Adriamycin (ADR) causes irreversible damage to the heart, leading to ADR-induced cardiomyopathy (ACM). Angiotensin-(1–9) [Ang-(1–9)] is a peptide from the counter-regulatory renin-angiotensin system, but the effects on ACM is unclear. Our study was aimed to explore the effects and underlying molecular mechanisms of Ang-(1–9) against ACM in Wistar rats. Rats were injected intraperitoneally with ADR via six equal doses (each containing 2.5 mg/kg) within a period of 2 weeks to induce ACM. After 2 weeks of ADR treatment, the rats were treated with Ang-(1–9) (200 ng/kg/min) or angiotensin type 2 receptor (AT2R) antagonist PD123319 (100 ng/kg/min) for 4 weeks. Although Ang-(1–9) treatment did not influence blood pressure, it significantly improved left ventricular function and remodeling in ADR-treated rats, by inhibiting collagen deposition, the expression of TGF-β1, inflammatory response, cardiomyocyte apoptosis and oxidative stress. Moreover, Ang-(1–9) reduced ERK1/2 and P38 MAPK phosphorylation. The therapeutic effects of Ang-(1–9) were blocked by the AT2R antagonist PD123319, which also offset the down-regulation protein expression of pERK1/2 and pP38 MAPK induced by Ang-(1–9). These data suggest that Ang-(1–9) improved left ventricular function and remodeling in ADR-treated rats by an AT2R/ ERK1/2 and P38 MAPK-dependent mechanism. Thus, the Ang-(1–9)/AT2R axis may provide a novel and promising target to the prevention and treatment of ACM.

This study investigated the effect of dapagliflozin on the neovascularization of carotid atherosclerotic plaques in patients with type 2 diabetes mellitus (T2DM) who failed to meet the initial treatment standard of metformin. Sixty patients with HbA1c 7.0-11.0% after metformin (2000 mg/day) treatment were included and randomized into two groups: group A (dapagliflozin) and group B (glimepiride). After 12 weeks of treatment, group A had lower mean blood glucose ( MBG) and higher time in range (TIR) compared to group B. After 48 weeks of treatment, group A showed significant differences in various indicators compared to group B, including lower MBG, higher TIR, lower fasting insulin (FINS), improved insulin resistance, reduced systolic blood pressure (SBP), and lower BMI, waist-to-hip ratio (WHR) and time intensity curve of carotid angiography. No statistical differences in HbA1c, fasting blood glucose (FBG), diastolic blood pressure, low-density lipoprotein cholesterol (LDL), ALT, AST, blood urea nitrogen (BUN), serum creatinine or glomerular filtration rate (eGFR) after 12- and 48-week treatment between either group. Dapagliflozin treatment in T2DM patients can effectively control blood glucose, improve insulin resistance, reduce SBP, lower BMI and WHR, and improve the time intensity curve of carotid angiography, delaying the progress of diabetic macrovascular complications.

BACKGROUND Circular RNAs (circRNAs) are novel non-coding RNAs that have important roles in tumor progression. This study aimed to measure the levels of hsa_circ_0000885 in serum samples and tumor tissue from patients with osteosarcoma compared with controls and to evaluate the findings with disease-free survival and overall survival. MATERIAL AND METHODS Fifty pairs of osteosarcoma tissues and matched adjacent normal tissue were obtained from patients who underwent the same chemotherapy regimen before surgery. Blood samples were obtained from 30 patients with osteosarcoma before and after chemotherapy, 25 patients with osteosarcoma before and after surgery, 27 patients with benign bone tumors, and 25 age-matched and sex-matched healthy controls. Circular RNA sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) were used to analyze hsa_circ_0000885 expression. RESULTS Hsa_circ_0000885 expression was significantly increased in tissue and serum samples from patients with osteosarcoma, compared with controls, with significantly increased expression levels in patients with Enneking stage IIB and III osteosarcoma, compared with early-stage osteosarcoma. Patients with high serum and tumor levels of hsa_circ_0000885 had lower rates of disease-free survival and overall survival. The serum expression levels of hsa_circ_0000885 were significantly higher in patients with osteosarcoma compared with patients with benign bone tumors or healthy controls. CONCLUSIONS Hsa_circ_0000885 was upregulated in osteosarcoma, and it could serve as a good prognostic biomarker indicating poor clinical outcomes of osteosarcoma. Hsa_circ_0000885 was upregulated in serum of osteosarcoma patients and could serve as a good diagnostic biomarker for osteosarcoma.

Toll-like receptors (TLRs) are extremely significant pattern recognition receptors. When nerve injury occurs, a variety of inflammatory factors are generated, leading to an exceedingly complex micro-environment. TLRs recognize damage-associated molecular patterns. To investigate the correlation between TLR4 and recovery after sciatic nerve injury, the model of sciatic nerve injury was conducted using TLR4-mutated mice (C3H/HeJ) and wild mice (C3H/HeN). Our goal was to identify short-stage and long-stage changes after sciatic nerve injury, mainly by checking the expression changes of inflammation factors in the short-stage and the differences in the recovery of the injured sciatic nerve in the long-stage. The results show that the increase of changes in the HeN group of IL-1β, IL-6, TNF-α and MCP-1 are more obvious than in the HeJ group, with caspase1 expression higher and Nlrp3 expression lower in the former group. Further results reveal intense inflammation occurred in the HeN group showing more neutrophils and macrophages. Nlrp3 and caspase1 showed little difference by Immunohistochemistry, with Nlrp6 expression differing between the HeJ group and the HeN group. The results led us to conclude that better recovery of the injured sciatic nerve occurred in the HeJ group because the expression of GAP-43 and p75NTR was higher and had a better SFI figure. TLR4 mutation can decrease the expression of inflammatory factors and enhance the speed of recovery after sciatic nerve injury. The changes in the expression of Nlrp6, which are related to the TLR4 mutation, may influence recovery of the injured sciatic nerve. Further studies will be conducted to confirm these results.

Cellular therapies offer novel opportunities for the treatment of type 2 diabetes mellitus (T2DM). The present study evaluated the long-term efficacy and safety of infusion of Wharton's jelly-derived mesenchymal stem cells (WJ-MSC) on T2DM. A total of 61 patients with T2DM were randomly divided into two groups on the basis of basal therapy; patients in group I were administered WJ-MSC intravenous infusion twice, with a four-week interval, and patients in group II were treated with normal saline as control. During the 36-month follow-up period, the occurrence of any adverse effects and the results of clinical and laboratory examinations were recorded and evaluated. The lack of acute or chronic adverse effects in group I was consistent with group II.. Blood glucose, glycosylated hemoglobin, C-peptide, homeostasis model assessment of pancreatic islet β-cell function and incidence of diabetic complications in group I were significantly improved, as compared with group II during the 36-month follow-up. The results of the present study demonstrated that infusion of WJ-MSC improved the function of islet β-cells and reduced the incidence of diabetic complications, although the precise mechanisms are yet to be elucidated. The infusion of WJ-MSC may be an effective option for the treatment of patients with type 2 diabetes.

BACKGROUND: Human miRNAs have emerged as potentially useful diagnostic and prognostic markers in cancer within the past decade. Abnormal expression of microRNA-146 (miR-146) has been found in several classes of cancers.OBJECTIVE: To explore expression and clinical associations of miR-146a and miR-146b in papillary thyroid carcinoma.METHODS: We investigated expressions of miR-146a and miR-146b in tissues and peripheral blood among 128 patients with primary PTC, 120 patients with nodular goiter and 120 healthy controls by RT-PCR. Furthermore, the associations between the miR-146a and miR-146b expression and clinical parameters of PTC were analyzed.RESULTS: Levels of miR-146a and miR-146b expression in PTC tissues were higher compared to the nodular goiter tissues (P = 0.014 and 0.001) and perineoplastic thyroid tissues (P = 0.023 and 0.002). Positive associations were found between levels of miR-146a expression in PTC tissues and gender (female), cervical lymph node metastasis, multifocality, extra tyroidal invasion and advanced clinical TNM stages (III and IV). For miR-146b, there were positive association between levels of miR-146b expression and female, extra tyroidal invasion and advanced clinical TNM stages.CONCLUSIONS: Up-regulation of miR-146a and miR-146b expression in tissues was related to carcinogenesis and deterioration of PTC. MicroRNA-146a and miR-146b expressed in thyroid tissue may act as potential biomarkers for PTC patients.

The effects and possible mechanisms of adipose-derived stem cells (ASC) infusion on type 2 diabetic rats were investigated in this study. Twenty normal male Sprague-Dawley rats were included in normal control group, and 40 male diabetic rats were randomly divided into diabetic control group and ASC group (which received ASC infusion). After therapy, levels of fasting plasma glucose (FPG), HbA1c, serum insulin and C-peptide, recovery of islet cells, inflammatory cytolcines, and insulin sensitivity were analyzed. After ASC infusion, compared with diabetic control group, hyperglycemia in ASC group was ameliorated in 2 weeks and maintained for about 6 weeks, and plasma concentrations of insulin and C-peptide were significantly improved (P<0.01). Number of islet beta cells and concentration of vWF in islets in ASC group increased, while activity of caspase-3 in islets was reduced. Moreover, concentrations of TNF-alpha, IL-6 and IL-1 beta in ASC group obviously decreased (P<0.05). The expression of GLUT4, INSR, and phosphorylation of insulin signaling molecules in insulin target tissues were effectively improved. ASC infusion could aid in T2DM through recovery of islet beta cells and improvement of insulin sensitivity. Autologous ASC infusion might be an effective method for T2DM.

BACKGROUND:Results of several studies have shown a possible beneficial effect of renin-angiotensin system (RAS) inhibitors on diabetic retinopathy, but the findings were contradictory. We did a systematic review and meta-analysis to assess the effect of RAS inhibitors on diabetic retinopathy. METHODS:We identified relevant publications in PubMed, Embase, Cochrane Library Central Register of Controlled Trials, and abstracts from main annual meetings. Only randomised controlled trials comparing angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) monotherapy with other antihypertensive drugs or placebo in type 1 or type 2 diabetes were eligible for inclusion in the analysis. The primary outcomes were progression and regression of diabetic retinopathy in all patients and several subgroups. Risk ratios (RRs) with corresponding 95% CIs were pooled. We also did a network meta-analysis to assess the effect of different antihypertensive drugs on diabetic retinopathy by ranking order. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42013004548. FINDINGS:21 randomised clinical trials with 13,823 participants were included in the meta-analysis. RAS inhibitors were associated with reduced risk of progression (absolute risk difference -3%, 95% CI -5 to -1; pooled RR 0.87, 95% CI 0.80-0.95; p=0.002) and increased possibility of regression of diabetic retinopathy (8%, 1-16; RR 1.39, 95% CI 1.19-1.61; p=0.00002). In normotensive patients, RAS inhibitors decreased risk of diabetic retinopathy progression (0.81, 0.69-0.94; p=0.007) and increased possibility of regression (1.43, 1.14-1.79; p=0.002). In hypertensive patients, RAS inhibitors were not associated with difference in risk of progression of diabetic retinopathy (0.93, 0.79-1.10; p=0.42) or possibility of diabetic retinopathy regression (2.21, 0.92-5.31; p=0.08). ACE inhibitors were associated with reduced risk of diabetic retinopathy progression (0.84, 0.75-0.94; p=0.002) and higher possibility of disease regression (1.50, 1.20-1.86; p=0.0003). ARBs were associated with a higher possibility of diabetic retinopathy regression (1.32, 1.07-1.61; p=0.008), but had no effect on disease progression (0.92, 0.80-1.06; p=0.25). Network meta-analysis showed the association of antihypertensive drugs with risk of diabetic retinopathy progression was lowest for ACE inhibitors, followed by ARBs, β blockers, calcium channel blockers, and placebo in rank order. The association of antihypertensive drugs with possibility of diabetic retinopathy regression was highest for ACE inhibitors, followed by ARBs, placebo, and calcium channel blockers in rank order. INTERPRETATION:In patients with diabetes, RAS inhibitors reduce the risk of diabetic retinopathy, and increase the possibility of diabetic retinopathy regression. ACE inhibitors might be better than ARBs for treating diabetic retinopathy, and might exert the most beneficial effect on diabetic retinopathy of all widely used antihypertensive drug classes.

Type 1 diabetes is an autoimmune disease that results from an inflammatory destruction of β-cells in islets. Mesenchymal stem cells derived from Wharton's jelly (WJ-MSCs) own a peculiar immunomodulatory feature and might reverse the inflammatory destruction and repair the function of β-cells. Sixty NOD mice were divided into four groups, including normal control group, WJ-MSCs prevention group (before onset), WJ-MSCs treatment group (after onset), and diabetic control group. After homologous therapy, onset time of diabetes, levels of fasting plasma glucose (FPG), fed blood glucose and C-peptide, regulation of cytokines, and islet cells were examined and evaluated. After WJ-MSCs infusion, FPG and fed blood glucose in WJ-MSCs treatment group decreased to normal level in 6-8 days and maintained for 6 weeks. Level of fasting C-peptide of these mice was higher compared to diabetic control mice (P=0.027). In WJ-MSCs prevention group, WJ-MSCs played a protective role for 8-week delayed onset of diabetes, and fasting C-peptide in this group was higher compared to the other two diabetic groups (P=0.013, 0.035). Compared with diabetic control group, frequencies of CD4+CD25+Foxp3+ Tregs in WJ-MSCs prevention group and treatment group were higher, while levels of IL-2, IFN-γ, and TNF-α were lower (P<0.001); the degree of insulitis was also depressed, especially for WJ-MSCs prevention group (P<0.05). Infusion of WJ-MSCs could aid in T1DM through regulation of the autoimmunity and recovery of islet β-cells no matter before or after onset of T1DM. WJ-MSCs might be an effective method for T1DM.

Type 2 diabetes mellitus is the most common endocrine disease all over the world, while existing therapies can only ameliorate hyperglycemia or temporarily improve the response to insulin in target tissues, they cannot retard or improve the progressive β-cell dysfunction persistently. Combined therapy of stem cells and sitagliptin might resolve this problem, we verified this hypothesis in a diabetic rat model. Except ten Wistar rats in normal control group, diabetic rats were divided into diabetic control group, WJ-MSCs group, sitagliptin group and WJ-MSCs + sitagliptin group and received homologous therapy. Ten weeks after therapy, diabetic symptoms, FPG and GHbA1c in WJ-MSCs group, sitagliptin group and WJ-MSCs + sitagliptin group were significantly less than those in diabetic control group (P < 0.05), while fasting C-peptide and number of β cells in WJ-MSCs group and WJ-MSCs + sitagliptin group was significantly higher than those in diabetic control and sitagliptin group (P < 0.01). Glucagon and number of α cells in sitagliptin group and WJ-MSCs + sitagliptin group were significantly lower than those in WJ-MSCs group and diabetic control group (P < 0.01). No symptoms of rejection and toxic effect were observed. Combined therapy of WJ-MSCs and sitagliptin can effectively ameliorate hyperglycemia, promote regeneration of islet β cells and suppress generation of islet α cells in diabetic rats, presenting a new therapy for type 2 diabetes although the exact mechanisms are unclear.

This study demonstrates a strong association of high urinary iodine with thyroid nodules and papillary thyroid cancer as well as aggressive cancer features, suggesting that high urinary iodine is a risk factor for thyroid cancer. The risk of high iodine intake for thyroid cancer has been suggested but not established. The objective of the study was to evaluate the relationship between urine iodine levels and thyroid nodule and thyroid cancer. We preoperatively tested fasting urine iodine in 154 thyroid nodule patients and correlated the results with pathological diagnoses and compared with 306 subjects as normal control. The median urine iodine (MUI) was 331.33 μg/L in patients with benign thyroid nodules versus 466.23 μg/L in patients with papillary thyroid cancer (PTC) (P=0.003), both of which were in the excessive iodine state and higher than the MUI of 174.30 μg/L in the control group (P < 0.001), which was in the sufficient iodine state. Excessive iodine state (MUI>300 μg/L) was seen in 62.75% of patients with benign thyroid nodules and 66.99% of patients with PTC, both of which were significantly higher than the iodine excessive rate of 19.93% in the control group (P<0.001). Moreover, MUI in patients with PTC with lymph node metastasis was significantly higher than that of PTC patients without lymph node metastasis (P<0.001). Urine iodine of thyroid cancer patients with stage III and IV disease was significantly higher than that of patients with stage I and II diseases (P<0.001). Multivariable analyses showed that, like sand calcification of thyroid nodule and TSH, urine iodine was an independent risk factor for PTC. These data demonstrate a significant association between high urinary iodine and benign and malignant thyroid nodules and PTC aggressiveness, supporting high urinary iodine as a risk factor for thyroid malignancy. Further studies are warranted to confirm these findings.

TP53 Arg72Pro polymorphism has been proposed to have some effects on host's susceptibility to cancer. Several studies were published to assess the association between TP53 Arg72Pro polymorphism and thyroid carcinoma, but they reported controversial results. We performed a systemic review and meta-analysis to assess the association between TP53 Arg72Pro polymorphism and thyroid carcinoma. Odds ratio (OR) with 95 % confidence interval (95 % CI) was used to assess the association. Fourteen individual studies with 3,483 subjects were finally included into the meta-analysis. Overall, there was an obvious association between TP53 Arg72Pro polymorphism and thyroid carcinoma under the recessive model (ProPro vs. ArgArg/ArgPro, OR = 2.02, 95 % CI 1.13 to 3.62, P = 0.02). Subgroup analysis by race showed that TP53 Arg72Pro polymorphism was associated with thyroid carcinoma in Caucasians (ProPro vs. ArgArg/ArgPro, OR = 2.31, 95 % CI 1.08 to 4.93, P = 0.03). Subgroup analysis by histological type showed that TP53 Arg72Pro polymorphism was not associated with a risk of different types of thyroid carcinoma. In summary, the meta-analysis suggests that TP53 Arg72Pro polymorphism is associated with thyroid carcinoma risk in Caucasians. Besides, more studies with large sample size are needed to further assess the associations above.

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder resulted from T cell-mediated destruction of pancreatic β-cells, how to regenerate β-cells and prevent the autoimmune destruction of remnant and neogenetic β-cells is a tough problem. Immunomodulatory propertity of mesenchymal stem cell make it illuminated to overcome it. We assessed the long-term effects of the implantation of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) from the umbilical cord for Newly-onset T1DM. Twenty-nine patients with newly onset T1DM were randomly divided into two groups, patients in group I were treated with WJ-MSCs and patients in group II were treated with normal saline based on insulin intensive therapy. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 21 months, the occurrence of any side effects and results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I compared with group II, both the HbA1c and C peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of WJ-MSCs for the treatment of newly-onset T1DM is safe and effective. This therapy can restore the function of islet β cells in a longer time, although precise mechanisms are unknown, the implantation of WJ-MSCs is expected to be an effective strategy for treatment of type1 diabetes.

Previous studies have shown that several types of stem cells can differentiate into insulin-secreting islet beta-cells and that these cells can reduce blood glucose in some trials, but there has been no report of a long-term follow-up. We assessed the long-term effects of the use of autologous bone marrow mononuclear cells in the treatment of type 2 diabetes mellitus (T2DM). Based on the willingness to receive implantation of bone marrow mononuclear cells, One hundred and eighteen patients with T2DM were divided into two groups; the patients in group I were treated with autologous bone marrow mononuclear cells and patients in group II were treated with insulin intensification therapy. Mononuclear cells from bone marrow were injected back into the patient's pancreas via a catheter. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 33 months, the occurrence of any side effects and the results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I and both the HbA1c and C-peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of autologous bone marrow mononuclear cells for the treatment of T2DM is safe and effective. This therapy can partially restore the function of islet beta-cells and maintain blood glucose homeostasis in a longer time.