Causality between serum uric acid and diabetic microvascular complications - a mendelian randomization study.

BACKGROUND: The aim of this study was to investigate whether a causal relationship exists between serum uric acid (SUA) and diabetic microvascular complications using a two-sample Mendelian randomization (MR) method. METHODS: We used the MR approach, utilizing genome-wide association study (GWAS) summary statistics, to estimate the causal effect of SUA on diabetic microvascular complications in European individuals. The summary statistical data of SUA were obtained from the open database (IEU OPEN GWAS PROJECT) (p < 5 × 10- 8), and data on diabetic microvascular complications (diabetic nephropathy, diabetic neuropathy, diabetic retinopathy) were obtained from the FinnGen consortium. F-statistics were calculated to assess the correlation between instrumental variables (IVs) and SUA, and single nucleotide polymorphisms (SNPs) associated with confounders or outcomes were excluded by consulting the PhenoScanner database. Inverse variance weighting (IVW) was used for primary estimation, and MR‒Egger, weighted median (WM), and Mendelian randomization pleiotropy residuals sum and outliers (MR-PRESSO) were used for additional assessment. Heterogeneity was assessed using the Cochran's Q test, and polytropy was assessed using the MR‒Egger intercept. RESULTS: MR analysis revealed a causal relationship between a genetically predicted increase in SUA and diabetic nephropathy [OR = 1.32, 95%(CI) = 1.07-1.63, p = 0.008]. The results were consistent with those after MR-PRESSO [OR = 1.30, 95%(CI) = 1.07-1.58, p = 0.008]. There was a causal relationship between type 2 diabetes mellitus (T2DM) and renal complication IVW [OR = 1.27, 95%(CI) = 1.00-1.62, p = 0.049]. These results were consistent with those after MR-PRESSO [OR = 1.27, 95%(CI) = 1.00-1.62, p = 0.050]. There was no significant causal relationship between the genetically predicted increase in SUA and diabetic retinopathy [OR 1.09, 95%(CI) = 0.94-1.26, p = 0.249] or diabetic neuropathy [OR = 1.08, 95%(CI) = 0.84-1.40, p = 0.549]. CONCLUSIONS: This MR analysis suggests a causal relationship between genetically predicted uric acid increases and diabetic microvascular complications. A significant causal relationship exists between SUA and diabetic nephropathy but not between SUA and diabetic retinopathy or diabetic neuropathy.

SGLT2i in Patients with Type 1 Diabetes: Benefits, Risks, and Preventive Strategies.

Sodium-glucose cotransporter inhibitors (SGLT2i) play an increasingly important role in type 2 diabetes mellitus (T2DM) due to their significant cardiovascular benefits and renal protection in addition to their hypoglycemic effects. In recent years, the application of SGLT2i in patients with type 1 diabetes mellitus (T1DM) has attracted more and more attention. Studies have shown that SGLT2i improves glycemic control, reduces total daily insulin dose, decrease body weight in patients with T1DM, without increasing the risk of severe hypoglycemia. SGLT2i also reduces urinary protein levels, prevents atherosclerosis, and offers cardiorenal benefits in patients with T1DM. But simultaneously, they significantly increased risk of diabetic ketoacidosis (DKA), which leads to increased hospitalization and mortality. Hence SGLT2i is recommended to T1DM who are motivated, adhere to self-glucose monitoring, well-trained in identifying DKA, and closely followed to ensure the efficacy and safety.

New insights into X-linked adrenal hypoplasia congenita from a novel splice-site variant of NR0B1 and adrenal CT images.

BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder, often manifesting as primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), and caused by variants of NR0B1, most of which are frame-shifting variants, and few splice-site variants. METHODS AND RESULTS: Here, a novel splice-site variant of NR0B1 (NM_000475.4), c.1169-2A>T (patient 1), and a stop-loss variant of NR0B1 c.1411T>C (patient 2) are described in this study. We perform minigene assays for the splice-site variant (c.1169-2A>T) and determine that the variant causes exon 2 skipping. Moreover, the defect of NR0B1 protein may bring about the severe phenotype of the patient. Through 8 years of follow-up, we compare the CT images from 8 years ago with the latest image, and observe the CT image change of adrenal in patient 2 (from the increased thickness of adrenal to adrenal atrophy). CONCLUSION: X-linked adrenal hypoplasia congenita is produced by variants of NR0B1. We report a case that presents a novel splice-site variant, which has been verified that it could lead to the exon 2 skipping in the RNA splicing progress. Moreover, we report the adrenal CT image change of patient 2, which has never been referred to before, and expand the spectrum of X-linked AHC characteristics.

Predictive ability of obesity- and lipid-related indicators for metabolic syndrome in relatively healthy Chinese adults.

Background and objective: Metabolic syndrome (MetS) is an important risk factor for cardiovascular complications and kidney damage. Obesity- and lipid-related indices are closely related to MetS, and different indices have different predictive abilities for MetS. This study aimed to evaluate the predictive value of eight obesity- and lipid-related indicators, namely, body mass index (BMI), lipid accumulation product (LAP), body roundness index (BRI), Chinese visceral adiposity index (CVAI), body adiposity index (BAI), abdominal volume index (AVI), triglyceride glucose index (TYG), and visceral adiposity index (VAI), for MetS. Methods: A total of 1,452 relatively healthy people in Beijing were enrolled in 2016, and the correlation between the eight indicators and MetS was analyzed by multivariate logistic regression. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to analyze the predictive ability of the eight indicators for MetS. The Delong test was used to compare the AUC values of the eight indicators. MetS was defined according to the Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 edition), the revised National Cholesterol Education Program Adult Treatment Group (NCEP-ATPIII), and the International Diabetes Federation (IDF). Results: Using these three sets of criteria, LAP, TYG, CVAI, and VAI, which are based on blood lipids, had higher AUC values for MetS prediction than BMI, BRI, AVI, and BAI, which are based on anthropometry. LAP had the highest AUC values of 0.893 (0.874-0.912), 0.886 (0.869-0.903), and 0.882 (0.864-0.899), separately, based on the three sets of criteria. Conclusion: The eight obesity- and lipid-related indicators had screening value for MetS in relatively healthy people, and of the eight indicators, LAP performed the best.

Case Report: A novel WRN mutation in Werner syndrome patient with diabetic foot disease and myelodysplastic syndrome.

Werner syndrome is an autosomal recessive rare disease caused by a WRN gene mutation, which is rarely reported in the Chinese population. We report the clinical and genetic data of a Chinese patient with Werner syndrome. The proband was a 40-year-old male patient who presented with diabetic foot ulcers, accompanied by short stature, cataracts, hypogonadism, and hair thinning, and myelodysplastic syndrome (MDS) occurred after 18 months. Genetic sequencing showed there were compound heterozygous mutations as c.3384-1G>C and c.3744dupA in the WRN gene. The c.3744dupA mutation is a novel pathogenic variation for Werner syndrome.

Artesunate protects pancreatic ß-cells from streptozotocin-induced diabetes via inhibition of the NLRP3/caspase-1/GSDMD pathway.

BACKGROUND: Reports in recent years have shown that pancreatic ß-cell pyroptosis represents a critical mechanism involved with the progressive failure of pancreatic function. Previous research from our laboratory has indicated that artemether can increase the number of cells in pancreatic islets of db/db mice. In this study, we further examined whether artesunate (ART) protects pancreatic ß-cells from the damage of streptozotocin (STZ) by inhibiting pyroptosis. MATERIALS AND METHODS: In vitro, MIN6 cells exposed to 1 mM STZ were treated with ART (0.8 or 1.6 µM). The effects of ART on STZ-treated cells were evaluated through CCK-8 assay, flow cytometry and western blot, and further compared the effects of ART with the NLRP3 inhibitor, Mcc950 upon pyroptosis pathway proteins using western blot. In vivo, Male C57 mice were administered with a single intraperitoneal injection of STZ, and those with confirmed diabetes mellitus were given ART (0.5 or 1.0 mg/ml in drinking water) for 18 days. The effects of ART on STZ-induced diabetes were assessed by the observation of the general situation, glucose tolerance test, hematoxylin-eosin (HE) staining and immunohistochemistry. RESULTS: In MIN6 cells treated with STZ, we found that ART increased cell viability, decreased the number of late apoptotic cells (including pyroptosis cells) and inhibited the expression of proteins associated with the pyroptosis pathway. In STZ-induced animal model, the administration of ART reduced blood glucose levels, improved the consumption status within this diabetic mouse model and inhibited the expression of proteins include in the pyroptosis pathway in mice pancreats. CONCLUSIONS: Inhibition of pyroptosis may be a critical mechanism through which artesunate exerts protective effects upon pancreatic ß cells.

Comparison the effects of finerenone and SGLT2i on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus: A network meta-analysis.

Background: Finerenone and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), while the relative efficacy has not been determined. Methods: The databases of PubMed, Embase and Cochrane were searched for relevant cardiovascular or renal outcome trials of SGLT2i or finerenone. The end points were major adverse cardiovascular events (MACE), nonfatal stroke (NS), myocardial infarction (MI), hospitalization for heart failure (HHF), cardiovascular death (CVD), and renal composite outcome (RCO). Network meta-analysis was performed using Bayesian networks to obtain pooled hazard ratios (HR) and 95% confidence intervals (CI). The probability values for ranking active and placebo interventions were calculated using cumulative ranking curves. Results: 1024 articles were searched, and only 9 studies were screened and included in this meta-analysis with 71793 randomized participants. Sotagliflozin (HR 0.72 95%CI 0.59-0.88, SUCAR=0.93) and canagliflozin (HR 0.80 95%CI 0.67-0.97, SUCAR=0.73) can significantly reduce the risk of MACE compared with placebo. Canagliflozin (HR 0.64 95%CI 0.48-0.86, SUCAR=0.73), sotagliflozin (HR 0.66 95%CI 0.50-0.87, SUCAR=0.69) and empagliflozin (HR 0.65 95%CI 0.43-0.98, SUCAR=0.68) can significantly reduce the risk of HHF compared with placebo. Empagliflozin (HR 0.62 95%CI 0.43-0.89, SUCAR=0.96) can significantly reduce the risk of CVD compared with placebo. Empagliflozin (HR 0.61 95%CI 0.39-0.96, SUCAR=0.74), canagliflozin (HR 0.66 95%CI 0.46-0.92, SUCAR=0.63), and dapagliflozin (HR 0.53 95%CI 0.32-0.85, SUCAR=0.88) can significantly reduce the risk of RCO compared with placebo. Finerenone has reduced the risk of MACE, MI, HHF, CVD and RCO to varying degrees, but they do not show significant difference from placebo and each SGLT2i. Conclusion: Both SGLT2i and finerenone could reduce the risk of MACE, HHF, MI, CVD, RCO. Finerenone has no obvious advantage than SGLT2i on the effects of cardiovascular and renal protective. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022375092.

An Essential NRP1-Mediated Role for Tagln2 in Gastric Cancer Angiogenesis.

Knowledge about the precise biological role and underlying mechanism of Tagln2 in tumor progression is relatively limited, especially in angiogenesis focused on tumor derived endothelial cells (ECs) has rarely been reported. Here, the function, molecular mechanism and potential clinical value of Tagln2 in gastric cancer (GC) angiogenesis were investigated. GC tissue microarrays were used to assess the expression of Tagln2 in ECs. The relationships between expression and clinicopathological features were analyzed to evaluate the clinical value of Tagln2. Gain- and loss-of-function approaches were performed in ECs to investigate the functions of Tagln2 in angiogenesis. A combination of angiogenesis antibody array, RNA-Seq analyses and a series of in vitro experiments were performed to reveal the proangiogenic mechanism mediated by NRP1. Immunohistochemistry performed on an independent tissue chip (n=75) revealed significant upregulation of Tagln2 in tumor-derived ECs which were specifically immunolabeled with CD34. Additionally, high Tagln2 levels correlated significantly with the presence of lymph node as well as distant metastases. Gain- and loss-of-function approaches highlighted the function of Tagln2 in promoting EC proliferation, motility, and capillary-like tube formation and in reducing apoptosis. Tagln2 upregulation led to significantly increased mRNA and protein levels of NRP1 and subsequently activated the NRP1/VEGFR2 and downstream MAPK signaling pathways. These data indicate the importance of Tagln2 in angiogenesis, as a potential therapeutic target, and as a candidate prognostic marker in GC.

Analysis of Glycemic Improvement in Hemodialysis Patients Based on Time in Range, Assessed by Flash Glucose Monitoring.

INTRODUCTION: This study aimed to investigate the application value of "time in ranges (TIRs)" in dialysis patients with diabetes and summarize the experience of optimizing glycemic control by flash glucose monitoring (FGM) system. METHODS: In this monocentric 2-week pilot study, FGM was applied for 14 days in 57 type 2 diabetes mellitus medically stable patients under maintenance hemodialysis to determine their glycemic improvement. The diagnostic value of TIR versus HbA1c in detecting glucose fluctuations and levels was evaluated using receiver operating characteristic analysis. RESULTS: Average glucose exhibited stronger association with TIR (r = -0.785, p < 0.001) than HbA1c (r = 0.644, p < 0.001), and mean amplitude of glycemic excursion (MAGE) had the same conclusion (r = -0.568, p < 0.001 for TIR vs. r = 0.423, p = 0.016 for HbA1c). TIR exhibited a higher area under curve than HbA1c in detecting significant derangements in glucose fluctuation, using a 14-day average FGM-derived coefficient of variation >36% as the reference standard (difference between areas: 0.237; 95% CI 0.092-0.383, p = 0.001). We found a significant improvement in TIR (58.38 ± 19.42 vs. 46.45 ± 24.42 mmol/L, p < 0.001) and a significant decline in MAGE (median 5.64 vs.7.42 mmol/L, p < 0.001) compared to the baseline without deterioration of time spent in hypoglycemia. CONCLUSION: TIR seems to be feasible and clinically useful for AGP analysis in dialysis patients with diabetes, and FGM can be used to improve glycemic control.

A novel missense pathogenic variant in NEFH causing rare Charcot-Marie-Tooth neuropathy type 2CC.

The purpose of this research is to explore the underlying genes of Charcot-Marie-Tooth (CMT). Technologies such as electrophysiological testing and gene sequencing have been applied. We identified a novel variant NEFH c.2215C>T(p.P739S)(HGNC:7737) in a heterozygous state, which was considered to be pathogenic for CMT2CC(OMIM:616924).The proband and his brothers presented with muscle atrophy of hand and calf and moderately decreased conduction velocities. By whole exome sequencing analysis, we found the novel missense pathogenic variant in the proband, his brother and mother. This report broadened current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with NEFH. In addition, the proband carried other five variants {HSPD1c.695C>A (p.S232X), FLNCc.1073A>G (p.N358S), GUSBc.323C>A (p.P108Q), ACY1 c.1063-1G>A and APTX c.484-2A>T}, which have not been reported until now. The NEFH c.2215C>T (p.P739S) give us a new understanding of CMT, which might provide new therapeutic targets in the future.

Clinical Characteristics and Genetic Analysis of a Family With Birt-Hogg-Dubé Syndrome and Congenital Contractural Arachnodactyly.

Background: Birt-Hogg-Dubé (BHD) syndrome and congenital contractural arachnodactyly (CCA) or Beals-Hecht syndrome are clinically rare autosomal dominant genetic diseases. In this study, we describe an extremely rare family with BHD syndrome and CCA. Objective: To investigate the clinical and genetic characteristics of a family with BHD syndrome and CCA. Methods: We describe the clinical characteristics, family history, and clinical manifestations of the patient's family members. The patient underwent a blood test, computed tomography (CT) of the chest, color Doppler ultrasound of the abdomen and heart, and digital radiography of the hands. Whole exome sequencing was performed on his family members. Results: Two years ago, the male proband developed chest tightness and shortness of breath that was accompanied by an irritating cough as well as repeated (four times) spontaneous pneumothorax. The chest CT indicated spontaneous pneumothorax on the right side and cyst and bullae in both lungs. He had no kidney tumors or skin lesions. His son had a history of pulmonary bullae and experienced spontaneous pneumothorax twice. The proband, his mother, and his son were all born with a hand deformity. The sequencing results demonstrated that both the proband and his son had heterozygous variations of the folliculin (FLCN) gene c.1015C > T (p. Gln339Ter) and fibrillin-2 (FBN2) gene c.3485G > A (p. Cys1162Tyr), which are associated with BHD syndrome and CCA, respectively. Conclusion: For patients with chest tightness, shortness of breath, recurrent spontaneous pneumothorax, and congenital hand deformity without inducement, genetic testing should be carried out as soon as possible to make a clear diagnosis, which can then guide treatment and genetic counseling.

Combination of Composite Autonomic Symptom Score 31 and Heart Rate Variability for Diagnosis of Cardiovascular Autonomic Neuropathy in People with Type 2 Diabetes.

OBJECTIVE: Cardiovascular autonomic neuropathy (CAN) is a common but severe problem of diabetes, which a timely diagnosis may have important clinical implications. This study was carried out to investigate the diagnostic performance of Composite Autonomic Symptom Score 31 (COMPASS 31) combined with heart rate variability (HRV) for cardiovascular autonomic neuropathy in type 2 diabetes. METHODS: A total of 103 hospitalized subjects with type 2 diabetes were recruited in the study. All cases received clinical data collection, laboratory examination, and related complication examinations. Cardiovascular autonomic function was assessed using CARTs, COMPASS 31, and HRV analyses. A score of at least 2 based on CARTs was defined as CAN. RESULTS: Of the 103 subjects with type 2 diabetes, 41.8% were diagnosed with confirmed CAN. Participants with CAN had considerably higher COMPASS 31 scores. The CAN group showed a significant decrease in all HRV indices. COMPASS 31 scores and HRV indices were closely correlated with CARTs (P < 0.05). Receiver operating characteristics (ROC) curve results showed that COMPASS 31 score identified CAN with an AUC value of 0.816, while the AUC values of HRV indices were 0.648 to 0.919, among which SDNN and LF had the best diagnostic value, with the AUC values of 0.919 and 0.865, respectively. When combining COMPASS 31 score with SDNN and LF, the AUC value increased to 0.958, with a sensitivity of 90.7% and a specificity of 86.7%. CONCLUSIONS: The combination of COMPASS 31 and HRV could improve the diagnostic performance of CAN in type 2 diabetes, which might be conducive to the diagnosis of CAN.

Effects of NRP1 on angiogenesis and vascular maturity in endothelial cells are dependent on the expression of SEMA4D.

Angiogenesis and vascular maturation play important roles in tumorigenesis and tumor development. The expression of neuropilin 1 (NRP1) is closely associated with angiogenesis in tumors; however, the molecular mechanisms of action in angiogenesis and tumor maturation, as well as the potential clinical value of NRP1 remain unclear. The importance of NRP1 expression in tumor progression was determined using The Cancer Genome Atlas (TCGA) database analysis. Gain­ and loss­of­function experiments of NRP1 were performed in vascular endothelial cells (ECs) to investigate the functions in angiogenesis. CCK­8, flow cytometry, Transwell experiments and a series of in vitro experiments were used to detect cell functions. A combination of angiogenesis antibody arrays and RNA­Seq analyses were performed to reveal the proangiogenic mechanisms of action. The function of semaphorin 4D (SEMA4D) was also investigated separately. NRP1 mRNA levels were significantly increased in primary tumors compared with normal tissues based on TCGA data (P<0.01) and were associated with tumor development in patients. Gain­ and loss­of­function experiments highlighted the function of NRP1 in promoting EC proliferation, motility and capillary­like tube formation and in reducing apoptosis. NRP1 overexpression led to significantly decreased EC markers (PECAM­1, angiogenin, PIGF and MMP­9) expression levels and reduced the vascular maturity. MAPK7, TPM1, RRBP1, PTPRK, HSP90A, PRKD2, PFKFB3, RGS4 and SPARC were revealed to play important roles in this process. SEMA4D was revealed to be a key protein associated with NRP1 in ECs. These data indicated that NRP1­promoted angiogenesis may be induced at the cost of reducing maturity of the ECs. NRP1 may also be a therapeutic target for antiangiogenic strategies and a candidate prognostic marker for tumors.

Serum and tissue proteomic signatures of patients with hepatocellular carcinoma using 2­D gel electrophoresis.

Hepatocellular carcinoma (HCC) accounts for ~85% of primary liver cancer cases and is a leading cause of mortality worldwide. Effective early diagnosis is difficult for HCC; however, effective biomarkers may be beneficial for diagnosis. In the current study, serum samples, and HCC and adjacent tissue samples were obtained from patients with HCC for the detection of biomarkers using 2­D gel electrophoresis (2­DE) and matrix­assisted laser desorption/ionization­time of flight (TOF)/TOF mass spectrometry. The crude serum samples did not need to be prepared for removal of high abundance proteins. The mRNA expression levels of HCC­associated proteins were detected in tissues using reverse transcription­quantitative PCR. Statistical analysis and database matching were used to identify the differentially expressed proteins detected in the serum and tissue groups. Immunohistochemistry (IHC) was performed to detect the expression of significant proteins in HCC and adjacent tissues. The results revealed ~800 protein spots on a 2­DE gel that were detected in serum samples, and 1,200 spots were identified in the tissue samples. The protein and mRNA expression levels of oxysterol binding protein­like 11 (OSBPL11) in HCC serum and tissue samples were consistent. Pathway analysis demonstrated that members of the apolipoprotein family, particularly apolipoprotein E (APOE), and RAS family members were closely associated in HCC, either directly or via ferratin heavy polypeptide 1. IHC results demonstrated that the APOE protein serves an important role in liver cancer development. The lysis buffer used in the current study was effective for serum protein separation in 2­DE sample preparation. In addition, the present study revealed that downregulated OSBPL11 may be a potential indicator for HCC, and the apolipoprotein family, particularly APOE, and the RAS family may cooperatively serve an important role.

Antidiabetic and Antiobesity Effects of Artemether in db/db Mice.

This study is designed to investigate the effect of artemether on type 2 diabetic db/db mice. The experiments consisted of three groups: normal control (NC, db/+, 1% methylcellulose, intragastric administration), diabetic control (DM, db/db, 1% methylcellulose, intragastric administration), and artemether treated (artemether, db/db, 200 mg/kg of artemether, intragastric administration). The treatment lasted for two weeks. The food intake, body weight, and fasting blood glucose of mice were measured every three days. At the start and end of the experiment, the intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (IPITT) were performed. We determined the serum insulin and glucagon levels by ELISA kits and calculated insulin resistance index (HOME-IR). HE staining was used to observe the morphologies of pancreas and liver in mice. The damage of pancreatic beta cells was evaluated by TUNEL staining and immunofluorescence. We found the following: (1) compared with the DM group, the food intake and weight increase rate of artemether group significantly reduced (P < 0.05); (2) compared with pretreatment, artemether significantly reduced the fasting blood glucose levels, and the areas under the curves (AUCs) of IPGTT were decreased significantly, increasing the tolerance to glucose of db/db mice. (P < 0.05); (3) artemether improved hyperinsulinemia and decreased the AUCs of IPITT and HOME-IR, increasing the insulin sensitivity of db/db mice. (4) Artemether significantly ameliorated islet vacuolar degeneration and hepatic steatosis in db/db mice. (5) Artemether reduced the apoptosis of pancreatic beta cells and increased insulin secretion in db/db mice compared with DM group (P < 0.05). Our results indicated that artemether significantly improved glucose homeostasis and insulin resistance and had the potential activity to prevent obesity, reduced the severity of fatty liver, and protected pancreatic beta cells, promising to treat type 2 diabetes.

Enhanced antitumor efficacy of cisplatin for treating ovarian cancer in vitro and in vivo via transferrin binding.

Cisplatin is a widely used anticancer drug, while non-targeted delivery, development of drug resistance, and serious side effects significantly limit its clinical use. In order to improve the tumor-targeting properties of cisplatin, transferrin (Tf) was employed as a carrier to transfer cisplatin into cancer cells via transferrin receptor 1 (TfR1) mediated endocytosis. The binding ability of cisplatin and Tf could be improved by pretreating Tf with 10% ethanol, and the binding number of cisplatin for each Tf molecule could reach to 40 without structural or functional impairment of Tf. The Tf-cisplatin complex could be delivered into human ovarian carcinoma cells high efficiently. In tumor-bearing nude-mice model, the Tf-cisplatin complex inhibited tumor growth in vivo more effectively than free cisplatin, with less toxicity in other tissues. Tumor targeting efficiency of the Tf-cisplatin complex was supported by in vivo and ex vivo imaging and platinum residues detected in each ex vivo organ. These data suggested that Tf-cisplatin was more effective and less drug-resistance than cisplatin, with targeting to tumor cells. Therefore, Tf-mediated delivery of cisplatin is a potential strategy for targeted delivery into tumor cells.

Distribution, pharmacokinetics and primary metabolism model of tramadol in zebrafish.

The current study aimed to develop a rapid, robust and adequately sensitive method for simultaneous determination of the concentration of tramadol and its active metabolites in zebrafish. The pharmacokinetic and elimination pattern of tramadol and its major phase I metabolites following oral or intramuscular administration in zebrafish tissues was achieved using electrospray ionization­quadrupole­time of flight/mass spectrometry (ESI­Q­TOF/MS) and gas chromatography/mass spectrometry (GC­MS). Following administration, the metabolisms were detected in the brain, eyes, muscle and gill tissues within 1 h. Two tramadol metabolites, O­ and N­desmethyltramadol, were detected in brain tissue, with N­desmethyltramadol detected at a higher level. Following GC­MS detection the curve indicated an initial rapid phase, corresponding to the detection of the tramadol within 1 min, and reached peak value in the brain at 5 min. Faster drug clearance was detected in low­dose groups, and concentration had dropped around the to initial level (1.11 µg) at 20 min, but was detectable for up to 3 h. However, it took 80 min to fall back to the initial value (1.73 µg) in the high­dose groups, and tramadol was detectable for up to 4 h. This study developed and validated a simple and high throughput analytical procedure to determine the distribution and pharmacokinetic profiles of tramadol, and its primary metabolites in tissues of zebrafish.

Data from a comparative proteomic analysis of tumor-derived lung-cancer CD105(+) endothelial cells.

Increasing evidence indicates that tumor-derived endothelial cells (TECs) are more relevant for the study of tumor angiogenesis and for screening antiangiogenic drugs than normal ECs (NECs). In this data article, high-purity (>98%) primary CD105(+) NECs and TECs purified from a mouse Lewis lung carcinoma model bearing 0.5 cm tumors were identified using 2D-PAGE and Matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS). All the identified proteins were categorized functionally by Gene Ontology (GO) analysis, and gene-pathway annotated by Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, protein-protein interaction networks were also built. The proteomics and bioinformatics data presented here provide novel insights into the molecular characteristics and the early modulation of the TEC proteome in the tumor microenvironment.

Identification and verification of transgelin-2 as a potential biomarker of tumor-derived lung-cancer endothelial cells by comparative proteomics.

UNLABELLED: To investigate heterogeneity of endothelial cells (ECs) in the tumor microenvironment and biomarkers for antitumor angiogenesis therapy, high-purity (>98%) normal (NECs) and tumor-derived CD105(+) ECs (TECs) were purified from a mouse Lewis lung carcinoma model bearing 0.5 cm tumors by immunomagnetic separation. Proteomics analysis revealed that 48 proteins (28 upregulated and 20 downregulated) were differentially regulated by at least 1.5-fold in TECs, and that these proteins were involved in metabolism, energy pathways, protein folding, cell growth and/or functioned as structural constituents of the cytoskeleton. Upregulation of heat shock protein 60 (Hspd1) and transgelin-2 (Tagln2) was revealed in TECs, and by immunohistochemistry (IHC) in paired tissues from 30 consecutive lung cancer (LC) patients. Higher expression levels of Hspd1, Tagln2 were detected in microvascular ECs of paratumor and tumor tissues than in paired normal counterparts. Stronger Tagln2 staining was associated with clinical stage, tumor size, and histological neural invasion. Higher Hspd1 (area under the curve [AUC], 0.82) and lower Tagln2 (AUC, 0.90) levels were detected in LC patient sera. Pearson correlation analysis revealed a positive correlation between serum Hspd1 and Tagln2 levels. In conclusion, higher Tagln2 levels were associated with tumor development, lymph node metastasis, and neural invasion in LC and may thus serve as a potential biomarker of tumor angiogenesis. SIGNIFICANCE: High-purity endothelial cells (normal and tumor derived) were prepared to characterize ECs heterogeneity in the tumor microenvironment and to explore biomarkers of early stages of tumor development by proteomics. Candidate proteins Hspd1 and Tagln2, were further verification in the sera and tumor tissues of lung cancer patients. Moreover, higher Tagln2 was significantly associated with clinical tumor development, metastasis, and neural invasion. All these results indicated a crucial role for Tagln2 in TECs for tumor development and metastasis.