The relationship between sex hormones and glycated hemoglobin in a non-diabetic middle-aged and elderly population.

BACKGROUND: Sex hormones are strongly linked to the occurrence and development of diabetes, and influence glycated hemoglobin (HbA1c) levels in diabetic population; but, the relationship between sex hormones and HbA1c in non-diabetic population remains unknown. This study aimed to explore the extent of influence of sex hormones on HbA1c levels in non-diabetic population. METHODS: A total of 1409 non-diabetic subjects, including 601 men and 808 postmenopausal women were recruited from Shanghai community. HbA1c was detected using high performance liquid chromatography, and hemoglobin level was determined by sodium lauryl sulfate colorimetry. Serum estradiol (E2), total testosterone (TT), and sex hormone binding globulin (SHBG) were measured by chemiluminescent microparticle immunoassays. RESULTS: The level of HbA1c was 5.6 (5.4-5.9) % in all subjects, with 5.6 (5.4-5.8) % in men and 5.7 (5.5-5.9) % in postmenopausal women. After adjusting for age, body mass index (BMI), and hemoglobin, E2 was positively correlated with HbA1c in men (r = 0.122, P = .003), and SHBG was inversely correlated with HbA1c (r = - 0.125, P < .001) in women. Other hormones were not correlated with HbA1c (all P > .05). Multivariate linear regression analysis showed that, except for traditional factors, such as age, hemoglobin, and BMI, E2 was another determinant of HbA1c (standardized ß = 0.137, P = .003) in men; besides, in women, SHBG was another determinant of HbA1c (standardized ß = - 0.178, P < .001), except for age and systolic blood pressure. CONCLUSION: After controlling for confounding factors, two sex hormones, as E2 and SHBG could influence HbA1c levels in non-diabetic population.

Development of Multimarker Diagnostic Models from Metabolomics Analysis for Gestational Diabetes Mellitus (GDM).

Although metabolomics are desirable to understand the pathophysiology of gestational diabetes mellitus (GDM), comprehensive metabolomic studies of GDM are rare. We aimed to offer a holistic view of metabolites alteration in GDM patients and investigate the possible multimarker models for GDM diagnosis. Biochemical parameters and perinatal data of 131 GDM cases and 138 controls were collected. Fasting serum samples at 75 g oral glucose tolerance test were used for metabolites by ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometry, ultra performance liquid chromatography-triple triple-quadrupole-mass spectrometry and gas chromatography- time-of- flight mass spectrometry platforms. Significant changes were observed in free fatty acids, bile acids, branched chain amino acids, organic acids, lipids and organooxygen compounds between two groups. In receiver operating characteristic (ROC) analysis, different combinations of candidate biomarkers and metabolites in multimarker models achieved satisfactory discriminative abilities for GDM, with the values of area under the curve (AUC) ranging from 0.721 to 0.751. Model consisting of body mass index (BMI), retinol binding protein 4 (RBP4), n-acetylaspartic acid and C16:1 (cis-7) manifested the best discrimination [AUC 0.751 (95% CI: 0.693-0.809), p < 0.001], followed by model consisting of BMI, Cystatin C, acetylaspartic acid and 6,7-diketoLCA [AUC 0.749 (95% CI: 0.691-0.808), p < 0.001]. Metabolites alteration reflected disorders of glucose metabolism, lipid metabolism, amino acid metabolism, bile acid metabolism as well as intestinal flora metabolism in GDM state. Multivariate models combining clinical markers and metabolites have the potential to differentiate GDM subjects from healthy controls.

Heterogeneity of insulin resistance and beta cell dysfunction in gestational diabetes mellitus: a prospective cohort study of perinatal outcomes.

BACKGROUND: Insulin resistance and beta cell dysfunction were reported to be responsible for gestational diabetes mellitus (GDM). However, little is known about the heterogeneity of these factors and its influences on perinatal outcomes. We investigated whether subtypes of insulin resistance and beta cell dysfunction in gestational diabetes mellitus have different impacts on perinatal outcomes. METHODS: In this prospective cohort study, we followed 554 pregnant women and glucose challenge test was performed at 24-28th weeks of their gestation. Women with plasma glucose ≥ 7.8 mmol/L would be included and advised to undergo the diagnostic 75-g, 3-h oral glucose tolerance test. According to indices of measuring insulin resistance or beta cell function were below the 25th percentile of women with normal glucose tolerance (NGT), women with GDM were defined as three subtypes: GDM with the beta cell dysfunction, GDM with the insulin resistance defect or GDM with both traits mentioned above (GDM-mixed). Perinatal outcomes were documented. RESULTS: The levels of prepregnancy and maternal BMI in the GDM-mix group were higher compared to women in the NGT group (23.2 ± 4.0 vs 20.8 ± 3.7 kg/m2, P < 0.001; 24.5 ± 4.3 vs 21.8 ± 3.4 kg/m2, P < 0.001, respectively). Furthermore, women in GDM-mix group more likely to be subjected to LGA (P = 0.008) adverse perinatal outcomes (P = 0.005), although these differences were normalized after adjusting age, prepregnancy and maternal BMI (GDM-mix vs. NGT: P = 0.141 for LGA and P = 0.186 for adverse outcomes). On the other hand, all perinatal outcomes were similar between other two GDM subgroups and NGT group. CONCLUSIONS: Women with GDM display respective characteristics on metabolism disorders and confer discriminating risks of adverse perinatal outcomes because of this heterogeneity.

High cystatin C levels predict undesirable outcome for diabetic foot ulcerations.

We investigated the relationship between serum cystatin C levels and the prognosis of diabetic foot ulcerations (DFU). A population-based cohort study involving 1018 patients with type 2 diabetes was conducted. These patients recruited and divided into two groups: nondiabetic foot ulcer group (NDF, n = 865, 85.5%) and diabetic foot ulcer group (DFU, n = 147, 14.5%).After a 1-year-follow-up, DFUs were grouped into healing (n = 110, 74.8%) and nonhealing (n = 37, 25.2%) group based on the clinical prognosis. Compared with the healing group, the nonhealing group were older, had long diabetic duration and had significantly increased serum cystatin C concentrations in DFU (p < 0.01). After adjustments for age, diabetes duration, renal function and infection control, multiple logistical regression analysis revealed that cystatin C remained associated increased risk of undesirable DFU outcome (OR = 7.279, 95% CI: 1.299-40.784, p < 0.05). When divided into quartiles according to cystatin C levels, the healing rate of Quartile 4 was significantly lower (57.9%) compared with other groups (p < 0.01). The odd is ratio (OR) analysis showed that the risk of undesirable DFU outcome in Quartile 4 was significantly higher (OR = 4.554, 95% CI: 3.14-5.12, p < 0.05) compared with that in Quartile 1. We concluded that there was a strong and independent association between serum cystatin C and diabetic foot ulceration prognosis, cystatin C > 1.35 mg/L predicts more than sixfold increased risk of incurable foot ulceration.

Association between serum osteocalcin level and visceral obesity in Chinese postmenopausal women.

BACKGROUND: A low serum osteocalcin level, visceral obesity and postmenopausal status are recognized risk factors for cardiovascular disease. OBJECTIVE: We investigated the relationship between the serum osteocalcin level and visceral fat content in a population of Chinese postmenopausal women. DESIGN AND PATIENTS: In total, 1481 postmenopausal women (mean age ± standard deviation, 57·1 ± 4·8 years) were selected from the Shanghai Obesity Study. MEASUREMENTS: Abdominal fat accumulation was quantified using magnetic resonance imaging. Subjects with a visceral fat area (VFA) of ≥80 cm(2) were classified as abdominally obese. The total serum osteocalcin level was measured by electrochemiluminescence immunoassay. RESULTS: The median serum osteocalcin level was 20·66 µg/l (interquartile range, 16·88-25·42 µg/l). The overall prevalence of abdominal obesity was 49·1% (n = 727). Abdominally obese subjects had lower serum osteocalcin levels than did nonabdominally obese subjects [19·14 (16·02-23·82) vs 21·97 (18·14-26·77) µg/l, respectively; P < 0·001]. Partial correlation analysis showed that the serum osteocalcin level was still negatively correlated with VFA after adjusting for age, years since menopause and body mass index (P < 0·01). Moreover, VFA was independently associated with the serum osteocalcin level after adjustment for confounding factors (P < 0·05). A low serum osteocalcin level was an independent risk factor for abdominal obesity (odds ratio, 0·972; 95% confidence interval, 0·953-0·991; P = 0·004). CONCLUSION: The serum osteocalcin level was inversely correlated with the visceral fat content in these Chinese postmenopausal women.

Associations of glycated haemoglobin A1c and glycated albumin with subclinical atherosclerosis in middle-aged and elderly Chinese population with impaired glucose regulation.

The aim of this study was to investigate the correlations of glycated haemoglobin A1c (HbA1c) and glycated albumin (GA) with subclinical atherosclerosis in middle-aged and elderly Chinese populations with impaired glucose regulation (IGR). In total, 640 subjects with IGR and no history of cardiovascular disease or carotid artery plaque were recruited for this study (256 men, 384 women; age range, 40-70 years). The carotid intima-media thickness (C-IMT) measured by carotid ultrasonography was used as an indicator of subclinical atherosclerosis. Increased C-IMT was defined as ≥ 0.70 mm (upper quartile). HbA1c and GA were measured with high-performance liquid chromatography and enzymatic method, respectively. The average HbA1c and GA among all 640 subjects were 5.7 ± 0.3% and 14.0 ± 1.1%, respectively. HbA1c and GA were higher in subjects with increased C-IMT than in subjects with normal C-IMT (5.8 ± 0.3% vs 5.7 ± 0.3% and 14.2 ± 1.0% vs 13.9 ± 1.1%, respectively; both P < 0.01). Correlation analysis showed that both HbA1c and GA were positively correlated with C-IMT (r = 0.135 and 0.112, respectively; both P < 0.01). Logistic regression analysis revealed that both HbA1c (odds ratio (OR), 2.630; 95% confidence interval (95% CI), 1.401-4.935; P = 0.003) and GA OR, 1.215; 95% CI, 1.008-1.466; P = 0.041) were independent risk factors for increased C-IMT. Both HbA1c and GA reflect the risk of subclinical atherosclerosis in middle-aged and elderly Chinese populations with IGR.

Serum lipocalin-2 levels positively correlate with coronary artery disease and metabolic syndrome.

BACKGROUND: The lipocalin-2 (LCN2) cytokine, primarily known as a protein of the granules of human neutrophils, has been recently reported to be implicated in metabolic and inflammatory disorders. This study was designed to evaluate the relationship between serum LCN2 levels and coronary artery disease (CAD). METHODS: Serum LCN2 levels of 261 in-patients who underwent coronary angiography were measured by sandwich enzyme immunoassay. Demographic (169 men and 92 postmenopausal women) and clinical (metabolic syndrome (MS), triglyceride (TG) and C-reactive protein (CRP) levels) characteristics were collected to assess independent factors of CAD (CAD: 188 and non-CAD: 73) and serum LCN2 levels by multiple logistic regression and multivariate stepwise regression analyses, respectively. RESULTS: Serum LCN2 levels were significantly higher in men (37.5 (27.4-55.4) vs. women: 28.2 (18.7-45.9) ng/mL, p < 0.01) and men with CAD (39.2 (29.3-56.5) vs. non-CAD men: 32.7 (20.5-49.7) ng/mL, p < 0.05), and showed significant positive correlation with CAD in men (odds ratio = 2.218, 95% confidence interval: 1.017-4.839). Similarly, serum LCN2 levels were significantly higher in men with MS (40.2 (31.9-59.4) vs. non-MS: 32.0 (21.7-47.6) ng/mL, p < 0.01) and showed a significant positive correlation with the number of MS components (p for trend < 0.05). No significant differences or correlations were seen in women. TG and neutrophils (standard ß = 0.238 and 0.173) were independent factors of serum LCN2 levels in men, and only neutrophils (standard ß = 0.286) affected levels in women (all p < 0.05). CONCLUSIONS: Increased serum LCN2 levels are positively correlated with the presence of CAD and MS in a Chinese cohort.

[Relationship between glycated albumin level and pancreatic ß cell function in newly diagnosed type 2 diabetics].

OBJECTIVE: To explore the relationship between glycated albumin (GA) level and pancreatic ß cell function in newly diagnosed type 2 diabetics. METHODS: The subjects sought the confirmation of diabetes diagnosis or underwent diabetes screening tests in high-risk patients from January 2008 to October 2010. All of them underwent 75 g oral glucose tolerance test (OGTT) and insulin releasing test. The levels of GA and hemoglobin A1c (HbA1c) were analyzed by liquid enzymatic method and high performance liquid chromatography respectively. Homeostasis model assessment (HOMA) was used to evaluate the basal insulin resistance (HOMA-IR) and pancreatic ß cell function (HOMA-ß). ΔI30/ΔG30 was used to evaluate early-phase insulin secretion after a glucose load. RESULTS: (1) Among 500 type 2 diabetics according to the diagnostic criteria of WHO (1999), 279 were males and 221 were females. Average age was 56.3 ± 12.3, GA (21.1 ± 5.4)% and HbA1c (7.0 ± 1.3)%. (2) A significantly positive relationship was shown between HbA1c and GA (r = 0.691, P < 0.01). GA was also positively correlated with fasting plasma glucose (FPG), 0.5 hPG, 1 hPG, 2 hPG and 3 hPG after a glucose load of OGTT test (r = 0.511 - 0.627, P < 0.01). (3) GA was negatively correlated with body mass index (BMI) (r = -0.112, P < 0.01), HOMA-ß (r = -0.350, P < 0.01) and ΔI30/ΔG30 (r = -0.263, P < 0.01). (4) Multivariant stepwise regression analysis showed that HbA1c, FPG, 3 hPG and ΔI30/ΔG30 were independent factors of GA level. CONCLUSION: Glycated albumin level is closely correlated with the function of early-phase insulin secretion in newly diagnosed type 2 diabetics.

[Associations of glycated albumin level with coronary artery disease].

OBJECTIVE: To explore the associations of the level of glycated albumin (GA) with coronary artery disease (CAD). METHODS: A total of 306 patients undergoing coronary angiography (CA) were collected. There were 201 males and 105 females with an age range of 38-86 years. CA was the major diagnostic criteria of CAD. Metabolic syndrome was diagnosed according to the Guideline on Prevention & Treatment of Blood Lipid Abnormality in Chinese Adults. RESULTS: (1) CAD was found in 227 patients (74.2%). The levels of 2 h postprandial glucose, GA and hemoglobin A1c in the CAD patients were higher than those in the non-CAD counterparts (all P < 0.05). (2) In the subgroup of normal glucose tolerance (NGR), the CAD patients had a higher level of GA than the non-CAD patients ((15.0 ± 2.1)% vs (13.3 ± 1.7)%, P < 0.01). And the level of GA was higher in the patients with 1-vessel ((14.8 ± 2.1)% vs (13.3 ± 1.7)%, P < 0.05) and multi-vessel lesions ((15.1 ± 2.1)% vs (13.3 ± 1.7)%, P < 0.05) than that in the non-CAD counterparts (all P < 0.05). Similar results were obtained in the hyperglycemia subgroup. (3) Logistic regression demonstrated that the level of GA was independently correlated with CAD after adjusting other traditional factors among all subjects, NGR and hyperglycemia subgroup. CONCLUSIONS: The serum level of GA becomes significantly elevated the CAD patients. And it is an independent risk factor of CAD in both hyperglycemic and NGR patients.

Targeting the lncRNA DUXAP8/miR-29a/PIK3CA Network Restores Doxorubicin Chemosensitivity via PI3K-AKT-mTOR Signaling and Synergizes With Inotuzumab Ozogamicin in Chemotherapy-Resistant B-Cell Acute Lymphoblastic Leukemia.

Purpose: This study aimed to determine the expression profiles of long non-coding RNA (lncRNA), microRNA (miRNA), and mRNA in chemotherapy-resistant B-cell acute lymphoblastic leukemia (B-ALL). Methods: LncRNA, miRNA, and mRNA profiles were assessed by RNA-seq in diagnostic bone marrow samples from 6 chemotherapy-resistant and 6 chemotherapy-sensitive B-ALL patients. The lncRNA DUXAP8/miR-29a/PIK3CA signaling network was identified as the most dysregulated in chemoresistant patient samples, and its effect on cellular phenotypes, PI3K-AKT-mTOR signaling, and chemosensitivity of doxorubicin (Dox)-resistant Nalm-6 (N6/ADR), and Dox-resistant 697 (697/ADR) cells were assessed. Furthermore, its synergy with inotuzumab ozogamicin treatment was investigated. Results: 1,338 lncRNAs, 75 miRNAs, and 1620 mRNAs were found to be dysregulated in chemotherapy-resistant B-ALL in comparison to chemotherapy-sensitive B-ALL patient samples. Through bioinformatics analyses and RT-qPCR validation, the lncRNA DUXAP8/miR-29a/PIK3CA network and PI3K-AKT-mTOR signaling were identified as significantly associated with B-ALL chemotherapy resistance. In N6/ADR and 697/ADR cells, LncRNA DUXAP8 overexpression and PIK3CA overexpression induced proliferation and inhibited apoptosis, and their respective knockdowns inhibited proliferation, facilitated apoptosis, and restored Dox chemosensitivity. MiR-29a was shown to affect the lncRNA DUXAP8/PIK3CA network, and luciferase reporter gene assay showed direct binding between lncRNA DUXAP8 and miR-29a, as well as between miR-29a and PIK3CA. Targeting lncRNA DUXAP8/miR-29a/PIK3CA network synergized with inotuzumab ozogamicin's effect on N6/ADR and 697/ADR cells. Conclusion: Targeting the lncRNA DUXAP8/miR-29a/PIK3CA network not only induced an apoptotic effect on Dox-resistant B-ALL and restored Dox chemosensitivity via PI3K-AKT-mTOR signaling but also showed synergism with inotuzumab ozogamicin treatment.

Lymphoma cell-derived extracellular vesicles inhibit autophagy and apoptosis to promote lymphoma cell growth via the microRNA-106a/Beclin1 axis.

Lymphoma is a common malignant tumor globally. Tumor-derived extracellular vesicles (Evs) participate in genetic information exchange between tumor cells. We investigated the role and mechanism of human Burkitt lymphoma cells Raji-derived Evs (Raji-Evs) in lymphoma cells. Effects of Evs on lymphoma cell proliferation, invasion, autophagy, and apoptosis were assessed using Cell Counting Kit-8 method, Transwell assay, laser confocal microscopy, Western blotting, and flow cytometry. microRNA (miR)-106a expression in lymphoma cells was determined using reverse transcription-quantitative polymerase chain reaction and then downregulated in Raji cells and then Evs were isolated (Evs-in-miR-106a) to evaluate its role in lymphoma cell growth. The binding relationship between miR-106a and Beclin1 was verified using RNA pull-down and dual-luciferase assays. Beclin1 was overexpressed in SU-DHL-4 and Farage cells and SU-DHL-4 cell autophagy and apoptosis were detected. The levels of miR-106a and Beclin1 in SU-DHL-4 cells were detected after adding autophagy inhibitors. The tumorigenicity assay in nude mice was performed to validate the effects of Raji-Evs in vivo. Raji-Evs promoted lymphoma cell proliferation and invasion and increased miR-106a. miR-106a knockdown reversed Evs-promoted lymphoma cell proliferation and invasion. miR-106a carried by Raji-Evs targeted Beclin1 expression. Beclin1 overexpression or miR-106a inhibitor reversed the effects of Evs on lymphoma cell autophagy and apoptosis. Autophagy inhibitors elevated miR-106a expression and lowered Beclin1 expression. Raji-Evs-carried miR-106a inhibited Beclin1-dependent autophagy and apoptosis in lymphoma cells, which were further verified in vivo, together with promoted tumor growth. We proved that Raji-Evs inhibited lymphoma cell autophagy and apoptosis and promoted cell growth via the miR-106a/Beclin1 axis.

Corrigendum to "Identification and characterization of the cellular subclones that contribute to the pathogenesis of mantle cell lymphoma" [Genes Dis 6(4) 2019 407-418].

[This corrects the article DOI: 10.1016/j.gendis.2018.12.002.].

Relationship between serum osteocalcin and glycaemic variability in Type 2 diabetes.

1. Recent reports have described the role of osteocalcin in glucose metabolism and glycaemic variability has been proven to be associated with an increased risk of diabetes complications. However, the relationship between osteocalcin and glycaemic variability remains unclear. The aim of the present study was to examine the relationship between serum osteocalcin and glycaemic variability, as determined by a continuous glucose monitoring (CGM) system in patients with Type 2 diabetes mellitus (T2DM). 2. Fifty-nine T2DM patients with glycosylated haemoglobin (HbA1c) levels between 7.0% and 10.9% were recruited to the present study. Biochemical information and CGM parameters were collected at baseline and after 8 weeks of antihyperglycaemic therapy (either sulphonylurea, sulphonylurea + an α-glucosidase inhibitor or insulin + metformin combination therapy). 3. Compared with baseline, serum osteocalcin increased significantly (P = 0.014), whereas parameters related to glucose variability, including the mean amplitude of glycaemic excursions (MAGE) and the standard deviation of blood glucose values, decreased significantly (P < 0.001) after the 8 week treatment period. At baseline, there was a positive correlation between serum osteocalcin levels and fasting C-peptide levels (P = 0.004) and homeostatic model assessment of ß-cell function (P = 0.048), but a negative correlation between serum osteocalcin levels and fasting plasma glucose (P = 0.023), HbA1c (P = 0.020), glycated albumin (P = 0.019) and 24 h mean blood glucose (P < 0.001). Multiple stepwise regression analysis indicated that baseline osteocalcin was the single parameter that best predicted the change in MAGE (ß = -0.122; P = 0.039). 4. In conclusion, serum osteocalcin concentrations increased with improved glucose control. High initial osteocalcin levels were associated with subsequent improvements in glucose variability during glucose-lowering treatment.

[Combined utility of hemoglobin A1c and glycated albumin in diabetic screening].

OBJECTIVE: To assess the validity of combined detection of hemoglobin A1c (HbA1c) and glycated albumin (GA) in diabetic screening. METHODS: A total of 1480 subjects at our out-patient department from March 2007 to December 2009. Those suspected of diabetes or at a high risk of diabetes were enrolled. The study population included 677 males and 803 females with a mean age of 52.7 years. All subjects received an oral glucose tolerance test (OGTT) after a 10-hour fasting. Glycated albumin (GA) and hemoglobin A1c (HbA1c) were measured with liquid enzyme method and high pressure liquid chromatography respectively. RESULTS: (1) According to World Health Organization diabetes diagnosis criteria, there were 562 subjects with normal glucose tolerance (NGT), 411 subjects with impaired glucose regulation (IGR) and 507 subjects with newly diagnosed diabetes mellitus (DM). The level of HbA1c and GA had a rising tendency among NGT, IGR and DM groups (P < 0.01). (2) Pearson correlation analysis demonstrated that HbA1c had a positive association with GA (r = 0.75, P < 0.01). (3) Using OGTT as golden standard of diabetic diagnosis, receiver operator characteristic (ROC) curve indicated that HbA1c and GA were strong predictors of diabetes. The area under curve (AUC) was 0.882 and 0.881 respectively with no significant difference (P > 0.05). (4) The sensitivity of combined use of HbA1c and GA at optimal cut-off points of 6.1% and 17.1% was significantly higher than that of single use of HbA1c or GA in diabetic screening (94.7% vs 81.1%, 88.4%, P < 0.01). CONCLUSION: A combined detection of HbA1c and GA may improve the efficacy of diabetic screening. The subject with HbA1c ≥ 6.1% or GA ≥ 17.1% is recommended to undergo OGTT for confirming a diagnosis of diabetes.

Potential of the tumor­derived extracellular vesicles carrying the miR­125b­5p target TNFAIP3 in reducing the sensitivity of diffuse large B cell lymphoma to rituximab.

Diffuse large B­cell lymphoma (DLBCL) is the most common and aggressive form of non­Hodgkin's lymphoma. Extracellular vesicles (EVs) derived from cancer cells are known to modify the tumor microenvironment. The aim of the present study was to investigate the role of miR­125b­3p carried by EVs in DLBCL in vitro and in vivo. TNFAIP3 expression in patient lesions was measured and the upstream miR that regulates TNFAIP3 was predicted using the starBase database. EVs were isolated from DLBCL cells and identified. DLBCL cells were transfected with pcDNA to overexpress TNFAIP3 or inhibit miR­125b­5p expression, incubated with EVs, and treated with rituximab to compare cell growth and TNFAIP3/CD20 expression. DLBCL model mice were administered EVs, conditioned medium, and rituximab to observe changes in tumor size, volume, and weight. TNFAIP3 was downregulated in patients with DLBCL and its levels further decreased in patients with drug­resistant DLBCL. Overexpression of TNFAIP3 in DLBCL cells enhanced the inhibitory effect of rituximab and increased CD20 expression. miR­125b­5p targeted TNFAIP3. Inhibition of miR­125b­5p enhanced the inhibitory effect of rituximab in DLBCL cells. The EV­carried miR­125b­5p reduced the sensitivity of DLBCL cells to rituximab, which was averted by overexpression of TNFAIP3. EVs reduced the sensitivity of DLBCL model mice to rituximab via the miR­125b­5p/TNFAIP3 axis. The study findings indicate that the tumor­derived EVs carrying miR­125b­5p can enter DLBCL cells and target TNFAIP3, thus reducing the sensitivity of DLBCL to rituximab, which may provide a novel therapeutic approach for DLBCL.

[Effect of Autophagy to Drug Resistance of B-cell Lymphoma Cells].

OBJECTIVE: To investigate the effect of autophagy on the drug resistance of different human lymphoma cells. METHODS: Human Burkitt's lymphoma cell Daudi, human B lymphoma cell SUDHL-4, and human mantle cell lymphoma cell JeKo-1 were taken as the research subjects. The expression of Atg5 was inhibited by the treatments of autophagy inhibitors or stable interference via lentivirus infection. The autophagy activity of B lymphoma cell was changed, and the changes of lymphoma cells to the drug resistance of ADR and VCR was observed. RESULTS: JeKo-1 cells showed the strongest resistance to ADR and VCR, followed by SUDHL-4, and Daudi cells showed the weakest resistance to ADR and VCR. At the same time, JeKo-1 cells showed the strongest autophagy activity, followed by SUDHL-4, and Daudi cells showed the weakest autophagy activity. After the treatments of autophagy inhibitors or stable Atg5 interference, the resistance of lymphoma cells to ADR and VCR was significantly weakened, and there was the positive correlation at the drug resistance and the autophagy activity of B lymphoma cell. CONCLUSION: The higher autophagy activity in lymphoma cells, the lower chemotherapy resistance of the lymphoma cells after autophagy was inhibited.

S100A8 promotes chemoresistance via augmenting autophagy in B­cell lymphoma cells.

B­cell lymphomas (BCLs) are malignant lymphoid tumours originating from the malignant proliferation and transformation of mature lymphocytes at various stages of differentiation and clonal expansion of the lymphatic and circulatory systems. Efforts to control or even eradicate BCLs are frequently hampered by the development of drug resistance. Autophagy is an evolutionarily conserved biological process of the energy metabolism. By degrading intracellular organelles and proteins, autophagy provides cells with biochemical reaction substrates for the maintenance of homeostasis under nutrient deprivation or other stressful conditions. Accumulating evidence indicates that autophagy plays an important role in chemotherapy resistance. S100A8 is an important member of the calcium­binding protein family that plays an important role in regulating tumour resistance to chemotherapy, while the specific molecular regulatory mechanisms remain unclear. In the present study, by employing three BCL cell lines (Daudi, SUDHL­4 and JeKo­1), it was demonstrated that BCL cells with a strong drug resistance also exhibited active autophagy. In addition, S100A8 was found to be crucial for regulating drug resistance and promoting autophagy in BCL cells. Interference of S100A8 significantly downregulated Bcl­2/adenovirus E1B 19­kDa protein­interacting protein 3 located in the mitochondria and endoplasmic reticulum to further inhibit autophagy. In addition, S100A8 interference markedly inhibited the formation of the BECN1­PI3KC3 complex and promoted B­cell lymphoma 2 expression, which collectively inhibited autophagy.

SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin.

AIM: To investigate the potential relationship between the SLC22A2 gene polymorphism and blood lactate concentration in Shanghai Hans suffering from type 2 diabetes mellitus (T2DM). METHODS: The SLC22A2 single nucleotide polymorphism (SNP) 808G/T was genotyped in 400 T2DM patients, including a metformin-treated group (n=200) and a non-metformin-treated group (n=200). Fasting plasma lactic acid levels were measured with an enzyme-electrode assay. Biochemical indexes, including plasma alanine aminotransferase (ALT), creatinine (Cr), and glycolated hemoglobin (HbA1c), were also measured. RESULTS: The fasting plasma lactate concentration in the metformin-treated group was significantly higher than that in the non-metformin-treated group (1.29+/-0.45 mmol/L vs 1.18+/-0.44 mmol/L, P=0.015). Additionally, the ratio of patients with hyperlactacidemia was 8% (16/200) for the metformin-treated group and 5.5% (11/200) for the non-metformin-treated group, with no lactic acidosis found in either group. The frequency of the SLC22A2 808G/T T allele was 12.9%. Patients with the mutant genotype (TT) had a higher blood lactate concentration in the metformin-treated group than those in the non-metformin-treated group (t=2.492, P=0.013). This trend was not observed in the GG and GT genotypes when compared with metformin-treated and non-metformin-treated groups. Patients with the mutant genotype (TT) in the metformin-treated group also had a higher incidence of hyperlactacidemia compared with the GG genotype (40.0% vs 6.9%, P=0.050) in the metformin-treated group and the GG (6.0%, P=0.042) or GT (4.3%, P=0.043) genotypes in the non-metformin-treated group. In the metformin-treated group, there were significant gender differences in lactate concentrations in the TT (2.18+/-0.15 vs 1.04+/-0.27 mmol/L, P=0.008) and GG genotypes (1.40+/-0.51 vs 1.19+/-0.35 mmol/L, P=0.004). The lactate levels of women with the TT genotype were the highest in the metformin-treated group, but differences in lactate levels among the genotypes were not observed in the non-metformin-treated group. CONCLUSION: There is an 808G/T polymorphism in the SLC22A2 gene in Chinese Hans with T2DM. The 808G>T variance in the SLC22A2 gene can affect the plasma lactate level and the incidence of hyperlactacidemia in T2DM patients undergoing metformin therapy. Additionally, the female patients carrying the TT genotype are prone to lactatemia.

Glipizide controlled-release tablets, with or without acarbose, improve glycaemic variability in newly diagnosed Type 2 diabetes.

1. The aim of the present study was to compare the effects of glipizide controlled-release (CR) tablets monotherapy with that of glipizide CR tablets plus acarbose on glycaemic variability in newly diagnosed Type 2 diabetes (T2DM) patients using a continuous glucose-monitoring system (CGMS). 2. Forty newly diagnosed T2DM patients whose glycated haemoglobin A1c (HbA1c) levels ranged from 7.0% to 9.8% were randomized to either monotherapy or combination therapy. Overall glycaemic control and blood glucose variability were evaluated by CGMS parameters. 3. After 8 weeks treatment, fasting and postprandial blood glucose, HbA1c, glycated albumin (GA), mean blood glucose (MBG), mean amplitude of glycaemic excursions (MAGE), postprandial incremental area under the curve (AUC(pp)) and homeostasis model assessment of insulin resistance decreased significantly in both groups (P < 0.01). There was also a significant decrease in the mean of daily differences (MODD) in the combination therapy group. Mean changes in MBG, MAGE, MODD and AUC(pp) were significantly greater in the combination therapy group than in the monotherapy group (all P < 0.01), whereas no significant differences were found in the mean changes of HbA1c and GA. Multivariate regression analysis showed that the decrement in AUC(pp) was significantly associated with decreases in MAGE. 4. In conclusion, glipizide CR tablets alone or in combination with acarbose can improve overall blood glucose levels and glycaemic variability. Combination therapy using glipizide CR tablets and acarbose was more effective in reducing intraday and day-to-day glycaemic variability than glipizide CR tablet monotherapy.

Combined assessment of glycated albumin and fasting plasma glucose improves the detection of diabetes in Chinese subjects.

1. The aim of the present study was to assess the validity of glycated albumin (GA) and fasting plasma glucose (FPG) as a screening tool for the early detection of diabetes in Chinese subjects. 2. A total of 1971 outpatient subjects underwent a 75 g oral glucose tolerance test (OGTT) and GA measurement. The receiver operating characteristic curve (ROC) was plotted to examine the sensitivity, specificity, and positive and negative predictive values of GA and FPG in detecting undiagnosed diabetes at the different cut-off levels. 3. The prevalence of impaired glucose regulation and diabetes was 27.40% and 38.30%. For these diabetic individuals, 4.64% had isolated fasting hyperglycemia, 50.86% had isolated postprandial hyperglycemia and 44.50% had both. Using ROC analysis, a GA of 17.1% gave an optimal sensitivity of 76.82% (95% confidence interval: 73.64-79.79%) and specificity of 76.89% (74.42-79.23%) for the diagnosis of diabetes. Likewise, a FPG of 6.1 mmol/L gave an optimal sensitivity of 80.93% (77.94-83.67%) and specificity of 85.94% (83.86-87.84%). If subjects met both criteria, they were regarded as having diabetes; the positive predictive value of the combined criteria, FPG ≥ 6.1 mmol/L and GA ≥ 17.1%, was relatively high (84.79% (81.62-87.60%)), and this would have avoided 76% of the OGTT in our survey. 4. In conclusion, a GA value of 17.1%, an optimal cut-off in Chinese subjects, identified a high proportion of potential diabetic individuals. Simultaneous measurement of FPG and GA would enhance the sensitivity of diabetes screening in our population and avoid 76% of OGTT.