Curcumin protects retinal photoreceptors in Glaucoma by activating prostaglandin D2 synthase-dependent NRF2 signaling.

Objective: To investigate prostaglandin D2 synthase (PTGDS) expression in non-small cell lung carcinoma (NSCLC) and clarify whether PTGDS could be a biomarke. Methods: Firstly, the protein expression level of PTGDS in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were analyzed respectively through Gene Expression Omnibus (GEO)dataset. Then, the results were verified by using tissue microarray (TMA). At last, in order to explore the inner mechanism, lung adenocarcinoma cell lines A549 and Calu-3 were selected to over-express PTGDS, and then transwell chamber assay and Western blotting were used to detect associated changes. Results: PTGDS expression is down-regulated in both ADC and SCC, however, no statistical difference has been found between the two groups, and PTGDS was only related to the progression of ADC. Furthermore, After over-expression of PTGDS, the invasiveness of ADC cells was significantly decreased. Western blotting showed that the inner mechanisms may be related to mitogen-activated protein kinase (MAPK) signal pathway. Conclusions: This study revealed that PTGDS was down-regulated in NSCLC and only related to the development of ADC. It may be a potential biomarker for the diagnosis and prognosis of NSCLC. However, whether it could be used for the treatment of NSCLC still needs more research.

Targeting Glycosylated Ptgds Displays Anti-Tumor Activities in Diffuse Large B-Cell Lymphoma through Down-Regulation of Wnt Pathway

A Parkinson's disease gene, DJ-1, regulates anti-inflammatory roles of astrocytes through prostaglandin D2 synthase expression

Esophageal squamous cell carcinoma (ESCC) exhibits poor survival linked to M2 macrophage-polarized microenvironment. This study aimed to elucidate the role of prostaglandin D2 synthase (PTGDS) in modulating tumor microenvironment (TME) and its prognostic implications in ESCC. Transcriptomic datasets (GSE53624, GSE121931) were analyzed using immune deconvolution and weighted gene co-expression network analysis to identify genes associated with M2 macrophage infiltration. Differentially expressed genes between tumor and normal tissues were assessed in Gaozhou-RNA cohort. Cox regression analyses were conducted to evaluate prognostic factors. A nomogram incorporating PTGDS expression and clinicopathological parameters was developed and validated by immunohistochemistry (IHC) which was performed in the Gaozhou-IHC cohort. In vitro experiments were used to validate the role of PTGDS. PTGDS expression was significantly downregulated in ESCC tissues and reduced PTGDS expression was identified as a significantly prognostic factor for worse overall survival (OS). A combined nomogram demonstrated strong predictive accuracy, with area under the curve (AUC) values of 0.63, 0.77, and 0.83 for 1-, 3-, and 5-year OS predictions in the GSE53624 cohort, which remained consistent across validation cohorts (GSE121931 and Gaozhou-IHC cohort). Lower PTGDS expression was significantly associated with increased myeloid-derived suppressor cells recruitment, reduced T cell infiltration, and impaired T cell cytotoxicity. IHC confirmed elevated CD206 + M2 macrophage infiltration in PTGDS-low tumors. In vivo and in vitro experiments further demonstrated PTGDS overexpression effectively suppressed M2 macrophage polarization. PTGDS deficiency promotes immunosuppressive TME remodeling and predicts unfavorable clinical outcomes in ESCC, which might be a potential prognostic biomarker in ESCC.

Prostaglandin D2 synthase related to estrogen in the female reproductive tract

Glycoprotein prostaglandin D2 synthase (PTGDS) is a member of the lipocalin superfamily and plays dual roles in prostaglandins metabolism and lipid transport. PTGDS has been involved in various cellular processes including the tumorigenesis of solid tumors, yet its role in carcinogenesis is contradictory and the significance of PTGDS in hematological malignancies is ill-defined. Here, we aimed to explore the expression and function of PTGDS in diffuse large B-cell lymphoma (DLBCL), especially the potential role of PTGDS inhibitor, AT56, in lymphoma therapy. Remarkable high expression of PTGDS was found in DLBCL, which was significantly correlated with poor prognosis. PTGDS overexpression and rhPTGDS were found to promote cell proliferation. Besides, in vitro and in vivo studies indicated that PTGDS knockdown and AT56 treatment exerted an anti-tumor effect by regulating cell viability, proliferation, apoptosis, cell cycle, and invasion, and enhanced the drug sensitivity to adriamycin and bendamustine through promoting DNA damage. Moreover, the co-immunoprecipitation-based mass spectrum identified the interaction between PTGDS and MYH9, which was found to promote DLBCL progression. PTGDS inhibition led to reduced expression of MYH9, and then declined activation of the Wnt-β-catenin-STAT3 pathway through influencing the ubiquitination and degradation of GSK3-β in DLBCL. The rescue experiment demonstrated that PTGDS exerted an oncogenic role through regulating MYH9 and then the Wnt-β-catenin-STAT3 pathway. Based on point mutation of glycosylation sites, we confirmed the N-glycosylation of PTGDS in Asn51 and Asn78 and found that abnormal glycosylation of PTGDS resulted in its nuclear translocation, prolonged half-life, and enhanced cell proliferation. Collectively, our findings identified for the first time that glycoprotein PTGDS promoted tumorigenesis of DLBCL through MYH9-mediated regulation of Wnt-β-catenin-STAT3 signaling, and highlighted the potential role of AT56 as a novel therapeutic strategy for DLBCL treatment.

PurposeWe aimed to analyse the correlation between prostaglandin D2 synthase (PTGDS) and a diffuse large B-cell lymphoma (DLBCL) prognosis.MethodsWe retrospectively collected two hundred paraffin-embedded tissue specimens that were pathologically diagnosed as DLBCL in the Fujian Tumour Hospital between January 2014 and December 2018. An abundance of paraffin-embedded tumour tissues were obtained. Twenty patients with lymphocyte-rich, benign, tissue-reactive, hypertrophic tonsillitis were selected as controls. Wax blocks were selected for primary cases and the controls were screened by professional pathologists. The levels of prostaglandin D2 synthase (PTGDS) and the EMT-related molecules, E-cadherin and vimentin, were detected by immunohistochemistry in clinical samples. A chi-square test revealed the correlations between PTGDS expression and clinicopathological characteristics, including age, sex, primary site, clinical stage, immunotyping, and International Prognostic Index (IPI) score. The Kaplan–Meier survival analysis was performed, and the diagnostic value was evaluated by receiver operating characteristic (ROC) curve analysis.ResultsA total of 138 cases (69%) were found to be PTGDS positive (> 30% positive cells). PTGDS staining was negative (< 30% positive cells) in 62 cases (31%). We collected the corresponding clinicopathological information and found that PTGDS expression was not significantly related to the patients’ age, tumour stage, presence of extranodal invasion, or IPI score. According to the follow-up data, patients with low PTGDS expression had poor progression-free survival (PFS) and overall survival (OS), with 2-year PFS and OS rates of 41.7% and 50%, respectively. The 2-year PFS and OS rates of PTGDS-positive patients were 89.3% and 92.9%, respectively (P < 0.0001), and the differences were significant.ConclusionWe found that the expression level of PTGDS is significantly correlated with the prognosis of diffuse large B-cell lymphoma.

Tumour-infiltrating immune cells have been indicated to play an important role in prognosis prediction and therapy sensitivity for breast cancer. In recent years, estimating the abundance of immune cells based on tumour transcriptome data has provided a novel way to analyse the clinical significance of various immune cell subsets. This study integrated breast cancer tissue transcriptome datasets from the Gene Expression Omnibus (GEO), the Cancer Genome Atlas-Breast Cancer (TCGA-BRCA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. A novel breast cancer immunotyping and a new prognostic model based on tumour-infiltrating immune cell subsets have been established, aiming to provide new clues regarding prognostic prediction and precision therapy for breast cancer. The key differentially expressed gene between different breast cancer immunotypes has also been identified. We performed unsupervised clustering analysis and construct a novel immunotyping which could classify breast cancer cases into immunotype A (B_cellhigh NKhigh CD8+_Thigh CD4+_memory_T_activatedhigh γδTlow Mast_cell_activatedlow Neutrophillow) and immunotype B (B_celllow NKlow CD8+_Tlow CD4+_memory_T_activatedlow γδThigh Mast_cell_activatedhigh Neutrophilhigh) in luminal B, HER2-enriched and basal-like subtypes. The 5-year (85.7% vs. 73.4%) and 10-year OS (75.60% vs. 61.73%) of immunotype A population were significantly higher than those of immunotype B. A novel tumour-infiltrating immune cell-based prognostic model had also been established and the result immunorisk score (IRS) could serve as a new prognostic factor for luminal B, HER2-enriched and basal-like breast cancer. The higher IRS was, the worse prognosis was. We further screened the differentially expressed genes between immunotype A and B and identified a novel breast cancer immune-related gene, prostaglandin D2 synthase (PTGDS) and higher PTGDS mRNA expression level was positively correlated with earlier TNM stage. Immune-related signaling pathways analysis and immune cell subsets correlation analysis revealed that PTGDS expression was related with abundance of B cells, CD4+ T cells and CD8+ T cells, which was finally validated by immunohistochemical and immunofluorescence staining. We established a novel immunotyping and a tumour-infiltrating immune cell-based prognostic prediction model in luminal B, HER2-enriched and basal-like breast cancer by analyzing the prognostic significance of multiple immune cell subsets. A novel breast cancer immune signature gene PTDGS was discovered, which might serve as a protective prognostic factor and play an important role in breast cancer development and lymphocyte-related immune response.

There is increasing evidence of sex differences in underlying mechanisms causing pain in preclinical models, and in clinical populations. There are also important disconnects between clinical pain populations and the way preclinical pain studies are conducted. For instance, osteoarthritis pain more frequently affects women, but most preclinical studies have been conducted using males in animal models. The most widely used painkillers, nonsteroidal anti-inflammatory drugs (NSAIDs), act on the prostaglandin pathway by inhibiting cyclooxygenase (COX) enzymes. The purpose of this study was to analyze the preclinical and clinical literature on the role of prostaglandins and COX in inflammation and pain. We aimed to specifically identify studies that used both sexes and investigate whether any sex-differences in the action of prostaglandins and COX inhibition had been reported, either in clinical or preclinical studies. We conducted a PubMed search and identified 369 preclinical studies and 100 clinical studies that matched our inclusion/exclusion criteria. Our analysis shows that only 17% of preclinical studies on prostaglandins used both sexes and, out of those, only 19% analyzed or reported data separated by sex. In contrast, 79% of the clinical studies analyzed used both sexes. However, only 6% of those reported data separated by sex. Interestingly, 14 out of 15 preclinical studies and 5 out of 6 clinical studies that analyzed data separated by sex have identified sex-differences. This builds on the increasing evidence of sex-differences in prostaglandin signaling and the importance of sex as a biological variable in data analysis. The preclinical literature identifies a sex difference in prostaglandin D2 synthase (PTGDS) expression where it is higher in female than in male rodents in the nervous system. We experimentally validated that PTGDS expression is higher in female human dorsal root ganglia (DRG) neurons recovered from organ donors. Our semi-systematic literature review reveals a need for continued inclusivity of both male and female animals in prostaglandins studies and data analysis separated by sex in preclinical and clinical studies. Our finding of sex-differences in neuronal PTGDS expression in humans exemplifies the need for a more comprehensive understanding of how the prostaglandin system functions in the DRG in rodents and humans.

Hrev107, also called HRASLS3 or PLA2G16, is a member of the HREV107 type II tumor suppressor gene family which includes HREV107, Retinoid-inducible gene 1 (RIG1), and HRASLS. The protein in this family contains an NC domain, with unknown function at the N-terminus, and a hydrophobic membrane-anchoring domain at the C-terminus. HREV107 has shown that expressed at high levels in differentiated tissues of post-meiotic testicular germ cells but not in human testicular germ cell tumors. Prostaglandin D2 (PGD2) has shown that can induce SOX-9 nuclear translocation and subsequent Sertoli cell differentiation. In addition, expression of the Prostaglandin D2 synthase (PTGDS) has been detected in the cellular lineage. This gives rise to the Sertoli cells, and the Sertoli cells appear to express the PTGDS only during the VI-VIII stages of the spermatogenic cycle after spermiation. These results suggested that PGD2 may play an important role in the testis differentiation. Our previous result showed that RIG1 (as RIG1 is expressed in the human species only) can interact with PTGDS. We further examined the effect of mouse Hrev107 on the growth of mouse testicular cells. When Hrev107 was expressed in TM3 or TM4 mouse testicular cancer cells, the cell migration and invasion were inhibited. Further, we found PTGDS was co-localized with Hrev107 in TM4 testis cells. In Hrev107-expressing NT2/D1 cells, elevated levels of PGD2, cAMP, and SRY-related high-mobility group box 9 (SOX9) were observed. This result indicated that Hrev107 can enhance PTGDS activity. Silencing of PTGDS expression significantly decreased h-REV107-mediated cAMP and PGD2 production. Furthermore, silencing of PTGDS or SOX9 alleviated Hrev107-mediated suppression of migration and invasion. These results suggest that Hrev107 will suppress cell migration/invasion through the PGD2 signaling pathway. In conclusion, Hrev107 can interact with PTGDS to enhance its function and to further suppress NT2/D1 cell migration and invasion. Citation Format: Fu-Ming Tsai, Chang-Chieh Wu, Rong-Yaun Shyu, Shun-Yuan Jiang. Hrev107 enhances prostaglandin D2 synthase-mediated cancer cells suppression in the testis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5384. doi:10.1158/1538-7445.AM2013-5384

Immune dysregulation significantly contributes to skin fibrosis in systemic sclerosis (SSc), with pro-inflammatory fibroblasts playing a pivotal role in this process. Prostaglandin D2 synthase (PTGDS) has garnered interest due to its enriched expression in pro-inflammatory fibroblasts associated with skin fibrosis. This study aims to elucidate the role of PTGDS in skin fibrosis in SSc and evaluate its potential as a therapeutic target. PTGDS expression in skin tissues from SSc patients was analysed through bioinformatics and validated using immunohistochemistry, RT-PCR, and Western blotting. The biological role of PTGDS in fibroblast inflammatory priming was examined using PTGDS-overexpressed BJ cells and the PTGDS inhibitor AT56 in vitro. The therapeutic effect of targeting PTGDS in skin inflammation and fibrosis was validated using a bleomycin (BLM)-induced skin fibrosis mouse model. PTGDS expression levels were significantly elevated in the dermal fibroblasts of SSc patients. In vitro, overexpression of PTGDS resulted in the upregulation of various chemokines in skin fibroblasts, subsequently enhancing the migration of CD4+ T cells, particularly the Th2 subset, which was effectively reversed by inhibition of PTGDS with the inhibitor AT56. PTGDS-overexpressed fibroblasts promoted Th2 cell infiltration and skin fibrosis, and oral administration of AT56 significantly attenuated BLM-induced skin inflammation and fibrosis in vivo. PTGDS-induced pro-inflammatory fibroblasts caused Th2 cell infiltration and skin fibrosis. Inhibition of PTGDS attenuated the inflammation and fibrosis in the skin. These results demonstrate that PTGDS is a critical regulator of the pro-inflammatory function of skin fibroblasts, providing a promising therapeutic target for SSc.

AMP-activated protein kinase (AMPK), an evolutionarily conserved serine-threonine kinase that senses cellular energy status, is activated by stress and neurohumoral stimuli. We investigated the mechanisms by which adrenergic signaling alters AMPK activation in vivo. Brown adipose tissue (BAT) is highly enriched in sympathetic innervation, which is critical for regulation of energy homeostasis. We performed unilateral denervation of BAT in wild type (WT) mice to abolish neural input. Six days post-denervation, UCP-1 protein levels and AMPK α2 protein and activity were reduced by 45%. In β(1,2,3)-adrenergic receptor knock-out mice, unilateral denervation led to a 25-45% decrease in AMPK activity, protein expression, and Thr(172) phosphorylation. In contrast, acute α- or β-adrenergic blockade in WT mice resulted in increased AMPK α Thr(172) phosphorylation and AMPK α1 and α2 activity in BAT. But short term blockade of α-adrenergic signaling in β(1,2,3)-adrenergic receptor knock-out mice resulted in decreased AMPK activity in BAT, which strongly correlated with enhanced phosphorylation of AMPK on Ser(485/491), a site associated with inhibition of AMPK activity. Both PKA and AKT inhibitors attenuated AMPK Ser(485/491) phosphorylation resulting from α-adrenergic blockade and prevented decreases in AMPK activity. In vitro mechanistic studies in BAT explants showed that the effects of α-adrenergic blockade appeared to be secondary to inhibition of oxygen consumption. In conclusion, adrenergic pathways regulate AMPK activity in vivo acutely via alterations in Thr(172) phosphorylation and chronically through changes in the α catalytic subunit protein levels. Furthermore, AMPK α Ser(485/491) phosphorylation may be a novel mechanism to inhibit AMPK activity in vivo and alter its biological effects.

Reduction in the mRNA and protein expression of lipocalin-like prostaglandin D(2) (PGD(2)) synthase (PGDS), the main arachidonic acid metabolite produced in neurons and glial cells of the central nervous system, is a significant biological event involved in the malignant progression of astrocytomas and is predictive of poor survival. In vitro, the addition of the main PGDS metabolite, PGD(2), to A172 glioblastoma cells devoid of PGDS resulted in antiproliferative activity and cell death. In vitro PGD(2) substitution also enhanced the efficacy of cyclo-oxygenase-2 inhibitors. This finding has exciting implications for early interventional efforts for the grade 2 and 3 astrocytomas.

Head and neck squamous cell carcinoma (HNSCC) constitutes a significant global disease burden. Evasion of programmed cell death (PCD) is a hallmark of HNSCC progression. Cancer-associated fibroblasts (CAFs) are a major cellular component of the HNSCC tumor microenvironment (TME). However, the mechanism by which CAFs contribute to PCD resistance remains poorly understood. This study included 24 single-cell sequencing samples, the Cancer Genome Atlas (TCGA) data, and spatial transcriptome data from HNSCC samples. Single-cell data were clustered using the Seurat package, and pseudotemporal trajectory analysis of CAF subsets was performed with Monocle2. The random forest algorithm was used to assess the prognostic importance of candidate genes. The ssGSEA and CIBERSORT algorithms were used to assess immune cell infiltration patterns in the TCGA samples. Gain-of-function assays, Western blotting, and immunohistochemistry were conducted to validate the biological functions of key targets. Here, we identified seven CAF subsets and clarified their potential differentiation directions. Thirty-two CAF-associated PCD regulators with prognostic significance were identified, among which, prostaglandin D2 synthase (PTGDS) and squalene epoxidase (SQLE) are the most important genes. PTGDS is significantly downregulated in HNSCC and associated with favorable prognosis. PTGDS overexpression significantly inhibited clonogenicity, proliferation, and invasion while promoting apoptosis in HNSCC cells (p < 0.05). In addition, PTGDS expression is significantly enriched in B cell-related pathways. Mechanistically, PTGDS overexpression increased chemokine (C-X-C motif) ligand 13 (CXCL13) expression and enhanced immune cell infiltration. These findings identified PTGDS as a central regulator linking CAF-mediated PCD resistance and B cell immune modulation in HNSCC, suggesting its potential as both a diagnostic biomarker and therapeutic target.

The myocardium possesses intrinsic protective mechanisms against ischemia and reperfusion injury (I/R). 5′AMP-activated protein kinase (AMPK) is known as regulator of cellular energy status and is reduced during diabetes mellitus. Recently, AMPK is also implicated in ischemic preconditioning leading to cardioprotection against I/R. We hypothesize that AMPK is involved in anesthetic-induced cardioprotection and that this AMPK activation is evoked by production of reactive oxygen species (ROS). Isolated Langendorff-perfused rat hearts were subjected to 35 minutes of global ischemia followed by 120 minutes of reperfusion. Hearts were divided into 2 groups: a Control group and a Sevo group receiving three times 5-minute episodes of 2.5 vol% sevoflurane before I/R. AMPK phosphorylation was determined with Western Blot analysis. Cardioprotection was assessed as recovery of left ventricular pressure after I/R and as infarct size using triphenyltetrazolium chloride staining. In the Control group, I/R resulted in a twofold increase in phosphorylation levels of AMPK (Control 1.0 ± 0.1 vs. Control-I/R: 2.3 ± 0.1 a.u., n = 4, p &lt; 0.05). Sevoflurane preconditioning did not immediately, prior to ischemia, affect the AMPK phosphorylation (Sevo 0.9 ± 0.2 vs. Control 1.0 ± 0.2, n = 6), but doubled the increase in AMPK phosphorylation to control after ischemia (Sevo-I: 2.0 ± 0.5 (vs. Control-I), n = 6, p &lt; 0.05), as well as after I/R (Sevo-I/R: 2.1 ± 0.3 vs. (Control-I/R), n = 6, p &lt; 0.05). The AMPK-inhibitor compound C (1 and 10 μM) reduced the increase in AMPK phosphorylation and abolished the cardioprotection derived from functional recovery and infarct size. In addition, the ROS-scavenger n-(2-mercaptopropionyl)-glycine (MPG, 1mM) also reduced the sevoflurane-mediated increase in AMPK phosphorylation and completely prevented cardioprotection. These results demonstrate for the first time a direct link between AMPK activation and the production of ROS in cardioprotection. We conclude that anesthetic-induced AMPK activation protects the heart against I/R and relies on production of ROS, which might be especially important in the context of impaired cardioprotection in the diabetic myocardium.