Targeting of G protein-coupled receptor 39 alleviates angiotensin II-induced renal damage by reducing ribonucleotide reductase M2.

Renal fibrosis, apoptosis and autophagy are the main pathological manifestations of angiotensin II (Ang II)-induced renal injury. G protein-coupled receptor 39 (GPR39) is highly expressed in various tissues including the kidney, but its role in the kidney is entirely unclear. This study was performed to investigate the underlying mechanism by which knockdown of GPR39 alleviated Ang II-induced renal injury. In vivo, GPR39 knockout (KO) mice were constructed and infused with Ang II for 4 weeks, followed by renal function tests. In vitro, Ang II-induced cells were treated with si-GPR39 for 48 h. Fibrosis, apoptosis and autophagy were detected in both cells and mice. The underlying mechanism was sought by mRNA transcriptome sequencing and validated in vitro. GPR39 was upregulated in renal tissues of mice with Ang II-mediated renal injury. Knockdown of GPR39 ameliorated renal fibrosis, apoptosis, and autophagy, and decreased the expression of ribonucleotide reductase M2 (RRM2). In vitro, knockdown of GPR39 was also identified to improve the Ang II-induced cell fibrosis, apoptosis, and autophagy. mRNA transcriptome results showed that knockout of GPR39 reduced the expression of RRM2 in Ang II-induced kidney tissue. Activation of RRM2 could reverse the therapeutic effect of GPR39 knockout, and the inhibitor of RRM2 could improve the cell fibrosis, apoptosis and autophagy caused by GPR39 agonist. These results indicated that targeting of GPR39 could alleviate Ang II-induced renal fibrosis, apoptosis, and autophagy via reduction of RRM2 expression, and GPR39 may serve as a potential target for Ang II-induced renal injury.

The potential for synthesized invasive plant biochar with hydroxyapatite to mitigate allelopathy of Solidago canadensis.

Few studies tried to explore the mitigation effect and underlying mechanisms of biochar and their complex for negative allelopathy from invasive plants, which may provide a new way in the invasive plant management. Herein, an invasive plant (Solidago canadensis)-derived biochar (IBC) and its composite with hydroxyapatite (HAP/IBC) were synthesized by high temperature pyrolysis, and characterized by scanning electron microscopy, energy dispersion spectrometer, X-ray diffraction, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. Then, both the batch adsorption and pot experiments were conducted to compare the removal effects of kaempferol-3-O-ß-D-glucoside (C21 H20 O11 , kaempf), an allelochemical from S. canadensis, on IBC and HAP/IBC, respectively. HAP/IBC showed a stronger affinity for kaempf than IBC due to its higher specific surface area, more functional groups (P-O, P-O-P, PO4 3- ), stronger crystallization [Ca3 (PO4 )2 ]. The maximum kaempf adsorption capacity on HAP/IBC was six times higher than on IBC (10.482 mg/g > 1.709 mg/g) via π-π interactions, functional groups, and metal complexation. The kaempf adsorption process could be fitted best by both pseudo-second-order kinetic and Langmuir isotherm models. Furthermore, HAP/IBC addition into soils could enhance and even recover the germination rate and/or seedling growth of tomato inhibited by negative allelopathy from the invasive S. canadensis. These results indicate that the composite of HAP/IBC could more effectively mitigate the allelopathy from S. canadensis than IBC, which may be a potential efficient approach to control the invasive plant and improve invaded soils.

Plasma Epstein-Barr virus DNA and risk of nasopharyngeal carcinoma in a prospective seropositive population.

OBJECTIVE: Plasma Epstein-Barr virus (EBV) DNA is considered a biomarker for nasopharyngeal carcinoma (NPC). However, its long-term role in NPC development is unclear. MATERIALS AND METHODS: A total of 1363 participants seropositive for EBV VCA-IgA and EBNA1-IgA in a community-based NPC screening program in southern China were tested for plasma EBV DNA levels by real-time qPCR between 2008 and 2015. New NPC cases were confirmed by active follow-up approach and linkage to local cancer registry through the end of 2016. Cox proportional hazards regression analysis was performed to calculate the hazard ratios (HRs) for NPC risk with plasma EBV DNA. RESULTS: Thirty patients were newly diagnosed during a median 7.5 years follow-up. NPC incidence increased with the plasma EBV DNA load ranging from 281.46 to 10,074.47 per 100,000 person-years in participants with undetectable and ≥ 1000 copies/ml levels; the corresponding cumulative incidence rates were 1.73 and 50%. Furthermore, plasma EBV DNA loads conferred an independent risk for NPC development after adjustment for other risk factors, with HRs of 7.63 for > 3-999 copies/ml and 39.79 for ≥1000 copies/ml. However, the HRs decreased gradually after excluding NPC cases detected in the first 2 to 3 years and became statistically nonsignificant by excluding cases detected during the first 4 years. CONCLUSION: Elevated plasma EBV DNA can predict NPC risk over 3 years. Monitoring plasma EBV DNA can be used as a complementary approach to EBV serological antibody-based screening for NPC.

High-Resolution U-Net: Preserving Image Details for Cultivated Land Extraction.

Accurate and efficient extraction of cultivated land data is of great significance for agricultural resource monitoring and national food security. Deep-learning-based classification of remote-sensing images overcomes the two difficulties of traditional learning methods (e.g., support vector machine (SVM), K-nearest neighbors (KNN), and random forest (RF)) when extracting the cultivated land: (1) the limited performance when extracting the same land-cover type with the high intra-class spectral variation, such as cultivated land with both vegetation and non-vegetation cover, and (2) the limited generalization ability for handling a large dataset to apply the model to different locations. However, the "pooling" process in most deep convolutional networks, which attempts to enlarge the sensing field of the kernel by involving the upscale process, leads to significant detail loss in the output, including the edges, gradients, and image texture details. To solve this problem, in this study we proposed a new end-to-end extraction algorithm, a high-resolution U-Net (HRU-Net), to preserve the image details by improving the skip connection structure and the loss function of the original U-Net. The proposed HRU-Net was tested in Xinjiang Province, China to extract the cultivated land from Landsat Thematic Mapper (TM) images. The result showed that the HRU-Net achieved better performance (Acc: 92.81%; kappa: 0.81; F1-score: 0.90) than the U-Net++ (Acc: 91.74%; kappa: 0.79; F1-score: 0.89), the original U-Net (Acc: 89.83%; kappa: 0.74; F1-score: 0.86), and the Random Forest model (Acc: 76.13%; kappa: 0.48; F1-score: 0.69). The robustness of the proposed model for the intra-class spectral variation and the accuracy of the edge details were also compared, and this showed that the HRU-Net obtained more accurate edge details and had less influence from the intra-class spectral variation. The model proposed in this study can be further applied to other land cover types that have more spectral diversity and require more details of extraction.

NLRP3 inflammasome: A likely target for the treatment of allergic diseases.

Allergic diseases, such as asthma, rhinitis, dermatitis, conjunctivitis, and anaphylaxis, have recently become a global public health concern. According to previous studies, the NLRP3 inflammasome is a multi-protein complex known to be associated with many inflammatory conditions. In response to allergens or allergen/damage-associated molecular signals, NLRP3 changes its conformation to allow the assembly of the NLRP3 inflammasome complex and activates caspase-1, which is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines IL-1ß and IL-18. Subsequently, active caspase-1 cleaves pro-IL-1 and pro-IL-18. Recently, accumulating human and mouse experimental evidence has demonstrated that the NLRP3 inflammasome, IL-1ß, and IL-18 are critically involved in the development of allergic diseases. Furthermore, the application of specific NLRP3 inflammasome inhibitors has been demonstrated in animal models. Therefore, these inhibitors may represent potential therapeutic methods for the management of clinical allergic disorders. This review summarizes findings related to the NLRP3 inflammasome and its related factors and concludes that specific NLRP3 inflammasome inhibitors may be potential therapeutic agents for allergic diseases.

An overview of the treatments for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a very prevalent inherited disease with a wide global distribution and a prevalence rate of approximately 0.2% in the general population. Left ventricular hypertrophy (LVH) caused by sarcomere mutation is the primary reason of HCM. The histopathology feature is that cardiomyocyte hypertrophy, myocyte disorder and myocardial fibrosis lead to diminished diastolic function, left ventricular outflow tract obstruction (LVOTO) and arrhythmia, all of which result in serious cardiac complications. Previously, HCM was considered a malignant disease that was almost untreatable. With the improvement of medical standards and increasing awareness of HCM, it has become a highly treatable disease in contemporary times, with a significant decrease in mortality rates. However, there are still significant unmet requirements in the therapy of HCM. This paper draws on more than 100 references from the past four decades and summarizes current advances in the treatment of HCM. The article will review the pathogenesis and types, recent development in pharmacotherapy, invasive treatments and gene therapies, as well as dilemma and future development of HCM.

A new recombinant pituitary adenylate cyclase-activating peptide-derived peptide efficiently promotes glucose uptake and glucose-dependent insulin secretion.

The recombinant peptide, DBAYL, a promising therapeutic peptide for type 2 diabetes, is a new, potent, and highly selective agonist for VPAC2 generated through site-directed mutagenesis based on sequence alignments of pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), and related analogs. The recombinant DBAYL was used to evaluate its effect and mechanism in blood glucose metabolism and utilization. As much as 28.9 mg recombinant DBAYL peptide with purity over 98% can be obtained from 1 l of Luria-Bertani medium culture by the method established in this study and the prepared DBAYL with four mutations (N10Q, V18L, N29Q, and M added to the N-terminal) were much more stable than BAY55-9837. The half-life of recombinant DBAYL was about 25 folds compared with that of BAY55-9837 in vitro. The bioactivity assay of DBAYL showed that it displaced [(125)I]PACAP38 and [(125)I]VIP from VPAC2 with a half-maximal inhibitory concentration of 48.4 ± 6.9 and 47.1 ± 4.9 nM, respectively, which were significantly lower than that of BAY55-9837, one established VPAC2 agonists. DBAYL enhances the cAMP accumulation in CHO cells expressing human VPAC2 with a half-maximal stimulatory concentration (EC(50)) of 0.68 nM, whereas the receptor potency of DBAYL at human VPAC1 (EC(50) of 737 nM) was only 1/1083 of that at human VPAC2, and DBAYL had no activity toward human PAC1 receptor. Western blot analysis of the key proteins of insulin receptor signaling pathway: insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT4) indicated that the DBAYL could significantly induce the insulin-stimulated IRS-1 and GLUT4 expression more efficiently than BAY55-9837 and VIP in adipocytes. Compared with BAY55-9837 and PACAP38, the recombinant peptide DBAYL can more efficiently promote insulin release and decrease plasma glucose level in Institute of Cancer Research (ICR) mice. These results suggested that DBAYL could efficiently improve glucose uptake and glucose-dependent insulin secretion by VPAC2-mediated effect.

A New Recombinant PACAP-Derived Peptide Efficiently Promotes Corneal Wound Repairing and Lacrimal Secretion.

PURPOSE: A new recombinant pituitary adenylate cyclase-activating polypeptide (PACAP)-derived peptide, MPAPO, which has higher stability and PAC1-specific potency, was generated. The actions of MPAPO on corneal wound repairing and lacrimal secretion were examined. METHODS: MPAPO was prepared and identified by gene recombination, high-performance liquid chromatography (HPLC), and electrospray ionization mass spectrometry (ESI-MS). Stability assay was performed by HPLC-ESI-MS. PAC1-specific binding and potency assays were performed using PAC1-CHO cells. C57BL/6 mice and Japanese white rabbits were respectively used to analyze the effects of MPAPO on corneal wound repairing and lacrimal fluid secretion. Tetrazolium-based colorimetric assay (MTT), immunofluorescence, gene microarrays, and Western blot assay were performed to measure the effects of MPAPO on corneal epithelial cell proliferation, synapse growth, and gene differential expression of trigeminal ganglion cells. RESULTS: As compared with the wild PACAP, the in vitro stability and PAC1-specific potency of MPAPO with four mutations (M17L, L27K and M, K, respectively, added to the N- and C-terminus) were increased approximately 31- and 2-fold, respectively. MPAPO can significantly promote the proliferation of mouse corneal epithelium cells and the synapse growth of trigeminal ganglion cells. In experimental animals, MPAPO performed a complete corneal epithelial wound closure in 30 hours and significantly inhibited corneal neovascularization, and the effects were obviously stronger than for wild PACAP and recombinant bovine (rb)-bFGF (an anti-corneal wound drug). Furthermore, MPAPO can increase the lacrimal secretion, which may efficiently improve dry eye. CONCLUSIONS: MPAPO may represent a promising external therapeutic peptide for corneal wound repairing or dry eye.

Fumonisins production by Fusarium proliferatum strains isolated from asparagus crown.

The present work deals with the capability for producing fumonisin by Fusarium proliferatum strains isolated from asparagus in China. Fifty of F. proliferatum strains were randomly selected and incubated on cultures of maize grain and asparagus spear, respectively. Fumonisin levels (FB(1) and FB(2)) were determined by high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). The results showed that all 50 strains produced fumonisins in maize culture within a wide range of concentrations, 10-11,499 microg/g and 2-6,598 microg/g for FB(1) and FB(2), respectively. On culture of asparagus spear,48 strains (96%) produced fumonisins in the range 0.2-781.6 microg/g and no detected to 40.3 microg/g for FB(1) and FB(2), respectively. All of F. proliferatum strains produced much higher levels of FB(1), FB(2) and total fumonisins (FB(1 )+ FB(2)) in maize grain culture than in asparagus spear culture. Meanwhile, fumonisin B(3) (FB(3)) was identified in all maize culture extracts and most of asparagus spear culture extracts. This is the first study carried out the fumonisin-producing ability of F. proliferatum strains isolated from asparagus in China. The information obtained is useful for assessing the risk of fumonisins contamination in asparagus spear.

Occurrence of fumonisins B1 and B2 in asparagus from Shandong province, PR China.

Thirty samples of asparagus spears were collected from the fields in Shandong province, China, in July 2004, and were analysed for the occurrence of fumonisins B1 and B2 (FB1 and FB2) by HPLC coupled with electrospray ionization tandem mass spectrometry. Twenty-four samples (80%) contained fumonisins, ranging from 24 to 670 ng g(-1) (average 123 ng g(-1)) and 17 to 138 ng g(-1)(average 35 ng g(-1)) for FB1 and FB2, respectively. The total amount of fumonisins (FB1 and FB2) in all samples ranged from 47 to 714 ng g(-1) (average 158 ng g(-1)) (based on dry weight). This is the first report on the natural occurrence of FB1 and FB2 in asparagus spears in China.