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PloS One 2024The Maternal and Perinatal Death Surveillance and Response (MPDSR) was introduced in Kenya in 2016 and implemented at Kiambu Level 5 Hospital (KL5H) three years later in... (Comparative Study)
Comparative Study
BACKGROUND
The Maternal and Perinatal Death Surveillance and Response (MPDSR) was introduced in Kenya in 2016 and implemented at Kiambu Level 5 Hospital (KL5H) three years later in 2019. During a routine MPDSR meeting at KL5H, committee members identified a possible link between the off-label use of 200mcg misoprostol tablets divided eight times to achieve the necessary dose for labour induction (25mcg) and maternal deaths. Following this, an administrative decision was made to switch from misoprostol to dinoprostone for the induction of labour in June of 2019. This study aimed to assess the overall impact of MPDSR as well as the effect of replacing misoprostol with dinoprostone on uterine rupture, maternal and neonatal deaths at KL5H.
METHODS
We conducted a retrospective cohort study of women who gave birth at KL5H between January 2018 and December 2020. We defined the pre-intervention period as January 2018-June 2019, and the intervention period as July 2019-December 2020. We randomly selected the records of 411 mothers, 167 from the pre-intervention period and 208 from the intervention period, all of whom were induced. We used Bayes-Poisson Generalised Linear Models to fit the risk of uterine rupture, maternal and perinatal death. 12 semi-structured key person questionnaires was used to describe staff perspectives regarding the switch from misoprostol to dinoprostone. Inductive and deductive data analysis was done to capture the salient emerging themes.
RESULTS
We reviewed 411 patient records and carried out 12 key informant interviews. Mothers induced with misoprostol (IRR = 3.89; CI = 0.21-71.6) had an increased risk of death while mothers were less likely to die if they were induced with dinoprostone (IRR = 0.23; CI = 0.01-7.12) or had uterine rupture (IRR = 0.56; CI = 0.02-18.2). The risk of dying during childbearing increased during Jul 2019-Dec 2020 (IRR = 5.43, CI = 0.68-43.2) when the MPDSR activities were strengthened. Induction of labour (IRR = 1.01; CI = 0.06-17.1) had no effect on the risk of dying from childbirth in our setting. The qualitative results exposed that maternity unit staff preferred dinoprostone to misoprostol as it was thought to be more effective (fewer failed inductions) and safer, regardless of being more expensive compared to misoprostol.
CONCLUSION
While the period immediately following the implementation of MPDSR at KL5H was associated with an increased risk of death, the switch to dinoprostone for labour induction was associated with a lower risk of maternal and perinatal death. The use of dinoprostone, however, was linked to an increased risk of uterine rupture, possibly attributed to reduced labour monitoring given that staff held the belief that it is inherently safer than misoprostol. Consequently, even though the changeover was warranted, further investigation is needed to determine the reasons behind the rise in maternal mortalities, even though the MPDSR framework appeared to have been put in place to quell such an increase.
Topics: Humans; Misoprostol; Female; Labor, Induced; Pregnancy; Retrospective Studies; Adult; Dinoprostone; Oxytocics; Uterine Rupture; Infant, Newborn; Young Adult; Perinatal Death; Maternal Mortality
PubMed: 38820427
DOI: 10.1371/journal.pone.0304631 -
Physiology International Jun 2024This study explored the effects of fructose-induced obesity and metabolic disorders on peripheral inflammatory hyperalgesia, employing quantitative sensory testing with...
This study explored the effects of fructose-induced obesity and metabolic disorders on peripheral inflammatory hyperalgesia, employing quantitative sensory testing with the von Frey test and measuring paw edema to assess inflammatory responses. Wistar rats were administered water or 10% fructose solution ad libitum over a period of 5 weeks. After intraplantar administration of inflammatory agents such as carrageenan (1 mg/paw), lipopolysaccharide (LPS; 100 µg/paw), or prostaglandin E2 (PGE2, 100 ng/paw), we conducted mechanical hyperalgesia tests and paw edema evaluations. The fructose diet resulted in dyslipidemia, elevated insulin and leptin plasma levels, insulin resistance, and increased epididymal and retroperitoneal adiposity compared to control animals. In response to inflammatory agents, the fructose group displayed significantly enhanced peripheral hyperalgesia and more pronounced paw edema. Our results demonstrate that fructose not only contributes to the development of obesity and metabolic disorder but also exacerbates peripheral inflammatory pain responses by enhancing prostaglandin sensitivity.
Topics: Animals; Fructose; Rats, Wistar; Male; Hyperalgesia; Rats; Inflammation; Metabolic Diseases; Obesity; Carrageenan; Dinoprostone; Edema; Insulin Resistance; Lipopolysaccharides; Disease Models, Animal
PubMed: 38819928
DOI: 10.1556/2060.2024.00376 -
World Journal of Gastroenterology May 2024Chronic enteropathy associated with the gene (CEAS) is a complex gastroenterological condition characterized by multiple ulcers in the small intestine with chronic... (Review)
Review
Chronic enteropathy associated with the gene (CEAS) is a complex gastroenterological condition characterized by multiple ulcers in the small intestine with chronic bleeding and protein loss. This review explores the potential mechanisms underlying the pathogenesis of CEAS, focusing on the role of -encoded prostaglandin transporter OATP2A1 and its impact on prostaglandin E2 (PGE2) levels. Studies have suggested that elevated PGE2 levels contribute to mucosal damage, inflammation, and disruption of the intestinal barrier. The effects of PGE2 on macrophage activation and Maxi-Cl channel functionality, as well as its interaction with nonsteroidal anti-inflammatory drugs play crucial roles in the progression of CEAS. Understanding the balance between its protective and pro-inflammatory effects and the complex interactions within the gastrointestinal tract can shed light on potential therapeutic targets for CEAS and guide the development of novel, targeted therapies.
Topics: Humans; Organic Anion Transporters; Intestinal Mucosa; Chronic Disease; Dinoprostone; Intestine, Small; Anti-Inflammatory Agents, Non-Steroidal; Intestinal Diseases; Animals; Gastrointestinal Hemorrhage; Ulcer
PubMed: 38817656
DOI: 10.3748/wjg.v30.i19.2505 -
Scientific Reports May 2024Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully...
Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully established to determine the anti-obesity properties of t10c12-CLA in male mice that could produce endogenous t10c12-CLA. To test whether there is a different impact of t10c12-CLA on lipid metabolism in both sexes, this study investigated the adiposity and metabolic profiles of female Pai mice that exhibited a dose-dependent expression of foreign Pai gene and a shift of t10c12-CLA content in tested tissues. Compared to their gender-match wild-type littermates, Pai mice had no fat reduction but exhibited enhanced lipolysis and thermogenesis by phosphorylated hormone-sensitive lipase and up-regulating uncoupling proteins in brown adipose tissue. Simultaneously, Pai mice showed hepatic steatosis and hypertriglyceridemia by decreasing gene expression involved in lipid and glucose metabolism. Further investigations revealed that t10c10-CLA induced excessive prostaglandin E2, adrenaline, corticosterone, glucagon and inflammatory factors in a dose-dependent manner, resulting in less heat release and oxygen consumption in Pai mice. Moreover, fibroblast growth factor 21 overproduction only in monoallelic Pai/wt mice indicates that it was sensitive to low doses of t10c12-CLA. These results suggest that chronic t10c12-CLA has system-wide effects on female health via synergistic actions of various hormones.
Topics: Animals; Female; Fibroblast Growth Factors; Mice, Transgenic; Mice; Linoleic Acids, Conjugated; Corticosterone; Dinoprostone; Glucagon; Epinephrine; Thermogenesis; Male; Lipid Metabolism; Adipose Tissue, Brown; Fatty Liver; Lipolysis; Hypertriglyceridemia; Adiposity
PubMed: 38816541
DOI: 10.1038/s41598-024-63282-7 -
The International Journal of... Jul 2024Elevated levels of prostaglandin E have been implicated in the pathophysiology of various diseases. Anti-inflammatory drugs that act through the inhibition of...
Elevated levels of prostaglandin E have been implicated in the pathophysiology of various diseases. Anti-inflammatory drugs that act through the inhibition of cyclooxygenase enzymatic activity, thereby leading to the suppression of prostaglandin E, are often associated with several side effects due to their non-specific inhibition of cyclooxygenase enzymes. Consequently, the targeted suppression of prostaglandin E production with innovative molecules and/or mechanisms emerges as a compelling therapeutic strategy for the treatment of inflammatory-related diseases. Therefore, in this study, a systematic analysis of 28 pyrazole derivatives was conducted to explore their potential mechanisms for reducing prostaglandin E levels. In this context, the evaluation of these derivatives extended to examining their capacity to reduce prostaglandin Ein vitro in human whole blood, inhibit cyclooxygenase-1 and cyclooxygenase-2 enzymes, modulate cyclooxygenase-2 expression, and suppress oxidative burst in human leukocytes. The results enabled the establishment of significant structure-activity relationships, elucidating key determinants for their activities. In particular, the 4-styryl group on the pyrazole moiety and the presence of chloro substitutions were identified as key determinants. Pyrazole 8 demonstrated the capacity to reduce prostaglandin E levels by downregulating cyclooxygenase-2 expression, and pyrazole-1,2,3-triazole 18 emerged as a dual-acting agent, inhibiting human leukocytes' oxidative burst and cyclooxygenase-2 activity. Furthermore, pyrazole 26 demonstrated effective reduction of prostaglandin E levels through selective cyclooxygenase-1 inhibition. These results underscore the multifaceted anti-inflammatory potential of pyrazoles, providing new insights into the substitutions and structural frameworks that are beneficial for the studied activity.
Topics: Humans; Pyrazoles; Dinoprostone; Respiratory Burst; Leukocytes; Cyclooxygenase 2; Cyclooxygenase 1; Anti-Inflammatory Agents; Structure-Activity Relationship; Cyclooxygenase Inhibitors
PubMed: 38797495
DOI: 10.1016/j.biocel.2024.106599 -
Life Sciences Aug 2024To understand the mechanism of prostaglandin E2 (PGE2)-mediated immunosuppression in dendritic cells (DCs).
AIM
To understand the mechanism of prostaglandin E2 (PGE2)-mediated immunosuppression in dendritic cells (DCs).
MAIN METHODS
In vivo experiments were conducted on 4T1 tumor bearing mice (TBM). In vitro experiments were performed in bone marrow-derived DCs (BMDCs), or spleen cells. Cytokines were monitored by ELISA/ELIspot. Gene expression was monitored by RT-PCR/flow cytometry.
KEY FINDINGS
In silico, in vitro, and in vivo experiments in 4T1 TBM revealed that PGE2 induced IL-6/pSTAT3 signaling through EP4 receptors in DCs, resulting in their dysfunction. These effects were reversed by EP4 antibody neutralization, EP4 antagonist, and STAT3 inhibitory peptides. PGE2 induced IL-6 was regulated by miR-365, as its mimic inhibited PGE2 induced IL-6 and the inhibitor increased lL-6 levels in DC. Bio-informatic analysis in human mammary cancers also revealed a strong compared co-relation between PGE2 and IL-6 (Correlation AnalyzeR) (R = 0.94). Mice bearing PTGS-2 KD 4T1 tumors had decreased tumor burden, PGE2, EP4, IL-6, and pSTAT3 signaling, along with improved DCs and T cell functions. Treatment of mice with a cyclooxygenase-2 (COX-2) inhibitor or EP4 antagonist decreased tumor burden, and this effect of EP4 antagonist was abrogated upon in vivo depletion of CD11c cells, indicating the crucial role of PGE2 signaling in DCs in tumor progression.
SIGNIFICANCE
In summary, our data highlights the importance of dendritic cells in mediating PGE2-mediated immunosuppression and the use of EP4 or STAT3 inhibitors or miR365 mimics can restore immunogenicity in cancer.
Topics: Animals; STAT3 Transcription Factor; Dendritic Cells; MicroRNAs; Mice; Dinoprostone; Interleukin-6; Signal Transduction; Female; Humans; Mice, Inbred BALB C; Cell Line, Tumor; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 38797363
DOI: 10.1016/j.lfs.2024.122751 -
Clinical Oral Investigations May 2024Mechano-sensitive odontoblast cells, which sense mechanical loading and various stresses in the tooth structure, synthesize early signaling molecules such as... (Comparative Study)
Comparative Study
The importance of mechanosensitive cell mediated prostaglandin and nitric oxide synthesis in the pathogenesis of apical periodontitis: comparative with chronic periodontitis.
OBJECTIVES
Mechano-sensitive odontoblast cells, which sense mechanical loading and various stresses in the tooth structure, synthesize early signaling molecules such as prostaglandin E2 (PGE2) and nitric oxide (NO) as an adaptive response. It is thought that these synthesized molecules can be used for the diagnosis and treatment of periodontal and periapical diseases. The aim of this study was to investigate the relationship between the severity of apical periodontitis (AP) and chronic periodontitis (CP) and serum (s) TNF-α, IL-10, PGE2 and NO levels, as well as PGE2 and NO levels in gingival crevicular fluid (GCF) samples.
MATERIALS & METHODS
A total of 185 subjects were divided into three categories: AP group (n = 85), CP group (n = 50) and healthy control group (n = 50). The AP group was divided into 3 subgroups according to abscess scoring (AS-PAI 1, 2 and 3) based on the periapical index. The CP group was divided into 4 subgroups according to the periodontitis staging system (PSS1, 2,3 and 4). After recording the demographic and clinical characteristics of all participants, serum (s) and gingival crevicular fluid (GCF) samples were taken. TNF-α, IL-10, PGE2 and NO levels were measured in these samples.
RESULTS
Unlike serum measurements (sTNF-α, sIL-10, sNO and sPGE2), GCF-NO and GCF-PGE levels of the AP group were significantly higher than the control group in relation to abscess formation (54.4 ± 56.3 vs. 22.5 ± 12.6 µmol/mL, p < 0.001 and 100 ± 98 vs. 41 ± 28 ng/L, p < 0.001, respectively). Confirming this, the GCF-NO and GCF-PGE levels of the AS-PAI 1 group, in which abscesses have not yet formed, were found to be lower than those in AS-PAI 2 and 3, which are characterized by abscess formation [(16.7(3.7-117.8), 32.9(11.8-212.8) and 36.9(4.3-251.6) µmol/mL, p = 0,0131; 46.0(31.4-120.0), 69.6(40.3-424.2) and 74.4(32.1-471.0) ng/L, p = 0,0020, respectively]. Consistent with the increase in PSS, the levels of sTNF [29.8 (8.2-105.5) vs. 16.7(6.3-37.9) pg/mL, p < 0.001], sIL-10 [542(106-1326) vs. 190(69-411) pg/mL, p < 0.001], sNO [182.1(36.3-437) vs. 57.0(15.9-196) µmol/mL, p < 0.001], sPGE2 [344(82-1298) vs. 100(35-1178) ng/L, p < 0.001], GCF-NO [58.9 ± 33.6 vs. 22.5 ± 12.6 ng/L, p < 0.001] and GCF-PGE2 [ 99(37-365) vs. 30(13-119), p < 0.001] in the CP group were higher than the control group. Comparison ROC analysis revealed that the GCF-PGE2 test had the best diagnostic value for both AP and CP (sensitivity: 94.1 and 88.0; specificity: 64.0 and 78.0, respectively; p < 0.001).
CONCLUSIONS
GCF-PE2 and GCF-NO have high diagnostic value in the determination of AP and CP, and can be selected as targets to guide treatment. In addition, the measurements of PGE2 and NO in GCF can be used as an important predictor of pulpal necrosis leading to abscess in patients with AP.
CLINICAL RELEVANCE
In this article, it is reported that syntheses of early signaling molecules such as PGE2 and NO can be used for the diagnosis and treatment target of periapical and periodontal infections.
Topics: Humans; Periapical Periodontitis; Male; Female; Chronic Periodontitis; Nitric Oxide; Gingival Crevicular Fluid; Adult; Dinoprostone; Interleukin-10; Tumor Necrosis Factor-alpha; Middle Aged; Enzyme-Linked Immunosorbent Assay; Case-Control Studies
PubMed: 38795217
DOI: 10.1007/s00784-024-05721-3 -
Marine Drugs May 2024Utilizing plant-based resources, particularly their by-products, aligns with sustainability principles and circular bioeconomy, contributing to environmental...
Utilizing plant-based resources, particularly their by-products, aligns with sustainability principles and circular bioeconomy, contributing to environmental preservation. The therapeutic potential of plant extracts is garnering increasing interest, and this study aimed to demonstrate promising outcomes from an extract obtained from an underutilized plant waste. , an invasive macroalga found in the Orbetello Lagoon, thrives in eutrophic conditions, forming persistent mats covering approximately 400 hectares since 2005. The biomass of undergoes mechanical harvesting and is treated as waste, requiring significant human efforts and economic resources-A critical concern for municipalities. Despite posing challenges to local ecosystems, the study identified as a natural source of bioactive metabolites. Phytochemical characterization revealed lipids, amino acids, and other compounds with potential anti-inflammatory activity in extract. In vitro assays with LPS-stimulated RAW 264.7 and TNF-α/IFN-γ-stimulated HaCaT cells showed the extract inhibited reactive oxygen species (ROS), nitric oxide (NO), and prostaglandin E2 (PGE2) productions, and reduced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions via NF-κB nuclear translocation, in RAW 264.7 cells. It also reduced chemokines (TARC/CCL17, RANTES/CCL5, MCP-1/CCL2, and IL-8) and the cytokine IL-1β production in HaCaT cells, suggesting potential as a therapeutic candidate for chronic diseases like atopic dermatitis. Finally, in silico studies indicated palmitic acid as a significant contributor to the observed effect. This research not only uncovered the untapped potential of but also laid the foundation for its integration into the circular bioeconomy, promoting sustainable practices, and innovative applications across various industries.
Topics: Animals; Anti-Inflammatory Agents; Mice; RAW 264.7 Cells; Humans; Phytochemicals; Plant Extracts; HaCaT Cells; Nitric Oxide; Reactive Oxygen Species; Cyclooxygenase 2; Nitric Oxide Synthase Type II; NF-kappa B; Dinoprostone; Chlorophyta; Seaweed
PubMed: 38786617
DOI: 10.3390/md22050226 -
Journal of Microbiology and... Jun 2024is a medicinal plant of the Ehretiaceae family used to treat inflammatory disorders, but the underlying mechanisms are not fully elucidated. The anti-inflammatory...
is a medicinal plant of the Ehretiaceae family used to treat inflammatory disorders, but the underlying mechanisms are not fully elucidated. The anti-inflammatory potential was determined based on enzyme cyclooxygenase-2 (COX-2) inhibition, which showed that the 95% ethanol extract (95ECH) was most effective with a half-maximal inhibitory concentration (IC) value of 34.09 μg/mL. The effects of 95ECH on phagocytosis, NO production, gene, and protein expression of the cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) and inducible nitric oxide synthase/nitric oxide (iNOS/NO) pathways in lipopolysaccharide (LPS)-induced RAW264.7 cells were examined using the neutral red uptake and Griess assays, reverse-transcriptase polymerase chain reactions (RTPCR), and enzyme-linked immunosorbent assays (ELISA). The results showed that 95ECH suppressed phagocytosis and the NO production in activated macrophage cells ( < 0.01). Conversely, 95ECH regulated the expression levels of mRNAs for cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) as well as the corresponding proteins. In addition, PGE2 production was inhibited in a dose-dependent manner by 95ECH, and the expression of iNOS and COX-2 mRNAs was decreased in activated macrophage cells, as expected. Therefore, 95ECH from leaves contains potentially valuable compounds for use in inflammation management.
Topics: Animals; Mice; Plant Extracts; RAW 264.7 Cells; Anti-Inflammatory Agents; Lipopolysaccharides; Macrophages; Phagocytosis; Nitric Oxide; Cyclooxygenase 2; Dinoprostone; Nitric Oxide Synthase Type II; Tumor Necrosis Factor-alpha; Cytokines; Interleukin-6; Interleukin-1beta
PubMed: 38783718
DOI: 10.4014/jmb.2403.03006 -
Nature Communications May 2024Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of...
Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4/CD44/CD62L and CD4/CD44/CD62L/CD27 T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.
Topics: Animals; Pneumonia, Pneumococcal; Disease Models, Animal; Mice; Dinoprostone; Mice, Inbred C57BL; Streptococcus pneumoniae; Receptors, Prostaglandin E, EP4 Subtype; Macrophages; Lung; Macrophages, Alveolar; Integrin alpha Chains; Female; Antigens, CD; T-Lymphocytes
PubMed: 38773113
DOI: 10.1038/s41467-024-48138-y