PTGS2 Expression Research Articles

Activation of Piezo1 downregulates renin in juxtaglomerular cells and contributes to blood pressure homeostasis

BackgroundThe synthesis and secretion of renin in juxtaglomerular (JG) cells are closely regulated by the blood pressure. To date, however, the molecular identity through which JG cells respond to the blood pressure remains unclear.ResultsHere we discovered that Piezo1, a mechanosensitive ion channel, was colocalized with renin in mouse kidney as well as As4.1 cells, a commonly used JG cell line. Activation of Piezo1 by its agonist Yoda1 induced an intracellular calcium increase and downregulated the expression of renin in these cells, while knockout of Piezo1 in JG cells abolished the effect of Yoda1. Meanwhile, mechanical stress using microfluidics also induced an intracellular calcium increase in wildtype but not Piezo1 knockout JG cells. Mechanistically, we demonstrated that activation of Piezo1 upregulated the Ptgs2 expression via the calcineurin-NFAT pathway and increased the production of Ptgs2 downstream molecule PGE2 in JG cells. Surprisingly, we discovered that increased PGE2 could decreased the renin expression through the PGE2 receptor EP1 and EP3, which inhibited the cAMP production in JG cells. In mice, we found that activation of Piezo1 significantly downregulated the renin expression and blood pressure in wildtype but not adeno-associated virus (AAV)-mediated kidney specific Piezo1 knockdown mice.ConclusionsIn summary, these results revealed that activation of Piezo1 could downregulate the renin expression in JG cells and mice, subsequently a reduction of blood pressure, highlighting its therapeutic potential as a drug target of the renin-angiotensin system.

Asiatic acid alleviates LPS-induced acute kidney injury in broilers by inhibiting oxidative stress and ferroptosis via activation of the Nrf2 pathway

Asiatic acid (AA), a triterpenoid compound isolated from Centella asiatica, has anti-inflammatory, antioxidant and anticancer biological characteristics. To explore the effect of AA on LPS-induced acute kidney injury (AKI) in broilers, a total of 60 one-day-old broilers were randomly divided into 6 groups, including the normal group, AKI model group, AKI+AA 15mg/kg group, AKI+AA 30mg/kg group, AKI+AA 60mg/kg group and normal+AA 60mg/kg group. Hematoxylin-eosin staining was used to observe the histopathology in kidney tissue, and the mRNA and protein expressions related to oxidative stress and ferroptosis were tested by qPCR and western blotting respectively. AA mitigated vacuolar degeneration and enlarged glomerular space caused by LPS in kidney tissue. Additionally, AA significantly increased the mRNA levels of Nrf2, HO-1, NQO1, GCLC, GCLM, GPX4, SLC7A11 and FTH1, and decreased the mRNA levels of Keap1 and PTGS2 in LPS-induced AKI. Likewise, AA significantly upregulated the protein expressions of Nrf2, HO-1, NQO1, GPX4, SLC7A11 and FTH1, and downregulated the protein expressions of Keap1 and PTGS2 in LPS-induced AKI. These results suggested that AA alleviated LPS-induced AKI by inhibiting oxidative stress and ferroptosis through targeting regulation of the Nrf2 pathway in broilers.

Prostate cancer expressing membrane-bound TGF-α induces bone formation mediated by the autocrine effect of prostaglandin E2 in osteoblasts

Prostate cancer highly metastasizes to bone, and such cancer is associated with severe bone resorption and bone formation at the site of metastasis. Prostaglandin E2 (PGE2) promotes bone resorption in inflammatory diseases; however, the roles in prostate cancer-induced bone formation are still unclear. In the present study, we investigated the effects of membrane-bound TGF-α on prostate cancer-induced bone formation through autocrine PGE2 signaling in osteoblasts. In the prostate cancer explant experiment into tibiae, injected prostate cancer cells induced bone formation with the increased expression of osteogenic genes, such as Runx2 and Wnt5a, and prostaglandin synthase Ptgs2. In osteoblasts, PGE2 increased the number of calcified bone nodules with enhanced expression of Runx2 and Wnt5a. We also screened the factors involved in cancer progression, and 11 EGF family members were found to be expressed in the human prostate cancer cell line PC3. PC3 highly expressed amphiregulin, HB-EGF, and especially TGF-α. Treatment with recombinant TGF-α increased the Ptgs2 expression and PGE2 production in osteoblasts, which promoted the formation of calcified bone nodules, suggesting that the interaction between PC3 and osteoblasts promoted PGE2 production. In co-culture of osteoblasts and fixed PC3 cells, the phosphorylation of EGFR and ERK and subsequent Ptgs2 expression and PGE2 production were increased, an effect that was attenuated by treatment with inhibitors of EGFR and ERK. These results indicate that membrane-bound TGF-α enhances ERK signaling while also inducing PGE2-mediated bone formation in osteoblasts, thus suggesting that prostate cancer regulates both PGE2-mediated bone resorption and bone formation at the site of bone metastasis of prostate cancer.

The coasting time affects the quality of cumulus-oocyte complexes in superstimulated ewes

We hypothesized that the coasting time may be beneficial to the quality of cumulus-oocyte complexes recovered from live ewes, as reported in cattle. The present study assessed the effect of coasting times on the quantity and quality of cumulus-oocyte complexes (COCs) in sheep. All ewes were subjected to the “Day 0 protocol”, followed by an ovarian stimulation (80 mg of pFSH in three decreasing doses), varying only the coasting time [12 (G12), 36 (G36), or 60 h (G60]. In Experiment 1, data regarding follicular population was assessed. In Experiment 2, the COC quality was checked by their morphology, brilliant cresyl blue (BCB) test, evaluation of chromatin condensation pattern, and oocyte diameter. In Experiment 3, genes related to oocyte developmental competence were evaluated in BCB + COCs. The oocytes in the G60 group had more (P < 0.05) large follicles than the other groups and oocytes with a greater diameter than the G12. Oocyte morphology was similar (P > 0.05) among groups, as well as the BCB + COCs quantity. The G60-oocytes presented a better (P < 0.05) configuration of chromatin condensation compared with the other groups and a greater (P < 0.05) gene expression of BMP15, MATER, ZAR1, and PTGS2 compared with G12, and PTGS2 and HAS2 compared with G36 group. In conclusion, 60 h of coasting time positively affects the quality of COCs recovered after subjecting ewes to the “Day 0 protocol” and ovarian superstimulation. Implementing the appropriate coasting time to a given protocol can positively impact the in vitro embryo production outcomes in sheep.

Ameliorative effect of the oil components derived from sweet potato shochu on impaired short-term memory in mice after amyloid β25-35 injection

Sweet potato shochu oil is a by-product of shochu production and usually discarded although some physiological functions are considered. In this study, we investigated the effects of shochu oil on short-term memory using a murine model of spontaneous alternating behavior induced by the intracerebroventricular (ICV) administration of amyloid β25-35 (Aβ25-35). Mice were orally administered shochu oil for 15 days. Experiments with a Y-maze model revealed that the Aβ25-35 caused a significant decrease in spontaneous alternation behavior, and supplementation with shochu oil significantly improved this behavior. DNA microarray analysis revealed that the administration of shochu oil downregulated the expression of S100a9 and Ptgs2, which reportedly exacerbate amyloid β deposition in Alzheimer's disease. The administration of shochu oil upregulated the expression of Dnaja1 and PP2A, which is typically downregulated in Alzheimer's disease. These data suggest that shochu oil possible ameliorates on impaired short-term memory in mice after amyloid β25-35 injection, as indicated by its effects on improving spontaneous alternation behavior and modulating the expressions of related genes.

Integrated bioinformatic analysis to understand the association between phthalate exposure and breast cancer progression

Phthalates have been extensively used as plasticizers while manufacturing plastic-based consumer products. Estradiol mimicking properties and association studies suggest phthalates may contribute to breast cancer (BC). We performed an in-silico analysis and functional studies to understand the association between phthalate exposure and BC progression. Search for phthalate-responsive genes using the comparative toxicogenomics database identified 20 genes as commonly altered in response to multiple phthalates exposure. Of the 20 genes, 12 were significantly differentially expressed between normal and BC samples. In BC samples, 9 out of 20 genes showed a negative correlation between promoter methylation and its expression. AHR, BAX, BCL2, CAT, ESR2, IL6, and PTGS2 expression differed significantly between metastatic and non-metastatic BC samples. Gene set enrichment analysis identified metabolism, ATP-binding cassette transporters, insulin signaling, and type II diabetes as highly enriched pathways. The diagnostic assessment based on 20 genes expression suggested a sensitivity and a specificity >0.91. The aberrantly expressed phthalate interactive gene influenced the overall survival of BC patients. Drug-gene interaction analysis identified 14 genes and 523 candidate drugs, including 19 BC treatment-approved drugs. Di(2-ethylhexyl) phthlate (DEHP) exposure increased the growth, proliferation, and migration of MCF-7 and MDA-MB-231 cells in-vitro. DEHP exposure induced morphological changes, actin cytoskeletal remodeling, increased ROS content, reduced basal level lipid peroxidation, and induced epithelial to mesenchymal transition (EMT). The present approach can help to explore the potentially damaging effects of environmental agents on cancer risk and understand the underlined pathways and molecular mechanisms.

YPEL3 Negatively Regulates Endometrial Function via the Wnt/β-Catenin Pathways during Early Pregnancy in Goats.

In ruminants, the establishment of pregnancy requires a series of structural and functional changes in the endometrium under the action of hormones, thereby providing an optimal environment for the implantation of the embryo. In this study, we explored the molecular mechanism by which YPEL3 regulates endometrial function during gestation in goats. We found YPEL3 expression was significantly downregulated during early gestation and that YPEL3 overexpression inhibited the expression of ISG15, but had no significant effects on the expression of RSAD2 and CXCL10 in goat endometrial epithelial cells (gEECs). In addition, YPEL3 silencing significantly inhibited PGF2α secretion and the expression of the prostaglandin synthesis-related rate-limiting enzyme-encoding genes PGFS and PTGES, with no significant effect on the expression of PTGS1 and PTGS2. Moreover, YPEL3 inhibited the expression of vimentin and β-catenin and pretreatment of gEECs with the β-catenin activator CHIR99021 prevented a YPEL3-induced decrease in vimentin expression. Collectively, our findings confirm that, as a hormone-regulated factor, YPEL3 regulates endometrial function by inhibiting the Wnt/β-catenin signaling pathway and provide new insights for further clarification of the mechanism by which YPEL3 functions during early pregnancy in ruminants.

Mechanism of Tripterygium wilfordii Hook.F.- Trichosanthes kirilowii Maxim decoction in treatment of diabetic kidney disease based on network pharmacology and molecular docking.

Background: Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease. The effective treatment of DKD would rely on the incorporation of a multi-disciplinary. Studies have shown that Tripterygium wilfordii Hook.F. and Trichosanthes kirilowii Maxim have remarkable curative effects in treating DKD, but their combination mechanism has not been fully elucidated. Methods: We explored the mechanism of Tripterygium wilfordii Hook.F.-Trichosanthes kirilowii Maxim decoction (Leigongteng-Tianhuafen Decoction,LTD) in the treatment of DKD by network pharmacology and molecular docking. The main active components and action targets of LTD were collected from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The speculative targets of DKD were obtained from GeneCards, DisGeNET, and Online Mendelian Inheritance in Man (OMIM) databases. Then, an herb-component-target network was constructed based on the above analyses. The biological function of targets was subsequently investigated, and a protein-protein interaction (PPI) network was constructed to identify hub targets of DKD. The gene ontology (GO) function enrichment analysis and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed by RStudio. Finally, molecular docking was performed by AutoDock Vina and PyMOL software to explore the interaction between compounds and targets. Furthermore, the DKD model of human renal tubular cells (HK-2) induced by high glucose (HG) was selected, and the predicted results were verified by western blot analysis and immunofluorescence. Results: A total of 31 active components of LTD were screened out, and 196 targets were identified based on the TCMSP database. A total of 3,481 DKD related targets were obtained based on GeneCards, DisGeNET, and OMIM databases. GO function enrichment analysis included 2,143, 50, and 167 GO terms for biological processes (BPs), cellular composition (CCs), and molecular functions (MFs), respectively. The top 10 enrichment items of BP annotations included response to lipopolysaccharide, response to molecule of bacterial origin, response to extracellular stimulus, etc. CC was mainly enriched in membrane raft, membrane microdomain, plasma membrane raft, etc. The MF of LTD analysis on DKD was predominately involved in nuclear receptor activity, ligand-activated transcription factor activity, RNA polymerase II-specific DNA-binding transcription factor binding, etc. The involvement signaling pathway of LTD in the treatment of DKD included AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, insulin resistance, TNF signaling pathway, etc. Molecular docking results showed that kaempferol, triptolide, nobiletin, and schottenol had a strong binding ability to PTGS2 and RELA. Furthermore, the in vitro experiments confirmed that LTD effectively decreased the expression of PTGS2, NF-κB, JNK, and AKT in the HG-induced DKD model. Conclusion: The findings of this study revealed that the therapeutic efficacy of LTD on DKD might be achieved by decreasing the expression of PTGS2, NF-κB, JNK, and AKT, which might improve insulin resistance, inflammation, and oxidative stress. These findings can provide ideas and supply potential therapeutic targets for DKD.

EVI1 upregulates PTGS1 (COX1) and decreases the action of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia cells.

Tyrosine kinase inhibitors (TKIs) are highly effective in treating chronic myelogenous leukemia (CML). However, primary and acquired drug resistance to TKIs have been reported. In this study, we used RNA sequencing followed by RQ-PCR to show that the proto-oncogene EVI1 targets the drug-metabolizing gene PTGS1 in CML. The PTGS1 promoter element had an EVI1 binding site, and CHIP assay confirmed its presence. Data from a publicly available CML microarray dataset and an independent set of CML samples showed a significant positive correlation between EVI1 and PTGS1 expression in CML. Downregulation of EVI1 in K562 cells and subsequent treatment with TKIs resulted in a lower IC50 in the control cells. Furthermore, combined inhibition of BCR-ABL with imatinib and PTGS1 with FR122047 (PTGS1 inhibitor) synergistically reduced the viability of imatinib-resistant K562 cells. We conclude that elevated EVI1 expression contributes to TKIs resistance and that combined inhibition of PTGS1 and BCR-ABL may represent a novel therapeutic approach.

Dietary supplementation of botanical blends enhanced performance and disease resistance of weaned pigs experimentally infected with enterotoxigenic Escherichia coli F18.

Botanicals exhibit promising impacts on intestinal health, immune-regulation, and growth promotion in weaned pigs. However, these benefits may vary depending on major active components in the final feed additive products. Therefore, this study aimed to investigate two types of botanical blends (BB) that were comprised of 0.3% capsicum oleoresin and 12% garlic extracts from different sources on performance, diarrhea, and health of weaned piglets experimentally infected with a pathogenic Escherichia coli F18. Sixty weanling pigs (7.17 ± 0.97 kg body weight (BW)) blocked by weight and gender were assigned to one of five dietary treatments: negative control (NC), positive control (PC), or dietary supplementation with 100 mg/kg of BB1, 50 mg/kg or 100 mg/kg of BB2. This study lasted 28 d with 7 d before and 21 d after the first E. coli inoculation (day 0). All pigs, except negative control, were orally inoculated with 1010 cfu E. coli F18/3-mL dose for 3 consecutive days. Blood samples were collected periodically to analyze systemic immunity. Intestinal tissues and mucosa were collected on days 5 and 21 PI for analyzing histology and gene expression. All data, except for frequency of diarrhea, were analyzed by ANOVA using the PROC MIXED of SAS. The Chi-square test was used for analyzing frequency of diarrhea. Escherichia coli infection reduced (P < 0.05) growth rate and feed intake and increased (P < 0.05) frequency of diarrhea of weaned pigs throughout the experiment. Supplementation of 100 mg/kg BB1 or BB2 alleviated (P < 0.05) frequency of diarrhea of E. coli challenged pigs during the entire experiment. Escherichia coli infection also enhanced (P < 0.05) serum TNF-α and haptoglobin concentrations on day 4 post-inoculation (PI) but reduced (P < 0.05) duodenal villi height and area on day 5 PI, while pigs supplemented with 100 mg/kg BB1 or BB2 had lower (P < 0.05) serum TNF-α than pigs in PC on day 4 PI. Pigs fed with 100 mg/kg BB2 had higher (P < 0.05) jejunal villi height than pigs in PC on day 5 PI. Pigs fed with 100 mg/kg BB2 had reduced (P < 0.05) gene expression of IL1B, PTGS2, and TNFA in ileal mucosa than pigs in PC on day 21 PI. In conclusion, dietary supplementation of botanical blends at 100 mg/kg could enhance disease resistance of weaned pigs infected with E. coli F18 by enhancing intestinal morphology and regulating local and systemic immunity of pigs.

Highlights from Recent Cancer Literature

Breaking Insights| October 04 2022 Highlights from Recent Cancer Literature Author & Article Information Online ISSN: 1538-7445 Print ISSN: 0008-5472 ©2022 American Association for Cancer Research2022American Association for Cancer Research Cancer Res (2022) 82 (19): 3407–3408. https://doi.org/10.1158/0008-5472.CAN-82-19-BI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record October 4 2022 Citation Highlights from Recent Cancer Literature. Cancer Res 1 October 2022; 82 (19): 3407–3408. https://doi.org/10.1158/0008-5472.CAN-82-19-BI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search The final and critical step of metastasis is colonization in a secondary tissue, which requires suppression of the immune system to prevent tumor cell clearance. Gong and colleagues used mouse models of breast cancer metastasis to investigate whether an immunosuppressive niche in the lung supports metastasis. They found that in the lung, dendritic cell antigen presentation and T-cell stimulation were reduced compared with other organ tissues, due to a population of fibroblasts that expressed PTGS2, the gene encoding cyclooxygenase 2 (COX2), which converts arachidonic acid to prostaglandin E2 (PGE2). Neutrophils, often found at the sites of metastatic cancers, were found to produce high amounts of IL1β that boosted the expression of PTGS2 in lung fibroblasts. The generation of PGE2 was critical for the immunosuppressive activity of the lung fibroblasts, as receptor antagonists for PGE2 could reverse the immunosuppressive phenotype in the lung. Furthermore, blocking the activity of PGE2 synergized... You do not currently have access to this content.

EIF3B stabilizes PTGS2 expression by counteracting MDM2-mediated ubiquitination to promote the development and progression of malignant melanoma.

Malignant melanoma (MM) is a neoplasm that develops from human melanocytes. It was reported that eukaryotic translation initiation factor 3 subunit B (EIF3B) is associated with multiple types of cancers, but its role in MM has not been reported. In the present study, we found that EIF3B was abundantly expressed in MM and was strongly related to lymphatic metastasis and pathological stage of MM patients. In addition, EIF3B depletion could block the progression of MM in vitro and in vivo. In contrast, EIF3B overexpression increased cell proliferation and migration in melanoma cells. More importantly, we identified that EIF3B's driver role in MM was mediated by PTGS2. In detail, we found that EIF3B stabilized PTGS2 expression by inhibiting PTGS2 ubiquitination, which is mediated by the E3 ligase MDM2. Moreover, like EIF3B, silencing PTGS2 could suppress MM development, and more interestingly, it could reverse the situation caused by overexpression of EIF3B in vitro and in vivo. Furthermore, the proliferation and migration inhibited by silencing of EIF3B were also partially recovered by overexpression of PTGS2. Overall, our findings revealed the potential of EIF3B as a therapeutic target for MM. Identification of EIF3B's function in MM may pave the way for future development of more specific and more effective targeted therapy strategies against MM.

Transcriptomic analysis of mRNA expression in giant congenital melanocytic nevi

Background and objective: GCMN is a sporadic disease with an incidence ranging from 1/20,000 to 1/500000. So far, several studies have found that GCMN is related to somatic mutations, but most of them have focused on known pathogenic genes, and transcriptome sequencing based on large datasets is relatively uncommon. At present, the use of next-generation sequencing technologies and bioinformatics platforms makes genomic information study more comprehensive and efficient. In this study, the transcriptome differences between GCMN lesions and surrounding normal skin tissues were investigated using high-throughput transcriptome sequencing, and hub genes and pathways related to pathogenesis were identified, providing a theoretical foundation for further research into the pathogenesis of GCMN.Methods: Pathological skin tissue and surrounding normal skin tissue from GCMN patients, namely the pathological group (PG) and the control group (CG), were obtained.1. All specimens were stained with HE to ensure that the samples met the experimental requirements.2. Ten pairs of specimens were selected for high-throughput transcriptome sequencing, and the differentially expressed genes (DEGs) between the PG and the CG were obtained. The DEGs were analyzed by clusterProfiler R software for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The function of the subnetwork was analyzed and the hub genes were identified by the STRING database and Cytoscape software.3. The expression differences of hub genes PTGS2, EGF, and SOX10 in pathological skin tissues and normal skin tissues were verified by qRT-PCR and immunofluorescence staining.Results: 1. HE staining revealed a lot of melanocytes in the dermis and subcutaneous tissues. They were found around the hair follicles, sweat glands, sebaceous glands, and blood vessel walls, or in a specific pattern.2. The screening threshold was set at p < 0.01 and |log2fc|<1, and a total of 1163 DEGs were discovered between the PG and CG, with 519 genes up-regulated and 644 genes down-regulated in the pathological tissues. According to the GO functional analysis, 29 biological processes, 18 cell compositions, and 17 molecular functions were significantly enriched, with the majority of them being related to keratinocytes and the extracellular matrix. There were 779 nodes and 2359 interactions in the protein interaction network. Using the MCODE plug-in, the network was divided into 25 functional clusters. According to ClueGO results, Cluster5 was involved in melanin biosynthesis and melanocyte proliferation. Using 11 operation methods in the Cytohubba plug-in, PTGS2, EGF, and SOX10 in Cluster5 were chosen as hub genes.3. qRT-PCR and immunofluorescent staining revealed that compared to normal skin tissue, the expression of SOX10 was significantly up-regulated, and the expression of PTGS2 and EGF was significantly down-regulated in pathological skin tissue(P < 0.001).Conclusions: In GCMN, keratinocytes and extracellular matrix may directly and indirectly affect melanocyte activity. PTGS2, EGF, and SOX10 are important genes and significantly differentially expressed in pathological and normal skin tissues. These findings may serve as a springboard for future research.

Utilizing network pharmacology and experimental validation to investigate the underlying mechanism of phellodendrine on inflammation.

BackgroundPhellodendrine, one of the characteristic and important active components of Cortex phellodendri, has been proven to show anti-inflammatory effects. However, the underlying mechanism of phellodendrine on inflammation remains largely unclear.Aim of the studyIn this study, network pharmacology and experimental validation were used to explore the underlying mechanism of phellodendrine on inflammation.Materials and MethodsPubChem and SwissADME database were used to evaluate the drug-likeness and other characteristics of phellodendrine. The targets of phellodendrine for the treatment of inflammation were analyzed with multiple databases. Other extensive analyses including protein–protein interaction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were accomplished with the STRING database, Cytoscape software, and DAVID database. Moreover, the effect of phellodendrine on anti-inflammation was proven in RAW264.7.ResultsThe network pharmacology results indicated that phellodendrine had drug potential. Phellodendrine acted directly on 12 targets, including PTGS1, PTGS2, HTR1A, and PIK3CA, and then regulated cAMP, estrogen, TNF, serotonergic synapse, and other signaling pathways to exert anti-inflammatory effects. The experimental results showed that phellodendrine reduced the levels of IL-6 compared with the LPS group in 24 h and changed the mRNA expression of PTGS1, PTGS2, HSP90ab1, AKT1, HTR1A, PI3CA, and F10.ConclusionOur research preliminarily uncovered the therapeutic mechanisms of phellodendrine on inflammation with multiple targets and pathways. Phellodendrine may be a potential treatment for inflammation-related diseases related to the cAMP and TNF signaling pathways.

LncRNA-CASC15 knockdown inhibits the progression of esophageal squamous cell carcinoma through targeting miR-33a-5p/PTGS2 axis.

LncRNA CASC15 has been determined as a novel tumor-related lncRNA in many cancers. However, the in-detail role of CASC15 remains elusive in esophageal squamous cell carcinoma (ESCC). CASC15 expression level was detected in 113 ESCC tissues and paired adjacent normal tissues and in human ESCC cell lines. The effects of CASC15 on ESCC proliferation, migration, and invasion were assessed using CCK-8 and transwell assays. In addition, the potential downstream molecules of CASC15 were searched and confirmed by software algorithms, RT-qPCR, western blot, dual-luciferase reporter, and rescue experiments. CASC15 was upregulated in ESCC tissues and cell lines. CASC15 overexpression was associated with poorer prognosis in ESCC patients. Functionally, CASC15 knockdown inhibited cell proliferation, migration, and invasion of ESCC cells. Mechanistically, it was confirmed that CASC15 acts as competing endogenous RNA for miR-33a-5p to regulate PTGS2 expression. In addition, rescue assay showed that miR-33a-5p knockdown or PTGS2 overexpression abolished the cell proliferation, migration, and invasion inhibition role of CASC15 knockdown. In conclusion, this study indicates that CASC15 was upregulated in ESCC and CASC15 knockdown hindered ESCC progression through targeting the miR-33a-5p/PTGS2 axis. CASC15 might serve as a novel biomarker and therapeutic target for ESCC.

HIF-1α is essential for the augmentation of myometrial contractility during labor†.

Uterine contraction is crucial for a successful labor and the prevention of postpartum hemorrhage. It is enhanced by hypoxia; however, its underlying mechanisms are yet to be elucidated. In this study, transcriptomes revealed that hypoxia-inducible factor-1alpha was upregulated in laboring myometrial biopsies, while blockade of hypoxia-inducible factor-1alpha decreased the contractility of the myometrium and myocytes in vitro via small interfering RNA and the inhibitor, 2-methoxyestradiol. Chromatin immunoprecipitation sequencing revealed that hypoxia-inducible factor-1alpha directly binds to the genome of contraction-associated proteins: the promoter of Gja1 and Ptgs2, and the intron of Oxtr. Silencing the hypoxia-inducible factor-1alpha reduced the expression of Ptgs2, Gja1, and Oxtr. Furthermore, blockade of Gja1 or Ptgs2 led to a significant decrease in myometrial contractions in the hypoxic tissue model, whereas atosiban did not remarkably influence contractility. Our study demonstrates that hypoxia-inducible factor-1alpha is essential for promoting myometrial contractility under hypoxia by directly targeting Gja1 and Ptgs2, but not Oxtr. These findings help us to better understand the regulation of myometrial contractions under hypoxia and provide a promising strategy for labor management and postpartum hemorrhage treatment.

A network pharmacology approach to identify the mechanisms and molecular targets of curcumin against Alzheimer disease.

Background:Alzheimer disease (AD) is a degenerative brain disease, which may lead to severe memory loss and other cognitive disorders. However, few effective drugs are available in the clinic at present. Curcumin, a major ingredient of traditional Chinese medicine, Curcuma Longa, has various pharmacological activities. Therefore, exploring clinical drugs based on the inhibition of AD pathological features is imperative.Methods:First, we utilized the HERB database and Swisstarget Prediction database to get the related targets of curcumin and intersected with the AD targets. The intersection targets were used to construct the protein-protein interaction network and performed gene ontology and kyoto encyclopedia of genes and genomes analyses. Further, we obtained targets of curcumin against AD-related tau and aβ pathology via the AlzData database. These targets were applied to perform GEO and receiver operating characteristic analyses. Finally, the reliability of the core targets was evaluated using molecular docking technology.Results:We identified 49 targets of curcumin against AD, and kyoto encyclopedia of genes and genomes pathway enrichment analysis demonstrated that the Alzheimer disease pathway (has05010) was significantly enriched. Even more, we obtained 16 targets of curcumin-related Aβ and tau pathology. Among these targets, 8 targets involved the Alzheimer disease pathway and the biological process analyses showed that positive regulation of cytokine production (GO:0001819) was significantly enriched. Bioinformatic analyses indicated that HMOX1, CSF1R, NFKB1, GSK3B, BACE1, AR, or PTGS1 expression was significantly different compared to the control group in the AD patients. Finally, molecular docking studies suggested these genes have a good binding force with curcumin.Conclusions:In this study, we identified curcumin exerted the effect of treating AD by regulating multitargets and multichannels through the method of network pharmacology.

Agomelatine Changed the Expression and Methylation Status of Inflammatory Genes in Blood and Brain Structures of Male Wistar Rats after Chronic Mild Stress Procedure.

The preclinical research conducted so far suggest that depression development may be influenced by the inflammatory pathways both at the periphery and within the central nervous system. Furthermore, inflammation is considered to be strongly connected with antidepressant treatment resistance. Thus, this study explores whether the chronic mild stress (CMS) procedure and agomelatine treatment induce changes in TGFA, TGFB, IRF1, PTGS2 and IKBKB expression and methylation status in peripheral blood mononuclear cells (PBMCs) and in the brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or agomelatine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our findings confirm that both CMS and antidepressant agomelatine treatment influenced the expression level and methylation status of the promoter region of investigated genes in PBMCs and the brain. What is more, the present study showed that response to either stress stimuli or agomelatine differed between brain structures. Concluding, our results indicate that TGFA, TGFB, PTGS2, IRF1 and IKBKB could be associated with depression and its treatment.

Distinctive gene expression patterns in pregnancy-associated breast cancer.

Pregnancy-associated breast cancer (PABC) is diagnosed during pregnancy or within 1 year postpartum, but the unique aspects of its etiology and pathogenesis have not been fully elucidated. This study aimed to ascertain the molecular mechanisms of PABC to facilitate diagnosis and therapeutic development. The Limma package was used to characterize the differentially expressed genes in PABC as compared to non-pregnancy-associated breast cancer (NPABC) and normal breast tissue. A total of 871 dysregulated genes were identified in the PABC versus NPABC groups and 917 in the PABC versus normal groups, with notable differences in the expression of MAGE and CXCL family genes. The dysregulated genes between the PABC and normal groups were mainly associated with signal transduction and immune response, while Kyoto Encyclopedia of Genes and Genomes analysis revealed that the dysregulated genes were enriched in immune-related pathways, including the major histocompatibility complex (MHC) class II protein complex, the type I interferon signaling pathway, regulation of α-β T-cell proliferation, and the T-cell apoptotic process. Through protein-protein interaction network construction, CD44 and BRCA1 were identified as prominent hub genes with differential expression in PABC versus NPABC. Furthermore, a cluster with eleven hub genes was identified in PABC versus normal adjacent tissues, of which the expression of EGFR, IGF1, PTGS2, FGF1, CAV1, and PLCB1 were verified to be differentially expressed in an independent cohort of PABC patients. Notably, IGF1, PTGS2, and FGF1 were demonstrated to be significantly related to patient prognosis. Our study reveals a distinctive gene expression pattern in PABC and suggests that IGF1, PTGS2, and FGF1 might serve as biomarkers for diagnosis and prognosis of PABC.

LTBP2 Knockdown Promotes Ferroptosis in Gastric Cancer Cells through p62-Keap1-Nrf2 Pathway.

Gastric cancer (GC) is one of the most common gastrointestinal malignancies. Ferroptosis is a new type of peroxidation-driven and iron-dependent cell death. However, the biological functions and exact regulatory mechanisms of ferroptosis in GC remain elusive. Here, we performed RNAi and gene transfection, cell viability assay, lipid peroxidation assay, reactive oxygen species (ROS) assay, glutathione assay, qRT-PCR, Western blotting, and transmission electron microscopy (TEM) to study ferroptosis in gastric cancer. The results revealed that silencing latent transforming growth factor β binding proteins (LTBP2) can significantly inhibit GC cell proliferation and decrease cellular GSH levels, reduce GPX4 activity, and increase ROS generation and malondialdehyde (MDA) levels, leading to ferroptosis in GC cells. In addition, we demonstrate that suppression of LTBP2 could regulate the p62-Keap1-Nrf2 pathway, thereby downregulating the GPX4 and xCT expression and upregulating the PTGS2 and 4HNE expression. Our findings described a new role of LTBP2 in regulating ferroptosis, which heralds the prospect of ferroptosis-mediated cancer therapy.