Search Results (753)

This review highlights recent findings on the potent anti-angiogenic serpin protein, pigment epithelium-derived factor (PEDF) as it relates to metabolic disease, diabetes, angiogenesis and cardiovascular disease (CVD), listing a majority of all the publicly available studies reported to date. PEDF is involved in various physiological roles in the body, and when awry, it triggers various disease states clinically. Biomarkers such as insulin, AMP-activated protein kinase alpha (AMPK-α), and peroxisome proliferator-activated receptor gamma (PPAR-γ) are involved in PEDF effects on metabolism. Wnt, insulin receptor substate (IRS), Akt, extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase (MAPK) are implicated in diabetes effects displayed by PEDF. For CVD, oxidised LDL, Wnt/β-catenin, and reactive oxygen species (ROS) are players intertwined with PEDF activity. The review also presents an outlook on where efforts could be devoted to bring this serpin closer to clinical trials for these diseases and others in general. Full article

Atherosclerosis (AS), a progressive inflammatory disease of coronary arteries, the aorta, and the internal carotid artery, is considered one of the main contributors to cardiovascular disorders. Blood flow is restricted by accumulating lipid-rich macrophages (foam cells), calcium, fibrin, and cellular debris into plaques on the intima of arterial walls. Butyrate maintains gut barrier integrity and modulates immune responses. Butyrate regulates G-protein-coupled receptor (GPCR) signaling and activates nuclear factor kappa-B (NF-κB), activator protein-1 (AP-1), and interferon regulatory factors (IFRs) involved in the production of proinflammatory cytokines. Depending on the inflammatory stimuli, butyrate may also inactivate NF-κB, resulting in the suppression of proinflammatory cytokines and the stimulation of anti-inflammatory cytokines. Butyrate modulates mitogen-activated protein kinase (MAPK) to promote or suppress macrophage inflammation, muscle cell growth, apoptosis, and the uptake of oxidized low-density lipoprotein (ox-LDL) in macrophages. Activation of the peroxisome proliferator-activated receptor γ (PPARγ) pathway plays a role in lipid metabolism, inflammation, and cell differentiation. Butyrate inhibits interferon γ (IFN-γ) signaling and suppresses NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) involved in inflammation and scar tissue formation. The dual role of butyrate in AS is discussed by addressing the interactions between butyrate, intestinal epithelial cells (IECs), endothelial cells (ECs) of the main arteries, and immune cells. Signals generated from these interactions may be applied in the diagnosis and intervention of AS. Reporters to detect early AS is suggested. This narrative review covers the most recent findings published in PubMed and Crossref databases. Full article

Background: Previously, we found that the pathological changes in the corpus spongiosum (CS) in hypospadias were mainly localized within smooth muscle tissue, presenting as a transformation from the contraction phenotype to synthesis. The role of low-intensity pulsed ultrasound (LIPUS) in regulating smooth muscle cells (SMCs) and angiogenesis has been confirmed. Objectives: To demonstrate the feasibility of regulating the phenotypic transformation of corpus spongiosum smooth muscle cells (CSSMCs) in hypospadias using LIPUS and to explore the potential mechanisms. Materials and Methods: The CSSMCs were extracted from CS in patients with proximal hypospadias. In vitro experiments were conducted to explore the appropriate LIPUS irradiation intensity and duration which could promote the phenotypic transformation of CSSMCs. A total of 71 patients with severe hypospadias were randomly divided into a control group and a LIPUS group to verify the in vivo transition effect of LIPUS. Consequently, the potential mechanisms by which LIPUS regulates the phenotypic transformation of CSSMCs were explored in vitro. Results: In vitro experiments showed that LIPUS with an intensity of 100 mW/cm² and a duration of 10 min could significantly increase the expression of contraction markers in CSSMCs and decrease the expression of synthesis markers. Moreover, LIPUS stimulation could alter the phenotype of CSSMCs in patients with proximal hypospadias. RNA sequencing results revealed that peroxisome proliferator-activated receptor gamma (PPAR-γ) significantly increased after LIPUS stimulation. Overexpression of PPAR-γ significantly increased the expression of contraction markers in CSSMCs, and the knockdown of PPAR-γ blocked this effect. Conclusions: LIPUS can regulate the transition of CSSMCs from a synthetic to a contractile phenotype in hypospadias. The PPAR-γ-mediated signaling pathway is a possible mechanism involved in this process. Full article

Medulloblastoma (MB) is the most common malignant brain tumor in children and typically arises in the cerebellum, likely due to disruptions in neuronal precursor development. The primary inhibitory neurotransmitter in the central nervous system (CNS), γ-aminobutyric acid (GABA), exerts its effects through GABA_A, GABA_B, and GABA_C receptors. GABA receptor activity regulates the development and function of cerebellar neurons, including glutamatergic cerebellar granule cells (CGCs). Beyond the nervous system, GABA is also a common metabolite in non-neuronal cell types. An increasing body of evidence indicates that GABA can influence cell proliferation, differentiation, and migration in several types of adult solid tumors, including brain cancers. GABA and GABA_A receptor agonists can impair the viability and survival of MB cells, primarily acting on GABA_A receptors containing the α5 subunit. A marked expression of the gene encoding the α5 subunit is found across all MB tumor molecular subgroups, particularly Group 3 MB, which has a poor prognosis. Importantly, high levels of the γ-aminobutyric acid type A receptor subunit α5 (GABRA5) gene are associated with shorter patient overall survival in Group 3 and Group 4 MB. In contrast, high γ-aminobutyric acid type A receptor subunit β1 (GABRB1) gene expression is related to longer survival in all MB subgroups. The GABAergic system may, therefore, regulate MB cell function and tumor progression and influence patient prognosis, and is worthy of further investigation as a biomarker and therapeutic target in MB. Full article

Camelina seeds are rich in α-linolenic acid (ALA), but also contain small amounts of erucic acid, which is considered toxic to laboratory rats. This experiment compares the dietary inclusion of camelina oil to that of flaxseed oil, a well-known source of ALA, and evaluates their effects on the nutritional and metabolic status of growing rats. The oils were chemically analyzed and incorporated into a semi-purified diet for 4 weeks. The experiment was divided into 3 groups: PO (control-fed palm oil with a trace of ALA), FO (comparative-fed flaxseed oil), and CO (experimental-fed camelina seed oil). Both CO and FO showed a higher percentage of lean body mass, greater lean mass gain, and a lower fat percentage compared to PO. Similar to the body composition, the blood lipid profile also improved in CO and FO, with higher HDL cholesterol and lower triglyceride levels, which was associated with upregulation of the peroxisome proliferator-activated receptor γ gene. However, in FO and CO, higher plasma liver enzyme activity and malondialdehyde concentrations were observed in the heart and liver. The results suggest that camelina oil has a similarly beneficial impact on the metabolic processes of the growing body as flaxseed oil, while also indicating a potential for increased organ-specific lipid peroxidation and hepatic burden when consumed in excess. Full article

Background/Objective: Ganoderma spp. have long been studied for their bioactive pharmacological properties, and their biomass and extracts have been obtained from various sources. This study adopts a novel approach: enriching a liquid culture of Ganoderma mexicanum with a vineyard pruning waste extract to identify bioactive compounds with antiproliferative activity through enriched chromatographic fractions. Methods: The ethanolic extract from a mycelial culture was separated following a partitioning process, and the hexane fraction was subsequently separated in a chromatographic column. The fractions were evaluated for their antiproliferative properties against cancer cell lines. The interactions of the molecules identified with peroxisome proliferator-activated receptor gamma (PPAR-γ) were analyzed via molecular docking. Results: Three chromatographic fractions (FH11–FH13) exhibited antiproliferative activity which was significantly more effective against non-small lung cancer cells (A549). The cells treated with the crude extract and fractions presented a balloon-like morphology. A chemical analysis of the active fractions allowed us to identify four compounds: one fatty acid (9-Hydroxy-10E,12Z-octadecadienoic acid) and three triterpenes (ganoderic acids DM, TQ, and X). These compounds showed interactions with the PPAR-γ receptor through molecular docking. Conclusions: Ganoderma mexicanum is a promising source of compounds with antiproliferative activity that could serve as natural ligands for PPAR-γ and has possible applications in lung cancer therapy. Full article

Galectin-12, a member of the galectin family of glycan-binding proteins, exhibits restricted tissue distribution, primarily in adipocytes and sebocytes. In sebocytes, it modulates the cell cycle, influences lipid metabolism through interactions with peroxisome proliferator-activated receptor γ (PPARγ), and exerts immunomodulatory functions by activating immune signaling pathways. Dysregulation of sebocyte homeostasis, lipid metabolism, and immune responses contributes to the pathogenesis of a number of skin diseases, underscoring the therapeutic potential of targeting galectin-12. The review summarizes and discusses current developments in the field to foster future research in this important but underexplored galectin. Full article

Testicular orphan receptors TR2 and TR4 serve as central regulators of erythropoiesis, orchestrating the entire continuum of erythroid progenitor cell proliferation, differentiation, and maturation. As core components of the direct repeat erythroid determinant (DRED) complex, they activate erythroid-specific transcriptional programs to dynamically control the spatiotemporal expression of globin genes. These nuclear receptors not only engage in functional interactions with key erythroid transcription factors GATA1 and KLF1 to coregulate erythroid differentiation and maturation but also recruit epigenetic modifier complexes such as DNMT1 and LSD1 to modulate chromatin states dynamically. Research has established that dysfunctions in TR2/TR4 are implicated in β-thalassemia and sickle cell disease (SCD): β-thalassemia is associated with the defective silencing of γ-globin genes, while in SCD, TR2/TR4 antagonizes BCL11A to reactivate fetal hemoglobin (HbF) expression. This review systematically dissects the molecular regulatory networks of TR2/TR4 in erythroid cells, interprets their dual regulatory properties across different stages of erythroid differentiation, and explores the therapeutic potential of targeting TR2/TR4 for treating erythroid-related disorders such as β-thalassemia and SCD, thereby providing novel directions for hematological disorder therapy. Full article

With industrial development, endocrine-disrupting chemicals have continued to accumulate in the environment, attracting growing attention due to their potential effects on biological health. The reproductive toxicity of diethylstilbestrol (DES), a synthetic estrogen widely present in the environment, is widely documented; however, studies on its effects on the immune system remain limited. In this study, adult male golden hamsters were subcutaneously administered varying doses of DES (0, 0.01, 0.1, and 1.0 mg/kg) for seven consecutive days to assess its immunomodulatory impact on peripheral blood and the spleen. We found that the DES treatment significantly reduced spleen index, white pulp area, and splenic lymphocyte proliferation while increasing caspase-3-positive apoptotic cells and inducible nitric oxide synthase expression. In peripheral blood, DES induced a dose-dependent suppression of lymphocyte proliferation, with lipopolysaccharide- and concanavalin A-stimulated proliferation reduced by 47.68–71.76% and 44.23–72.7%, respectively. Concurrently, DES significantly downregulated the pro-inflammatory cytokines IL-2 and IFN-γ (p < 0.01) while upregulating the anti-inflammatory cytokines IL-4 and IL-10 (p < 0.01). Furthermore, DES treatment impaired antioxidant defenses, decreasing the activity of superoxide dismutase, glutathione peroxidase, and catalase while elevating malondialdehyde levels. Notably, DES led to the upregulation of G protein-coupled estrogen receptor and estrogen receptor α at both transcriptional and protein levels, whereas estrogen receptor β mRNA expression increased despite a decline in protein levels. This study provides critical experimental evidence elucidating the immunoregulatory effects of endocrine-disrupting environmental estrogens. Full article

Background: Interleukin-15 (IL-15) stimulates the proliferation of natural killer cells or T cells, which, in combination with photodynamic therapy (PDT), has emerged as an effective strategy for cancer photoimmunotherapy. Instead of direct cytokine receptor activation, IL-15 necessitates first binding to the IL-15 receptor α chain subunit (IL-15Rα), followed by trans-presentation to the IL-15 receptor β/γ chain subunit on the effector cells for pharmacologic activation. Therefore, the delivery of IL-15 remains a major challenge owing to its short half-life, its lack of targeting activity, and the limited availability of IL-15Rα. Methods: A co-hitchhiking delivery approach using recombinant IL-15 (rIL-15) and a photosensitizer, pheophorbide A (PhA), is developed for enhanced combinatorial cancer immunotherapy with PDT. A recombinant IL-15Rα-sushi-Fc fusion protein (rILR-Fc) is designed to load rIL-15 through the IL-15Rα sushi domain, which mimics its trans-presentation. Moreover, the Fc moiety of rILR-Fc can load PhA based on its high binding affinity. Results: Through self-assembly, rILR-Fc/PhA/rIL-15 nanoparticles (NPs) are formulated to co-hitchhike PhA and rIL-15, which improves the tumor accumulation of PhA and rIL-15 through receptor-mediated transcytosis. Moreover, the nanoparticles prolong the blood half-life of rIL-15 but do not alter the elimination rate of PhA from the blood. The rILR-Fc/PhA/rIL-15 NPs effectively elicit potent systemic antitumor immunity and long-lasting immune memory against tumor rechallenge in model mice bearing orthotopic colon tumors. Conclusions: The enhanced antitumor therapeutic effect demonstrates that the co-hitchhiking delivery strategy, optimizing the pharmacokinetics of both the photosensitizer and IL-15, provides a promising strategy for combinatorial photodynamic and IL-15 immunotherapy. Full article

Cell-based therapy using mesenchymal stem cells (MSCs) shows promise for treating several diseases due to their anti-inflammatory and immunomodulatory properties. To enhance the therapeutic potential of MSCs, in vitro priming strategies have been explored. Cannabidiol (CBD), a non-psychoactive compound derived from cannabis, may influence MSC proliferation, differentiation, and immunomodulatory properties. This study evaluates the immunomodulatory potential of equine adipose tissue-derived MSCs (EqAT-MSCs) primed with a CBD-rich cannabis extract. EqAT-MSCs (P3) were primed with CBD concentrations of 5 µM and 7 µM for 24 h. Morphological analysis, MTT assay, β-galactosidase activity, apoptosis assays, and gene expression of interleukins IL-1β, IL-6, IL-10, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) were conducted. Additionally, cannabinoid receptor 1 (CB1) and 2 (CB2) expression were evaluated in naïve EqAT-MSCs (P2–P5). The naïve EqAT-MSCs expressed CB1 and CB2 receptors. Priming with 5 µM significantly increased the expression of IL-10, TNF-α, and IFN-γ, while 7 µM decreased IL-1β and IL-6 expression. No significant changes were observed in other cytokines, MTT, β-galactosidase activity, or apoptosis. These findings demonstrate that naïve EqAT-MSCs express CB1 and CB2 receptors and priming with the extract modulates the expression of pro- and anti-inflammatory cytokines, highlighting its potential immunomodulatory role in EqAT-MSC-based therapies. Full article

Thyroid hormone (TH) plays a vital role in ovarian follicle development, and glucose-regulated protein 78 (GRP78) is involved in these processes, which is regulated by TH. However, the mechanisms are still unclear. To evaluate the possible mechanism of TH on the regulation of GRP78 expression, Cleavage Under Targets and Tagmentation (CUT & Tag) sequencing, luciferase assays, and Electrophoretic Mobility Shift Assays (EMSA) were employed to delineate the binding sites of thyroid hormone receptor β (TRβ) on the GRP78 promoter and to confirm the interactions. Additionally, Co-Immunoprecipitation (Co-IP) and Immunofluorescence (IF) assays were used to investigate the interactions between TRβ and the coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) after triiodothyronine (T₃) treatment with different concentrations. Our findings identified a thyroid hormone response element (TRE) on the GRP78 promoter and demonstrated that TRβ can activate GRP78 expression by interacting with PGC-1α. In order to simulate the condition of hyperthyroidism, granulosa cells (GCs) extracted from rats were treated by T₃ with high concentrations, which decreased the expression of PGC-1α, resulting in decreased expressions of GRP78 and other ferroptosis-related markers such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11, xCT), thereby inducing ferroptosis in GCs. Taken together, the present study demonstrates that T₃ induces cellular ferroptosis by binding TRE of the GRP78 promoter in ovarian GCs via TRβ. As a switcher, PGC-1α is also involved in these processes. Full article

The soluble cytoplasmic tail of the prototypic receptor-like protein tyrosine phosphatase (PTP) CD45 (ct-CD45) is cleaved and released into the human plasma by activated phagocytes. Released ct-CD45 was found to inhibit T cell proliferation and cytokine production via engagement of Toll-like receptor 4 (TLR4). In this study, we analyzed the impact of the ct-CD45/TLR4 pathway on the function of human monocyte-derived dendritic cells (DCs). We could demonstrate that activation of DCs by ct-CD45 upregulated the expression of certain cell surface markers (e.g., CD71 and CD86) and induced IL-10 production via TLR4. Yet, in contrast to stimulation with LPS, other typical cell surface markers and cytokines were not upregulated or induced in DCs by ct-CD45. The T cell proliferation–stimulatory capacity of DCs was not modulated by ct-CD45 treatment. However, treatment of DCs with ct-CD45 modulated the cytokine profile in co-cultured T cells. While IFN-γ production induced by DCs was strongly inhibited, the release of IL-4 was increased in T cells upon stimulation with ct-CD45-treated DCs. In contrast, ct-CD45-stimulated DCs induced IL-2 and IL-10 production in co-cultured T cells comparable to untreated DCs. In summary, we could demonstrate that ct-CD45 acts as an immunoregulatory factor for DCs via a non-canonical TLR4-dependent activation pathway. Full article

Peroxisome proliferator-activated receptors (PPARs), composed of the α/δ/γ subtypes, are ligand-activated nuclear receptors/transcription factors that sense endogenous fatty acids or therapeutic drugs to regulate lipid/glucose metabolism and oxidative stress. PPAR forms a multiprotein complex with a retinoid X receptor and corepressor complex in an unliganded/inactive state, and ligand binding induces the replacement of the corepressor complex with the coactivator complex to initiate the transcription of various genes, including the metabolic and antioxidant ones. We investigated the processes by which the corepressor is replaced with the coactivator or in which two coactivators compete for the PPARα/δ/γ-ligand-binding domains (LBDs) using single- and dual-emission fluorescence resonance energy transfer (FRET) assays. Single-FRET revealed that the respective PPARα/δ/γ-selective agonists (pemafibrate, seladelpar, and pioglitazone) induced the dissociation of the two corepressor peptides, NCoR1 and NCoR2, from the PPARα/δ/γ-LBDs and the recruitment of the two coactivator peptides, CBP and TRAP220. Meanwhile, dual-FRET demonstrated that these processes are simultaneous and that the four coactivator peptides, CBP, TRAP220, PGC1α, and SRC1, were competitively recruited to the PPARα/δ/γ-LBDs with different preferences upon ligand activation. Furthermore, the five newly obtained cocrystal structures using X-ray diffraction, PPARα-LBDs–NCoR2/CBP/TRAP220/PGC1α and PPARγ-LBD–NCoR2, were co-analyzed with those from our previous studies. This illustrates that these coactivators bound to the same PPARα-LBD loci via their consensus LXXLL motifs in the liganded state; that NCoR1/NCoR2 corepressors bound to the same loci via the IXXXL sequences within their consensus LXXXIXXXL motifs in the unliganded state; and that ligand activation induced AF-2 helix 12 formation that interfered with corepressor binding and created a binding space for the coactivator. These PPARα/γ-related biochemical and physicochemical findings highlight the coregulator dynamics on limited PPARα/δ/γ-LBDs loci. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant global public health issue. Luteolin possesses several beneficial biological properties, including antioxidation and anti-inflammation. This study investigated luteolin’s effect and potential mechanisms on MAFLD in high-fat diet (HFD)-fed rats. Rats were administered an HFD supplemented with fructose for 12 weeks to induce MAFLD. After that, the HFD-fed rats were given either luteolin (50 or 100 mg/kg/day) or metformin (100 mg/kg/day) for 4 weeks. Luteolin improved metabolic parameters induced by the HFD, since it decreased body weight, blood pressure, fasting blood glucose, serum insulin, free fatty acids, cholesterol, and triglyceride levels (p < 0.05). Luteolin reduced hepatic injury and inflammatory markers in HFD-fed rats (p < 0.05). Additionally, HFD-fed rats treated with luteolin showed reduced malondialdehyde and raised catalase activity in plasma (p < 0.05). Luteolin attenuated hepatic steatosis compared to the untreated rats (p < 0.05). Luteolin also increased plasma adiponectin levels accompanied by upregulation of adiponectin receptor 1 (AdipoR1), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor γ (PPAR-γ) protein expression in liver (p < 0.05). These findings revealed that luteolin ameliorated HFD-induced MAFLD in rats, possibly by reducing metabolic alterations and oxidative stress and restoring AdipoR1, AMPK, and PPARγ protein expression in HFD-fed rats. Full article