Adipocytes-Derived Exosomal microRNA-1224 Inhibits M2 Macrophage Polarization in Obesity-Induced Adipose Tissue Inflammation via MSI2-Mediated Wnt/ß-Catenin Axis.

SCOPE: Phenotypic switch of macrophage polarization in adipose tissue has been associated with obesity-induced adipose tissue inflammation (OATI). Therefore, this study aims to explore the possible mechanism of adipocytes-derived exosomes (ADEs) carrying microRNA-1224 (miR-1224) in M2 macrophage polarization of OATI. METHODS AND RESULTS: miR-1224-knockout (miR-1224-KO) mice for this study, and isolated primary adipocytes from high-fat diet (HFD) or normal diet (SD)-fed mice are developed. ADEs are extracted and cocultured with bone marrow-derived macrophages (BMDMs). The macrophagic crown-like structures (CLS) and M1 and M2 phenotype macrophages in epididymal white adipose tissue (epiWAT) are observed by immunohistochemistry and flow cytometry. The obtained data indicate that miR-1224 is highly expressed in adipose tissues and adipocytes of obese mice. miR-1224 knockout decreases CLS number and increases M2 macrophages polarization in epiWAT. In addition, miR-1224 can be transferred to BMDMs via ADEs, which targeted musashi RNA binding protein 2 (MSI2) expression and inactivated Wnt/ß-catenin pathway, inhibiting macrophage M2 polarization and promoting inflammatory factor release. CONCLUSION: Exosomal miR-1224 derived by adipocytes targets MSI2 and blocks the Wnt/ß-catenin pathway, which inhibits macrophage M2 polarization and promotes inflammatory factor release, ultimately promoting OATI.

Identification and Validation of Novel Genes in Anaplastic Thyroid Carcinoma via Bioinformatics Analysis.

PURPOSE: The conventional interventions of anaplastic thyroid carcinoma (ATC) patients are mainly through surgery, chemotherapy, and radiotherapy; however, it is hardly to improve survival rate. We aimed to investigate the differential expressed genes (DEGs) between ATC and normal thyroid gland through bioinformatics analysis of the microarray datasets and find new potential therapeutic targets for ATC. METHODS: Microarray datasets GSE9115, GSE29265, GSE33630, GSE53072, and GSE65144 were downloaded from Gene Expression Omnibus (GEO) database. Compared with the normal tissue, GEO2R was conducted to screen the DEGs in each chip under the condition of |log FC| > l, adjusted P-values (adj. P) < 0.05. The Retrieval of Interacting Genes (STRING) database was used to calculate PPI networks of DEGs with a combined score >0.4 as the cut-off criteria. The hub genes in the PPI network were visualized and selected according to screening conditions in Cytoscape software. In addition, the novel genes in ATC were screened for survival analysis using Kaplan-Meier plotter from those hub genes and validated by RT-qPCR. RESULTS: A total of 284 overlapping DEGs were obtained, including 121 upregulated and 161 downregulated DEGs. A total of 232 DEGs were selected by STRING database. The 50 hub genes in the PPI network were chosen according to three screening conditions. In addition, the Kaplan-Meier plotter database confirmed that high expressions of ANLN, CENPF, KIF2C, TPX2, and NDC80 were negatively correlated with poor overall survival of ATC patients. Finally, RT-qPCR experiments showed that KIF2C and CENPF were significantly upregulated in ARO cells and CAL-62 cells when compared to Nthy-ori 3-1 cells, TPX2 was upregulated only in CAL-62 cells, while ANLN and NDC80 were obviously decreased in ARO cells and CAL-62 cells. CONCLUSION: Our study suggested that CENPF, KIF2C, and TPX2 might play a significant role in the development of ATC, which could be further explored as potential biomarkers for the treatment of ATC.

Nevirapine Increases Sodium/Iodide Symporter-Mediated Radioiodide Uptake by Activation of TSHR/cAMP/CREB/PAX8 Signaling Pathway in Dedifferentiated Thyroid Cancer.

Nevirapine has been proved to be effective in inducing re-differentiation and suppressing tumor growth in several tumor cells. This study aims to investigate the therapeutic potential of nevirapine in dedifferentiated thyroid cancer (DeTC), which refractory to radioiodine treatment and the underlying mechanisms. The results indicated that nevirapine significantly inhibited the proliferation and increased the expressions of thyroid differentiation-related genes, thyroid stimulating hormone receptor (TSHR), sodium/iodide symporter (NIS), thyroid peroxidase (TPO), and transcriptional factor paired box 8 (PAX8) in dedifferentiated thyroid cancer cells (WRO 82-1 and dFTC-133). Furthermore, nevirapine also enhanced radioiodide uptake significantly both in vitro and in vivo, and inhibited the growth of xenograft tumors. Nevirapine might improve radioiodine sensitivity via the activation of TSHR/cAMP/CREB/PAX8 signaling pathway. This study demonstrates that nevirapine could be potentially used to improve radioiodine therapeutic efficacy in dedifferentiated thyroid cancer patients.

Nevirapine inhibits migration and invasion in dedifferentiated thyroid cancer cells.

BACKGROUND: Metastatic or recurrent thyroid cancer often behaves aggressively, and approximately two-thirds of patients present with radioiodine resistance. Effective therapies to suppress thyroid cancer metastasis are urgently needed. Nevirapine has been proved to suppress tumor growth and induce differentiation in several tumor cells, but has not previously been evaluated in metastasis of thyroid cancer. The present study aimed to investigate the effect of nevirapine on migration and invasion in dedifferentiated thyroid cancer cells. METHODS: Human dedifferentiated thyroid cancer cell line (WRO 82-1) was subject to real-time quantitative PCR, western blot and transwell migration/invasion assays. The liver metastasis in tumor xenografts of nude mice was subject to hematoxylin-eosin (HE) staining. RESULTS: Nevirapine significantly repressed cell migration and invasion in WRO 82-1 cells, and surprisingly significantly decreased liver metastatic tumor in the nude mouse model of dedifferentiated thyroid cancer compared with that of the control. Moreover, nevirapine significantly decreased the expression of IL-6 mRNA and phosphorylation of JAK2 (Y1007+Y1008) and STAT3 (Tyr 705) in WRO 82-1 cells compared with those in control cells. CONCLUSION: Our findings suggest that nevirapine significantly repressed migration and invasion/metastasis in WRO 82-1 cells and tumor xenografts, which may be related to inhibition of IL-6/STAT3 signaling pathway. It promises great potential as a novel therapy for thyroid cancer, especially for those patients with metastasis.

Salidroside inhibits migration and invasion of poorly differentiated thyroid cancer cells.

BACKGROUND: No effective treatment is currently available for poorly differentiated thyroid cancer which is resistant to radioiodine, especially with migration and invasion. A great number of researches have revealed the anticancer effects of salidroside, but none have studied the effects of salidroside on thyroid cancer. This study aimed to investigate the effect of salidroside on migration and invasion of poorly differentiated thyroid cancer cells. METHODS: The effects of salidroside on migration, invasion and apoptosis of poorly differentiated thyroid cancer WRO cells and normal thyroid follicular epithelial Nthy-ori 3-1 cells were measured by wound-healing assay, transwell migration/invasion assay and flow cytometry, respectively. The expression levels of MMP2 and MMP9 at RNA and protein levels in WRO cells were detected by qRT-PCR and western blot. The phosphorylation levels of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and the apoptosis-related protein levels of Bax, cleaved caspase 3 and Bcl-2 were assessed by western blot. RESULTS: Salidroside significantly suppressed migration/invasion and induced apoptosis in poorly differentiated thyroid cancer WRO cells. We further illustrated that salidroside significantly inhibited expressions of MMP2 and MMP9 at mRNA and protein levels and the phosphorylation activation of JAK2/STAT3 in WRO cells. In addition, salidroside increased expressions of pro-apoptotic factors (Bax and cleaved caspase 3) and decreased expression of anti-apoptotic factor (Bcl-2) significantly in WRO cells. CONCLUSION: The present study demonstrates that salidroside inhibits migration and invasion of WRO cells (a kind of poorly differentiated cancer cell line) significantly, which might be via suppressing JAK2-STAT3 signaling pathway.

Pituitary resistance to thyroid hormone caused by a novel mutation (H435A) in the thyroid hormone receptor beta: A case report.

RATIONALE: In patients with pituitary thyroid hormone resistance, the ability of the pituitary gland to detect (and down-regulate) the increase of triiodothyronine is selectively impaired, while the periphery remains sensitive to triiodothyronine levels, producing symptoms of peripheral thyrotoxicity. Subsequently, there is no feedback of pituitary production of thyroid-stimulating hormone (TSH), which is responsible for this hyperthyroidism. PATIENT CONCERNS: We report a case of a 46-year-old Chinese woman diagnosed with a thyroid nodule, with normal thyroid function. She underwent conventional subtotal thyroidectomy, and replacement therapy (levothyroxine) was used for as convention. However, it was later proven that she had pituitary resistance to thyroid hormone, as supra-physiological doses of levothyroxine were required to normalize TSH levels, which resulted in peripheral thyrotoxicity. DIAGNOSES: Based on the patient's symptoms, laboratory tests results, imaging examinations, and genetic analysis (which noted a gene mutation), a diagnosis of pituitary resistance to thyroid hormones was confirmed. INTERVENTIONS: The dose of levothyroxine was adjusted periodically and ß-adrenergic blocker was used as symptomatic treatment. OUTCOMES: The outcome in the reported case has been satisfactory despite the persistence of non-suppressed TSH. LESSONS: An inappropriate level of TSH should always be evaluated. We found a new mutation (H435A) of the thyroid hormone receptor beta gene, which allowed for the establishment of a definitive diagnosis.

Calcium Dobesilate Prevents Diabetic Kidney Disease by Decreasing Bim and Inhibiting Apoptosis of Renal Proximal Tubular Epithelial Cells.

Apoptosis of renal proximal tubular epithelial cells (PTECs) plays a vital role in the pathogenesis and progression of diabetic kidney disease (DKD). Calcium dobesilate is a vascular protective compound used for treatment of diabetic retinopathy and chronic venous insufficiency. The aim of this study was to determine whether calcium dobesilate can protect PTECs from glucose-induced apoptosis and the potential mechanism of this effect. It is indicated that high glucose promoted abnormal apoptosis of HK2 cells, which was inhibited by treatment of calcium dobesilate, while Bim expression decreased in response to calcium dobesilate in high-glucose-treated HK2 cells. These findings confirmed the therapeutic effects of calcium dobesilate on DKD and emphasized the importance of it as a potentially crucial drug in treatment of DKD.

Efficacy of statins in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials.

BACKGROUND: The effects of statins in patients with diabetic nephropathy are controversial. With increasing interest in the potential therapeutic role of statins in diabetic nephropathy, it is essential to evaluate its real effects. METHODS: PubMed, EMBASE, Web of Science databases, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure were systematically searched for randomized controlled trials (RCTs) of statins in patients with diabetic nephropathy. RESULTS: Fourteen trials with 2866 participants were included in our meta-analysis. Compared with placebo, albuminuria and urinary albumin excretion rates in the statin group were reduced by 0.46 [95 % confidence interval (CI),-0.68 to -0.25, P < 0.0001] and 1.68 (95 % CI, -3.23 to -0.12, P = 0.03), respectively. The reduction of albuminuria was greater in patients of type 2 diabetes mellitus with diabetic nephropathy [standardized mean difference (SMD), -0.56; 95 % CI, -0.80 to -0.32, P < 0.00001] and the decrease was significant during the 1 to 3 years period of statin therapy (SMD, -0.57; 95 % CI, -0.95 to -0.19, P = 0.003). Subgroup analysis demonstrated the effects of statins were much stronger in subjects with pathologic albuminuria: change of -0.71 (95 % CI, -1.09 to -0.33, P = 0.0003) for those with urinary protein excretion 30 to 300 mg/day, -0.37 (95 % CI, -0.67 to -0.06, P = 0.02) for those with excretion more than 300 mg/day and -0.29 (95 % CI, -0.78 to 0.21, P = 0.26) for those with excretion less than 30 mg/day. In contrast, statins did not significantly reduce estimated glomerular filtration rate, serum creatinine and blood urea nitrogen levels. CONCLUSIONS: Statins decrease the albuminuria and urinary albumin excretion rates significantly. The efficacy of statins on renal function is time dependent and better in type 2 diabetic patients with nephropathy.

Expression of Pax8 is decreased and bortezomib does not increase the iodine uptake in thyroid carcinoma cells.

Fundamental treatment for papillary thyroid carcinoma (PTC) involves total or subtotal thyroidectomy. Iodine-131 ((131)I) is routinely utilized to target remnant thyroid cancer and metastasis after thyroidectomy. The effectiveness of other therapeutic modalities remains unsatisfactory; thus, these patients have a poor prognosis. The manner in which the ability of (131)I uptake can be improved is vital for their prognosis. Bortezomib has been used as a re-differentiation agent for the treatment of patients with multiple myeloma; however, little is reported about the role of bortezomib in thyroid cancer. To evaluate the therapeutic potential of bortezomib in a human PTC cell line, expression of paired-box 8 (Pax8) protein was determined using Western blot in PTC, normal thyroid, and anaplastic/undifferentiated thyroid carcinoma (ATC) cells. The expression of Pax8 protein in PTC cells pretreated with bortezomib was determined using the same method. Iodine uptake was determined using (131)I radioactivity assay. The level of Pax8 protein in normal thyroid cells was significantly higher than in PTC (P < 0.05) and ATC cells (P < 0.05); its expression in PTC cells was also significantly higher than in ATC cells (P < 0.05). The PTC cells in the bortezomib-treated group showed a higher expression of Pax8 protein than the control group (P < 0.05). These findings indicate that bortezomib can increase the expression of Pax8, but does not significantly increase the iodine uptake of PTC cells.

Methylation of sodium iodide symporter promoter correlated with aggressiveness and metastasis in papillary thyroid carcinoma: a meta-analysis.

BACKGROUND: Methylation of sodium iodide symporter promoter has been reported to increase the incidence of papillary thyroid carcinoma (PTC). In this meta-analysis stratified via methylation of sodium iodide symporter promoter, we evaluate the relationship between methylation of sodium iodide symporter promoter and PTC. The association between methylation with aggressiveness and metastasis potential of PTC is also discussed. METHODS: We searched electronic databases for original articles and references of included studies both in English and Chinese from 1966 to 2014. Two reviewers selected the case-control study and extracted data from relevant literature independently. RESULTS: Seven articles, including 360 cases and 268 controls, were involved in this meta-analysis. The prevalence of PTC in patients with methylated sodium iodide symporter promoter was significantly higher than those with non-methylated promoter (OR=7.36, 95% CI: 4.25-12.74, P<0.001). Stratified analysis showed that PTC patients with multiple lesions, capsule invasion and lymphatic metastasis had significantly higher rates of methylation (OR=2.22, 95% CI: 1.12-4.41, P=0.02; OR=2.14, 95% CI: 1.12-4.08, P=0.02; OR=3.56, 95% CI: 1.97-6.46, P<0.0001). But no relationship was found among the methylation of sodium iodide symporter and age, gender and size of tumor. CONCLUSIONS: The methylation of sodium iodide symporter promoter is related with PTC and its aggressive and metastatic potential. Due to the limited sample size, more clinical researches should be taken in the future.

Matrix Metalloproteinase 9 Gene Promoter (rs 3918242) Mutation Reduces the Risk of Diabetic Microvascular Complications.

BACKGROUND: Many studies have evaluated the association between matrix metalloproteinase 9 (MMP9) gene promoter polymorphism and diabetic microvascular complications. However, the results are conflicting and inconclusive. The aim of this meta-analysis was to evaluate the association more precisely. MATERIALS AND METHODS: Studies were retrieved from the PubMed, Embase, Medline, China National Knowledge Infrastructure, Web of Science, and Cochrane databases. All statistical analyses were performed using Review Manager 5.2. RESULTS: Data were abstracted from four case-control studies that included 446 patients with diabetic microvascular complications and 496 diabetic control subjects. The MMP9-1562 C/T genotype was significantly associated with the risk of diabetic nephropathy after stratification by specific type of microvascular complication (CT + TT vs. CC: OR = 0.42, 95% CI = 0.26-0.69, p = 0.0006; TT vs. CC + CT: OR = 0.37, 95% CI = 0.19-0.76, p = 0.006). CONCLUSIONS: This study adds to the evidence that MMP9-1562 T gene mutation might reduce the risk of diabetic nephropathy.

Association between sodium iodide symporter and differentiated Thyroid cancer: a meta-analysis of 9 studies.

CONTEXT: As many studies proved that sodium iodide symporter (NIS) plays a key role in radioactive iodide (RAI) therapy of thyroid cancer, however, a growing number of studies suggests that part of differentiated thyroid carcinomas (DTC) with overexpression of NIS are insensitive to RAI well. OBJECTIVE: The aim of this meta-analysis is to assess the expression of NIS in differentiated thyroid cancer, compared with normal thyroid tissue. DATA SOURCES: PUBMED, Sinomed, CNKI, Wanfang and VIP were searched for relevant case-control studies up to now. STUDY SELECTION: Studies that concerning the qualitative expression NIS in DTC were included. DATA EXTRACTION: Working independently, authors used a standard form to extract data. For quality assessment, Newcastle-Ottawa Scale (NOS) were applied. DATA SYNTHESIS: Totally nine eligible studies included, involving 765 cases and 473 controls. The results revealed that the expression of NIS had a statistically increased in DTC, compared with controls (OddsRadio OR: 1.47, 95% CI: 1.12 to 1.94, Z=2.78, P=0.005). Since the existence of the significant heterogeneity, subgroup analysis and sensitivity analysis were performed and found that the heterogeneity came from the different criteria evaluate positive NIS expression (Liu 2008, Mu 2010) and the small simple size of the control group (Lin. J D2001). The heterogeneity disappeared or dropped to below 50% after remove these studies. CONCLUSION: Our study shows that the expression of NIS is significantly increased in DTC, which could help explain the reason for individual with a poor response to RAI therapy. In other word, the reduced iodide uptake in thyroid cancer may not caused by the decreased expression of NIS, function of NIS protein or its post-transcriptional translocation might be the point.

Efficacy and safety of vitamin D3 in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials.

BACKGROUND: Several studies found that vitamin D3 might alter glucose metabolism, protect kidney from injury and even proposed the mechanisms. But results from previous studies have been conflicting. The aim of this study was to evaluate the efficacy and safety of vitamin D3 in patients with diabetic nephropathy. The underlying mechanism of vitamin D3 decreasing proteinuria is also discussed. METHODS: We conducted a search of English and Chinese articles using database of Pubmed, Embase, Sinomed, CNKI, Wanfang and clinical trial register centers, for randomized controlled trials of vitamin D3 in diabetic nephropathy patients. Two reviewers performed independently. Meta-analysis was used when studies were homogeneous enough. RESULTS: Twenty studies, including 1 497 patients with diabetic nephropathy, were involved in this systemic review. Vitamin D3-treated patients with diabetic nephropathy had a statistically significant reduction in 24-hour proteinuria (weighted mean difference -0.44, 95% CI -0.54 to -0.34, Z = 8.80, P < 0.000 01) and urine albumin/creatine ratio (standardized mean difference -0.29, 95% CI -0.48 to -0.10, Z = 2.96, P = 0.003). But vitamin D3 supplementation did not significantly reduce blood pressure and hemoglobin A1c compared with control group. The potential mechanisms about the renal protection of vitamin D3, including the inhibition of rennin-angiotensin system, the protection of kidney from inflammation, fibrosis and the structure change of kidney are discussed. In addition, vitamin D3 did not significantly increase the incidence of adverse effects, including total adverse effects, gastrointestinal adverse effects and fluctuation of blood pressure. CONCLUSIONS: Vitamin D3 can ameliorate proteinuria and protect kidney from injury in patients with diabetic nephropathy. This renoprotective effect is independent of blood pressure and glucose reduction. And it does not increase any adverse effects than control, even in combination therapy with angiotensin converting enzyme inhibitors/angiotensin receptor blockers. But due to the limited randomized controlled trials of high quality, more clinical researches should be taken in the future.

Radix Hedysari polysaccharide suppresses lipid metabolism dysfunction in a rat model of non­alcoholic fatty liver disease via adenosine monophosphate­activated protein kinase pathway activation.

Oxidative stress and excess hepatic lipid accumulation contribute to non­alcoholic fatty liver disease. Radix Hedysari polysaccharides (RHP) have attracted interest due to their antioxidant properties and immunomodulatory effects. However, the effect of RHP on hepatic lipid metabolism remains to be elucidated. In the present study, the response of Sprague­Dawley rat livers to a high­fat diet and RHP treatment was investigated by evaluating body weight, liver histology, hepatic lipid content, adenosine monophosphate­activated protein kinase (AMPK) activity and lipid metabolism gene transcriptional profiles. The present study demonstrated that RHP ameliorated lipid metabolism disorders, regulated hepatic lipid content, improved liver inflammation and damage, activated AMPK via phosphorylation, upregulated peroxisome proliferator­activated receptor α and downregulated the mRNA expression of sterol regulatory element binding protein­1c in rat livers, which reduced lipogenesis and increased lipolysis. Taken together, these results suggested that RHP effectively ameliorates lipid metabolism disorders in rat livers; thus, RHP may be a potential therapeutic agent in the prevention of hepatic steatosis.