Search Results (20)

Background: Peritoneal stretching from CO₂ insufflation is a primary mechanism of pain associated with laparoscopy. Cyclooxygenase-2 inhibitors are promising anti-inflammatory and analgesic agents. This study aimed to evaluate the effect of celecoxib on postoperative pain reduction and associated changes in peritoneal gene expression after laparoendoscopic single-site (LESS) surgery for benign gynecologic disease. Methods: In this randomized, double-blind, placebo-controlled pilot study, 70 patients were randomly assigned to receive either celecoxib or placebo (400 mg) 40 min before surgery. Peritoneal tissues were collected before and after CO₂ insufflation. We analyzed changes in expressions of prostaglandin I₂ synthase, prostaglandin E synthase (PTGES), PTGES3, aldo-keto reductase family 1 member C1, and 15-hydroxyprostaglandin dehydrogenase (HPGD). Numeric Rating Scale (NRS) pain scores were also compared between groups. Results: A total of 62 patients completed the study: 30 in the celecoxib group and 32 in the placebo group. The mean CO₂ exposure time was 60.4 min. In a quantitative real-time polymerase chain reaction analysis, HPGD mRNA expression significantly increased after surgery in patients exposed to CO₂ for more than 60 min. Patients treated with celecoxib showed a significantly higher rate of grade 3 expression (83.3% vs. 37.5%; p = 0.01) and a level 2 increase in HPGD expression on in situ hybridization (58.3% vs. 12.5%; p = 0.01), despite no significant difference on immunohistochemistry. Moreover, celecoxib effectively reduced NRS pain scores compared to placebo. Conclusions: In this pilot study, celecoxib appeared to reduce postoperative pain and was associated with increased HPGD mRNA expression in the peritoneal tissue of patients with prolonged CO₂ exposure during LESS surgery. These exploratory findings warrant confirmation in larger trials with functional validation of HPGD expression (ClinicalTrials.gov, NCT03391570). Full article

Severe kinds of uterine inflammation in animals cause reproductive and economic problems. Although there are changes in prostaglandin (PG) production and noradrenergic uterine innervation during endometritis, the role of noradrenaline (NA) and adrenoreceptors (ARs) in PGF2α formation is not yet fully understood. To recognize noradrenergic control of the PGF2α generation on the cellular level during endometritis, the action of NA as well as α1-, α2- and β-ARs on protein abundances of PGF synthase (PGFS) and PG 9-ketoreductase/carbonyl reductase (CBR1) in the Escherichia coli lipopolysaccharide (LPS)-influenced pig endometrial epithelial cells and PGF2α release from these cells were studied. The epithelial cells were exposed to LPS and NA alone; LPS with NA; LPS with agonists of α1-, α2- and β-Ars; LPS with antagonists of β1-, β2- and β3-ARs with NA; and LPS with antagonists of β1-, β2- and β3-ARs in combinations with agonists of β1-, β2-, and β3-ARs for 24 h. PGFS and CBR1 protein abundances in cells were determined by Western blotting and PGF2α medium content by ELISA. LPS alone increased CBR1 protein abundance and PGF2α release by epithelial cells in reference to the control value. NA alone exerted a stimulatory effect on PGFS and CBR1 protein abundances and PGF2α secretion. After the exposure of cells to LPS with NA together, CBR1 protein abundance, as well as PGF2α release, was higher than in response to LPS and NA alone. PGFS protein abundance was increased by LPS with NA together compared to LPS action alone. In LPS-exposed endometrial epithelial cells, NA acting by β2- and β3-ARs leads to a rise in CBR1 protein abundance and PGF2α secretion. β2-ARs also participate in the NA excitatory effect on PGFS protein abundance. The NA effect on all the parameters tested is not mediated by α1- and α2-ARs. β2- and β3-ARs mediate the stimulatory effect of NA on PGF2α generation and secretion by the LPS-exposed pig endometrial epithelial cells. The results suggest that these cells may be a significant source of PGF2α under noradrenergic stimulation in the inflamed endometrium, and NA affects processes controlled by PGF2α during endometritis in an indirect manner. Full article

Background: Alpiniae oxyphyllae Fructus (AOF) is a medicinal and edible resource that holds potential to ameliorate hyperuricemia (HUA), yet its mechanism of action warrants further investigation. Methods: We performed network pharmacology, molecular docking, molecular dynamics simulation, and in vitro experiments to investigate the potential action and mechanism of AOF against HUA. Results: The results indicate that 48 potential anti-HUA targets for 4 components derived from AOF were excavated and predicted through public databases. Gene Ontology (GO) enrichment analysis indicated that there are 190 entries related to biological process, 24 entries related to cellular component, 42 entries related to molecular function, and 44 entries related to Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. The results of molecular docking showed that the main active ingredients of AOF may have potential therapeutic effects on immune system disorders and inflammation caused by HUA by binding to targets including peroxisome-proliferator-activated receptor gamma (PPARG), estrogen receptor 1 (ESR1), prostaglandin G/H synthase 2 (PTGS2), and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Subsequently, we further determined the stability of the complex between the core active ingredient and the core target proteins by molecular dynamics simulation. The results of cell experiments demonstrated that stigmasterol as the core active ingredient derived from AOF significantly upregulated the expression levels of ESR1 and PPARG (p < 0.001) to exert an anti-HUA effect. Conclusions: In summary, we have systematically elucidated that the mechanism of main active ingredients derived from AOF mainly exert their pharmacological effects by acting on multiple targets in this study. Our studies will provide a scientific basis for the precise development and utilization of AOF. Full article

Age-dependent loss of muscle mass and function is associated with oxidative stress. DJ-1/Park7 acts as an antioxidant through multiple signalling pathways. DJ-1-knockout zebrafish show a decline in swimming performance and loss of weight gain between 6 and 9 months of age. Here, we address the degree to which this is associated with muscle degeneration and identify molecular changes preceding dysregulation of muscle performance. Loss of DJ-1 reduced the skeletal muscle fibre cross-section area. The highly mitochondrial-dependent red slow muscle was more affected than the white muscle, and degeneration of sub-sarcolemma red muscle mitochondria was observed. Using TandemMassTag-based quantitative proteomics, we identified a total of 3721 proteins in the multiplex sample of 4 and 12-month-old muscles. A total of 68 proteins, mainly associated with inflammation and mitochondrial function, were dysregulated in the young DJ-1-null adults, with Annexin A3, Sphingomyelin phosphodiesterase acid-like 3B, Complement C3a, and 2,4-dienoyl CoA reductase 1 being the most affected. The loss of DJ-1 also accelerated molecular features associated with sarcopenia, such as a decrease in the NAD⁺/NADH ratio and a reduction in Prostaglandin reductase 2 and Cytosolic glycerol-3-phosphate dehydrogenase levels. In view of the experimental power of zebrafish, the DJ-1-null zebrafish makes a valuable model for understanding the connection between oxidative stress and age-dependent muscle loss and function. Full article

Androgenetic alopecia (AGA) is the most common form of hair loss, significantly affecting both men and women worldwide. Characterized by progressive hair thinning and loss, AGA is primarily mediated by dihydrotestosterone (DHT). Recent research has identified numerous single-nucleotide polymorphisms (SNPs) associated with AGA, particularly in genes involved in androgen metabolism, prostaglandin pathways, and vasodilation. These genetic markers offer insights into AGA pathophysiology and potential therapeutic targets. Pharmacogenetics, the study of how genetic variations influence drug response, holds promise for personalized AGA treatment. Identifying SNPs that affect the efficacy of treatments like minoxidil and finasteride enables the development of tailored therapeutic strategies. For instance, genetic variants in the SRD5A2 gene, which affects DHT metabolism, can predict responsiveness to 5-alpha-reductase inhibitors. Beyond pharmacogenetics, RNA interference (RNAi) technologies, e.g., small interfering RNAs (siRNAs), present new therapeutic avenues. Studies have shown the efficacy of RNAi-based treatments in targeting androgen receptors, promoting hair growth in AGA models. Integrating genetic and pharmacogenetic research into clinical practice can transform AGA management, enhancing treatment efficacy and patient outcomes. In conclusion, genetic and pharmacogenetic insights are crucial for developing personalized treatments for AGA, while emerging RNAi technologies offer promising new interventions. These advancements represent significant steps toward more effective and individualized AGA therapies. Full article

In this current review, research spanning the last decade (such as transcriptomic studies, phenotypic observations, and confirmed comorbidities) has been synthesized into an updated etiology of hair loss and applied to the new cosmeceutical paradigm of hair rejuvenation. The major etiological components in scalps with hair loss are denoted as the ‘big eight strikes’, which include the following: androgens, prostaglandins, overactive aerobic metabolism of glucose, bacterial or fungal over-colonization, inflammation, fibrosis, metabolism or circulation problems, and malnutrition. The relevance of the ‘big eight’ to nine categories of hair loss is explained. In cases of androgenetic alopecia or female pattern hair loss, both elevated DHT and increased frequency of androgen receptors lead to problems with the metabolism of glucose (sugar), redox imbalance, disruption to the electron transport chain, and PPAR-γ overactivity (the latter is unique to androgenetic alopecia, where the reverse occurs in other types of hair loss). These etiological factors and others from ‘the big eight’ are the focal point of our hypothetical narrative of the attenuative mechanisms of commercial cosmeceutical hair serums. We conclude that cosmeceuticals with the potential to improve all eight strikes (according to published in vitro or clinical data) utilize bioactive peptides and plant compounds that are either flavonoids (isoflavones, procyanidins, flavanols, and flavonols) or sterols/triterpenes. It is noteworthy that many therapeutic interventions are generic to the multiple types of hair loss. Lastly, suggestions are made on how scalp and hair health can be improved by following the cosmeceutical approach. Full article

Chagas disease is a zoonotic infectious disease caused by the protozoan parasite Trypanosoma cruzi. It is distributed worldwide, affecting around 7 million people; there is no effective treatment, and it constitutes a leading cause of disability and premature death in the Americas. Only two drugs are currently approved for the treatment, Benznidazole and Nifurtimox, and both have to be activated by reducing the nitro-group. The T. cruzi aldo-keto reductase (TcAKR) has been related to the metabolism of benznidazole. TcAKR has been extensively studied, being most efforts focused on characterizing its implication in trypanocidal drug metabolism; however, little is known regarding its biological role. Here, we found that TcAKR is confined, throughout the entire life cycle, into the parasite mitochondria providing new insights into its biological function. In particular, in epimastigotes, TcAKR is associated with the kinetoplast, which suggests additional roles of the protein. The upregulation of TcAKR, which does not affect TcOYE expression, was correlated with an increase in PGF₂α, suggesting that this enzyme is related to PGF₂α synthesis in T. cruzi. Structural analysis showed that TcAKR contains a catalytic tetrad conserved in the AKR superfamily. Finally, we found that TcAKR is also involved in Nfx metabolization. Full article

Epoxyeicosatrienoic acids (EETs) are signaling lipids produced by the cytochrome P450-(CYP450)-mediated epoxygenation of arachidonic acid. EETs have numerous biological effects on the vascular system, but aspects including their species specificity make their effects on vascular tone controversial. CYP450 enzymes require the 450-reductase (POR) for their activity. We set out to determine the contribution of endothelial CYP450 to murine vascular function using isolated aortic ring preparations from tamoxifen-inducible endothelial cell-specific POR knockout mice (ecPOR^−/−). Constrictor responses to phenylephrine were similar between control (CTR) and ecPOR^−/− mice. Contrastingly, sensitivity to the thromboxane receptor agonist U46619 and prostaglandin E2 (PGE2) was increased following the deletion of POR. Ex vivo incubation with a non-hydrolyzable EET (14,15-EE-8(Z)-E, EEZE) reversed the increased sensitivity to U46619 to the levels of CTR. EETs had no effect on vascular tone in phenylephrine-preconstricted vessels, but dilated vessels contracted with U46619 or PGE2. As U46619 acts through RhoA-dependent kinase, this system was analyzed. The deletion of POR affected the expression of genes in this pathway and the inhibition of Rho-GTPase with SAR407899 decreased sensitivity to U46619. These data suggest that EET and prostanoid crosstalk at the receptor level and that lack of EET production sensitizes vessels to vasoconstriction via the induction of the Rho kinase system. Full article

In the horse, mobility of the conceptus is required for maternal recognition of pregnancy depending on secretion of prostaglandins by the conceptus. The aim of this study was to determine the expression and localization of key enzymes of the different pathways leading to synthesis of prostaglandin E2 and F2α in the equine conceptus during the mobility phase. Enzyme expression was analyzed via quantitative RT-PCR in total RNA samples of equine conceptuses collected on days 10 (n = 5), 12 (n = 12), 14 (n = 5) and 16 (n = 7) from healthy mares. Relative abundance of cyclooxygenase (COX)-2 mRNA was higher (p < 0.05) than of COX-1 irrespective of conceptus age and for phospholipase A2 on day 16 in comparison to all other days (p < 0.01). Abundance of mRNA of cytosolic and microsomal prostaglandin E synthase (PGES) and of carbonyl reductase (CBR) 1 was not influenced by conceptus age. Immunohistochemically, COX-1, COX-2, as well as cytosolic and microsomal PGES were present in both the ectodermal and endodermal layer of the yolk sac wall. CBR-1 was restricted to periembryonic disc area. The localisation of the key enzymes explains the mechanism of embryo mobility. In vitro incubation of primary trophoblast cell cultures with oxytocin had no effect on key enzyme synthesis. Full article

This paper is focused on eicosanoid signaling in insect immunology. We begin with eicosanoid biosynthesis through the actions of phospholipase A₂, responsible for hydrolyzing the C18 polyunsaturated fatty acid, linoleic acid (18:2n-6), from cellular phospholipids, which is subsequently converted into arachidonic acid (AA; 20:4n-6) via elongases and desaturases. The synthesized AA is then oxygenated into one of three groups of eicosanoids, prostaglandins (PGs), epoxyeicosatrienoic acids (EETs) and lipoxygenase products. We mark the distinction between mammalian cyclooxygenases and insect peroxynectins, both of which convert AA into PGs. One PG, PGI₂ (also called prostacyclin), is newly discovered in insects, as a negative regulator of immune reactions and a positive signal in juvenile development. Two new elements of insect PG biology are a PG dehydrogenase and a PG reductase, both of which enact necessary PG catabolism. EETs, which are produced from AA via cytochrome P450s, also act in immune signaling, acting as pro-inflammatory signals. Eicosanoids signal a wide range of cellular immune reactions to infections, invasions and wounding, including nodulation, cell spreading, hemocyte migration and releasing prophenoloxidase from oenocytoids, a class of lepidopteran hemocytes. We briefly review the relatively scant knowledge on insect PG receptors and note PGs also act in gut immunity and in humoral immunity. Detailed new information on PG actions in mosquito immunity against the malarial agent, Plasmodium berghei, has recently emerged and we treat this exciting new work. The new findings on eicosanoid actions in insect immunity have emerged from a very broad range of research at the genetic, cellular and organismal levels, all taking place at the international level. Full article

The aldo-keto reductase (AKR) superfamily is gaining attention in cancer research. AKRs are involved in important biochemical processes and have crucial roles in carcinogenesis and chemoresistance. The enzyme AKR1C3 has many functions, which include production of prostaglandins, androgens and estrogens, and metabolism of different chemotherapeutics; AKR1C3 is thus implicated in the pathophysiology of different cancers. Endometrial and ovarian cancers represent the majority of gynecological malignancies in developed countries. Personalized treatments for these cancers depend on identification of prognostic and predictive biomarkers that allow stratification of patients. In this study, we evaluated the immunohistochemical (IHC) staining of AKR1C3 in 123 paraffin-embedded samples of endometrial cancer and 99 samples of ovarian cancer, and examined possible correlations between expression of AKR1C3 and other clinicopathological data. The IHC expression of AKR1C3 was higher in endometrial cancer compared to ovarian cancer. In endometrioid endometrial carcinoma, high AKR1C3 IHC expression correlated with better overall survival (hazard ratio, 0.19; 95% confidence interval, 0.06−0.65, p = 0.008) and with disease-free survival (hazard ratio, 0.328; 95% confidence interval, 0.12–0.88, p = 0.027). In patients with ovarian cancer, there was no correlation between AKR1C3 IHC expression and overall and disease-free survival or response to chemotherapy. These results demonstrate that AKR1C3 is a potential prognostic biomarker for endometrioid endometrial cancer. Full article

Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. The initiation and progression of CRC is a multi-step process that proceeds via precursor lesions to carcinoma, with each stage characterized by its distinct molecular and tissue microenvironment changes. Precursor lesions of CRC, aberrant crypt foci, and adenoma exhibit drastic changes in genetic, transcriptomic, and proteomic profiles compared to normal tissue. The identification of these changes is essential and provides further validation as an initiator or promoter of CRC and, more so, as lesion-specific druggable molecular targets for the precision chemoprevention of CRC. Mutated/dysregulated signaling (adenomatous polyposis coli, β-catenin, epidermal growth factor receptor, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), tumor protein53, Akt, etc.), inflammatory (cyclooxygenase-2, microsomal prostaglandin E synthase-1, inducible nitric oxide synthase, and other pro-inflammatory mediators), and metabolic/growth factor (fatty acid synthase, β-Hydroxy β-methylglutaryl-CoA reductase, and ornithine decarboxylase) related targets are some of the well-characterized molecular targets in the precision chemoprevention of CRC. In this review, we discuss precursor-lesion specific targets of CRC and the current status of pre-clinical studies regarding clinical interventions and combinations for better efficacy and safety toward future precision clinical chemoprevention. In addition, we provide a brief discussion on the usefulness of secondary precision chemopreventive targets for tertiary precision chemoprevention to improve the disease-free and overall survival of advanced stage CRC patients. Full article

Ferroptosis has emerged as a new type of cell death in different pathological conditions, including neurological and kidney diseases and, especially, in different types of cancer. The hallmark of this regulated cell death is the presence of iron-driven lipid peroxidation; the activation of key genes related to this process such as glutathione peroxidase-4 (gpx4), acyl-CoA synthetase long-chain family member-4 (acsl4), carbonyl reductase [NADPH] 3 (cbr3), and prostaglandin peroxidase synthase-2 (ptgs2); and morphological changes including shrunken and electron-dense mitochondria. Iron overload in the liver has long been recognized as both a major trigger of liver damage in different diseases, and it is also associated with liver fibrosis. New evidence suggests that ferroptosis might be a novel type of non-apoptotic cell death in several liver diseases including non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), drug-induced liver injury (DILI), viral hepatitis, and hemochromatosis. The interaction between iron-related lipid peroxidation, cellular stress signals, and antioxidant systems plays a pivotal role in the development of this novel type of cell death. In addition, integrated responses from lipidic mediators together with free iron from iron-containing enzymes are essential to understanding this process. The presence of ferroptosis and the exact mechanisms leading to this non-apoptotic type of cell death in the liver remain scarcely elucidated. Recognizing ferroptosis as a novel type of cell death in the liver could lead to the understanding of the complex interaction between different types of cell death, their role in progression of liver fibrosis, the development of new biomarkers, as well as the use of modulators of ferroptosis, allowing improved theranostic approaches in the clinic. Full article

Recently, the identity of the marine hydrindane natural product (−)-mucosin was revised to the trans-fused structure 6, thereby providing a biogenetic puzzle that remains to be solved. We are now disseminating some of our insights with regard to the possible machinery delivering the established architecture. Aspects with regard to various modes of cyclization in terms of concerted versus stepwise processes are held up against the enzymatic apparatus known to be working on arachidonic acid (8). To provide a contrast to the tentative polyunsaturated fatty acid biogenesis, the structural pattern featured in (−)-mucosin (6) is compared to some marine hydrinane natural products of professed polyketide descent. Our appraisal points to a different origin and strengthens the hypothesis of a polyunsaturated fatty acids (PUFA) as the progenitor of (−)-mucosin (6). Full article

Prostacyclin synthase (PTGIS; EC 5.3.99.4) catalyzes isomerization of prostaglandin H₂ to prostacyclin, a potent vasodilator and inhibitor of platelet aggregation. At present, limited data exist on functional coupling and possible ways of regulating PTGIS due to insufficient information about protein–protein interactions in which this crucial enzyme is involved. The aim of this study is to isolate protein partners for PTGIS from rat tissue lysates. Using CNBr-activated Sepharose 4B with covalently immobilized PTGIS as an affinity sorbent, we confidently identified 58 unique proteins by mass spectrometry (LC-MS/MS). The participation of these proteins in lysate complex formation was characterized by SEC lysate profiling. Several potential members of the PTGIS subinteractome have been validated by surface plasmon resonance (SPR) analysis. SPR revealed that PTGIS interacted with full-length cytochrome P450 2J2 and glutathione S-transferase (GST). In addition, PTGIS was shown to bind synthetic peptides corresponding to sequences of for GSTA1, GSTM1, aldo-keto reductase (AKR1A1), glutaredoxin 3 (GLRX3) and histidine triad nucleotide binding protein 2 (HINT2). Prostacyclin synthase could potentially be involved in functional interactions with identified novel protein partners participating in iron and heme metabolism, oxidative stress, xenobiotic and drugs metabolism, glutathione and prostaglandin metabolism. The possible biological role of the recognized interaction is discussed in the context of PTGIS functioning. Full article