Type 1 and type 2 diabetes mortality burden: Predictions for 2030 based on Bayesian age-period-cohort analysis of China and global mortality burden from 1990 to 2019.

AIMS: This study assessed diabetes (type 1 and type 2) mortality in China and globally from 1990 to 2019, predicting the next decade's trends. MATERIALS AND METHODS: Data came from the Global Burden of Disease (GBD) database. The annual percentage change (AAPC) in age-standardized mortality rates (ASMR) for diabetes (type 1 and type 2) during 1990-2019 was calculated. A Bayesian age-period-cohort (BAPC) model predicted diabetes (type 1 and type 2) mortality from 2020 to 2030. RESULTS: In China, type 1 diabetes deaths declined from 6,005 to 4,504 cases (AAPC -2.827), while type 2 diabetes deaths rose from 64,084 to 168,388 cases (AAPC -0.763) from 1990 to 2019. Globally, type 1 diabetes deaths increased from 55,417 to 78,236 cases (AAPC 0.223), and type 2 diabetes deaths increased from 606,407 to 1,472,934 cases (AAPC 0.365). Both China and global trends showed declining type 1 diabetes ASMR. However, female type 2 diabetes ASMR in China initially increased and then decreased, while males had a rebound trend. Peak type 1 diabetes deaths were in the 40-44 age group, and type 2 diabetes peaked in those over 70. BAPC predicted declining diabetes (type 1 and type 2) mortality burden in China and globally over the next 10 years. CONCLUSIONS: Type 2 diabetes mortality remained high in China and globally despite decreasing type 1 diabetes mortality over 30 years. Predictions suggest a gradual decrease in diabetes mortality over the next decade, highlighting the need for continued focus on type 2 diabetes prevention and treatment.

Photoredox-Catalyzed Cascade sp2 C-H Bond Functionalization to Construct Substituted Acridine with Diarylamine and Hypervalent Iodine(III) Reagents.

A photocatalyzed cascade double C-C formation via sp2 C-H bond activation of diarylamines with hypervalent iodine diazo reagents was developed. A variety of diarylamines and hypervalent iodine(III) reagents were tolerated well, and a range of substituted acridines with yields ranging from moderate to excellent was provided efficiently. The protocol introduces diazo groups onto diarylamines and enables subsequent late-stage assembly point functionalization with the diazonium structure, forming two new C-C bonds in a sequential fashion.

ALK7 Knockdown Plays a Protective Role on HG-Stimulated MCs through Activation of the Nrf2/HO-1 Pathway.

Objective: Activin receptor-like kinase 7 (ALK7) is a member of the ALK family that has a key role in diabetes. However, the role of ALK7 in diabetic nephropathy (DN) remains unclear. Methods: Herein, we evaluated the effects of ALK7 on mesangial cells (MCs). MCs were transfected with si-ALK7 or pcDNA3.0-ALK7, and then stimulated with 40 mM glucose for 24 h. Cell proliferation was detected by MTT assay. Relative ROS level was detected using DCFH-DA staining. The contents of inflammatory cytokines were determined by ELISA. Western blot analysis was used to determine the expression levels of FN, Col IV, Nrf2, and HO-1 in MCs. Results: Our results showed that ALK7 expression was induced by HG in MCs. Knockdown of ALK7 inhibited HG-induced cell proliferation. The HG-induced ROS was mitigated by si-ALK7 with decreased ROS level and NOX activity. In addition, ALK7 knockdown exhibited anti-inflammatory activity in HG-stimulated MCs. Moreover, ALK7 knockdown attenuated fibronectin (FN) and collagen IV (Col IV) expression in MCs. Knockdown of ALK7 enhanced Nrf2/HO-1 pathway in MCs. Inhibition of Nrf2 reversed the protective effects of ALK7 knockdown on HG-stimulated MCs. Conclusion: ALK7 knockdown exerted protective effects on HG-stimulated MCs through activation of the Nrf2/HO-1 pathway. Thus, targeting ALK7 might be a therapeutic approach for the treatment of DN.

Acid-Promoted Redox-Annulation toward 1,2-Disubstituted-5,6-dihydropyrrolo[2,1-α]isoquinolines: Synthesis of the Lamellarin Core.

An efficient synthesis of a variety of 1,2-disubstituted-5,6-dihydropyrrolo[2,1-α]isoquinoline derivatives via an acid-promoted cyclization reaction between 1,2,3,4-tetrahydroisoquinoline (THIQ) and substituted α,ß-unsaturated aldehyde derivatives is reported. This cycloaddition allows access to structurally diverse multisubstituted dihydropyrrolo[2,1-α]isoquinolines in moderate to good yields, which was the core scaffold of marine natural alkaloid lamellarins.

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.

Synthesis of [1,2,3]Triazolo-[1,5-a]quinoxalin-4(5H)-ones through Photoredox-Catalyzed [3 + 2] Cyclization Reactions with Hypervalent Iodine(III) Reagents.

An efficient synthesis of a variety of [1,2,3]triazolo-[1,5-a]quinoxalin-4(5H)-ones via a [3 + 2] cyclization reaction by photoredox catalysis between quinoxalinones and hypervalent iodine(III) reagents is reported. A range of quinoxalinones and hypervalent iodine(III) reagents were tolerated well. This cyclization reaction allows access to structurally diverse [1,2,3]triazolo-[1,5-a]quinoxalin-4(5H)-ones in moderate to good yields.

An electrochemiluminescence aptasensor for diethylstilbestrol assay based on resonance energy transfer between Ag3PO4-Cu-MOF(II) and silver nanoparticles.

In this work, a novel electrochemiluminescence (ECL) aptasensor based on the resonance energy transfer (RET) effect between Ag3PO4-Cu-MOF (ii) and silver nanoparticles (Ag NPs) is proposed. The ECL emission spectra of Ag3PO4-Cu-MOF and the ultraviolet absorption spectra of Ag NPs showed a good spectral overlap. Based on this, we designed an "on-off-on" ECL sensing strategy for the sensitive and specific detection of diethylstilbestrol (DES). Under the optimal conditions, the linear range of the sensor for DES detection was 1.0 × 10-12-1.0 × 10-4 M, with a detection limit of 7.2 × 10-13 M (S/N = 3). The method showed simple and fast operation, high sensitivity and selectivity, a strong anti-interference ability and good stability. More importantly, the developed aptasensor exhibited excellent recognition towards residual DES in actual water samples. The sensor has superior measurement capability and potential application value in the field of environment water quality monitoring.

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.

Ampelopsin inhibits high glucose-induced extracellular matrix accumulation and oxidative stress in mesangial cells through activating the Nrf2/HO-1 pathway.

Oxidative stress plays an important role in diabetic nephropathy (DN), which is a diabetic complication. Ampelopsin (AMP) is a natural flavonoid that has been found to possess antidiabetic and antioxidative activities. However, the effect of AMP on DN remains unclear. In this study, we aimed to evaluate the protective effect of AMP on glomerular mesangial cells (MCs) exposed to high glucose (HG). We found that AMP improved HG-caused cell viability reduction in MCs. AMP significantly suppressed the intracellular ROS production and expression levels of ROS producing enzymes NADPH oxidase 2 (NOX2) and NOX4. Increased of NOX activity in HG-stimulated MCs was suppressed by AMP. Pretreatment with AMP inhibited extracellular matrix (ECM) accumulation in HG-stimulated MCs with decreased expression levels of fibronectin (FN) and collagen type IV (Col IV). Furthermore, AMP elevated the expression levels of nuclear Nrf2 and heme oxygenase-1 (HO-1), as well as increased the mRNA levels of Nrf2-driven genes NAD(P)H dehydrogenase quinone-1 (NQO-1) and HO-1 in HG-treated MCs. Knockdown of Nrf2 reversed the protective effects of AMP against HG-induced oxidative stress and EMC accumulation in MCs. In conclusion, these findings indicated that AMP protected MCs from HG-induced oxidative damage and ECM accumulation, which might be mediated by Nrf2/HO-1 pathway.

Identification of biomarkers and mechanisms of diabetic cardiomyopathy using microarray data.

BACKGROUND: The study aimed to uncover the regulation mechanisms of diabetic cardiomyopathy (DCM) and provide novel prognostic biomarkers. METHODS: The dataset GSE62203 downloaded from the Gene Expression Omnibus database was utilized in the present study. After pretreatment using the Affy package, differentially expressed genes (DEGs) were identified by the limma package, followed by functional enrichment analysis and protein- protein interaction (PPI) network analysis. Furthermore, module analysis was conducted using MCODE plug-in of Cytoscape, and functional enrichment analysis was also performed for genes in the modules. RESULTS: A set of 560 DEGs were screened, mainly enriched in the metabolic process and cell cycle related process. Hub nodes in the PPI network were LDHA (lactate dehydrogenase A), ALDOC (aldolase C, fructose-bisphosphate) and ABCE1 (ATP Binding Cassette Subfamily E Member 1), which were also highlighted in Module 1 or Module 2 and predominantly enriched in the processes of glycolysis and ribosome biogenesis. Additionally, LDHA were linked with ALDOC in the PPI network. Besides, activating transcription factor 4 (ATF4) was prominent in Module 3; while myosin heavy chain 6 (MYH6) was highlighted in Module 4 and was mainly involved in muscle cells related biological processes. CONCLUSIONS: Five potential biomarkers including LDHA, ALDOC, ABCE1, ATF4 and MYH6 were identified for DCM prognosis.

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.

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.

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 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.

Synergistic effects of baicalein with cefotaxime against Klebsiella pneumoniae through inhibiting CTX-M-1 gene expression.

BACKGROUND: Generation of extended- spectrum ß- lactamases is one of the major mechanisms by which clinical Klebsiella pneumoniae develop resistance to antibiotics. Combined antibiotics prove to be a relatively effective method of controlling such resistant strains. Some of Chinese herbal active ingredients are known to have synergistic antibacterial effects. This study is aimed to investigate synergistic effects of Chinese herbal active ingredients with cefotaxime on the extended- spectrum ß- lactamase positive strains of Klebsiella pneumoniae, and to analyze mechanism of synergistic action, providing experimental evidence for clinical application of antimicrobial drugs. RESULTS: For total sixteen strains including fifteen strains of cefotaxime resistant K. pneumoniae and one extended- spectrum ß- lactamase positive standard strain, the synergy rates of cefotaxime with baicalein, matrine, and clavulanic acid were 56.3 %, 0 %, and 100 %, respectively. The fractional inhibitory concentration index of combined baicalein and cefotaxime was correlated with the percentage decrease of cefotaxime MIC of all the strains (r = -0.78, p <0.01). In the group of synergy baicalein and cefotaxime, the transcribed mRNA level of CTX-M-1 after treatment of baicalein was decreased significantly (p <0.05). Moreover, the CTX-M-1 mRNA expression percentage inhibition (100 %, 5/5) was significantly higher than non- synergy group (25 %, 1/4) (p <0.05). CONCLUSIONS: Our study demonstrated that baicalein exhibited synergistic activity when combined with cefotaxime against some of extended- spectrum ß- lactamases positive K. pneumoniae strains by inhibiting CTX-M-1 mRNA expression. However, no direct bactericidal or bacteriostatic activity was involved in the synergistic action. Baicalein seems to be a promising novel effective synergistic antimicrobial agent.

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.

[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.

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.