Urinary N-acetyl-ß-d-glucosaminidase-creatine ratio is a valuable predictor for advanced diabetic kidney disease.

BACKGROUND: Many biomarkers show high diagnostic values for diabetic kidney disease (DKD), but fewer studies focus on the predictive assessment of DKD progression by blood and urinary biomarkers. AIM: This study aims to find powerful risk predictors and identifying biomarkers in blood and urine for DKD progression. METHODS: A total of 117 patients with type 2 DKD including early and advanced stages and their laboratory parameters were statistically assessed. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the significance of discriminating between early and advanced DKD, and the predictive power for advanced DKD was analyzed by regression analysis and trisector grouping. RESULTS: N-acetyl-ß-d-glucosaminidase-creatine (NAG/CR) level in advanced DKD was statistically higher than that in early DKD (p < 0.05), and there was a higher incidence of advanced DKD (72% vs. 56%) and high odds ratio (OR: 3.917, 95% CI: 1.579-10.011) of NAG/CR with ≥2.79 U/mmol compared with <2.79 U/mmol (p < 0.05). NAG/CR ratio also showed a higher area under the ROC curve of 0.727 (95% CI: 0.616-0.828, p = 0.010) with a high sensitivity (0.75) and a moderate specificity (0.66) when 1.93 U/mmol was set as the optimal cutoff value. The adjusted-multivariable analysis revealed that NAG/CR had an OR of 1.021 (95% CI: 1.024-1.038) and 2.223 (95% CI: 1.231-4.463) based on a continuous and categorical variable, respectively, for risk of advanced DKD. Moreover, the prevalence of advanced DKD exhibited an increasing tendency by an increment of the trisector of NAG/CR. CONCLUSIONS: This study suggests that NAG/CR ratio is an independent predictor for advanced DKD, and it also can be used as a powerful identifying marker between early and advanced DKD.

Clinical and predictive significance of Plasma Fibrinogen Concentrations combined Monocyte-lymphocyte ratio in patients with Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the most common causes of blindness and visual impairment. Therefore, early prediction of its occurrence and progression is important. This study aimed to assess the clinical and predictive significance of plasma fibrinogen concentrations combined monocyte-lymphocyte ratio (FC-MLR) in patients with DR. A total of 307 patients with type 2 diabetes (T2D) were enrolled. Plasma fibrinogen concentrations and peripheral white blood cells were measured, and MLR was calculated, and the associations of FC-MLR with DR and severity of disease were assessed. Regression analysis and receiver operating characteristic (ROC) curves were performed to evaluate the risk factors and predictive power of FC-MLR for DR and severity of disease, respectively. DR patients showed higher fibrinogen concentrations and a higher MLR than did T2D patients without complications (P<0.01); Moreover, DR patients in proliferative stage also showed higher fibrinogen concentrations and a higher MLR than did those in non-proliferative stage (P<0.01). FC-MLR was closely associated with occurrence and severity of DR (P<0.01), and was an independent risk factor for them (OR=6.123, 95%CI: 3.122-17.102; and 7.932, 95%CI: 4.315-16.671, respectively; P<0.001). The predictive sensitivity and specificity for DR and severity of disease were 0.86 and 0.68, and 0.85 and 0.73, respectively. The study suggests that FC-MLR may be used as a predictor for the risk and progression of diabetic retinopathy.

The mean reticulocyte volume is a valuable index in early diagnosis of cancer-related anemia.

Background: Cancer-related anemia (CRA) is a functional iron deficient anemia, and the early diagnosis will improve the prognosis of the patients. This prospective study aimed to investigate the utility of mean reticulocyte volume (MRV) in the early diagnosis of CRA. Methods: A total of 284 first-diagnosed cancer patients were enrolled, and the subjects were assigned anemia and non-anemia groups by hemoglobin (Hb) concentrations. The mature RBC and reticulocyte indices were detected with BC-7500 blood analyzer, and the MRV, reticulocyte hemoglobin (RHE) content, and reticulocyte production index (RPI) were obtained. ROC curves were constructed in identifying anemia diagnosed by the combination of RHE and RPI. An adjusted multivariate analyse and quartiles were used to assess the associations of MRV with early CRA diagnosed by combining RBC indices (MCV, MCH and MCHC), respectively. Results: No statistical differences were observed in MCV, RHE and MRV levels between anemia and non-anemia subjects (p > 0.05). MRV exhibited a complete or high correlation with the RHE levels (r = 1.000, p < 0.001), or MCV, MCH, and MCHC in anemia patients (R: 0.575-0.820, p < 0.001). ROC curves analyse indicated a highest area under curve of 0.829 (95% CI [0.762-0.895]) and 0.884 (95% CI [0.831-0.936]) for MRV in identifying anemia in male and female patients, respectively (p < 0.001). When the optimal cutoff values of MRV were set at 100.95 fl in males and 98.35 fl in females, the sensitivity and specificity were 1.00 and 0.68, and 1.00 and 0.73, respectively. The regression analyse showed that, when being as a categorical variable, MRV showed an odds ratio of 19.111 (95% CI [6.985-52.288]; p < 0.001) for the incidence of CRA. The incidence of overall anemia demonstrated a more significant decrease trend along with the increase of MRV quartiles (p-trend < 0.001). Conclusion: This study revealed that the MRV can be used as a convenient and sensitive index in early diagnosis of cancer-related anemia, and decreased MRV level may be the powerful predictor of overt anemia in cancer patients.

PDE-5-Inhibited BMSCs Alleviate High Glucose-Induced Myocardial Fibrosis and Cardiomyocyte Apoptosis by Activating the cGMP/PKG Pathway.

BACKGROUND: Phosphodiesterase-5 (PDE-5) inhibitors have been found to play an important cardio-protective role. This study aimed to clarify the inhibitory effects of PDE-5-silenced bone marrow mesenchymal stem cells (BMSCs) on high glucose-induced myocardial fibrosis and cardiomyocyte apoptosis. METHODS: Cardiomyocytes and fibroblasts of neonatal rats were treated with high glucose (HG), and co-cultured with PDE-5-overexpressed or -knocked down BMSCs. The viability and apoptosis as well as the levels of cytokines, Cardiac troponin I and Vimentin of cardiomyocytes and fibroblasts were studied. The expressions of PDE-5, cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG), in both cells were evaluated. RESULTS: BMSCs that silenced PDE-5 facilitated the viability of cardiomyocytes, decreased the viability of fibroblasts, and inhibited the apoptosis of cardiomyocytes and fibroblasts. The contents of collagen-I, collagen-III, tissue inhibitor of metalloproteinase (TIMP)-1 and Dermin in fibroblasts were decreased by the PDE-5 inhibitor, but the levels of matrix metalloproteinase (MMP)-1 in fibroblasts and troponin-I in cardiomyocytes were increased by the PDE-5 inhibitor. PDE-5 inhibitor also suppressed the expression of PDE-5 but up-regulated cGMP and PKG expression in cardiomyocytes and fibroblasts. CONCLUSIONS: PDE-5-inhibited BMSCs can decrease HG-induced myocardial fibrosis and cardiomyocyte apoptosis by activating the cGMP/PKG pathway, and may play a role in the prevention and treatment of diabetic cardiomyopathy.

An AMPK agonist suppresses the progress of colorectal cancer by regulating the polarization of TAM to M1 through inhibition of HIF-1α and mTOR signal pathway.

OBJECTIVE: This study aimed to evaluate the impact of an adenosine monophosphate-activated protein kinase (AMPK) agonist, metformin (MET), on the antitumor effects of macrophages and to determine the underlying mechanism involved in the process. MATERIALS AND METHODS: M0 macrophages were derived from phorbol-12-myristate-13-acetate-stimulated THP-1 cells. RESULTS: The levels of tumor necrosis factor-alpha (TNF-α) and human leukocyte antigen-DR (HLA-DR) were decreased in macrophages incubated with HCT116 cells, whereas those of arginase-1 (Arg-1), CD163, and CD206 were elevated; these effects were reversed by MET. The transfection of small interfering (si) RNA abrogated the influence of MET on the expression of the M1/M2 macrophage biomarkers. MET significantly suppressed the proliferation and migration abilities of HCT116 cells incubated with M0 macrophages; these actions were reversed by siRNA transfection against AMPK. The hypoxia-inducible factor 1-alpha (HIF-1α), phosphorylated protein kinase B (p-AKT), and phosphorylated mammalian target of rapamycin (p-mTOR) levels were reduced by the introduction of MET and promoted by siRNA transfection against AMPK. In addition, the levels of HIF-1α, p-AKT, and p-mTOR suppressed by MET were markedly increased following the transfection of siRNA against AMPK. CONCLUSION: These findings indicate that MET can repress the progression of colorectal cancer by transforming tumor-associated macrophages to the M1phenotype via inhibition of the HIF-1α and mTOR signaling pathways.

Papain exerts an anti-atherosclerosis effect with suppressed MPA-mediated foam cell formation by regulating the MAPK and PI3K/Akt-NF-κB pathways.

BACKGROUND: Papain possesses a potential anti-atherosclerosis (AS) effect. This study aimed to explore the inhibitory effects of papain on the monocyte-platelet aggregates (MPAs)-mediated production of foam cells in vitro and AS in vivo. RESEARCH DESIGN AND METHODS: THP-1 cells were treated by platelet, papain, nuclear factor-κB (NF-κB) inhibitor or activator. An AS rat model was treated with papain. The THP-1 cells, macrophages, and foam cells were detected, and CD36, CD11b and CCR2 (macrophages) and CD14 and CD41 (MPAs) were measured. The levels of inflammatory factors, lipoprotein, and MAPK and PI3K/Akt -NF-κB pathways proteins were determined. Finally, injury of the thoracic aorta of AS rats was observed. RESULTS: Papain reduced macrophage production, lipid accumulation, and foam cell formation in vitro and downregulated the expression of monocyte chemoattractant protein 1 (MCP-1), prostaglandin E2 (PGE2), and cyclooxygenase 2 (COX2), and that of p38, JNK, Akt, and p65. Moreover, NF-κB activator could reversed the inhibitory effects of papain. Similarly, papain alleviated aortic smooth muscle hyperplasia, lipid droplet accumulation, and collagen diffusion and inhibited the expression of inflammatory factors and p38, JNK, Akt, and p65 in vivo. CONCLUSIONS: Papain inhibited MPA-induced foam cell formation by inactivating the MAPK and PI3K/Akt-NF-κB pathways, thereby exerting an anti-AS effect.

Plasma thrombin-activatable fibrinolysis inhibitor and the 1040C/T polymorphism are risk factors for diabetic kidney disease in Chinese patients with type 2 diabetes.

Background: Inflammatory and hemostatic disorders in diabetic microangiopathy (DMA) can be linked to thrombin-activatable fibrinolysis inhibitor (TAFI) and its own gene polymorphisms. Thus, the study aimed to investigate the associations of plasma TAFI and gene polymorphisms with DMA in Chinese patients with type 2 diabetes (T2D). Methods: Plasma TAFI of 223 patients with T2D was measured, and the genotypes and alleles of the 1040C/T, 438G/A, and 505G/A polymorphisms of the TAFI gene were analyzed. A ROC curve was constructed to evaluate the identifying power of TAFI between patients with T2D and DMA, and logistic regression analysis was used to observe the correlation of plasma TAFI and gene polymorphisms with the risk for DMA. Results: Plasma TAFI was higher in patients with DMA than in patients with only T2D (p < 0.05). TAFI exhibited the largest area under ROC in identifying diabetic kidney disease (DKD) from only T2D (0.763, 95% CI [0.674-0.853], p < 0.01), and adjusted multivariate analysis showed a high odds ratio (OR: 15.72, 95% CI [4.573-53.987], p < 0.001) for DKD. Higher frequencies of the CT genotype and T allele of the 1040C/T polymorphism were found in DKD compared with only T2D (respectively p < 0.05), and the CT genotype exhibited a high OR (1.623, 95% CI [1.173-2.710], p < 0.05) for DKD. DKD patients with the CT genotype had higher plasma TAFI levels, while T2D and DKD patients with CC/TT genotypes had lower plasma TAFI levels. Conclusion: Plasma TAFI and the CT genotype and T allele of the 1040C/T polymorphism are independent risk factors for DKD in Chinese T2D patients.

Predictive significance of joint plasma fibrinogen and urinary alpha-1 microglobulin-creatinine ratio in patients with diabetic kidney disease.

BACKGROUND: Although many biomarkers have high diagnostic and predictive power for diabetic kidney disease (DKD), less studies were performed for the predictive assessment in DKD and its progression with combined blood and urinary biomarkers. This study aims to explore the predictive significance of joint plasma fibrinogen (FIB) concentration and urinary alpha-1 microglobulin-creatinine (α1-MG/CR) ratio in DKD. METHODS: A total of 234 patients with type 2 diabetes were enrolled, and their clinical and laboratory data were retrospectively assessed. A ROC curve analysis was performed to evaluate the power of plasma FIB and urinary α1-MG/CR ratio for identifying DKD and advanced DKD, respectively. The predictive power for DKD and advanced DKD was analyzed by regression analysis. RESULTS: Plasma FIB and urinary α1-MG/CR levels were higher in patients with DKD than with pure T2D (p<0.001). The multivariate-adjusted odds ratios (ORs) were 5.047 (95%CI: 2.276-10.720) and 2.192 (95%CI: 1.539-3.122) (p<0.001) for FIB and α1-MG/CR as continuous variables for DKD prediction, respectively. The optimal cut-off values were 3.21 g/L and 2.11mg/mmol for identifying DKD, and 5.58 g/L and 11.07 mg/mmol for advanced DKD from ROC curves. At these cut-off values, the sensitivity and specificity of joint FIB and α1-MG/CR were 0.95 and 0.92 for identifying DKD, and 0.62 and 0.67 for identifying advanced DKD, respectively. The area under curve was 0.972 (95%CI: 0.948-0.995) (p<0.001) and 0.611, 95%CI: 0.488-0.734) (p>0.05). The multivariate-adjusted ORs for joint FIB and α1-MG/CR at the cut-off values were 214.500 (95%CI: 58.054-792.536) and 3.252 (95%CI: 1.040-10.175) (p<0.05), respectively. CONCLUSION: The present study suggests that joint plasma FIB concentration and urinary α1-MG/CR ratio can be used as a powerful predictor for general DKD, but it is less predictive for advanced DKD.

Stratification of diabetic kidney diseases via data-independent acquisition proteomics-based analysis of human kidney tissue specimens.

Aim: The aims of this study were to analyze the proteomic differences in renal tissues from patients with diabetes mellitus (DM) and diabetic kidney disease (DKD) and to select sensitive biomarkers for early identification of DKD progression. Methods: Pressure cycling technology-pulse data-independent acquisition mass spectrometry was employed to investigate protein alterations in 36 formalin-fixed paraffin-embedded specimens. Then, bioinformatics analysis was performed to identify important signaling pathways and key molecules. Finally, the target proteins were validated in 60 blood and 30 urine samples. Results: A total of 52 up- and 311 down-regulated differential proteins were identified as differing among the advanced DKD samples, early DKD samples, and DM controls (adjusted p<0.05). These differentially expressed proteins were mainly involved in ion transport, apoptosis regulation, and the inflammatory response. UniProt database analysis showed that these proteins were mostly enriched in signaling pathways related to metabolism, apoptosis, and inflammation. NBR1 was significantly up-regulated in both early and advanced DKD, with fold changes (FCs) of 175 and 184, respectively (both p<0.01). In addition, VPS37A and ATG4B were significantly down-regulated with DKD progression, with FCs of 0.140 and 0.088, respectively, in advanced DKD and 0.533 and 0.192, respectively, in early DKD compared with the DM control group (both p<0.01). Bioinformatics analysis showed that NBR1, VPS37A, and ATG4B are closely related to autophagy. We also found that serum levels of the three proteins and urine levels of NBR1 decreased with disease progression. Moreover, there was a significant difference in serum VPS37A and ATG4B levels between patients with early and advanced DKD (both p<0.05). The immunohistochemistry assaay exhibited that the three proteins were expressed in renal tubular cells, and NBR1 was also expressed in the cystic wall of renal glomeruli. Conclusion: The increase in NBR1 expression and the decrease in ATG4B and VPS37 expression in renal tissue are closely related to inhibition of the autophagy pathway, which may contribute to DKD development or progression. These three proteins may serve as sensitive serum biomarkers for early identification of DKD progression.

Papain ameliorates monocyte-platelet aggregate formation-mediated inflammatory responses in monocytes by upregulating miRNA-146a transcription.

BACKGROUND: MicroRNA-146a (miRNA-146a) is a nuclear factor κB (NF-κB)-inducible and inflammation-sensitive miRNA, while papain elicits anti-inflammatory effects by inhibiting monocyte-platelet aggregate (MPA)-mediated NF-κB pathway activation in monocytes. This study aimed to demonstrate the underlying effects of papain on MPA formation-initiated miRNA-146a expression and subsequent action in monocytes. METHODS: THP-1 cells were exposed to papain, miRNA-146a mimic and inhibitor, NF-κB inhibitor (BAY11-7082), and platelets. Flow cytometry was used to measure the MPA formation-initiated monocyte activation. Levels of miRNA-146a, cyclooxygenase 2 (COX-2) mRNA and protein, and monocyte chemoattractant protein 1 (MCP-1) were analyzed in monocytes by RT-PCR, western blot, and ELISA. RESULTS: The NF-κB inhibitor and miRNA-146a mimics upregulated miRNA-146a expression but suppressed subsequent monocyte activation and expression of COX-2 and MCP-1. Following exposure to papain, the enhanced miRNA-146a transcription induced by MPA-formation was found along with significant inhibition of monocyte activation in a dose-dependent manner. However, the inhibitory tendency was significantly reversed by miRNA-146a inhibitors. Expression of COX-2 mRNA and protein, as well as MCP-1, was inhibited in monocytes by papain, whereas miRNA-146a inhibitors promoted COX-2 and MCP-1 expression. CONCLUSION: Our findings suggest that papain can inhibit MPA formation-mediated expression of inflammatory mediators in activated monocytes by upregulating miRNA-146a transcription.

Monocyte-lymphocyte ratio is a valuable predictor for diabetic nephropathy in patients with type 2 diabetes.

Diabetic nephropathy (DN) is serious threat to human health. Therefore, early prediction of its occurrence is important. This study aimed to assess the predictive significance of monocyte-lymphocyte ratio (MLR) for DN.A total of 301 patients with type 2 diabetes (T2D), including 212 T2D patients without diabetic-related complications and 99 DN patients, were enrolled. Peripheral white blood cells were measured before treatment to calculate MLR, and the risk factors and predictive significance for T2D and DN were assessed.T2D patients without diabetic-related complications had higher MLR than control patients (P < .01). However, MLR was significantly higher in DN patients than in T2D patients without diabetic-related complications (P < .001). According to MLR quartiles, higher MLR in DN patients was correlated with higher serum creatinine, estimated glomerular filtration rate, and urinary albumin excretion (UAE) levels (P < .01 or P < .001). Furthermore, MLR was positively correlated with UAE level (R = 0.5973; P < .01) and an independent predictor for DN (odds ratio: 7.667; 95% confidence interval [CI]: 3.689-21.312; P < .001). The area under the receiver-operating characteristic (ROC) curve for MLR was 0.874 (95%CI: 0.830-0.918, P < .001). When the optimal cutoff value was 0.23, the sensitivity and specificity of MLR for DN prediction were 0.85 and 0.74, respectively.The present findings suggest that MLR is a powerful independent predictor for DN.

Predicting significance of COX-2 expression of peripheral blood monocyte in patients with coronary artery disease.

BACKGROUND: Cyclooxygenase-2 (COX-2) plays an important role in the monocyte-platelet aggregate (MPA)-medicated inflammatory response and possible coronary artery disease (CAD). This study aimed to assess the predicting significance of COX-2 expression in peripheral blood monocyte for CAD. METHODS: A total of 66 patients with CAD including stable angina (SA) and unstable angina (UA) were enrolled. The inflammatory indexes including white blood cell (WBC) count, high-sensitive C reactive protein (hs-CRP), serum monocyte chemoattractant protein-1 (MCP-1) and MPA levels were measured. The western-blotting assay and reverse transcription-polymerase chain reaction (RT-PCR) analysis were used to detect the COX-2 expression in peripheral blood monocytes. Furthermore, the correlation between COX-2 expression and MPA levels, and the association of COX-2 expression with CAD risk were assessed. RESULTS: The UA patients demonstrated higher levels of inflammatory indexes than the SA patients (P<0.001). Simultaneously, higher MPA levels and enhanced COX-2 expression were observed in the UA patients (P<0.01). The patients with enhanced COX-2 expression exhibited higher MPA than those without (P<0.01), and patients with increased MPA also demonstrated enhanced COX-2 expression (P<0.001). Moreover, the levels of COX-2 protein expression was positively related to the MPA formation rates (R2=0.4933, P<0.01), and enhanced COX-2 expression was independently associated with CAD risk [odds ratio (OR): 6.322, 95% confidence interval (CI): 4.544-8.978 ]. CONCLUSIONS: The COX-2 expression of peripheral blood monocytes can be used as an independent predictor for CAD.

Clinical and prognostic significance of combined plasma fibrinogen concentrations and the monocyte-to-lymphocyte ratio in patients with ovarian cancer.

BACKGROUND: Fibrinogen concentrations and the monocyte-to-lymphocyte ratio (FC-MLR) are associated with progression and outcomes of many malignancies. This study aimed to assess the clinical and prognostic significance of the combination of plasma FC-MLR in patients with ovarian cancer. METHODS: A total of 155 patients with epithelial ovarian cancer (EOC) and 102 patients with benign gynecological disease were retrospectively reviewed. The clinical and pathological data of all patients with EOC were analyzed. Plasma fibrinogen concentrations and the white blood cell (WBC) count were measured to calculate the MLR and neutrophil-to-lymphocyte ratio (NLR). Furthermore, the association of fibrinogen concentrations, the MLR, and FC-MLR with tumor stage, lymphatic and venous metastasis, and 5-year survival was assessed. Regression analysis was performed to evaluate the risk factors for progression of EOC. Receiver operating characteristic (ROC) curves were constructed to assess the prognostic power of plasma fibrinogen concentrations, the MLR, and FC-MLR, and to determine the optimal cutoff values of fibrinogen and the MLR. On the basis of the cutoff values, patients with EOC were divided into three groups: no abnormality, either increased, and both increased groups, respectively. The effect of FC-MLR on overall survival was calculated by the Kaplan-Meier method and compared by the log-rank test in the three groups. RESULTS: Patients with EOC had higher fibrinogen concentrations and a higher MLR than did controls (both P<0.01), and FC-MLR was closely associated with tumor stage and lymphatic and venous metastasis (all P<0.001). Furthermore, FC-MLR was an independent risk factor for progression of EOC (OR =8.985; 95% CI: 4.912-27.166; P<0.001), and patients with high fibrinogen concentrations and a high MLR showed a lower 5-year survival rate (P<0.001). CONCLUSIONS: FC-MLR may be used as a predictor of tumor progression and prognosis for ovarian cancer.

Papain Ameliorates the MPAs Formation-Mediated Activation of Monocytes by Inhibiting Cox-2 Expression via Regulating the MAPKs and PI3K/Akt Signal Pathway.

Monocytes activation and subsequent inflammatory response mediated by monocyte-platelet aggregates (MPAs) formation play the key roles in the early pathogenesis of atherosclerosis (AS). Exploration of novel drugs to ameliorate MPAs formation-mediated monocytes activation would be helpful for the treatment of AS patients. Papain has definite pharmacological effects including antiplatelet, thrombolysis, and anti-inflammation. However, its effect on MPAs formation and the following monocytes activation remains vague. This study aimed to illustrate the underlying mechanisms of papain on MPAs formation-initiated monocytes activation in vitro. In this study, Papain, Cox-2 inhibitor (NS-398), and NF-κB agonist (TNF-α) were used as the treating agents, respectively. MPAs formation and activated monocytes were measured by flow cytometry (FCM). Cox-2 mRNA, MCP-1, and proteins of Cox-2 and NF-κB signal pathway were detected by qRT-PCR, ELISA, and western blotting, respectively. As we observed, papain exhibited the powerful inhibitory effects on thrombin-mediated MPAs formation and monocytes activation in a concentration-dependent manner as what Cox-2 inhibitor demonstrated. However, the inhibitory tendency was significantly reversed by TNF-α. We also discovered that both Cox-2 mRNA and protein expression as well as the release of MCP-1 of monocyte was inhibited by either papain or NS-398, but TNF-α stimulated Cox-2 expression and release of MCP-1. The results of western blotting assay indicated that thrombin-mediated proteins expression of MAPKs and PI3K/Akt signal pathway was inhibited by papain and NS-398. However, TNF-α notably abated the inhibitory effects of papain on the process of MPAs-initiated monocytes activation. Our findings suggest that papain can inhibit the MPAs formation-mediated activation of monocytes by inhibiting the MAPKs and PI3K/Akt signal pathway.

Thyroid stimulating hormone and free triiodothyronine are valuable predictors for diabetic nephropathy in patient with type 2 diabetes mellitus.

BACKGROUND: Diabetes seriously threatens human health, and diabetic nephropathy (DN) is one of the serious diabetic complications. Therefore, it is valuable to predict the occurrence of DN early. This study aims to evaluate the predicting significance of thyroid hormones for DN. METHODS: A total of 301 type 2 diabetes mellitus (T2DM) patients were enrolled. Thyroid hormones before treatment were measured, and the risk factors and their predicting significance for T2DM and DN were assessed. RESULTS: The results indicated that there was no statistical difference in any investigated variable between controls and patients without complications (P>0.05). However, patients with DN exhibited lower levels of triiodothyronine (T3) and free triiodothyronine (FT3), but higher levels of thyroid stimulating hormone (TSH) than T2DM patients without complications (P<0.001). Multivariate analysis did not demonstrate any thyroid hormone as the independent risk factor for T2DM without complications, but revealed increased TSH and decreased T3 and FT3 as the independent risk factors for patients with DN [odds ratio (OR): 2.087, 95% CI: 1.525-3.303; 1.335, 95% CI: 1.101-1.621; 7.414, 95% CI: 4.319-13.986; P<0.001, respectively]. The area under receiver operating characteristic (ROC) curve of TSH, FT3 and T3 was 0.850 (95% CI: 0.776-0.923), 0.824 (95% CI: 0.751-0.897), and 0.620 (95% CI: 0.515-0.725) for DN prediction. Based on their cutoff values of 1.85 mIU/L, 2.31 ng/L, and 0.61 µg/L, the sensitivity was 82%, 78%, and 64%, and the specificity was 77%, 79%, and 85%, respectively. CONCLUSIONS: Our findings suggest that TSH and FT3 are useful predictors for DN in patients with T2DM.

Clinical Significance of Hemostatic Parameters in the Prediction for Type 2 Diabetes Mellitus and Diabetic Nephropathy.

It would be important to predict type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN). This study was aimed at evaluating the predicting significance of hemostatic parameters for T2DM and DN. Plasma coagulation and hematologic parameters before treatment were measured in 297 T2DM patients. The risk factors and their predicting power were evaluated. T2DM patients without complications exhibited significantly different activated partial thromboplastin time (aPTT), platelet (PLT), and D-dimer (D-D) levels compared with controls (P < 0.01). Fibrinogen (FIB), PLT, and D-D increased in DN patients compared with those without complications (P < 0.001). Both aPTT and PLT were the independent risk factors for T2DM (OR: 1.320 and 1.211, P < 0.01, resp.), and FIB and PLT were the independent risk factors for DN (OR: 1.611 and 1.194, P < 0.01, resp.). The area under ROC curve (AUC) of aPTT and PLT was 0.592 and 0.647, respectively, with low sensitivity in predicting T2DM. AUC of FIB was 0.874 with high sensitivity (85%) and specificity (76%) for DN, and that of PLT was 0.564, with sensitivity (60%) and specificity (89%) based on the cutoff values of 3.15 g/L and 245 × 109/L, respectively. This study suggests that hemostatic parameters have a low predicting value for T2DM, whereas fibrinogen is a powerful predictor for DN.

Opposite effects of Agrimonia pilosa Ledeb aqueous extracts on blood coagulation function.

BACKGROUND: Agrimonia pilosa Ledeb (APL) has showed anticoagulant and antithrombotic activities in some studies, whereas its actual effects on blood coagulation are still unclear. This study was designed to observe the in vitro effects of APL aqueous extracts on blood coagulation, as well as to investigate the underlying mechanisms. METHODS: Studies were divided into four groups: 0, 4, 20, and 80 g/L of APL aqueous extracts mixed with plasma or whole blood samples. Clotting time of whole blood, plasma coagulation tests, activities of plasma coagulation factors, plasma calcium ion, platelet aggregation test, and platelet fibrinogen receptor as well as the blood viscosity were measured. RESULTS: It was observed that the APL aqueous extracts in 4 g/L significantly prolonged the whole blood clotting time and activated partial thromboplastin time, shortened prothrombin time, decreased activities of coagulation factor VIII, IX and XI, and levels of platelet aggregation and fibrinogen receptor expression. However, coagulation factor VII activity, and blood viscosity were increased after the extracts treatment. And the effects of APL extracts were in a concentration-dependent manner (0-80 g/L). CONCLUSIONS: The results suggest that APL aqueous extracts have a total anticoagulant activity, whereas they exhibit opposite effects of greater anticoagulant activity than pro-coagulant activity.

Tissue Factor Pathway Inhibitor-1 Is a Valuable Marker for the Prediction of Deep Venous Thrombosis and Tumor Metastasis in Patients with Lung Cancer.

Activation of blood coagulation contributes to cancer progression. Tissue factor pathway inhibitor-1 (TFPI-1) is the main inhibitor of extrinsic coagulation pathway. The aim of this study is to assess the predicting significance of TFPI-1 for thrombotic complication and metastasis in lung cancer patients. Total of 188 non-small cell lung cancer (NSCLC) patients were included in this study. Plasma TFPI-1, D-dimer (D-D), antithrombin (AT), Fibrinogen (Fbg), and coagulating factor VIII activity (FVIII:C) were measured. In NSCLC patients, significantly decreased TFPI-1 and AT and increased D-D, Fbg, and FVIII:C levels were observed, and there was a significant correlation between TFPI-1 and other hemostatic parameters (P < 0.001, resp.). NSCLC patients with deep venous thrombosis (DVT) or metastasis had significantly lower TFPI-1 levels than those without DVT or metastasis (P < 0.01, resp.). Multivariate regression revealed that TFPI-1 acted as a predictor for DVT or tumor metastasis in NSCLC patients [OR: 4.15 or 3.28, P < 0.05, resp.]. The area under ROC curve of TFPI-1 was 0.905 (95% CI, 0.842~0.967) or 0.828 (95% CI, 0.742~0.915) for predicting DVT or metastasis (P < 0.001, resp.). The optimal point of TFPI-1 was 57.7 or 54.3 ng/mL for predicting DVT or metastasis, respectively. Combination of TFPI-1 and D-D measurements can improve the predicting power for DVT or metastasis in NSCLC patients. Our findings suggested that TFPI-1 was a valuable predictor of DVT and tumor metastasis in NSCLC patients.

Clinical and Prognostic Significance of Lupus Anticoagulant Measurement in Patients With Lung Cancer.

Lupus anticoagulants is related to both recurrent thrombosis and cancer. Thrombotic complications occur more frequently in patients with lung cancer. The aim of this study is to investigate the association of lupus anticoagulants with hypercoagulability and thrombotic complications, as well as prognostic significance of lupus anticoagulants for patients with lung cancer. The study comprised 205 patients with non-small cell lung cancer. Plasma normalized LAC ratio, D-dimer, fibrinogen, activities of antithrombin, and FVIII before treatment were analyzed by coagulation analyzer, and routine hematologic and biochemical parameters were also evaluated. In patients, normalized LAC ratio, D-dimer, fibrinogen, and procoagulant activity of coagulating factor VIII levels significantly increased, whereas antithrombin activity significantly decreased compared with healthy controls (P < .001). Normalized LAC ratio was positively correlated with D-dimer, fibrinogen, and procoagulant activity of coagulating factor VIII, and negatively correlated with antithrombin activity, respectively (P < .01). D-dimer, procoagulant activity of coagulating factor VIII, and antithrombin levels revealed statistical difference in non-deep venous thrombosis patients with elevated or normal normalized LA ratio (P < .05). The incidence of deep venous thrombosis and tumor metastasis was higher, and 1-year survival rate was lower in elevated normalized LAC ratio patients than in normal ones, respectively (P < .01). There was higher normalized LAC ratio level in patients with deep venous thrombosis and/or metastasis (P < .05). In 1-year deceased patients, normalized LAC ratio level and the incidence of deep venous thrombosis and metastasis were higher than those in survivors, respectively (P < .05). Hazard regression analysis demonstrated normalized LAC ratio was independently associated with short survival time in patients with non-small cell lung cancer (hazard regression: 2.871, 95%confidence interval: 1.704-4.835; χ2: 19.130; P < .01). Our study suggests that lupus anticoagulants is a useful marker to predict thrombotic complications and prognosis in patient with lung cancer.

D-Dimer levels are correlated with disease activity in Crohn's patients.

Various indices have been used to assess Crohn's disease (CD). However, the question of whether the Crohn's Disease Activity Index (CDAI) is associated with coagulation function has not been fully confirmed. In this study, we examined the association between CDAI and the coagulation and fibrinolysis parameters. In a retrospective and observational cohort study, the CDAI of 108 patients from two hospital centers was calculated, and its correlations with the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), international normalization ratio (INR), fibrinogen (Fg) and plasma D-Dimer were investigated. Significant differences were found for PT, APTT, TT, INR, Fg and D-Dimer between the healthy controls and CD patients. However, no significant difference was found between the CDAI-High and CDAI-Low groups of CD patients. Moreover, the CDAI was positively correlated with the level of D-Dimer in CD patients of two hospitals, regardless of the detection method (hospital 1: r=0.3268, p= 0.0042; hospital 2: r=0.5553, p=0.0008). Among the blood coagulation and fibrinolysis parameters, the D-Dimer level was highly correlated with CDAI in CD patients. Thus, the level of D-Dimer expression may be a promising new marker for assessing CD disease activity.