Search Results (374)

Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that A190, a novel, potent, and selective PPARα agonist, effectively alleviates chemotherapy-induced peripheral neuropathy and CFA-induced inflammatory pain as a non-opioid therapeutic agent. However, A190 alone has solubility and permeability issues that limits its oral delivery. To overcome this challenge, in this study, four new-generation ester prodrugs of A190; A190-PD-9 (methyl ester), A190-PD-14 (ethyl ester), A190-PD-154 (isopropyl ester), and A190-PD-60 (cyclic carbonate) were synthesized and evaluated for their enzymatic bioconversion and chemical stability. The lead candidate, A190-PD-60, was further formulated as a microemulsion (A190-PD-60-ME) and optimized via Box–Behnken design. A190-PD-60-ME featured nano-sized droplets (~120 nm), low polydispersity (PDI < 0.3), and high drug loading (>90%) with significant improvement in artificial membrane permeability. Crucially, pharmacokinetic evaluation in rats demonstrated that A190-PD-60-ME reached a 16.6-fold higher Cmax (439 ng/mL) and a 5.9-fold increase in relative oral bioavailability compared with an A190-PD-60 dispersion. These findings support the combined prodrug-microemulsion approach as a promising strategy to overcome oral bioavailability challenges and advance PPARα-targeted therapies. 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

The focus on selecting broilers for rapid growth rates and enhanced breast muscle yield has resulted in a decline in meat quality. The differences in carcass characteristics and meat quality between Hubbard white broilers (HWs, a commercial breed) and Xueshan chickens (XSs, an indigenous breed) at market age were analyzed to determine the potential mechanisms responsible for these differences. The results show that HWs exhibited significantly better carcass performance than XSs, including the larger weight of the carcass, the breast muscle, and the thigh muscle (p < 0.01). In addition, based on HE staining analysis, HWs’ breast muscles had a considerably larger average myofiber area and diameter than those of XSs (p < 0.01). Furthermore, the physical characteristics of the meat revealed that XSs had higher redness and yellowness and also higher lightness. HW meat had a higher pH and thermal loss, but a lower shear force and drip loss than XS meat (p < 0.01). The content of saturated fatty acids (SFAs) and polyunsaturated fatty acids (PUFAs) was, remarkably, lower in the breast muscles of HWs than of XSs (p < 0.01). In contrast, HWs had a larger concentration of monounsaturated fatty acids (MUFAs) than XSs (p < 0.01). Finally, the breast muscles of XSs had lower levels of mRNA expression for genes linked to lipid metabolism, such as fatty acid binding protein 4 (Fabp4) and peroxisome proliferator-activated receptor alpha (Pparα), and had higher levels of the phosphofructokinase muscle type (Pfkm) compared to HWs (p < 0.01). These results indicate that a lower carcass yield was observed in XSs compared with HWs, but that XSs showed better performance in terms of meat quality than HW. Full article

Andrographolide (AP), a bioactive compound from Andrographis paniculata, is known for its anti-inflammatory and antioxidant properties, both essential for wound healing. However, its effects on energy metabolism during tissue repair and its role in UVB-induced photoaging remain poorly understood. This study explored AP’s multitarget therapeutic effects on wound healing under photoaging conditions (PhA/WH) using network pharmacology and experimental validation. Scratch wound assays showed that AP promoted keratinocyte migration in UVB-exposed HaCaT cells. Bioinformatic analysis identified 10 key targets in PhA/WH, including TNF-α, IL-1β, JUN, PPARγ, MAPK3, TP53, TGFB1, HIF-1α, PTGS2, and CTNNB1. AP suppressed UVB-induced pro-inflammatory gene expression (IL-1β, IL-6, IL-8, and COX-2) and inhibited the phosphorylation of ERK1/2 and P38, while enhancing Hypoxia-Inducible Factor-1alpha (HIF-1α) and peroxisome proliferator-activated receptors (PPARγ) expression. GC/MS-based metabolomics revealed that AP reversed UVB-induced disruptions in fatty acid metabolism, glycolysis/gluconeogenesis, and tricarboxylic acid (TCA) cycle, indicating its role in restoring the metabolic balance necessary for tissue regeneration. In conclusion, andrographolide modulates key inflammatory and metabolic pathways involved in wound repair and photoaging. These mechanistic insights contribute to a better understanding of the molecular processes underlying skin regeneration under photodamage and may inform future therapeutic strategies. 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

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

Palmitoylethanolamide (PEA) is an endogenous lipid mediator belonging to the N-acyl-ethanolamine family, widely recognized for its multifaceted effects on neuroprotection, chronic pain management, and immune modulation. As a naturally occurring compound, PEA plays a crucial role in maintaining homeostasis under conditions of cellular stress and inflammation. Its pharmacological effects are primarily mediated through peroxisome proliferator-activated receptor-alpha (PPAR-α) activation, alongside indirect modulation of cannabinoid receptors CB1 and CB2, as well as interactions with novel targets such as GPR55 and TRPV1. These molecular mechanisms underpin its broad therapeutic potential, particularly in the management of neuroinflammatory and neurodegenerative disorders, pain syndromes, and immune dysregulation. A major advancement in PEA research has been the development of ultramicronized palmitoylethanolamide (umPEA), which significantly enhances its bioavailability and therapeutic efficacy by facilitating better tissue absorption and interaction with key molecular pathways. Preclinical and clinical studies have demonstrated that umPEA is particularly effective in reducing neuroinflammation, stabilizing mast cells, and enhancing endocannabinoid system activity, making it a promising candidate for integrative approaches in neuropsychiatric and chronic inflammatory diseases. Given its well-established safety profile, umPEA represents an attractive alternative or adjunct to conventional anti-inflammatory and analgesic therapies. This communication provides a comprehensive overview of the mechanisms of action and therapeutic applications of both PEA and umPEA, emphasizing their emerging role in clinical practice and personalized medicine. Full article

To study the pathological contribution of fatty acid (FA) metabolism regulators including fatty acid binding protein 4 (FABP4), FABP5, peroxisome proliferator-activated receptor alpha (PPARα), and PPARγ in ovarian carcinoma, non-cancerous human ovarian surface epithelium (HOSE) cells and two epithelial ovarian carcinoma (EOC) cell lines, AMOC-2 and ES2 established from ovarian serous adenocarcinoma and ovarian clear cell carcinoma, respectively, were subjected to (1) an analysis of the physical properties of spheroids, (2) qPCR analysis, (3) cellular metabolic analysis, and (4) multiomic pan-cancer analysis using the Cancer Genome Atlas (TCGA). In contrast to globe-shaped spheroids of HOSE cells, AMOC-2 and ES2 cells formed non-globe-shaped spheroids and ES2 spheroids were much more fragile than AMOC-2 spheroids. Gene expression levels of FABP4 and FABP5 in AMOC-2 cells and those of PPARγ in AMOC-2 cells were significantly higher than those in HOSE cells. Metabolic phenotypes and the effectiveness against antagonists for regulators were significantly different in the two types of cancerous cells. Those regulators were identified by a multiomic pan-cancer analysis as novel factors for the prediction of the prognosis of ovarian serous adenocarcinoma. The results show that dysregulated FA metabolism in AMOC-2 and ES2 suggests that the regulation of FA metabolism may be a critical factor in the pathogenesis of EOC. 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

Irisin is a peptide derived from fibronectin type III domain-containing protein 5 (FNDC5) and is primarily produced by muscle fibers under the regulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) during exercise. Irisin has been the subject of extensive research due to its potential as a metabolic regulator and its antioxidant properties. Notably, it has been associated with protective actions within the brain. Despite growing interest, many questions remain regarding the molecular mechanisms underlying its effects. This review summarizes recent findings on irisin, highlighting its pleiotropic functions and the biological processes and molecular cascades involved in its action, with a particular focus on the central nervous system. Irisin plays a crucial role in neuron survival, differentiation, growth, and development, while also promoting mitochondrial homeostasis, regulating apoptosis, and facilitating autophagy—processes essential for normal neuronal function. Emerging evidence suggests that irisin may improve conditions associated with non-communicable neurological diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis. Given its diverse benefits, irisin holds promise as a novel therapeutic agent for preventing and treating neurological diseases. Full article

Ischemic stroke is a leading cause of death and disability worldwide. Currently, there is an unmet clinical need for pharmacological treatments that can improve ischemic stroke outcomes. In this study, we investigated the role of brain peroxisome proliferator-activated receptor alpha (PPARα) in ischemic stroke pathophysiology. We used a well-established model of cerebral ischemia in PPARα transgenic mice and conducted the RNA sequencing (RNA-seq) of mouse stroke brains harvested 48 h post-middle cerebral artery occlusion (MCAO). PPARα knockout (KO) increased brain infarct size following stroke, indicating a protective role of PPARα in brain ischemia. Our RNA-seq analysis showed that PPARα KO altered the expression of genes in mouse brains with known roles in ischemic stroke pathophysiology. We also identified many other differentially expressed genes (DEGs) upon the loss of PPARα that correlated with increased infarct size in our stroke model. Gene set enrichment analysis (GSEA) and Gene Ontology (GO) analysis revealed the upregulation of gene signatures for the positive regulation of leukocyte proliferation, apoptotic processes, acute-phase response, and cellular component disassembly in mouse stroke brains with PPARα KO. In addition, pathway analysis of our RNA-seq data revealed that TNFα signaling, IL6/STAT3 signaling, and epithelial–mesenchymal transition (EMT) gene signatures were increased in PPARα KO stroke brains. Our study highlights PPARα as an attractive drug target for ischemic stroke due to its transcriptional regulation of inflammation-, apoptosis-, and EMT-related genes in brain tissue following ischemia. Full article

Cancer stem cells (CSCs) are described as a subpopulation of cells with capabilities of self-renewal, chemoresistance, and invasiveness. CSCs reside in tumor niches and can be studied in vitro through their enrichment in spheroids (Stem). Molecular iodine (I₂) induces apoptosis and differentiation in various cancer cells. I₂ can activate peroxisome proliferator-activated receptors type gamma (PPARγ), and its pathways are associated with its oxidant/antioxidant capacity. This work aimed to compare the effect of I₂ supplementation in progenitor and CSC populations with low (MCF-7 and S-K-NAS) and high invasiveness (MDA-MB231 and SK-N-BE2) in mammary and neuroblastoma (NB) cell lines. Results showed that the CSC population enriched by the spheroid culture overexpressed stem messengers CD44, SOX2, and NMYC and exhibited the highest mitochondrial metabolism (membrane mitochondrial potential and O₂⁻). The presence of I₂ increases PPARγ expression and induces apoptosis through the Bax/Bcl2 index in all populations but silences NMYC expression and reduces mitochondrial metabolism in Stem NB. I₂ also enhances the expression of nuclear erythroid factor 2 (Nrf2) in all populations, but the target antioxidant superoxide dismutase 2 (SOD2) is only elevated in progenitor cells. In contrast, the mitophagy inductors PTEN-induced putative kinase 1 (Pink1) and microtubule-associated protein1 light chain3 alpha (LC3) were overexpressed in Stem populations. I₂-preselected SK-N-BE2 populations exhibited minor implantation and invasion capacities in the in vivo zebrafish model. These data indicate that I₂ interferes with viability, implantation, and invasion capacity in all cell lines, but the molecular mechanisms vary depending on the progenitor or Stem condition. Full article

Background/Objectives: The interplay between genetics and athletic performance has garnered significant attention, particularly regarding performance-enhancing polymorphisms (PEPs) and their role in determining key traits that are critical for athletic success. Therefore, this study investigates the genetic predispositions related to peroxisome proliferator-activated receptor alpha (PPARα), angiotensin converting enzyme (ACE), and creatine kinase muscle-type (CKM) gene variants and their potential influence on elite point-fighting (PF) athletes. Methods: A total of 24 elite PF athletes (12 women and 12 men; age = 22.1 ± 5.8 years; body mass = 66.1 ± 15.4 kg; and height = 173.0 ± 9.5 cm, BMI = 21.8 ± 3.2 kg·m⁻²) participated in the study. Saliva samples were collected for DNA extraction and genotyping, analyzing the prevalence of key genetic markers, including the D allele and ID genotype for the ACE variant, the G allele and GG genotype for PPARα, and the A allele and AA genotype for CKM. Results: Genotyping revealed a high prevalence of key genetic markers among participants, with the D allele (58.33%) and ID genotype (66.67%) for the ACE variant, the G allele (77.08%) and GG genotype (54.17%) for PPARα, and the A allele (77.08%) with an AA genotype (62.50%) for CKM. The Total Genetic Score (TGS) analysis indicated a mixed-oriented genetic predisposition across the sample. Conclusions: Although PF athletes showed mixed aerobic/anaerobic genetic profiles, their training routines were primarily strength-oriented, suggesting a possible misalignment between genetic predispositions and their current training approach. These findings offer preliminary insights into the genetic characteristics of elite PF athletes and may inform future investigations into the potential role of genetic information in guiding training strategies. Full article

When subclinical ketosis (SCK) occurs in dairy cows, it leads to an excessive production of β-hydroxybutyrat (BHBA), which disrupts liver lipid metabolism and triggers a series of inflammatory responses. Rutin (RT), a flavonoid extracted from plants, exhibits diverse biological activities. However, its potential to mitigate BHBA-induced liver inflammation and lipid accumulation in dairy cows remains unexplored. In this study, we investigated the effect of RT on the BHBA-induced injury of hepatocytes and the possible mechanism. First, hepatocytes were treated with BHBA (0, 0.3, 0.6, 1.2, 2.4 mM) to assess its effects on inflammation impairment and lipid accumulation. Second, hepatocytes were pretreated with RT (0, 25, 50, 100, 150 μg/mL) to evaluate its protective effects. Third, hepatocytes were divided into five treatment groups: blank control, BHBA treatment, RT + BHBA treatment, NF-κB activator (PDTC) + BHBA treatment, and RT + PDTC + BHBA treatment. This experiment further explored the underlying mechanism of RT in mitigating BHBA-induced hepatocyte injury. The results demonstrated that RT at 100 and 150 μg/mL mitigated the increases in hepatocyte interleukin-1 beta (IL-1β), IL-6, triglyceride (TG), and total cholesterol (TC) contents induced by high concentrations of BHBA (p < 0.05). Compared to the BHBA treatment, 100 μg/mL RT significantly downregulated the relative protein expression of P-NF-κB p65 and the relative mRNA expression of NF-κB p65, tumor necrosis factor-alpha (TNF-α), IL-1β, IL-6, peroxisome proliferator-activated receptor gamma (PPARγ), and microsomal triglyceride transfer protein (MTP), while upregulating the relative mRNA expression of IKBα (p < 0.05). Additionally, these effects were more pronounced with the combined pretreatment of the PDTC and RT. In conclusion, RT inhibits BHBA-triggered hepatocyte inflammation and lipid accumulation by modulating the NF-κB signaling pathway, implying that RT may be a promising target for ameliorating damage in SCK cows. Full article

This study systematically elucidates the regulatory mechanisms and potential therapeutic value of the exercise-induced hormone Irisin in the pathological progression of cardiac fibrosis. Through comprehensive analysis and multidimensional data integration, we constructed a complete regulatory network of Irisin within the cardiovascular system, spanning its secretion, signal transduction, and precise regulatory control. Our findings demonstrate that exercise intervention significantly elevates circulating Irisin levels via the skeletal muscle–peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)–fibronectin type III domain-containing protein 5 (FNDC5) signaling axis. Irisin establishes a multidimensional molecular barrier against cardiac fibrosis by targeting Sirtuin 1 (Sirt1) activation, inhibiting the transforming growth factor-beta (TGF-β)/Smad3 signaling pathway, and modulating the transcriptional activity of the mitochondrial biogenesis core factors PGC-1α and nuclear respiratory factor 1 (NRF-1). Moreover, the dual regulatory mechanism of the exercise–skeletal muscle–heart axis not only effectively suppresses the aberrant activation of cardiac fibroblasts but also significantly reduces collagen deposition, oxidative stress, and inflammatory infiltration by restoring mitochondrial dynamics balance. Taken together, this study reveals a novel exercise-mediated cardioprotective mechanism at the molecular interaction network level, thereby providing a theoretical basis for the development of non-pharmacological bio-intervention strategies targeting the Irisin signaling pathway and laying a translational foundation for precise exercise prescriptions in cardiovascular diseases. Full article