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Taiwanese Journal of Obstetrics &... Nov 2023To evaluate the efficacy and safety of dinoprostone tablet and continuous vaginal insert (Propess®) in low-risk nulliparous women at term with insufficient cervical...
OBJECTIVE
To evaluate the efficacy and safety of dinoprostone tablet and continuous vaginal insert (Propess®) in low-risk nulliparous women at term with insufficient cervical ripening receiving elective induction.
MATERIALS AND METHODS
A retrospective study was conducted between March 2020 and February 2022 and included 230 women who underwent elective induction with dinoprostone tablet or vaginal insert. The primary endpoint was failure of induction. Secondary endpoints included time to vaginal delivery, vaginal delivery rate, as well as maternal and neonatal complications and adverse outcomes.
RESULTS
No statistically significant differences were found between the two groups regarding the main outcome measures; however, the high responders had a significant higher proportion of hyperstimulation and non-reassuring fetal status. The high responder in the Propess group was statistically significant younger (31.68 ± 4.73 vs. 33.82 ± 4.39, p = 0.027), while they had a significantly lower BMI at delivery time of the tablet group (24.49 ± 2.24 vs. 27.42 ± 4.32, p = 0.024). Factors associated with success of vaginal delivery within 24 h (p = 0.015, OR = 0.9, 95%CI = 0.82-0.98) and the Cesarean section (p < 0.001, OR = 1.17, 95%CI = 1.08-1.27) was BMI at delivery time.
CONCLUSION
Slow-release vaginal insert and dinoprostone tablet had similar efficacy and safety for elective induction in low risk nulliparous women at term. Women with younger maternal age or lower BMI at delivery time may have a better response to dinoprostone and had a significantly higher proportion of hyperstimulation and non-reassuring fetal status.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Dinoprostone; Oxytocics; Cesarean Section; Retrospective Studies; Labor, Induced; Administration, Intravaginal; Tablets
PubMed: 38008505
DOI: 10.1016/j.tjog.2023.03.016 -
Journal of Cancer Research and Clinical... Jul 2023In recent years, incidence of vulvar cancer has been on the rise, whereas therapeutic options are still restricted. Therefore, new prognosticators and therapeutic...
PURPOSE
In recent years, incidence of vulvar cancer has been on the rise, whereas therapeutic options are still restricted. Therefore, new prognosticators and therapeutic targets are essential. Chronic inflammation plays an important role in carcinogenesis and COX-2, and its product prostaglandin E2 and its receptors EP1-4 are known to be important mediators in cancer initiation and progression.
METHODS
EP1 expression in vulvar cancer specimens (n = 129) was investigated via immunohistochemistry and evaluated using the well-established immunoreactive score (IRS). Subsequently, the values were correlated with clinicopathological parameters.
RESULTS
Our analysis did not reveal EP1 expression as a negative prognostic factor in overall and disease-free survival. However, in the subgroup of patients with lymph-node metastasis, overall survival was significantly shorter in tumors with high EP1 expression. Moreover, EP1 expression correlated positively with good differentiation of the tumor, but not with p16 status or COX-2 expression.
CONCLUSIONS
This study shed first light on EP1 expression in vulvar carcinoma. EP1 expression correlated significantly with the grading of the tumor, suggesting that it influences cell differentiation. Further research on EP1 signaling may lead to a deeper understanding of the molecular mechanisms of carcinogenesis.
Topics: Female; Humans; Cyclooxygenase 2; Dinoprostone; Vulvar Neoplasms; Receptors, Prostaglandin E, EP1 Subtype; Carcinogenesis
PubMed: 36436093
DOI: 10.1007/s00432-022-04487-z -
Cancer Research Communications Aug 2023While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be...
UNLABELLED
While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8 T cells as compared with single EP antagonists. CD8 T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC) spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist.
SIGNIFICANCE
Prostaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule.
Topics: Humans; Animals; Mice; Prostaglandins; Dinoprostone; Receptors, Prostaglandin E, EP2 Subtype; Celecoxib; CD8-Positive T-Lymphocytes; Receptors, Prostaglandin E, EP4 Subtype; Cyclooxygenase 2 Inhibitors; Neoplasms; Tumor Microenvironment
PubMed: 37559947
DOI: 10.1158/2767-9764.CRC-23-0249 -
Andrology Jul 2020Several layers of slender, smooth muscle-like, peritubular cells and extracellular matrix (ECM) form the peritubular compartment of the human testis. Peritubular cells... (Review)
Review
BACKGROUND
Several layers of slender, smooth muscle-like, peritubular cells and extracellular matrix (ECM) form the peritubular compartment of the human testis. Peritubular cells are the least explored testicular cells.
MATERIALS AND METHODS
Human testicular peritubular cells (HTPCs) can be isolated from small testicular fragments of patients and studied in vitro. We have used this cellular model, in combination with human testicular samples, to examine how peritubular cells may contribute to male (in)fertility.
RESULTS
Human testicular peritubular cells (HTPCs) retain contractile abilities in vitro and secrete many proteins. Among them are factors, which serve intra-testicular roles, for example, glial cell line-derived neurotrophic factor (GDNF), thought to be important for the renewal of spermatogonial stem cells (SSCs). Studies in mutant mice indicated that peritubular cell-derived GDNF is crucial for lifelong spermatogenesis. Thus, peritubular cells are a functional part of the SSC niche. Peritubular cells of mice and men express androgen receptors (AR). In mouse peritubular cells, androgens enhanced GDNF production, but not in HTPCs. Rather, AR activation increased the levels of AR and smooth muscle proteins and thereby enhanced the smooth muscle-like phenotype. Following the lead of a proteomic analysis, which identified the key prostaglandin (PG)-synthesizing enzyme (PTGS1 = COX1), we found that HTPCs secrete PGE . COX1, and PGE receptors (EP1, 2, and 4) were identified in peritubular cells in situ, supporting in vivo relevance. In HTPCs, activation of EP1/4 increased GDNF and a smooth muscle protein. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID), which blocks PG synthesis. Added to HTPCs it reduced PGE and GDNF production and lowered smooth muscle protein levels. If applicable to the in vivo situation, the results suggest that ibuprofen and possibly other NSAIDs may impair important peritubular cell functions and consequently testicular functions.
CONCLUSION
The few examples highlighted, together with others not mentioned here, indicate that HTPCs provide an experimental window into the human testis.
Topics: Animals; Dinoprostone; Extracellular Matrix; Humans; Male; Mice; Spermatogenesis; Spermatogonia; Testis
PubMed: 31237067
DOI: 10.1111/andr.12669 -
Sheng Li Xue Bao : [Acta Physiologica... Feb 2024Prostaglandin E (PGE2) is an important lipid molecule derived from arachidonic acid, which regulates a variety of physiological and pathological activities. Based on the... (Review)
Review
Prostaglandin E (PGE2) is an important lipid molecule derived from arachidonic acid, which regulates a variety of physiological and pathological activities. Based on the inhibition of inflammatory PGE production, non-steroidal anti-inflammatory drugs (NSAIDs) are considered as the most commonly used drugs to treat inflammatory diseases and to relieve fever and pain symptoms. PGE mediates its functions via four different G protein-coupled receptors, named EP1-EP4. Though the limited distribution and low PGE affinity of EP1, it plays important roles in the maintenance of many physiological functions and homeostasis. Moreover, EP1 is widely involved in the inflammatory response, pain perception and multisystem pathological function regulation. In this review, we will briefly summarize the recent advances on the physiological and pathophysiological function of EP1 and its targeted drugs development.
Topics: Humans; Arachidonic Acid; Dinoprostone; Homeostasis; Pain
PubMed: 38444136
DOI: No ID Found -
International Journal of Molecular... Dec 2022The stria vascularis (SV) contributes to cochlear homeostasis and consists of three layers, one of which contains the blood-labyrinthic barrier (BLB), with a large...
The stria vascularis (SV) contributes to cochlear homeostasis and consists of three layers, one of which contains the blood-labyrinthic barrier (BLB), with a large number of bovine cochlear pericytes (BCPs). Cisplatin is a chemotherapeutic drug that can damage the SV and cause hearing loss. In this study, cell viability, proliferation rate, cytotoxicity and reactive oxygen species production were evaluated. The protein content of phospho-extracellular signal-regulated kinases (ERK) 1/2, total ERK 1/2, phospho-cytosolic phospholipase A (cPLA), total cPLA and cyclooxygenase 2 (COX-2) and the release of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) from BCPs were analyzed. Finally, the protective effect of platelet-derived growth factor (PDGF-BB) on BCPs treated with cisplatin was investigated. Cisplatin reduced viability and proliferation, activated ERK 1/2, cPLA and COX-2 expression and increased PGE2 and VEGF release; these effects were reversed by Dexamethasone. The presence of PDGF-BB during the treatment with cisplatin significantly increased the proliferation rate. No studies on cell regeneration in ear tissue evaluated the effect of the PDGF/Dex combination. The aim of this study was to investigate the effects of cisplatin on cochlear pericytes and propose new otoprotective agents aimed at preventing the reduction of their vitality and thus maintaining the BLB structure.
Topics: Animals; Cattle; Stria Vascularis; Pericytes; Cisplatin; Vascular Endothelial Growth Factor A; Becaplermin; Cyclooxygenase 2; Dinoprostone; Platelet-Derived Growth Factor
PubMed: 36555432
DOI: 10.3390/ijms232415790 -
Frontiers in Endocrinology 2022Prostaglandin E2 (PGE2) is an important prostanoid expressing throughout the kidney and cardiovascular system. Despite the diverse effects on fluid metabolism and blood... (Review)
Review
Prostaglandin E2 (PGE2) is an important prostanoid expressing throughout the kidney and cardiovascular system. Despite the diverse effects on fluid metabolism and blood pressure, PGE2 is implicated in sustaining volume and hemodynamics homeostasis. PGE2 works through four distinct E-prostanoid (EP) receptors which are G protein-coupled receptors. To date, pharmacological specific antagonists and agonists of all four subtypes of EP receptors and genetic targeting knockout mice for each subtype have helped in uncoupling the diverse functions of PGE2 and discriminating the respective characteristics of each receptor. In this review, we summarized the functions of individual EP receptor subtypes in the renal and blood vessels and the molecular mechanism of PGE2-induced fluid metabolism and blood pressure homeostasis.
Topics: Animals; Blood Pressure; Dinoprostone; Mice; Mice, Knockout; Receptors, Prostaglandin E; Water-Electrolyte Balance
PubMed: 35813612
DOI: 10.3389/fendo.2022.875425 -
Biomedicine & Pharmacotherapy =... Dec 2022Neuroblastoma (NB) is the most common pediatric extracranial solid tumor arising from neural crest cells of the developing sympathetic nervous system. Despite marked... (Review)
Review
Neuroblastoma (NB) is the most common pediatric extracranial solid tumor arising from neural crest cells of the developing sympathetic nervous system. Despite marked advances in cancer treatment, the survival rate of high-risk NB remains unsatisfactory. As a key pro-inflammatory mediator regulating tumor microenvironment, prostaglandin E2 (PGE) promotes NB proliferation, angiogenesis, and immune evasion via acting on four G protein-coupled receptors, particularly the EP2 subtype. Recent studies have been vigorously focused on developing and evaluating compounds targeting PGE-regulated tumor inflammation in animal models of NB. In this review, we revisit these translational efforts and examine the feasibility of pharmacological inhibition of enzymes responsible for PGE biosynthesis or its signaling receptors as emerging therapeutic strategies for NB. We also explore the potential downstream oncogenic pathways upon the activation of PGE receptors, aiming to bridge the knowledge gap between tumorigenesis and the role of elevated PGE/EP2 signaling, which is widely observed in high-risk NBs.
Topics: Animals; Dinoprostone; Neuroblastoma; Receptors, Prostaglandin E; Signal Transduction; Tumor Microenvironment
PubMed: 36411643
DOI: 10.1016/j.biopha.2022.113966 -
International Journal of Molecular... Dec 2019The number of colorectal cancer (CRC) patients is increasing worldwide. Accumulating evidence has shown that the tumor microenvironment (TME), including macrophages,... (Review)
Review
The number of colorectal cancer (CRC) patients is increasing worldwide. Accumulating evidence has shown that the tumor microenvironment (TME), including macrophages, neutrophils, and fibroblasts, plays an important role in the development and progression of CRC. Although targeting the TME could be a promising therapeutic approach, the mechanisms by which inflammatory cells promote CRC tumorigenesis are not well understood. When inflammation occurs in tissues, prostaglandin E2 (PGE2) is generated from arachidonic acid by the enzyme cyclooxygenase-2 (COX-2). PGE2 regulates multiple functions in various immune cells by binding to the downstream receptors EP1, EP2, EP3, and EP4, and plays an important role in the development of CRC. The current therapies targeting PGE2 using non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors have failed due to the global prostanoid suppression resulting in the severe adverse effects despite the fact they could prevent tumorigenesis. Therefore, therapies targeting the specific downstream molecules of PGE2 signaling could be a promising approach. This review highlights the role of each EP receptor in the TME of CRC tumorigenesis and their therapeutic potential.
Topics: Animals; Colorectal Neoplasms; Dinoprostone; Humans; Inflammation; Molecular Targeted Therapy; Signal Transduction; Tumor Microenvironment
PubMed: 31835815
DOI: 10.3390/ijms20246254 -
Scientific Reports Nov 2023Tumor-associated inflammation plays a vital role in cancer progression. Among the various stromal cells, cancer-associated fibroblasts are promising targets for cancer...
Tumor-associated inflammation plays a vital role in cancer progression. Among the various stromal cells, cancer-associated fibroblasts are promising targets for cancer therapy. Several reports have indicated potent anti-inflammatory effects attributed to Curcumin. This study aimed to investigate whether inhibiting the inflammatory function of cancer-associated fibroblasts (CAFs) with Curcumin can restore anticancer immune responses. CAFs were isolated from breast cancer tissues, treated with Curcumin, and co-cultured with patients' PBMCs to evaluate gene expression and cytokine production alterations. Blood and breast tumor tissue samples were obtained from 12 breast cancer patients with stage II/III invasive ductal carcinoma. Fibroblast Activation Protein (FAP) + CAFs were extracted from tumor tissue, treated with 10 μM Curcumin, and co-cultured with corresponding PBMCs. The expression of smooth muscle actin-alpha (α-SMA), Cyclooxygenase-2(COX-2), production of PGE2, and immune cell cytokines were evaluated using Real-Time PCR and ELISA, respectively. Analyzes showed that treatment with Curcumin decreased the expression of genes α-SMA and COX-2 and the production of PGE2 in CAFs. In PBMCs co-cultured with Curcumin-treated CAFs, the expression of FoxP3 decreased along with the production of TGF-β, IL-10, and IL-4. An increase in IFN-γ production was observed that followed by increased T-bet expression. According to our results, Curcumin could reprogram the pro-tumor phenotype of CAFs and increase the anti-tumor phenotype in PBMCs. Thus, CAFs, as a component of the tumor microenvironment, are a suitable target for combination immunotherapies of breast cancer.
Topics: Humans; Female; Breast Neoplasms; Cancer-Associated Fibroblasts; Curcumin; Cyclooxygenase 2; Dinoprostone; Fibroblasts; Inflammation; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38008819
DOI: 10.1038/s41598-023-48073-w