7-Ketocholesterol accelerates pancreatic ß-cell senescence by inhibiting the SIRT1/CDK4-Rb-E2F1 signaling pathway.

Pancreatic ß-cell dysfunction is a key factor in the development of type 2 diabetes. Pancreatic ß-cell senescence accelerates abnormal glucose metabolism, which decreases insulin secretion and cell regeneration ability, eventually leading to diabetes. A cholesterol oxidation product, 7-ketocholesterol (7-KC) can affect pancreatic ß-cell function. However, its role in pancreatic ß-cell senescence has not been reported. We investigated the role of 7-KC in pancreatic ß-cell senescence and its underlying molecular mechanism in MIN6 cells. MIN6 cells were treated with 25 µmol/L 7-KC for 24 h and the proportion of senescent cells was detected based on senescence-associated ß-galactosidase (SA-ß-gal) activity. The cell cycle, DNA damage, and the senescence-associate secretory phenotype (SASP) and protein expression were detected by flow cytometry, immunofluorescence, and western blotting, respectively. 7-KC can significantly increase SA-ß-gal activity, promoted G0/G1 arrest, DNA damage, and interleukin-1ß expression in MIN6 cells and significantly inhibited insulin synthesis. Further studies indicated that 7-KC induced ß-cell senescence by inhibiting the SIRT1/CDK4-Rb - E2F1 signaling pathway.

4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes.

BACKGROUND: Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. A tricarboxylic acid cycle metabolite that can strongly activate NF-E2-related factor 2 (Nrf2) in macrophages, itaconate is important in a series of inflammatory-associated diseases via anti-inflammatory and antioxidant properties. However, its role in type 1 diabetes is unclear. We used 4-octyl itaconate (OI), the cell-permeable itaconate derivate, to explore its preventative and therapeutic effects in mouse models of type 1 diabetes and the potential mechanism of macrophage phenotype reprogramming. METHODS: The mouse models of streptozotocin (STZ)-induced type 1 diabetes and spontaneous autoimmune diabetes were used to evaluate the preventative and therapeutic effects of OI, which were performed by measuring blood glucose, insulin level, pro- and anti-inflammatory cytokine secretion, histopathology examination, flow cytometry, and islet proteomics. The protective effect and mechanism of OI were examined via peritoneal macrophages isolated from STZ-induced diabetic mice and co-cultured MIN6 cells with OI-pre-treated inflammatory macrophages in vitro. Moreover, the inflammatory status of peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients was evaluated after OI treatment. RESULTS: OI ameliorated glycemic deterioration, increased systemic insulin level, and improved glucose metabolism in STZ-induced diabetic mice and non-obese diabetic (NOD) mice. OI intervention significantly restored the islet insulitis and beta cell function. OI did not alter the macrophage count but significantly downregulated the proportion of M1 macrophages. Additionally, OI significantly inhibited MAPK activation in macrophages to attenuate the macrophage inflammatory response, eventually improving beta cell dysfunction in vitro. Furthermore, we detected higher IL-1ß production upon lipopolysaccharide stimulation in the PBMCs from type 1 diabetes patients, which was attenuated by OI treatment. CONCLUSIONS: These results provided the first evidence to date that OI can prevent the progression of glycemic deterioration, excessive inflammation, and beta cell dysfunction predominantly mediated by restricting macrophage M1 polarization in mouse models of type 1 diabetes.

Sulfated Fucogalactan From Laminaria Japonica Ameliorates ß-Cell Failure by Attenuating Mitochondrial Dysfunction via SIRT1-PGC1-α Signaling Pathway Activation.

As mitochondrial metabolism is a major determinant of ß-cell insulin secretion, mitochondrial dysfunction underlies ß-cell failure and type 2 diabetes mellitus progression. An algal polysaccharide of Laminaria japonica, sulfated fucogalactan (SFG) displays various pharmacological effects in a variety of conditions, including metabolic disease. We investigated the protective effects of SFG against hydrogen peroxide (H2O2)-induced ß-cell failure in MIN6 cells and islets. SFG significantly promoted the H2O2-inhibited proliferation in the cells and ameliorated their senescence, and potentiated ß-cell function by regulating ß-cell identity and the insulin exocytosis-related genes and proteins in H2O2-induced ß-cells. SFG also attenuated mitochondrial dysfunction, including alterations in ATP content, mitochondrial respiratory chain genes and proteins expression, and reactive oxygen species and superoxide dismutase levels. Furthermore, SFG resulted in SIRT1-PGC1-α pathway activation and upregulated the downstream Nrf2 and Tfam. Taken together, the results show that SFG attenuates H2O2-induced ß-cell failure by improving mitochondrial function via SIRT1-PGC1-α signaling pathway activation. Therefore, SFG is implicated as a potential agent for treating pancreatic ß-cell failure.

Advanced Glycation End Products (AGEs) Inhibit Macrophage Efferocytosis of Apoptotic ß Cells through Binding to the Receptor for AGEs.

Pancreatic ß cell apoptosis is important in the pathogenesis of type 2 diabetes mellitus (T2DM). Generally, apoptotic ß cells are phagocytosed by macrophages in a process known as "efferocytosis." Efferocytosis is critical to the resolution of inflammation and is impaired in T2DM. Advanced glycation end products (AGEs), which are increased in T2DM, are known to suppress phagocytosis function in macrophages. In this study, we found that AGEs inhibited efferocytosis of apoptotic ß cells by primary peritoneal macrophages in C57BL/6J mice or mouse macrophage cell line Raw264.7. Mechanistically, AGEs inhibit efferocytosis by blocking Ras-related C3 botulinum toxin substrate 1 activity and cytoskeletal rearrangement through receptor for advanced glycation end products/ras homolog family member A/Rho kinase signaling in macrophages. Furthermore, it was observed that AGEs decreased the secretion of anti-inflammatory factors and promoted the proinflammatory ones to modulate the inflammation function of efferocytosis. Taken together, our results indicate that AGEs inhibit efferocytosis through binding to receptor for advanced glycation end products and activating ras homolog family member A/Rho kinase signaling, thereby inhibiting the anti-inflammatory function of efferocytosis.

Hemoglobin concentration is associated with the incidence of metabolic syndrome.

BACKGROUND: An association between hemoglobin and metabolic syndrome (MetS) has been reported. However, the relationships between hemoglobin and individual MetS components remain unclear. Therefore, we investigated these associations at baseline and at the 3-year follow-up. METHODS: We enrolled 9960 middle-aged and elderly subjects (6726 women and 3234 men) and performed a 3-year follow-up cohort study. All subjects completed a questionnaire and underwent anthropometric measurements and laboratory tests. Logistic regression models were developed to assess the association between hemoglobin and MetS and its components. RESULTS: MetS was present in 45.1% of women and 41.4% of men at baseline. The hemoglobin concentration was positively correlated with SBP, DBP, TGs, WC, FPG, insulin, HOMA-IR, BMI and uric acid (p < 0.05). The mean hemoglobin concentration was higher in subjects with hypertension, high TGs, abdominal obesity or elevated FPG (p < 0.01). At follow-up, elevated hemoglobin correlated with an increased incidence and ORs for MetS, high TGs, low HDL-c, hyperuricemia and NAFLD but not abdominal obesity, BP or FPG in women. Increased hemoglobin corresponded with an increased incidence and ORs for MetS, abdominal obesity, low HDL-c, hyperuricemia and NAFLD but not BP, high TGs or FPG in men. CONCLUSIONS: Hemoglobin may play a role in predicting new-onset MetS in both women and men. Hemoglobin was notably correlated with future risk of high TGs, low HDL-c, hyperuricemia, and NAFLD among women and abdominal obesity, low HDL-c, hyperuricemia, and NAFLD among men.

Visceral adiposity index is associated with lung function impairment: a population-based study.

BACKGROUND: The effects of visceral adiposity on decreased lung function have drawn much attention. Recently, the visceral adiposity index (VAI) has been proposed as a visceral fat distribution and dysfunction marker. However, the relationship between the VAI and lung function has not been investigated. The objective of the study was to analyze the association between the VAI and lung function and evaluate the potential of VAI as a predictor of lung function. METHODS: We collected data from a population-based study of 1786 subjects aged 40 years or older. All subjects completed a questionnaire and underwent anthropometric measurements and laboratory tests. Linear and logistic regression models were developed to assess the association between the VAI and lung function. RESULTS: The VAI was inversely related to FVC%predicted in men and negatively associated with both FVC%predicted and FEV1%predicted in women. In the linear regression analysis, the decrease in FVC%predicted associated with each 10% increase in the VAI was 1.127% in men and 1.943% in women; the decrease in FEV1%predicted associated with each 10%increase in the VAI was 0.663% in men and 1.738% in women. Further regression analysis revealed that the VAI was positively correlated with FVC and FEV1 impairment in women. CONCLUSIONS: We were the first to show a clear correlation between the VAI and lung function impairment in the Chinese population. The VAI could be a simple and reliable approach in daily practice, and individuals, especially women with a high VAI, should receive additional screening and preventive interventions for respiratory disease.

Resistant dextrin reduces obesity and attenuates adipose tissue inflammation in high-fat diet-fed mice.

Resistant dextrin (RD), a short chain glucose polymer, has been shown to improve type 2 diabetes mellitus (T2DM) in clinical studies. However, the improvement of adipose tissue inflammation and specific mechanisms of RD supplementation in obesity have not been fully investigated. Therefore, we examined whether RD attenuates obesity and adipose tissue inflammation in high-fat diet (HFD)-fed mice. Male C57BL/6 mice were fed a chow diet, a HFD or a HFD with RD supplementation for 12 weeks. Body weight (BW), fasting blood glucose (FBG), epididymal fat accumulation, serum total triglyceride (TG), free fatty acid (FFA) and inflammatory cytokine levels (TNF-α, IL-1ß, IL-6, IL-10) were measured. Inflammation markers and macrophage infiltration in epididymal adipose tissue were observed. After 12 weeks of intervention, the body weight gain of mice in RD supplementation group was less than that in HFD group. FBG, epididymal fat accumulation, serum TG and FFA levels were reduced in RD supplementation group compared with HFD group. Moreover, serum and mRNA levels of IL-6 were significantly reduced in the RD supplementation group. In addition, RD supplementation reduced macrophage infiltration, regulated polarization of macrophage and inhibited NF-κB signaling in epididymal adipose tissue. In conclusion, RD reduces obesity and attenuates adipose tissue inflammation in HFD-fed mice, and the inhibition of NF-κB signaling may be a presumed mechanism for its effects.

Advanced glycation end products enhance M1 macrophage polarization by activating the MAPK pathway.

BACKGROUND: ß-cell dysfunction is one of the core pathogenetic mechanisms of type 2 diabetes mellitus (T2DM). However, there are currently no effective therapeutic strategies to preserve ß-cell mass and function. The role of islet macrophage phenotype reprogramming in ß-cell dysfunction has attracted great attention. Given that advanced glycation end products (AGEs) are major pathogenic factors in T2DM, we investigated the effect of AGEs on macrophage activation and their role in ß-cell dysfunction. METHODS: We examined cytokine secretion, M1 and M2 macrophage-associated marker expression and MAPK phosphorylation levels in AGEs-stimulated macrophages. MIN6 cells were cocultured with AGEs-pretreated macrophages to study the effect of AGEs-induced macrophage activation on ß-cell dysfunction. RESULTS: We found that AGEs treatment significantly enhanced macrophage secretion of proinflammatory cytokines. The expression of M1 macrophage markers, such as iNOS and the surface marker CD11c, was significantly upregulated, whereas the expression of M2 macrophage markers, such as Arg1 and CD206, was reciprocally downregulated upon AGEs stimulation. AGEs treatment predominantly activated the MAPK pathway, and the inhibition of the MAPK pathway partially attenuated the AGEs-induced polarization of macrophages. In addition, coculture with AGEs-pretreated macrophages significantly inhibited the expression of molecules involved in ß-cell function and was accompanied by the impairment of glucose-stimulated insulin secretion (GSIS) in MIN6 cells. CONCLUSION: AGEs enhance the expression of proinflammatory molecules by activating the MAPK pathway. Moreover, these data imply that AGEs induce macrophage M1 phenotype polarization but restrain M2 polarization, which might contribute to ß-cell dysfunction in the pathogenesis of T2DM.

The Combined Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Microporous Porcine Acellular Dermal Matrices on the Regeneration of Skin Accessory Cells In Vivo.

We investigated the effects of microporous porcine acellular dermal matrices (MPADM)-containing bone marrow-derived mesenchymal stem cells (BMMSCs) on accessory skin cell regeneration in vivo. Two kinds of the porcine acellular dermal matrices were prepared: one with microsized pores (the MPADM) and another without pores (the PADM). BMMSC populations from a Sprague-Dawley (SD) rat were seeded on both PADMs and MPADMs and cultured in vitro for 5 days. These rats were randomly divided into four groups: BMMSCs on an MPADM and covered with a PADM layer (group A), MPADM without cells and covered with a split-thickness skin graft (SSG) (group B), BMMSCs on an MPADM and covered with an SSG (group C), and BMMSCs on a PADM and covered with an SSG (group D). On post-surgery day (PSD) 5, all groups survived, except for group D. On PSD 7, there was no significant difference in the functional vascularization between groups A, B, and C. On PSD 14, large quantities of new capillaries, a larger rough endoplasmic reticulum in fibroblasts, and de novo unmyelinated nerve endings could be observed at the junction between the skin graft and the dermal matrix in group C; however, these structures were absent in groups A and B. The experimental results showed that MPADM could induce exogenous differentiation of BMMSCs in vivo and promote reconstruction of skin accessory cells.

Acellular Dermal Matrix Combined with Autologous Skin Grafts for Closure of Chronic Wounds after Reconstruction of Skull Defects with Titanium Mesh.

Objective The closure of chronic wounds after skull defect reconstruction with titanium mesh is one of the most challenging problems for plastic and reconstructive surgeons. Current approaches are disappointing. Methods In 10 patients, we explored the role of acellular dermal matrix (ADM) in combination with autologous skin grafts (ASGs) for closure of chronic wounds after skull reconstruction with titanium. Results ADM and ASG survived in all patients. Grade A healing (healing well without defect) was achieved. The average operating time was 30 to 45 minutes, and the average blood loss 30 to 50 mL. After 3 months, the wound was still closed in all patients. Conclusion The combination of ADM plus ASG obtained a high wound closure rate. ADM plus ASG allows avoiding other procedures such as rotational flaps and free flaps that require more operating time, special equipment, and adequate training.

Optimal adjuvant therapy for resected hepatocellular carcinoma: a systematic review with network meta-analysis.

OBJECTIVES: Major adjuvant therapies (ATs) for resected hepatocellular carcinoma (HCC) include chemotherapy, internal radiation therapy (IRT), interferon therapy (IFNT) and immunotherapy but the optimum regimen remains inconclusive. We aim to compare these therapies in terms of patient survival and recurrence rates. METHODS: We searched PubMed, EMBASE and Cochrane library databases for randomized trials comparing the above four therapies until 31 March 2014. We estimated the HRs for survival and ORs for overall recurrence among different therapies. Toxic effects were also evaluated. RESULTS: Fourteen eligible articles were included. IFNT improved 5-year survival greatly (HR 1.81, 95% CI 1.01-3.81, P = 0.034), whereas chemotherapy (HR 0.33, 95% CI 0.03-2.02), IRT (HR 0.31, 95% CI 0.02-3.33) and immunotherapy (HR 0.73, 95% CI 0.05-9.12) all provided a poorer survival outcome after 1-year. Similarly, for 5-year survival rates, although differing, IRT did not provide a significant improvement in survival (HR 1.38, 95% CI 0.34-5.19) compared with IFNT. Chemotherapy (HR 0.49, 95% CI 0.18-1.14) and immunotherapy (HR 0.56, 95% CI 0.17-1.59) did not appear to provide benefit over IFNT. Chemotherapy was ranked the worst in overall recurrence (OR 0.99, 95% CI 0.18-5.38) and most likely to cause toxic effects. CONCLUSIONS: IFNT was the most efficacious AT regimen both for short and long term survivals. Immunotherapy and IFNT were the most two effective in preventing overall relapse for resected HCC.

Systematic review with network meta-analysis: adjuvant chemotherapy for resected colorectal liver metastases.

There are 5 major adjuvant chemotherapies (ACTs) for hepatic metastases for colorectal cancer; however, the optimal treatment regimen remains inconclusive. Here, we aim to compare these therapies in terms of patient survival rate, intrahepatic recurrence rate, and adverse events.Different databases were searched for controlled trials up to June 30, 2014. The pooled hazards ratios for death and odds ratios (ORs) for intrahepatic recurrence and adverse events were estimated. A mean ranking and the probability of optimal therapeutic regime was obtained for each treatment analyzed in the network meta-analysis.Eleven eligible articles were included. Systemic chemotherapy (SCT) was ranked the most efficacious intervention among ACTs in both 1-year and 5-year survival; however, no statistical difference could be determined. Combination of bevacizumab (BEV) and hepatic arterial infusion (HAI) plus SCT was the most effective in preventing intrahepatic recurrence when compared with HAI alone (OR 1.21, 95% confidence interval [CI] 0.01-131.12), SCT (OR 2.37, 95% CI 0.03-234.16), HAI plus SCT (OR 0.97, 95% CI 0.03-35.30), SCT plus irinotecan (OR 1.01, 95% CI 0.00-278.14) and observation alone (OR 0.83, 95% CI 0.01-59.53). BEV and HAI plus SCT provided the least survival benefit after both 1 and 5 years compared with remaining therapies, and also was ranked the regiment with the least favorable adverse event profile among ACTs.SCT may be the most efficacious intervention, however, the potential benefit should be carefully considered with the regime's associated toxicities. Combination of BEV and HAI plus SCT was effective in preventing intrahepatic relapse but was associated with the highest risk for adverse events in patients with resected hepatic metastases for colorectal cancer.