Ziwen Liang

Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: A double-blind, randomized, controlled trial

AIMS To identify better cells for the treatment of diabetic critical limb ischemia (CLI) and foot ulcer in a pilot trial. METHODS Under ordinary treatment, the limbs of 41 type 2 diabetic patients with bilateral CLI and foot ulcer were injected intramuscularly with bone marrow mesenchymal stem cells (BMMSCs), bone marrow-derived mononuclear cells (BMMNCs), or normal saline (NS). RESULTS The ulcer healing rate of the BMMSC group was significantly higher than that of BMMNCs at 6 weeks after injection (P=0.022), and reached 100% 4 weeks earlier than BMMNC group. After 24 weeks of follow-up, the improvements in limb perfusion induced by the BMMSCs transplantation were more significant than those by BMMNCs in terms of painless walking time (P=0.040), ankle-brachial index (ABI) (P=0.017), transcutaneous oxygen pressure (TcO(2)) (P=0.001), and magnetic resonance angiography (MRA) analysis (P=0.018). There was no significant difference between the groups in terms of pain relief and amputation and there was no serious adverse events related to both cell injections. CONCLUSIONS BMMSCs therapy may be better tolerated and more effective than BMMNCs for increasing lower limb perfusion and promoting foot ulcer healing in diabetic patients with CLI.

Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α (PGC-1α) Enhances Engraftment and Angiogenesis of Mesenchymal Stem Cells in Diabetic Hindlimb Ischemia

To examine whether the peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α), a key regulator linking angiogenesis and metabolism, could enhance the engraftment and angiogenesis of mesenchymal stem cells (MSCs) in diabetic hindlimb ischemia, we engineered the overexpression of PGC-1α within MSCs using an adenoviral vector encoding green fluorescent protein and PGC-1α, and then tested the survivability and angiogenesis of MSCs in vitro and in vivo. Under the condition of hypoxia concomitant with serum deprivation, the overexpression of PGC-1α in MSCs resulted in a higher expression level of hypoxia-inducible factor-1α (Hif-1α), a greater ratio of B-cell lymphoma leukemia-2 (Bcl-2)/Bcl-2–associated X protein (Bax), and a lower level of caspase 3 compared with the controls, followed by an increased survival rate and an elevated expression level of several proangiogenic factors. In vivo, the MSCs modified with PGC-1α could significantly increase the blood perfusion and capillary density of ischemic hindlimb of the diabetic rats, which was correlated to an improved survivability of MSCs and an increased level of several proangiogenic factors secreted by MSCs. We identified for the first time that PGC-1α could enhance the engraftment and angiogenesis of MSCs in diabetic hindlimb ischemia.

The SGLT-2 Inhibitor Dapagliflozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE−/− Mice

Background. Our study aimed to observe the effect of sodium glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin on diabetic atherosclerosis and investigate the subsequent mechanism. Methods. Aortic atherosclerosis was induced in streptozotocin induced diabetic ApoE−/− mice by feeding with high-fat diet, and dapagliflozin was administrated intragastrically for 12 weeks as treatment. Effects of dapagliflozin on indices of glucose and fat metabolism, IL-1β, IL-18, NLRP3 protein levels, and the reactive oxygen species (ROS) were measured. The atherosclerosis was evaluated by oil red O and hematoxylin-eosin staining. The effects of dapagliflozin on the IL-1β production in culturing primary macrophages of wild type and NLRP3−/− knockout mice were investigated for mechanism analyses. Results. Dapagliflozin treatment showed favorable effects on glucose and fat metabolism, partially reversed the formation of atherosclerosis, inhibited macrophage infiltration, and enhanced the stability of lesion. Also, reduced production of IL-1β, IL-18, NLRP3 protein, and mitochondrial ROS in the aortic tissues was detected with dapagliflozin treatment. In vitro, NLRP3 inflammasome was activated by hyperglucose and hyperlipid through ROS pathway. Conclusions. Dapagliflozin may be of therapeutic potential for diabetic atherosclerosis induced by high-fat diet, and these benefits may depend on the inhibitory effect on the secretion of IL-1β by macrophages via the ROS-NLRP3-caspase-1 pathway.

Serum retinol-binding protein 4 levels are elevated but do not contribute to insulin resistance in newly diagnosed Chinese hypertensive patients.

BackgroundInsulin resistance (IR) is closely correlated with cardiovascular disease (CVD). Retinol-binding protein 4 (RBP4) is a novel adipokine that modulates the action of insulin in various diseases. This study addressed the relationship between RBP4 and IR in newly diagnosed essential hypertension.MethodsSerum RBP4, anthropometric and metabolic parameters were determined in 267 newly diagnosed essential hypertensive patients not taking antihypertensive medications. The patients along with 64 control (NC) normotensive and lean subjects paired by age and sex were divided into two groups depending on body mass index (BMI), hypertension with obesity (HPO) and hypertension without obesity (HP).ResultsA striking difference was observed in RBP4 levels between the HP and NC groups. Significantly higher levels were noted in the HP group compared with the NC group; slightly, but not significantly, lower levels were observed in the HPO group compared with the HP group. After adjusting for BMI, WC and WHR, a modestly linear relationship was observed between RBP4 levels and SBP (r = 0.377; p = 0.00), DBP (r = 0.288; p = 0.00) and HOMA-β(r = 0.121; p = 0.028). Multiple stepwise regression analysis showed that SBP, WHR and drinking were independently related with serum RBP4 levels.ConclusionsThe results of this study indicated that RBP4 levels were increased in naive hypertensive patients; however, no differences were observed in obese or non-obese hypertensive subjects. Our data suggest for the first time that RBP4 levels are significantly increased but do not contribute to the development of IR in newly diagnosed hypertensive Chinese patients.

Transcutaneous oxygen pressure (TcPO2): A novel diagnostic tool for peripheral neuropathy in type 2 diabetes patients

AIMS The assessment of transcutaneous oxygen pressure (TcPO2) may serve as a non-invasive and lower-cost alternative to nerve conduction studies (NCSs) for the diagnosis of diabetic peripheral neuropathy (DPN). The aim of this study was to determine whether the measurement of TcPO2 is useful for evaluating DPN. METHODS We performed a cross-sectional study of 381 consecutive hospitalized diabetic patients classified by clinical examination and NCS as having DPN. Anthropometric and metabolic parameters were assessed. The TcPO2 examination was performed in both supine and sitting positions. RESULTS Three hundred and one patients had DPN. The TcPO2 in both the supine and sitting positions was highest in the Non-DPN group and lower in the confirmed DPN group than the other three groups (p<0.001). The Non-DPN group had the lowest sitting-supine position difference in TcPO2 among the groups (p<0.001). The risk factors strongly associated with DPN included sitting-supine position difference in TcPO2 (OR=4.971, p<0.001), diabetic retinopathy (DR) (odds ratio [OR]=3.794, p=0.002), and HbA1c (OR=1.534, p=0.033). The area under the curve (AUC) of the sitting-supine position difference in TcPO2 was 0.722 and revealed an optimal cut-off point for the identification of DPN (19.5 mmHg) that had a sensitivity of 0.611 and a specificity of 0.738 based on AUC analysis. CONCLUSIONS This large study of diabetic patients confirms that the sitting-supine position difference in TcPO2 is higher in DPN patients than control subjects, indicating that TcPO2 examination is a promising valuable diagnostic tool for DPN.

Assessment of Left Ventricular Structural Remodelling in Patients with Diabetic Cardiomyopathy by Cardiovascular Magnetic Resonance

Background. Diabetic cardiomyopathy (DCM) is always accompanied with alteration of left ventricular structure and function. The aims of this study were to assess the structural remodelling in patients with DCM by cardiovascular magnetic resonance (CMR) and correlation of structural remodelling with severity of DCM. Methods. Twenty-five patients (53.8 ± 8.8 years, 52.0% males) with DCM and thirty-one normal healthy controls (51.9 ± 13.6 years, 45.2% males) were scanned by CMR cine to assess function and structure of left ventricular. Length of diabetic history and results of cardiac echocardiography (E′, A′, and E′/A′) were also measured. Results. Compared with normal controls group, DCM group was associated with significantly increased ratio of left ventricular mass at end diastole to end-diastolic volume (MVR) (P < 0.05) and no significant difference was in mass at end diastole (P > 0.05). The ratio correlated with both length of diabetic history and echocardiographic Doppler tissue imaging E′ (all P < 0.05). Conclusions. CMR can be a powerful technique to assess LV remodelling, and MVR may be considered as an imaging marker to evaluate the severity of LV remodelling in patients with DCM.

Platelet-rich plasma, bilayered acellular matrix grafting and negative pressure wound therapy in diabetic foot infection

UNLABELLED Management and treatment of acute severe diabetic foot disease in patients with suboptimal glycaemic control is a critical issue in wound repair. This paper discusses the clinical efficacy of an aggressive surgical intervention combined with targeted use of regenerative medical therapies in limb preservation. Negative pressure wound therapy (NPWT), platelet-rich plasma (PRP), bilayered acellular matrix grafting and split-thickness skin grafting were combined to treat a patient with diabetes, foot necrotising fasciitis and gaseous gangrene. The wound was completely healed. The clinical outcome revealed that a multi-intervention strategy could be effective for large necrotising fasciitis wounds. Early clinical observation, suggests aggresive surgical intervention preserving intact tissue and targeted use of new regenerative technologies can lead to preservation of a limb. DECLARATION OF INTEREST The authors have received no financial support for the material presented in this study outside of the scope of standard patient care reimbursement. This work was supported by the National Natural Science Foundation of China (NO. 81500596) awarded to Dr Wuquan Deng.

Identification of a novel de novo GATA3 mutation in a patient with HDR syndrome

We describe the case of a 21-year-old male with hypocalcaemia, hyperphosphataemia, recurrent limb twitch, deafness, proteinuria, increased serum creatinine and urea nitrogen levels, and shrinkage of both kidneys. Brain computed tomography showed intracranial calcifications. The patient was diagnosed with hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome. DNA sequence analysis of the GATA3 gene showed a novel de novo mutation, c. 529dupC (p. Arg177profs*126), in exon 2, resulting in a frameshift mutation with a premature stop codon after a new 126 amino acid sequence. We provide further evidence that HDR syndrome is caused by haploinsufficiency of GATA3.

Association between Serum Cystatin C and Diabetic Foot Ulceration in Patients with Type 2 Diabetes: A Cross-Sectional Study

Serum cystatin C (CysC) has been identified as a possible potential biomarker in a variety of diabetic complications, including diabetic peripheral neuropathy and peripheral artery disease. We aimed to examine the association between CysC and diabetic foot ulceration (DFU) in patients with type 2 diabetes (T2D). 411 patients with T2D were enrolled in this cross-sectional study at a university hospital. Clinical manifestations and biochemical parameters were compared between DFU group and non-DFU group. The association between serum CysC and DFU was explored by binary logistic regression analysis. The cut point of CysC for DFU was also evaluated by receiver operating characteristic (ROC) curve. The prevalence of coronary artery disease, diabetic nephropathy (DN), and DFU dramatically increased with CysC (P < 0.01) in CysC quartiles. Multivariate logistic regression analysis indicated that the significant risk factors for DFU were serum CysC, coronary artery disease, hypertension, insulin use, the differences between supine and sitting TcPO2, and hypertension. ROC curve analysis revealed that the cut point of CysC for DFU was 0.735 mg/L. Serum CysC levels correlated with DFU and severity of tissue loss. Our study results indicated that serum CysC was associated with a high prevalence of DFU in Chinese T2D subjects.

Changes in the Expression of Endothelial-overexpressed Lipopolysaccharide-associated Factor 1 in Grafts during Acute Rejection following Liver Transplantation in Rats

This study investigated changes in expression of endothelial-overexpressed lipopolysaccharide-associated factor 1 (EOLA1) in grafts following liver transplantation in rats. Thirty Lewis rats received liver transplants from Lewis rats (tolerance group); 30 received liver transplants from dark Agouti rats (acute rejection group). Changes in serum biochemical indexes (alanine aminotransferase and total bilirubin), graft histology and EOLA1 expression were measured on days 1, 3, 5, 7 and 10 post-operatively. Mean survival time was >100 days in the tolerance group and 16.2 ± 1.4 days in the acute rejection group. Pathological evidence of acute rejection in grafts was seen after day 5 in the acute rejection group. Serum biochemical indexes were significantly higher in the acute rejection group than in the tolerance group from day 5 post-operatively, whereas EOLA1 expression in the liver graft was significantly higher in the tolerance group than in the acute rejection group. EOLA1 expression seems to be negatively correlated with severity of rejection after liver transplantation.