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Frontiers in Physiology 2024Endothelial cells (ECs) play an important role in tissue homeostasis. Recently, EC lipid metabolism has emerged as a regulator of EC function. The liver X receptors...
OBJECTIVE
Endothelial cells (ECs) play an important role in tissue homeostasis. Recently, EC lipid metabolism has emerged as a regulator of EC function. The liver X receptors (LXRs) are involved in the transcriptional regulation of genes involved in lipid metabolism and have been identified as a potential target in cardiovascular disease. We aimed to decipher the role of LXRs in the regulation of lipid metabolism in human aortic endothelial cells.
APPROACH AND RESULTS
Lipid composition analysis of endothelial cells treated with the LXR agonist T0901317 revealed that LXR activation increased the proportion of polyunsaturated fatty acids (PUFAs) and decreased the proportion of saturated fatty acids. The LXR agonist decreased the uptake of fatty acids (FAs) by ECs. This effect was abolished by LXRα silencing. LXR activation increased the activity and the expression of lysophosphatidylcholine acyltransferase, LPCAT3, which is involved in the turnover of FAs at the sn-2 position of phospholipids. Transcriptomic analysis also revealed that LXRs increased the expression of key genes involved in the synthesis of PUFAs, including FA desaturase one and 2, FA elongase 5 and fatty acid synthase. Subsequently, the LXR agonist increased PUFA synthesis and enhanced arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid content in the EC phospholipids. Modification of the FA composition of ECs by LXRs led to a decrease of arachidonate and linoleate derived prostaglandins synthesis and release. No change on markers of inflammation induced by plasma from sickle cell patient were observed in presence of LXR agonist.
CONCLUSION
These results identify LXR as a key regulator of lipid metabolism in human aortic endothelial cells and a direct effect of LXR agonist on lysophosphatidylacyl transferase (LPCAT3).
PubMed: 38694208
DOI: 10.3389/fphys.2024.1388404 -
Frontiers in Bioscience (Landmark... Apr 2024Diabetic bladder dysfunction (DBD) is driven in part by inflammation which dysregulates prostaglandin release in the bladder. Precise inflammatory mechanisms responsible...
BACKGROUND
Diabetic bladder dysfunction (DBD) is driven in part by inflammation which dysregulates prostaglandin release in the bladder. Precise inflammatory mechanisms responsible for such dysregulation have been elusive. Since prostaglandins impact bladder contractility, elucidating these mechanisms may yield potential therapeutic targets for DBD. In female Type 1 diabetic Akita mice, inflammation mediated by the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome is responsible for DBD. Here, we utilized female Akita mice crossbred with knock-out mice to determine how NLRP3-driven inflammation impacts prostaglandin release within the bladder and prostaglandin-mediated bladder contractions.
METHODS
Akita mice were crossbred with mice to yield four groups of non-diabetics and diabetics with and without the gene. Females were aged to 30 weeks when Akitas typically exhibit DBD. Urothelia and detrusors were stretched to release prostaglandins. Prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) were quantified using enzyme linked immunosorbent assays (ELISA). In separate samples, contractile force to PGE2 and PGF2α +/- the prostaglandin F (FP) receptor antagonist, AL8810, was measured. FP receptor protein expression was determined via western blotting.
RESULTS
Stretch-induced PGE2 release increases in urothelia but decreases in detrusors of diabetics. However, PGE2-mediated bladder contractions are not impacted. Conversely, diabetics show no changes in PGF2α release, but PGF2α-mediated contractions increase significantly. This is likely due to signaling through the FP receptors as FP receptor antagonism prevents this increase and diabetics demonstrate a four-fold increase in FP receptor proteins. Without NLRP3-mediated inflammation, changes in prostaglandin release, contractility, and receptor expression do not occur.
CONCLUSION
NLRP3-dependent inflammation dysregulates prostaglandin release and prostaglandin-mediated bladder contractions in diabetic female Akita mice via FP receptor upregulation.
Topics: Animals; Female; NLR Family, Pyrin Domain-Containing 3 Protein; Urinary Bladder; Receptors, Prostaglandin; Muscle Contraction; Diabetes Mellitus, Type 1; Mice, Knockout; Mice; Inflammation; Mice, Inbred C57BL; Diabetes Mellitus, Experimental
PubMed: 38682210
DOI: 10.31083/j.fbl2904154 -
Open Veterinary Journal Mar 2024Reproductive efficiency affects dairy cow profitability. Ovarian function in postpartum (P.P.) has been better understood using ultrasound and hormonal assays....
BACKGROUND
Reproductive efficiency affects dairy cow profitability. Ovarian function in postpartum (P.P.) has been better understood using ultrasound and hormonal assays. Optimizing ovulation synchronization and carefully timing artificial insemination (TAI) can greatly enhance reproductive rates in dairy cows.
AIM
This experiment was designed to investigate the reproductive performance and ovarian activity in early postpartum lactating dairy cows using the Presynch-PGF2α, Ovsynch protocol, and TAI.
METHODS
Randomly the cows were assigned to a control group and a treatment group, based on the chronological order of their calving date. On day 14 P.P., both groups received two cloprostenol treatments, 14 days apart. Ultrasonographic inspections were conducted on day 14 to check ovarian activity and uterine contents. On day 11, after presynchronization, cows in the treatment group were given 100 µg IM. of cystorelin, followed by a luteolytic dose of 500 µg IM., cloprostenol on day 7, and a second dose of cystorelin on day 8 (36 hours later). After the second cystorelin injection by 16-20 hours, cows were inseminated, while the control group had all cows displaying spontaneous estrus between day 0 and day 28 were artificially inseminated.
RESULTS
Ovarian activity began to improve at 82.61% on day 19 P.P., with complete recovery between days 24 and 27 P.P. The second cloprostenol injection approached, causing follicular size to reach 8.41 ± 1.04 mm. After the second injection, ovarian activity switched from follicular to luteal, with corpus luteum rates of 23.91% and 26.1%. The presynchronized PGF2α regimen significantly enhanced ovarian activity from days 19-35 P.P. Ovulation and pregnancy rates in the Ovsynch group were 54.2% and 41.7% at the first timed artificial insemination (TAI), compared to 54.5% and 31.8% in the control group. There was no significant impact between them; it was just high in the presynchronized Ovsynch group. However, the P.P. period was minimized to 47-49 days till the first AI reached a 41.7% pregnancy rate and 20.8% at the second AI, for an overall 62.5%.
CONCLUSION
The current study concludes that presynchronization during preservice in clinically normal P.P. dairy cows reduces P.P. duration, increases ovarian activity performance, and reduces ovarian dysfunctions from day 19 to day 35 P.P., as well as improves the pregnancy rate.
Topics: Libya; Female; Animals; Cattle; Postpartum Period; Estrus Synchronization; Ovary; Fertility; Progesterone; Ovulation; Ultrasonography; Dinoprost; Gonadotropin-Releasing Hormone; Cloprostenol; Insemination, Artificial
PubMed: 38682144
DOI: 10.5455/OVJ.2024.v14.i3.9 -
Open Veterinary Journal Mar 2024Mares are the only companion animals simulating women in the large diameter of their follicles. Horses start reproduction at the age of three years, and some of them...
BACKGROUND
Mares are the only companion animals simulating women in the large diameter of their follicles. Horses start reproduction at the age of three years, and some of them live for >30 years, so aging influences their reproductive capacity. Mares are sensitive to summer heat stress as they can sweat like humans.
AIM
The current work aimed to study the effects of age (young versus senile), season (cold versus hot), and the hormonal treatments during embryo collection on the dominant and subordinate follicular dynamics and hemodynamics and circulating ovarian hormones in embryo donor mares ovulated twice spontaneously before inducing ovulation for flushing embryos.
METHODS
Spontaneous oestrous cycles were studied for young mares (<10 years; = 6) or senile (>20 years; = 5) during months of the cold season (November to April) and hot season (May to August). In young embryo donor mares, oestrous cycles after inducing ovulation and luteolysis were studied using Doppler ultrasound. Estradiol (E2), progesterone (P4), nitric oxide (NO), total cholesterol, and lactate dehydrogenase (LDH) were measured in blood serum.
RESULTS
A decrease in the dominant follicle antrum diameter ( > 0.05) and LDH ( = 0.016) was observed after inducing luteolysis in young embryo donor mares. Both human chorionic gonadotropin (hCG) and PGF2α treatments increased dominant follicle area ( = 0.0001), antrum area ( = 0.001), perimeter ( = 0.001), granulosa area ( = 0.0001), cholesterol ( = 0.0001), NO ( = 0.0001), and E2 ( = 0.0001). The dominant follicle area, antrum area, perimeter, color area, granulosa area, LDH, cholesterol, NO, and E2 increased ( = 0.0001) during the oestrous cycles of the hot season, but the circulatory % ( = 0.0001) declined. Senile mares had lower dominant follicle area ( = 0.002), antrum area ( = 0.0001), granulosa area ( > 0.05), LDH ( = 0.001), cholesterol ( = 0.0001), NO ( = 0.0001), and E2 ( = 0.0001) but higher circulatory % ( = 0.0001) and color area % ( = 0.023). The dominant follicle possesses the largest diameter, area, perimeter, granulosa area, and color area but the lowest circulatory % during spontaneous oestrous cycles, after inducing ovulation, or luteolysis with significant effects of the day of the spontaneous oestrous cycles on their dynamics and hemodynamics.
CONCLUSION
During hot months, mares treated with hCG ovulated 24 hours later and prostaglandin-induced luteolysis was followed by new ovulation five days later. Follicles ovulated during the hot months were larger than those ovulated during the cold months and both had nearly the same color area %. Senile mares ovulated follicles with a lower area and antrum area but a higher color area %, so senile mares can be used as embryo or oocyte donors during the hot season.
Topics: Animals; Horses; Female; Seasons; Luteolysis; Ovarian Follicle; Hemodynamics; Embryo Transfer; Aging; Age Factors; Progesterone; Estradiol
PubMed: 38682132
DOI: 10.5455/OVJ.2024.v14.i3.13 -
Pharmaceuticals (Basel, Switzerland) Apr 2024Xiaochaihu granules (XCHG) are extensively used to treat fever. Nevertheless, the underlying mechanism remains elusive. This study aimed to explore the potential of XCHG...
Xiaochaihu granules (XCHG) are extensively used to treat fever. Nevertheless, the underlying mechanism remains elusive. This study aimed to explore the potential of XCHG in mitigating yeast-induced fever and the underlying metabolic pathways. The chemical composition of XCHG was ascertained using ultra-fast liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS), followed by integrated network analysis to predict potential targets. We then conducted experimental validation using pharmacological assays and metabolomics analysis in a yeast-induced mouse fever model. The study identified 133 compounds in XCHG, resulting in the development of a comprehensive network of herb-compound-biological functional modules. Subsequently, molecular dynamic (MD) simulations confirmed the stability of the complexes, including γ-aminobutyric acid B receptor 2 (GABBR2)-saikosaponin C, prostaglandin endoperoxide synthases (PTGS2)-lobetyolin, and NF-κB inhibitor IκBα (NFKBIA)-glycyrrhizic acid. Animal experiments demonstrated that XCHG reduced yeast-induced elevation in NFKBIA's downstream regulators [interleukin (IL)-1β and IL-8], inhibited PTGS2 activity, and consequently decreased prostaglandin E2 (PGE2) levels. XCHG also downregulated the levels of 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), corticotropin releasing hormone (CRH), and adrenocorticotrophin (ACTH). These corroborated the network analysis results indicating XCHG's effectiveness against fever in targeting NFKBIA, PTGS2, and GABBR2. The hypothalamus metabolomics analysis identified 14 distinct metabolites as potential antipyretic biomarkers of XCHG. In conclusion, our findings suggest that XCHG alleviates yeast-induced fever by regulating inflammation/immune responses, neuromodulation, and metabolism modules, providing a scientific basis for the anti-inflammatory and antipyretic properties of XCHG.
PubMed: 38675434
DOI: 10.3390/ph17040475 -
International Journal of Molecular... Apr 2024The lipocalin proteins are a large family of small extracellular proteins that demonstrate significant heterogeneity in sequence similarity and have highly conserved... (Review)
Review
The lipocalin proteins are a large family of small extracellular proteins that demonstrate significant heterogeneity in sequence similarity and have highly conserved crystal structures. They have a variety of functions, including acting as carrier proteins, transporting retinol, participating in olfaction, and synthesizing prostaglandins. Importantly, they also play a critical role in human diseases, including cancer. Additionally, they are involved in regulating cellular homeostasis and immune response and dispensing various compounds. This comprehensive review provides information on the lipocalin family, including their structure, functions, and implications in various diseases. It focuses on selective important human lipocalin proteins, such as lipocalin 2 (LCN2), retinol binding protein 4 (RBP4), prostaglandin D2 synthase (PTGDS), and α-microglobulin (A1M).
Topics: Humans; Lipocalins; Neoplasms; Structure-Activity Relationship; Animals; Intramolecular Oxidoreductases
PubMed: 38673873
DOI: 10.3390/ijms25084290 -
International Journal of Molecular... Apr 2024Inflammation is crucial to osteoarthritis (OA) pathogenesis. The aim of this study was to evaluate residue extract (NHGRE) obtained by extracting fruits with water as...
Inflammation is crucial to osteoarthritis (OA) pathogenesis. The aim of this study was to evaluate residue extract (NHGRE) obtained by extracting fruits with water as a potential food supplement for treating arthritis based on its analgesic, anti-inflammatory, and chondroprotective effects and the remaining residue with 70% ethanol. We observed the analgesic activity of NHGRE based on the acetic acid-induced writhing response in mice, examined its anti-inflammatory efficacy against carrageenan-induced paw oedema in mice, and investigated its effect on inflammatory cytokine expression in interleukin (IL)-1β-induced SW1353 cells. Furthermore, we determined its effects on cartilage protection in interleukin-1β (IL-1β)-treated SW1353 cells. NHGRE at 200 mg/kg significantly reduced the acetic acid-induced writhing response and prevented oedema formation in the carrageenan-induced paw oedema model. In IL-1β-induced SW1353 cells, NHGRE at 400 µg/mL reduced the expression of inflammation mediators such as tumour necrosis factor (TNF)-α (55.3%), IL-6 (35.4%), and prostaglandin E2 (PGE2) (36.9%) and down-regulated the expression of matrix metalloproteinase (MMP)-1 (38.6%), MMP-3 (29.3%), and MMP-13 (44.8%). Additionally, it restored degraded collagen II levels in chondrocytes. NHGRE plays a protective role in chondrocytes by regulating Nuclear factor kappa B (NF-κB) activation. Overall, NHGRE may be a useful therapeutic agent for OA by controlling pain, oedema formation, and inflammation-related mechanisms.
Topics: Animals; Anti-Inflammatory Agents; Mice; Plant Extracts; Analgesics; Edema; Male; Humans; Chondrocytes; Interleukin-1beta; Carrageenan; Osteoarthritis; Cytokines
PubMed: 38673854
DOI: 10.3390/ijms25084268 -
Chinese Medicine Apr 2024Chelidonium majus is a well-known traditional Chinese medicine, and has been reported of the effect in relieving cough and asthma. However, the mechanism of action is...
BACKGROUND
Chelidonium majus is a well-known traditional Chinese medicine, and has been reported of the effect in relieving cough and asthma. However, the mechanism of action is still unknown.
METHODS
Asthmatic SD rats were first sensitized and established through ovalbumin (OVA) motivation. Subsequently, Hematoxylin and eosin (H&E) staining, Masson's trichrome (Masson) staining, Periodic acid-Schiff (PAS) staining and inflammatory cytokines assay of interleukin (IL)-4, IL-6, IL-17 were implemented to evaluate the protective effects of Chelidonium majus on asthma. Then, the effects of Chelidonium majus and their molecular mechanisms of action on asthma were detected based on the integration of transcriptomics and metabolomics analyses.
RESULTS
After administration with Chelidonium majus, the histological injuries of inflammation, collagen deposition and mucus secretion in lungs were attenuated and the serum inflammatory cytokines perturbations were also converted. Furthermore, integrated analysis revealed that after Chelidonium majus treatment, 7 different expression genes (DEGs) (Alox15, P4ha1, Pla2g16, Pde3a, Nme1, Entpd8 and Adcy9) and 9 metabolic biomarkers (ADP, Xanthosine, Hypoxanthine, Inosine, prostaglandin E2 (PGE2), prostaglandin F2a (PGF2a), phosphatidylserine, Creatine and LysoPC (10:0)) were discovered to be connected with the enrichment metabolic pathways, including Purine metabolism, Arachidonic acid metabolism, Arginine and proline metabolism and Glycerophospholipid metabolism. The obtained metabolic biomarkers and DEGs were mainly related to energy metabolism and inflammation, and may be potential therapeutic targets.
CONCLUSION
Chelidonium majus relieved OVA-induced asthma in rats by regulating the Alox15, P4ha1, Pla2g16, Pde3a, Nme1, Entpd8 and Adcy9 genes expression to restore the disorders in energy metabolism and inflammation.
PubMed: 38671520
DOI: 10.1186/s13020-024-00932-y -
Tropical Medicine and Infectious Disease Apr 2024Glutathione transferases (GSTs EC 2.5.1.18) are critical components of phase II metabolism, instrumental in xenobiotics' metabolism. Their primary function involves... (Review)
Review
Glutathione transferases (GSTs EC 2.5.1.18) are critical components of phase II metabolism, instrumental in xenobiotics' metabolism. Their primary function involves conjugating glutathione to both endogenous and exogenous toxic compounds, which increases their solubility and enables their ejection from cells. They also play a role in the transport of non-substrate compounds and immunomodulation, aiding in parasite establishment within its host. The cytosolic GST subfamily is the most abundant and diverse in helminths, and sigma-class GST (GSTσ) belongs to it. This review focuses on three key functions of GSTσ: serving as a detoxifying agent that provides drug resistance, functioning as an immune system modulator through its involvement in prostaglandins synthesis, and acting as a vaccine antigen.
PubMed: 38668546
DOI: 10.3390/tropicalmed9040085 -
Nature May 2024Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer....
Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer. Interleukin-2 (IL-2) acts as a key regulator of CD8 cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE), a known negative regulator of immune response in the tumour microenvironment, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8 TILs via the PGE receptors EP2 and EP4. Mechanistically, PGE inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ chain, resulting in defective assembly of IL-2Rβ-IL2Rγ membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Cell Proliferation; Dinoprostone; Down-Regulation; Ferroptosis; Interleukin Receptor Common gamma Subunit; Interleukin-2; Interleukin-2 Receptor beta Subunit; Lymphocytes, Tumor-Infiltrating; Mitochondria; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Microenvironment
PubMed: 38658764
DOI: 10.1038/s41586-024-07352-w