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BACKGROUND: Diabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored. METHODS: Using hydrodynamic tail-vein injection, we overexpress Esm-1 in DKD-susceptible DBA/2 mice and delete Esm-1 in DKD-resistant C57BL/6 mice to study the contribution of Esm-1 to DKD. We analyze clinical indices of DKD, leukocyte infiltration, podocytopenia, and extracellular matrix production. We also study transcriptomic changes to assess potential mechanisms of Esm-1 in glomeruli. RESULTS: In DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. We show that overexpression of Esm-1 reduces albuminuria and diabetes-induced podocyte injury, independent of changes in leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice modestly increases the degree of diabetes-induced albuminuria versus wild-type controls. By glomerular RNAseq, we identify that Esm-1 attenuates expression of kidney disease–promoting and interferon (IFN)-related genes, including Ackr2 and Cxcl11. CONCLUSIONS: We demonstrate that, in DKD-susceptible mice, Esm-1 protects against diabetes-induced albuminuria and podocytopathy, possibly through select IFN signaling. Companion studies in patients with diabetes suggest a role of Esm-1 in human DKD.

BackgroundEsm-1, endothelial cell-specific molecule-1, is a susceptibility gene for diabetic kidney disease (DKD) and is a cytokine- and glucose-regulated, secreted proteoglycan, that is notably expressed in kidney and attenuates inflammation and albuminuria.Esm1has restricted expression at the vascular tip during development but little is known about its expression pattern in mature tissues, and its precise effects in diabetes.MethodsWe utilized publicly available single-cell RNA sequencing data to explore the characteristics ofEsm1expression in 27,786 renal endothelial cells obtained from four adult human and three mouse databases. We validated our findings using bulk transcriptome data from an additional 20 healthy subjects and 41 patients with DKD and using RNAscope. Using correlation matrices, we relate Esm1 expression to the glomerular transcriptome and evaluated these matrices with systemic over-expression of Esm-1.ResultsIn both mice and humans,Esm1is expressed in a subset of all renal endothelial cell types and represents a minority of glomerular endothelial cells. In patients,Esm1(+) cells exhibit a highly conserved enrichment for blood vessel development genes. With diabetes, these cells are fewer in number and profoundly shift expression to reflect chemotaxis pathways. Analysis of these gene sets highlight candidate genes such asIgfbp5for cross talk between cell types. We also find that diabetes induces correlations in the expression of large clusters of genes, within cell type-enriched transcripts.Esm1significantly correlates with a majority genes within these clusters, delineating a glomerular transcriptional polarization reflected by the magnitude ofEsm1deficiency. In diabetic mice, these gene clusters linkEsm1expression to albuminuria, and over-expression of Esm-1 reverses the expression pattern in many of these genes.ConclusionsA comprehensive analysis of single cell and bulk transcriptomes demonstrates that diabetes correlates with lowerEsm1expression and with changes in the functional characterization ofEsm1(+) cells.Esm1is both a marker for glomerular transcriptional polarization, and a mediator that re-orients the transcriptional program in DKD.

The occult pulmonary infection is the most common complications in elderly patients with type 2 diabetes mellitus (T2DM). Since its etiological characteristics has not been clarified, infection control remains a serious problem for public health. To investigate the prevalence and clinical significance of occult pulmonary infection in elderly T2DM patients, in this study, 573 elderly patients cochallenged with T2DM and community-acquired pulmonary infection from January 2018 to December 2020 were selected in the hospitals and divided into occult pneumonia group (OP, n = 249 ) and nonoccult pneumonia group (NOP, n = 324 ) according to the nature of infection. Clinical medical records were analyzed retrospectively to summarize the infection characteristics of elderly diabetics with occult pneumonia. The prevalence of the cases (278/324, 85.8%) in NOP group was not higher than that in OP group (206/249, 82.7%; P > 0.05 ). Also, there was not significant difference in the distribution of isolated pathogens among the positive patients. The length of hospitalization and mortality of OP patients were significantly higher than those NOP patients. Multivariate logistic regression showed that advanced age, comorbidities, hypothyroidism, senile dementia, and prolonged bed rest were independent risk factors for occult pneumonia in elderly diabetic patients. Therefore, the results demonstrated that the pulmonary infection in elderly patients with diabetes mellitus is often occult. Gram-negative bacteria are the predominant pathogens and cause poor prognosis. Advanced age, comorbidities (senile dementia, hypothyroidism), and prolonged bed rest are the independent risk factors for occult pneumonia.

The macro- and microphysical properties of clouds can reflect their vertical physical structure and evolution and are important indications of the formation and development of precipitation. We used four-year merged CloudSat-CALIPSO-MODIS products to distinguish the macro- and microphysical properties of precipitating and non-precipitating clouds over central-eastern China during the warm season (May–September). Our results showed that the clouds were dominated by single- and double-layer forms with occurrence frequencies > 85%. Clouds with a low probability of precipitation (POP) were usually geometrically thin. The POP showed an increasing trend with increases in the cloud optical depth, liquid water path, and ice water path, reaching maxima of 50%, 60%, and 75%, respectively. However, as cloud effective radius (CER) increased, the POP changed from an increasing to a decreasing trend for a CER > 22 μm, in contrast with our perception that large particles fall more easily against updrafts, but this shift can be attributed to the transition of the cloud phase from mixed clouds to ice clouds. A high POP > 60% usually occurred in mixed clouds with vigorous ice-phase processes. There were clear differences in the microphysical properties of non-precipitating and precipitating clouds. In contrast with the vertical evolution of non-precipitating clouds with weaker reflectivity, precipitating clouds were present above 0 dBZ with a significant downward increase in reflectivity, suggesting inherent differences in cloud dynamical and microphysical processes. Our findings highlight the differences in the POP of warm and mixed clouds, suggesting that the low frequency of precipitation from water clouds should be the focus of future studies.

The degradation of extracellular matrix (ECM) to increase drug permeability is an attractive approach to enhancing pancreatic cancer therapy efficiency. Herein, polypyrrole nanoparticles (PPy NPs) were prepared by a template-guided chemical oxidation method. These PPy NPs with abundant surface pores were used to load the anticancer drug doxorubicin (DOX). In order to intelligently control the DOX release, PPy/DOX NPs were further entrapped with a thermoresponsive ligand, lauric acid (LA), to form PPy-LA/DOX NPs. Bromelain (BL) was then grafted onto the surface of PPy-LA NPs or PPy-LA/DOX NPs through an amidation reaction with the carboxyl group of LA. It was found that the DOX release of PPy-LA/DOX NPs was pH and temperature responsive, reaching a maximum amount of 85.9% within 48 h at pH = 5.4 and 50 °C. Moreover, it was demonstrated that the resultant PLB (PPy-LA-BL) NPs could efficiently hydrolyze the collagen in ECM and enhance the permeability of DOX to the pancreatic tumor. Remarkably, PLB NPs not only featured admirable photothermal conversion but also exhibited obvious photoacoustic imaging capability, which enabled imaging-guided enhanced tumor ablation. This study is anticipated to provide a feasible strategy to improve the permeability of nanoparticles to tumors.

In this work, ultralow dielectric constant (ultralow-k) polysulfone (PSF) composites were prepared by adding hollow glass beads (HGB) modified with 1,3-divinyltetramethyldisiloxane (DVTM). The results indicated that the surface modification of HGB (m-HGB) effectively enhanced the interfacial compatibility between the inorganic fillers and PSF matrix. DSC and TGA measurements of the composite films were performed under a nitrogen atmosphere, and the results showed that the composite films possess high glass transition temperatures varying from 187 °C to 190 °C, and are thermally stable␣up to 445 °C. The mechanical properties of composite films with modified HGB fillers show a certain drop, but the values were still higher than 32 MPa. Furthermore, the obtained composite films show low dielectric constant, low dielectric loss, good permittivity-frequency stability and dielectric-temperature stability under 190 °C. Therefore, we shown an effective path to prepare composites with ultralow dielectric constant for use in high temperature resistant ultra large scale integration (ULSI) flexible insulation substrate field.

Background: Therapeutic cancer vaccines are designed to program a patient’s own immune system to recognize and eliminate tumor cells. We sought to harness gene-modified tumor cells as a vaccine platform and developed cancer vaccines composed of breast cancer cells expressing GM-CSF (SV-BR-1-GM). We have recently reported favorable clinical outcomes in patient populations that match SV-BR-1-GM at one or more HLA alleles. Mechanistically, SV-BR-1-GM cells can directly activate CD4+ T-cells in an antigen-specific HLA-restricted manner, as demonstrated by an in vitro antigen presentation assay (1). All these observations led us to hypothesize that semi-allogeneic cell-based cancer vaccines (partially matching host HLA genotype) would mount an enhanced immune response by forcing the host immune response to recognize tumor-associated antigens in the context of allogeneic HLA-I or II molecules or in proximity of strong non-self-antigens. Therefore, steps were taken to generate semi-allogeneic cancer cell lines expressing an extended repertoire of stimulatory molecules to induce optimal immune activation (Bria-OTS). Methods: SV-BR-1 (Breast cancer), PC-3 (prostate cancer), SK-MEL-24 (Melanoma), and NCI-H2228 (Lung cancer) were selected for vaccine development. To generate semi-allogeneic cell lines matching >99% of the population at least at 1 HLA allele, four cell lines (for each parental tumor cell line) were developed, each carrying two (2) HLA-A and two (2) HLA-DRB3/4/5 alleles, for a total of eight HLA-A and seven HLA-DRB3/4/5 alleles. We transduced selected co-stimulatory molecules and immune-modulatory cytokines. Next, the unique combinations of HLA-A and HLA-DRB3/4/5 alleles were transduced into the cells using lentiviral based vectors. Finally, functionality of the engineered cells was validated by using molecular and cellular based assays. Preliminary data: Four cell lines (for each tumor type) that secreted GM-CSF, IFNα, IL12, IL7 and expressed CD80, CD86, 4-1BBL, and different combinations of both Class I and Class II HLA alleles were selected. Using cell-based assays - including mixed lymphocyte reaction assays -, we demonstrated that the generated cells stimulate naïve T-cells. Evaluation of the cells ability to present antigens in an HLA-restricted antigen-specific manner is also planned. Discussion and conclusions: Different types of cancer vaccines have been developed with moderate success, often hampered by lack of strong immunogenicity and complex manufacturing. BriaCell’s Bria OTS provides a solution by increasing vaccine immunogenicity and decreasing manufacturing costs while personalizing the therapy based on matching the patient’s HLA type.1.Lacher MD et al, Front Immunol. 2018 May 15;9:776 Citation Format: Miguel A. Lopez-Lago, Vikas Bhardwaj, Xiaoyi Zheng, Sagarika pachhal, Renee Cortez, Charles Wiseman, William Williams. Engineering semi-allogeneic whole cancer vaccines with enhanced immunogenicity for the treatment of advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 685.

A series of novel cross-linkable PSF-6AF/DBA copolymers with different structure were successfully synthesized via nucleophilic aromatic substitution stepwise polymerization of 4,4′-dichlorodiphenyl sulfone (DCS) with hexafluorobisphenol A (6AF) and 4,4′-(propane-2,2-diyl)bis(2-allylphenol) (DBA) monomer. The 6AF and DBA moieties with a large number of pendant groups had been successfully introduced into the PSF polymer chain. Then, the PSF-6AF/DBA films were fabricated by casting the PSF-6AF/DBA/DMF solutions with the concentration of 10% on the clean glass plates, followed by heat-treating all the films at 300 °C for 4 h. The effects of both the component and cross-linking on the thermal, mechanical and dielectric properties of the obtained films were investigated in detail. Compared to PSF-6AF/DBA films, the cross-linked PSF-6AF/DBA (CS-PSF-6AF/DBA) films show high glass transition temperature (Tg= 184–197 °C) and outstanding mechanical strength (64–77 MPa). More importantly, all CS-PSF-6AF/DBA films display stable dielectric properties in the temperature range of 20–200 °C. The permittivity of CS-PSE-6AF/DBA film at 1 kHz is as low as 2.1, while the dielectric loss is only 0.007.

In this work, the encapsulated barium titanate (BT) (C-PEN@BT) nanoparticles were successfully prepared via rotary coating technology combined with a post-treatment chemical bonding process, by using carboxyl-functionalized poly(arylene ether nitrile) (C-PEN) as modification agent. The TEM, FTIR and TGA results confirmed that the polymer layer (about 8 nm) has been uniformly surrounded on the surface of BT nanoparticles. Then, a facilitated physical dispersion technology was employed to prepare C-PEN@BT filled composite films using crystalline PEN as matrix and 4,4′-bis(3,4-dicyanophenoxy)biphenyl (BPH) as a novel cross-linking agent. The effects of both the surface modification of BT nanoparticles and matrix cross-linking on the mechanical, thermal and dielectric properties of PEN-based composites were investigated in detail. Compared with PEN-I film, the latter results showed that the strong interface interactions exerted between polymer matrix and CPEN layer on BT surface, especially the formation of cross-linking network across the PEN matrix, resulted in increased tensile strength and Young’ modulus by 29% and 32%, respectively. More importantly, the PEN/C-PEN@BT composite film shows stable dielectric properties in the temperature range of 20–204 °C, which is very close to the glass transition temperature.

Composite materials applied to capacitors with high dielectric constant, low dielectric loss and outstanding thermal stability are concerned widely in the field of dielectrics. So committed to the development of dielectric materials with excellent performance is the key factor. In this work, the barium titanate/polyether sulfone (BaTiO3/PES) composite films were prepared by a physical dispersion technology, which utilized a ball milling machine by high-speed circulation, scattered the PES solution contained BaTiO3 in deionized water with the aid of a surfactant. Then, the BaTiO3/PES composite films were obtained through a series of operations, containing reclaimed organic solvent, washed with deionized water, filtered, dried and hot pressed. The morphology of the BaTiO3/PES emulsion was investigated by TEM and SEM. The results showed that the BaTiO3 particles were covered in the PES resin matrix homogeneously. For 50 wt% BaTiO3 reinforced PES composite film. The dielectric constant increased by ~ 227% compared with pure PES resin (4.1 at 1 kHz) and the dielectric loss maintained around 10−2 magnitude, which performed better dielectric properties. The tensile strength of 10 wt% BaTiO3/PES composite films (72 MPa) reached the highest value in comparison with those of pure PES (58 MPa) due to the strengthened interaction between particles and matrix. Further increase of BaTiO3 content, the tensile strength and elongation at break decreased slightly but remained an excellent flexibility from the PES matrix. The temperature at weight loss 5% (T5%) of composite film with 40 wt% of BaTiO3 content reached up to 503 °C in N2 atmosphere. All the BaTiO3/PES composite films performed the concentrated glass transition temperature (Tg) around 229 °C. In sum, excellent thermal stability and dielectric properties would make the BaTiO3/PES composite films become the fine potential candidates for dielectric composites in the capacitors.

Plasmonic heterojunction photocatalysts consisting of silver covered AgBr/BiVO4 structures (Ag@AgBr/BiVO4) were prepared by hydrothermal-photoreduction method. Their phase composition and microstructure were characterized by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron and transmission electron microscopies. The photo-generated electron–hole pair recombination rate was characterized by I–t curves and photoluminescence measurements. Visible light absorption range of Ag@AgBr/BiVO4 plasmonic heterojunction was significantly enhanced. Ag@AgBr/BiVO4 showed high efficiency for degradation of rhodamine B (RhB) under wLED light. RhB degraded by ~ 82% during 150 min reaction time. Ag@AgBr/BiVO4 photocatalyst remained constant after 8 cycles indicating its extreme stability. Enhancement mechanism of Ag@AgBr/BiVO4 plasmonic heterojunction photocatalyst is discussed.

To develop high performance of polymer-based composites, the dispersion state and interfacial interaction of nano-fillers are two key issues to be considered. Herein, we report the surface decoration of basalt fibers (BF) with nano-sized barium titanate (BT) particles and their dielectric application in poly(ether sulfone)-based composite laminates (PBCLs) was investigated in detail. Firstly, the nano-sized BT particles uniformly deposited along the BF surface through a simple and effective solvothermal method, as confirmed by SEM and XRD measurement. Then, novel ternary dielectric polymer-based composite laminates, consisting of BT particles decorated BF and poly(ether sulfone) (BT–BF/PES), were fabricated by hot-pressing method. Compared to raw BF filled PBCLs, the SEM images of BT–BF fibers reinforced PBCLs showed that all the BT–BF fibers strongly adhere to the PES matrix, and obscure fiber/PES interfaces are present without visible boundaries, indicating a improved interfacial interactions in this case. Thus, the mechanical, thermal and dielectric properties of the resultant PBCLs were characterized and results indicated that the BF and BT particles show enhanced synergistic effects. Following this strategy, the flexural strength and dielectric constant of BT–BF/PES blend with 40 wt% of BT were increased by 28 and 350%, respectively, in comparison with those of BF/PES composite laminates.

Excessive alcohol consumption causes liver injury–induced mortality. Here we systematically analyzed the structure of triterpenoids extracted from Antrodia cinnamomea mycelia (ACT) and investigated their protective effects against acute alcohol-induced liver injury in mice. Liquid chromatography–mass spectrometry and liquid chromatography with tandem mass spectrometry were performed to determine the structures of ACT constituents. Alcohol-induced liver injury was generated in C57BL/6 mice by oral gavage of 13 g/kg white spirit (a wine at 56% ABV). Mice were treated with either silibinin or ACT for 2 weeks. Liver injury markers and pathological signaling were then quantified with enzyme-linked immunosorbent assays, antibody array assays, and Western blots, and pathological examinations were performed using hematoxylin-eosin staining and periodic acid–Schiff staining. Triterpenoids extracted from A. cinnamomea mycelia contain 25 types of triterpenoid compounds. A 2-weeks alcohol consumption treatment caused significant weight loss, liver dyslipidemia, and elevation of alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, and alkaline phosphatase activities in the serum and/or liver. These effects were markedly reversed after 2-weeks ACT administration. Triterpenoids extracted from A. cinnamomea mycelia alleviated the organ structural changes and inflammatory infiltration of alcohol-damaged tissues. Triterpenoids extracted from A. cinnamomea mycelia inhibited proinflammatory cytokine levels and enhanced anti-inflammatory cytokine levels. Acute alcohol treatment promoted inflammation with significant correlations to hypoxia-inducible factor 1α (HIF-1α), which was reduced by ACT and was partially related to modulation of the protein kinase B (Akt)/70-kDa ribosomal protein S6 kinase phosphorylation (p70S6K) and Wnt/β-catenin signaling pathways. In conclusion, ACT protected against acute alcohol-induced liver damage in mice mainly through its suppression of the inflammatory response, which may be related to HIF-1α signaling.

The present study aimed to evaluate the antimicrobial activity and the possible mechanisms of activity of polypeptide‑enriched Gastrodia elata extracts (GEP) against the gram‑negative bacteria Escherichia coli and Pseudomonas aeruginosa, the gram‑positive bacterium Staphylococcus aureus and the fungus Candida albicans. The antimicrobial activity of GEP was first confirmed by determining the minimum inhibitory concentration by growth curve analysis. GEP was found to damage the cell wall and membrane of the microorganisms tested, as revealed by the morphological changes visible through scanning electron microscopy, and by the observed leakage of alkaline phosphatase and β‑galactosidase from cells. GEP was demonstrated to perturb the metabolism of the microorganisms, especially the tricarboxylic acid cycle, as indicated by the reduced intracellular activity of succinate dehydrogenase, malate dehydrogenase and ATPases, including the Na+/K+‑ATPase and the Ca2+‑ATPase. In addition, GEP caused the leakage of the genetic material of the bacteria and the fungus, as indicated by the increased OD260. The results of the present study indicated that GEP may exert its antimicrobial activity by damaging cell walls and membranes, causing the leakage of genetic material, and by perturbing cellular metabolism.

Regional heavy pollution events in eastern China (110–122° E, 28–40° N) are causing serious environmental problems. In this study, the relationship between the degree of regional pollution and the patterns of large-scale atmospheric circulation over eastern China in October is investigated using 10-year (2001–2010) Terra/MODIS aerosol optical depth and NCEP reanalysis data by both case study and composite analysis. Eighteen polluted and 10 clean episodes are selected and categorised into six polluted types and three clean types respectively. Generally speaking, weather patterns such as a uniform surface pressure field in eastern China or a steady straight westerly in the middle troposphere, particularly when being at the rear of the anticyclone at 850 hPa, are typically responsible for heavy pollution events. Meanwhile, clean episodes occur when strong southeastward cold air advection prevails below the middle troposphere or air masses are transported from sea to land. Uniform descending motion prevails over the study region, trapping pollutants in the lower atmosphere. Therefore, the value of vertical velocity averaged from 1000 to 100 hPa and divergence of wind field in the lower troposphere are used in this study to quantify the diffusion conditions in each circulation type. The results reveal that it is often a clean episode when both the mean downward motion (larger than 2.56 × 10−2 Pa s−1) and the divergence of low-level winds (larger than 1.79 × 10−2 s−1) are strong. Otherwise, it is more likely to be a polluted episode.

In this report, flexible cross-linked polyarylene ether nitrile/functionalized barium titanate(CPEN/F-BaTiO3) dielectrics films with high permittivitywere prepared and characterized. The effects of both the F-BaTiO3 and matrix curing on the mechanical, thermal and dielectric properties of the CPEN/F-BaTiO3 dielectric films were investigated in detail. Compared to pristine BaTiO3, the surface modified BaTiO3 particles effectively improved their dispersibility and interfacial adhesion in the polymer matrix. Moreover, the introduction of F-BaTiO3 particles enhanced dielectric properties of the composites, with a relatively high permittivity of 15.2 and a quite low loss tangent of 0.022 (1 kHz) when particle contents of 40 wt % were utilized. In addition, the cyano (–CN) groups of functional layer also can serve as potential sites for cross-linking with polyarylene ether nitrile terminated phthalonitrile (PEN-Ph) matrix and make it transform from thermoplastic to thermosetting. Comparing with the pure PEN-ph film, the latter results indicated that the formation of cross-linked network in the polymer-based system resulted in increased tensile strength by ~67%, improved glass transition temperature (Tg) by ~190 °C. More importantly, the CPEN/F-BaTiO3 composite films filled with 30 wt % F-BaTiO3 particles showed greater energy density by nearly 190% when compared to pure CPEN film. These findings enable broader applications of PEN-based composites in high-performance electronics and energy storage devices materials used at high temperature.

Diabetic nephropathy (DN) is the leading cause of kidney disease; however, there are no early biomarkers and no cure. Thus, there is a large unmet need to predict which individuals will develop nephropathy and to understand the molecular mechanisms that govern this susceptibility. We compared the glomerular transcriptome from mice with distinct susceptibilities to DN at four weeks after induction of diabetes, but before histologic injury, and identified differential regulation of genes that modulate inflammation. From these genes, we identified endothelial cell specific molecule-1 (Esm-1), as a glomerular-enriched determinant of resistance to DN. Glomerular Esm-1 mRNA and protein were lower in DN-susceptible, DBA/2, compared to DN-resistant, C57BL/6, mice. We demonstrated higher Esm-1 secretion from primary glomerular cultures of diabetic mice, and high glucose was sufficient to increase Esm-1 mRNA and protein secretion in both strains of mice. However, induction was significantly attenuated in DN-susceptible mice. Urine Esm-1 was also significantly higher only in DN-resistant mice. Moreover, using intravital microscopy and a biomimetic microfluidic assay, we showed that Esm-1 inhibited rolling and transmigration in a dose-dependent manner. For the first time we have uncovered glomerular-derived Esm-1 as a potential non-invasive biomarker of DN. Esm-1 inversely correlates with disease susceptibility and inhibits leukocyte infiltration, a critical factor in protecting the kidney from DN.

BMP, activin, membrane-bound inhibitor (BAMBI) acts as a pseudo-receptor for the transforming growth factor (TGF)-β type I receptor family and a negative modulator of TGF-β kinase signaling, and BAMBI(-/-) mice show mild endothelial dysfunction. Because diabetic glomerular disease is associated with TGF-β overexpression and microvascular alterations, we examined the effect of diabetes on glomerular BAMBI mRNA levels. In isolated glomeruli from biopsies of patients with diabetic nephropathy and in glomeruli from mice with type 2 diabetes, BAMBI was downregulated. We then examined the effects of BAMBI deletion on streptozotocin-induced diabetic glomerulopathy in mice. BAMBI(-/-) mice developed more albuminuria, with a widening of foot processes, than BAMBI(+/+) mice, along with increased activation of alternative TGF-β pathways such as extracellular signal-related kinase (ERK)1/2 and Smad1/5 in glomeruli and cortices of BAMBI(-/-) mice. Vegfr2 and Angpt1, genes controlling glomerular endothelial stability, were downmodulated in glomeruli from BAMBI(-/-) mice with diabetes. Incubation of glomeruli from nondiabetic BAMBI(+/+) or BAMBI(-/-) mice with TGF-β resulted in the downregulation of Vegfr2 and Angpt1, effects that were more pronounced in BAMBI(-/-) mice and were prevented by a MEK inhibitor. The downregulation of Vegfr2 in diabetes was localized to glomerular endothelial cells using a histone yellow reporter under the Vegfr2 promoter. Thus, BAMBI modulates the effects of diabetes on glomerular permselectivity in association with altered ERK1/2 and Smad1/5 signaling. Future therapeutic interventions with inhibitors of alternative TGF-β signaling may therefore be of interest in diabetic nephropathy.

Cordyceps militarishas long been used as a crude drug and folk tonic food in East Asia. The present study aims to evaluate the antidiabetic and antinephritic effects of the aqueous extract of theCordyceps militarisfruit body (CM) in diet-streptozotocin- (STZ-) induced diabetic rats. During four weeks of continuous oral administration of CM at doses of 0.5, 1.0, and 2.0 g/kg and metformin at 100 mg/kg, the fasting blood glucose and bodyweight of each rat were monitored. Hypoglycemic effects of CM on diabetic rats were indicated by decreases in plasma glucose, food and water intake, and urine output. The hypolipidemic activity of CM was confirmed by the normalization of total cholesterol, triglycerides, and low- and high-density lipoprotein cholesterol in diabetic rats. Inhibitory effects on albuminuria, creatinine, urea nitrogen, and n-acetyl-β-d-glucosaminidase verified CM’s renal protective activity in diabetic rats. Furthermore, CM exerted beneficial modulation of inflammatory factors and oxidative enzymes. Compared with untreated diabetic rats, CM decreased the expression of phosphor-AKT and phosphor-GSK-3βin the kidneys. Altogether, via attenuating oxidative stress, CM displayed antidiabetic and antinephritic activities in diet-STZ-induced diabetic rats.

Jia-Yuan-Qing pill (JYQP) composed of Porcellio laevis Latreille, Corydalis Rhizoma and Radix Cynanchi Paniculati at a ratio of 9:7:7 has been found to be an effective analgesic agent. The present study aimed to evaluate the safety, addictive potential and anti-cancer pain activity of JYQP in a rat model. During the 6-month chronic toxicity test, no significant changes in general behavior, defecation, postural abnormalities, dietary or water intake or blood biochemical parameters were observed in male and female rats. Although a high dose of JYQP (5 g/kg) caused swelling of the liver, spleen and kidney in male and female rats, no pathological changes were observed in all organs examined via hematoxylin and eosin staining. The analgesic effect of JYQP on bone cancer pain was successfully confirmed in a rat model of Walker 256 cell-induced bone cancer. In contrast to morphine, in a physical dependence test, JYQP produced no withdrawal symptoms following chronic administration. The data from this study provide experimental evidence supporting the clinical use of JYQP as an effective, safe and non-addictive agent for the treatment of bone cancer pain.