Gouty arthritis (GA) is a characteristically inflammatory disease often associated with lipid metabolism disorder. Huangqin Qingrechubi capsule (HQC) has been used for the treatment of GA.To explore the mechanism of HQC in the treatment of GA.A total of 30 GA patients (GA group) and 30 healthy subjects [normal control (NC) group] were recruited. The GA group was treated with HQC (3.6 g/d) for 10 days. Lipid metabolism and inflammation indexes were detected. Five herbal names of HQC, or 'gouty arthritis', 'hyperlipidemia' and 'inflammation' were used as key words to search related databases for network pharmacological analysis. Subsequently, GA-fibroblast-like synoviocytes (FLSs) were stimulated with GA-peripheral blood mononuclear cells (PBMCs) (3:1) and treated with HQC drug-containing serum (20%). RT-qPCR, Western blot, and ELISA were conducted to further explore the mechanism of HQC in improving GA.In clinical observation, HQC decreased the expression of lncRNA H19 and IL-1β, and increased the expression of adiponectin (APN) and IL-4 in the GA group (about half). Through network pharmacology, the PI3K/AKT signaling pathway was identified. Cell experiments showed that HQC treatment reduced the viability of GA-FLSs (49.61%), up-regulated the expression of IL-4 (155.18%), IL-10 (165.13%), and APN (31.24%), and down-regulated the expression of lncRNA H19 (33.70%), IL-1β (64.70%), TNF-α (78.32%), p-PI3K (48.80%), and p-AKT (53.48%).HQC improved lipid metabolism disorder and inflammatory response of GA by regulating the lncRNA H19/APN/PI3K/AKT. Maintaining the stability of lipid metabolism may be an effective way to alleviate GA.
The limitations and weaknesses of continuous melon cropping have worsened in recent years. A melon–broccoli rotation can possibly alleviate the problems associated with melon monoculture; however, the underlying mechanisms and their impact on the rhizosphere’s soil microbial community remain unclear. Thus, high-throughput sequencing was used to evaluate the rhizosphere soil’s microbial community’s relative abundance and diversity under melon–broccoli rotation and continuous melon monoculture cropping systems. We found that relative fungal and bacterial diversity and richness increased while fungi relative abundances, such as Fusarium spp. were significantly decreased under broccoli rotation. During continuous cropping, enriched Acidobacteria and Streptomyces spp., Sphingomonas spp., and Pseudomonas spp. were identified, which play important roles in alleviating melon continuous cropping obstacles. The soil under continuous cropping was rendered acidic, underwent secondary salinization, rapidly accumulated soil organic carbon and nitrogen, and lost abundant phosphorus and potassium. In contrast, broccoli rotation partially mitigated these negative physicochemical responses. Redundancy analysis revealed that the soil pH, soil soluble salt content, and soil organic carbon were linked to structures of the soil bacterial and fungal community. Melon–broccoli rotation could effectively equilibrate the soil microenvironment and overcome the challenges and deficiencies associated with continuous melon cropping.
Abstract Immune checkpoint blockade is effective in “hot” tumors like melanoma with pre-existing immune infiltrates; however, “cold” tumors like prostate cancer fail to respond. We found that prostate cancers harbor regions of hypoxia that resist T cell infiltration even in the context of anti-CTLA-4 (cytotoxic T lymphocyte associated protein-4) and anti-PD-1 (programmed cell death protein 1) blockade. These hypoxic zones serve as islands of immune privilege through the recruitment and suppressive polarization of immature myeloid cells into myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM). We found that targeted hypoxia ablation using TH-302, a hypoxia-activated prodrug, sensitized both transplantable and spontaneous models of prostate cancer to checkpoint blockade, coincident with enhanced T cell infiltration and effector function and loss of MDSC recruitment and suppressive function. Tumors treated with the combination of TH-302 and checkpoint blockade showed a reduced capacity to suppressively polarize new myeloid immigrants, implying a durable reconditioning of the tumor microenvironment (TME) into an immune-infiltrated, pro-inflammatory milieu. T cells infiltrating combination-treated tumors exhibited increased mitochondrial respiration, consistent with creation of a metabolically favorable milieu for T cell function. Based on these findings, we hypothesized that other approaches capable of metabolically rewiring the TME should promote anti-tumor immunity and sensitize checkpoint blockade-resistant tumors to immunotherapy. With this in mind, we performed a longitudinal study comparing a panel of different mitochondrial respiration inhibitors and a glutaminase inhibitor for their efficacy in reducing hypoxia, improving T cell infiltration and decreasing myeloid cell recruitment and suppressive polarization using immunofluorescence staining and confocal microscopy. Our preliminary data suggests that inhibitors targeting mitochondrial respiration, rather than those targeting glutamine metabolism synergize with checkpoint blockade and exhibit the highest efficacy in increasing T cell recruitment. We continue to characterize the dynamics of hypoxia reduction, duration of normalization following drug withdrawal, and impact on the immune microenvironment of these diverse approaches to metabolic reconditioning. Citation Format: Priyamvada Jayaprakash, Midan Ai, Arthur Liu, Pratha Budhani, Todd Bartkowiak, Jie Sheng, Casey Ager, Courtney Nicholas, Ashvin Jaiswal, Yanqiu Sun, Krishna Shah, Sadhana Balasubramanyam, Nan Li, Guocan Wang, Jing Ning, Anna Zal, Tomasz Zal, Michael Curran. Targeting hypoxia-induced immune suppression to overcome immunotherapy resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5011.
Objective To investigate the effect of serum containing Xinfeng capsule (XFC) on the angiogenesis of human umbilical vein endothelial cells (HUVEC) induced by rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and its mechanism of action. Methods An in vitro co-culture model of RA-FLS and HUVEC was established. Serum containing XFC was prepared by oral gavage of SD rats. CCK-8 was used to screen the optimal co-culture ratio and XFC serum concentration. The lncRNA HOTAIR overexpression plasmid (pcDNA3.1-lncRNA HOTAIR), along with the negative control group, were constructed and transfected into RA-FLS. The experiments were done in HUVEC control group, model group (co-culture of HUVEC and RA-FLS), XFC group (co-culture of RA-FLS treated with 200 mL/L XFC), HOTAIR negative control group (co-culture of RA-FLS transfected with pcDNA3.1-NC), HOTAIR overexpression group (co-culture of RA-FLS transfected with pcDNA3.1-lncRNA HOTAIR), and XFC-treated HOTAIR overexpression group (co-culture of RA-FLS transfected with pcDNA3.1-lncRNA HOTAIR and treated with 200 mL/L XFC). The proliferation ability of HUVEC was detected by CCK-8 method. The migration ability of HUVEC was detected by Transwell
In this paper, we consider the entire mean weighted first-passage time (EMWFPT) with random walks on a family of weighted treelike networks. The EMWFPT on weighted networks is proposed for the first time in the literatures. The dominating terms of the EMWFPT obtained by the following two methods are coincident. On the one hand, using the construction algorithm, we calculate the receiving and sending times for the central node to obtain the asymptotic behavior of the EMWFPT. On the other hand, applying the relationship equation between the EMWFPT and the average weighted shortest path, we also obtain the asymptotic behavior of the EMWFPT. The obtained results show that the effective resistance is equal to the weighted shortest path between two nodes. And the dominating term of the EMWFPT scales linearly with network size in large network.
Abstract Previous studies have shown that autophagic pathogenesis of rheumatoid arthritis (RA) is regulated by circular RNAs (circRNAs), which accelerate bone damage by participating in the immune inflammatory response. Therefore, exploring the mechanisms underlying circRNA regulation of autophagy is essential for maintaining homeostasis of the skeletal microenvironment in RA and may improve our understanding of the specific pathways involved in the development of therapeutics. In this review, we discuss autophagic imbalance in RA and the regulatory mechanisms of circRNAs. We also explore possible targets for circRNA regulation of autophagy in RA, which may provide us with improved knowledge regarding the pathogenesis of RA.
Wheat powdery mildew, caused by the biotrophic fungus Blumeria graminis f. sp. tritici ( Bgt ), is a serious disease of wheat worldwide that can cause significant yield losses. Growing resistant cultivars is the most cost-effective and eco-soundly strategy to manage the disease. Therefore, a high breeding priority is to identify genes that can be readily used either singly or in combination for effective resistance to powdery mildew and also in combination with genes for resistance to other diseases. Yunnan Province, with complex and diverse ecological environments and climates, is one of the main wheat growing regions in China. This region provides initial inoculum for starting epidemics of wheat powdery mildew in the region and other regions and thus, plays a key role in the regional and large-scale epidemics of the disease throughout China. The objectives of this study were to evaluate seedling resistance of 69 main wheat cultivars to powdery mildew and to determine the presence of resistance genes Pm3 , Pm8 , Pm13 , Pm16 , and Pm21 in these cultivars using gene specific DNA markers. Evaluation of 69 wheat cultivars with six Bgt isolates showed that only four cultivars were resistant to all tested isolates, indicating that the overall level of powdery mildew resistance of Yunnan wheat cultivars is inadequate. The molecular marker results showed that 27 cultivars likely have at least one of these genes. Six cultivars were found likely to have Pm3 , 18 likely to have Pm8 , 5 likely to have Pm16 , and 3 likely to have Pm21 . No cultivar was found to carry Pm13 . The information on the presence of the Pm resistance genes in Yunnan wheat cultivars can be used in future wheat disease breeding programs. In particular, cultivars carrying Pm21 , which is effective against all Bgt races in China, should be pyramided with other effective genes to developing new cultivars with durable resistance to powdery mildew.
Long non‑coding RNAs (lncRNAs) assume pivotal roles in various autoimmune diseases including ankylosing spondylitis (AS). Inflammation affects the progression of multiple diseases. The current research aimed at dissecting out the possible role and mechanism of lncRNAs NONHSAT227927.1 in the pathogenesis of AS. In clinical trials, 50 patients with AS and 30 healthy persons were enrolled, followed by the extraction of peripheral blood mononuclear cells (PBMCs). NONHSAT227927.1 expression was detected using reverse transcription quantitative PCR. Enzyme‑linked immunosorbent assay was used to determine the levels of inflammatory cytokines. Human fibroblast‑like synoviocytes (FLSs) were induced by PBMC supernatant, after which the activity of FLSs was measured by Cell Counting Kit‑8 and the signaling pathway were detected by western blotting. Cell migratory capacity was assessed by Transwell migration assay. NONHSAT227927.1 expression was obviously enhanced in the PBMCs of AS patients. NONHSAT227927.1 expression was positively correlated with immunoglobin A (IgA), erythrocyte sedimentation rate (ESR), complement C3 (C3), visual analog scale, IL‑17, and IL‑23 Levels but was negatively correlated with IL‑10 level. The results of association rules showed that the increase of NONHSAT227927.1 expression was strongly associated with the elevation of IgA, C3, ESR, self‑rating anxiety scale and IL‑17 levels. Overexpression of NONHSAT227927.1 remarkably augmented the proliferation and migration of AS‑PBMCs stimulated by AS‑FLSs, facilitated the levels of IL‑17 and IL‑23, and reduced the IL‑10 level. By contrast, NONHSAT227927.1 knockdown decreased cell proliferation and migration and cell viability as well as the levels of IL‑17 and IL‑23, but increased the level of IL‑10. overexpression of NONHSAT227927.1 promoted the phosphorylation of JAK2 and STAT3 proteins, while knockout of NONHSAT227927.1 decreased their phosphorylation. Conclusively, lncRNA NONHSAT227927.1 was overexpressed in AS, which activated the JAK2/STAT3 signaling pathway to upregulate inflammatory factors.
We propose the entire mean weighted first-passage time (EMWFPT) for the first time in the literature. The EMWFPT is obtained by the sum of the reciprocals of all nonzero Laplacian eigenvalues on weighted networks. Simplified calculation of EMWFPT is the key quantity in the study of infinite families of weighted tree networks, since the weighted complex systems have become a fundamental mechanism for diverse dynamic processes. We base on the relationships between characteristic polynomials at different generations of their Laplacian matrix and Laplacian eigenvalues to compute EMWFPT. This technique of simplified calculation of EMWFPT is significant both in theory and practice. In this paper, firstly, we introduce infinite families of weighted tree networks with recursive properties. Then, we use the sum of the reciprocals of all nonzero Laplacian eigenvalues to calculate EMWFPT, which is equal to the average of MWFPTs over all pairs of nodes on infinite families of weighted networks. In order to compute EMWFPT, we try to obtain the analytical expressions for the sum of the reciprocals of all nonzero Laplacian eigenvalues. The key step here is to calculate the constant terms and the coefficients of first-order terms of characteristic polynomials. Finally, we obtain analytically the closed-form solutions to EMWFPT on the weighted tree networks and show that the leading term of EMWFPT grows superlinearly with the network size.
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