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Circular RNAs (circRNAs), a novel type of endogenous RNAs with covalently closed-loop structures, have become a new research hotspot in the RNA world. Their diversity, stability, evolutionary conservation, and cell type- or tissue-specific expression patterns endow circRNAs with various important biological functions. As a consequence, circRNAs are emerging as important regulators of physiological development and disease pathogenesis. Growing evidence has shown that circRNAs can regulate parental gene expression through diverse mechanisms, such as transcription and splicing regulation, microRNA (miRNA) sponges, mRNA traps, translational modulation, and post-translational modification. The study of circRNAs and how circRNAs regulate the expression of parental genes will facilitate a deeper understanding of their biological functions and provide new perspectives on their clinical application. Herein, we review the biogenesis of circRNAs, with a particular focus on the molecular mechanisms of circRNAs regulating their parental gene expression and the biological significance of such regulation., Graphical Abstract, circRNAs are covalently closed continuous loops that exhibit multiple biological functions. This review summarizes recent advances in circRNAs’ regulatory roles in parental gene expression, including transcription and splicing regulation, ceRNA mechanisms, mRNA traps, and translational/post-translational regulation. It may provide new perspectives for the understanding and further investigation of circRNAs.

Aging is a complex biological process closely linked with the occurrence and development of age-related diseases. Despite recent advances in lifestyle management and drug therapy, the late diagnosis of these diseases causes severe complications, usually resulting in death and consequently impacting social economies. Therefore, the identification of reliable biomarkers and the creation of effective treatment alternatives for age-related diseases are needed. Circular RNAs (circRNAs) are a novel class of RNA molecules that form covalently closed loops capable of regulating gene expression at multiple levels. Several studies have reported the emerging functional roles of circRNAs in various conditions, providing new perspectives regarding cellular physiology and disease pathology. Notably, accumulating evidence demonstrates the involvement of circRNAs in the regulation of age-related pathologies, including cardio-cerebrovascular disease, neurodegenerative disease, cancer, diabetes, rheumatoid arthritis, and osteoporosis. Therefore, the association of circRNAs with these age-related pathologies highlights their potential as diagnostic biomarkers and therapeutic targets for better disease management. Here, we review the biogenesis and function of circRNAs, with a special focus on their regulatory roles in aging-related pathologies, as well as discuss their potential as biological biomarkers and therapeutic targets for these diseases.

Amyloid deposition is a histological hallmark of common human disorders including Alzheimer's disease (AD) and type 2 diabetes. Although some reports highlight that amyloid fibrils might activate the innate immunity system via pattern recognition receptors, here, we provide multiple lines of evidence for the protection by site-specific amyloid protein analogs and fibrils against autoimmune attacks: (1) strategies targeting clearance of the AD-related brain amyloid plaque induce high risk of deadly autoimmune destructions in subjects with cognitive dysfunction; (2) administration of amyloidogenic peptides with either full length or core hexapeptide structure consistently ameliorates signs of experimental autoimmune encephalomyelitis; (3) experimental autoimmune encephalomyelitis is exacerbated following genetic deletion of amyloid precursor proteins; (4) absence of islet amyloid coexists with T-cell-mediated insulitis in autoimmune diabetes and autoimmune polyendocrine syndrome; (5) use of islet amyloid polypeptide agonists rather than antagonists improves diabetes care; and (6) common suppressive signaling pathways by regulatory T cells are activated in both local and systemic amyloidosis. These findings indicate dual modulation activity mediated by amyloid protein monomers, oligomers, and fibrils to maintain immune homeostasis. The protection from autoimmune destruction by amyloid proteins offers a novel therapeutic approach to regenerative medicine for common degenerative diseases.

Background and aims Renal dysfunction is a potent risk factor for cardiovascular diseases, including stroke. This study aimed to evaluate the impact of admission estimated glomerular filtration rate (eGFR) levels on short-term (1-month) and long-term (1-year) mortality in patients with acute ischemic stroke. Methods From the Taiwan Stroke Registry data, we classified ischemic stroke patients, identified from April 2006 to December 2015, into 5 groups by eGFR at admission: ≥ 90, 60–89, 30–59, 15–29, and Results Among 52,732 ischemic stroke patients, 1480 died within one month. The 1-month mortality rate was over 5-fold greater in patients with eGFR Conclusions After acute ischemic stroke, patients with reduced eGFR are at elevated risks of short-term and long-term deaths in a graded relationship.

Malignancy following renal transplantation remains inconsistent with the reported safety of kidney donation during the long-term follow-up. We conducted searches of the published literature which included healthy participants, recipients, living kidney donors (LKDs), and the availability of outcome data for malignancy. Eight from 938 potentially relevant studies were analyzed by means of fixed-effects model or random-effects model, as appropriately. In 48,950 participants, the follow-up range was 18 months to 20 years, and the mean age of the subjects was approximately 41 years. The incidence rate with 95% confidence interval (CI) for malignancy after kidney transplantation was 0.03 (0.01–0.05) in recipients and 0.03 (0.1–0.07) in LKDs, giving a pooled incidence rate of 0.03 (95% CI 0.02–0.04). LKDs contrasted nondonors by the overall odds ratio and 95% CI for total cancer of 2.80 (2.69–2.92). Kidney transplantation was associated with an increased risk of cancer during a long-term follow-up. Long-term risk for cancer in LKDs and kidney recipients should be monitored.

Autoimmune diseases (ADs) are primarily mediated by the failure of immunological self-tolerance. Regulatory T cells (Tregs) play a critical role in the maintenance of induced tolerance to peripheral self-antigens, suppressing immoderate immune responses deleterious to the host and preventing the AD development. Tregs and suppressive cytokines are homeostatic with effective cells plus pro-inflammatory cytokines in healthy hosts which is defined as "Yang", and ADs are usually induced in case of disturbed homeostasis, which is defined as "Yin". Indeed, the Yin-Yang balance could explain the pathogenic mechanism of ADs. Tregs not only suppress CD4+ and CD8+ T cells but also can suppress other immune cells such as B cell, natural killer cell, DC and other antigen-presenting cell through cell-cell contact or secreting suppressive cytokines. In Tregs, Foxp3 as an intracellular protein displays a more specific marker than currently used other cell-surface markers (such as CD25, CD40L, CTLA-4, ICOS and GITR) in defining the naturally occurring CD4+ Tregs. Though the precise mechanism for the opposite effects of Tregs has not been fully elucidated, the importance of Tregs in ADs has been proved to be associated with kinds of immunocytes. At present, the surface marker, frequency and function of Tregs existed conflicts and hence the Tregs therapy in ADs faces challenges. Though some success has been achieved with Tregs therapy in few ADs both in murine models and humans, more effort should paid to meet the future challenges. This review summarizes the progress and discusses the phenotypic, numeric and functional abnormalities of Tregs and is the first time to systematically review the progress of Tregs therapy in kinds of ADs.

We investigated the impact of serum cholesterol levels on 30-day mortality after ischemic stroke in dialysis patients.From the Taiwan Stroke Registry data, we identified 46,770 ischemic stroke cases, including 1101 dialysis patients and 45,669 nondialysis patients from 2006 to 2013.Overall, the 30-day mortality was 1.46-fold greater in the dialysis group than in the nondialysis group (1.75 versus 1.20 per 1000 person-days). The mortality rates were 1.64, .62, 2.82, and 2.23 per 1000 person-days in dialysis patients with serum total cholesterol levels of 120 mg/dL, 120-159 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. Compared to dialysis patients with serum total cholesterol levels of 120-159 mg/dL, the corresponding adjusted hazard ratios of mortality were 4.20 (95% confidence interval [CI] = 1.01-17.4), 8.06 (95% CI = 2.02-32.2), and 6.89 (95% CI = 1.59-29.8) for those with cholesterol levels of 120 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively.Dialysis patients with serum total cholesterol levels of ≥160 mg/dL or 120 mg/dL on admission are at an elevated hazard of 30-day mortality after ischemic stroke.

This report aimed to explore the association between the change of circulating interleukin-6 (IL-6) in patients and the development of type 1 diabetes mellitus (T1DM).Four databases (PubMed, CNKI, WanFang and Civip) were used to search and list all clinical case-control studies about serum IL-6 level in T1DM patients between Jan 1, 2000 and Aug 31, 2016.A total of 20 case-control studies with 1238 T1DM patients and 742 healthy controls were included in this study. Compared to healthy controls, the serum content of IL-6 in patients with T1DM was significantly greater (overall: SMD, 1.49; 95% CI, 1.04 to 1.93; p0.001), and notably increased in all subgroup with different age, ethnic and disease duration (all p0.001). Furthermore, the analysis in subgroup exhibited that serum levels of IL-6 in the age greater than 20-year old (SMD, 1.64; 95% CI, 0.57-2.71; p0.001), the diseased duration among 0-10years (SMD, 2.43; 95% CI, 1.42-3.44; p0.001) and the sorted American group (SMD, 1.68; 95% CI, 0.85-2.51; p0.001) were higher than those in control groups.Patients with T1DM were found to be linked to elevated level of serum IL-6, which the age, ethnic and disease durations in T1DM patients had no effect on the serum IL-6 levels for promoting diabetes mellitus.

Association between ACE gene I/D polymorphism and the risk of overweight/obesity remains controversial. We investigated the possible relationship between ACE gene I/D polymorphism and obesity in Chinese type 2 diabetes mellitus (T2DM) patients. In this study, obesity was defined as a body mass index (BMI) value ≥ 25 kg/m2and subjects were classified into 4 groups (lean, normal, overweight, and obese). PCR (polymerase chain reaction) was used to detect the ACE gene I/D polymorphism in T2DM patients. Metabolic measurements including blood glucose, lipid profile, and blood pressure were obtained. Frequencies of the ACE genotypes (DD, ID, and II) were not significant among the 4 groups of BMI-defined patients (P=0.679) while ACE II carriers showed higher systolic blood pressure (SBP) and pulse pressure (PP) (allP<0.050). Hyperglycemia, hypertension, and dyslipidemia in these T2DM patients were found to be significantly associated with BMI. In conclusion, the relationship of ACE gene I/D polymorphism with obesity is insignificant in Chinese patients with T2DM. SBP and PP might be higher in the ACE II carriers than in the DD and ID carriers.

Supplemental Digital Content is available in the text, A positive family history is recognized as an important risk factor for type 2 diabetes mellitus (T2DM), but the association of family history with rennin-angiotensin system (RAS) gene polymorphisms has not been reported yet, thus we aim to investigate it. Family history records, clinical and biochemical data were obtained from 1239 T2DM patients. Polymerase chain reaction (PCR) was performed for angiotensin-converting enzyme (ACE) genotyping and PCR-restricted fragment length polymorphism was used for angiotensinogen (AGT) genotyping. Patients with a negative family history had higher level of triglyceride and blood pressure, whereas those with a positive family history showed younger onset age and lower body mass index value (All P

Aims: This study aims to investigate the association between renin-angiotensin system gene polymorphism and diabetic retinopathy (DR) in Chinese patients with type 2 diabetes. Methods: We consecutively included 1491 patients for the assessment of ACE I/D and AGT M/T gene polymorphisms in 345 DR cases and 1146 patients without retinopathy (DNR). Albuminuria was defined by urine albumin creatinine ratio and albumin excretion rate. Results: Compared with the NDR patients, the DR cases displayed a higher proportion of diabetic nephropathy (32.68% vs. 6.52%, χ2 = 150.713, p < 0.001). The DR cases and DNR individuals did not differ in the frequency of genotypes and alleles of ACE I/D and AGT M/T (all p > 0.05). Intriguingly, DR patients with obesity showed higher frequency of DD (χ2 = 4.181, p = 0.041), but no significant difference exists in the other stratified BMI and hypertension analyses (all p > 0.05). Binary logistic regression displays that the association of the ACE and AGT gene polymorphisms in DR patients is not significant after adjusting for confounding covariates in all the comparisons. Conclusions: The ACE and AGT gene polymorphisms are not associated with the progress of diabetes developing into retinopathy in Chinese patients with type 2 diabetes. However, more investigations are needed to further prove the association.

We are aimed to systematically assess the worldwide trend in incidence of childhood type 1 diabetes mellitus (CT1DM) from 1965 to 2012 and to discuss whether climate affect incidence of CT1DM. We searched the relevant literatures in detail to judge the effect of different climates on incidence of CT1DM. The climates included Mediterranean, monsoon, oceanic, continental, savanna, and rainforest. According to different climates, we further researched relevant factor such as sunshine durations and latitudes. The overall incidence of CT1DM in 72 countries was 11.43 (95% CI 10.31–12.55) per 100,000 children/yr. The incidence of CT1DM in Oceanic climate [10.56 (8.69–12.42)] is highest compared with other climates; the incidence in 40°–66°34′N/S [14.71 (12.30–17.29)] is higher than other latitude groups; the incidence in sunshine durations with 3–4 hours per day [15.17 (11.14–19.20)] is highest compared with other two groups; the incidence of CT1DM from 2000 to 2012 [19.58 (14.55–24.60)] is higher than other periods; all p

// Yong-Chao Qiao 1,2 , Wei Ling 1 , Yan-Hong Pan 1 , Yin-Ling Chen 1 , Dan Zhou 1 , Yan-Mei Huang 1 , Xiao-Xi Zhang 1,3 and Hai-Lu Zhao 1,2,3 1 Center of Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin Medical University, Guilin, China 2 Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, China 3 Department of Immunology, Faculty of Basic Medicine, Guilin Medical University, Guilin, China Correspondence to: Hai-Lu Zhao, email: // Keywords : tType 1 diabetes mellitus; pramlintide; postprandial glucose; adverse events; meta-analysis Received : January 20, 2017 Accepted : March 02, 2017 Published : March 08, 2017 Abstract Aims: We aim to assess the efficacy and safety of pramlintide plus insulin therapy in patients with type 1 diabetes. Methods: We included clinical studies comparing pramlintide plus insulin to placebo plus insulin. Efficacy was reflected by glycemic control and reduction in body weight and insulin use. Safety concerns were hypoglycemia and other adverse events. Subgroup analysis was performed for different doses (30, 60, 90 µg/meal) and durations (≤4, 26, 29, >29 weeks) of the treatment. Results: A total of 10 randomized placebo-controlled studies were included for this meta-analysis (pramlintide, n=1978; placebo, n=1319). Compared with controls, patients given pramlintide had significantly lower HbA1c ( p < 0.001), total daily insulin dose ( p = 0.024), mean mealtime insulin dose ( p < 0.001), body weight ( p < 0.001) and postprandial glucose level ( p = 0.002). The addition of pramlintide increased the incidence of nausea ( p < 0.001), vomiting ( p < 0.001), anorexia ( p < 0.001) and hypoglycemia ( p < 0.05) at the initiation of the treatment. The efficacy and adverse reactions of pramlintide were largely significant for the different doses and durations of the treatment. Conclusions: The addition of pramlintide to insulin therapy in patients with type 1 diabetes improves glycemic control and reduces insulin requirement and body weight while bringing transient hypoglycemia and digestive disorders.

Objectives The aim of this study was to investigate whether the concentrations of serum tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, increased in type 2 diabetes mellitus (T2DM) and type 2 diabetic nephropathy (T2DN) patients. Methods The four databases (PubMed, CNKI, WanFang and Chinese-Cqvip) were searched from Jan 1, 1999 to October 1, 2016 for all clinical case-control studies about the serum TNF-α concentrations in T2DM and T2DN patients. All relevant data were extracted from published reports. The meta-analysis was performed to compare the changes of serum TNF-α concentrations of T2DN and T2DM patients in Eastern and Western with healthy controls. We further evaluated concentrations of serum TNF-α in T2DN patients with mincroalbuminuria or macroalbuminuria. Random-effects models were adopted to assess the pooling data among various variations. Results In total of 6 studies (744 patients and 277 healthy controls) were included in this study. Compared with healthy controls (both p 0.01), the groups of different albuminuria levels and ethnicities both showed that the serum TNF-α levels were significantly elevated in T2DN patients as well as in eastern T2DN patients ( p = 0.001), but not significant changed in western T2DN patients ( p = 0.081). The results were stable through sensitivity analysis and no significant publications bias existed in this meta-analysis. Conclusions Serum TNF-α concentrations are obviously increased in T2DN and T2DM patients, but higher in T2DN patients, suggesting an elevated inflammatory burden in T2DN patients.

Introduction: The renal renin–angiotensin system (RAS) and the ultrasensitive energy sensor AMP-activated protein kinase (AMPK) have been implicated in normal and aberrant states of the kidney, but interaction between the RAS and AMPK remains unknown. Methods: Ninety-six rats were stratified into four groups: sham, uninephrectomised, uninephrectomised rats treated with the angiotensin-converting enzyme inhibitor lisinopril or the angiotensin receptor blocker losartan. Histopathological examination at 9 months post-operation and biochemical measurements at 3, 6 and 9 months were performed for changes in renal structure and function. The expression of AMPK and angiotensin II at 9 months was detected by immunofluorescence microscopy and western blot. Results: Compared with sham rats, uninephrectomised rats demonstrated progressive glomerulosclerosis, tubular atrophy with cast formation and chronic inflammatory infiltration, in parallel to elevated serum urea, creatinine, urine total protein to creatinine ratio and reduced serum albumin. Overexpression of angiotensin II coexisted with a 85.6% reduction of phosphorylated to total AMPK ratio in the remnant kidney of uninephrectomised rats. RAS blockade by the angiotensin-converting enzyme inhibitor or angiotensin receptor blocker substantially normalised AMPK expression, morphological and functional changes of the remnant kidney. Conclusions: Uninephrectomy-induced RAS activation and AMPK inhibition in the remnant kidney could be substantially corrected by RAS blockade, suggesting a cross-talk between AMPK and RAS components in uninephrectomised rats.

Objective. The aim of this study was to investigate the changes of regulatory T cells (Treg), interleukin-6 (IL-6), IL-10, transforming growth factor-β(TGF-β), and tumor necrosis factor-alpha (TNF-α) in patients with type 2 diabetes mellitus (T2DM).Methods. We performed a comprehensive search up to July 2016 for all clinical studies about the changes of Treg, IL-6, IL-10, IL-17, TGF-β, and TNF-αin T2DM patients versus healthy controls.Results. A total of 91 articles (5642 cases and 7378 controls) were included for this meta-analysis. Compared with the controls (allp<0.001), the patients had increased serum levels of IL-6, TGF-β, and TNF-αbut decreased the percentage of peripheral CD4+CD25+Foxp3+Treg and serum IL-10 level. Furthermore, the percentage of peripheral CD4+CD25+Foxp3+Treg (p<0.001) and serum IL-10 level (p=0.033) were significantly lower in the patients with complication and in the patients without complication, respectively. No significant changes about the percentage of CD4+CD25+Treg (p=0.360) and serum IL-17 level (p=0.459) were found in T2DM patients.Conclusions. T2DM patients have decreased the percentage of peripheral CD4+CD25+Foxp3+Treg and levels of serum IL-10 but elevated serum levels of IL-6, TGF-β, and TNF-α. Presence of diabetic complications further lowers the peripheral CD4+CD25+Foxp3+Treg number.

Objective The aim of this study was used meta-analysis to investigate changes of serum tumor necrosis factor-alpha (TNF-α) in patients with type 1 diabetes mellitus (T1DM). Methods Relevant literatures were identified from PubMed, Cochrane Library, CNKI, WanFang and Chinese-Cqvip databases (published from January 1, 1999 to September 30, 2016). Eligible reports were included for pooled analysis of serum TNF-α level and subgroup analysis was performed in relation with age, disease duration and ethnicity. Results A total of 23 articles (1631 T1DM cases, 1429 healthy controls) were included for this meta-analysis. Compared with the controls, the patients had significantly increased serum TNF-α level (P < 0.001). Similar results were also found among all subgroup analysis of different age, disease duration and ethnicity (with the exception of Asian) (all P < 0.05). Regression analysis indicated that age (P = 0.680), disease duration (P = 0.957), and ethnicity (P = 0.526) of patients were not significant impact factors for the high heterogeneity. The results were stable according to the sensitivity analysis and no publication bias existed in this meta-analysis. Conclusions Serum TNF-α level in T1DM patients has significantly elevated among all age, disease duration and ethnicity groups.

Background: The existing evidence indicates increased levels of transforming growth factor beta 1 (TGF-β1) in patients with type 2 diabetes mellitus (T2DM) and those with type 2 diabetic nephropathy (T2DN); yet no meta-analysis displays a reliable result. Here we conducted a meta-analysis to evaluate characteristic changes of TGF-β1 in T2DM and diabetic nephropathy. Methods: A systematic search was conducted for eligible studies, which reported the association of TGF-β1 withT2DM and T2DN patients, in PubMed, Wangfang, Chinese-Cqvip, and China National Knowledge Infrastructure database, from February 1, 1991 to December 15, 2015. The association of serum and urine TGF-β1 in T2DM and T2DN patients should be evaluated in case-control studies. The Newcastle-Ottawa Scale was used to access the quality of the included studies, and pooling data were synthesized as standard mean difference (SMD) and 95% confidence interval (CI). The collected data were synthesized according to Cochrane Handbook for Systematic Reviews criteria. Subgroup analysis was conducted by albuminuria and ethnicity. Regression analysis and sensitivity analysis were used to explore the sources of heterogeneity. Publication bias was judged by the Egger test. Results: Sixty-three case-control studies of 364 T2DM patients (1604 T2DN patients) and 2100 healthy controls were included for meta-analysis. Compared with the controls, the cases had increased TGF-β1 levels in both serum (T2DM: SMD 1.78 μg/L; 95% CI 0.98–2.59, P