Epithelium-derived kallistatin promotes CD4+ T-cell chemotaxis to TH2-type inflammation in chronic rhinosinusitis.

BACKGROUND: The function of kallistatin in airway inflammation, particularly chronic rhinosinusitis with nasal polyps (CRSwNP), has not been elucidated. OBJECTIVE: We sought to investigate the role of kallistatin in airway inflammation. METHODS: Kallistatin and proinflammatory cytokine expression levels were detected in nasal polyps. For the in vivo studies, we constructed the kallistatin-overexpressing transgenic mice to elucidate the role of kallistatin in airway inflammation. Furthermore, the levels of plasma IgE and proinflammatory cytokines in the airways were evaluated in the kallistatin-/- rat in vivo model under a type 2 inflammatory background. Finally, the Notch signaling pathway was explored to understand the role of kallistatin in CRSwNP. RESULTS: We showed that the expression of kallistatin was significantly higher in nasal polyps than in the normal nasal mucosa and correlated with IL-4 expression. We also discovered that the nasal mucosa of kallistatin-overexpressing transgenic mice expressed higher levels of IL-4 expression, associating to TH2-type inflammation. Interestingly, we observed lower IL-4 levels in the nasal mucosa and lower total plasma IgE of the kallistatin-/- group treated with house dust mite allergen compared with the wild-type house dust mite group. Finally, we observed a significant increase in the expression of Jagged2 in the nasal epithelium cells transduced with adenovirus-kallistatin. This heightened expression correlated with increased secretion of IL-4, attributed to the augmented population of CD4+CD45+Notch1+ T cells. These findings collectively may contribute to the induction of TH2-type inflammation. CONCLUSIONS: Kallistatin was demonstrated to be involved in the CRSwNP pathogenesis by enhancing the TH2 inflammation, which was found to be associated with more expression of IL-4, potentially facilitated through Jagged2-Notch1 signaling in CD4+ T cells.

N-cadherin cleavage: A critical function that induces diabetic retinopathy fibrosis via regulation of ß-catenin translocation.

Retinal fibrosis is a severe pathological change in the late stage of diabetic retinopathy and is also the leading cause of blindness. We have previously revealed that N-cadherin was significantly increased in type 1 and type 2 diabetic mice retinas and the fibrovascular membranes from proliferative diabetic retinopathy (PDR) patients. However, whether N-cadherin directly induces retinal fibrosis in DR and the related mechanism is unknown. Here, we investigated the pathogenic role of N-cadherin in mediating retinal fibrosis and further explored the relevant therapeutic targets. We found that the level of N-cadherin was significantly increased in PDR patients and STZ-induced diabetic mice and positively correlated with the fibrotic molecules Connective Tissue Growth Factor (CTGF) and fibronectin (FN). Moreover, intravitreal injection of N-cadherin adenovirus significantly increased the expression of FN and CTGF in normal mice retinas. Mechanistically, overexpression of N-cadherin promotes N-cadherin cleavage, and N-cadherin cleavage can further induce translocation of non-p-ß-catenin in the nucleus and upregulation of fibrotic molecules. Furthermore, we found a novel N-cadherin cleavage inhibitor, pigment epithelial-derived factor (PEDF), which ameliorated the N-cadherin cleavage and subsequent retinal fibrosis in diabetic mice. Thus, our findings provide novel evidence that elevated N-cadherin level not only acts as a classic EMT maker but also plays a causative role in diabetic retinal fibrosis, and targeting N-cadherin cleavage may provide a strategy to inhibit retinal fibrosis in DR patients.

The pathogenic role of succinate-SUCNR1: a critical function that induces renal fibrosis via M2 macrophage.

BACKGROUND: Renal fibrosis significantly contributes to the progressive loss of kidney function in chronic kidney disease (CKD), with alternatively activated M2 macrophages playing a crucial role in this progression. The serum succinate level is consistently elevated in individuals with diabetes and obesity, both of which are critical factors contributing to CKD. However, it remains unclear whether elevated succinate levels can mediate M2 polarization of macrophages and contribute to renal interstitial fibrosis. METHODS: Male C57/BL6 mice were administered water supplemented with 4% succinate for 12 weeks to assess its impact on renal interstitial fibrosis. Additionally, the significance of macrophages was confirmed in vivo by using clodronate liposomes to deplete them. Furthermore, we employed RAW 264.7 and NRK-49F cells to investigate the underlying molecular mechanisms. RESULTS: Succinate caused renal interstitial macrophage infiltration, activation of profibrotic M2 phenotype, upregulation of profibrotic factors, and interstitial fibrosis. Treatment of clodronate liposomes markedly depleted macrophages and prevented the succinate-induced increase in profibrotic factors and fibrosis. Mechanically, succinate promoted CTGF transcription via triggering SUCNR1-p-Akt/p-GSK3ß/ß-catenin signaling, which was inhibited by SUCNR1 siRNA. The knockdown of succinate receptor (SUCNR1) or pretreatment of anti-CTGF(connective tissue growth factor) antibody suppressed the stimulating effects of succinate on RAW 264.7 and NRK-49F cells. CONCLUSIONS: The causative effects of succinate on renal interstitial fibrosis were mediated by the activation of profibrotic M2 macrophages. Succinate-SUCNR1 played a role in activating p-Akt/p-GSK3ß/ß-catenin, CTGF expression, and facilitating crosstalk between macrophages and fibroblasts. Our findings suggest a promising strategy to prevent the progression of metabolic CKD by promoting the excretion of succinate in urine and/or using selective antagonists for SUCNR1.

IL-25-induced shifts in macrophage polarization promote development of beige fat and improve metabolic homeostasis in mice.

Beige fat dissipates energy and functions as a defense against cold and obesity, but the mechanism for its development is unclear. We found that interleukin (IL)-25 signaling through its cognate receptor, IL-17 receptor B (IL-17RB), increased in adipose tissue after cold exposure and ß3-adrenoceptor agonist stimulation. IL-25 induced beige fat formation in white adipose tissue (WAT) by releasing IL-4 and IL-13 and promoting alternative activation of macrophages that regulate innervation and up-regulate tyrosine hydroxylase (TH) up-regulation to produce more catecholamine including norepinephrine (NE). Blockade of IL-4Rα or depletion of macrophages with clodronate-loaded liposomes in vivo significantly impaired the beige fat formation in WAT. Mice fed with a high-fat diet (HFD) were protected from obesity and related metabolic disorders when given IL-25 through a process that involved the uncoupling protein 1 (UCP1)-mediated thermogenesis. In conclusion, the activation of IL-25 signaling in WAT may have therapeutic potential for controlling obesity and its associated metabolic disorders.

Imaging Rovibrational Excitation of Scattered YO Molecules in Inelastic Collisions with Kr and Ne.

Energy transfer between atoms and molecules is fundamental to many physical and chemical processes, and understanding the mechanisms and outcomes of energy transfer is crucial for various applications in physics and chemistry. Here, the rovibrational excitation of YO(X 2Σ+) molecules with the collision of Kr and Ne has been studied in the laser-ablation crossed beam and time-sliced ion velocity map imaging setup in combination with the resonance enhanced multiphoton ionization scheme. Significant changes in the angular distribution for different rovibrational excitations of YO molecules are observed with the collision of Kr. The sharp forward distribution for low rovibrational excitation of YO(v' = 0, 1) molecules suggest that the weak attractive potential between Kr and YO is dominant at large impact parameters. Comparatively, the strong sideway distribution for highly rovibrationally excited YO(v' = 1, 2, 3, and 5) is due to rainbow scattering from the stronger attractive potential of Kr···YO at relatively small impact parameters. The more isotropic angular distribution in the highly rovibrationally excited YO(v' = 11) indicates the formation of a short-lived complex. A change in the angular distribution of scattered YO with different rovibrational excitations was also observed in the collisions of Ne. For YO as a heteronuclear diatomic molecule, collisions of the Y- and the O-end of YO with rare gases would affect the contribution of inelastic processes at different impact parameters.

Creating a 3D diagnostic cast with realistic tooth shade and translucency using an open source nondental CAD software program: A dental technique.

This article describes a digital technique for acquiring a 3-dimensional (3D) diagnostic cast with authentic tooth shade and translucency using an open source nondental computer-aided design (CAD) software program detailing the operational methods and parameters. The resultant 3D diagnostic cast can be transmitted to a dental laboratory for the fabrication of definitive prostheses.

Succinate-SUCNR1 induces renal tubular cell apoptosis.

Succinate has long been known to be only an intermediate product of the tricarboxylic acid cycle until identified as a natural ligand for SUCNR1 in 2004. SUCNR1 is widely expressed throughout the body, especially in the kidney. Abnormally elevated succinate is associated with many diseases, including obesity, type 2 diabetes, nonalcoholic fatty liver disease, and ischemia injury, but it is not known whether succinate can cause kidney damage. This study showed that succinate induced apparent renal injury after treatment for 12 wk, characterized by a reduction in 24 h urine and the significant detachment of the brush border of proximal tubular epithelial cells, tubular dilation, cast formation, and vacuolar degeneration of tubular cells in succinate-treated mice. Besides, succinate caused tubular epithelial cell apoptosis in kidneys and HK-2 cells. Mechanistically, succinate triggered cell apoptosis via SUCNR1 activation. In addition, succinate upregulated ERK by binding to SUCNR1, and inhibition of ERK using PD98059 abolished the proapoptotic effects of succinate in HK-2 cells. In summary, our study provides the first evidence that succinate acts as a risk factor and contributes to renal injury, and further research is required to discern the pathological effects of succinate on renal functions.

Correlation Study of the Spin-Orbit State-Resolved Scattering of Al(2P) in Oxidation Reaction and Nonreactive Collision.

Spin-orbit coupling plays an important role in chemical reactivity, especially in reactions that require the change of electron spin states. However, it is difficult to measure and analyze the reaction dynamics between spin-orbit splitting states, particularly for splitting states with a small energy difference. In this study, we find that nonreactive scattering of spin-orbit splitting states can provide complementary information that is overlooked in chemical reaction studies. Here, the oxidation reactivities of spin-orbit Al(2P1/2,3/2) states with small energy difference of 112 cm-1 are clearly distinguished in the high rotational AlO(v = 0 and 1, N) products at low collision energy of 507 cm-1 using a laser ablation crossed-beam and time-sliced ion velocity mapping technique, in conjunction with state-selected nonreactive scattering studies. For both the AlO(v = 0 and 1) channels, the spin-orbit relative reactivity σ3/2/σ1/2 increases with the increase of rotational level N of AlO products. However, for AlO(v = 0), the reactivity of the Al(2P3/2) excited state is consistently lower than that of the Al(2P1/2) ground state, whereas for AlO(v = 1), the reactivity of Al(2P3/2) is higher than that of Al(2P1/2) at a higher rotational state. The relative reactivity of spin-orbit split Al(2P) states at different scattering angles shows a more pronounced enhancement of forward scattering relative to side and backward scattering for Al(2P3/2) when a higher rotationally excited AlO is produced. Nonreactive scattering studies of Al(2P) suggest that the Al(2P3/2) state is deexcited to the ground Al(2P1/2) state at the sideways and backward scattering directions, and the deexcitation is supposed to reduce the reactivity of the excited Al(2P3/2) at the corresponding direction.

Metformin selectively inhibits metastatic colorectal cancer with the KRAS mutation by intracellular accumulation through silencing MATE1.

Metastatic colorectal cancer (mCRC) patients have poor overall survival despite using irinotecan- or oxaliplatin-based chemotherapy combined with anti-EGFR (epidermal growth factor receptor) drugs, especially those with the oncogene mutation of KRAS Metformin has been reported as a potentially novel antitumor agent in many experiments, but its therapeutic activity is discrepant and controversial so far. Inspiringly, the median survival time for KRAS-mutation mCRC patients with diabetes on metformin is 37.8 mo longer than those treated with other hypoglycemic drugs in combination with standard systemic therapy. In contrast, metformin could not improve the survival of mCRC patients with wild-type KRAS Interestingly, metformin is preferentially accumulated in KRAS-mutation mCRC cells, but not wild-type ones, in both primary cell cultures and patient-derived xenografts, which is in agreement with its tremendous effect in KRAS-mutation mCRC. Mechanistically, the mutated KRAS oncoprotein hypermethylates and silences the expression of multidrug and toxic compound extrusion 1 (MATE1), a specific pump that expels metformin from the tumor cells by up-regulating DNA methyltransferase 1 (DNMT1). Our findings provide evidence that KRAS-mutation mCRC patients benefit from metformin treatment and targeting MATE1 may provide a strategy to improve the anticancer response of metformin.

A Novel Pipeline Corrosion Monitoring Method Based on Piezoelectric Active Sensing and CNN.

In this study, a piezoelectric active sensing-based time reversal method was investigated for monitoring pipeline internal corrosion. An effective method that combines wavelet packet energy with a Convolutional Neural Network (CNN) was proposed to identify the internal corrosion status of pipelines. Two lead zirconate titanate (PZT) patches were pasted on the outer surface of the pipeline as actuators and sensors to generate and receive ultrasonic signals propagating through the inner wall of the pipeline. Then, the time reversal technique was employed to reverse the received response signal in the time domain, and then to retransmit it as an excitation signal to obtain the focused signal. Afterward, the wavelet packet transform was used to decompose the focused signal, and the wavelet packet energy (WPE) with large components was extracted as the input of the CNN model to rapidly identify the corrosion degree inside the pipeline. The corrosion experiments were conducted to verify the correctness of the proposed method. The occurrence and development of corrosion in pipelines were generated by electrochemical corrosion, and nine different depths of corrosion were imposed on the sample pipeline. The experimental results indicated that the classification accuracy exceeded 99.01%. Therefore, this method can quantitatively monitor the corrosion status of pipelines and can pinpoint the internal corrosion degree of pipelines promptly and accurately. The WPE-CNN model in combination with the proposed time reversal method has high application potential for monitoring pipeline internal corrosion.

Trueness of 4 sectional-cast digital methods for transferring the interocclusal relationship in complete mouth rehabilitation.

STATEMENT OF PROBLEM: An accurate digital workflow for transferring the interocclusal relationship from complete arch diagnostic interim restorations to complete arch tooth preparations is essential in complete mouth rehabilitation. However, research on the accuracy of digital cross-mounting methods is lacking. PURPOSE: The purpose of this in vitro study was to compare the trueness of 4 sectional-cast digital cross-mounting methods in transferring the interocclusal relationship for complete mouth rehabilitation. MATERIAL AND METHODS: Maxillary and mandibular anatomic typodonts were used to build complete arch tooth preparations and diagnostic interim restorations for complete mouth rehabilitation in vitro. Four sectional casts were designed: an anterior cast (AR), a posterior cast (PO), a unilateral cast (UL), and a tripod cast (TR). Both extraoral scanning (EOS) and intraoral scanning (IOS) were used to obtain intermediate digital sectional casts, which were cross-registered with diagnostic interim restorations and definitive casts to transfer the interocclusal relationship. Trueness was determined by assessing tooth distance deviation and mandibular 3-dimensional (3D) deviation. Differences among the 4 sectional-cast methods were analyzed with the Kruskal-Wallis test, and differences between the 2 scanning methods were analyzed with the Mann-Whitney U test (α=.05). RESULTS: Significant differences in the trueness of interocclusal relationship transfer were observed among the 4 sectional-cast methods (P<.05). Regarding tooth overall distance deviation, TR-EOS found no statistically significant difference compared with PO-EOS (P>.05), but TR-EOS had half the overall distance deviation of PO-EOS. Both TR-EOS and PO-EOS had smaller deviations than the AR-EOS and UL-EOS groups (P<.05). TR-IOS had a smaller distance deviation than the AR-IOS, PO-IOS, and UL-IOS groups (P<.05). The overall distance deviation of EOS was significantly smaller than that of IOS in the TR and PO groups (P<.05). Regarding mandibular 3D deviation, TR-EOS found no statistically significant difference but had half the root mean square (RMS) of 3D deviation compared with the PO-EOS groups (P>.05). Both TR-EOS and PO-EOS groups had a smaller RMS than the AR-EOS and groups (P<.05). The TR-IOS group had a smaller RMS than the AR-IOS, PO-IOS, and UL-IOS groups (P<.05). The 3D deviation of EOS was significantly smaller than that of IOS in the PO group (P<.05). CONCLUSIONS: Both EOS and IOS with the tripod sectional-cast digital method accurately transferred the interocclusal relationship for complete mouth rehabilitation.

The comparison between experimental nursing and routine nursing interventions on the quality of life of stoma patients: A systematic review and meta-analysis.

The advance in nursing care for stoma patients is a challenging issue, which will influence the life quality. The quality of life is a major issue in the recovery of stoma patients. The evidence of experimental nursing has not been explored enough. A systematic search and a meta-analysis were performed for the studies of experimental nursing interventions versus routine warming interventions on patients with a stoma. The comparisons between nursing interventions were performed to find which kind of intervention will be superior in improving life quality. After a restricted selection, 10 studies, 460 subjects with experimental nursing intervention, and 478 controls with the routine nursing intervention were enrolled in a variety of causes of the stoma. The focused outcome was the quality of life. The meta-analysis was performed by Review Manager 5.4. Among the stoma patients, the meta-analysis favours the experimental nursing intervention group with higher scores of life quality when compared to the routine nursing intervention group. The meta-analysis results were with positive mean differences, significant tests for overall effect, and significant heterogeneities in the random-effects model. The experimental nursing intervention showed higher positive effects on the quality of life when compared to routine nursing intervention for stoma patients. Experimental nursing intervention might be an option for stoma nursing practitioners to improve stoma care.

Three-point sectional-cast digital method for transferring the interocclusal relationship for full-mouth rehabilitation of worn dentition.

For full-mouth rehabilitation of worn dentition, "diagnostic" interim restorations are required to reestablish the interocclusal relationship. It is important but challenging to transfer the interocclusal relationship and to map the basic form and contour of interim restorations to the final restorations. Alignment of interim restorations and working casts is difficult when using digital workflows because of a lack of consistent hard tissue reference points. The digital workflow presented in this study used a "3-point sectional-cast digital cross-mounting method" to transfer the interocclusal relationship during full-mouth rehabilitation. An intermediate cast was made with three interim restorations: one on an incisor and two on molars. The interocclusal relationship and occlusal morphologies of the diagnostic interim prostheses were transferred and aligned to working casts using the 3-point sectional casts.

Phytochemical Constituents from the Seeds of Capsella bursa-pastoris and Their Antioxidant Activities.

Phytochemical investigation of 70% EtOH extract of the seeds of Capsella bursa-pastoris led to the isolation of a new cyclobutane organic acid (1), and fourteen known compounds, including two organosulfur compounds (2, 3), two quinonoids (4, 5), five flavonoids (6-10), three sterols (11-13) and two other types (14, 15). The structures of the compounds were elucidated by extensive spectroscopic analyses as well as comparison of their spectroscopic data with those reported in the literature. The antioxidant capacities of all compounds and extractive fractions were evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging test and ferric reducing antioxidant power (FRAP) assay. Then the antioxidative substances were evaluated for their neuroprotective effects against H2O2-induced HT22 cell injury. The results indicated the strong scavenging ability to free radical of the extractive fractions and compounds 1-3, 8-10 and 13, and the ferric reducing antioxidant power of the extractive fractions and compounds 1-3, 8 and 10, which were close to or higher than that of the positive control trolox. The EtOAc fraction, n-BuOH fraction, and compounds 1, 3 and 8 can protect HT-22 cells from oxidative damage.

Pigment epithelium-derived factor modulates periodontal homeostasis in mice and induces osteogenic differentiation of human periodontal ligament fibroblasts.

AIM: The aim of this study was to investigate the influence of pigment epithelium-derived factor (PEDF) on periodontal homeostasis in mice and the osteogenic differentiation of human periodontal ligament fibroblasts (PDLFs). MATERIALS AND METHODS: Micro-computed tomography and histology were performed to compare the alveolar bone volume, density, and bone-related markers between PEDF-deficient (PEDF-/-) and wild-type (WT) mice. Furthermore, after recombinant human PEDF treatment, the PDLF viability and osteogenic differentiation were examined using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, alkaline phosphatase (ALP) activity assay, Von Kossa staining, Alizarin red staining, real-time quantitative polymerase chain reaction (qRT-PCR), and immunoblotting. RESULTS: The alveolar bone volume and density of PEDF-/- mice were significantly lower than those of the WT mice. Higher receptor activator for nuclear factor-κB ligand (RANKL) expression and lower osteoprotegerin (OPG) expression levels were observed in the PEDF-/- group. Moreover, PEDF treatment did not affect the PDLF proliferation. PEDF dose-dependently improved mineral deposition. Compared with the control group, 250 ng/mL PEDF promoted OPG mRNA expression in PDLFs on Day 3 but inhibited RANKL, Wnt5a, GSK3b mRNA, and non-phosphorylated ß-catenin protein expression. However, 250 ng/mL PEDF had no significant effect on the expression of Wnt3a. On Day 7, after culture with 250 ng/mL PEDF in osteogenic medium, the ALP and RUNX2 protein levels were upregulated. VEGF protein expression was reduced in a dose-dependent manner after PEDF stimulation. The PEDF protein expression increased as the osteogenic induction time increased. CONCLUSION: PEDF gene knockout suppresses periodontal homeostasis in mice, and PEDF treatment induces PDLF osteogenic differentiation in vitro.

A role for Snail-MnSOD axis in regulating epithelial-to-mesenchymal transition markers expression in RPE cells.

Age-related macular degeneration (AMD) is a common cause of vision loss. The epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, accompanied by oxidative damage, plays a crucial role in AMD. It is well known that manganese superoxide dismutase (MnSOD) encoded by SOD2 is a critical molecule in fighting against oxidative stress, and Snail encoded by SNAI1 is the essential transcription factor for EMT. However, the effect of MnSOD on EMT and the underlying mechanism in RPE cells remains unknown. In this study, we found that MnSOD knockdown triggered the EMT by upregulating Snail, while MnSOD overexpression reversed EMT even with TGFß treatment in RPE cells, and the anti-oxidative stress activity of MnSOD mediated this observation. In addition, Snail depletion increased both expression and activity of MnSOD while Snail overexpression decreased MnSOD expression and activity, and Dual-luciferase reporter and ChIP assays showed that Snail directly bound to E-box (CACCTG) in the SOD2 promoter. Moreover, MnSOD over-expression and Snail interference co-treatment strengthened the anti-oxidation and EMT reversing. Therefore, our findings demonstrate that MnSOD prevents EMT of RPE cells in AMD through inhibiting oxidative injury to RPE. Moreover, a critical EMT transcription factor, Snail, functions as a new negative transcriptional factor of SOD2. Herein, the Snail-MnSOD axis forms a mutual loop in the development of AMD, which may be a novel systemic treatment target for preventing AMD.

Elevated pigment epithelium-derived factor induces diabetic erectile dysfunction via interruption of the Akt/Hsp90ß/eNOS complex.

AIMS/HYPOTHESIS: Diabetes mellitus erectile dysfunction (DMED) is a common complication of diabetes. The level of pigment epithelium-derived factor (PEDF) is significantly upregulated in the serum of individuals with obesity and diabetes. However, whether elevated PEDF levels contribute to DMED remains unknown. This study aimed to investigate the pathogenic role of PEDF and its related mechanism in DMED. METHODS: We enrolled 65 men, of whom 20 were nondiabetic control participants, 21 participants with diabetes but without erectile dysfunction, and 24 with DMED. The International Index of Erectile Function (IIEF-5) questionnaire was administered to evaluate erectile function. Plasma PEDF in diabetic participants and streptozotocin (STZ)-induced diabetic animals was detected by ELISA. Erectile function was evaluated by measuring the intracavernous pressure (ICP) and the ICP/mean arterial pressure (MAP) ratio in STZ-induced diabetic rats treated with PEDF-neutralising antibody (PEDF-Ab), db/db mice treated with PEDF-Ab, and Pedf knockout mice with STZ-induced diabetes. The overexpression of PEDF was implemented by intraperitoneal injection of recombinant PEDF and intracavernous injection of PEDF-expressing adenovirus. A mechanistic study was performed by immunofluorescence staining, bimolecular fluorescence complementation (BiFC), immunoprecipitation and western blotting. RESULTS: We found that the plasma level of PEDF was significantly higher in participants with DMED compared with diabetic counterparts without erectile dysfunction and nondiabetic controls. Interestingly, PEDF levels were negatively correlated with plasma nitrite/nitrate levels and erectile function in DMED patients and STZ-induced diabetic rats. Furthermore, overexpression of PEDF significantly suppressed ICP and endothelial nitric oxide synthase (eNOS) phosphorylation in control rats. In contrast, the PEDF-Ab and Pedf knockout ameliorated ICP and eNOS phosphorylation in diabetic rats and mice. Mechanistically, PEDF promoted the membrane translocation of Hsp90ß and directly bound to the amino acid residues 341-724 of Hsp90ß on the endothelial cell surface, subsequently blocking intracellular Hsp90ß/Akt/eNOS complex formation and downregulating eNOS phosphorylation. CONCLUSIONS/INTERPRETATION: These results indicate that elevated PEDF levels contribute to impaired erectile function by suppressing Hsp90ß-mediated eNOS phosphorylation and that PEDF may represent a novel therapeutic target for diabetic erectile dysfunction. Graphical abstract.

Targeting ß3-adrenergic receptor signaling inhibits neuroblastoma cell growth via suppressing the mTOR pathway.

Neuroblastoma (NB), the most common extracranial solid tumor in childhood, always leads to an unfavorable prognosis. ß3-adrenergic receptor (ß3-AR) signaling plays an important role in lipid metabolism. Although previous studies have focused mainly on the role of ß2-AR in tumor cells; there are few studies about the cancer-related function of ß3-AR. Herein, we showed that ß3-AR expression was significantly increased in clinical NB tissue compared with that in the less malignant ganglioneuroma (GN) and ganglioneuroblastoma (GNB) tissues. Further cellular assays demonstrated that treatment of NB cells with SR59230A (a specific ß3-AR antagonist) suppressed NB cells growth and colony formation, and siRNA knockdown of ß3-AR expression also inhibited NB cell proliferation. The mechanistic study revealed that ß3-AR knockdown and SR59230A inhibited the phosphorylation and thereby the activation of the mTOR/p70S6K pathway. Activation of the mTOR pathway with the activator MHY1485 reversed the inhibitory effect of SR59230A on NB cell growth. Above all, our study clarifies a novel regulatory role of ß3-AR in NB cell growth and provides a potent therapeutic strategy for this disease by specific targeting of the ß3-AR pathway.

Tanshinoneâ ¡A phenanthroimidazole derivative polarizes macrophage to improve metabolic homeostasis.

Macrophages infiltrated in adipose tissue play a key role in obesity. Some traditional pharmaceutical compounds may shift the polarization of recruited macrophages to improve metabolic homeostasis. TanshinoneⅡA (TAN2A) is a major active component of Salvia miltiorrhiza, a traditional anti-inflammatory cardiovascular medicine. In our study, we firstly constructed a phenanthroimidazole derivative of TAN2A named TAN20 by chemical synthesis, then identified its structure by chromatography and hydrogen spectroscopy, and finally examined its effects on immunometabolic responses. We found that TAN20 significantly induced the alternatively-activated (M2) rather than the classically-activated macrophages (M1), mainly through releasing the type II cytokines. Such effects were more pronounced than that from TAN2A. Compared to TAN2A, TAN20 substantially reduced body weight, decreased serum free fatty acid and HOMA-IR, and increased insulin sensitivity in obesity-induced diabetic mice. These effects of TAN20 were further validated on diabetic cynomolgus monkeys, which are closer to human physiological conditions. Taken together, our findings explicitly showed that TAN20 significantly polarized the macrophage and improved metabolic homeostasis in obesity-induced diabetic models, suggesting that TAN20 may be a potential drug against diabetes and obesity.

Regulation of NF-κB/MAPK signaling pathway attenuates the acute lung inflammation in Klebsiella pneumonia rats by mollugin treatment.

Present study evaluates the protective effect of mollugin against Klebsiella pneumonia (KP) and also postulates the possible mechanism of its action. Klebsiella pneumoniae (2.4 × 108 CFU/ml) was used for the induction of KP. PMNs and WBC count was determined in the blood and bronchoalveolar lavage fluid (BALF) of Klebsiella pneumonia rat. Level of inflammatory cytokines in the blood of Klebsiella pneumonia rat was determined by ELISA methods. Moreover effect of mollugin was estimated by Western blot assay and RT-PCR method. Result of the study suggests that water content in lung was reduced in the mollugin treated group compared to pneumonia control group of rats. Count of PMNs and WBC were found to be reduced in mollugin treated group compared to pneumonia control group of rats. Level of inflammatory cytokines was also found to be reduced in the blood of mollugin treated group than pneumonia control group. Moreover treatment with mollugin attenuates the altered expression of p-MAPK, p-JNK and p-ERK protein and mRNA expression of NF-κB in the lung tissues of Klebsiella pneumonia rat. In conclusion, data of the study reveals that treatment with mollugin ameliorates Klebsiella pneumonia rat by reducing the lung inflammation. Inflammation of lung tissue was reduced by regulating the NF-κB/MAPK signaling pathway in mollugin treated group.