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Intrahepatic cholangiocarcinoma (ICC) is a rare but highly aggressive malignant tumor arising within the liver, with a 5-year survival rate of only 20–40% after surgery. The role of interleukin-8 (IL-8) in ICC progression remains elusive. A transcriptomic approach based on IL-8 stimulation first revealed significant upregulation of the prometastatic gene CD97 and key epithelial–mesenchymal transition (EMT) factors E-cadherin and vimentin. Immunohistochemistry of 125 ICC tissues confirmed the positive correlation between IL-8 and CD97. Multivariable Cox regression indicated that they are both independent predictors of ICC prognosis. Mechanistically, IL-8 treatment induced CD97 expression at 50 and 100 ng/ml in QBC-939 and QBE cells, respectively. Moreover, the induction of cell migration and invasion upon IL-8 treatment was attenuated by CD97 RNA interference, and the expression of EMT-associated genes was dramatically inhibited. To determine whether CXCR1 or CXCR2 are downstream effectors of IL-8, siCXCR2 was applied and shown to significantly attenuate the oncogenic effects of IL-8 by inhibiting the phosphorylation of PI3K/AKT. Finally, the induction of CD97 expression by the PI3K pathway was verified by treatment with the inhibitor LY294002. In vivo, the significant tumor growth and lung metastasis effects induced by intraperitoneal injection of IL-8 were greatly inhibited by silencing CD97 in nude mice. Collectively, the study presents a novel mechanism of the IL-8-CXCR2-PI3K/AKT axis in regulating CD97 expression, which leads to ICC metastasis mainly through EMT. The study may provide alternatives for targeting the tumor microenvironment in metastatic ICC. [ABSTRACT FROM AUTHOR]

Arbuscular mycorrhizal (AM) fungi enhance plant stress tolerance, but it is unclear whether AM fungi affect heat tolerance in cucumbers. This study aimed to analyze how an AM fungus, Diversispora versiformis, affected growth, chlorophyll, five osmolytes, and plasma membrane intrinsic proteins (PIPs) and heat shock protein 70 (Hsp70) gene expression in cucumber leaves after a short-term (80 h) heat stress. Heat treatment significantly reduced root AM fungal colonization rate (0.26 folds). Heat treatment also distinctly suppressed plant height, stem diameter, and biomass, whereas AM fungal inoculation improved these growth variables as well as the chlorophyll index, with the benefit being more obvious under heat than under no-heat stress conditions. Heat treatment triggered differential changes in osmolytes (sucrose, fructose, and betaine) of inoculated and uninoculated cucumbers, whereas inoculation with AM fungus significantly raised leaf sucrose, fructose, glucose, betaine, and proline levels when compared to non-AM fungal inoculation. Heat treatment increased the expression of two (CsPIP1;6 and CsPIP2;1) of eight CsPIPs in inoculated and uninoculated plants, whereas AM fungal inoculation up-regulated the expression of CsPIP1;6, CsPIP2;1, and CsPIP2;6 under heat stress conditions. Hsp70s expressed differently in inoculated and uninoculated plants under heat versus no-heat stress, with 6 of 11 CsHsp70s down-regulated in inoculated plants. Under heat stress conditions, AM fungus only up-regulated CsHsp70-8 expression in 11 Hsp70s, while another eight CsHsp70s were down-regulated. Heat treatment and AM fungal inoculation both increased the expression of CsHsp70-8 and CsPIP1;6. It was concluded that AM fungus-inoculated cucumbers have high levels of growth, chlorophyll, and osmolytes under heat stress and do not require high CsPIPs and CsHsp70s expression to tolerate a short-term heat treatment. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) differentially impairs female and male fetal endothelial cell function, which is associated with an increased risk of adult‐onset cardiovascular disorders in children born to mothers with PE. However, the underlying mechanisms are poorly defined. We hypothesize that dysregulation of microRNA‐29a‐3p and 29c‐3p (miR‐29a/c‐3p) in PE disturbs gene expression and cellular responses to cytokines in fetal endothelial cells in a fetal sex‐dependent manner. RT‐qPCR analysis of miR‐29a/c‐3p was performed on female and male unpassaged (P0) human umbilical vein endothelial cells (HUVECs) from normotensive (NT) pregnancies and PE. Bioinformatic analysis of an RNA‐seq dataset was performed to identify PE‐dysregulated miR‐29a/c‐3p target genes in female and male P0‐HUVECs. Gain‐ and loss‐of‐function assays were conducted to determine the effects of miR‐29a/c‐3p on endothelial monolayer integrity and proliferation in response to transforming growth factor‐β1 (TGFβ1) and tumour necrosis factor‐α (TNFα) in NT and PE HUVECs at passage 1. We observed that PE downregulated miR‐29a/c‐3p in male and female P0‐HUVECs. PE dysregulated significantly more miR‐29a/c‐3p target genes in female vs. male P0‐HUVECs. Many of these PE‐differentially dysregulated miR‐29a/c‐3p target genes are associated with critical cardiovascular diseases and endothelial function. We further demonstrated that miR‐29a/c‐3p knockdown specifically recovered the PE‐abolished TGFβ1‐induced strengthening of endothelial monolayer integrity in female HUVECs, while miR‐29a/c‐3p overexpression specifically enhanced the TNFα‐promoted cell proliferation in male PE HUVECs. In conclusion, PE downregulates miR‐29a/c‐3p expression and differentially dysregulates miR‐29a/c‐3p target genes associated with cardiovascular diseases and endothelial function in female and male fetal endothelial cells, possibly contributing to the fetal sex‐specific endothelial dysfunction observed in PE. Key points: Preeclampsia differentially impairs female and male fetal endothelial cell function in responses to cytokines. Pro‐inflammatory cytokines are elevated in maternal circulation during pregnancy in preeclampsia.MicroRNAs are critical regulators of endothelial cell function during pregnancy. We have previously reported that preeclampsia downregulated microRNA‐29a‐3p and 29c‐3p (miR‐29a/c‐3p) in primary fetal endothelial cells. However, it is unknown if PE differentially dysregulates the expression of miR‐29a/c‐3p in female and male fetal endothelial cells.We show that preeclampsia downregulates miR‐29a/c‐3p in male and female HUVECs and preeclampsia dysregulates cardiovascular disease‐ and endothelial function‐associated miR‐29a/c‐3p target genes in HUVECs in a fetal sex‐specific manner.MiR‐29a/c‐3p differentially mediate cell responses to cytokines in female and male fetal endothelial cells from preeclampsia.We have revealed fetal sex‐specific dysregulation of miR‐29a/c‐3p target genes in fetal endothelial cells from preeclampsia. This differential dysregulation may contribute to fetal sex‐specific endothelial dysfunction in offspring born to preeclamptic mothers. [ABSTRACT FROM AUTHOR]

Urological chronic pelvic pain syndrome (UCPPS) manifests as pelvic pain with frequent urination and has a 10% prevalence rate without effective therapy. Nanoceria (cerium oxide nanoparticles [CNPs]) were synthesized in this study to achieve potential long-term pain relief, using a commonly used UCPPS mouse model with cyclophosphamide-induced cystitis. Transcriptome sequencing analysis revealed that serpin family B member 2 (SerpinB2) was the most upregulated marker in mouse bladder, and SerpinB2 was downregulated with CNP pretreatment. The transcriptome sequencing analysis results agreed with quantitative polymerase chain reaction and western blot analysis results for the expression of related mRNAs and proteins. Analysis of Gene Expression Omnibus (GEO) datasets revealed that SerpinB2 was a differentially upregulated gene in human UCPPS. In vitro SerpinB2 knockdown downregulated proinflammatory chemokine expression (chemokine receptor CXCR3 and C-X-C motif chemokine ligand 10) upon treatment with 4-hydroperoxycyclophosphamide. In conclusion, CNP pretreatment may prevent the development of UCPPS, and reactive oxygen species (ROS) scavenging and SerpinB2 downregulation may modulate the immune response in UCPPS. [ABSTRACT FROM AUTHOR]

Objective: To analyze the expression of protein kinase C delta (PKCẟ, PRKCD) in Liver hepatocellular carcinoma and its clinical significance based on bioinformatics, in order to provide a new direction for the study of therapeutic targets for Liver hepatocellular carcinoma. Methods: The PRKCD gene expression data and patient clinical information data in Liver hepatocellular carcinoma tissues and adjacent tissues were downloaded from The TCGA (The Cancer Genome Atlas) and UCSC Xena databases. The mRNA expression of PRKCD in Liver hepatocellular carcinoma was analyzed, and the protein expression of PRKCD in Liver hepatocellular carcinoma was analyzed by Human Protein Atlas (HPA) databases. Furthermore, its relationship with clinicopathological features and prognosis in patients with Liver hepatocellular carcinoma was analyzed. GSEA enrichment analysis were carried out for PRKCD in Liver hepatocellular carcinoma. Finally, the causes of changes in PRKCD expression were analyzed from the perspective of genetic and epigenetics based on collated liver hepatocellular carcinoma data. Results: Both the mRNA and protein expression level of PRKCD gene in Liver hepatocellular carcinoma tissues was significantly higher than that in adjacent tissues. Its expression level was correlated with TNM stage, Histologic grade,Alpha fetoprotein (AFP) and Living status in clinicopathological features, and its expression level has certain clinical diagnostic accuracy. Kaplan-Meier analysis showed that the prognosis of patients with low PRKCD expression was significantly better than that with high PRKCD expression. Univariate and multivariate Cox regression analysis showed that PRKCD was an independent prognostic factor in patients with Liver hepatocellular carcinoma, and it was also found that the risk ratio of TNM stage III and stage IV survival curve (HR) was significantly greater than that of stage I and stage II. GSEA analysis showed that it was enriched in cell cycles and DNA replication, and was positively correlated with PRKCD. Enrichment analysis found that PRKCD is mainly involved in the chemokine signaling pathway, NOD-like receptor signaling pathway, PPAR signaling pathway, adipocytokine signaling pathway and T-cell receptor signaling pathway. Finally, through genetic and epigenetic analysis, it is found that the increase in the number of copies of genes will increase the expression level of PRKCD, and the methylation level is negatively correlated with the expression level of PRKCD. Conclusion: PRKCD gene is upregulated in Liver hepatocellular carcinoma tissues, and its overexpression level is closely related to patient poor prognosis. [ABSTRACT FROM AUTHOR]

• Whether and how soil AMF enhance heat stress tolerance of cucumber were studied. • Heat stress decreased root AMF colonization and soil hyphal length. • AMF increased cucumber biomass and leaf gas exchange under heat stress. • Most cshsp70s and cspips were up-regulated in inoculated plants under HS versus ST. • Under HS, AMF up-regulated expressions of 11 of 12 cshsp70s and 12 of 14 cspips. Cucumbers are frequently subjected to heat stress (HS) during the summer, which severely limits their growth and fruit yield and quality. Soil arbuscular mycorrhizal fungi (AMF) can enhance the abiotic stress tolerance of host plants, but it is unclear whether and how soil arbuscular mycorrhizal fungi (AMF) enhance the HS tolerance of cucumber. This work aimed to assess the effects of an arbuscular mycorrhizal fungus, Diversispora versiformis , on plant growth, leaf gas exchange, and expressions of plasma membrane intrinsic proteins (PIPs) and heat shock protein 70 (Hsp70) genes in roots of cucumber under HS (38 °C/30 °C, day/night temperature, 16 h/8 h) and suitable temperature (ST) (25 °C/18 °C, day/night temperature, 16 h/8 h) conditions. The HS treatment significantly decreased root mycorrhizal colonization and soil mycelium length by 0.26- and 0.55-fold, respectively, compared with the ST treatment. The biomass inhibition of cucumber by HS versus ST was more pronounced in uninoculated plants than inoculated plants. Inoculation with D. versiformis , however, significantly increased cucumber biomass and leaf gas exchange under both ST and HS conditions when compared to the uninoculated treatment. The HS treatment had almost no effect on or down-regulated the expression of CsHsp70s and CsPIPs genes in uninoculated plants, while most CsHsp70s and CsPIPs gene expressions were up-regulated in inoculated plants under HS versus ST conditions, suggesting the active heat resistance of mycorrhizal plants. Additionally, under ST conditions, D. versiformis up-regulated CsHsp70–11, CsPIP1;2 , and CsPIP2;6 expressions. Under HS conditions, D. versiformis increased the expression of 11 of 12 CsHsp70s by 1.17‒6.14 folds as well as 12 of 14 CsPIPs by 1.82‒144.43 folds, with CsPIP1.5 and CsPIP2;7 up-regulated up to 144.43- and 82.46-fold, respectively. It is concluded that D. versiformis -inoculated cucumbers exhibited higher heat tolerance than uninoculated plants, associated with up-regulated expression of most CsHsp70s and CsPIPs genes. [ABSTRACT FROM AUTHOR]

HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol de novo biosynthesis and its degradation may bring therapeutic benefits for the treatment of cardiovascular disease (CVD) and nonalcoholic steatohepatitis (NASH). Before, we disclosed compound HMG499 as a potent HMGCR degrader, which could be a promising agent for treating CVD, however its side-effect of promoting cholesterol accumulation in cells should be eliminated before progression. Herein, a series of novel heterocyclic ring-fused analogs of HMG499 were synthesized and investigated for their activities of stimulating HMGCR degradation using a HMGCR (TM1-8)-GFP reporting system. Among them, the most active compound 29 (QH536) showed an EC 50 of 0.22 μΜ in promoting HMGCR degradation, which was about 2 times more potent than HMG499 (EC 50 = 0.43 μM). Interestingly, 29 was different from HMG499, it had no side-effect of inducing cholesterol accumulation in cells. Mechanistic studies disclosed that 29 could significantly decrease statin-induced accumulation of HMGCR protein via ubiquitination and degradation of HMGCR through ubiquitin-proteasome pathway and inhibit the cholesterol biosynthesis in cells. Therefore, these heterocyclic ring-fused analogs could be used as promising leads for the development of new types of agents against CVD. Furthermore, 29 also lowered cholesterol levels and suppressed TGFβ1-induced proliferation of LX-2 hepatic stellate cells in a dose-dependent manner. In particular, 29 not only decreased the NASH associated fibrotic mRNA and protein expression of α-SMA, COL1A1, TIMP1 and TGFβ1 but also suppressed cholesterol levels and inflammatory genes of TNF-α, IL-6 an IL-1β in RAW264.7 macrophage cells, indicating that 29 may bring therapeutic benefit to treat NASH. A series of heterocyclic ring-fused analogs of HMG499 were synthesized and their activities of promoting HMG-CoA reductase degradation and side-effects of inducing cholesterol accumulation in cells were evaluated. [Display omitted] • A series of novel heterocyclic ring-fused analogs of HMG499 were synthesized. • The activities of promoting HMGCR degradation of these analogs were evaluated. • Compound 29 is the most potent HMGCR degrader. • Compound 29 possessed no side-effect of inducing cholesterol accumulation. [ABSTRACT FROM AUTHOR]