Protective effect of dehydroandrographolide on obstructive cholestasis in bile duct-ligated mice

Background: Dehydroandrographolide (DA) is the main contributor to the therapeutic properties of the medicinal plant Andrographis paniculata (AP). However, it is unknown whether DA has a hepatoprotective effect on obstructive cholestasis in mice and humans. Methods: We administered DA to mice for 5 days prior to bile duct ligation (BDL) and for the 7 days. Liver function markers, liver histology and necrosis, compensatory responses of hepatocytes, liver fibrosis and the expression of hepatic fibrogenesis markers were evaluated in BDL mice and/or human LX-2 cells. Results: Mice treated with DA demonstrated lower levels of serum alanine transarninase (ALT), milder liver damage, liver necrosis and fibrosis formation than in vehicle control with carboxymethylcellulose (CMC) mice after BDL. DA treatment also enhanced the Mrp3 expression of hepatocytes but not Mrp4 following BDL. Further, DA treatment in BDL mice significantly reduced liver mRNA and/or protein expression of Tgf-β, Col1a1, α-Sma and Mmp2. This result was also supported by hydroxyproline analysis. The molecular mechanisms of DA treatment were also assessed in human hepatic stellate cell line (LX-2 cell). DA treatment significantly inhibited Tgf-β-induced Col1a1, Mmp2 and α-Sma expression in human LX-2 cells. These data suggested that DA treatment reduced liver damage through development of a hepatic adaptive response and inhibition of the activation of HSCs, which led to a reduction in liver fibrosis formation in BDL mice. Conclusions: DA treatment protected against liver damage and fibrosis following BDL and might be an effective therapy for extrahepatic cholestasis due to bile duct obstruction

Anti-Inflammatory Activity of Dehydroandrographolide by TLR4/NF-κB Signaling Pathway Inhibition in Bile Duct-Ligated Mice

Background/Aims: Clinically, biliary obstruction is often accompanied by progressive inflammation. Dehydroandrographolide (DA) possesses anti-inflammatory properties. However, the anti-inflammatory activities of DA in cholestatic liver injury remain unclear. Methods: Mice were administered with DA by intraperitoneal injection after bile duct ligation (BDL) on day 1. Then mice were subjected to an ileocecal vein injection of lipopolysaccharide (LPS). Liver function markers, histology, pro-inflammatory cytokine levels, NF-κB activation and fibrosis formation were evaluated in BDL mice with LPS. LPS binding to primary Kupffer cells was examined by high-content cytometers. Results: DA was shown to greatly lower initially higher than normal levels of alanine aminotransferase (ALT) and total bilirubin (TBIL) in the serum and liver of BDL mice with LPS. DA exerted hepatic protective effects that were also confirmed by prolonged survival of BDL mice with LPS. Liver histopathology showed reduced inflammatory cellular infiltration, bile duct proliferation, and biliary necrosis with DA treatment. Furthermore, DA reduced the expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in liver tissue and plasma and showed decreased NF-κB activation in BDL mice with LPS. DA could prevent LPS binding to primary Kupffer cells in the normal liver and BDL mice liver. DA also suppressed LPS-stimulated inflammatory responses by blocking the interaction between LPS and TLR4 in primary Kupffer cells and human LX-2 cells, thereby inhibiting NF-κB activation. Conclusion: DA inhibition of inflammation against liver damage following BDL with LPS may be a promising agent for the treatment of cholestatic liver injury

Tumor-Derived Exosomal Protein Tyrosine Phosphatase Receptor Type O Polarizes Macrophage to Suppress Breast Tumor Cell Invasion and Migration

Tumor-derived exosomes, containing multiple nucleic acids and proteins, have been implicated to participate in the interaction between tumor cells and microenvironment. However, the functional involvement of phosphatases in tumor-derived exosomes is not fully understood. We and others previously demonstrated that protein tyrosine phosphatase receptor type O (PTPRO) acts as a tumor suppressor in multiple cancer types. In addition, its role in tumor immune microenvironment remains elusive. Bioinformatical analyses revealed that PTPRO was closely associated with immune infiltration, and positively correlated to M1-like macrophages, but negatively correlated to M2-like macrophages in breast cancer tissues. Co-cultured with PTPRO-overexpressing breast cancer cells increased the proportion of M1-like tumor-associated macrophages (TAMs) while decreased that of M2-like TAMs. Further, we observed that tumor-derived exosomal PTPRO induced M1-like macrophage polarization, and regulated the corresponding functional phenotypes. Moreover, tumor cell-derived exosomal PTPRO inhibited breast cancer cell invasion and migration, and inactivated STAT signaling in macrophages. Our data suggested that exosomal PTPRO inhibited breast cancer invasion and migration by modulating macrophage polarization. Anti-tumoral effect of exosomal PTPRO was mediated by inactivating STAT family in macrophages. These findings highlight a novel mechanism of tumor invasion regulated by tumor-derived exosomal tyrosine phosphatase, which is of translational potential for the therapeutic strategy against breast cancer

Protective Effect of Hydrogen on Sodium Iodate-Induced Age-Related Macular Degeneration in Mice

Oxidative stress is one of the main causes of AMD. Hydrogen has anti-oxidative stress and apoptotic effects on retinal injury. However, the effect of hydrogen on AMD is not clear. In this study, fundus radiography, OCT, and FFA demonstrated that HRW reduced the deposition of drusen-like structures in RPE layer, prevented retina from thinning and leakage of ocular fundus vasculature induced by NaIO3. ERG analysis confirmed that HRW effectively reversed the decrease of a-wave and b-wave amplitude in NaIO3-mice. Mechanistically, HRW greatly reduced the oxidative stress reaction through decreased MDA levels, increased SOD production, and decreased ROS content. The OGG1 expression was downregulated which is a marker of oxidative stress. Involvement of oxidative stress was confirmed using oxidative stress inhibitor ALCAR. Moreover, oxidative stress reaction was associated with expression of Sirt1 level and HRW significantly inhibited the downregulation of Sirt1 expression. This result was further confirmed with AICAR which restore Sirt1 expression and activity. In addition, NaIO3-induced retinal damage was related to apoptosis via caspase 8 and caspase 9, but not the caspase 3 pathways, which led to upregulation of Bax and p53, downregulation of Bcl-2, and increase in Jc-1-positive cells in mice. However, HRW effectively reversed these effects that apoptosis induced. These results suggest that HRW protects retinal functions against oxidative stress injury through inhibiting downregulation of Sirt1 and reducing retinal apoptosis. Therefore, we speculated that hydrogen administration is a promising treatment for AMD therapy

Animal3D: A Comprehensive Dataset of 3D Animal Pose and Shape

Accurately estimating the 3D pose and shape is an essential step towards understanding animal behavior, and can potentially benefit many downstream applications, such as wildlife conservation. However, research in this area is held back by the lack of a comprehensive and diverse dataset with high-quality 3D pose and shape annotations. In this paper, we propose Animal3D, the first comprehensive dataset for mammal animal 3D pose and shape estimation. Animal3D consists of 3379 images collected from 40 mammal species, high-quality annotations of 26 keypoints, and importantly the pose and shape parameters of the SMAL model. All annotations were labeled and checked manually in a multi-stage process to ensure highest quality results. Based on the Animal3D dataset, we benchmark representative shape and pose estimation models at: (1) supervised learning from only the Animal3D data, (2) synthetic to real transfer from synthetically generated images, and (3) fine-tuning human pose and shape estimation models. Our experimental results demonstrate that predicting the 3D shape and pose of animals across species remains a very challenging task, despite significant advances in human pose estimation. Our results further demonstrate that synthetic pre-training is a viable strategy to boost the model performance. Overall, Animal3D opens new directions for facilitating future research in animal 3D pose and shape estimation, and is publicly available.Comment: 11 pages, 5 figures, link to the dataset: https://xujiacong.github.io/Animal3D

Carbon Catabolite Repressor UvCreA is Required for Development and Pathogenicity in Ustilaginoidea virens

The rice false smut disease, caused by Ustilaginoidea virens, has emerged as a significant global threat to rice production. The mechanism of carbon catabolite repression plays a crucial role in the efficient utilization of carbon nutrients and enzyme regulation in the presence of complex nutritional conditions. Although significant progress has been made in understanding carbon catabolite repression in fungi such as Aspergillus nidulans and Magnaporthe oryzae, its role in U. virens remains unclear. To address this knowledge gap, we identified UvCreA, a pivotal component of carbon catabolite repression, in U. virens. Our investigation revealed that UvCreA localized to the nucleus. Deletion of UvCreA resulted in decreased growth and pathogenicity in U. virens. Through RNA-seq analysis, it was found that the knockout of UvCreA led to the up-regulation of 514 genes and down-regulation of 640 genes. Moreover, UvCreA was found to be involved in the transcriptional regulation of pathogenic genes and genes associated with carbon metabolism in U. virens. In summary, our findings indicated that UvCreA is important in fungal development, virulence, and the utilization of carbon sources through transcriptional regulation, thus making it a critical element of carbon catabolite repression

Sucrose non-fermenting protein kinase gene UvSnf1 is required for virulence in Ustilaginoidea virens

ABSTRACTRice false smut caused by Ustilaginoidea virens is becoming one of the most devastating diseases in rice production areas in the world. Revealing U. virens potential pathogenic mechanisms provides ideas for formulating more effective prevention and control strategies. Sucrose non-fermenting 1 (Snf1) protein kinase plays a critical role in activating transcription and suppressing gene expression, as well as in cellular response to various stresses, such as nutrient limitation. In our study, we identified the Snf1 homolog UvSnf1 and analyzed its biological functions in U. virens. The expression level of UvSnf1 was dramatically up-regulated during invasion, indicating that UvSnf1 may participate in infection. Phenotypic analyses of UvSnf1 deletion mutants revealed that UvSnf1 is necessary for hyphae growth, spore production, and virulence in U. virens. Moreover, UvSnf1 promotes U. virens to use unfavorable carbon sources when the sucrose is insufficient. In addition, deletion of UvSnf1 down-regulates the expression of the cell wall-degrading enzymes (CWDEs) genes under sucrose limitation conditions in U. virens. Further analyses showed that CWDEs (UvCut1 and UvXyp1) are not only involved in growth, spore production, and virulence but are also required for the utilization of carbon sources. In conclusion, this study demonstrates that UvSnf1 plays vital roles in virulence and carbon source utilization in U. virens, and one of the possible mechanisms is playing a role in regulating the expression of CWDE genes

Multi-Seasonal Nitrogen Recoveries from Crop Residue in Soil and Crop in a Temperate Agro-Ecosystem.

In conservation tillage systems, at least 30% of the soil surface was covered by crop residues which generally contain significant amounts of nitrogen (N). However, little is known about the multi-seasonal recoveries of the N derived from these crop residues in soil-crop systems, notably in northeastern China. In a temperate agro-ecosystem, 15N-labeled maize residue was applied to field surfaces in the 1st year (2009). From the 2nd to 4th year (2010-2012), one treatment halted the application of maize residue, whereas the soil in the second treatment was re-applied with unlabeled maize residue. Crop and soil samples were collected after each harvest, and their 15N enrichments were determined on an isotope ratio mass spectrometer to trace the allocation of N derived from the initially applied maize residue in the soil-crop systems. On average, 8.4% of the maize residue N was recovered in the soil-crop in the 1st year, and the vast majority (61.9%-91.9%) was recovered during subsequent years. Throughout the experiment, the cumulative recovery of the residue N in the crop increased gradually (18.2%-20.9%), but most of the residue N was retained in the soil, notably in the 0-10 cm soil layer. Compared to the single application, the sequential residue application significantly increased the recovery of the residue N in the soil profile (73.8% vs. 40.9%) and remarkably decreased the total and the initially applied residue derived mineral N along the soil profile. Our results suggested that the residue N was actively involved in N cycling, and its release and recovery in crop and soil profile were controlled by the decomposition process. Sequential residue application significantly enhanced the retention and stabilization of the initially applied residue N in the soil and retarded its translocation along the soil profile