Search Results (544)

The amygdala is composed of several nuclei, including the lateral nucleus which is the main receiving area for the input from cortical and subcortical brain regions. It mediates fear, anxiety, stress, and pain across species. Evidence suggests that the endocannabinoid system may be a promising target for modulating these processes. Cannabinoid and cannabinoid-related receptors have been identified in the amygdala of rodents, carnivores, and humans, but not in horses. This study aimed to investigate the gene expression of cannabinoid receptors 1 (CB1R) and 2 (CB2R), transient receptor potential vanilloid 1 (TRPV1), and peroxisome proliferator-activated receptor gamma (PPARγ) within the lateral nucleus of six equine amygdalae collected post mortem from an abattoir using quantitative real-time PCR, cellular distribution, and immunofluorescence. mRNA expression of CB1R and CB2R, but not TRPV1 or PPARγ, was detected. The percentage of immunoreactivity (IR) was calculated using ImageJ software. Cannabinoid receptor 1 immunoreactivity was absent in the somata but was strongly detected in the surrounding neuropil and varicosities and CB2R-IR was observed in the varicosities; TRPV1-IR showed moderate expression in the cytoplasm of somata and processes, while PPARγ-IR was weak-to-moderate in the neuronal nuclei. These findings demonstrate endocannabinoid system components in the equine amygdala and may support future studies on Cannabis spp. molecules acting on these receptors. Full article

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

Background/Objectives: HIF-1α and ERRα are both implicated in breast cancer progression, yet their functional interplay remains poorly understood. This study investigates their molecular crosstalk in the context of hypoxia-induced drug resistance. Methods: MCF-7 (estrogen receptor, ER-positive) spheroids and CoCl₂-treated SK-BR-3 (ER-negative) cells were used to model tumor hypoxia. Protein expression, coimmunoprecipitation, chromatin immunoprecipitation (ChIP), pharmacological inhibition, and siRNA-mediated gene silencing were employed to assess physical and functional interactions. Immunohistochemistry (IHC) on a tissue microarray (TMA) of 168 invasive breast carcinomas was performed to evaluate clinical relevance. Results: ERRα levels remained unchanged under hypoxia, while its coactivator, Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 α (PGC-1α), was upregulated. ERRα physically interacted with HIF-1α and was required for HIF-1 transcriptional activity under hypoxic conditions. ChIP assays showed that ERRα-driven overexpression of Permeability glycoprotein 1 (P-gp) and Vascular Endothelial Growth Factor (VEGF) was mediated by HIF-1α binding to the MDR1 and VEGF promoters. Inhibition or silencing of ERRα reversed P-gp overexpression and restored intracellular doxorubicin. TMA analysis confirmed the clinical correlation between ERRα, HIF-1α, and P-gp expression, highlighting the role of ERRα in hypoxia-induced drug resistance. ERRα expression was independent of ER status, suggesting an estrogen-independent function. Conclusions: This study identifies a novel physical and functional interaction between ERRα and HIF-1α that promotes chemoresistance in hypoxic breast tumors. Targeting ERRα may represent a promising therapeutic strategy to overcome drug resistance in aggressive, ER-independent breast cancer subtypes. 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

Objectives: Given the emerging role of peroxisome proliferator-activated receptor gamma (PPARgamma) in immune regulation and the increasing prevalence of allergic rhinitis (AR), we sought to understand how modulation of the PPARgamma pathway impacts the balance of CD4⁺ T-cell subsets, particularly regulatory T cells (Tregs) and T helper (TH)1, TH2, and TH17 cells, which are key players in the pathogenesis of AR. This knowledge is crucial for developing novel therapeutic strategies targeting the PPARgamma-CD4⁺ T-cell axis to manage AR more effectively. Methods: We used PPARgamma^f/fLyz2-Cre mice for PPARgamma deletion. In an ovalbumin (OVA)-induced AR mouse model, PPARgamma^+/-f/fLyz2-Cre mice were assessed for allergic symptoms, splenic Tregs, and nasal eosinophils. Additionally, the effects of a PPARgamma agonist on the polarization of naïve CD4⁺ T cells were examined. Results: PPARgamma^+/-f/fLyz2-Cre mice showed worsened allergic symptoms, reduced splenic Tregs, and increased nasal mucosa eosinophilic infiltration. PPARgamma agonist treatment promoted naïve CD4⁺ T-cell polarization into Tregs and inhibited their differentiation into TH1, TH2, and TH17 subsets. Conclusions: Our findings indicate that PPARgamma plays a crucial role in regulating TH-cell subsets in AR. PPARgamma agonists could be a potential therapeutic strategy to mitigate allergic inflammation in AR by promoting Treg development and suppressing pathogenic TH-cell responses. Full article

Poly-L-lactic acid (PLLA) filler, which increases volume and collagen synthesis, is used for skin rejuvenation. Subcutaneous adipose tissue (SAT) contains precursors that differentiate into mature adipocytes that secrete adiponectin, which modulates SAT function and increases adipogenesis. During aging, adiponectin and precursor cell functions decrease, reducing adipogenesis and facial volume. Adiponectin also increases collagen synthesis by stimulating fibroblasts. After hydrogen peroxide treatment to induce senescent adipocytes (3T3-L1) and aged skin, follow-up PLLA treatment increased adipogenesis by stimulating the nuclear factor erythroid-2-related factor 2 (NRF2)/peroxisome proliferator-activated receptor gamma (PPARγ)/CCAAT/enhancer binding protein alpha (C/EBPα) pathway. This resulted in increased adiponectin secretion, which promoted collagen synthesis and mitigated the loss of SAT volume. In the senescent adipocyte, PLLA increased NRF2/PPARγ/C/EBPα, adipogenesis factors (fatty acid binding protein 4, lipoprotein lipase, and cluster of differentiation 36), lipogenesis factors (ATP citrate lyase, acetyl-CoA carboxylase, and fatty acid synthase), adiponectin, and lipid droplet size. Treatment of senescent fibroblasts with conditioned medium from PLLA-treated adipocytes increased collagen1 and 3 and decreased matrix metalloproteinase1 and 3 expressions. Similarly, PLLA increased NRF2/PPARγ/C/EBPα, adipogenesis, and lipogenesis factors in aged mouse SAT. Also, PLLA increased adiponectin and adipocyte numbers without hypertrophy and increased collagen accumulation and dermal thickness. In summary, PLLA increased adipogenesis and adiponectin, which increased the volume of SAT and collagen synthesis, thereby rejuvenating aged skin. Full article

Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. In addition to its two major pathological hallmarks, extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), recent evidence highlights the critical roles of mitochondrial dysfunction and neuroinflammation in disease progression. Aβ impairs mitochondrial function, which, in part, can subsequently trigger inflammatory cascades, creating a vicious cycle of neuronal damage. Estrogen receptors (ERs) are widely expressed throughout the brain, and the sex hormone 17β-estradiol (E2) exerts neuroprotection through both anti-inflammatory and mitochondrial mechanisms. While E2 exhibits neuroprotective properties, its mechanisms against Aβ toxicity remain incompletely understood. In this study, we investigated the neuroprotective effects of E2 against Aβ-induced mitochondrial dysfunction and neuroinflammation in primary cortical neurons, with a particular focus on the role of AMP-activated protein kinase (AMPK). We found that E2 treatment significantly increased phosphorylated AMPK and upregulated the expression of mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α), leading to improved mitochondrial respiration. In contrast, Aβ suppressed AMPK and PGC-1α signaling, impaired mitochondrial function, activated the pro-inflammatory nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and reduced neuronal viability. E2 pretreatment also rescued Aβ-induced mitochondrial dysfunction, suppressed NF-κB activation, and, importantly, prevented the decline in neuronal viability. However, the pharmacological inhibition of AMPK using Compound C (CC) abolished these protective effects, resulting in mitochondrial collapse, elevated inflammation, and cell death, highlighting AMPK’s critical role in mediating E2’s actions. Interestingly, while NF-κB inhibition using BAY 11-7082 partially restored mitochondrial respiration, it failed to prevent Aβ-induced cytotoxicity, suggesting that E2’s full neuroprotective effects rely on broader AMPK-dependent mechanisms beyond NF-κB suppression alone. Together, these findings establish AMPK as a key mediator of E2’s protective effects against Aβ-driven mitochondrial dysfunction and neuroinflammation, providing new insights into estrogen-based therapeutic strategies for AD. 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

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss and limited therapeutic options. Metal-based drugs have emerged as promising alternatives in the search for effective treatments, and vanadium coordination complexes have shown significant potential due to their neuroprotective and anti-aggregant properties. This review explores the advances in the development of vanadium-based metallodrugs for AD, focusing on their ability to modulate amyloid-beta (Aβ) aggregation, oxidative stress, and neuroinflammation. Recent in vitro and in vivo studies highlight the efficacy of oxovanadium (IV) and peroxovanadium (V) complexes in inhibiting Aβ fibril formation and reducing neuronal toxicity. Additionally, the interaction of vanadium complexes with key biological targets, such as peroxisome proliferator-activated receptor gamma (PPARγ) and protein-tyrosine phosphatase 1B (PTP1B), suggests a multifaceted therapeutic approach. While these findings underscore the potential of vanadium compounds as innovative treatments for AD, further research is needed to optimize their bioavailability, selectivity, and safety for clinical applications. Full article

Background: Metabolic dysfunction-associated fatty liver disease (MASLD) is closely associated with immune dysregulation and macrophage-driven inflammation. The activation of PPARG plays a critical role in modulating macrophage polarization and lipid metabolism, suggesting its potential as a therapeutic target for MASLD. Methods: We used UPLC-Q/TOF-MS and network pharmacology to investigate the key components and targets of Swertia davidi Franch, focusing on Swertianin. In vitro experiments on macrophages were conducted to assess the modulation of M1 polarization, and a mouse model of MASLD was utilized to explore the therapeutic effects of Swertianin. Results: Swertianin activated PPARG, leading to significant inhibition of M1 macrophage polarization, a reduction in lipid accumulation, and decreased inflammatory marker levels both in vitro and in vivo. The treatment significantly improved liver pathology in mice, indicating its therapeutic potential for MASLD. Conclusions: Swertianin’s activation of PPARG provides a novel mechanism for treating MASLD, targeting both macrophage polarization and inflammation. Full article

Background/Objectives: Disruptions in adipose tissue dynamics contribute to obesity-related metabolic disorders, emphasizing the need for targeted therapies focusing on adipose tissue cells, including progenitor cells and adipocytes. Peroxisome proliferator-activated receptor gamma (PPARG) ligands are potent insulin sensitizers used in type 2 diabetes treatment. This study investigated the effects of rosiglitazone, a PPARG agonist, and betulinic acid, a PPARG antagonist, on adipogenesis and apoptosis in 3T3-L1 pre-adipocytes. Method: 3T3-L1 pre-adipocytes were treated with rosiglitazone or betulinic acid during adipogenic differentiation. Lipid droplet formation was used to evaluate adipogenesis. Cell growth and cell death were assessed using the resazurin-based cell viability assay, trypan blue exclusion assay, LDH assay, and Annexin V/PI staining. Quantitative PCR was conducted to examine the expression of genes associated with adipogenesis and apoptosis. Results: Betulinic acid reduced adipogenesis only when administered daily for eight days. Rosiglitazone did not alter the overall lipid quantity; however, it promoted a shift toward fewer but larger lipid droplets. Both compounds increased Adipoq and Cfd expression, and betulinic acid also elevated Fabp4. Rosiglitazone induced stronger cell aggregation. Despite increased cell death, overall viability was maintained. Apoptotic cell death was enhanced by both compounds and confirmed via Annexin V/PI staining and flow cytometry, accompanied by downregulation of Ccnd1 and Bcl2. Additionally, rosiglitazone markedly increased the expression of Cebpa, a key regulator that can modulate lipid droplet formation and the balance between cell growth and death. Conclusions: Rosiglitazone and betulinic acid differentially modulate adipogenesis and apoptosis in 3T3-L1 cells, revealing a complex interplay between lipid accumulation and programmed cell death. Together, the findings underscore the potential of dual PPARG-targeting approaches for metabolic disease interventions. Full article

Mesenchymal stem cells isolated from human adipose tissue (hASCs) are a promising tool for tissue repair due to their ability to differentiate into specific cell lineages. The possibility of modulating the adipogenic differentiation of hASCs is crucial in improving their therapeutic potential. This study aimed to investigate the effects of cannabidiol (CBD), a phytocannabinoid isolated from Cannabis sativa L., on hASCs. Few studies have evaluated its role in stem cell (SC) properties and their differentiation potential. hASCs were first treated with different concentrations of CBD (ranging from 0.1 to 10 μM) to assess its effects on viability, demonstrating that this molecule is non-toxic, except at the concentration of 10 μM. Subsequently, the role of CBD in the proliferation, metabolism and adipogenic potential of hASCs was analyzed. CBD promoted adipogenesis in a dose-dependent manner, even in the absence of differentiation medium. This result was evidenced by the presence of lipid vacuoles, the expression of adipogenic markers, cytoskeletal actin rearrangement and modulation in the expression of osteogenic genes. Although the results indicated a role of CBD in promoting hASC adipogenesis, further research will be needed to explore the mechanism of action of CBD in SC differentiation and to deepen its utility in SC-based approaches. Full article

β-hydroxybutyrate (BHB) serves as an alternative cellular fuel during states of low glucose availability, such as fasting or carbohydrate restriction, when the body shifts to using fats and ketone bodies for energy. While BHB has shown potential metabolic benefits, its mechanisms of action in the context of obesity are not fully understood. In this study, we examined the effects of BHB supplementation on subcutaneous adipose tissue (SAT) metabolism in a diet-induced obesity (DIO) mouse model. Adult male mice were first fed a high-fat diet for six weeks, followed by a standard diet with or without BHB supplementation for an additional six weeks. BHB supplementation led to significant body weight loss independent of food intake. This weight reduction was associated with decreased adipocyte differentiation, reflected by reduced peroxisome proliferator-activated receptor gamma (PPARγ) protein levels and lower uncoupling protein 1 (UCP1) expression, indicating altered SAT function. Transcriptomic analysis of SAT revealed upregulation of genes involved in fatty acid activation and transport (e.g., Slc27a2, Plin5, Acot4, Acsm3, Rik). Functional enrichment highlighted the activation of the PPAR signaling pathway and enrichment of peroxisomal components in the BHB group. Together, these results suggest that BHB promotes lipid remodeling in SAT, enhancing fatty acid metabolism while suppressing thermogenic pathways, and thus may represent a novel mechanism contributing to adiposity reduction and metabolic improvement. Full article

Objectives: Ritodrine, a tocolytic agent used to delay preterm labor, can cause several cardiovascular-associated adverse events (AEs). This study aimed to examine the relationship between gene polymorphisms in peroxisome proliferator-activated receptor gamma (PPARG) and PPARG coactivator-1α (PPARGC1A) and the occurrence of ritodrine-induced AEs. Additionally, a risk-scoring system was developed to identify patients at high risk of AEs. Methods: Patients aged 18 years or older who were administered ritodrine to manage preterm labor with intact membranes and uterine contractions occurring at 20–36 weeks of gestation were enrolled in this study. A total of 70 common PPARG and PPARGC1A variants (minor allele frequency ≥ 0.2) with low linkage disequilibrium (r² < 0.8) were selected from an Axiom™ Precision Medicine Research Array (AMPRA). Results: A total of 149 patients were included in the analysis. After adjusting for confounders (age, gestational age, and the maximum infusion rate), weight and rs2946385, rs35523565, and rs2240748 of PPARGC1A were identified as significant predictors associated with ritodrine-induced AEs. Based on the risk-scoring system, the predicted probabilities of AEs for patients with scores of 0, 1, 2, 3, 4, and 5 points were 4%, 9%, 18%, 35%, 55%, and 74%, respectively. The AUROC for the risk score predicting ritodrine-induced AEs was 0.729 (95% CI: 0.672–0.831, p < 0.001). Conclusions: This study indicates that ritodrine-induced AEs are related to PPARGC1A polymorphisms. A risk-scoring system based on genetic variants showed moderate predictive ability for ritodrine-induced AEs, suggesting potential utility in females with preterm labor. Full article

Type 2 diabetes mellitus represents a major global health burden and is often preceded by a prediabetic state characterized by insulin resistance and metabolic dysfunction. Mitochondrial alterations, oxidative stress, and disturbances in lipid metabolism are central to the prediabetes pathophysiology. Melatonin, a pleiotropic indolamine, is known to regulate metabolic and mitochondrial processes; however, its therapeutic potential in prediabetes remains poorly understood. This study investigated the effects of melatonin on energy metabolism, oxidative stress, and mitochondrial function in a rat model of prediabetes induced by chronic sucrose intake and low-dose streptozotocin administration. Following prediabetes induction, animals were treated with melatonin (20 mg/kg) for four weeks. Biochemical analyses were conducted to evaluate glucose and lipid metabolism, and mitochondrial function was assessed via gene expression, enzymatic activity, and oxidative stress markers. Additionally, hepatic mitochondrial dynamics were examined by quantifying key regulators genes associated with biogenesis, fusion, and fission. Prediabetic animals exhibited dyslipidemia, hepatic lipid accumulation, increased fat depots, and impaired glucose metabolism. Melatonin significantly reduced serum glucose, triglycerides, and total cholesterol levels, while enhancing the hepatic high-density lipoprotein content. It also stimulated β-oxidation by upregulating hydroxyacyl-CoA dehydrogenase and citrate synthase activity. Mitochondrial dysfunction in prediabetic animals was evidenced by the reduced expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and mitochondrial transcription factor A, both of which were markedly upregulated by melatonin. The indolamine also modulated mithocondrial dynamics by regulating fusion and fission markers, including mitosuin 1 and 2, optic atrophy protein, and dynamin-related protein. Additionally, melatonin mitigated oxidative stress by enhancing the activity of superoxide dismutase and catalase while reducing lipid peroxidation. These findings highlight melatonin’s protective role in prediabetes by improving lipid and energy metabolism, alleviating oxidative stress, and restoring mitochondrial homeostasis. This study provides novel insights into the therapeutic potential of melatonin in addressing metabolic disorders, particularly in mitigating mitochondrial dysfunction associated with prediabetes. Full article