miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model.

Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrate that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cell balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of patients with RA. Overall, the unique characteristics - including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues - position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.

Biomarkers of interstitial lung disease associated with primary Sjögren's syndrome.

OBJECTIVES: The aim of this study was to investigate serum biomarkers linked to primary Sjögren's syndrome (pSS)-associated interstitial lung disease (ILD). METHODS: 69 pSS patients were consecutively enrolled and evaluated via quantitative ILD scoring based on high-resolution computed tomography (HRCT). Biomarkers of interest were assessed by multiplex enzyme-linked immunosorbent assays (ELISAs). RESULTS: Among consecutively enrolled patients with pSS, the presence of pSS-ILD was 50% based on the presence of radiographically defined interstitial lung abnormalities (ILA) meeting specified criteria for mild/moderate (ILA 2) or severe (ILA 3) disease. Age, immunoglobulin M (IgM), C-reactive protein (CRP), and serum levels of eotaxin/CCL11, Krebs von den Lungen-6 (KL-6), TNFα, and TGFα were significantly higher in the combined pSS-ILD group (ILA 2 + ILA 3) than in the pSS-no-ILD and pSS-indeterminate ILD groups (ILA 0 and ILA 1, respectively) in unadjusted analyses (p < 0.05 for all variables). A binary logistic regression model revealed that disease duration and KL-6 levels were associated with the presence of pSS-ILD (p < 0.05). Complementary least absolute shrinkage and selection operator (LASSO) modeling showed that age, KL-6, and TNF-α effectively differentiated pSS-ILD (ILA 2 + ILA3) from pSS without ILD (ILA 0 + ILA 1), with an area under the curve (AUC) of 0.883 (p value < 0.0001). CONCLUSIONS: Patient age, disease duration, and serum levels of both KL-6 and TNFα were the most discriminating factors associated with the presence of ILD in our pSS patients. Higher levels of CRP, IgM, eotaxin, TGFα, and TNFα should also prompt the search for occult as well as clinically evident lung involvement based on statistically significant univariate associations with pSS-ILD. CLINICAL TRIAL REGISTRATION: None.

MiR-143 Targets IGF-1R to Suppress Autoimmunity in Thyroid-Associated Ophthalmopathy.

Objective: Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease that involves the remodeling of orbit and periorbital tissues. Thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R) may stimulate the activation of autoimmunity in TAO, but the exact mechanism is unclear. We investigated whether IGF-1R/TSHR modulation in TAO may involve microRNA regulation. Methods: We conducted microarray analysis using RNA from the orbital connective tissue samples of 3 healthy and 3 patients with TAO. The involvement of differentially regulated microRNA in IGF-1R/TSHR modulation in TAO was evaluated in orbital fibroblasts (OFs) and female BALB/c mice. Results: Using hierarchical cluster analysis, we identified that miR-143 was downregulated in TAO. The expression levels of miR-143 in OFs were significantly reduced under IL-1B stimulation. However, OF proliferation and inflammatory responses decreased when miR-143 is overexpressed. In contrast, the suppression of miR-143 increased levels of inflammatory markers (IL-6, IL-8, MCP1) and hyaluronan accumulation. Moreover, overexpression of miR-143 significantly lowers levels of IGF-1R and TSHR. A luciferase assay indicated that miR-143 targets the 3'-UTR of IGF-1R. Increases in the expression of IGF-1R increased the expression of the inflammasome marker NLRP3 and apoptotic marker cleaved caspase-1; however, miR-143 overexpression decreased levels of IGF-1R, TSHR, NLRP3, cleaved caspase 1, IL-1B, and IL-18. In a mouse model of TAO, overexpression of miR-143 significantly reduced levels of IGF-1R and attenuated the adipogenesis associated with TAO. Conclusion: We found that miR-143 directly targets IGF-1R to alleviate the inflammatory response in TAO by indirectly decreasing levels of TSHR and inactivating NLRP3.

Feasibility of sleep extension and its effect on cardiometabolic parameters in free-living settings: a systematic review and meta-analysis of experimental studies.

AIMS: Inadequate sleep is a global health issue and has been associated with an increased risk for cardiovascular diseases. As a part of sleep hygiene, intentional lengthening of night-time sleep duration (i.e. sleep extension) might be a behavioural intervention to improve cardiometabolic health. To examine the feasibility of sleep extension and its effects on cardiometabolic parameters in free-living settings. METHODS AND RESULTS: This review was registered in PROSPERO (CRD42019146174). Five databases were searched. Only experimental studies conducted in adults without a diagnosis of sleep disorder were included. The pooled mean difference was calculated by the inverse variance method. Narrative summaries were also used. Thirteen studies from 11 trials were included. The intervention ranged from 3 days to 6 weeks. Sleep extension increased total sleep time by 51 min [95% confidence interval (CI) 39-63]. Overall, sleep extension did not result in significant changes in blood pressure. However, sub-group analysis revealed that when 24 h mean blood pressure was obtained among those with pre-hypertension or Stage 1 hypertension, sleep extension reduced systolic (weighted mean difference = -7.8 mm/Hg; 95% CI -10.6 to -4.9), and diastolic blood pressure (weighted mean difference = -4.2 mm/Hg; 95% CI -6.7 to -1.8). The pooled effects on fasting glucose and insulin resistance were not significant. The effect of sleep extension on other parameters (e.g. heart rate) was not consistent. CONCLUSION: Sleep extension is feasible and could increase sleep in free-living settings. Sleep extension shows promise for reducing 24 h mean blood pressure among those with pre-hypertension or hypertension. More large-scale studies are needed to examine its long-term effects.

Fluctuations in Self-Reported Symptoms Predict Objective Physical Activity in Adults With Type 2 Diabetes.

PURPOSE: The purpose of this study was to examine the association between self-reported symptoms including fatigue and sleep disturbance with moderate-intensity physical activity among adults with type 2 diabetes. METHODS: This report was a secondary analysis of a cross-sectional study. Data from 53 participants with at least 6 days of repeated measures were used. Daytime physical activity and energy expenditure were assessed using a wrist-worn accelerometer at the free-living setting. Fatigue upon awakening was measured using a 0 to 10 scale. Sleep (eg, restorative sleep, sleep duration, and sleep efficiency) was measured using the Consensus Sleep Diary for Morning. Data were analyzed using linear mixed models by including within- and between-person effects. RESULTS: Participants were predominantly females (54.7%) with a mean age of 60.3 years. Controlling for the covariates, at the individual level (within-person), fluctuations in restorative sleep and fatigue upon awakening predicted moderate-intensity PA. Similarly, at the individual level, fluctuations in restorative sleep and fatigue upon awakening predicted average hourly energy expenditure. However, at the group level (between-person), no significant associations were found between fatigue and restorative sleep with moderate-intensity physical activity. CONCLUSIONS: The study findings suggest that within-person fluctuations in fatigue and restorative sleep upon awakening predict daytime moderate-intensity physical activity. At the individual level, reducing fluctuations in fatigue and restorative sleep might encourage participation in physical activity. More research is warranted to uncover the underlying causes of fluctuations in fatigue and restorative sleep. Meanwhile, diabetes care and education specialists should pay attention to the within-person fluctuations of fatigue and sleep.

Association of Interstitial Lung Disease With Clinical Characteristics of Chinese Patients With Systemic Lupus Erythematosus.

OBJECTIVES: This study aims to evaluate the frequency and clinical and laboratory features of interstitial lung disease (ILD) in Chinese patients with systemic lupus erythematosus (SLE) and to evaluate the association of ILD with the clinical features. PATIENTS AND METHODS: The study included 505 SLE patients (64 males, 441 females; mean age 35.3±15.3 years; range, 14 to 87 years) who were categorized into two groups as 449 patients without ILD and 56 patients with ILD based on evidence obtained from high-resolution computed tomography images. The demographic data, clinical and laboratory findings, SLE disease activity index score, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index of all patients were also recorded and statistically analyzed. RESULTS: The ILD frequency in patients with SLE was 11.1%. Compared to the group of SLE patients without ILD, the group of SLE patients with ILD possessed the following statistical differences: elderly age, longer illness duration, lower level of anti-double-stranded deoxyribonucleic acid, and higher level of serum complement 3, increased ratios of Raynaud's phenomenon, moist rales and tachypnea. Multivariate logistic regression results suggested that elderly age (≥60 years), long illness duration (1-10 years, ≥10 years), Raynaud's phenomenon, and tachypnea were statistically associated with the occurrence of ILD in SLE patients. CONCLUSION: Chinese SLE patients who possessed the factors that were statistically associated with ILD, namely, elderly age (≥60 years old), long illness duration (≥1 years), Raynaud's phenomenon, and tachypnea, were recommended to be monitored for the possibility of ILD.

Fatigue and Sleep Quality Predict Eating Behavior Among People With Type 2 Diabetes.

BACKGROUND: People with Type 2 diabetes frequently report increased fatigue and sleep disturbance. These symptoms might put them at a higher risk for unhealthy eating behavior-detrimental to diabetes control. OBJECTIVES: The aim of the study was to examine the effect of fatigue and sleep on eating behavior in people with Type 2 diabetes by using a daily diary approach. METHODS: Data from 56 patients were collected during a baseline interview and an 8-day ambulatory assessment period in the free-living setting. Each day, participants completed one diary upon awakening to assess their sleep duration and sleep quality during the previous night and morning fatigue. They also completed one diary before going to bed to assess their eating behavior during the day (e.g., uncontrolled eating, cognitive restraint, emotional eating, and snacking). Data from 7 days were analyzed using generalized estimating equations. RESULTS: During the 7 days, controlling for age, gender, and body mass index, between-person fatigue was a significant predictor of uncontrolled eating, emotional eating, and snacking. Similarly, controlling for the covariates, between-person sleep quality was a significant predictor of uncontrolled eating and emotional eating. No associations were found between sleep duration and eating behavior. DISCUSSIONS: At the between-person level, reporting higher fatigue or poorer sleep quality was associated with higher levels of unhealthy eating behavior. Patients with Type 2 diabetes with high fatigue or poor sleep quality may require additional attention to support their healthy eating.

High glucose upregulates osteopontin expression by FoxO1 activation in macrophages.

Hyperglycemia plays a major role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis, which are responsible for the most of disability and mortality in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis, and hyperglycemia enhances the transcriptional activity of FoxO1 which is closely association with insulin resistance and diabetes. Here, we showed that plasma OPN levels were significantly elevated in type 2 diabetic patients and positively correlated with glycated albumin (GA). The more atherosclerotic lesions were observed in the aorta of diabetic ApoE-/- mice analyzed by Sudan IV staining. High glucose increased both the mRNA and protein expression levels of OPN and inhibited the phosphorylation of FoxO1 in RAW 264.7 cells. Overexpression of WT or constitutively active mutant FoxO1 promoted the expression levels of OPN, while the dominant-negative mutant FoxO1 decreased slightly the expression of OPN. Conversely, knockdown of FoxO1 reduced the expression of OPN. Luciferase reporter assay revealed that high glucose and overexpression of FoxO1 enhanced the activities of the OPN promoter region nt -1918 ~ -713. Furthermore, the interactions between FoxO1 and the OPN promoter were confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results suggest that high glucose upregulates OPN expression via FoxO1 activation, which would play a critical role in the development of diabetic atherogenesis.

Expression of Nrf2 Promotes Schwann Cell-Mediated Sciatic Nerve Recovery in Diabetic Peripheral Neuropathy.

BACKGROUND/AIMS: High glucose-induced oxidative stress and inflammatory responses play an important role in painful diabetic neuropathy by activating the TLR4/NFκB signal pathway. Schwann cells (SCs) are integral to peripheral nerve biology, contributing to saltatory conduction along axons, nerve and axon development, and axonal regeneration. SCs provide a microenvironment favoring vascular regeneration but their low survival ratio in hyperglycemic conditions suppress the function to promote nerve growth. Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes remyelination after peripheral nerve injury. The aim of this study was to identify the role of Nrf2 in SC-mediated functional recovery after sciatic nerve injury. METHODS: We compared plasma inflammatory factors in diabetic patients (DN) with/without diabetic peripheral neuropathy (DPN) and assessed whether Nrf2 expression in SCs could repair peripheral nerve injury in a rat model. Nrf2, TLR4/NFκB signal pathway and apoptosis relative protein expression were detected by western blot. Apoptosis and angiogenesis were determined by immunofluorescence and tubule formation assay, respectively. Regenerated nerves were determined by transmission electron microscope. RESULTS: Higher levels of inflammatory factors and VEGF expression were found in DPN patients. Cellular experiments indicate that Nrf2 expression inhibits hyperglycemia-induced apoptosis and promotes angiogenesis by regulating the TLR4/NFκB signal pathway. Animal experiments show that nerve conduction velocity, myelin sheath thickness, and sciatic vasa nervorum are restored with transplantation of SCs overexpressing Nrf2. CONCLUSIONS: Taken together, the high survival ratio of SCs in a DPN rat model indicates that overexpression of Nrf2 restores nerve injury.

KATP channels in high glucose-induced rat mesangial cell proliferation and release of MMP-2 and fibronectin.

ATP-sensitive potassium (KATP) channels are well characterized in cardiac, pancreatic and many other muscle cells. The purpose of this study was to determine if KATP channels play a role in diabetic nephropathy (DN). In the present study, functional expression of the KATP channel was examined in rat mesangial cells with or without high glucose (HG) stimulation. The mesangial cell proliferation and the release of matrix metalloproteinase (MMP)-2 and fibronectin in response to high glucose with a selective opener of KATP (diazoxide, DZX), or with a selective inhibitor of KATP (5-hydroxydecanoate, 5-HD) were also measured. The cell proliferation was observed using Cell Counting Kit-8 assay, and the mRNA expressions of KATP subunit, including Kir6.1, Kir6.2, sulfonylurea receptor 1 (SUR1), SUR2A and SUR2B, were assessed using quantitative real-time PCR. MMP-2 and fibronectin release was measured by ELISA. The present study clarified expression of SUR subunit of KATP in plasma. HG treatment could cause increased cell proliferation and release of MMP-2 and fibronectin in a dose-dependent manner. HG also significantly decreased the expression of Kir6.1, SUR2A and SUR2B. Pretreatment of DZX markedly decreased the expression of SUR1, SUR2A and SUR2B, but had no effect on Kir6.1 expression compared with HG alone, while these changes were inhibited by 5-HD pretreatment. Moreover, DZX also inhibited cell proliferation and release of MMP-2 and fibronectin in HG-induced rat mesangial cells, and that was corrected by 5-HD. These data suggest that HG stimulates mesangial cell proliferation and cellular matrix release via inhibiting KATP channel activity, leading us to propose that KATP channel dysfunction may be involved in the development of DN.

High glucose stimulates cell proliferation and Collagen IV production in rat mesangial cells through inhibiting AMPK-KATP signaling.

PURPOSE: The present study investigated the putative mechanisms underlying effects of KATP channel on high glucose (HG)-induced mesangial cell proliferation and tissue inhibitors of metalloproteinases (TIMP)-2 and Collagen IV production. METHODS: Rat mesangial cells were subjected to whole cell patch clamp to record the KATP channel currents under high glucose (HG, 30 mM) condition. Cell proliferation was measured using a CCK-8 assay. The production of TIMP-2 and Collagen IV and AMP-activated protein kinase (AMPK)-signaling pathway activity was assessed by ELISA and Western blotting, respectively. AMPK agonist (AICAR) was used to analyze the role of this kinase. The expression of KATP subunit (Kir6.1, Kir6.2, SUR1, SUR2A and SUR2B) was examined using quantitative real-time PCR (RT-PCR). RESULTS: We found that HG was significant decreases in the expression of Kir6.1, SUB2A and SUB2B, three subunits of KATP, TIMP-2 production, KATP channel activity and AMPK activity, while it promoted the cell proliferation and Collagen IV production in rat mesangial cells. Pretreatment with KATP selective opener (diazoxide, DZX) significantly inhibited HG-induced mesangial cell proliferation, Collagen IV production and decrease in KATP channel activity in rat mesangial cells, which were reversed by pretreatment of 5-hydroxydecanoate, a selective inhibitor of KATP. Moreover, AICAR pretreatment inhibited HG-induced decrease in KATP channel activity. CONCLUSIONS: Taken together, activating AMPK-KATP signaling may protect against HG-induced mesangial cell proliferation and Collagen IV production, and, thereby, provides new insights into the molecular mechanisms underlying early diabetic nephropathy (DN).

Receptor for advanced glycation end as drug targets in diabetes-induced skin lesion.

The involvement of the receptor for advanced glycation end (RAGE) in different diseases has been reviewed in great detail, previously, but the effects of diabetic drugs on RAGE-induced skin lesion during long course diabetes remains poorly understood. In the present study, we have shown that RAGE was overexpressed in both diabetic rats and human keratinocytes (HaCaT cells). Cell cycle arrest and apoptosis as well as alternations of relative protein levels were also found in diabetic rats and HaCaT cells with overexpression of RAGE that were rectified by metformin (Met) treatment. Moreover, overexpression of RAGE was also found to induce secretions of TNF-α, IL-1ß, IL-6, ICAM-1 and COX-2 in HaCaT cells, and Met treatment corrected these inflammatory factor secretions. In addition, treatment with Met markedly reduced RAGE overexpression-induced p38 and NF-κB activation. Taken together, the findings of the present study have demonstrated, for the first time that Met protects HaCaT cells against diabetes-induced injuries and inflammatory responses through inhibiting activated RAGE.

Transplantation of betatrophin-expressing adipose-derived mesenchymal stem cells induces ß-cell proliferation in diabetic mice.

Recent progress in regenerative medicine has suggested that mesenchymal stem cell (MSC)-based therapy is a novel potential cure for diabetes. Betatrophin is a newly identified hormone that can increase the production and expansion of insulin-secreting ß-cells when administered to mice. In this study, we evaluated the effect of betatrophin overexpression by human adipose-derived MSCs (ADMSCs) by in vitro experiments, as well as following their transplantation into a mice with streptozotocin (STZ)-induced diabetes. The overexpression of betatrophin did not affect the ADMSCs in terms of proliferation, differentiation and morphology. However, the co-culture of human islets with ADMSCs overexpressing betatrophin (ADMSCs-BET) induced islet proliferation, ß-cell specific transcription factor expression, and the islet production of insulin under the stimulation of glucose or KCl and Arg. In addition, ADMSCs-BET enhanced the anti-inflammatory and anti-apoptotic effects of the co-cultured islets compared with ADMSCs cultured alone. In mice with STZ-induced diabetes, the transplantation of ADMSCs-BET ameliorated the hyperglycemia and weight loss associated with STZ-induced diabetes; ADMSCs-BET also significantly enhanced the ratio of ß-cells per islet compared to the transplantation of ADMSCs alone. Thus, our study demonstrates a novel strategy for inducing ß-cell regeneration. ADMSCs-BET may replace insulin injections by increasing the number of endogenous insulin-producing cells in patients with diabetes. This combined strategy of ADMSC transplantation and gene therapy may prove to be a useful therapy for the treatment of diabetes.

The effect of IGF-1 on symptoms of sleep deprivation in a rat model of inflammatory heart disease and metabolic syndrome.

Sleep deprivation (SD) has become a worldwide public health concern due to the many negative health consequences associated with suboptimal sleep. SD has been linked to a catabolic hormone signature, heart disease, hypertension, diabetes, and an increase in morbidity and mortality. Herein, we investigated the effects and mechanism of SD on cardiac and metabolic health and evaluated the impact of exogenously supplied IGF-1 on these symptoms. In the present study, we show that 5 days of acute SD negatively impacted all of the various indicators of cardiac and metabolic health. All symptoms of SD were ameliorated by daily administration of IGF-1, however. IGF-1 administration also reduced the phosphorylation of Akt and expression of Bax, a promoter of apoptosis. Conversely, the expression of Bcl-2, an inhibitor of apoptosis, was elevated by IGF-1, and all IGF-1 effects were suppressed by the PI3K/Akt inhibitor LY294002, reaffirming the importance of the PI3K/Akt pathway in the maintenance of cardiac and metabolic health.

CD8(+) T cell-mediated cytotoxicity toward Schwann cells promotes diabetic peripheral neuropathy.

BACKGROUND: Damage to Schwann cells has been reported in the development of diabetic peripheral neuropathy (DPN), but how Schwann cells are damaged has not been elucidated. METHODS: The highly expressed proteins in the PBMC of DPN patients were identified through MALDI-TOF/TOF and SELDI protein chip technology. The expression levels of CXCR3 were detected by qPCR and flow cytometric analysis. Transwell migration assay was to investigate the migration of CD8(+) T cells. Western-blot analysis was to detect the levels of p38 MAP kinases pathway related proteins and TNF-α, FasL, and PDL1. RESULTS: Two highly expressed proteins, CXCR3 and p38, were identified. Under high glucose conditions, CXCR3 was elevated in CD8(+) T cells via the activation of p38 MAP kinases. Moreover, CXCL9, CXCL10, and CXCL11 expression were induced in Schwann cells, leading to the recruitment and infiltration of CD8(+) T cells into DPN tissues. Further study demonstrated that Schwann cells promoted activation of CD8(+) T cells and induced expression of TNF-α, FasL, and PDL1 on CD8(+) T cells, in return, CD8(+) T cells induced obvious apoptosis of Schwann cells. CONCLUSION: Our study indicates that CD8(+) T cells mediate cytotoxicity toward Schwann cells and play an important role in the development of DPN.

XRCC1 gene polymorphisms and the risk of differentiated thyroid carcinoma (DTC): a meta-analysis of case-control studies.

BACKGROUND: Previous studies investigating the association between X-ray repair cross-complementing group 1 (XRCC1) polymorphisms and thyroid cancer risk have yielded inconsistent results. This meta-analysis was performed to derive a more precise estimation of the relationship between three XRCC1 polymorphisms and thyroid cancer risk. METHODS/PRINCIPAL FINDINGS: PubMed and EMBASE database were systematically searched to identify relevant studies. 10 publications were selected for this meta-analysis, including 11 studies for Arg399Gln polymorphism (1726 cases and 3774 controls), 7 studies for Arg194Trp polymorphism (1037 cases and 2487 controls) and 8 studies for Arg280His polymorphism (1432 cases and 3356 controls). The results in total population did not show any significant association between these three polymorphisms and the risk of DTC for all genetic models. However, when stratified by ethnicity, the results showed that Arg280His polymorphism was associated with an increased risk of DTC among Caucasians (Arg/His vs. Arg/Arg: OR = 1.45, 95% CI = 1.09-1.93; dominant model: OR = 1.43, 95% CI = 1.08-1.89; additive model: OR = 1.38, 95% CI = 1.05-1.80), whereas individuals carrying Arg/His genotype have a significantly reduced risk of DTC among Asians (Arg/His vs. Arg/Arg: OR = 0.71, 95% CI = 0.51-0.98). We also detected that 399Gln variant allele carriers might presented an overall decreased risk of DTC in mixed population. Furthermore, subgroup analyses by histological subtype revealed that Arg194Trp polymorphism was significantly associated with reduced risk for papillary thyroid carcinoma (PTC) (dominant model: OR = 0.71, 95% CI = 0.50-0.99). CONCLUSIONS: This meta-analysis suggests that Arg280His polymorphism might contribute to the susceptibility of DTC among Caucasians, whereas it might provide protective effects in Asians against the risk of DTC. Additionally, our results support the protective role of Arg194Trp polymorphism in developing PTC, and show evidence of an association between Arg399Gln polymorphism and decreased risk of DTC in mixed population.

High glucose induces renal mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which is inhibited by resveratrol.

Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. Hyperglycemia-induced oxidative stress is implicated in the etiology of diabetic nephropathy. Resveratrol has potent antioxidative and protective effects on diabetic nephropathy. We aimed to examine whether high glucose (HG)-induced NADPH oxidase activation and reactive oxygen species (ROS) production contribute to glomerular mesangial cell proliferation and fibronectin expression and the effect of resveratrol on HG action in mesangial cells. By using rat mesangial cell line and primary mesangial cells, we found that NADPH oxidase inhibitor (apocynin) and ROS inhibitor (N-acetyl cysteine) both inhibited HG-induced mesangial cell proliferation and fibronectin expression. HG-induced elevation of NADPH oxidase activity and production of ROS in mesangial cells was inhibited by apocynin. These results suggest that HG induces mesangial cell proliferation and fibronectin expression through NADPH oxidase-mediated ROS production. Mechanistic studies revealed that HG upregulated NADPH oxidase subunits p22(phox) and p47(phox) expression through JNK/NF-κB pathway, which resulted in elevation of NADPH oxidase activity and consequent ROS production. Resveratrol prevented HG-induced mesangial cell proliferation and fibronectin expression through inhibiting HG-induced JNK and NF-κB activation, NADPH oxidase activity elevation and ROS production. These results demonstrate that HG enhances mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol. Our findings provide novel therapeutic targets for diabetic nephropathy.

Association of two polymorphisms within and near SOCS3 gene with obesity in three nationalities in Xinjiang province of China.

AIM: SOCS3 gene plays an important role in the pathogenesis of obesity in animal models, but the data from human studies are relatively limited. To address this issue, a genetic association analysis on nationalities with different genetic background living in the similar environmental conditions was performed. METHODS: Two thousand seven hundred eleven subjects were randomly recruited from the Kazakh, Uygur and Han nationalities in Xinjiang of China. SNP polymorphisms rs4969168 and rs9892622 within or near the SOCS3 gene were genotyped using TaqMan-MGB™ assay. Association study between the two polymorphisms and obesity-related traits (body mass index [BMI]; waist-to-hip ratio [WHR]; weight; height, waist, and hip measurements) was conducted. RESULTS: Significant association was found between rs4969168 and the obesity-related traits, including BMI (25.32 ± 3.49 kg/m(2) for AA, 24.60 ± 3.70 kg/m(2) for AG, 24.39 ± 3.42 kg/m(2) for GG, P=0.042), weight (65.58 ± 11.42 kg for AA, 63.50 ± 11.30 kg for AG, 62.00 ± 10.78 kg for GG, P=0.011) in the Han nationality, but not in the Kazakh or Uygur nationalities. Rs9892622 was significantly associated with BMI, WHR, and WAIST in the Uygur males. Rs9892622 was also associated with BMI in Kazakh males. Linear regression analysis verified the above findings. However, neither of the two polymorphisms was associated with obesity-related traits in the total population. CONCLUSION: The polymorphism rs4969168 within or near the SOCS3 gene has a significant effect in the Han nationality, while rs9892622 was associated with obesity in Uygur and Kazakh nationalities in Xinjiang of China.

Serum biomarker of diabetic peripheral neuropathy indentified by differential proteomics.

At least one in four diabetic patients is affected by peripheral neuropathy. In this study, the MALDI-TOF-MS mass spectra of peptides and proteins were generated following WCX CLINPROT bead fractionation of 39 diabetic peripheral neuropathy (DPN), 39 diabetes mellitus (DM), and 35 control (CON) serum samples. The spectra were analyzed statistically using flexAnalysisTM and Clin-ProtTM bioinformatics software. Identification of the selected markers was performed and affinity bead-purified plasma protein was subjected to LTQ Orbitrap XL MS/MS analysis followed by Mascot identification of the peptide sequences. 89 differentially expressed peaks of serum proteins were identified. 17, 10 and 4 most significant peaks between CON vs. DM, CON vs. DPN, DM vs. DPN, respectively, were selected out using the ClinProTool software package and used to train a Supervised Neural Network. A veracity rate of 100% was obtained for all sets. Following this analysis, a 6631-Da marker was identified as a fragment of the Apolipoprotein C-I precursor. The peptides identified may have clinical utility as surrogate markers for detection and classification of DM and DPN.

Mechanistic study of endogenous skin lesions in diabetic rats.

Pathological and physiological changes in dermal tissue in a rat model of diabetes mellitus (DM) were investigated. Sixteen male 8-week-old Sprague-Dawley rats were randomized into two groups of eight, the DM group (Group DM) and the normal control group (Group (NC) normal control). Group DM rats were injected with streptozotocin (STZ) intraperitoneally at a dose of 65 mg/kg body weight. Group NC rats were injected with the same volume of citric acid buffer. All rats were sacrificed 12 weeks later. The impact of exposure to (AGE) advanced glycation end products-modified human serum albumin (AGE-HSA) on epidermal cells and ECV304 cells was evaluated in cell culture experiments. The diabetic rats exhibited changes in skin tissue, including a decrease in thickness, disappearance of the multilayer epithelium structure, degeneration of collagen fibres and an increase in the infiltration of inflammatory cells, in addition to a significant increase in skin glucose and AGEs. Moreover, diabetic rats had increased plasma glycosylated protein (GSP) and malondialdehyde (MDA) and decreased plasma glutathione (GSH). The percentage of epidermal cells in S phase was similar between the two group rats; however, there was a marked decrease in the G2/M phase in Group DM. Additionally, exposure of ECV304 cells to AGE-HSA led to a time-dependent and dose-dependent increase in apoptosis. Therefore, the high glucose in the skin tissue, coupled with the accumulation of toxic substances such as AGEs, promote the dysfunction of dermal cells and/or the matrix. This may be a significant mechanism of diabetes-induced early-stage endogenous skin damage.