Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes.

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs-NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.

Effect of Silicon Source (Fly Ash, Silica Dust, Gangue) on the Preparation of Porous Mullite Ceramics from Aluminum Dross.

Aluminum dross (AD) is a waste product produced during aluminum processing and can be used to prepare mullite ceramic materials. However, the research on the preparation of mullite porous ceramics entirely from solid waste is still in the development stage. In this paper, porous mullite ceramics were successfully fabricated using a solid-phase sintering process with AD and different silicon sources (fly ash, silica dust, and gangue) as raw materials. The bulk density, apparent porosity, and compressive strength of the specimens were obtained, and the phase compositions and microstructures of the sintered specimens were measured using XRD and SEM, respectively. The average activation energy of the phase transition of fly ash, silica dust, and gangue as silicon sources were 984 kJ/mol, 1113 kJ/mol, and 741 kJ/mol, respectively. The microstructures of the mullite in the specimens were prisms, random aggregates, and needle-shaped, respectively. The formation of needle-shaped mullite combined with the substrate enhanced the mechanical strength of the porous mullite ceramics. The apparent porosity, density, and compressive strength of the specimens with gangue as the silicon source were 33.13%, 1.98 g/cm3, and 147.84 MPa, respectively, when sintered at 1300 °C for 2 h.

Isoliquiritigenin prevents hyperglycemia-induced renal injuries by inhibiting inflammation and oxidative stress via SIRT1-dependent mechanism.

Diabetic nephropathy (DN) as a global health concern is closely related to inflammation and oxidation. Isoliquiritigenin (ISL), a natural flavonoid compound, has been demonstrated to inhibit inflammation in macrophages. Herein, we investigated the effect of ISL in protecting against the injury in STZ-induced type 1 DN and in high glucose-induced NRK-52E cells. In this study, it was revealed that the administration of ISL not only ameliorated renal fibrosis and apoptosis, but also induced the deterioration of renal function in diabetic mice. Mediated by MAPKs and Nrf-2 signaling pathways, respectively, upstream inflammatory response and oxidative stress were neutralized by ISL in vitro and in vivo. Moreover, as further revealed by the results of molecular docking, sirtuin 1 (SIRT1) binds to ISL directly, and the involvement of SIRT1 in ISL-mediated renoprotective effects was confirmed by studies using in vitro models of SIRT1 overexpression and knockdown. In summary, by reducing inflammation and oxidative stress, ISL has a significant pharmacological effect on the deterioration of DN. The benefits of ISL are associated with the direct binding to SIRT1, the inhibition of MAPK activation, and the induction of Nrf-2 signaling, suggesting the potential of ISL for DN treatment.

Isoliquiritigenin attenuates diabetic cardiomyopathy via inhibition of hyperglycemia-induced inflammatory response and oxidative stress.

BACKGROUND: Inflammation and oxidative stress play essential roles in the occurrence and progression of diabetic cardiomyopathy (DCM). Isoliquiritigenin (ISL), a natural chalcone, exhibits strong anti-inflammatory and antioxidant activities. HYPOTHESIS/PURPOSE: In this study, we aimed to investigate the protective effects of ISL on DCM using high glucose (HG)-challenged cultured cardiomyocytes and streptozotocin (STZ)-induced diabetic mice. STUDY DESIGN AND METHODS: Embryonic rat heart-derived H9c2 cells challenged with a high concentration of glucose were used to evaluate the anti-inflammatory and antioxidant effects of ISL. STZ-induced diabetic mice were used to study the effects of ISL in DCM in vivo. Furthermore, cardiac fibrosis, hypertrophy, and apoptosis were explored both in vitro and in vivo. RESULTS: ISL effectively inhibited HG-induced hypertrophy, fibrosis, and apoptosis probably by alleviating the inflammatory response and oxidative stress in H9c2 cells. Results from in vivo experiments showed that ISL exhibited anti-inflammatory and antioxidant stress activities that were characterized by the attenuation of cardiac hypertrophy, fibrosis, and apoptosis, which resulted in the maintenance of cardiac function. The protective effects of ISL against inflammation and oxidative stress were mediated by the inhibition of mitogen-activated protein kinases (MAPKs) and induction of nuclear factor-erythroid 2 related factor 2 (Nrf2) signaling pathway, respectively. CONCLUSION: Our results provided compelling evidence that ISL, by virtue of neutralizing excessive inflammatory response and oxidative stress, could be a promising agent in the treatment of DCM. Targeting the MAPKs and Nrf2 signaling pathway might be an effective therapeutic strategy for the prevention and treatment of DCM.

Correction to: Isoliquiritigenin Provides Protection and Attenuates Oxidative Stress-Induced Injuries via the Nrf2-ARE Signaling Pathway After Traumatic Brain Injury.

The original version of this article unfortunately contained a mistake. The Fluorescence Immunoassays text written in Materials and Methods section and Fig. 1i, j is incorrect. In Fig. 1j, the images corresponding to Sham and TBI + ILG are incorrect. In Fig. 1i the figure caption "TBI + EDA" are incorrect. The corrected text and Fig. 1i, j are given below.

A GLP­1 receptor agonist attenuates human islet amyloid polypeptide­induced autophagy and apoptosis in MIN6 cells.

Type 2 diabetes mellitus (T2DM) is characterized by the dysfunction and loss of pancreatic islet ß­cells, in part due to islet amyloid deposits derived from islet amyloid polypeptide (IAPP). The glucagon­like peptide­1 (GLP­1) receptor agonist exendin­4 enhances the insulin secretory response by increasing ß­cell mass in T2DM. However, it is unknown whether exendin­4 protects ß­cells from IAPP­mediated autophagy and apoptosis. In the present study, reverse transcription­quantitative polymerase chain reaction, ELISA and western blotting were used to detected the mRNA and protein expression of insulin/hIAPP and other signaling molecules, while the mechanisms underlying these effects were also determined. Exendin­4 increased the level of insulin secretion, which was greater than that of IAPP, leading to a beneficial IAPP/insulin secretion pattern. In MIN6 cells incubated with 25 mM glucose, exendin­4 decreased the ratio of light chain 3 (LC3)­II/I, which was accompanied by an increase in p62 protein. In a hIAPP­overexpressing MIN6 cell model, exendin­4 prevented the hIAPP­induced increase in the LC3II/I ratio and decrease in p62 expression. In addition, exendin­4 pretreatment reduced hIAPP­induced activation of cleaved caspase­3, suggesting that exendin­4 may protect MIN6 cells against apoptosis. Taken together, the results highlight hIAPP as a critical mediator of ß­cell loss and suggest that the GLP­1 receptor agonist exendin­4 may be a potential therapeutic agent for hIAPP­induced ß­cell damage.

Isoliquiritigenin Provides Protection and Attenuates Oxidative Stress-Induced Injuries via the Nrf2-ARE Signaling Pathway After Traumatic Brain Injury.

Traumatic brain injury (TBI) is a serious public health and medical problem worldwide. Oxidative stress plays a vital role in the pathogenesis of TBI. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important factor in the cellular defense against oxidative stress, is activated following TBI. In this study, the protective effects of Isoliquiritigenin (ILG), a promising antioxidant stress drug, was evaluated as a protective agent against TBI. In a mouse model of controlled cortical impact Injury, we found that the ILG administration reduced the Garcia neuroscore, injury histopathology, brain water content, cerebral vascular permeability, the expression of cleaved caspase3, aquaporin-4, glial fibrillary acidic protein and the increased the expression of neurofilament light chain protein, indicating the protective effects against TBI in vivo. ILG treatment after TBI also restored the oxidative stress and promoted the Nrf2 protein transfer from the cytoplasm to the nucleus. We then used Nrf2-/- mice to test the protective effect of Nrf2 during ILG treatment of TBI. Our findings indicated that Nrf2-/- mice had greater brain injury and oxidative stress than wild-type (WT) mice and ILG was less effective at inhibiting oxidative stress and repairing the brain injury than in the WT mice. In vitro studies in SY5Y cells under oxygen glucose deprivation/re-oxygenation stimulation yielded results that were consistent with those obtained in vivo showing that ILG promotes Nrf2 protein transfer from the cytoplasm to the nucleus. Taken together, our findings demonstrate that Nrf2 is an important protective factor against TBI-induced injuries, which indicates that the protective effects of ILG are mediated by inhibiting oxidative stress after TBI via a mechanism that involves the promotion of Nrf2 protein transfer from the cytoplasm to the nucleus.

The Possible Mechanisms of HSV-TK/Hyperthermia Combined with 131I-antiAFPMcAb-GCV Nanospheres to Treat Hepatoma.

Our previous findings showed a good therapeutic effect of the combination of suicide gene HSV-TK, nuclide 131I, and magnetic fluid hyperthermia (MFH) on hepatoma by using magnetic nanoparticles as linkers, far better than any monotherapy involved, with no adverse effects. This combination therapy might be an eligible strategy to treat hepatic cancer. However, it is not clear how the combination regimen took the therapeutic effects. In the current study, to explore the possible mechanisms of radionuclide-gene therapy combined with MFH to treat hepatoma at tissue, cellular, and molecular levels and to provide theoretical and experimental data for its clinical application, we examined the apoptosis induction of the combination therapy and investigated the expression of the proteins related to apoptosis such as survivin, livin, bcl-2, p53, and nucleus protein Ki67 involved in cell proliferation, detected VEGF, and MVD involved in angiogenesis of tumor tissues and analyzed the pathologic changes after treatment. The results showed that the combination therapy significantly induced the hepatoma cell apoptosis. The expression of survivin, VEGF, bcl-2, p53, livin, Ki67, and VEGF proteins and microvascular density (MVD) were all decreased after treatment. The therapeutic mechanisms may be involved in the downregulation of Ki67 expression leading to tumor cell proliferation repression and inhibition of survivin, bcl-2, p53, and livin protein expression inducing tumor cell apoptosis, negatively regulating VEGF protein expression, and reducing vascular endothelial cells, which results in tumor angiogenesis inhibition and microvascular density decrease and tumor cell necrosis. These findings offer another basic data support and theoretical foundation for the clinical application of the combination therapy.

Association Between 25-Hydroxyvitamin D and Epicardial Adipose Tissue in Chinese Non-Obese Patients with Type 2 Diabetes.

BACKGROUND Epicardial adipose tissue (EAT) is recognized as a useful indicator for type 2 diabetes mellitus (T2DM) and obesity. However, studies on the association between vitamin D status and EAT thickness in type 2 diabetes (T2D) are limited. In this study, we aimed to evaluate the association of vitamin D (Calcifediol) status and EAT thickness (EATT) in Chinese non-obese patients with T2D. MATERIAL AND METHODS A cross-sectional study was performed among 167 non-obese T2D Chinese patients and 82 non-diabetic patients, who are age- and gender-matched during the winter months. EATT was evaluated by two-dimensional transthoracic echocardiography. Serum 25-hydroxyvitamin D [25(OH)D, Calcifediol] was examined in the diabetic patients and in the control group. RESULTS The concentration of 25(OH)D was 32.00 nmol/l (19.30-53.70 nmol/l) among diabetic patients. Most (93.4%) of the diabetic patients had hypovitaminosis D. We confirmed a clear negative association between 25(OH)D level and EATT in non-obese T2D patients (p=0.01). EATT was significantly correlated with 25(OH)D level (p=0.001) and HOMA-IR (p=0.001). Results of multivariate logistic regression analysis demonstrated increased EATT, which was remarkably associated with 25(OH)D levels (p=0.039), systolic blood pressure (SBP) (p=0.013), HOMA-IR (p=0.030), and waist circumference (p<0.001) in T2D patients after adjusting for the confounding factors. CONCLUSIONS Increased EATT was found in Chinese T2D patients with normal BMI. 25(OH)D and HOMA-IR were independently associated with increased EATT after adjusting for multiple confounders.

The Recent Advances on Liver Cancer Stem Cells: Biomarkers, Separation, and Therapy.

As the third major reason of mortality related to cancer in the world, liver cancer is also the fifth most frequent cancer. Unluckily, a majority of patients succumb and relapse though many progresses have been made in detection and therapy of liver cancer. It has been put forward that in liver cancer, cancer stem cells (CSCs) hold main responsibility for the formation, invasion, metastasis, and recurrence of tumor. Strategies that are intended to target liver CSCs are playing a more and more significant role in supervising the development of liver cancer treatment and assessing new therapeutic methods. Herein, a brief review about molecule markers, signal pathways, separation, and treatment on liver cancer stem cells (LCSCs) is provided in this paper.

Hepatoma-Targeted Radionuclide Immune Albumin Nanospheres: (131)I-antiAFPMcAb-GCV-BSA-NPs.

An effective strategy has been developed for synthesis of radionuclide immune albumin nanospheres ((131)I-antiAFPMcAb-GCV-BSA-NPs). In vitro as well as in vivo targeting of (131)I-antiAFPMcAb-GCV-BSA-NPs to AFP-positive hepatoma was examined. In cultured HepG2 cells, the uptake and retention rates of (131)I-antiAFPMcAb-GCV-BSA-NPs were remarkably higher than those of (131)I alone. As well, the uptake rate and retention ratios of (131)I-antiAFPMcAb-GCV-BSA-NPs in AFP-positive HepG2 cells were also significantly higher than those in AFP-negative HEK293 cells. Compared to (131)I alone, (131)I-antiAFPMcAb-GCV-BSA-NPs were much more easily taken in and retained by hepatoma tissue, with a much higher T/NT. Due to good drug-loading, high encapsulation ratio, and highly selective affinity for AFP-positive tumors, the (131)I-antiAFPMcAb-GCV-BSA-NPs are promising for further effective radiation-gene therapy of hepatoma.

Up-regulation of iNOS by hypoxic postconditioning inhibits H9c2 cardiomyocyte apoptosis induced by hypoxia/re-oxygenation.

Apoptosis is a crucial mode of cell death induced by ischemia and reperfusion, and ischemic postconditioning (PostC) has been reported to inhibit cell apoptosis. Inducible nitric oxide synthase (iNOS) has been confirmed to play an important role in triggering and mediating the late cardio-protection against ischemia/hypoxia. In this study, we found that hypoxic PostC remarkably up-regulated the expression of iNOS and decreased cardiomyocyte apoptosis. Pre-treatment with 1400w (a highly selective inhibitor of iNOS) or iNOS siRNA weakened the anti-apoptotic effect of hypoxic PostC. These findings suggested that iNOS may be one of the key molecular mechanisms responsible for the inhibition of apoptosis by hypoxic PostC.

Influential Factors and Synergies for Radiation-Gene Therapy on Cancer.

Radiation-gene therapy, a dual anticancer strategy of radiation therapy and gene therapy through connecting radiation-inducible regulatory sequence to therapeutic gene, leading to the gene being induced to express by radiation while radiotherapy is performed and finally resulting in a double synergistic antitumor effect of radiation and gene, has become one of hotspots in the field of cancer treatment in recent years. But under routine dose of radiation, especially in the hypoxia environment of solid tumor, it is difficult for this therapy to achieve desired effect because of low activity of radiation-inducible regulatory elements, low level and transient expression of target gene induced by radiation, inferior target specificity and poor biosecurity, and so on. Based on the problems existing in radiation-gene therapy, many efforts have been devoted to the curative effect improvement of radiation-gene therapy by various means to increase radiation sensitivity or enhance target gene expression and the expression's controllability. Among these synergistic techniques, gene circuit, hypoxic sensitization, and optimization of radiation-induced sequence exhibit a good application potential. This review provides the main influential factors to radiation-gene therapy on cancer and the synergistic techniques to improve the anticancer effect of radiation-gene therapy.

[Progress in the effects of injury and regeneration of gustatory nerves on the taste functions in animals].

The sensor of the taste is the taste bud. The signals originated from the taste buds are transmitted to the central nervous system through the gustatory taste nerves. The chorda tympani nerve (innervating the taste buds of the anterior tongue) and glossopharyngeal nerve (innervating the taste buds of the posterior tongue) are the two primary gustatory nerves. The injuries of gustatory nerves cause their innervating taste buds atrophy, degenerate and disappear. The related taste function is also impaired. The impaired taste function can be restored after the gustatory nerves regeneration. The rat model of cross-regeneration of gustatory nerves is an important platform for research in the plasticity of the central nervous system. The animal behavioral responses and the electrophysiological properties of the gustatory nerves have changed a lot after the cross-regeneration of the gustatory nerves. The effects of the injury, regeneration and cross-regeneration of the gustatory nerves on the taste function in the animals will be discussed in this review. The prospective studies on the animal model of cross-regeneration of gustatory nerves are also discussed in this review. The study on the injury, regeneration and cross-regeneration of the gustatory nerves not only benefits the understanding of mechanism for neural plasticity in gustatory nervous system, but also will provide theoretical basis and new ideas for seeking methods and techniques to cure dysgeusia.

[Esthetic restoration for anterior teeth with the hot pressed porcelain laminate veneers].

PURPOSE: To evaluate the esthetic effect of anterior porcelain veneers fabricated with the heat pressed glass ceramic. METHODS: Thirty-two patients, who wanted to receive a aesthetic restorative treatment for 206 anterior teeth were selected. Among them, 20 were for dental fluorosis, 8 were for light tetracycline stained teeth, the other 4 were labial enamel hypoplasia or obvious crack on the surface of enamel. According to the color of adjacent teeth,skin and lips, heat pressed IPS e.max ingots of different color were chosen to mold the restorations. Afterwards, special straining technique was conducted on the marginal ridge and incisor ridge of the veneers after carefully trimmed in the mouth. Restorations were them bonded with Variolink II resin cement. After 7 years of follow-up, a modified USPHS criterion was used to evaluate the esthetic effect. RESULTS: The translucency of veneers was superior. Marginal integrity of the veneers was perfect and it docked well with the marginal terminate line of the abutment. There was no edge coloring after the veneers were used for 7 years, and the veneers produce an excellent chameleon effect by absorbing the color of adjacent teeth and gums, at the same time, veneers could produce a feature of surface morphology of natural enamel after careful carve. In the long-term clinical observation, 5 of the 206 veneers were fractured or fell off. CONCLUSIONS: This porcelain laminate veneers fabricated from the heat pressed IPS e.max Press ingots include the following advantages, such as simple operating procedure, high mechanical strength, very little dental tissue was ground off and nice aesthetic effect. Ultra-thin veneers are especially suitable for aesthetic practice to dental fluorosis, light tetracycline and natural worn teeth.

[Effect of veneering technologies on color and translucency of Y2O3 stabilized tetragonal zirconia polycrystals all-ceramic restorations].

OBJECTIVE: To compare color parameters and transmittance of Y2O3 stabilized tetragonal zirconia polycrystals (Y-TZP) all-ceramic restorations using different veneering technologies. METHODS: Fifteen disc specimens with 10 mm in diameter and (0.50 +/- 0.01) mm in thickness were fabricated of IPS e. max ZirCAD core material, and ZL1 IPS e. max ZirLiner was layered in 0.10 mm thickness. The specimens were divided into three groups randomly (n=5 per group). Group ZP was veneered 0.60 mm by heat-pressing; group ZC was veneered 0.60 mm by layering; group ZPC was veneered 0.30 mm by heat-pressing and then 0.30 mm by layering. Color parameters L*, a*, b* and transmittance of zirconia specimens were measured before and after veneering with ShadeEye NCC dental chromameter and spectrophotometer. Color saturation C* ab and color difference deltaE were calculated in the following formulae: C* ab = [(a*)2 + (b*)2](1/2), deltaE = [(deltaL*)2 + (deltaa*)2 + (deltab*)2](1/2) One-way analysis of variance and Turkey's multiple comparison test were used to analyze data (alpha = 0.05) by SPSS 10.0 statistic software. Color parameters of A2 shade tabs were measured, and color differences between each group and tab were calculated. RESULTS: As to ZP,ZPC,ZC groups, the value of a* increased (-1.35 +/- 0.07, -0.64 +/- 0.06, -0.36 +/- 0.05) (P < 0.05), the value of b* decreased (27.01 +/- 0.07, 25.48 +/- 0.11, 23.28 +/- 0.25) (P < 0.05), and the value of C* ab decreased (27.04 +/- 0.08, 25.49 +/- 0.11, 23.28 +/- 0.25) (P < 0.05). L* and transmittance were maximum in ZP group (87.53 +/- 0.48, 1.64 +/- 0.03) and minimum in ZPC group (82.14 +/- 0.18, 1.47 +/- 0.01) (P < 0.05). Compared with standard A2 shade tab, the color difference of ZC group was minimum (delta = 1.04), and the color difference of ZP group was maximum (deltaE = 4.86). CONCLUSIONS: Y-TZP all-ceramic restoration veneered by heat-pressing was the most transparent and lightest; while veneered by both heat-pressing and layering, the restoration was worst in translucency and the least light. The color of zirconia all-ceramic restoration veneered by layering was the most similar to standard shade tab, and the color difference was minimum.

[Esthetics restoration after rapid orthodontic extrusion of subgingivally fractured incisor: a case report].

A case of a patient with subgingivally fractured incisor was presented. Two weeks after root canal therapy, the subgingival fragment was restored with fiber post, resin core and temporary crown. Gingivoplasty was performed around. after the subgingival fragment had been elevated in the axial direction by means of edgewise fixed appliance. Stabilized and held for 6 months, the incisor was restored with all ceramic crown. Optimal esthetic was achieved when restoration was performed after rapid orthodontic extrusion which had lifted up the fracture line above the level of the gingival line within 14 days. At 6-month follow-up, the periodontal tissues were normal and neither luxation nor relapse was noted.