Biodegradable controlled-release polymer containing butylidenephthalide to treat a recurrent cervical spine glioblastoma with promising result: a compassionate trial report.

Intramedullary spinal glioblastoma multiforme (GBM) tends to recur within 11 months of surgical resection, even after adjuvant chemoradiation therapy. Treatment options for recurrent spinal GBM are often limited. (Z)-n-butylidenephthalide [(Z)-BP] is a natural compound that induces apoptosis, antiproliferation, anti-invasion and antistemness effects in GBM cells. The Cerebraca wafer consists of (Z)-BP within a biodegradable wafer that can be implanted in the parenchyma of the central nervous system to treat high-grade glioma. We present a 44-year-old woman with a recurrent spinal GBM who underwent microscopic surgical tumor excision under fluorescein sodium guidance and intraoperative neurophysiologic monitoring. Four Cerebraca wafers were implanted into the cord and intradural space during the operation. MRI revealed that both tumor volume and spinal cord edema had decreased 4 days after surgery; both had substantially decreased 16 months after surgery. Neurologic functions and quality of life were improved after salvage therapy. No adverse events were reported. Cerebraca wafer implantation during surgical re-excision of spinal GBM may be a novel therapeutic approach for reduction of the tumor size and subsequent spinal cord edema with no toxicity to the spinal cord.

Correlation between serum interleukin-6 level and type 1 diabetes mellitus: A systematic review and meta-analysis.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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; p<0.001), and notably increased in all subgroup with different age, ethnic and disease duration (all p<0.001). 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; p<0.001), the diseased duration among 0-10years (SMD, 2.43; 95% CI, 1.42-3.44; p<0.001) and the sorted American group (SMD, 1.68; 95% CI, 0.85-2.51; p<0.001) were higher than those in control groups. CONCLUSIONS: 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.

State- and frequency-dependence in autonomic rebalance mediated by intradermal auricular electroacupuncture stimulation.

Background: Vagus nerve stimulation (VNS) improves diseases such as refractory epilepsy and treatment-resistant depression, likely by rebalancing the autonomic nervous system (ANS). Intradermal auricular electro-acupuncture stimulation (iaES) produces similar effects. The aim of this study was to determine the effects of different iaES frequencies on the parasympathetic and sympathetic divisions in different states of ANS imbalance. Methods: We measured heart rate variability (HRV) and heart rate (HR) of non-modeled (normal) rats with the treatment of various frequencies to determine the optimal iaES frequency. The optimized iaES frequency was then applied to ANS imbalance model rats to elucidate its effects. Results: 30 Hz and 100 Hz iaES clearly affected HRV and HR in normal rats. 30 Hz iaES increased HRV, and decreased HR. 100 Hz iaES decreased HRV, and increased HR. In sympathetic excited state rats, 30 Hz iaES increased HRV. 100 Hz iaES increased HRV, and decreased HR. In parasympathetic excited state rats, 30 Hz and 100 Hz iaES decreased HRV. In sympathetic inhibited state rats, 30 Hz iaES decreased HRV, while 100 Hz iaES decreased HR. In parasympathetic inhibited rats, 30 Hz iaES decreased HR and 100 Hz iaES increased HRV. Conclusion: 30 Hz and 100 Hz iaES contribute to ANS rebalance by increasing vagal and sympathetic activity with different amplifications. The 30 Hz iaES exhibited positive effects in all the imbalanced states. 100 Hz iaES suppressed the sympathetic arm in sympathetic excitation and sympathetic/parasympathetic inhibition and suppressed the vagal arm and promoted the sympathetic arm in parasympathetic excitation and normal states.

Circular RNA: an important player with multiple facets to regulate its parental gene expression.

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.

[Parasympathetic innervation contributes to the increase of survival rate and anti-inflammatory effect of electroacupuncture at "Ciliao"(BL32) in rats with lethal endotoxemia].

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Ciliao" (BL32) on the survival rate and serum inflammatory cytokine levels in rats with lethal endotoxemia, and to explore its parasympathetic mechanism in suppressing severe systemic inflammation. METHODS: A total of 82 male SD rats were used in the present study. In the first part of this study, 40 rats were randomized into model and EA-BL32 groups (n=20/group). The endotoxemia model was established by intraperitoneal injection of lethal amount of lipopolysaccharide (LPS, 10 mg/kg). EA (30 Hz, 6 mA) was applied to bilateral BL32 for 30 min before and after LPS injection. The survival rate in 7 days was then recorded. In the second part of this study, 42 rats were randomized into normal control, model, EA-BL32, EA-BL32+cervical vagotomy, EA-BL32+truncal (subdiagrammatical) vagotomy and EA-BL32+pelvic neurectomy groups (n=7/group). The endotoxemia model was established by intraperitoneal injection of LPS (6 mg/kg) 30 min after the neurectomy. Rats of the control group received intraperitoneal injection of 6 mg/kg saline. EA with the same parameters mentioned above was applied to bilateral BL32 for 30 min before and after LPS injection. Blood sample was collected from the abdominal aorta 3 h after LPS injection for detecting the levels of TNF-α, IL-1ß and IL-6 by ELISA. RESULTS: ① The EA survival rate was 25% in the model group and 60% in the EA -BL32group, being significantly improved after EA (P<0.05). ② The contents of serum TNF-α, IL-1ß and IL-6 were significantly higher in the model group than those in the control group (P<0.000 1). After EA intervention, and compared with the model group, the levels of TNF-α, IL-1ß and IL-6 were significantly decreased in the EA-BL32, EA-BL32+cervical vagotomy, EA-BL32+truncal vagotomy and EA-BL32+pelvic neurectomy groups (P<0.000 1，P<0.01). After neurectomy and compared to the EA-BL32 group, the contents of TNF-α and IL-6 in the EA+cervical vagotomy and EA+pelvic neurectomy groups, IL-1ß in the EA+pelvic neurotomy group were significantly higher (P<0.0000 1, P<0.05), suggesting an elimination of EA effects after neurectomy. No significant differences were found among the 3 neurectomy groups in the levels of TNF-α, IL-1ß and IL-6 (P>0.05). CONCLUSION: EA of BL32 can improve the survival rate and attenuate the level of inflammatory cytokines in rats with lethal endotoxemia, which is closely related to the intact of parasympathetic pathway including the vagus nerve and pelvic nerve.

Median Nerve Stimulation Facilitates the Identification of Somatotopy of the Subthalamic Nucleus in Parkinson's Disease Patients under Inhalational Anesthesia.

Deep brain stimulation (DBS) improves Parkinson's disease (PD) symptoms by suppressing neuropathological oscillations. These oscillations are also modulated by inhalational anesthetics used during DBS surgery in some patients, influencing electrode placement accuracy. We sought to evaluate a method that could avoid these effects. We recorded subthalamic nucleus (STN) neuronal firings in 11 PD patients undergoing DBS under inhalational anesthesia. Microelectrode recording (MER) during DBS was collected under median nerve stimulation (MNS) delivered at 5, 20, and 90 Hz frequencies and without MNS. We analyzed the spike firing rate and neuronal activity with power spectral density (PSD), and assessed correlations between the neuronal oscillation parameters and clinical motor outcomes. No patient experienced adverse effects during or after DBS surgery. PSD analysis revealed that peripheral 20 Hz MNS produced significant differences in the dorsal and ventral subthalamic nucleus (STN) between the beta band oscillation (16.9 ± 7.0% versus 13.5 ± 4.8%, respectively) and gamma band oscillation (56.0 ± 13.7% versus 66.3 ± 9.4%, respectively) (p < 0.05). Moreover, 20-Hz MNS entrained neural oscillation over the dorsal STN, which correlated positively with motor disabilities. MNS allowed localization of the sensorimotor STN and identified neural characteristics under inhalational anesthesia. This paradigm may help identify an alternative method to facilitate STN identification and DBS surgery under inhalational anesthesia.

Circular RNAs: Promising Biomarkers for Age-related Diseases.

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.

Plasma-Derived Exosomal Circular RNA hsa_circ_0005540 as a Novel Diagnostic Biomarker for Coronary Artery Disease.

BACKGROUND: Exosomes exist in almost all body fluid and contain diverse biological contents which may be reflective of disease state. Circular RNAs (circRNAs) are stable in structure and have a long half-life in exosomes without degradation, thus making them reliable biomarkers. However, the potential of exosomal circRNAs as biomarkers of coronary artery disease (CAD) remains to be established. Here, we aimed to investigate the expression levels and the potential use of exosomal circRNAs as diagnostic biomarkers for CAD. METHODS: CircRNA expression levels in exosomes obtained from three plasma samples of CAD patients and three paired controls were analyzed using RNA sequencing. Exosomal circRNAs obtained in the profiling phase were then verified in two-center validation cohorts. Finally, the ability of exosomal circRNAs, adjusting for Framingham Heart Study (FHS) risk factors, was determined to discriminate between CAD patients and non-CAD controls. RESULTS: 355 circRNAs were differentially expressed between these two groups: 164 were upregulated, and 191 were downregulated. Here, we selected the potential circRNAs (fold change > 4, P < 0.05) as candidate biomarkers for further validation. Our data showed that only hsa_circ_0005540 was significantly associated with CAD (P < 0.0001). After adjustment for risk factors, hsa_circ_0005540 showed a high discriminatory power for CAD in ROC analyses (AUC = 0.853; 95%confidence interval (CI) = 0.799 - 0.906, P < 0.001). CONCLUSION: Our results suggest that plasma exosomal hsa_circ_0005540 can be used as a promising diagnostic biomarker of CAD.

Prognostic factors of subthalamic stimulation in Parkinson's disease: a comparative study between short- and long-term effects.

BACKGROUND/AIMS: Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) has been shown to have long-term benefits in Parkinson's disease (PD). Through analyzing different variables, this study identified prognostic factors for the short- and long-term effects of STN-DBS. METHODS: Thirty-six PD patients underwent bilateral STN-DBS. Clinical evaluations were performed 1 month before and 3 months after surgery, with additional follow-up examinations for a mean of 31.3 months. RESULTS: There was a trend for long-term STN-DBS-induced improvements in the Unified Parkinson's Disease Rating Scale (UPDRS) part II and part III measures to be greater in younger patients. Preoperative levodopa responsiveness only led to consistent UPDRS part III improvement from STN-DBS at 3 months, and this predictive value did not exist in the long term. The preoperative levodopa response of tremor and axial symptoms in motor disability predicted long-term DBS effect only. Preoperative cognitive function positively correlated with postoperative improvement from DBS in UPDRS part III during long-term follow-up only. CONCLUSIONS: The prognostic factors for STN-DBS benefit were different for short- and long-term follow-ups. Good prognostic factors for long-term STN-DBS for PD patients were good cognitive function and tremor dominance. Poor prognostic factors were related to older age and non-dopaminergic-responsive axial disability.

Amyloids in Site-Specific Autoimmune Reactions and Inflammatory Responses.

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.

Interaction of renin-angiotensin system gene polymorphisms with hypertension in Chinese patients with type 1 diabetes and retinopathy.

BACKGROUND: The objective of this research was to investigate the interaction of RAS gene polymorphisms in Chinese patients with type 1 diabetes mellitus (T1DM) and diabetic retinopathy (DR). METHODS: Genomic DNA was extracted from peripheral blood leukocytes and genotyping for the angiotensin converting enzyme (ACE) gene I/D and angiotensinogen (AGT) gene M/T polymorphisms was performed using the polymerase chain reaction method. 311 T1DM patients were recruited for the assessment of ACE and AGT polymorphisms relating to DR. RESULTS: Compared with the diabetic non-retinopathy (DNR) patients, DR patients had lower proportion of diabetic nephropathy (p<0.001) and M allele (p=0.013). Intriguingly, the frequency D allele (p=0.035) was lower in DR patients with hypertension, as well as DD (p=0.003) and DI genotype (p=0.012) in DR patients with normal blood pressure after multiple tests with Bonferroni correction, but D allele (p=0.025) displayed higher in normotensive patients with T1DM. Logistic regression analyses indicated that no significant relationship existed about the genotype and allele polymorphisms with the progress of DR after adjusting for confounding factors. CONCLUSIONS: Interaction of hypertension and the RAS gene polymorphisms might have a role in the DR development in Chinese T1DM patients.

The relationship between ACE/AGT gene polymorphisms and the risk of diabetic retinopathy in Chinese patients with type 2 diabetes.

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.

Risk for cancer in living kidney donors and recipients.

OBJECTIVE: Malignancy following renal transplantation remains inconsistent with the reported safety of kidney donation during the long-term follow-up. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Climates on incidence of childhood type 1 diabetes mellitus in 72 countries.

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 < 0.01. Incidence of CT1DM was increasing from 1965 to 2012, but incidence in Oceanic climate is higher than other climates. Furthermore, it is higher in centers with higher latitude and lower sunshine durations. The climates might play a key role in inducing CT1DM.

Efficacy and safety of pramlintide injection adjunct to insulin therapy in patients with type 1 diabetes mellitus: a systematic review and meta-analysis.

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.

The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: A systematic review and meta-analysis.

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.

Family history and renin-angiotensin system gene polymorphisms in Chinese patients with type 2 diabetes mellitus.

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 < .05), these findings were age-dependent. The percentage of hypertension was lower with a higher percentage of overweight among the patients with a positive family history (All P < .05). Patients with a positive family history and those with a negative family history had comparable genotype and allele distribution of ACE gene insertion/deletion polymorphisms and AGT gene M/T polymorphisms.A positive family history of diabetes was not associated with the RAS gene polymorphisms.

The Yin and Yang of regulatory T cell and therapy progress in autoimmune disease.

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.

Changes of transforming growth factor beta 1 in patients with type 2 diabetes and diabetic nephropathy: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: The existing evidence indicates increased levels of transforming growth factor beta 1 (TGF-ß1) 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-ß1 in T2DM and diabetic nephropathy. METHODS: A systematic search was conducted for eligible studies, which reported the association of TGF-ß1 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-ß1 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-ß1 levels in both serum (T2DM: SMD 1.78 µg/L; 95% CI 0.98-2.59, P < .001; T2DN: SMD 4.70 µg/L, 95% CI 3.55-5.85, P < .001) and urine samples (T2DM: SMD 1.27 pg/mg.creatinine, 95% CI 0.16-2.38, P < .001; SMD 1.19 ng/L, 95% CI 0.77-1.62, P < .001; T2DN: SMD 3.14 pg/mg.creatinine, 95% CI 2.15-4.13, P < .001; SMD 4.50 ng/L, 95% CI 3.16-5.83, P < .001). The increase of serum TGF-ß1 persisted in patients with either microalbuminuria or macroalbuminuria (all P < .001) in Chinese and non-Chinese population. High heterogeneity exists in some comparisons and small-sample studies. CONCLUSIONS: Patients with T2DM and those with albuminuria, Chinese or non-Chinese, had increased serum and urine TGF-ß1 levels.

Serum TNF-α concentrations in type 2 diabetes mellitus patients and diabetic nephropathy patients: A systematic review and meta-analysis.

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.