative Ugi Reactions with Molecular Oxygen via Homo- and Cross-Coupling of Amines.

Metal-free, oxidative four-component Ugi reactions (U-4CRs) were conducted to synthesize dipeptides from two different amines, isocyanides, and carboxylic acids using 2,4,6-trihydroxybenzoic acid catalyst in O2 atmosphere. The organocatalytic U-4CRs proceed via oxidative cross-coupling of benzylamines with other aliphatic or aromatic amines to form imines, followed by condensation with isocyanides and carboxylic acids. The U-4CRs via cross-coupling of amines are rare, and the simple, metal-free procedures are advantageous for further applications in drug and heterocycle syntheses.

Efficacy of low-protein diet in diabetic nephropathy: a meta-analysis of randomized controlled trials.

PURPOSE: We aimed to systematically assess the efficacy of low-protein diet preventing progression of diabetic nephropathy based on randomized controlled trials (RCTs). METHODS: A systematic and electronic search was conducted. Initial searches of literature updated to September 2018 were made using the following databases including CNKI, VIP, Wanfang, Cochrane, PubMed, and Embase using the index words for qualified RCTs. Additional searches were performed to identify linked literature sources. Data of RCTs on low-protein diet versus control diet, efficacy analysis of kidney function, nutritional status or proteinuria were extracted. Random effects model and fixed effects model were applied to combine the data which were further analyzed by Chi-squared test and I2tests. The main outcomes were then analyzed through the use of relative risks (RR), mean difference (MD) and its 95% confidence interval (95% CI). RESULTS: Twenty articles were included in the present meta-analysis with a total of 690 patients in the low-protein diet group (LPD) and a total of 682 patients in the control group. Moderate to strong evidence indicated that LPD was significantly effective for decreasing the urinary albumin excretion rate (SMD:0.62, 95%CI:0.06-1.19) and proteinuria (SMD:0.69, 95%CI:0.22-1.16) versus the control group. No statistical difference, however, was found in glycosylated hemoglobin (SMD:0.17, 95%CI:-0.18-0.51), serum creatinine (SMD:0.20, 95%CI:-0.26-0.66), as well as glomerular filtration rate (SMD:0.21, 95%CI:-0.29-0.71) between the two groups. CONCLUSION: The current meta-analysis reveals an effective role of low-protein diet in improving diabetic nephropathy. However, the small number of involved patients may limit the accuracy of results. High-quality RCTs with a larger sample size in the future are required to confirm the current findings.

Metal-Free Blue Dye Synthesis: Oxidative Coupling of Benzylamines and N,N-Dimethylanilines to Yield 4,4'-Diaminotriarylmethanes in the Presence of Salicylic Acid as a Co-oxidant.

A convenient, novel, and metal-free method for the synthesis of 4,4'-diaminotriarylmethanes (DTMs) is described. This process is based on a one-pot condensation of benzylamines with N,N-dimethylaniline derivatives using 4,6-dihydroxysalicylic acid as a co-oxidant and N-iodosuccinimide as an oxidant. To the best of our knowledge, the present method provides the first reported synthesis of DTMs from benzylamines via oxidative C-N bond cleavage and subsequent double C-C bond formations. The obtained DTMs were then easily converted into a series of blue dyes upon treatment with tetrachloro-1,4-benzoquinone (chloranil). Although the production of triarylmethane dyes tends to require the use of toxic heavy metals, the present method is advantageous in that it is a metal-free and straightforward process.

Development of Albumin Coupled, Cholesterol Stabilized, Lipid Nanoemulsion of Methotrexate, and TNF-α Inhibitor for Improved In Vivo Efficacy Against Rheumatoid Arthritis.

Methotrexate (MTX; an anti-folate) and etanercept (ET; a TNF-α inhibitor) are used against arthritis; however, limitations like short biological half-life, low cutaneous absorption, and acidic instability limit their clinical relevance. Therefore, the aim of the investigation was to develop albumin coupled lipid nanoemulsion of MTX and ET for improved efficacy by virtue of their controlled release and specificity at the arthritic site. This emulsion was prepared by high-speed homogenization and stabilized using cholesterol. Lipid nanoemulsion of MTX and ET (MTX+ET-LNE) was coupled with albumin (MTX+ET-ALNE). MTX+ET-ALNE was characterized on the basis of particle size (410 ± 25.4 nm), PDI (0.160), and zeta potential (+38.6 ± 5.6 mV) and evaluated for pH (6.15), drug content (97.7 ± 2.17%), entrapment efficiency (76 ± 4.6%), in vitro release, and in vitro cytotoxicity. About 82.6 ± 9.60% release of MTX+ET was observed in 24 h from the developed MTX+ET-ALNE which may help maintain therapeutic level of drugs in blood at least for one day. No toxicity was observed when Raw 264.7 cells were treated with MTX+ET-ALNE, and no causalities of mice were observed at experimental in vivo dose (10 mg/kg BW) of MTX+ET in MTX+ET-ALNE-treated group. MTX+ET-ALNE treatment has alleviated arthritic scores and inflammatory cytokines level in a very significant manner when compared with MTX+ET-LNE and MTX+ET solutions. MTX+ET-ALNE-treated group restored histological alterations (cartilage/bone erosion, inflammatory cell infiltration, synovial hyperplasia, and narrower joint space) as observed in diseased treated groups. In conclusion, MTX+ET-ALNE can be opted as efficacious and clinically pertinent option to the current medication systems of arthritis.

[Analysis of urine screening results for school-age children in Zhucheng City of Shandong Province of China in 2013].

OBJECTIVE: To study the significance of urine screening for school-age children by analyzing urine screening results of school-age children from Zhucheng City, Shandong Province, China, in 2013. METHODS: A total of 37 344 school-age children were randomly selected from children 6 to 12 years of age in Zhucheng City. Morning urine was tested by routine screening test, and the children who tested positive were re-tested after two weeks. RESULTS: There were 2 388 children (6.39%) tested positive in the first screening, and 388 children (1.04%) tested positive again in the second screening. The positive rates in the first and second screening tests were 9.52% and 2.01%, respectively, in girls, which were significantly higher than those in boys (3.79% and 0.23%, respectively; P<0.05). Among the children who had positive test results in the second screening, 302 (0.81%) were diagnosed with urinary system diseases. CONCLUSIONS: Urine screening is an effective way for the early detection of some occult kidney diseases, which provides great benefits for early prevention and treatment of kidney diseases in children.

DMAP-catalyzed [3 + 2] and [4 + 2] cycloaddition reactions between [60]fullerene and unmodified Morita-Baylis-Hillman adducts in the presence of Ac2O.

One-step DMAP-catalyzed [3 + 2] and [4 + 2] cycloaddition reactions between C(60) and unmodified Morita-Baylis-Hillman adducts in the presence of Ac(2)O have been developed for the easy preparation of cyclopentene- and cyclohexene-fused [60]fullerene derivatives. When the MBH adducts bear an alkyl group, two different reaction pathways could be controlled selectively depending on the conditions.

Highly stereoselective, one-pot synthesis of azetidines and 2,4-dioxo-1,3-diazabicyclo[3.2.0] compounds mediated by I2.

We report here a convenient method to construct polysubstituted azetidines and 2,4-dioxo-1,3-diazabicyclo[3.2.0] compounds with high stereoselectivities in a one-pot reaction mediated by I2. The tetramethylguanidine (TMG)/I2-mediated formal [2 + 2] cycloaddition reaction of α-amidomalonate 1 with enones 2 affords functionalized azetidine derivatives 4 in moderate to good yields with high diastereoselectivity. When the α-ureidomalonate 5 is used instead of 1, 2,4-dioxo-1,3-diazabicyclo[3.2.0]heptanes 8 and 2,4-dioxo-1,3-diazabicyclo[3.2.0]heptenes 9 can be prepared selectively through the control of solvent and temperature. 2,4-Dioxo-1,3-diazabicyclo[3.2.0]heptanes 8 can further undergo ring-opening reactions with different nucleophilic reagents to afford the corresponding polyfunctionalized azetidine derivatives 13-16 with high steroselectivities.

Long noncoding RNA ANRIL up-regulates CCND1 via sponging miR-98-5p to promote TGF-ß1-induced human airway smooth muscle cell proliferation, migration, and extracellular matrix deposition.

Excessive proliferation and migration of airway smooth muscle cell (ASMC) contribute to asthma pathogenesis. Long noncoding RNAs (lncRNAs) are reported to take part in asthma pathogenesis. This study is targeted at deciphering the role of the lncRNA antisense noncoding RNA in the INK4 locus (ANRIL) in ASMC proliferation, migration and extracellular matrix (ECM) deposition. qRT-PCR was performed to determine ANRIL, miR-98-5p, and cyclin D1 (CCND1) mRNA expression levels in transforming growth factor-ß1 (TGF-ß1)-treated ASMCs. CCK-8 and Transwell assays were employed to examine ASMC proliferation and migration, respectively. Dual-luciferase reporter gene assay and RNA immunoprecipitation assay were carried out for analyzing the targeted relationship of miR-98-5p with ANRIL or CCND1 mRNA 3'-UTR. The levels of CCND1 and ECM proteins (such as fibronectin, COL3A1, and COL1A2) in ASMCs were detected through Western blot. In this work, we found that ANRIL and CCND1 were up-regulated in TGF-ß1-treated ASMCs, whereas miR-98-5p was down-regulated. ANRIL overexpression facilitated the proliferation, ECM deposition and migration of TGF-ß1-induced ASMCs, while knocking down ANRIL had the opposite effect. Furthermore, ANRIL targeted miR-98-5p directly, and CCND1 was miR-98-5p's downstream target. ANRIL indirectly increased CCND1 expression in ASMCs via competitively binding to miR-98-5p. MiR-98-5p inhibition or CCND1 overexpression counteracted the inhibiting effect that ANRIL knockdown had on TGF-ß1-stimulated ASMC proliferation, migration and ECM deposition. In conclusion, ANRIL indirectly up-regulates CCND1 expression by targeting miR-98-5p to promote ASMC proliferation, migration and ECM deposition, thus facilitating the pathogenesis of asthma.

Metal-Free Synthesis of 2-Substituted Quinazolines via Green Oxidation of o-Aminobenzylamines: Practical Construction of N-Containing Heterocycles Based on a Salicylic Acid-Catalyzed Oxidation System.

Conventional quinazoline synthesis methods involve a highly multistep reaction, and often require excess amounts of substrate to control the product selectivity, leading to significant resource wastage. Hence, in this study, from the viewpoint of green chemistry, we developed a novel metal-free synthetic method for 2-substituted quinazoline derivatives by the 4,6-dihydroxysalicylic acid-catalyzed oxidative condensation of o-aminobenzylamines and benzylamines using atmospheric oxygen. In this system, the use of a catalytic amount of BF3‧Et2O (10 mol%) as a Lewis acid successfully led to the efficient oxidative condensation and intramolecular cyclization of these amines, followed by aromatization to afford the corresponding 2-arylquinazolines in up to 81% yield with excellent atom economy and environmental factor. Furthermore, to expand this green oxidation method to gram-scale synthesis, we investigated the development of an oxidation process using salicylic acid itself as an organocatalyst, and established a method for the practical green synthesis of a series of nitrogen-containing heterocycles. We expect that the findings will contribute to the development of practical synthesis methods for pharmaceutical manufacturing and industrial applications, along with further advancements in green chemistry.

4,6-Dihydroxysalicylic Acid-Catalyzed Oxidative Condensation of Benzylic Amines and Aromatic Ketones for the Preparation of 2,4,6-Trisubstituted Pyridines and Its Application to Metal-Free Synthesis of G-Quadruplex Binding Ligands.

4,6-Dihydroxysalicylic acid was activated under air to catalyze the one-pot oxidative condensation reaction of benzylamines with acetophenones in the presence of BF3·Et2O, affording 2,4,6-trisubstituted pyridines in yields of 59-91%. During this metal-free oxidative condensation reaction, the benzylamines not only provided the aryl moiety at the 4-position of the pyridines but also acted as the nitrogen donor. This method can be applied to the metal-free synthesis of G-quadruplex binding ligands by the sequential addition of 4-chlorobutyryl chloride and pyrrolidine to the reaction system of the 2,4,6-trisubstituted pyridine synthesis.

[Association of the Pro12Ala and C1431T polymorphism of the PPAR gamma2 gene and their haplotypes with obesity and type 2 diabetes].

OBJECTIVE: To study the association of the Pro12Ala and C1431T polymorphism of the PPAR gamma2 gene and their haplotypes with obesity and type 2 diabetes in Chinese population. METHODS: PCR-restriction fragment length polymorphism was used to determine the Pro12Ala and C1431T polymorphisms in 207 patients with type 2 diabetes and 101 non-diabetic control subjects. RESULTS: (1) In non-diabetic control population, the Ala allele frequency was 0.064, the T1431 allele frequency was 0.252. Haplotype analysis showed that the Pro12Ala and C1431T polymorphisms were in linkage disequilibrium (Do=0.63, r(2)=0.074), which constituted three major haplotypes Pro-C, Pro-T and Ala-T. (2) There were no significant differences of the distribution frequencies of the Pro12Ala and C1431T polymorphism and their haplotypes between the type 2 diabetes mellitus group and non-diabetic control group (P > 0.05). (3) The Pro12Ala polymorphism was associated with blood pressure and lipidemia in diabetic patients. The Ala allele significantly decreased the diastolic blood pressure of non-obese diabetic patients (P < 0.05), but it did not benefit to the obese diabetic patients for the lipidemia (P < 0.05). The C1431T polymorphism was associated with overweight and obesity in diabetic patients. The T1431 allele frequency in the body mass index > or = 25 layer was significantly higher than that in the body mass index < 25 layer (P < 0.05). CONCLUSION: The Pro12Ala and C1431T polymorphisms of the PPAR gamma2 gene might not be a major etiological factor for type 2 diabetes; the C1431T polymorphism was associated with overweight or obesity in diabetic patients.

Synthesis of Aryl Iodides from Arylhydrazines and Iodine.

A metal- and base-free method is developed for the synthesis of aryl iodides from arylhydrazine hydrochlorides and iodine. A wide variety of aryl iodides can be conveniently synthesized by an equimolar reaction of arylhydrazine hydrochlorides and I2 in dimethyl sulfoxide at 60 °C for 6 h. In the iodination step, arylhydrazines are oxidized by iodine to form arenediazonium salts, which undergo single-electron transfer from iodide anion to give aryl and iodine radicals; subsequent combination of them affords the corresponding aryl iodides.

Metal-Free Oxidative Coupling of Benzylamines to Imines under an Oxygen Atmosphere Promoted Using Salicylic Acid Derivatives as Organocatalysts.

The oxidative coupling of benzylamines proceeds efficiently using salicylic acid derivatives as organocatalysts under an oxygen atmosphere, affording the corresponding N-benzylidenebenzylamines in high yields. Electron-rich salicylic acid derivatives such as 4,6-dimethoxysalicylic acid and 4,6-dihydroxysalicylic acid exhibit excellent catalytic activities for the oxidative coupling of benzylamines to give the corresponding imines. This amine oxidation can also be applied to the synthesis of nitrogen-containing heterocycles such as benzimidazole derivatives. Furthermore, to recycle the catalyst, silica gel supported with 4.7 wt % of 4,6-dihydroxysalicylic acid is prepared, which acts as a recyclable catalyst, oxidizing benzylamine to imine four times successfully.