ABSTRACT
To determine the annual incidence and clinically relevant risk factors for foot ulceration in a large cohort study of diabetic foot ulcer (DFU) patients and diabetes mellitus (DM) patients ...in China. To investigate a cohort of 1,333 patients comprising 452 DFU patients and 881 DM patients, who underwent foot screening, physical examination, and laboratory tests in eight hospitals. The patients were assessed at baseline in terms of their demographic information, medical and social history, peripheral neuropathy disease (PND) screening, periphery artery disease (PAD) screening, assessment of nutritional status, and diabetic control. One year later, the patients were followed up to determine the incidence of new foot ulcers, amputation, and mortality. By univariate analysis, statistically significant differences were found in age, location, gender, living alone (yes/no), occupation, smoking, hypertension, PND, PAD, nephropathy, retinopathy, cataracts, duration of diabetes, Glycosylated hemoglobin A (HbA1c), fasting plasma glucose level, postprandial blood glucose level, insulin level, blood urea nitrogen, creatinine, cholesterol, triglyeride, high density lipoprotein (HDL), serum albumin, white blood cell, and body mass index. A binary logistic regression model was used to examine which of these risk factors were independent risk factors for foot ulceration. A total of 687 (51.5%) of the 1,333 patients were followed up for an average of 12 months; there were 458 DM patients and 229 DFU patients. A total of 46 patients died during the follow‐up period; 13 were DM patients, and 33 were DFU patients. Of the 641 patients, 445 (69.4%) patients were DM patients, and 196 (30.6%) were DFU patients. At follow‐up, 36/445 DM patients (8.1%), and 62/196 DFU patients (31.6%), developed new ulcers; 10/196 DFU patients underwent an amputation. The annual incidence of ulceration for DM patients and amputation for DFU patients were 8.1 and 5.1%, respectively. The annual mortality of the DM patients and DMF patients were 2.8 and 14.4%, respectively. A binary logistic regression model was used to examine which risk factors were independent risk factors for foot ulceration during the follow‐up period, and the final results showed that nephropathy (odds ratio 2.32), insulin level (odds ratio 3.136, 2.629), and decreased HDL (odds ratio 0.427) were associated with increased risks for foot ulceration. Complications of diabetes affecting the feet represent a serious problem in China. The incidence of foot ulcers and amputation are much higher than that of Western countries. More intensive surveillance and aggressive care following a diagnosis of DFU and earlier referral to specialty care might improve the patient outcome.
Objective. Mesenchymal stem cells (MSCs) are considered a promising therapy for wound healing. Here, we explored the role of c-Jun in diabetic wound healing using human umbilical cord-derived MSCs ...(hUC-MSCs). Methods. Freshly isolated hUC-MSCs were subjected to extensive in vitro subcultivation. The cell proliferative and migratory capacities were assessed by the Cell Counting Kit-8 and scratch assays, respectively. c-Jun expression was evaluated by RT-PCR and western blot analysis. The function of c-Jun was investigated with lentivirus transduction-based gene silencing and overexpression. Diabetes mellitus was induced in SD rats on a high-glucose/fat diet by streptozocin administration. Wounds were created on the dorsal skin. The effects of c-Jun silencing and overexpression on wound closure by hUC-MSCs were examined. Reepithelialization and angiogenesis were assessed by histological and immunohistochemical analysis, respectively. Platelet-derived growth factor A (PDGFA), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) levels were determined by western blot analysis. Results. hUC-MSCs showed gradually decreased cell proliferation, migration, and c-Jun expression during subcultivation. c-Jun silencing inhibited cell proliferation and migration, while c-Jun overexpression enhanced proliferation but not migration. Compared with untransduced hUC-MSCs, local subcutaneous injection of c-Jun-overexpressing hUC-MSCs accelerated wound closure, enhanced angiogenesis and reepithelialization at the wound bed, and increased PDGFA and HGF levels in wound tissues. Conclusion. c-Jun overexpression promoted hUC-MSC proliferation and migration in vitro and accelerated diabetic wound closure, reepithelization, and angiogenesis by hUC-MSCs in vivo. These beneficial effects of c-Jun overexpression in diabetic wound healing by hUC-MSCs were at least partially mediated by increased PDGFA and HGF levels in wound tissues.
Diabetic foot ulcers are a serious complication of diabetes, with high mortality and a lack of effective clinical treatment, which leads to a considerable financial burden. Pien-Tze-Huang (PZH) is a ...Chinese traditional medicine with a long history that has been found to be an effective and convenient treatment for inflammatory diseases such as skin abscesses and ulcers. In this study, we assessed the effects of PZH on diabetic wounds and the underlying mechanisms. The wounds were established on the backs of streptozotocin-induced type 1 diabetic rats and type 2 diabetic mouse models. We found that PZH treatment used locally or by gavage significantly promoted wound healing, accelerated re-epithelialization and vasculature in the wound tissue, upregulated the expression of the growth factors VEGF-A, PDGF, and EGF, and activated the Nrf2/ARE pathway in the wound tissue.
assays showed that PZH improved the proliferation, migration and angiogenic function of human umbilical vein endothelial cells (HUVECs) cultured in palmitic acid, reduced the expression of the apoptotic proteins p53, Bax, and cleaved-caspase3, and activated Nrf2/ARE signaling; however, these protective effects were abrogated after Nrf2 was knocked down by specific siRNA. In addition, the levels of the serum inflammatory cytokines IL-1β, TNF-α, and IL-6 were reduced after PZH gavage treatment. In conclusion, the positive role of PZH in diabetic wound healing might be related to the activation of the Nrf2/ARE pathway to regulate the level of oxidative stress
and increase the expression of growth factors to improve angiogenesis.
Metabolic syndrome (MS) is a serious health problem worldwide; it is characterized by a group of metabolic disorders, including central obesity, insulin resistance/type 2 diabetes, hyperlipidemia ...with accelerated atherosclerosis, hypertension, non-alcoholic fatty liver disease, and elevated uric acid with increased risk of gout. The incidence of MS has increased considerably in recent decades and has attracted considerable attention. A number of clinical and translational laboratory studies have implicated the activation of nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in the development of MS, therefore establishing a strong link between chronic inflammation and metabolic diseases. This paper aims to review new developments on NLRP3 inflammasome in MS for better understanding of chronic inflammation in metabolic diseases. We will also provide new insights into using NLRP3 inflammasome as an innovative therapeutic target.
Multiple symmetric lipomatosis (MSL) is a rare disease characterized by symmetric and abnormal distribution of subcutaneous adipose tissue (SAT); however, the etiology is largely unknown. We report ...here that miR-125a-3p and miR-483-5p are upregulated in the SAT of MSL patients, promoting adipogenesis through suppressing the RhoA/ROCK1/ERK1/2 pathway. TaqMan microRNA (miR) array analysis revealed that 18 miRs were upregulated in the SAT of MSL patients. Transfection of human adipose-derived mesenchymal stem cells (hADSCs) with the individual agomirs of these 18 miRs showed that miR-125a-3p and miR-483-5p significantly promoted adipogenesis. A dual-luciferase assay showed that RhoA and ERK1 were the targets of miR-125a-3p and miR-483-5p, respectively. Moreover, transfection of hADSCs with mimics of miR-125a-3p and miR-483-5p resulted in a pronounced decrease of ERK1/2 phosphorylation in the nucleus; conversely, transfection of hADSCs with inhibitors of miR-125a-3p and miR-483-5p led to a significant increase of ERK1/2 phosphorylation in the nucleus. Most importantly, we found that miR-125a-3p and miR-483-5p promoted de novo adipose tissue formation in nude mice. These results demonstrated that miR-125a-3p and miR-483-5p coordinately promoted adipogenesis through suppressing the RhoA/ROCK1/ERK1/2 pathway. Our findings may provide novel strategies for the management and treatment of MSL or obesity.
Objectives. The aim of this study was to investigate the effects of compound C on an in vivo mouse model of high-fat diet- (HFD-) induced obesity and hepatosteatosis. Methods. C57BL/6 mice were fed ...with a standard diet (n = 5) for 16 weeks and then injected saline once a day for 4 weeks as the normal chow group. Mice (n = 10) were fed with HFD for 16 weeks to induce obesity and hepatosteatosis and then divided into two groups: HFD + vehicle group injected with the vehicle solution (saline) and HFD + compound C group injected with compound C in saline (5 mg/kg i.p., once a day) for 4 weeks. Liver histology was observed. The expression levels of genes related to lipid metabolism and proinflammation in liver tissue were examined. NLRP3 inflammasome expression in liver tissue was detected by the western blot assay. HepG2 cells were pretreated with compound C and/or AICAR for 1 h and then treated with palmitic acid (PA) for 3 h. The cells were collected, and mRNA levels were determined. Results. There was a significant reduction in body-weight gain and daily food intake in the HFD + compound C group compared with the HFD + vehicle group (p<0.05). The glucose tolerance test (GTT) and insulin tolerance test (ITT) showed that compound C alleviated insulin resistance. Histology analysis showed a significant reduction of hepatic steatosis by compound C. Compound C also significantly decreased fatty acid synthesis genes, while increased fatty acid oxidation genes. Furthermore, compound C significantly reduced the expression of proinflammatory markers and NLRP3 inflammasome (p<0.05). Compound C enhanced mRNA levels of SOD1, SOD2, catalase, GPx1, and GPx4 and reduced the p-AMPK/AMPK ratio, which were stimulated by palmitic acid (PA). The effect was enhanced by AICAR. Conclusion. Our data suggest that compound C is a potent NAFLD suppressor and an attractive therapeutic target for hepatic steatosis and related metabolic disorders.
The transcription factor, nuclear factor E2‐related factor 2 (Nrf2), is highly sensitive to oxidative burst products, including reactive oxygen species (ROS) and reactive nitrogen species. In the ...cell nucleus, Nrf2 activates various antioxidant genes by binding to the antioxidant response elements. As an adapter for cullin 3/ring‐box 1, kelch‐like ECH‐associated protein 1 (Keap1) ubiquitinates and degrades Nrf2 under physiological conditions. Conversely, with the aggravation of oxidative stress, Keap1‐Nrf2 interaction could be much more easily dissociated. ROS play a key role in regulating the redox signaling pathway and affect the vasculature in a dose‐dependent manner. Long‐term production or high concentration of ROS are harmful to the vascular system, while moderate ROS can promote angiogenesis and tissue regeneration. Furthermore, appropriate regulation of oxidative stress mediated via the Keap1‐Nrf2 pathway would be beneficial in various diseases associated with abnormal angiogenesis, including diabetes and cancers. Nrf2 deficiency has also been shown to result in significantly impaired survival, proliferation, and angiogenic capacity of endothelial cells in a hind limb ischemia model. Thus, this review will briefly summarize the underlying molecular mechanisms of Keap1‐Nrf2 pathway in regulating oxidative stress and also help elucidate the critical role of Keap1‐Nrf2 in angiogenesis under physiological and pathological conditions.
Background. This study is aimed at investigating the effect of combined transplantation of umbilical cord mesenchymal stem cells (UCMSCs) and umbilical cord blood-derived endothelial colony-forming ...cells (ECFCs) on diabetic foot ulcer healing and at providing a novel therapy for chronic diabetic foot ulcer. Methods. We reported the treatment of refractory diabetic foot ulcers in twelve patients. Among them, five patients had two or more wounds; thus, one wound in the same patient was treated with cell injection, and other wounds were regarded as self-controls. The remaining seven patients had only one wound; therefore, the difference between the area of wound before and after treatment was estimated. The UCMSCs and ECFCs were injected into the wound along with topically applied hyaluronic acid (HA). Results. In this report, we compared the healing rate of multiple separate wounds in the same foot of the same patient: one treated with cell injection combined with topically applied HA-based hydrogel and was later covered by the hydrocolloid dressings, while the self-control wounds were only treated with conventional therapy and covered by the hydrocolloid dressings. The wound underwent cell injection showed accelerated healing in comparison to control wound within the first week after treatment. In other diabetic patients with only one refractory wound, the healing rate after cell transplantation was significantly faster than that before injection. Two large wounds healed without needing skin grafts after combination therapy of cell injection and HA. After four weeks of combination treatment, wound closure was reached in six patients, and the wounds of the other six patients were significantly reduced in size. Conclusions. Our study suggests that the combination of UCMSCs, ECFCs, and HA can safely synergize the accelerated healing of refractory diabetic foot ulcers.
Gitelman syndrome (GS) is a rare autosomal recessive renal tubular disease, caused by mutations in the SLC12A3 gene, which encodes the renal thiazide-sensitive Na/Cl cotransporter (NCCT) in the ...distal renal tubule.
A 23-year-old woman was admitted with limb numbness, recurrent tetany and palpitation. Laboratory tests showed hypokalemic alkalosis, hypomagnesemia, hypocalcemia and secondary hyperaldosteronism, as well as hypocalciuria and transient decreased PTH. Next-generation sequencing detected a novel homozygous mutations c.2039delG in the SLC12A3 gene, and her father and children were all heterozygous carriers.
We reported a case of GS with a novel homozygous frame-shift mutation of SLC12A3, and reviewed recent literatures about diagnosis, differential diagnosis and treatments. Hypocalcemia in Gitelman syndrome is rare, and may be related to inhibited PTH secretion induced by hypomagnesemia.
Stem cells and progenitor cells have been identified as potential new therapeutic options for severe limb ischemia to induce angiogenesis, and hyaluronic acid (HA) is commonly applied as a ...biomaterial in tissue engineering. However, the efficiency of HA combined with human umbilical cord blood-derived endothelial colony forming cells (ECFCs) and human umbilical-derived mesenchymal stem cells (MSCs) on angiogenesis is unclear. In the present study, we showed that HA promoted angiogenesis induced by MSCs-ECFCs in Matrigel plugs and promoted blood perfusion of murine ischemic muscles. Laser confocal microscopy revealed that human-derived cells grew into the host vasculature and formed connections, as shown by mouse-specific CD31
/human-specific CD31
double staining.
assays revealed that HA supported cell proliferation and migration, enhanced CD44 expression and reduced microRNA (miR)-139-5p expression. Further analysis revealed that miR-139-5p expression was negatively regulated by CD44 in ECFCs. Flow cytometry assays showed that HA increased CD31 positive cells proportion in MSC-ECFC and could be reversed by miR-139-5p mimics transfection. Moreover, the improvement of MSC-ECFC proliferation and migration induced by HA could be blocked by upregulation of miR-139-5p expression. In conclusion, HA facilitates angiogenesis of MSCs-ECFCs, and this positive effect be associated with activation of the CD44/miR-139-5p pathway, providing a promising strategy for improving severe limb ischemia.
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