The Cell Envelope Integrity Protein Homologue D0Y85_RS06240 of Stenotrophomonas Confers Multiantibiotic Resistance.

Background: The potential role of cell envelope integrity proteins in mediating antibiotic resistance is not well understood. In this study, we investigated whether the cell envelope integrity protein D0Y85_RS06240 from the multiantibiotic resistant strain Stenotrophomonas sp. G4 mediates antibiotic resistance. Methods: Bioinformatics analysis was conducted to identify proteins related to the D0Y85_RS06240 protein. The D0Y85_RS06240 gene was heterologously expressed in Escherichia coli, both antibiotic MICs and the effect of efflux pump inhibitors on antibiotic MICs were determined by the broth microdilution method. A combination of antibiotic and efflux pump inhibitor was used to investigate bacterial killing kinetics, and binding of D0Y85_RS06240 to antibiotic molecules was predicted by molecular docking analysis. Results: Sequence homology analysis revealed that D0Y85_RS06240 was related to cell envelope integrity proteins. The D0Y85_RS06240 heterologous expression strains were resistant to multiple antibiotics, including colistin, tetracycline, and cefixime. However, the efflux pump inhibitor N-methylpyrrolidone (NMP) reduced the antibiotic MICs of the D0Y85_RS06240 heterologous expression strain, and bacterial killing kinetics revealed that NMP enhanced the bactericidal rate of tetracycline to the drug-resistant bacteria. Molecular docking analysis indicated that D0Y85_RS06240 could bind colistin, tetracycline, and cefixime. Conclusion: The cell envelope integrity protein D0Y85_RS06240 in Stenotrophomonas sp. G4 mediates multiantibiotic resistance. This study lays the foundation for an in-depth analysis of D0Y85_RS06240-mediated antibiotic resistance mechanisms and the use of D0Y85_RS06240 as a target for the treatment of multiantibiotic-resistant bacterial infections.

PGC-1 coactivators regulate MITF and the tanning response.

The production of pigment by melanocytes tans the skin and protects against skin cancers. UV-exposed keratinocytes secrete α-MSH, which then activates melanin formation in melanocytes by inducing the microphthalmia-associated transcription factor (MITF). We show that PPAR-γ coactivator (PGC)-1α and PGC-1ß are critical components of this melanogenic system in melanocytes. α-MSH signaling strongly induces PGC-1α expression and stabilizes both PGC-1α and PGC-1ß proteins. The PGC-1s in turn activate the MITF promoter, and their expression correlates strongly with that of MITF in human melanoma cell lines and biopsy specimens. Inhibition of PGC-1α and PGC-1ß blocks the α-MSH-mediated induction of MITF and melanogenic genes. Conversely, overexpression of PGC-1α induces pigment formation in cell culture and transgenic animals. Finally, polymorphism studies reveal expression quantitative trait loci in the PGC-1ß gene that correlate with tanning ability and protection from melanoma in humans. These data identify PGC-1 coactivators as regulators of human tanning.

Identification of biomarkers correlated with diagnosis and prognosis of endometrial cancer using bioinformatics analysis.

Endometrial cancer (EC) is one of the most common malignancies in the female genital system, characterized by high mortality and recurrence rates. This study attempted to screen key genes and potential prognostic biomarkers for EC using bioinformatics analysis. Twenty-seven normal endometrial tissues and 135 EC samples were collected from four Gene Expression Omnibus (GEO) databases, then we identified the differentially expressed genes (DEGs) and conducted downstream analyses. Moreover, we screened hub genes by constructing a protein-protein interaction (PPI) network. Finally, we assessed the prognostic values and molecular mechanism of the potential prognostic genes using the Kaplan-Meier curve and Gene Set Enrichment Analysis (GSEA). As a result, 28 upregulated and 94 downregulated genes were determined after gene integration of these four GEO data sets. Gene Ontology analysis indicated that DEGs were mainly involved in transcriptional regulation and cell proliferation. The Kyoto Encyclopedia of Gene and Genome pathway analysis primarily related to transcriptional misregulation and apoptosis. Moreover, the PPI analysis revealed 10 hub genes (JUN, UBE2I, GATA2, WT1, PIAS1, FOXL2, RUNXI, EZR, TCF4, and NR2F2) with a high degree of connectivity, among them, the expression tendency of nine genes except UBE2I were consistent with messenger RNA level from The Cancer Genome Atlas data. Furthermore, only FOXL2, TCF4, and NR2F2 were significantly correlated with prognosis of EC patients, and their low expression associated biological pathways were enriched in the cell cycle and fatty acid metabolism. In conclusion, this study identified three key genes as biomarkers and potential therapeutic targets of EC on the basis of integrated bioinformatics analysis. The findings will improve our comprehension of the molecular mechanisms underlying the pathogenesis and prognosis of EC.

PGC-1α induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle.

RATIONALE: Mechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and peripheral artery disease but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and patients with diabetes mellitus. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. Peroxisome proliferation activator receptor-γ coactivator-1α (PGC-1α), a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle. OBJECTIVE: To test whether, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle. METHODS AND RESULTS: Here, we show that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types and leads to patent, nonleaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of vascular endothelial growth factor alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 and the recruitment of macrophages. Secreted phosphoprotein 1 stimulates macrophages to secrete monocyte chemoattractant protein-1, which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in secreted phosphoprotein 1(-/-) mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hindlimb ischemia model of peripheral artery disease. CONCLUSIONS: PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.

PGC-1α regulates normal and pathological angiogenesis in the retina.

Neovascular diseases of the eye are the most common causes of blindness worldwide. The mechanisms underlying pathological neovascularization in the retina remain incompletely understood. PGC-1α is a transcriptional coactivator that plays a central role in the regulation of cellular metabolism. In skeletal muscle, PGC-1α induces VEGFA expression and powerfully promotes angiogenesis, suggesting a similar role in other tissues. This study investigates the role of PGC-1α during normal and pathological vascularization in the retina. We show that PGC-1α induces the expression of VEGFA in numerous retinal cells, and that PGC-1α expression is strongly induced during postnatal retinal development, coincident with VEGFA expression and angiogenesis. PGC-1α(-/-) mice have a significant reduction of early retinal vascular outgrowth, and reduced density of capillaries and number of main arteries and veins as adults. In the oxygen-induced retinopathy model of retinopathy of prematurity, PGC-1α expression is dramatically induced in the inner nuclear layer of the retina, suggesting that PGC-1α drives pathological neovascularization. In support of this, PGC-1α(-/-) mice subjected to oxygen-induced retinopathy had decreased expression of VEGFA and were protected against pathological neovascularization. These results demonstrate that PGC-1α regulates VEGFA in the retina and is required for normal vessel development and for pathological neovascularization. The data highlight PGC-1α as a novel target in the treatment of neovascular diseases of the eye.

Linarin Ameliorates Restenosis After Vascular Injury in Type 2 Diabetes Mellitus via Regulating ADAM10-Mediated Notch Signaling Pathway.

Vascular lesions frequently arise as complication in patients diagnosed with diabetes mellitus (DM). Presently, percutaneous coronary intervention (PCI) and antithrombotic therapy serve as primary treatments. However, in-stent restenosis persists as a challenging clinical issue following PCI, lacking sustained and effective treatment. Linarin (LN) exhibits diverse pharmacological activities and is regarded as a potential drug for treating various diseases, including DM. But its specific role in restenosis after vascular injury in DM patients remains unclear. A rat model of diabetes-related restenosis was established to evaluate the role of LN on neointimal hyperplasia. Vascular smooth muscle cells (VSMCs) stimulated by high glucose (HG, 30 mM) underwent LN treatment. Additionally, an overexpression plasmid of A disintegrin and metalloproteinases (ADAM10) was constructed to transfect VSMCs. We employed CCK-8, Brdu, wound-healing scratch, and transwell migration assays to evaluate the proliferation and migration of VSMCs. Furthermore, western blot and immunofluorescence assays were utilized to investigate the expressions of ADAM10 and the downstream Notch signaling pathway in vivo and in vitro models. LN notably alleviated intimal hyperplasia after vascular injury in DM rats and reduced the protein expression of ADAM10, alongside its downstream Notch1 signaling pathway-related proteins (Notch1, NICD and Hes1) in rat carotid artery tissues. LN effectively suppressed the proliferation and migration of VSMCs induced by HG, downregulating the protein expression of ADAM10, Notch1, NICD and Hes1. Moreover, our findings indicated that ADAM10 overexpression significantly reversed LN's effects on proliferation, migration, and the expression of Notch1 signaling pathway-related proteins in HG-treated VSMCs. LN demonstrates potential therapeutic efficacy in addressing restenosis after diabetic-related vascular injury, with the ADAM10 mediated Notch signaling pathway playing a pivotal role.

Short multiwall carbon nanotubes promote neuronal differentiation of PC12 cells via up-regulation of the neurotrophin signaling pathway.

Numerous unique properties of carbon nanotubes make them attractive for applications in neurobiology such as drug delivery, tissue regeneration, and as scaffolds for neuronal growth. In this study, the critical roles of the length of multiwall carbon nanotubes (MWCNTs) on a neuronal-like model cell line PC12 cells are investiaged. Incubation of PC12 cells with carboxylated MWCNTs did not significantly affect cellular morphology and viability at lower concentrations. Short MWCNTs show higher cellular uptake and more obvious removal compared to longer ones, which can result in higher ability to promote PC12 cell differentiation. Pre-incubation of short MWCNTs can up-regulate the expression of neurotrophin signaling pathway-associated TrkA/p75 receptors and Pincher/Gap43/TH proteins, which might be the underlying mechanism for the improved differentiation in PC12 cells. The current results provide insight for future applications of MWCNTs in neuron drug delivery and neurodegenerative disease treatment.

Assessing impact of land use change on ecosystem service value in Dasi River Basin of China based on an improved evaluation model.

The aim of this study was to provide a new method for dynamic and continuous assessment of ecosystem service value (ESV) and reveal the impact of land use change on ESV in Dasi River Basin within Jinan's startup area from replacing old growth drivers with new ones. Based on four remote sensing images from 2002 to 2020, four ecological indicators were extracted, and the ecological environmental quality index (EEQI) was obtained through the approach of principal component analysis (PCA). Then, the traditional ESV evaluation method was modified by using the EEQI, grain yield, the biomass factor of cropland ecosystem, and the consumer price index (CPI). Finally, the impact of land use change on ESV was further analyzed based on the improved evaluation model. The result showed that (1) during 2002-2020, the area of forestland, grassland, and built-up land showed an increasing trend. The area of cropland and bare land showed a decreasing trend, and the water body area showed a slightly decreasing trend. (2) The total ESVS overall increased by 2.1759 × 107 yuan; the increased ESVS from air quality regulation, maintain biodiversity, and climate regulation were the main reasons for the increased of total ESVS, with contribution rates of 53.18%, 12.46%, and 11.29% respectively. (3) The sensitivity of ecosystem services to land use change showed a decreasing trend, and the order of elasticity index of different land use types was cropland > water body > forestland > grassland > bare land. The conversion of cropland and bare land to forestland was the main type of ESVs increase, with contribution rates of 18.35% and 10.13%, respectively. The cropland reclamation and built-up land expansion were the most significant land use changes that lead to the decline of ESVS, with contribution rates of 20.14% and 19.03% respectively. (4) The ESV showed a significant positive auto-correlation in terms of spatial distribution. The area of high-high region was mainly distributed in water body, forestland, and its surrounding areas. The area of low-low region was mainly distributed in built-up land and wasteland areas where human disturbance is relatively serious. The high-low and low-high regions were affected by landscape transition process and randomly distributed around the low-low and high-high regions, respectively. This study cannot only put forward a new method for the dynamic continuous evaluation of ESV, but also provide a reference for the rational allocation of land resources in the startup area to realize the balanced development of regional environment and economy.

LncRNA PEG11as aggravates cerebral ischemia/reperfusion injury after ischemic stroke through miR-342-5p/PFN1 axis.

AIM: LncRNAs are highly expressed in the CNS and regulate pathophysiological processes. However, the potential role of lncRNAs inischemic stroke (IS) remains unknown. In this study, we investigated the functions and possible molecular mechanism of lncRNA paternal expressed gene 11 antisense (PEG11as) in this process. METHODS: Middle cerebral artery occlusion/reperfusion (MCAO/R) mice model and N2a cells model from oxygen-glucose deprivation/reoxygenation (OGD/R) were used to simulate cerebral I/R in vivo and in vitro. High-throughput sequencing (RNA-Seq) was used todetect differential expression of lncRNAs in cerebral I/R. QRT-PCR was used to detect the expression of PEG11as and miR-342-5p. Bioinformatics analysis, FISH, luciferase reporter assay, RIP, Western blot, and immunofluorescence were used to detect the interaction between PEG11as, miR-342-5p and PFN1. The effect on neuronal apoptosis was analyzed using loss-of-function combined with TUNEL, Hoechst, and caspase3 activity assays. KEY FINDINGS: 254 lncRNAs were differentially expressed in MCAO1h/R6h mice. Among them, PEG11as was significantly up-regulated. PEG11as down-regulated could markedly attenuate the brain infarct volume, alleviate neurological deficit in vivo, and effectively promote neuron survival, attenuate neuronal apoptosis both in vivo and in vitro. FISH assay discovered that PEG11as was mainly located in the cytoplasm. Furthermore, we demonstrated that PEG11as was able to bind miR-342-5p to inhibit miR-342-5p activity, whereas the down-regulated of miR-342-5p resulted in profilin 1 (PFN1) overexpression and thus promoting apoptosis. SIGNIFICANCE: This study suggests that PEG11as regulates neuronal apoptosis by miR-342-5p/PFN1 axis, which may contribute to our understanding of pathogenesis and provide a potential therapeutic option for cerebral I/R.

Death associated protein­3 (DAP3) and DAP3 binding cell death enhancer­1 (DELE1) in human colorectal cancer, and their impacts on clinical outcome and chemoresistance.

Death associated protein­3 (DAP3) was identified as a responsive protein to interferon­gamma­induced cell death which possibly exerts this regulation by interacting with DAP3 binding cell Death enhancer­1 (DELE1), a newly discovered mitochondrial stress protein in response to cell stress signals. Whilst DAP3 has been shown to be aberrantly expressed in several cancer types (i.e. breast cancer), little is known about the relationship between DAP3 and DELE1 in cancers. The present study examined the expression levels of both DAP3 and DELE1 in clinical colorectal cancers (CRCs), as well as their implication on chemoresistance and mechanism behind the action. Firstly, transcript levels of both DAP3 and DELE1 were quantitatively assessed in a clinical cohort of CRC (n=94). Tumour tissues had significantly higher levels of DAP3, but not DELE1 compared with normal tissues. Levels of DAP3 and DELE1 had a significant association with patient's clinical outcomes and local recurrence. DAP3 and DELE1 significantly correlated in normal colorectal tissues but not in tumour tissues. Secondly, the protein levels of DAP3 and DELE1 were evaluated in both normal and tumour colon tissues which showed that both proteins were highly aberrant in CRC tissues. In addition, both DAP3 and DELE1 at transcript and protein levels were identified as prognostic factors for patient's clinical outcomes. Furthermore, in in vitro assays, knocking down DAP3 or DELE1, and in particular both DAP3 and DELE1 together rendered the CRC cells more sensitive to chemotherapy drugs, consistent with clinical findings of the TCGA­COAD datasets. The acquisition of drug sensitivity following the genetic knockdown was independent of the mitochondrial metabolism, as neither DAP3 knockdown nor DELE1 knockdown showed a significant change. In summary, DAP3 and DELE1 are highly aberrant in CRCs, and both molecules are prognostic factors for patient's clinical outcomes and local recurrence, and are indicators for chemoresistance.

PGC-1 coactivators in cardiac development and disease.

The beating heart requires a constant flux of ATP to maintain contractile function, and there is increasing evidence that energetic defects contribute to the development of heart failure. The last 10 years have seen a resurgent interest in cardiac intermediary metabolism and a dramatic increase in our understanding of transcriptional networks that regulate cardiac energetics. The PPAR-γ coactivator (PGC)-1 family of proteins plays a central role in these pathways. The mechanisms by which PGC-1 proteins regulate transcriptional networks and are regulated by physiological cues, as well as the roles they play in cardiac development and disease, are reviewed here.

Safety and efficacy of a new modified intravenous recombinant tissue plasminogen activator (rt-PA) regimen in Chinese patients with acute ischemic stroke: A descriptive retrospective cohort study with subgroup-analysis of different rt-PA dose.

Evidence for effects of the dose of recombinant tissue plasminogen activator(rt-PA) in Asian populations is inconclusive. The standard dose may cause drug waste and increase economic burden in developing country. Therefore, we preliminarily describe the safety and efficacy of a new modified dose of rt-PA regimen(0.6 or 0.9 mg/kg, with a maximum dose of 50 mg) in real world settings. 265 consecutive patients with ischemic stroke were treated with intravenous(IV) rt-PA alone from all the 323 consecutive patients treated with reperfusion therapy between January 1, 2017 and March 31, 2020. Safety and Efficacy was assessed by early neurological improvement(ENI), early neurological deterioration(END), symptomatic intracranial hemorrhage(sICH) and 90-day outcome defined by modified Rankin scale(mRS). Subgroup analysis was conducted to draw comparisons between different dose groups ([0.5,0.6)mg/kg, [0.6,0.7)mg/kg, [0.7,0.8)mg/kg, [0.8,0.9]mg/kg). Among the 265 patients, 150(56.60%) had a favorable outcome at 3 months(3 M); Mortality occurred in 17(6.40%) in 3 M; sICH in 12(4.50%); ENI in 70(26.40%); END2 in 29(10.90%) and END4 in 18(6.80%). In subgroup analysis, there was a significant difference in sICH that more patients developed sICH in [0.8-0.9]mg/kg group(P = 0.044) in univariate analysis of different dose. After adjusting, there was no significant difference between 4 dosage groups. Significant differences were seen in gender, atrial fibrillation and baseline NIHSS in the multivariable model of favorable outcome at 3 M. Our study preliminarily shows a good safety and efficacy of our modified rt-PA regimen, indicating that this regimen should be worthy of further study especially in developing country to reduce the financial burden of patients and avoid drug waste.

Location, function and role of stromal cell­derived factors and possible implications in cancer (Review).

Despite improvements in therapy and management, cancer represents and remains a major cause of mortality and morbidity worldwide. Although genetics serve an important role in tumorigenesis and tumour progression, the tumour microenvironment (TME) in solid tumours is also important and has been indicated to contribute to these processes. Stromal cell­derived factors (SDFs) represent an important family within the TME. The family includes SDF­1, SDF­2, SDF2­like 1 (SDF2L1), SDF­3, SDF­4 and SDF­5. SDF­1 has been demonstrated to act as a positive regulator in a number of types of tumour, such as oesophago­gastric, pancreatic, lung, breast, colorectal and ovarian cancer, while the biology and functions of other members of the SDF family, including SDF­2, SDF2L1, SDF­4 and SDF­5, in cancer are different, complex and controversial, and remain mainly unknown. Full identification and understanding of the SDFs across multiple types of cancer is required to elucidate their function and establish potential key targets in cancer.

Influence of anaesthetics on the production of cancer cell motogens, stromal cell-derived factor-1 and hepatocyte growth factor by fibroblasts.

Anaesthetics have been implicated to influence cancer cells and progression. Similarly, crosstalk between cancer cells and stromal components within the microenvironment is also an important factor driving progression. Stromal cell-derived factor-1 (SDF-1) and hepatocyte growth factor (HGF) are key chemokines/cytokines produced by fibroblasts which have been established as influential factors in cancer progression. The present study explored the capacity of anaesthetics to influence the expression of these key molecules in fibroblasts. The anaesthetics rocuronium bromide (RB), vecuronium bromide (VB), suxamethonium chloride CRS (SCC), dexmedetomidine hydrochloride (DH) and lidocaine were used to treat MRC-5 fibroblasts over a range of concentrations. Following treatment, transcript expression of SDF-1 and HGF was quantified using quantitative PCR. Treatment of MRC-5 cells with RB brought about a reduction of SDF-1 expression which was found to be significant in the 45 µg/ml treatment group. Treatment with the other anaesthetics brought about some alterations in SDF-1 expression but these were not found to be statistically significant. Treatment with the tested anaesthetics did not have any significant effect on HGF transcript expression within MRC-5 cells, although again some alterations were observed. The results indicated that anaesthetics may have an impact on the fibroblast component of the tumour microenvironment, potentially influencing SDF-1 and HGF expression which in turn could influence tumour progression.

Preparation of Copper Nitride Films with Superior Photocatalytic Activity through Magnetron Sputtering.

TiO2 possesses a wide forbidden band of about 3.2 eV, which severely limits its visible light absorption efficiency. In this work, copper nitride (Cu3N) films were prepared by magnetron sputtering at different gas flow ratios. The structure of the films was tested by scanning electron microscope, X-ray diffractometer, and X-ray photoelectron spectroscope. Optical properties were investigated by UV-vis spectrophotometer and fluorescence spectrometer. Results show that the Cu3N crystal possesses a typical anti-ReO3 crystal structure, and the ratio of nitrogen and Cu atoms of the Cu3N films was adjusted by changing the gas flow ratio. The Cu3N films possess an optical band gap of about 2.0 eV and energy gap of about 2.5 eV and exhibit excellent photocatalytic activity for degrading methyl orange (degradation ratio of 99.5% in 30 min). The photocatalytic activity of Cu3N mainly originates from vacancies in the crystal and Cu self-doping. This work provides a route to broaden the forbidden band width of photocatalytic materials and increase their photoresponse range.

Preparation of Cu3N/MoS2 Heterojunction through Magnetron Sputtering and Investigation of Its Structure and Optical Performance.

Cu3N/MoS2 heterojunction was prepared through magnetron sputtering, and its optical band gap was investigated. Results showed that the prepared Cu3N/MoS2 heterojunction had a clear surface heterojunction structure, uniform surface grains, and no evident cracks. The optical band gap (1.98 eV) of Cu3N/MoS2 heterojunction was obtained by analyzing the ultraviolet-visible transmission spectrum. The valence and conduction band offsets of Cu3N/MoS2 heterojunction were 1.42 and 0.82 eV, respectively. The Cu3N film and multilayer MoS2 formed a type-II heterojunction. After the two materials adhered to form the heterojunction, the interface electrons flowed from MoS2 to Cu3N because the latter had higher Fermi level than the former. This behavior caused the formation of additional electrons in the Cu3N and MoS2 layers and the change in optical band gap, which was conducive to the charge separation of electrons in MoS2 or MoS2 holes. The prepared Cu3N/MoS2 heterojunction has potential application in various high-performance photoelectric devices, such as photocatalysts and photodetectors.

Compound 13 activates AMPK-Nrf2 signaling to protect neuronal cells from oxygen glucose deprivation-reoxygenation.

Oxygen glucose deprivation-reoxygenation (OGD-R) causes the production of reactive oxygen species (ROS) and oxidative injury in neuronal cells. We tested the potential neuroprotective function of compound 13 (C13), a novel AMP-activated protein kinase (AMPK) activator, against OGD-R. We show that C13 pretreatment protected SH-SY5Y neuronal cells and primary hippocampal neurons from OGD-R. C13 activated AMPK signaling in SH-SY5Y cells and primary neurons. It significantly inhibited OGD-R-induced apoptosis activation in neuronal cells. Conversely, AMPKα1 shRNA or knockout reversed C13-mediated neuroprotection against OGD-R. C13 potently inhibited OGD-R-induced ROS production and oxidative stress in SH-SY5Y cells and primary neurons. Furthermore, C13 induced Keap1 downregulation and Nrf2 activation, causing Nrf2 stabilization, nuclear accumulation, and expression of Nrf2-dependent genes. Nrf2 silencing or knockout in SH-SY5Y cells abolished C13-mediated neuroprotection against OGD-R. In conclusion, C13 activates AMPK-Nrf2 signaling to protect neuronal cells from OGD-R.

Sitagliptin improves renal function in diabetic nephropathy in male Sprague Dawley rats through upregulating heme oxygenase-1 expression.

PURPOSE: Oxidative stress is an important mechanism for diabetic nephropathy. Studies showed that hemo oxygenase-1 (HO-1) expression in renal tissue of patients with diabetic nephropathy has upregulated, while the HO-1 can protect the body through anti-oxidative stress. The study aimed to preliminarily explore the molecular mechanism by observing the effect of Sitagliptin on HO-1 expression in renal tissue of rats with diabetic nephropathy. METHODS: The diabetic nephropathy rat model was established by STZ injection followed by intraperitoneal injection of sitagliptin with different concentrations. The mRNA expressions of HO-1 were detected by real-time PCR and Western blot and HO-1 enzyme activity change was detected by colorimetry. Human renal mesangial cell (HRMC) were cultured in vitro with high glucose concentration (30 µmol/L), phosphatidylinositol-3-kinase (PI3K) level and nuclear factor erythroid-2-related factor (Nrf2) content in cytoplasm and cell nucleus were observed before and after treatment with sitagliptin, as well as the action of in meditating HO-1 expression. RESULTS: HO-1 mRNA, protein level, and HO-1 enzyme activity in renal tissue of rats with diabetic nephropathy were significantly increased after treatment with sitagliptin (P < 0.05). As comparison, the 24 h urinary microalbumin, creatinine, and boold urea nitrogen were all decreased after treatment of sitagliptin (P < 0.05). Similar results were observed after CoPP (an agonist of HO-1) treatment (P < 0.05). In contrast, ZnPP, an inhibitor of HO-1, significantly abrogated the inhibitory effect of sitagliptin (P < 0.05). Phosphorylation of PI3K and Nrf2 nuclear translocation under high-glucose concentration condition was induced by sitagliptin in HRMC. HO-1 expression was suppressed by pretreating HRMC with PI3K inhibitor or RNA interference. CONCLUSIONS: Sitagliptin may induce HO-1 expression via activation of PI3K and Nrf2 in rats with diabetic nephropathy; HO-1 can improve the oxidative stress of diabetic nephropathy, eventually protect from diabetic nephropathy.

Expression of VLDLR in the retina and evolution of subretinal neovascularization in the knockout mouse model's retinal angiomatous proliferation.

PURPOSE: Very-low-density lipoprotein receptor (VLDLR) in knockout mice (vldlr(-/-)) has been reported to induce subretinal neovascularization. Therefore, VLDLR expression in the wild-type mouse retina was investigated and the retinal angiogenic process in vldlr(-/-) mice was characterized. METHODS: VLDLR expression in the retina and in purified retinal vascular endothelial cells (RECs) and retinal pigment epithelial (RPE) cells was determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Angiogenic evolution in vldlr(-/-) mice was examined by fundus fluorescein angiography, histology, double-staining of FITC-dextran perfusion and elastin immunohistochemistry, isolectin staining, and confocal fluorescence microscopy. RESULTS: VLDLR mRNA was detected in the wild-type mouse retina and in purified RECs and RPE cells. The VLDLR protein was localized in the RPE layer, vessels in the ganglion cell layer, and around the outer limiting membrane of the retina. The retinal pathogenic process in vldlr(-/-) mice recapitulates key features of retinal angiomatous proliferation (RAP) in humans, a subtype of neovascular age-related macular degeneration (AMD). These include neovascular growth originating from retinal vessels and progressing to the subretinal space with intraretinal, subretinal, and choroidal angiogenic stages, RPE disruption and Bruch membrane exposure, retinal-choroidal anastomosis, subsequent photoreceptor degeneration, RPE hyperplasia, and subretinal fibrosis at the end stage. CONCLUSIONS: VLDLR is expressed in the wild-type mouse retina, especially in RECs and RPE cells. The vldlr(-/-) mouse exhibits histologic and angiographic characteristics of RAP and is a reproducible animal model facilitating studies of the molecular mechanisms of RAP.

High-Performance Lithium-Sulfur Batteries With an IPA/AC Modified Separator.

To inhibit the polysulfide-diffusion in lithium sulfur (Li-S) batteries and improve the electrochemical properties, the commercial polypropylene (PP) was decorated by an active carbon (AC) coating with lots of electronegative oxygenic functional group of -OH. Owing to the strong adsorption of AC and the electrostatic repulsion between the -OH and negatively charged polysulfide ions, the Li-S batteries demonstrated a high initial discharge capacity of 1,656 mAh g-1 (approximately 99% utilization of sulfur) and the capacity can still remain at 830 mAh g-1 after 100 cycles at 0.2 C. Moreover, when the rate was increased to 1 C, the batteries could also possess a discharge capacity of 1,143 mAh g-1. The encouraging cycling stability make clear that this facile approach can successfully restrain the shuttle effect of polysulfides and make further progress to the practical application of Li-S batteries.