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Proceedings of the National Academy of... Jul 2023To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize...
To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, , re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, , 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, , 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that G-biased signaling, but not G activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-G, EP4-G, and EP4-G in complex with endogenous prostaglandin E (PGE)or two synthetic agonists and comparing with PGE-EP2-G structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the G/G transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their G/G coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for G/G coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.
Topics: Dinoprostone; Signal Transduction; Receptors, Prostaglandin; GTP-Binding Protein alpha Subunits, Gs; Hormones; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype
PubMed: 37478163
DOI: 10.1073/pnas.2216329120 -
Nutrients Sep 2023Recently, the prevalence of atopic dermatitis has increased drastically, especially in urban populations. This multifactorial skin disease is caused by complex... (Review)
Review
Recently, the prevalence of atopic dermatitis has increased drastically, especially in urban populations. This multifactorial skin disease is caused by complex interactions between various factors including genetics, environment, lifestyle, and diet. In eczema, apart from using an elimination diet, the adequate content of fatty acids from foods (saturated, monounsaturated, and polyunsaturated fatty acids) plays an important role as an immunomodulatory agent. Different aspects regarding atopic dermatitis include connections between lipid metabolism in atopic dermatitis, with the importance of the MUFA levels, as well as of the omega-6/omega-3 balance that affects the formation of long-chain (C20 eicosanoic and C22 docosaenoic) fatty acids and bioactive lipids from them (such as prostaglandins). Impair/repair of the functioning of epidermal barrier is influenced by these fatty acid levels. The purpose of this review is to drive attention to membrane fatty acid composition and its involvement as the target of fatty acid supplementation. The membrane-targeted strategy indicates the future direction for dermatological research regarding the use of nutritional synergies, in particular using red blood cell fatty acid profiles as a tool for checking the effects of supplementations to reach the target and influence the inflammatory/anti-inflammatory balance of lipid mediators. This knowledge gives the opportunity to develop personalized strategies to create a healthy balance by nutrition with an anti-inflammatory outcome in skin disorders.
Topics: Humans; Fatty Acids; Dermatitis, Atopic; Nutritional Status; Prostaglandins; Food; Fatty Acids, Omega-3
PubMed: 37686888
DOI: 10.3390/nu15173857 -
Hepatology (Baltimore, Md.) Aug 2023Nonalcoholic fatty liver disease (NAFLD), a complex metabolic syndrome, has limited therapeutic options. Microsomal prostaglandin E synthase-2 (mPGES-2) was originally...
BACKGROUND AND AIMS
Nonalcoholic fatty liver disease (NAFLD), a complex metabolic syndrome, has limited therapeutic options. Microsomal prostaglandin E synthase-2 (mPGES-2) was originally discovered as a prostaglandin E 2 (PGE 2 ) synthase; however, it does not produce PGE 2 in the liver. Moreover, the role of mPGES-2 in NAFLD remains undefined. Herein, we aimed to determine the function and mechanism of mPGES-2 in liver steatosis and steatohepatitis.
APPROACH AND RESULTS
To evaluate the role of mPGES-2 in NAFLD, whole-body or hepatocyte-specific mPGES-2-deficient mice fed a high-fat or methionine-choline-deficient diet were used. Compared with control mice, mPGES-2-deficient mice showed reduced hepatic lipid accumulation, along with ameliorated liver injury, inflammation, and fibrosis. Furthermore, the protective effect of mPGES-2 deficiency against NAFLD was dependent on decreased cytochrome P450 4A14 and increased acyl-CoA thioesterase 4 levels regulated by the heme receptor nuclear receptor subfamily 1 group D member 1 (NR1D1), but not PGE 2 . Heme regulated the increased NR1D1 activity mediated by mPGES-2 deficiency. Further, we confirmed the protective role of the mPGES-2 inhibitor SZ0232 in NAFLD therapy.
CONCLUSION
Our study indicates the pathogenic role of mPGES-2 and outlines the mechanism in mediating NAFLD, thereby highlighting the therapeutic potential of mPGES-2 inhibition in liver steatosis and steatohepatitis.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Prostaglandin-E Synthases; Heme; Disease Models, Animal; Liver; Mice, Inbred C57BL
PubMed: 35839302
DOI: 10.1002/hep.32671 -
Phytomedicine : International Journal... Dec 2023Liver cancer is a topical global health issue. The treatment of liver cancer meets significant challenges in the high recurrence rate and invasive incidence. Therefore,...
BACKGROUND
Liver cancer is a topical global health issue. The treatment of liver cancer meets significant challenges in the high recurrence rate and invasive incidence. Therefore, the treatment strategies that target epithelial-mesenchymal transition (EMT) induced by cyclooxygenase 2 (COX2)/ prostaglandin E2 (PGE2) pathway have become epidemic. Ginsenoside Rh2 has been proved to inhibit the EMT. However, the underlying mechanisms remain unclear. Moreover, the octyl ester derivative of Rh2 (Rh2-O) exhibited superior anti-proliferative and immunomodulatory effects than Rh2 in our previous researches, which indicated that Rh2-O might also exert inhibitory effects on invasion and metastasis.
PURPOSE
The aim of current study is to explore the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis of hepatocellular carcinoma, and to investigate whether these effects are dependent on the c-Jun/COX2/PGE2 pathway.
STUDY DESIGN
The Huh-7 liver cancer cells and the H22 tumor-bearing mice were treated with Rh2 and Rh2-O.
METHOD
In this paper, the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis were tested by wound healing, trans-well assay and tumor-bearing mice, and the involvement of c-Jun/COX2/PGE2 pathway were verified by exogenous PGE2, activation of COX2 and overexpression of c-Jun.
RESULTS
The results showed that Rh2 and Rh2-O could efficiently inhibit the invasion and metastasis in a dose-dependent manner (p < 0.05). And the Rh2-O showed stronger effects than Rh2. Moreover, the exogenous PGE2, activation of COX2 by exogenous LPS and the overexpression of c-Jun by transfection all reversed the inhibitory effects of Rh2 and Rh2-O on metastasis or EMT (p < 0.05).
CONCLUSION
Rh2 and Rh2-O could inhibit the invasion and metastasis of hepatocellular carcinoma via restraining the EMT, which was mediated by c-Jun/COX2/PGE2 pathway.
Topics: Animals; Mice; Carcinoma, Hepatocellular; Dinoprostone; Liver Neoplasms; Cyclooxygenase 2; Esters; Ginsenosides; Cell Line, Tumor
PubMed: 37806155
DOI: 10.1016/j.phymed.2023.155131 -
Obesity (Silver Spring, Md.) Oct 2023This study aimed to assess the association of shift work with blood glucose and the mediating role of oxidative stress.
OBJECTIVE
This study aimed to assess the association of shift work with blood glucose and the mediating role of oxidative stress.
METHODS
Fasting plasma glucose (FPG) and urinary concentrations of oxidative stress biomarkers (8-hydroxy-2'-deoxyguanosine [8-OHdG], 4-hydroxy-2-nonenal-mercapturic acid, and 8-iso-prostaglandin F [8-isoPGF ]) were measured among 831 participants.
RESULTS
Positive dose-response relationships among shift work duration, FPG (p < 0.001), and abnormal glucose regulation (AGR; p = 0.035) were found. Compared with participants without shift work, three-shift work was associated with a higher level of FPG (percentage change: 6.49%, 95% CI: 4.21%-8.83%) and a higher prevalence of impaired fasting glucose (odds ratio: 1.886, 95% CI: 1.114-3.192) and AGR (odds ratio: 1.929, 95% CI: 1.197-3.111). A dose-response relationship was found between shift work duration and 8-OHdG (p = 0.002) and 8-isoPGF (p = 0.019). Urinary 8-OHdG and 8-isoPGF partially mediated the association between shift work duration and FPG levels and the prevalence of impaired fasting glucose and AGR, with mediating proportions ranging from 4.77% to 20.76%.
CONCLUSIONS
These findings suggest that shift work is positively associated with blood glucose, and the association is partially mediated by oxidative stress.
Topics: Humans; Adult; Blood Glucose; East Asian People; Shift Work Schedule; Fasting; Oxidative Stress
PubMed: 37724057
DOI: 10.1002/oby.23845 -
Journal of Cellular Physiology Dec 2023Understanding the factors that influence the biological response to inflammation is crucial, due to its involvement in physiological and pathological processes,...
Understanding the factors that influence the biological response to inflammation is crucial, due to its involvement in physiological and pathological processes, including tissue repair/healing, cancer, infections, and autoimmune diseases. We have previously demonstrated that in vivo stretching can reduce inflammation and increase local pro-resolving lipid mediators in rats, suggesting a direct mechanical effect on inflammation resolution. Here we aimed to explore further the effects of stretching at the cellular/molecular level in a mouse subcutaneous carrageenan-inflammation model. Stretching for 10 min twice a day reduced inflammation, increased the production of pro-resolving mediator pathway intermediate 17-HDHA at 48 h postcarrageenan injection, and decreased both pro-resolving and pro-inflammatory mediators (e.g., PGE and PGD ) at 96 h. Single-cell RNA sequencing analysis of inflammatory lesions at 96 h showed that stretching increased the expression of both pro-inflammatory (Nos2) and pro-resolution (Arg1) genes in M1 and M2 macrophages at 96 h. An intercellular communication analysis predicted specific ligand-receptor interactions orchestrated by neutrophils and M2a macrophages, suggesting a continuous neutrophil presence recruiting immune cells such as activated macrophages to contain the antigen while promoting resolution and preserving tissue homeostasis.
Topics: Animals; Mice; Carrageenan; Dinoprostone; Inflammation; Inflammation Mediators; Macrophages; Neutrophils; Single-Cell Analysis; Mice, Inbred C57BL; Transcriptome
PubMed: 37909412
DOI: 10.1002/jcp.31133 -
Prostaglandins & Other Lipid Mediators Oct 2023Ischemic cerebral stroke is a severe medical condition that affects about 15 million people every year and is the second leading cause of death and disability globally.... (Review)
Review
Ischemic cerebral stroke is a severe medical condition that affects about 15 million people every year and is the second leading cause of death and disability globally. Ischemic stroke results in neuronal cell death and neurological impairment. Current therapies may not adequately address the deleterious metabolic changes and may increase neurological damage. Oxygen and nutrient depletion along with the tissue damage result in endoplasmic reticulum (ER) stress, including the Unfolded Protein Response (UPR), and neuroinflammation in the affected area and cause cell death in the lesion core. The spatio-temporal production of lipid mediators, either pro-inflammatory or pro-resolving, decides the course and outcome of stroke. The modulation of the UPR as well as the resolution of inflammation promotes post-stroke cellular viability and neuroprotection. However, studies about the interplay between the UPR and bioactive lipid mediators remain elusive and this review gives insights about the crosstalk between lipid mediators and the UPR in ischemic stroke. Overall, the treatment of ischemic stroke is often inadequate due to lack of effective drugs, thus, this review will provide novel therapeutical strategies that could promote the functional recovery from ischemic stroke.
Topics: Humans; Ischemic Stroke; Unfolded Protein Response; Endoplasmic Reticulum Stress; Inflammation; Lipids
PubMed: 37331425
DOI: 10.1016/j.prostaglandins.2023.106760 -
Odontology Oct 2023Porphyromonas gingivalis is a keystone pathogen associated with periodontitis development, a chronic inflammatory pathology characterized by the destruction of the... (Review)
Review
Porphyromonas gingivalis is a keystone pathogen associated with periodontitis development, a chronic inflammatory pathology characterized by the destruction of the supporting teeth structure. Macrophages are recruited cells in the inflammatory infiltrate from patients with periodontitis. They are activated by the P. gingivalis virulence factors arsenal, promoting an inflammatory microenvironment characterized by cytokine production (TNF-α, IL-1β, IL-6), prostaglandins, and metalloproteinases (MMPs) that foster the tissular destruction characteristic of periodontitis. Furthermore, P. gingivalis suppresses the generation of nitric oxide, a potent antimicrobial molecule, through its degradation, and incorporating its byproducts as a source of energy. Oral antimicrobial peptides can contribute to controlling the disease due to their antimicrobial and immunoregulatory activity, which allows them to maintain homeostasis in the oral cavity. This study aimed to analyze the immunopathological role of macrophages activated by P. gingivalis in periodontitis and suggested using antimicrobial peptides as therapeutic agents to treat the disease.
Topics: Humans; Porphyromonas gingivalis; Antimicrobial Peptides; Macrophages; Periodontitis; Immunomodulation
PubMed: 36897441
DOI: 10.1007/s10266-023-00798-w -
Molecular Medicine Reports Oct 2023Endometriosis is highly dependent on angiogenesis and lymphangiogenesis. Prostaglandin E2, an arachidonic acid metabolite, has been shown to promote the formation of new...
Endometriosis is highly dependent on angiogenesis and lymphangiogenesis. Prostaglandin E2, an arachidonic acid metabolite, has been shown to promote the formation of new blood and lymphatic vessels. However, the role of another arachidonic acid metabolite, thromboxane A (TXA) in angiogenesis and lymphangiogenesis during endometriosis remains largely unexplored. Using a murine model of ectopic endometrial transplantation, fragments from the endometrium of WT donor mice were transplanted into the peritoneal walls of recipient WT mice (WT→WT), resulting in an increase in both the area and density of blood and lymphatic vessels. Upon transplantation of endometrial tissue from thromboxane prostanoid (TP) receptor (TXA receptor)‑deficient (TP) mice into TP mice (TP→TP), an increase in implant growth, angiogenesis, and lymphangiogenesis were observed along with upregulation of pro‑angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs). Similar results were obtained using a thromboxane synthase (TXS) inhibitor in WT→WT mice. Furthermore, TP→TP mice had a higher number of F4/80 cells than that of WT→WT mice, with increased expression of genes related to the anti‑inflammatory macrophage phenotype in endometrial lesions. In cultured bone marrow (BM)‑derived macrophages, the levels of VEGF‑A, VEGF‑C, and VEGF‑D decreased in a TP‑dependent manner. Furthermore, TP signaling affected the polarization of cultured BM‑derived macrophages to the anti‑inflammatory phenotype. These findings imply that inhibition of TP signaling promotes endometrial implant growth and neovascularization.
Topics: Animals; Female; Mice; Arachidonic Acid; Dinoprostone; Endometriosis; Neovascularization, Pathologic; Prostaglandins; Thromboxanes; Receptors, Thromboxane A2, Prostaglandin H2
PubMed: 37654213
DOI: 10.3892/mmr.2023.13079 -
Biomedicine & Pharmacotherapy =... Dec 2023Mikania cordata (Burm. f.) B.L. Rob. has been traditionally used in tropical countries throughout Asia and Africa to treat gastric ulcers, dyspepsia, and dysentery....
Regulation of anti-inflammatory and antioxidant responses by methanol extract of Mikania cordata (Burm. f.) B. L. Rob. leaves via the inactivation of NF-κB and MAPK signaling pathways and activation of Nrf2 in LPS-induced RAW 264.7 macrophages.
Mikania cordata (Burm. f.) B.L. Rob. has been traditionally used in tropical countries throughout Asia and Africa to treat gastric ulcers, dyspepsia, and dysentery. However, the mechanisms responsible for its anti-inflammatory and antioxidant activities are not fully understood. Therefore, this study sought to investigate the anti-inflammatory and antioxidant effects of methanol extracts of M. cordata (MMC) on inflammation and oxidative stress in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages and elucidate its underlying regulatory mechanism. MMC significantly suppressed the production of nitric oxide (NO) and prostaglandin E (PGE) in LPS-stimulated RAW 264.7 macrophages by downregulating the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) at both the mRNA and protein levels. Moreover, MMC effectively reduced the mRNA expression levels and production of pro-inflammatory cytokines, including interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α). These suppressive effects of MMC on pro-inflammatory mediators and cytokines were mediated through the inhibition of transforming growth factor beta-activated kinase 1 (TAK1), which subsequently blocked the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). MMC also upregulated the nuclear factor erythroid-2-related factor 2 (Nrf2) by inducing the degradation of Kelch-like ECH-related protein 1 (Keap1), an Nrf2-specific E3 ligase. Accordingly, MMC enhanced Nrf2 target gene expression of anti-oxidative regulators such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). However, it had minimal effect on the DPPH radical scavenging capacity in vitro. Collectively, these findings demonstrate that MMC holds promise as a potential therapeutic agent for alleviating inflammation-related diseases and oxidative stress.
Topics: Animals; Mice; Anti-Inflammatory Agents; Antioxidants; Cytokines; Inflammation; Kelch-Like ECH-Associated Protein 1; Lipopolysaccharides; Macrophages; MAP Kinase Signaling System; Methanol; Mikania; NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide Synthase Type II; RAW 264.7 Cells; RNA, Messenger
PubMed: 37864893
DOI: 10.1016/j.biopha.2023.115746