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PloS One 2024This study aims to investigate the protective mechanism of dihydromyricetin PLGA nanoparticles (DMY-PLGA NPs) against myocardial ischemia-reperfusion injury (MIRI) in...
PURPOSE
This study aims to investigate the protective mechanism of dihydromyricetin PLGA nanoparticles (DMY-PLGA NPs) against myocardial ischemia-reperfusion injury (MIRI) in vitro and the improvement of oral bioavailability in vivo.
METHODS
DMY-PLGA NPs was prepared and characterized by emulsifying solvent volatilization, and the oxidative stress model of rat H9c2 cardiomyocyte induced by H2O2 was established. After administration, cell survival rate, lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected, and the expressions of PGC1α and PPARα were detected by western blot (WB). At the same time, the pharmacokinetics in rats were studied to explore the improvement of bioavailability.
RESULTS
DMY-PLGA NPs can significantly increase cell survival rate, decrease LDH and MDA content, increase SOD content and PGC1α、PPARα protein expression. Compared with DMY, the peak time of DMY-PLGA NPs was extended (P<0.1), and the bioavailability was increased by 2.04 times.
CONCLUSION
DMY-PLGA NPs has a significant protective effect on H9c2 cardiomyocytes, which promotes the absorption of DMY and effectively improves bioavailability.
Topics: Rats; Animals; Hydrogen Peroxide; PPAR alpha; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Oxidative Stress; Myocardium; Myocytes, Cardiac; Superoxide Dismutase; Apoptosis; Flavonols
PubMed: 38625956
DOI: 10.1371/journal.pone.0301036 -
Current Osteoporosis Reports Jun 2024This review summarizes evidence on osteocyte support of extramedullary and bone marrow adipocyte development and discusses the role of endogenous osteocyte activities of... (Review)
Review
PURPOSE OF REVIEW
This review summarizes evidence on osteocyte support of extramedullary and bone marrow adipocyte development and discusses the role of endogenous osteocyte activities of nuclear receptors peroxisome proliferator-activated receptor gamma (PPARG) and alpha (PPARA) in this support.
RECENT FINDINGS
PPARG and PPARA proteins, key regulators of glucose and fatty acid metabolism, are highly expressed in osteocytes. They play significant roles in the regulation of osteocyte secretome and osteocyte bioenergetics; both activities contributing to the levels of systemic energy metabolism in part through an effect on metabolic function of extramedullary and bone marrow adipocytes. The PPARs-controlled osteocyte endocrine/paracrine activities, including sclerostin expression, directly regulate adipocyte function, while the PPARs-controlled osteocyte fuel utilization and oxidative phosphorylation contribute to the skeletal demands for glucose and fatty acids, whose availability is under the control of adipocytes. Bone is an inherent element of systemic energy metabolism with PPAR nuclear receptors regulating osteocyte-adipocyte metabolic axes.
Topics: Osteocytes; Humans; PPAR gamma; Bone Marrow; Adipose Tissue; Adipocytes; Energy Metabolism; PPAR alpha; Animals
PubMed: 38625510
DOI: 10.1007/s11914-024-00871-5 -
Brain Research Bulletin Jun 2024Existing evidence suggests that the composition of the gut microbiota is associated with neuropathic pain (NP), but the mechanistic link is elusive. Peroxisome...
BACKGROUND
Existing evidence suggests that the composition of the gut microbiota is associated with neuropathic pain (NP), but the mechanistic link is elusive. Peroxisome proliferator-activated receptor α (PPARα) has been shown to be a pharmacological target for the treatment of metabolic disorders, and its expression is also involved in inflammatory regulation. The aim of this study was to investigate the important modulatory effects of PPARα on gut microbiota and spinal cord metabolites in mice subjected to chronic constriction injury.
METHODS
We analyzed fecal microbiota and spinal cord metabolic alterations in mice from the sham, CCI, GW7647 (PPARα agonist) and GW6471 (PPARα antagonist) groups by 16 S rRNA amplicon sequencing and untargeted metabolomics analysis. On this basis, the intestinal microbiota and metabolites that were significantly altered between treatment groups were analyzed in a combined multiomics analysis. We also investigated the effect of PPARα on the polarization fractionation of spinal microglia.
RESULTS
PPARα agonist significantly reduce paw withdrawal threshold and paw withdrawal thermal latency, while PPARα antagonist significantly increase paw withdrawal threshold and paw withdrawal thermal latency. 16 S rRNA gene sequencing showed that intraperitoneal injection of GW7647 or GW6471 significantly altered the abundance, homogeneity and composition of the gut microbiome. Analysis of the spinal cord metabolome showed that the levels of spinal cord metabolites were shifted after exposure to GW7647 or GW6471. Alterations in the composition of gut microbiota were significantly associated with the abundance of various spinal cord metabolites. The abundance of Licheniformes showed a significant positive correlation with nicotinamide, benzimidazole, eicosanoids, and pyridine abundance. Immunofluorescence results showed that intraperitoneal injection of GW7647 or GW6471 altered microglial activation and polarization levels.
CONCLUSION
Our study shows that PPARα can promote M2-type microglia polarization, as well as alter gut microbiota and metabolites in CCI mice. This study enhances our understanding of the mechanism of PPARα in the treatment of neuropathic pain.
Topics: Animals; Male; Mice; Feces; Gastrointestinal Microbiome; Metabolomics; Mice, Inbred C57BL; Microglia; Neuralgia; Oxazoles; PPAR alpha; RNA, Ribosomal, 16S; Spinal Cord; Tyrosine
PubMed: 38614408
DOI: 10.1016/j.brainresbull.2024.110943 -
Molecules (Basel, Switzerland) Apr 2024Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous lipids that act as agonists of the peroxisome proliferator-activated receptor α (PPARα)....
Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous lipids that act as agonists of the peroxisome proliferator-activated receptor α (PPARα). Recently, an interest in the role of these lipids in malignant tumors has emerged. Nevertheless, the effects of OEA and PEA on human neuroblastoma cells are still not documented. Type I interferons (IFNs) are immunomodulatory cytokines endowed with antiviral and anti-proliferative actions and are used in the treatment of various pathologies such as different cancer forms (i.e., non-Hodgkin's lymphoma, melanoma, leukemia), hepatitis B, hepatitis C, multiple sclerosis, and many others. In this study, we investigated the effect of OEA and PEA on human neuroblastoma SH-SY5Y cells treated with IFNβ. We focused on evaluating cell viability, cell proliferation, and cell signaling. Co-exposure to either OEA or PEA along with IFNβ leads to increased apoptotic cell death marked by the cleavage of caspase 3 and poly-(ADP ribose) polymerase (PARP) alongside a decrease in survivin and IKBα levels. Moreover, we found that OEA and PEA did not affect IFNβ signaling through the JAK-STAT pathway and the STAT1-inducible protein kinase R (PKR). OEA and PEA also increased the phosphorylation of p38 MAP kinase and programmed death-ligand 1 (PD-L1) expression both in full cell lysate and surface membranes. Furthermore, GW6471, a PPARα inhibitor, and the genetic silencing of the receptor were shown to lower PD-L1 and cleaved PARP levels. These results reveal the presence of a novel mechanism, independent of the IFNβ-prompted pathway, by which OEA and PEA can directly impair cell survival, proliferation, and clonogenicity through modulating and potentiating the intrinsic apoptotic pathway in human SH-SY5Y cells.
Topics: Humans; Neuroblastoma; B7-H1 Antigen; Janus Kinases; PPAR alpha; Poly(ADP-ribose) Polymerase Inhibitors; STAT Transcription Factors; Signal Transduction; Apoptosis; Palmitic Acids; Amides; Ethanolamines; Oleic Acids; Endocannabinoids
PubMed: 38611871
DOI: 10.3390/molecules29071592 -
Foods (Basel, Switzerland) Apr 2024Obesity poses a significant threat to various health conditions such as heart diseases, diabetes, high blood pressure, and heart attack, with the gut microbiota playing...
Obesity poses a significant threat to various health conditions such as heart diseases, diabetes, high blood pressure, and heart attack, with the gut microbiota playing a crucial role in maintaining the body's energy balance. We identified a novel probiotic fungal strain, JSA 18 ), which was isolated from yak milk and was found to possess anti-obesity properties. Additionally, CGMCC 8198 (LP8198) from our previous study was also included to evaluate its anti-obesity properties. The findings indicated that caused a notable reduction in weight gain, liver and fat indexes, and hyperlipidemia in mice fed a high-fat diet (HFD). Administering and LP8198 to mice on a high-fat diet resulted in a reduction of serum triglyceride levels. Furthermore, the supplements reduced ALT and AST activity, and inhibited the production of inflammatory cytokines such as TNF-α and IL-1β. In addition, lipid metabolism was enhanced by the downregulation of ACC1, PPAR-γ, SREBP-1, and Fasn. Moreover, this study found that and LP8198 have little effect on gut bacteria. Additionally, partially influenced intestinal fungi, while LP8198 had a minor influence on gut mycobiota. The main goal of this research was to show how effective can be as a probiotic in combating obesity.
PubMed: 38611428
DOI: 10.3390/foods13071124 -
Journal of Dairy Science Apr 2024This study is aimed at investigating the effects of dietary supplementation with Artemisia ordosica crude polysaccharides (AOCP) on lactation performance, antioxidant...
Rectal microbiomes and serum metabolomics reveal the improved effect of Artemisia ordosica crude polysaccharides on the lactation performance, antioxidant and immune responses of lactating donkeys.
This study is aimed at investigating the effects of dietary supplementation with Artemisia ordosica crude polysaccharides (AOCP) on lactation performance, antioxidant status, and immune status of lactating donkeys and analyzing rectal microbiomes and serum metabolomes. Fourteen lactating Dezhou donkeys with similar age (6.16 ± 0.67 years of BW ± SD), weight (250.06 ± 25.18 kg), days in milk (39.11 ± 7.42 d), and averaged parity of 3 were randomly allocated into 2 treatments: a control group (CON, basal diet) and an AOCP group (AOCP, basal diet with 1.0 g/kg DM AOCP). Ten weeks were allotted for the experiment, 2 weeks for adaptation, and 8 weeks for collecting data and samples. The results showed that supplementation of donkey diets with AOCP increased lactation performance, including dry matter intake, milking yield, estimated milk yield, solids-corrected milk, energy-corrected milk, milk fat yield, milk protein yield, milk lactose yield, milk total solids yield, and milk solid not fat yield. The digestibility of dry matter, crude protein, acid detergent fiber, and neutral detergent fiber was increased in the AOCP group compared with the CON group. The AOCP group increased the concentrations of immunoglobulin A, immunoglobulin G, and immunoglobulin M, the activities of the superoxide dismutase, catalase and total antioxidant capacity in the serum. AOCP decreased the concentrations of tumor necrosis factor-α, nitric oxide, reactive oxygen species, and malondialdehyde in the serum. Compared with the CON group, AOCP increased propionate, butyrate, isovalerate, and total VFA concentrations in rectal feces (P < 0.05). The addition of AOCP to increased diversity (Shannon index) and altered structure of the rectal microflora. As a result of AOCP supplementation, there has been a significant improvement in the colonization of beneficial bacteria, including Lactobacillus, Unclassified_f_Prevotellacea, Ruminococcus, and Fibrobacter genera. In contrast, a decrease in the colonization of the Clostridium_sensu_stricto_1 bacterial genus and other pathogenic bacteria was observed. Meanwhile, metabolomics analysis found that AOCP supplementation upregulated metabolites L-tyrosine content while downregulating 9(S)-HODE, choline, sucrose, LysoPC (18:0), LysoPC (18:1(9Z), and LysoPC (20:2(11Z,14Z)) concentrations. These altered metabolites were involved in the PPAR signaling pathway, prolactin signaling pathway, glycerophospholipid metabolism, carbohydrate digestion and absorption, and tyrosine metabolism pathways, which were mainly related to antioxidant capacity, immune responses, and protein metabolism in the lactating donkeys. As a consequence of feeding AOCP diets, beneficial bacteria were abundant, and antioxidant and protein metabolism-related pathways were enriched, which may enhance lactation performance in donkeys. Therefore, supplementing AOCP diets is a desirable dietary strategy to improve donkey health and lactation performance.
PubMed: 38608958
DOI: 10.3168/jds.2023-24570 -
Molecular Metabolism Jun 2024During fasting, liver pivotally regulates blood glucose levels through glycogenolysis and gluconeogenesis. Kidney also produces glucose through gluconeogenesis....
OBJECTIVES
During fasting, liver pivotally regulates blood glucose levels through glycogenolysis and gluconeogenesis. Kidney also produces glucose through gluconeogenesis. Gluconeogenic genes are transactivated by fasting, but their expression patterns are chronologically different between the two organs. We find that renal gluconeogenic gene expressions are positively correlated with the blood β-hydroxybutyrate concentration. Thus, we herein aim to investigate the regulatory mechanism and its physiological implications.
METHODS
Gluconeogenic gene expressions in liver and kidney were examined in hyperketogenic mice such as high-fat diet (HFD)-fed and ketogenic diet-fed mice, and in hypoketogenic PPARα knockout (PPARα) mice. Renal gluconeogenesis was evaluated by rise in glycemia after glutamine loading in vivo. Functional roles of β-hydroxybutyrate in the regulation of renal gluconeogenesis were investigated by metabolome analysis and RNA-seq analysis of proximal tubule cells.
RESULTS
Renal gluconeogenic genes were transactivated concurrently with blood β-hydroxybutyrate uprise under ketogenic states, but the increase was blunted in hypoketogenic PPARα mice. Administration of 1,3-butandiol, a ketone diester, transactivated renal gluconeogenic gene expression in fasted PPARα mice. In addition, HFD-fed mice showed fasting hyperglycemia along with upregulated renal gluconeogenic gene expression, which was blunted in HFD-fed PPARα mice. In vitro experiments and metabolome analysis in renal tubular cells showed that β-hydroxybutyrate directly promotes glucose and NH production through transactivating gluconeogenic genes. In addition, RNA-seq analysis revealed that β-hydroxybutyrate-induced transactivation of Pck1 was mediated by C/EBPβ.
CONCLUSIONS
Our findings demonstrate that β-hydroxybutyrate mediates hepato-renal interaction to maintain homeostatic regulation of blood glucose and systemic acid-base balance through renal gluconeogenesis regulation.
Topics: Animals; Gluconeogenesis; Mice; Ketone Bodies; Liver; Male; Kidney; Mice, Knockout; Mice, Inbred C57BL; 3-Hydroxybutyric Acid; Diet, High-Fat; PPAR alpha; Blood Glucose; Diet, Ketogenic
PubMed: 38604598
DOI: 10.1016/j.molmet.2024.101934 -
Frontiers in Cellular and Infection... 2024Commensal gut bacteria use oleate hydratase to release a spectrum of hydroxylated fatty acids using host-derived unsaturated fatty acids. These compounds are thought to...
Commensal gut bacteria use oleate hydratase to release a spectrum of hydroxylated fatty acids using host-derived unsaturated fatty acids. These compounds are thought to attenuate the immune response, but the underlying signaling mechanism(s) remain to be established. The pathogen also expresses an oleate hydratase and 10-hydroxyoctadecanoic acid (18:0) is the most abundant oleate hydratase metabolite found at Staphylococcal skin infection sites. Here, we show 18:0 stimulates the transcription of a set of lipid metabolism genes associated with the activation of peroxisome proliferator activated receptor (PPAR) in the RAW 264.7 macrophage cell line and mouse primary bone marrow-derived macrophages. Cell-based transcriptional reporter assays show 18:0 selectively activates PPARα. Radiolabeling experiments with bone marrow-derived macrophages show [1-C]18:0 is not incorporated into cellular lipids, but is degraded by β-oxidation, and mass spectrometry detected shortened fragments of 18:0 released into the media. The catabolism of 18:0 was >10-fold lower in bone marrow-derived macrophages isolated from knockout mice, and we recover 74-fold fewer cells from the skin infection site of knockout mice compared to wildtype mice. These data identify PPARα as a target for oleate hydratase-derived hydroxy fatty acids and support the existence of an oleate hydratase-PPARα signaling axis that functions to suppress the innate immune response to .
Topics: Mice; Animals; PPAR alpha; Staphylococcus aureus; Oleic Acid; Fatty Acids; Mice, Knockout
PubMed: 38601738
DOI: 10.3389/fcimb.2024.1352810 -
Neuroreport May 2024Intracerebral hemorrhage (ICH) is a severe stroke subtype. Secondary injury is a key factor leading to neurological deficits after ICH. Electroacupuncture (EA) can...
Electroacupuncture reduces oxidative stress response and improves secondary injury of intracerebral hemorrhage in rats by activating the peroxisome proliferator-activated receptor-γ/nuclear factor erythroid2-related factor 2/γ-glutamylcysteine synthetase pathway.
Intracerebral hemorrhage (ICH) is a severe stroke subtype. Secondary injury is a key factor leading to neurological deficits after ICH. Electroacupuncture (EA) can improve the neurological function after ICH, however, its internal mechanism is still unclear. The aim of this study is to investigate whether EA could ameliorate secondary injury after ICH through antioxidative stress and its potential regulatory mechanism. A rat model of ICH was established by injecting autologous blood into striatum. After the intervention of EA and EA combined with peroxisome proliferator-activated receptor-γ (PPARγ) blocker, Zea-longa scores, modified neurological severity scores and open field tests were used to evaluate the neurological function of the rats. Flow cytometry detected tissue reactive oxygen species (ROS) levels. Tissue tumor necrosis factor-α (TNF-α) levels were analyzed by enzyme-linked immunosorbent assays. The protein expressions of PPAR γ, nuclear factor erythroid2-related factor 2 (Nrf2) and γ-glutamylcysteine synthetase (γ-GCS) were detected by Western blot. Immunohistochemistry was used to observe the activation of microglia. The demyelination degree of axon myelin was observed by transmission electron microscope. Compared with the model group, EA intervention improved neurological function, decreased ROS and TNF-α levels, increased the protein expression of PPARγ, Nrf2 and γ-GCS, and reduced the activation of microglia, it also alleviated axonal myelin sheath damage. In addition, the neuroprotective effect of EA was partially attenuated by PPARγ blocker. EA ameliorated the neurological function of secondary injury after ICH in rats, possibly by activating the PPARγ/Nrf2/γ-GCS signaling pathway, reducing microglia activation, and inhibiting oxidative stress, thus alleviating the extent of axonal demyelination plays a role.
Topics: Animals; PPAR gamma; NF-E2-Related Factor 2; Electroacupuncture; Oxidative Stress; Cerebral Hemorrhage; Rats; Male; Rats, Sprague-Dawley; Glutamate-Cysteine Ligase; Signal Transduction; Reactive Oxygen Species
PubMed: 38597270
DOI: 10.1097/WNR.0000000000002026 -
Molecular Cancer Apr 2024Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the...
BACKGROUND AND AIMS
Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC.
MATERIALS AND METHODS
A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array.
RESULTS
CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC.
CONCLUSION
Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.
Topics: Humans; Mice; Animals; Sorafenib; Carcinoma, Hepatocellular; RNA, Long Noncoding; Liver Neoplasms; RNA, Guide, CRISPR-Cas Systems; PPAR alpha; Proteomics; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic
PubMed: 38582885
DOI: 10.1186/s12943-024-01988-y