BackgroundDiabetic foot ulcer (DFU) is an intractable diabetic complication. Patients suffering from diabetes mellitus (DM) frequently present with infected DFUs. In this study, a wound healing model on diabetic rat foot was established to mimic the pathophysiology of clinical patients who suffer from DFUs. Our study aimed to explore the localization of human adipose-derived stem cells (hADSCs) and the role of these cells in the repair of foot ulcerated tissue in diabetic rats, and thus to estimate the possibilities of adipose-derived stem cells for diabetic wound therapy.MethodSprague–Dawley rats were used to establish diabetic models by streptozotocin injection. A full-thickness foot dorsal skin wound was created by a 5 mm skin biopsy punch and a Westcott scissor. These rats were randomly divided into two groups: the hADSC-treated group and the phosphate-buffered saline (PBS) control group. The hADSC or PBS treatment was delivered through the left femoral vein of rats. We evaluated the localization of hADSCs with fluorescence immunohistochemistry and the ulcer area and ulcerative histology were detected dynamically.ResultThe hADSCs had a positive effect on the full-thickness foot dorsal skin wound in diabetic rats with a significantly reduced ulcer area at day 15. More granulation tissue formation, angiogenesis, cellular proliferation, and higher levels of growth factors expression were also detected in wound beds.ConclusionsOur data suggest that hADSC transplantation has the potential to promote foot wound healing in diabetic rats, and transplantation of exogenous stem cells may be suitable for clinical application in the treatment of DFU.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0412-2) contains supplementary material, which is available to authorized users.

The aim of this study was to investigate the correlation of the proinflammatory marker tumor necrosis factor-α (TNF-α) and the tubular marker neutrophil gelatinase-associated lipocalin (NGAL) with the progression of the early stage of type 2 diabetic nephropathy (DN). Baseline levels of urinary TNF-α and NGAL were measured in 63 non-diabetic controls and 201 patients with type 2 diabetes and different albuminuria statuses. The patients with diabetes (n=125) with normo- or microalbuminuria were subsequently followed-up for 28 (25–32) months, with routine measurements of creatinine and urinary albumin excretion (UAE). It was observed that baseline levels of urinary TNF-α and NGAL were significantly elevated and correlated with the severity of albuminuria in patients with diabetes. During the follow-up, the urinary levels of TNF-α and NGAL were observed to be significantly correlated with a rapid decline in the estimated glomerular filtration rate (eGFR). Following adjustment for other progression promoters, including albuminuria, TNF-α remained a significant predictor of eGFR decline. These results suggest that inflammation is important in the pathogenesis of DN and indicate that TNF-α may be used as an independent predictor for the progression of DN at the early stage.

Actin filaments are a major component of the cytoskeleton in eukaryotic cells and play an important role in cancer metastasis. Dynamics and reorganization of actin filaments are regulated by numerous regulators, including Rho GTPases, PAKs (p21-activated kinases), ROCKs (Rho-associated coiled-coil containing kinases), LIMKs (LIM domain kinases), and SSH1 (slingshot family protein phosphate 1). Ubiquitination, as a ubiquitous post-transcriptional modification, deceases protein levels of actin cytoskeleton regulatory factors and thereby modulates the actin cytoskeleton. There is increasing evidence showing cytoskeleton regulation by long noncoding RNAs (lncRNAs) in cancer metastasis. However, which E3 ligases are activated for the ubiquitination of actin-cytoskeleton regulators involved in tumor metastasis remains to be fully elucidated. Moreover, it is not clear how lncRNAs influence the expression of actin cytoskeleton regulators. Here, we summarize physiological and pathological mechanisms of lncRNAs and ubiquitination control mediators of actin cytoskeleton regulators which that are involved in tumorigenesis and tumor progression. Finally, we briefly discuss crosstalk between ubiquitination and lncRNA control mediators of actin-cytoskeleton regulators in cancer.

The involvement of brain glycogen in the progress of chronic stress-induced impairment of hippocampal astrocyte structural plasticity and depression-like behavior is yet to be clarified. The present study designed three experiments to determine the role of brain glycogen in the plasticity and behavioral consequences of chronic stress. Time course studies on brain glycogen, astrocytes, and behavioral responses to stress were conducted in Experiment 1. Chronic stress decreased the hippocampal glycogen levels, reduced astrocytic size and protrusion length in the hippocampus, and induced depression-like behavior. Glycogen synthase 1 mRNA in the hippocampus was silenced by lentiviral vector-based RNA interference (RNAi) in Experiment 2. This RNAi produced a lack of glycogen in the hippocampus, decreased the hippocampal astrocyte size, and induced depressive behavior in rats. The mechanisms of chronic stress-induced brain glycogen decrease were investigated in Experiment 3. Chronic stress promoted hippocampal glycogen breakdown and increased hippocampal glycogen synthesis. Results suggest that decreased glycogen content was associated with chronic stress-induced atrophy of hippocampal astrocyte size and depression-like behavior. Furthermore, the decrease of glycogen content in the hippocampus might be due to the compensation of glycogen synthesis for breakdown in an insufficient manner.Astrocytes are star-shaped glial cells in the central nervous system (CNS). These cells play an important role in the normal functioning of the CNS. Astrocytes regulate brain homeostasis, support neuronal health and metabolism, and are actively involved in the signaling processes 1 . Recently, an increasing number of data demonstrate that astrocyte structural plasticity (such as astrocyte protrusion length, branching, and volume) is disrupted after long-term exposure to stress, which may be the underlying mechanism of stress-induced depression-like behavior 2,3 . In Tynan et al.'s study 4 , for example, three weeks of restraint stress produced profound atrophy in astrocyte process length, branching, and volume in the prefrontal cortex of rats. A recent study showed that traumatic stress was capable of altering astrocytic morphology in the hippocampus, as shown by the reductions observed in the total number of primary processes 5 . However, the mechanism underlying the impairment of stress-induced astrocyte plasticity is yet to be clarified because of the relative newness of this field of research.Glycogen, a complex glucose polymer found in a variety of tissues, is normally considered to function as storage for glucose. Certainly, the function of glycogen in securing a constant blood glucose level under a variety of conditions in the liver is well recognized. Glycogen in the brain is located mainly in astrocytes in the hippocampus, striatum, and cortex 6,7 . Although brain glycogen content is limited to an average of 3 μ mol/g to 12 μ mol/g tissue, the role of brain glycogen has been associated with the preservation of neuronal function...

Background/Aims: The diagnosis of type 2 diabetic nephropathy (T2DN) patients is important to prevent the long-term damaging effects of kidney loss in patients with diabetes and is decisive for patient outcomes. The aim of this study was to explore urine retinol binding protein (RBP) and neutrophil gelatinase-associated lipocalin (NGAL) in T2DN patients with and without albuminuria. Methods: A total of 293 T2DN patients were divided into three groups according to their urine albumin/urine creatinine ratio (UACR): normoalbuminuria group (UACR<30 mg/g, n=100), microalbuminuria group (UACR 30–300 mg/g, n=100) and macroalbuminuria group (UACR>300 mg/g, n=93); 50 non-diabetic subjects were recruited as the control group. The levels of urine RBP, NGAL, TNF-α and IL-18 in T2DN patients and non-diabetic subjects were measured using ELISA assays. Results: We first analyzed the clinical characteristics of the control and T2DN groups and found that urine NGAL, RBP, TNF-α and IL-18 levels were significantly increased and significantly correlated with the degree of albuminuria. In addition, univariate linear regression analysis showed that urine RBP was associated with UACR, BMI, Scr, BUN, TG, disease duration, SBP, NGAL, TNF-α and IL-18 levels, and urine NGAL was positively correlated with UACR, Scr, BUN, RBP, TNF-α and IL-18 levels. Conclusion: The results indicate that urine levels of NGAL and RBP may be independently associated with albuminuria in T2DN and may serve as novel biomarkers for the identification of T2DN.

SummaryEndometrial injury is an important cause of intrauterine adhesion (IUA), amenorrhea and infertility in women, with limited effective therapies. Recently, stem cells have been used in animal experiments to repair and improve injured endometrium. To date, our understanding of adipose-derived stem cells (ADSCs) in endometrial injury repair and their further therapeutic mechanisms is incomplete. Here, we examined the benefit of ADSCs in restoration of injured endometrium by applying a rat endometrial injury model. The results revealed by immunofluorescence showed that green fluorescent protein (GFP)-labelled ADSCs can differentiate into endometrial epithelial cells in vivo. At 30 days after ADSCs transplantation, injured endometrium was significantly improved, with increased microvessel density, endometrial thickness and glands when compared with the model group. Furthermore, the fertility of rats with injured endometrium in ADSCs group was improved and had a higher conception rate (60% vs 20%, P = 0.014) compared with the control phosphate-buffered saline (PBS) group. However, there was no difference in the control group compared with the sham group. In addition, expression levels of the oestrogen receptor Eα/β (ERα, ERβ) and progesterone receptor (PR) detected by western blot and enzyme-linked immunosorbent assay (ELISA) were higher in the ADSCs group than in the PBS group. Taken together, these results suggested that ADSC transplantation could improve endometrial injury as a novel therapy for IUA.

RasGRP1 is upregulated in HCC and promotes HCC cell proliferation. Thus, RasGRP1 may be a novel therapeutic target for HCC.

This study aimed to investigate the effects of epidermal growth factor (EGF) on the proliferation and differentiation of adipose stem cells (ASC) during the repeated passaging and probe the underlying signal pathway. Results showed that the Ki67 positive rate remained at a high level, the number of ASCs in G0/G1 phase reduced significantly, but ASCs in G2/M phase and S phase increased markedly in ASCs treated with EGF when compared with ASCs without EGF treatment, indicating that EGF made more ASCs in proliferation phase. The adipogenic capability of ASCs without EGF was compromised when compared with that of ASCs after EGF treatment, although significant difference was not observed. The osteogenic and chondrogenic potencies increased significantly in ASC with EGF treatment indicating EGF could maintain differentiative capacity of ASCs. Gene Set Enrichment Analysis showed EGF upregulated the expression of molecules in the epithelial mesenchymal transition and G2/M checkpoint signal pathways. GeneMANIA database analysis indicated the network interaction between EGF and STAT. EGF receptor (EGFR) inhibitor and STAT3 inhibitor were independently used to validate the role of both pathways in these effects. After inhibition of EGFR or STAT3, the proliferation of ASCs was significantly inhibited, and Western blotting showed EGF was able to markedly increase the expression of EGFR and STAT3. These findings suggest EGF not only promotes the proliferation of ASCs and delays their senescence, but also maintains the differentiation potency of ASCs, which are related to the EGF-induced activation of STAT signal pathway.