LDL receptor-related protein 5 rs648438 polymorphism is associated with the risk of skeletal fluorosis.

To investigate the potential association between LRP5 rs648438 polymorphism and the risk of skeletal fluorosis (SF) was evaluated in a cross-sectional case-control study conducted in Shanxi, China, in 2019. A total of 973 individuals were enrolled in this study, in which cases and controls were 346 and 627, respectively. SF was diagnosed according to the standard WS/192-2008 (China). The LRP5 rs648438 was detected by the multiple PCR and sequencing. LRP5 rs648438 was found to follow a dominant genetic model using a web-based SNP-STATS software. Logistic regression analysis found that the TC/CC genotype of LRP5 rs648438 might be a protective factor for SF. When stratified by gender, this protective effect of TC/CC genotype in rs648438 was pronounced in males. There was an interaction between gender and rs648438 on risk of SF. Our study suggested that TC/CC genotype of rs648438 might be a protective factor for water-drinking-type skeletal fluorosis, especially in male participants.

Ultrasensitive CRISPR/Cas13a-Mediated Photoelectrochemical Biosensors for Specific and Direct Assay of miRNA-21.

Sensitive and specific assay of microRNAs (miRNAs) is beneficial to early disease screening. Herein, we for the first time proposed clustered regularly interspaced short palindromic repeats (CRISPR)/Cas13a-mediated photoelectrochemical biosensors for the direct assay of miRNA-21. In this study, compared with traditional nucleic acid-based signal amplification strategies, the CRISPR/Cas13a system can greatly improve the specificity and sensitivity of target determination due to its accurate recognition and high-efficient trans-cleavage capability without complex nucleic acid sequence design. Moreover, compared with the CRISPR/Cas12a-based biosensing platform, the developed CRISPR/Cas13a-mediated biosensor can directly detect RNA targets without signal transduction from RNA to DNA, thereby avoiding signal leakage and distortion. Generally, the proposed biosensor reveals excellent analysis capability with a wider linear range from 1 fM to 5 nM and a lower detection limit of 1 fM. Additionally, it also shows satisfactory stability in the detection of human serum samples and cell lysates, manifesting that it has great application prospects in the areas of early disease diagnosis and biomedical research.

Association between arsenic (+3 oxidation state) methyltransferase gene polymorphisms and arsenic methylation capacity in rural residents of northern China: a cross-sectional study.

Arsenic is a toxic metal-like element. The toxic reaction of the body to arsenic is related to the ability of arsenic methylation metabolism. As the rate-limiting enzyme of arsenic methylation metabolism, the genetic single nucleotide polymorphisms (SNPs) of arsenic (+ 3 oxidation state) methyltransferase (AS3MT) gene are related to capacity of arsenic methylation. In this paper, we investigated the association of five SNPs (rs7085104, rs3740390, 3740393, rs10748835, and rs1046778) in AS3MT with arsenic methylation metabolizing using the data and samples from a cross-sectional case-control study of arsenic and Type 2 diabetes mellitus conducted in Shanxi, China. A total of 340 individuals were included in the study. Urinary total arsenic (tAs, µg/L) was detected by liquid chromatography-atomic fluorescence spectrometry (LC-AFS). According to "safety guidance value of urinary arsenic for population" as specified in WS/T665-2019 (China), participants were divided into the control group (tAs ≤ 32 µg/L, n = 172) and arsenic-exposed group (tAs > 32 µg/L, n = 168). iAs%, MMA%, and DMA% are as the indicator of arsenic methylation capacity. The genotypes of AS3MT SNPs were examined by Multiple PCR combined sequencing. Linear regression analysis showed that AG + GG genotype in rs7085104 was associated with decreased iAs% and increased DMA%. Moreover, AG + AA genotype in rs10748835 and TC + CC genotype in rs1046778 were associated with decreased iAs% and MMA% and increased DMA%. The interaction between rs7085104 and arsenic is associated with iAs% and DMA%. The interaction of rs3740390 and rs10748835 with arsenic is associated with iAs%. Haplotype CTAC (rs3740393-rs3740390-rs10748835-rs1046778) was associated with lower iAs% and higher DMA%, but this association disappeared after adjusting for age, gender, drink, smoking, BMI and tAs. Haplotype GCAC was associated with decreased MMA%. Our study provides additional support for revealing the factors influencing the metabolic capacity of arsenic methylation and might be helpful to identify the population susceptible to arsenic exposure through individualized screening in the future.

Method and Device of All-in-Focus Imaging with Overexposure Suppression in an Irregular Pipe.

To avoid depth-of-field mismatches caused by the changes in pipe structure and image overexposures caused by highly reflective surfaces while radial imaging irregular pipes, this paper proposes a novel all-in-focus, adaptable, and low scene-coupling method that suppresses overexposures in support of fault detection. Firstly, the pipeline's radial depth distribution data are obtained by sensors, and an optimal all-in-focus imaging scheme is established by combining camera parameters. Secondly, using digital imaging technology, the high reflection effect produced by disparate light sources is comprehensively evaluated for overexposure suppression. Thirdly, a device is designed for imaging non-Lambertian free-form surface scenes under low illumination, providing the sequence images needed for the next step. Lastly, specific digital fusions are made to the sequential images to obtain an all-in-focus final image without overexposure. An image-quality analysis method is then used to measure the efficacy of the system in obtaining the characteristic information of the inner surfaces of an irregular pipe. Results of the experiment show that the method and device used are able to distinguish small 0.5 mm wide lines ranging from 40-878 mm depth and are capable of providing efficient image support for defect inspection of irregular pipes and free-form surfaces amongst other irregular surfaces.

The ROS/NF-κB/HK2 axis is involved in the arsenic-induced Warburg effect in human L-02 hepatocytes.

Arsenic has been identified as a carcinogen, although the molecular mechanism underlying itscarcinogenesis has not been fully elucidated. To date, only a few studies have attempted to confirm a direct link between oxidative stress and the Warburg effect . This study demonstrated that 0.2 µmol/L As3+ induced the Warburg effect to contribute to abnormal proliferation of L-02 cells, that was mediated by upregulation of hexokinase 2 (HK2), a key enzyme in glycolysis. Further study indicated that arsenic-induced accumulation of reactive oxygen species (ROS) activated the nuclear factor kappa B (NF-κB) signaling pathway by phosphorylation of p65 at the Ser536 and Ser276 sites, leading to upregulated expression of HK2. We therefore concluded that the ROS/NF-κB/HK2 axis contributes to the Warburg effect and cell proliferation induced by low doses of arsenic.AbbreviationsROS, Reactive oxygen species; NAC, N-acetyl-L-cysteine; 2-DG, 2-deoxy-D-glucose; 2-NBDG, 2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose.

Glasgow prognostic score is a practical predictive index for postoperative intra-abdominal septic complications after bowel resection in Crohn's disease patients.

PURPOSE: Postoperative intra-abdominal septic complications (IASCs) are not uncommon in patients with Crohn's disease (CD). The appropriate index to predict postoperative IASCs in these individuals remains unknown. This study investigates whether the inflammation-based Glasgow prognostic score (GPS) is predictive in the setting of postoperative IASC CD patients who underwent elective bowel resection. METHODS: A consecutive cohort of 163 CD patients who underwent elective intestinal resection from July 2012 to March 2016 was retrospectively analyzed. Patients were divided into two GPS groups, one lower and one higher. The GPS was defined by serum levels of C-reactive protein and albumin. Univariate and multivariate analyses were conducted to identify risk factors for postoperative IASCs. RESULTS: Postoperative IASCs occurred in 25 (15.3%) patients. Compared with patients in the lower GPS group, patients with a higher GPS had a higher incidence of postoperative IASCs (9.85 vs. 38.71%, P < 0.001) and experienced longer postoperative hospital stay (10.53 ± 7.00 vs. 15.71 ± 9.17, P = 0.001). Univariate and multivariate analyses revealed preoperative GPS [odds ratio (OR) 5.016, 95% confidence interval (CI) 1.134-22.193, P = 0.034] and penetrating behavior (OR 4.495, 95% CI 1.377-14.670, P = 0.013) to be independent risk factors for postoperative IASCs. CONCLUSIONS: A preoperative GPS can serve as a useful index for predicting manifestation of postoperative IASCs after bowel resection in patients with CD. Perioperative optimization is required to improve postoperative outcomes for patients with higher GPS.

Exploration of early-life candidate biomarkers for childhood asthma using antibody arrays.

BACKGROUND: Proteomic approaches identifying biomarkers have been applied to asthma to only a very limited extent. METHODS: With an antibody array (RayBiotech, Norcross, GA, USA), the relative intensity and rank differences of 444 proteins were compared in 24 plasma samples obtained at age 3, 11 from children with and 12 without asthma diagnoses at ages 5 and 9. Protein candidates identified by antibody array were quantitated by ELISA in an enlarged sample. Proteins found to differentiate children with and without asthma were also examined for association with known Year 1 asthma risk factors, eczema, and wheeze. RESULTS: In the antibody array, four proteins had rank differences between asthma and non-asthma groups (FDR <0.1). By ELISA, mean log (±s.e.m.) erythropoietin (EPO) level (IU/l) was lower (0.750 ± 0.048 vs. 0.898 ± 0.035; p = 0.006) and mean (±s.e.m.) soluble GP130 (sGP130) level (ng/ml) was higher in the asthma vs. the non-asthma group (302 ± 13 vs. 270 ± 8; p = 0.041). The other 2 array proteins (galactin-3 and eotaxin-3) did not differ by ELISA by asthma. EPO related to the asthma risk factor, first year eczema, whereas sGP130 related to first year wheeze. CONCLUSIONS: Through two independent assessments, age 3 plasma levels of EPO and sGP130 were found related to childhood asthma.

[The effects of sleeve gastrectomy on renal function in type 2 diabetic rats].

OBJECTIVE: To examine the renal function changes and mechanisms on rats with diabetes through a sleeve gastrectomy operation. METHODS: Thirty-six rats were induced diabetes through injection of streptozotocin (STZ), and 30 of these diabetic rats that blood glucose levels at the midrange (blood sugar 17.88-23.65 mmol/L, mean: 20.32 mmol/L) were randomly assigned to the sleeve gastrectomy group, Sham-operation group and control group. The serum creatinine, lipid parameters were measured postoperatively. The 24 h urine volume obtained and urine albumin excretion rate (UAER) was calculated. Serum and urinary creatinine were examined and glomerular filtration rate (GFR) was counted. Kidney sections were stained with periodic acid-Schiff, and then the index of mesangial expansion was determined. The expression of synaptopodin for podocytes was also performed through the immunohistochemical procedure. A one-way ANOVA and t-test were performed to evaluate differences between groups and each other. RESULTS: Only one rat of SG group died after operation. The GFR ((8.44 ± 2.10) ml · g⁻¹ · d⁻¹), 24 h UAER ((36.04 ± 11.10) mg/d), plasma lipids level (total cholesterol (1.66 ± 0.23) mmol/L, triglycerides (1.25 ± 0.17) mmol/L), kidney weight ((1.61 ± 0.06) g), the index of mesangial expansion ((6.14 ± 1.50)%) and synaptopodin expression ((20.44 ± 2.99)%) were improved in the SG group compared with the sham-operation group ((15.05 ± 3.01) ml · g⁻¹ · d⁻¹, (57.01 ± 11.34) mg/d, (2.15 ± 0.29) mmol/L, (1.65 ± 0.23) mmol/L, (1.93 ± 0.07) g, (11.32 ± 2.09)%, (10.34 ± 1.43)%) and control group ((14.79 ± 2.38) ml · g⁻¹ · d⁻¹, (62.71 ± 16.46) mg/d, (2.23 ± 0.21) mmol/L, (1.59 ± 0.20) mmol/L, (1.91 ± 0.06) g, (10.82 ± 1.79)%, (11.13 ± 2.43)%) (t = 0.781-5.025, all P < 0.05). CONCLUSION: The sleeve gastrectomy procedure can improve the renal function in a diabetes rat model may be through protecting the podocytes function and preventing the mesangial expansion of glomeruli.

SIRT1/P53 pathway is involved in the Arsenic induced aerobic glycolysis in hepatocytes L-02 cells.

Arsenic is a known human carcinogen. Low doses of arsenic can induce cell proliferation, but the mechanism remains elusive. Aerobic glycolysis, also known as the Warburg effect, is one of the characteristics of tumour cells and rapidly proliferating cells. P53 is a tumour suppressor gene that has been shown to be a negative regulator of aerobic glycolysis. SIRT1 is a deacetylase that inhibits the function of P53. In this study, we found that P53 was involved in low dose of arsenic-induced aerobic glycolysis through regulating HK2 expression in L-02 cells. Moreover, SIRT1 not only inhibited P53 expression but also decreased the acetylation level of P53-K382 in arsenic-treated L-02 cells. Meanwhile, SIRT1 influenced the expression of HK2 and LDHA, which then promoted arsenic-induced glycolysis in L-02 cells. Therefore, our study demonstrated that the SIRT1/P53 pathway is involved in arsenic-induced glycolysis, thereby promoting cell proliferation, which provides theoretical basis for enriching the mechanism of arsenic carcinogenesis.

Curcumin Inhibits the Proliferation of Renal Cancer 786-O Cells through MTOR Signaling Pathway and Its Mechanism.

Objectives: The mechanism of curcumin inhibiting renal cancer 786-O cells proliferation through MTOR signaling pathway was investigated. Methods: Human renal cancer 786-O cells were cultured with curcumin for 48 h. The OD values were measured by the MTT method, and the growth inhibition rate of 786-O cells was calculated. The cell cycle distribution and apoptosis rate were detected by flow cytometry (FCM). Transwell chamber was introduced to detect cell invasion ability. Cell migration ability was detected by the cell scratch test. The protein expression was assessed by Western blot. Results: With curcumin concentration increasing, the expressions of MMP2, MMP9, MTOR, and p-MTOR proteins and the number of cells in the S phase decreased gradually, while number of cells in G1 and G2/M phases and cells apoptosis rate increased continuously. With the increasing of concentration and time, growth of 786-O cells in each treatment group was inhibited to varying degrees. The higher the inhibition rate was, the cells migration and transmembrane cells proportion decreased significantly. Conclusions: Curcumin inhibits the proliferation, migration, and invasion and induces apoptosis of renal cancer 786-O cells by blocking the MTOR signaling pathway. It may be related to the downregulation of MMP2 and MMP9 proteins.

Sinomenine Inhibits the Progression of Bladder Cancer Cells by Downregulating LncRNA-HEIH Expression.

BACKGROUND: Sinomenine has been reported to effectively repress the progression of lung cancer and breast cancer. However, the effects of sinomenine in bladder cancer are not well understood. The purpose of this study was to evaluate the effects of sinomenine in bladder cancer. METHODS: The mRNA expression of HEIH in bladder cancer cells was measured by RT-qPCR. T24 and SW780 cells were treated with sinomenine for 24 hours. Cell viability was detected by the MTT assay. Cell migration and invasion were detected by the transwell assay. Western blotting assay was performed to assess the protein expression of Bcl-2, Bax, and caspase-3. RESULTS: Sinomenine significantly suppressed cell viability in T24 and SW780 cells. Moreover, cell migration and invasion were significantly inhibited by sinomenine. Sinomenine accelerated the expression of Bax and caspase-3 but decreased the expression of Bcl-2. HEIH was upregulated in bladder cancer cells compared with normal bladder epithelial cells. Besides this, we noticed that HEIH knockdown blocked cell proliferation, migration, and invasion but facilitated cell apoptosis in bladder cancer cells. Additionally, HEIH reversed the suppression of the progression induced by sinomenine. CONCLUSION: Sinomenine was observed to suppress cell progression of bladder cancer cells by inhibiting HEIH expression. Our findings suggested that the use of sinomenine might be an effective treatment for bladder cancer.

2-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives: Simplification and modification of aconitine scaffold for the discovery of novel anticancer agents.

The molecular chaperone heat shock protein 90 (Hsp90) is a promising target for cancer therapy. Natural product aconitine is a potential Hsp90 inhibitor reported in our previous work. In this study, we designed and synthesized a series of 2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC50 value of 0.02 µM and a significant Hsp90α inhibitory activity with an IC50 value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycle at G1/S phase and induce cell apoptosis via up-regulation of bax and cleaved-caspase 3 protein expressions while inhibiting the expressions of bcl-2. Moreover, 14t could inhibit cell migration in LoVo and SW620 cell lines. Consistent with in vitro results, 14t significantly repressed tumor growth in the SW620 xenograft mouse model.

Identification of floR Variants Associated With a Novel Tn4371-Like Integrative and Conjugative Element in Clinical Pseudomonas aeruginosa Isolates.

Florfenicol is widely used to control respiratory diseases and intestinal infections in food animals. However, there are increasing reports about florfenicol resistance of various clinical pathogens. floR is a key resistance gene that mediates resistance to florfenicol and could spread among different bacteria. Here, we investigated the prevalence of floR in 430 Pseudomonas aeruginosa isolates from human clinical samples and identified three types of floR genes (designated floR, floR-T1 and floR-T2) in these isolates, with floR-T1 the most prevalent (5.3%, 23/430). FloR-T2 was a novel floR variant identified in this study, and exhibited less identity with other FloR proteins than FloRv. Moreover, floR-T1 and floR-T2 identified in P. aeruginosa strain TL1285 were functionally active and located on multi-drug resistance region of a novel incomplete Tn4371-like integrative and conjugative elements (ICE) in the chromosome. The expression of the two floR variants could be induced by florfenicol or chloramphenicol. These results indicated that the two floR variants played an essential role in the host's resistance to amphenicol and the spreading of these floR variants might be related with the Tn4371 family ICE.

An Integrated Network, RNA Sequencing, and Experiment Pharmacology Approach Reveals the Active Component, Potential Target, and Mechanism of Gelsemium elegans in the Treatment of Colorectal Cancer.

In this study, a combination of network pharmacology, bioinformatics analysis, molecular docking and transcriptomics was used to investigate the active ingredient and potential target of Gelsemium elegans in the treatment of colorectal cancer. Koumine was screened as the active component by targeting PDK1 through network pharmacology and reverse docking. RNA-Seq, enrichment analysis and validation experiment were then further employed to reveal koumine might function in inhibiting Akt/mTOR/HK2 pathway to regulate cell glycolysis and detachment of HK2 from mitochondria and VDAC-1 to activate cell apoptosis both in vitro and in vivo. In the present study, we provide a systematical approach for the identification of effective ingredient and potential target of herbal medicine. Our results have important implication for the intensive study of koumine as novel anticancer agents for colorectal cancer and could be supportive in its further structural modification.

Characterization of a Novel Chromosomal Class C ß-Lactamase, YOC-1, and Comparative Genomics Analysis of a Multidrug Resistance Plasmid in Yokenella regensburgei W13.

Yokenella regensburgei, a member of the family Enterobacteriaceae, is usually isolated from environmental samples and generally resistant to early generations of cephalosporins. To characterize the resistance mechanism of Y. regensburgei strain W13 isolated from the sewage of an animal farm, whole genome sequencing, comparative genomics analysis and molecular cloning were performed. The results showed that a novel chromosomally encoded class C ß-lactamase gene with the ability to confer resistance to ß-lactam antibiotics, designated bla YOC - 1, was identified in the genome of Y. regensburgei W13. Kinetic analysis revealed that the ß-lactamase YOC-1 has a broad spectrum of substrates, including penicillins, cefazolin, cefoxitin and cefotaxime. The two functionally characterized ß-lactamases with the highest amino acid identities to YOC-1 were CDA-1 (71.69%) and CMY-2 (70.65%). The genetic context of the bla YOC - 1 -ampR-encoding region was unique compared with the sequences in the NCBI nucleotide database. The plasmid pRYW13-125 of Y. regensburgei W13 harbored 11 resistance genes (bla OXA - 10, bla LAP - 2, dfrA14, tetA, tetR, cmlA5, floR, sul2, ant(3″)-IIa, arr-2 and qnrS1) within an ∼34 kb multidrug resistance region; these genes were all related to mobile genetic elements. The multidrug resistance region of pYRW13-125 shared the highest identities with those of two plasmids from clinical Klebsiella pneumoniae isolates, indicating the possibility of horizontal transfer of these resistance genes between bacteria of various origins.

Characterization of Two Macrolide Resistance-Related Genes in Multidrug-Resistant Pseudomonas aeruginosa Isolates.

In analyzing the drug resistance phenotype and mechanism of resistance to macrolide antibiotics of clinical Pseudomonas aeruginosa isolates, the agar dilution method was used to determine the minimum inhibitory concentrations (MICs), and PCR (polymerase chain reaction) was applied to screen for macrolide antibiotics resistance genes. The macrolide antibiotics resistance genes were cloned, and their functions were identified. Of the 13 antibiotics tested, P. aeruginosa strains showed high resistance rates (ranging from 69.5-82.1%), and MIC levels (MIC90 > 256 µg/ml) to macrolide antibiotics. Of the 131 known macrolide resistance genes, only two genes, mphE and msrE, were identified in 262 clinical P. aeruginosa isolates. Four strains (1.53%, 4/262) carried both the msrE and mphE genes, and an additional three strains (1.15%, 3/262) harbored the mphE gene alone. The cloned msrE and mphE genes conferred higher resistance levels to three second-generation macrolides compared to two first-generation ones. Analysis of MsrE and MphE protein polymorphisms revealed that they are highly conserved, with only 1-3 amino acids differences between the proteins of the same type. It can be concluded that even though the strains showed high resistance levels to macrolides, known macrolide resistance genes are seldom present in clinical P. aeruginosa strains, demonstrating that a mechanism other than this warranted by the mphE and msrE genes may play a more critical role in the bacteria's resistance to macrolides.

The role of exclusive enteral nutrition in the preoperative optimization of laparoscopic surgery for patients with Crohn's disease: A cohort study.

BACKGROUND: Growing evidence has shown that there are significant advantages associated with the use of laparoscopic surgery for Crohn's disease (CD). However, the impact of preoperative exclusive enteral nutrition (EEN) on postoperative complications and CD recurrence following laparoscopic surgery have not been investigated. METHODS: A total of 120 CD patients undergoing bowel resection with laparoscopic surgery were eligible for this study. Patient data were collected from a prospectively maintained database. Before laparoscopic surgery, 45 CD patients received EEN for at least 4 weeks, and 75 CD patients had no EEN. Postoperative complications, and endoscopic and clinical recurrence were subsequently measured and compared after laparoscopic surgery and during follow-up assessments. RESULTS: Patients who received EEN had significant improvements in their nutritional (albumin, prognostic nutritional index (PNI), and hemoglobin) and inflammatory (C-reactive protein) status after the EEN treatment prior to surgery (P < 0.05). Patients who received EEN also experienced fewer postoperative complications, decreased surgical site infections, and a lower comprehensive complication index (P < 0.05). The endoscopic recurrence rates 6 months after surgery were also decreased significantly in patients who received EEN (P < 0.05). However, the incidence of clinical recurrence was similar in the 2 groups at 1-year follow-up. Endoscopic recurrence was correlated with ileocolonic disease, EEN before surgery, and PNI (P < 0.05). PNI remained independently associated with endoscopic recurrence after surgery. CONCLUSIONS: Preoperative EEN for at least 4 weeks improved CD patients' nutritional and inflammatory status, which in turn reduced postoperative complications following laparoscopic surgery and endoscopic recurrence on follow-up.

Discovery of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido) phenylurea-based thymidylate synthase (TS) inhibitor as a novel multi-effects antitumor drugs with minimal toxicity.

Thymidylate synthase (TS) is a hot target for tumor chemotherapy, and its inhibitors are an essential direction for anti-tumor drug research. To our knowledge, currently, there are no reported thymidylate synthase inhibitors that could inhibit cancer cell migration. Therefore, for optimal therapeutic purposes, combines our previous reports and findings, we hope to obtain a multi-effects inhibitor. This study according to the principle of flattening we designed and synthesized 18 of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)phenyl urea derivatives as multi-effects inhibitors. The biological evaluation results showed that target compounds could significantly inhibit the hTS enzyme, BRaf kinase and EGFR kinase activity in vitro, and most of the compounds had excellent anti-cell viability for six cancer cell lines. Notably, the candidate compound L14e (IC50 = 0.67 µM) had the superior anti-cell viability and safety to A549 and H460 cells compared with pemetrexed. Further studies had shown that L14e could cause G1/S phase arrest then induce intrinsic apoptosis. Transwell, western blot, and tube formation results proved that L14e could inhibit the activation of the EGFR signaling pathway, then ultimately achieve the purpose of inhibiting cancer cell migration and angiogenesis in cancer tissues. Furthermore, in vivo pharmacology evaluations of L14e showed significant antitumor activity in A549 cells xenografts with minimal toxicity. All of these results demonstrated that the L14e has the potential for drug discovery as a multi-effects inhibitor and provides a new reference for clinical treatment of non-small cell lung cancer.

Cigarette smoking and risk of albuminuria in patients with type 2 diabetes: a systematic review and meta-analysis of observational studies.

BACKGROUND: The aim of this study was to assess the effects of smoking on albuminuria risk in adults with type 2 diabetes mellitus (T2DM). METHODS: A literature search was conducted using MEDLINE, EMBASE, and China National Knowledge Infrastructure from the established date to October 2017. Summary relative risks (SRR) and 95% confidence intervals (CI) were computed utilizing a random effect inverse variance method. RESULTS: This meta-analysis included a total of 19 relevant observational studies (four prospective cohort, seven case-control, and eight cross-sectional studies), reporting 105,031 participants and 23,366 albuminuria events. Compared with never-smokers with T2DM, the SRRs of albuminuria were 1.43 (95% CIs 1.27-1.61) for ever-smokers, 2.61 (95% CIs 1.86-3.64) for current smokers, and 1.86 (95% CIs 1.37-2.52) for former smokers. Considerable heterogeneity was observed among these studies, and study design was a significant modifier for this association. There were significantly elevated risk associations for microalbuminuria (SRRs = 1.24, 95% CIs 1.05-1.46) and for macroalbuminuria (SRRs = 1.65, 95% CIs 1.03-2.66), respectively. CONCLUSIONS: Our systematic review and meta-analysis indicates that cigarette smoking might be a potential factor for the development of albuminuria in adults with T2DM. Future studies are required to investigate the association between smoking cessation and intensity and incident albuminuria in adults with T2DM.

The N-terminal zinc finger domain of Tgf2 transposase contributes to DNA binding and to transposition activity.

Active Hobo/Activator/Tam3 (hAT) transposable elements are rarely found in vertebrates. Previously, goldfish Tgf2 was found to be an autonomously active vertebrate transposon that is efficient at gene-transfer in teleost fish. However, little is known about Tgf2 functional domains required for transposition. To explore this, we first predicted in silico a zinc finger domain in the N-terminus of full length Tgf2 transposase (L-Tgf2TPase). Two truncated recombinant Tgf2 transposases with deletions in the N-terminal zinc finger domain, S1- and S2-Tgf2TPase, were expressed in bacteria from goldfish cDNAs. Both truncated Tgf2TPases lost their DNA-binding ability in vitro, specifically at the ends of Tgf2 transposon than native L-Tgf2TPase. Consequently, S1- and S2-Tgf2TPases mediated gene transfer in the zebrafish genome in vivo at a significantly (p < 0.01) lower efficiency (21%-25%), in comparison with L-Tgf2TPase (56% efficiency). Compared to L-Tgf2TPase, truncated Tgf2TPases catalyzed imprecise excisions with partial deletion of TE ends and/or plasmid backbone insertion/deletion. The gene integration into the zebrafish genome mediated by truncated Tgf2TPases was imperfect, creating incomplete 8-bp target site duplications at the insertion sites. These results indicate that the zinc finger domain in Tgf2 transposase is involved in binding to Tgf2 terminal sequences, and loss of those domains has effects on TE transposition.