Spectroscopic Evidence for Electron-Boson Coupling in Electron-Doped Sr_{2}IrO_{4}.

The pseudogap, d-wave superconductivity and electron-boson coupling are three intertwined key ingredients in the phase diagram of the cuprates. Sr_{2}IrO_{4} is a 5d-electron counterpart of the cuprates in which both the pseudogap and a d-wave instability have been observed. Here, we report spectroscopic evidence for the presence of the third key player in electron-doped Sr_{2}IrO_{4}: electron-boson coupling. A kink in nodal dispersion is observed with an energy scale of ∼50 meV. The strength of the kink changes with doping, but the energy scale remains the same. These results provide the first noncuprate platform for exploring the relationship between the pseudogap, d-wave instability, and electron-boson coupling in doped Mott insulators.

Corrigendum to "Wingless-Type MMTV Integration Site Family Member 5a Is a Key Secreted Islet Stellate Cell-Derived Product that Regulates Islet Function".

[This corrects the article DOI: 10.1155/2019/7870109.].

Wingless-Type MMTV Integration Site Family Member 5a Is a Key Secreted Islet Stellate Cell-Derived Product that Regulates Islet Function.

BACKGROUND: Emerging evidence suggests that T2DM is attributable to the dysfunction of ß-cells and the activation of islet stellate cells (ISCs). The wingless-type MMTV integration site family member 5a (Wnt5a)/frizzled 5 (Fzd5) signalling pathway might take part in this process. Our study is aimed at defining the status of ISCs during ß-cell insulin secretion homeostasis by determining the role of the Wnt5a protein in the regulation of insulin production. We examined the effects of the status of ISCs on ß-cell insulin secretion in normoglycemic db/m and hyperglycaemic db/db mice. METHODS: iTRAQ protein screening and RNA interference were used to determine novel ISC-derived secretory products that may use other mechanisms to influence the function of islets. RESULTS: We showed a significant reduction in insulin secretion by ß-cells in vitro when they were cocultured with db/db ISCs compared to when they were cocultured with ISCs isolated from normoglycemic db/m mice; in addition, both Wnt5a and its receptor Fzd5 were more highly expressed by quiescent ISCs than by activated db/db ISCs. Treatment with exogenous Wnt5a increased the secretion of insulin in association with the deactivation of ISCs. CONCLUSION: Our observations revealed that the Wnt5a protein is a key effector of ISC-mediated improvement in islet function.

Increased urinary glucose excretion is associated with a reduced risk of hyperuricaemia.

AIM: To investigate the association of urinary glucose excretion with levels of serum uric acid in adults with newly diagnosed diabetes. METHODS: A total of 597 people with newly diagnosed diabetes, confirmed in an oral glucose tolerance test, were included in the present study. The participants were divided into two groups: 142 participants with low urinary glucose excretion and 455 with high urinary glucose excretion. Demographic characteristics and clinical variables were evaluated. The association of urinary glucose excretion with uric acid was analysed using multivariable regression analysis. RESULTS: The low urinary glucose excretion group had a significantly higher prevalence of hyperuricaemia than the high urinary glucose excretion group. Moreover, urinary glucose excretion was negatively associated with uric acid level. The correlation remained significant after adjusting for potential confounders, including gender, age, fasting plasma glucose, 2-h plasma glucose and BMI. The results also showed that participants with high urinary glucose excretion were at decreased risk of hyperuricaemia (odds ratio 0.47, 95% CI 0.27-0.80; P = 0.006). CONCLUSION: Urinary glucose excretion was independently associated with uric acid level in participants with newly diagnosed diabetes. In addition to lowering blood glucose, promoting urinary glucose excretion may also be an effective approach to reducing serum uric acid levels, especially for people with diabetes complicated with hyperuricaemia.

Effects of miR-455 on PIK3R1 gene expression regulation and kidney cancer cell functions.

OBJECTIVE: Migration and proliferation of kidney cancer cells are critical factors affecting effective treatment. Abnormal gene expression exists during cancer pathogenesis. The study showed certain effects of PIK3R1 gene on migration and proliferation of kidney cancer cells, although a few studies have been performed regulatory mechanism of microRNA on PIK3R1 gene. Previous sequencing of PIK3R1 gene found the existence of mir-455 binding site. This study confirmed the regulation of PIK3R1 gene expression in kidney cancer cells of mir-455 by in vitro assay, and analyzed its effects on migration or proliferation of kidney cancer cells. MATERIALS AND METHODS: mir-455 agonist and inhibitor sequences were designed and synthesized to transfect kidney cancer cell line CAKI-1, which were further divided into agonist, inhibitor, and control group. qRT-PCR was used to test expression of mir-455 and PIK3R1 at 12 h, 24 h and 48 h after transfection. PIK3R1 protein expression was measured by Western blot. MTT and cell scratch assay were employed to measure cell proliferation and migration potency. RESULTS: 12 h after transfection with mir-455, no significant difference of the level of PIK3R1was found among the three groups (p>0.05). However, at 24 h and 48 h post-transfection, PIK3R1 expression in agonist group was significantly elevated, along with weakened cell proliferation or migration potency (p<0.05 with significant between-group comparison). By contrast, the level of PIK3R1 was statistically decreased in inhibitor group, in which cell proliferation and migration were enhanced (p<0.05). CONCLUSIONS: In kidney carcinoma cell CAKI-1, mir-455 expression regulation can positively alter PIK3R1 gene expression. Over-expression of PIK3Ra gene could reduce the proliferation or migration potency of CAKI-1 cells.

Up-regulation of serum miR-4262 predicts clinical outcome of patients with acute myeloid leukemia.

OBJECTIVE: The aim of this study was to investigate whether miR-4262 was associated with the prognosis of acute myeloid leukemia (AML) patients. PATIENTS AND METHODS: Serum and bone marrow miR-4262 expression were investigated in 186 AML patients and 115 healthy normal controls by using Real-time PCR. Associations between miR-4262 expressions and various clinicopathological characteristics were analyzed. Overall survival and relapse-free survival were evaluated using the Kaplan-Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazard analysis. RESULTS: Expression levels of miR-4262 in the bone marrow and serum of AML patients were both significantly higher than those in healthy controls (both p<0.01). Moreover, increased miR-4262 expression was significantly associated with FAB classification (p=0.001) and cytogenetics (p=0.001). Patients with high miR-4262 expression had poorer overall survival time and relapse-free survival time than those with low miR-4262 expression. Finally, multivariate analysis identified high miR-4262 expression as an independent prognostic factor for AML (p<0.001). CONCLUSIONS: Our data revealed that the evaluation of miR-4262 expression in the bone marrow and serum was an ideal tool for predicting the progression of AML and prognosis.

Correlations of TNF-α gene promoter polymorphisms with the risk of thymoma-associated myasthenia gravis in a northern Chinese Han population.

This study was performed with the aim to investigate the correlations of tumor necrosis factor-alpha (TNF-α) gene promoter polymorphisms with the risk of thymoma-associated myasthenia gravis (T-MG) in a northern Chinese Han population. Between June 2005 and June 2015, 305 MG patients (150 males and 155 females, MG group) and 293 healthy volunteers (negative control (NC) group) were enrolled in this study. Among the MG patients, there were 121 patients with thymoma-associated MG (T-MG group) and 184 without T-MG (NT-MG group). Enzyme-linked immunosorbent assay (ELISA) was used for the serum TNF-α level. Polymerase chain reaction-restriction fragment length polymorphism was conducted to determine genotype and allele frequencies of TNF-α gene promoter -1031T/C, -857C/T and -863C/A. The haplotype was analyzed with the SHEsis software. Logistic regression analysis was performed for correlations between TNF-α gene promoter polymorphisms and the risk of T-MG. The T-MG group had higher frequencies of the CT/TT genotype and T allele of -857C/T than the NT-MG and NC groups. The frequencies of the CC genotype and C allele of -1031T/C were higher in the T-MG group than in the NT-MG and NC groups, and higher in male patients in the T-MG group than in male patients in the NC group. TTA and TTC haplotypes exhibited lower frequencies in the T-MG group than in the NT-MG group. The ocular MG patients exhibited lower frequencies of the TT genotype and T allele of -857C/T than the generalized MG patients did. The TNF-α level was elevated in the T-MG group compared with that in the NC and NT-MG groups, indicating that the TC+CC and CT+TT genotypes were increased compared with the TT and CC genotypes in the -1031T/C and -857C/T, respectively. Logistic regression analysis suggested that expressions of anti-acetylcholine receptor antibodies, Osserman's classification, -1031T/C and -857C/T polymorphisms and the TTA haplotype were the independent risk factors for T-MG. These findings reveal that TNF-α -1031T/C and -857C/T polymorphisms and the TTA haplotype may be correlated with the occurrence of T-MG in a Northern Chinese Han population.

MicroRNA-143 inhibits cell growth by targeting ERK5 and MAP3K7 in breast cancer

This study aimed to investigate the function and mechanism of microRNA-143 (miR-143) in the occurrence and development of breast cancer (BC). A total of 30 BC tissues, 30 corresponding noncancerous tissues, and 10 normal control (NC) breast tissues were obtained to detect the levels of miR-143, extracellular signal-regulated kinase 5 (ERK5) and mitogen-activated protein 3 kinase 7 (MAP3K7) using RT-qPCR, western blotting or immunohistochemistry. The correlation of miR-143 with ERK5 or MAP3K7 was evaluated using Pearson correlation analysis. MCF-7 cells were transiently transfected with miR-143 mimic, miR-143 inhibitor, miR-143 mimic/inhibitor + si-ERK5, si-MAP3K7 or si-cyclin D1. Then, cell growth was evaluated by MTT assay and the expressions of phospho-ERK5 (p-ERK5), ERK5, p-MAP3K7, MAP3K7 and cyclin D1 were detected by western blotting. Results showed that, compared with noncancerous tissues or NC breast tissues, miR-143 level was decreased, while p-ERK5, ERK5, p-MAP3K7 and MAP3K7 expressions were increased in BC tissues (all P<0.01). The miR-143 level was negatively correlated with the mRNA level of ERK5 or MAP3K7 (r=-4.231 or r=-4.280, P<0.01). In addition, up-regulated miR-143 significantly decreased the expressions of p-ERK5, ERK5, p-MAP3K7, MAP3K7 and cyclin D1 (all P<0.01), as well as cell viability in MCF-7 cells (all P<0.05) while the effect of down-regulated miR-143 was the opposite. In conclusion, both ERK5 and MAP3K7 may be the target genes of miR-143. Increased expression of miR-143 can inhibit cell growth, which may be associated with ERK5 and MAP3K7 expressions in BC.

Prognostic value of ZFP36 and SOCS3 expressions in human prostate cancer

Purpose: ZFP36 ring finger protein (ZFP36) and the suppressor of cytokine signaling 3 (SOCS3) have been reported to, respectively, regulate NF-jB and STAT3 signaling pathways. To better understand the correlation of NF-jB and STAT3 negative regulates pathway, we have investigated the involvement of ZFP36 and SOCS3 expressions in human prostate cancer (PCa). Methods: In the present study, paired patient tissue microarrays were analyzed by immunohistochemistry, and the ZFP36 protein expression was quantitated as immunoreactive scores in patients with PCa. Associations between ZFP36/SOCS3 expression and various clinicopathological features and prognosis of PCa patients were statistically analyzed based on the Taylor database. Then, the functions of ZFP36 and SOCS3 in cancerous inflammation were determined using qPCR and immunohistochemistry in vitro and in vivo. Results: ZFP36 protein expression in PCa tissues was significantly lower than those in non-cancerous prostate tissues (P < 0.05). In mRNA level, ZFP36 and SOCS3 had a close correlation with each other (P < 0.01, Pearson r = 0.848), and its upregulation was both significantly associated with low Gleason score (P < 0.001 and P < 0.001, respectively), negative metastasis (P < 0.001 and P < 0.001, respectively), favorable overall survival (P < 0.001 and P < 0.05, respectively), and negative biochemical recurrence (P < 0.001 and P < 0.001, respectively). Functionally, LPS treatment could lead to the overexpression of ZFP36 and SOCS3 in vitro and vivo. Conclusions: Our data offer the convincing evidence for the first time that the aberrant expressions of ZFP36 and SOCS3 may be involved into the progression and patients’ prognosis of PCa, implying their potentials as candidate markers of this cancer

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Prognostic value of ZFP36 and SOCS3 expressions in human prostate cancer.

PURPOSE: ZFP36 ring finger protein (ZFP36) and the suppressor of cytokine signaling 3 (SOCS3) have been reported to, respectively, regulate NF-κB and STAT3 signaling pathways. To better understand the correlation of NF-κB and STAT3 negative regulates pathway, we have investigated the involvement of ZFP36 and SOCS3 expressions in human prostate cancer (PCa). METHODS: In the present study, paired patient tissue microarrays were analyzed by immunohistochemistry, and the ZFP36 protein expression was quantitated as immunoreactive scores in patients with PCa. Associations between ZFP36/SOCS3 expression and various clinicopathological features and prognosis of PCa patients were statistically analyzed based on the Taylor database. Then, the functions of ZFP36 and SOCS3 in cancerous inflammation were determined using qPCR and immunohistochemistry in vitro and in vivo. RESULTS: ZFP36 protein expression in PCa tissues was significantly lower than those in non-cancerous prostate tissues (P < 0.05). In mRNA level, ZFP36 and SOCS3 had a close correlation with each other (P < 0.01, Pearson r = 0.848), and its upregulation was both significantly associated with low Gleason score (P < 0.001 and P < 0.001, respectively), negative metastasis (P < 0.001 and P < 0.001, respectively), favorable overall survival (P < 0.001 and P < 0.05, respectively), and negative biochemical recurrence (P < 0.001 and P < 0.001, respectively). Functionally, LPS treatment could lead to the overexpression of ZFP36 and SOCS3 in vitro and vivo. CONCLUSIONS: Our data offer the convincing evidence for the first time that the aberrant expressions of ZFP36 and SOCS3 may be involved into the progression and patients' prognosis of PCa, implying their potentials as candidate markers of this cancer.

Kaempferol improves carcase characteristics in broiler chickens by regulating ANGPTL3 gene expression.

1. The objective of this study was to examine the beneficial effects of kaempferol, a naturally occurring polyphenol, on carcase characteristics in broiler chickens and the mechanisms involved in this regulation. 2. Broiler chickens were randomly divided into 7 groups: control, carrier control, kaempferol (0·3%), kaempferol (0·6%), hypercholesterolemic (HLD), HLD and kaempferol (0·3%), HLD and kaempferol (0·6%). 3. Seven weeks after treatment, carcase characteristics, lipid levels in the blood and liver, expression of hepatic Angiopoietin-like protein 3 (ANGPTL3) mRNA, and expression of adipose lipoprotein lipase (LPL) protein were determined. 4. Treatment with kaempferol (0·3 or 0·6%) significantly increased plasma high-density lipoprotein cholesterol levels, decreased percentage of abdominal fat, thickness of subcutaneous fat, plasma and hepatic total cholesterol and triglyceride concentrations, muscle malondialdehyde level and down-regulated expression of ANGPTL3 mRNA concomitantly with up-regulated expression of LPL protein in normal and hypercholesterolemic broiler chickens. 5. Kaempferol (0·3 or 0·6%) treatment had no significant effect on the values of percentage of breast muscle, percentage of leg muscle, carcase weight and eviscerated percentage. 6. The results suggest that kaempferol improves carcase characteristics by decreasing expression of ANGPTL3 in broiler chickens.

Neuroprotective effect of grafting GDNF gene-modified neural stem cells on cerebral ischemia in rats.

Previous studies indicated the beneficial effects of glial cell line-derived neurotrophic factor (GDNF) and transplanted neural stem cells (NSCs) on stroke. Here, we explored whether transplantation of neural stem cells (NSCs) modified by GDNF gene provides a better therapeutic effect than native NSCs after stroke. Primary rat NSCs were transfected with GDNF plasmid (GDNF/NSCs, labeled by green fluorescent protein from AdEasy-1, GFP). Adult rats were subjected to two-hour middle cerebral artery occlusion and reperfusion, followed by infusion of NSCs (labeled with5-bromo-2'-deoxyuridine before infusion, BrdU), GDNF/NSCs and saline at 3 days after reperfusion (NSCs group, GDNF/NSCs group, control group), respectively. All rats were sacrificed at 1, 2, 3, 5, and 7 weeks after reperfusion. Modified Neurological Severity Scores (mNSS) test and H and E staining were respectively performed to evaluate neurological function and lesion volume. Immunohistochemistry was used to identify implanted cells and observe the expressions of Synaptophysin (Syp) and postsynaptic density-95 (PSD-95) and caspase-3. TdT-mediated dUTP-biotin nick-end labeling (TUNEL) was employed to observe apoptotic cells. Western blotting was used to detect brain-derived neurotrophic factor (BDNF) and NT-3 protein expression. Significant recovery of mNSS was found in GDNF/NSCs rats at 2 and 3 weeks after reperfusion compared with NSCs rats. Lesion volume in the NSCs and GDNF/NSCs groups was reduced significantly compared with control group. The number of NSCs in the GDNF/NSCs group was significantly increased in comparison with NSCs group. Moreover, Syp-immunoreactive product at 2 and 3 weeks after reperfusion and PSD-95 immunoreactive product in the GDNF/NSCs group were significantly increased compared with NSCs group. In contrast, caspase-3 positive cells and TUNEL-positive cells in the GDNF/NSCs group were significantly decreased compared with NSCs group. Significant increase of BDNF protein in the GDNF/NSCs and NSCs groups was observed compared to the control group at different time points of reperfusion, and GDNF/NSCs grafting significantly increased BDNF protein expression compared to NSCs grafting. In addition, significant increase of NT-3 protein in GDNF/NSCs and NSCs groups was detected only at 1 week of reperfusion compared to control group. The results demonstrate that grafting NSCs modified by GDNF gene provides better neuroprotection for stroke than NSCs grafting alone.

Neuroprotective effects of ginsenoside Rb1 on transient cerebral ischemia in rats.

Previous experiments showed that ginsenoside Rb1 (GRb1) reduced infarct and neuronal deficit in rats followed by transient cerebral ischemia. The mechanism of this neuroprotective function is unclear. Here, we tested whether the effect of GRb1 can be achieved through preventing ischemic neuronal death, modulating apoptotic-related genes and affecting glial-derived neurotrophic factor (GDNF) expression in rats subjected to occlusion of the middle cerebral artery. When GRb1(40 mg/kg, i.p.) was administered immediately after reperfusion, the apoptotic cells in the GRb1 group were decreased significantly from 12 to 72 h of reperfusion compared to the ischemia group by TdT-mediated dUTP-biotin nick-end labeling. Immunostaining and Western blotting analysis showed that the expression of GDNF from 3 to 120 h of the GRb1 group was significantly increased compared to the ischemia group, and GDNF expression peaked at 48 h after reperfusion. The enhanced GDNF mRNA in the GRb1 group was not detected by RT-PCR and in situ hybridization compared to the ischemia group, but GDNF mRNA at 48 h after reperfusion was strongly increased in both the ischemia and GRb1 group when compared to other time points. The number of bcl-2-positive cells was significantly increased from 12 to 120 h of reperfusion compared to the ischemia group. However, the number of bax-positive cells in the GRb1 group was significantly declined compared to the ischemia group. In the GRb1 group, the number of neuronal apoptosis inhibitory protein-positive cells from 12 to 120 h after reperfusion was evidently higher than that in the ischemia group. Therefore, ginsenoside Rb1 prevents ischemic neuronal death induced by transient cerebral ischemia, and this mechanism of which is related to increase the expression of the antiapoptotic genes and modulate the expression of GDNF.

Monoclonal antibodies to native mouse angiotensin-converting enzyme (CD143): ACE expression quantification, lung endothelial cell targeting and gene delivery.

We demonstrated previously that the monoclonal antibody 9B9 to angiotensin-converting enzyme (ACE), which accumulates very selectively into the rat lung after systemic injection, is a powerful tool for immunotargeting of therapeutic agents or genes to the rat lung vascular bed. Bearing in mind a high research and therapeutic potential of lung targeting via ACE, we obtained a new set of rat monoclonal antibodies to different epitopes of mouse ACE in order to expand this approach to mice. Nine new monoclonal antibodies, recognizing epitopes on the N- and C-domains of catalytically active mouse ACE, were obtained and examined for their efficacy to bind ACE both in vitro and in vivo. This set of monoclonal antibodies was proved to be useful for ACE quantification (by flow cytometry and cell enzyme-linked immunosorbent assay) on the surface of different mouse ACE-expressing cells: endothelial cells, monocytes, macrophages, dendritic cells and spermatozoa. Moreover, gene delivery into mouse ACE-expressing cells using adenoviruses increased 40-fold after redirecting of these viruses to ACE (by coating these viruses with anti-ACE monoclonal antibodies). Radiolabelled (I(125)) monoclonal antibodies specifically accumulated in the mouse lung after systemic injection. Monoclonal antibodies 3G8.17, 4B10.5 and 4B10.17 demonstrated the highest level of lung uptake, 40-50% of injected dose, and high selectivity of lung uptake. Influence of monoclonal antibodies on ACE shedding was negligible, except monoclonal antibody 1D10.11. None of the tested monoclonal antibodies inhibited ACE activity in vitro. In conclusion, a new set of rat monoclonal antibodies to mouse ACE was obtained suitable to study ACE biology in mice and for ACE expression quantification on mouse cells in particular. These monoclonal antibodies also demonstrated highly efficient and selective lung accumulation and thus has the potential for targeting drugs/genes to the pulmonary vasculature in different mouse models of human lung diseases, including numerous knockout models.

Development and characterization of rat monoclonal antibodies to denatured mouse angiotensin-converting enzyme.

Four new rat monoclonal antibodies, generated to denatured mouse somatic angiotensin-converting enzyme (ACE, CD143), detect mouse ACE with high sensitivity in Western blotting. Epitope mapping for the monoclonal antibodies--B12, 4G6 and 5C4--was also performed. Two monoclonal antibodies--B12 and 5C4--are directed to various epitopes on the N-domain--i.e., they recognized only the somatic isoform of mouse ACE. The monoclonal antibody H7 recognized an epitope on the C-domain of mouse ACE. The monoclonal antibody 4G6 was directed to a sequence on the N-domain of mouse ACE, which is homologous to a region of the C-domain and, as a result, also recognizes mouse testicular ACE (tACE) by means of Western blotting. In paraffin-embedded mouse tissues, all monoclonal antibodies detected all known expression sites of somatic ACE (sACE), e.g., the epithelial cells of the kidney proximal tubules, intestine and epididymis, and heterogeneously in endothelial cells. The monoclonal antibodies 4G6 and H7 additionally stained mouse tACE in spermatozoa and in mature spermatids. The monoclonal antibody 4G6 also demonstrated cross-reactivity with sACE from a broad spectrum of animal species, including human, rat, rabbit and bovine. However, this monoclonal antibody did not recognize the testicular isoform of ACE of these species. This set of monoclonal antibodies is useful for identifying even subtle changes in mouse ACE conformation because of denaturation. These monoclonal antibodies are also sensitive tools for the detection of mouse ACE in biological fluids and tissues by using proteomics approaches. Their high reactivity in paraffin-embedded tissues opens up opportunities to study possible changes in the pattern of ACE expression in knockout mouse models and may prove useful for correlating ACE expression in these models with human diseases.