PPARα Activation Research Articles

Selective abrogation of S6K2 identifies lipid homeostasis as a survival vulnerability in MAPK inhibitor-resistant NRAS-mutant melanoma.

Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant (NRASMUT) tumors. Here, we report that selectively silencing the ribosomal protein S6 kinase 2 (S6K2) while preserving the activity of S6K1 perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation in NRASMUT melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces endoplasmic reticulum stress and peroxisome proliferator-activated receptor α (PPARα) activation, triggering cell death selectively in MAPK inhibitor-resistant melanoma. We found that combining PPARα agonists and polyunsaturated fatty acids phenocopied the effects of S6K2 abrogation, blocking tumor growth in both patient-derived xenografts and immunocompetent murine melanoma models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRASMUT melanomas that are resistant to global MAPK pathway inhibitors.

Comparative study on gene expression profiles in the liver of male neonatal mice prenatally exposed to PFOA and its alternative HFPO-DA.

Hexafluoropropylene oxide dimer acid (HFPO-DA), which belongs to the class of perfluoroalkyl ether carboxylic acid (PFECA), is a new alternative to perfluorooctanoic acid (PFOA). However, whether HFPO-DA is a safer alternative to PFOA in neonates remains unclear. In this study, we evaluated neonatal hepatic toxicity on postnatal days 9-10 by orally exposing pregnant CD-1 mice to 0.3 or 3.0mg/kg/day (low or high doses) of HFPO-DA or PFOA from gestation days 15 to 17. The results showed that exposure of pregnant mice to HFPO-DA and PFOA induced similar phenotypic effects, including significant decreases in neonatal body weight (BW) and significant increases in liver weight relative to BW in the high-dose. Notably, HFPO-DA exposure significantly decreased in neonatal BW in the low-dose group, whereas PFOA did not. Comprehensive gene expression analysis revealed significant alterations in 408 and 1402 differentially expressed genes (DEGs) in the liver of neonates from the low- and high-dose HFPO-DA groups, respectively, while PFOA significantly altered 0 and 292 DEGs in the corresponding groups. Gene set enrichment analysis indicated that the DEGs induced by HFPO-DA and PFOA were enriched in pathway related to "PPAR signaling", "fatty acid metabolism", and "biological oxidations". In addition, transactivation assays revealed that mouse (m)PPARα and mPPARγ activity of HFPO-DA exceeds that of PFOA and molecular docking simulations analysis predicted that the binding conformation differ between PFOA and HFPO-DA. Overall, our findings demonstrate that HFPO-DA consistently affected neonatal phenotypes, liver gene expression and the molecular initiating events involving PPARα/γ, at lower concentrations than PFOA.

New PPARα Agonist A190-Loaded Microemulsion for Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of anticancer agents with limited effective preventive or therapeutic interventions. Although fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, has demonstrated neuroprotective and analgesic properties, its clinical utility is hindered by low receptor affinity, poor subtype selectivity, and suboptimal bioavailability. A190, a highly selective and potent nonfibrate PPARα agonist, offers a promising alternative but is limited by poor aqueous solubility, resulting in reduced oral bioavailability and therapeutic efficacy. To address these limitations, an optimized oil-in-water (o/w) microemulsion formulation was developed using Box-Behnken design to enhance the solubility and intestinal permeability of A190. The A190 microemulsion exhibited physical stability with a droplet size of approximately 100 nm and a drug loading efficiency of greater than 95%. The effective and apparent permeability of A190 from the microemulsion was significantly higher compared to that of free A190 dispersion, respectively. Additionally, no significant impact on the cell viability was observed, indicating less toxicity and a good biocompatibility of the formulation components. The oral bioavailability of A190 microemulsion was approximately 5-fold higher compared to A190 dispersion, demonstrating the microemulsion's potential to greatly enhance the oral bioavailability of hydrophobic drugs. Furthermore, our findings reveal that orally administered A190 microemulsion effectively reduced CIPN-induced mechanical hypersensitivity, likely mediated through PPARα activation. A190 microemulsion was found to be equally effective at reducing the chronic inflammatory complete Freund's adjuvant-induced pain. These results underscore A190s potential as a nonopioid therapeutic candidate, utilizing a novel microemulsion formulation for the management of chemotherapy-induced neuropathic pain and chronic inflammatory pain.

Dual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis.

Dysregulated lipid metabolism is linked to tumor progression. In this study, we identified Niemann-Pick C1-like 1 (NPC1L1) as a downstream effector of PKM2. In breast cancer cells, PKM2 knockout (KO) enhanced NPC1L1 expression while downregulating peroxisome proliferator-activated receptor α (PPARα) signaling pathway. PPARα and nuclear factor-E2 p45-related factor 1/2(Nrf1/2) are transcription factors regulating NPC1L1. In vitro PKM2 KO enhanced recruitment of Nrf1/2 to the NPC1L1 promoter region. Fenofibrate, a PPARα activator, promoted NPC1L1 expression; ezetimibe, an NPC1L1 inhibitor and effective Nrf2 activator, also elevated NPC1L1 expression. Combined administration of fenofibrate and ezetimibe significantly induced cytoplasmic vacuolation, and cell apoptosis. Mechanistically, this combined administration activated inositol required enzyme 1α(IRE1α) and produced the spliced form of X-box binding protein (XBP1s), which in turn enhanced lysine demethylase 6B (KDM6B) transcription. XBP1s interacts with KDM6B to activate genes involved in the unfolded protein response by demethylating di- and tri-methylated lysine 27 of histone H3 (H3K27), consequently increasing H3K27 acetylation levels in breast cancer cell lines. Fenofibrate and ezetimibe synergistically inhibited tumor growth in vivo. Our findings reveal that dual targeting of PPARα and NPC1L1 may represent a novel therapeutic regimen for breast cancer therapy.

Current understanding of human bioaccumulation patterns and health effects of exposure to perfluorooctane sulfonate (PFOS).

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant of global concern due to its environmental presence,bioaccumulative potential and toxicological impacts. This review synthesizes current knowledge regarding PFOS exposure, bioaccumulation patterns and adverse health outcomes in human population. Analysis of worldwide biomonitoring data, and epidemiological studies reveals PFOS systemic effects, including immunological dysfunction (decreased vaccine response), developmental toxicity (reduced birth weight), hepatic metabolic disruption, potential carcinogenogenicity, and reproductive abnormalities. At the molecular level, PFOS induces toxicity through multiple pathways, including PI3K/AKT/mTOR pathway inhibition, PPARα activation, NF-κB signaling modulation, and oxidative stress induction. Recent advances in analytical methodologies have enhanced our understanding of PFOS distribution and fate, while evolving egulatory frameworks attempts to address its risk. This review identifies critical research gaps and emphasized the need for coordinated multidisciplinary approaches to address this persistent environmental contaminant.

Boeravinone C ameliorates lipid accumulation and inflammation in diabetic kidney disease by activating PPARα signaling.

The roots of Oxybaphus himalaicus Edgew. is a traditional Tibetan herbal medicine with kidney reinforcing and tonifying effects, which is commonly applied to treat nephritis. Boeravinone C has been identified as one of the primary constituents of O. himalaicus. However, the potential renal protective effects of boeravinone C remains unclear. This research aimed to investigate the protective effects of boeravinone C on diabetic kidney disease and the underlying mechanisms. Streptozotocin (100 mg/kg) was intraperitoneally injected to induce DKD in mice. High glucose (50 mM)-induced HK-2 cells were utilized to investigate the mechanisms of boeravinone C against tubular injuries in vitro. Anti-DKD activity was assessed by measuring reactive oxygen species (ROS) levels, analyzing apoptosis through flow cytometry, and evaluating inflammation, apoptosis, and FAO-related proteins via Western blotting. Additionally, serum biochemical assays, as well as histopathological and immunohistochemical analyses of kidney tissues, were performed to explore the pharmacological effects of boeravinone C. In vivo, boeravinone C administered significantly reduced the creatinine (CRE), blood urea nitrogen (BUN), triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels in serum of DKD mice. In vitro, boeravinone C significantly restored the apoptosis induced by HG in HK-2 cells, which is further validated by an upregulation of the apoptosis-inhibiting protein Bcl-2, along with a decreased expression of the apoptosis-promoting proteins Bax and caspase-3. Mechanistically, boeravinone C reversed HG-induced downregulation of peroxisome proliferator-activated receptor α (PPARα) expression. As a transcription factor, elevated expression of PPARα led to upregulation of CPT1A and ACOX1, which then enhanced fatty acid oxidation (FAO) to reduce lipid accumulation in HK-2 cells. Furthermore, boeravinone C-mediated high expression of PPARα sequestered p65 subunit of NF-κB in the cytoplasm, leading to reduced expression of proinflammatory cytokines such as iNOS, TNF-α and IL-6. To verify that the therapeutic effects of boeravinone C in diabetic kidney disease (DKD) are mediated via PPARα activation, we developed a PPARα knockdown HK-2 cell line. Our findings revealed that PPARα downregulation modified biological effects of boeravinone C, especially regarding fatty acid metabolism and the inflammatory response, with significant repercussions on apoptosis. This study demonstrates that the major component boeravinone C from O. himalaicus promotes the fatty acid oxidation and suppresses inflammatory response by upregulating PPARα expression, thereby reducing apoptosis in HG-induced renal tubule cells. Consequently, boeravinone C restores tubular function in DKD mice. Collectively, this study provides a pharmacological basis for utilizing of O. himalaicus in treating DKD.

The PPAR-α agonist oleoyethanolamide (OEA) ameliorates valproic acid-induced steatohepatitis in rats via suppressing Wnt3a/β-catenin and activating PGC-1α: Involvement of network pharmacology and molecular docking.

Liver damage is one of the most severe side effects of valproic acid (VPA) therapy. Research indicates that PPAR-α prevents Wnt3a/β-catenin-induced PGC-1α dysregulation, which is linked to liver injury. Although PPAR-α activation has hepatoprotective effects, its role in preventing VPA-induced liver injury remains unclear. Our research used network analysis, molecular docking, and in-vivo validation to predict and assess targets and pathways associated with the hepatoprotective effects of oleoylethanolamide (OEA), a PPAR-α agonist, on VPA-induced steatohepatitis. For in-vivo experiments, 24 rats were assigned to V, OEA, VPA, and OEA+VPA. Liver functions, TGs, cholesterol, and LDL were tested. Hepatic levels of PPAR-α, ACO, TNF-α, IL-1β, HO-1, MDA, and TAC, along with Wnt3a/β-catenin, PGC-1α, and Nrf2 expression were assessed. Further, NF-κB, Bax, Bcl-2, and caspase-3 expression were detected immunohistochemically. Network pharmacology identified 258 targets for OEA-steatohepatitis connection, including NFKB1, PPARA, and NFE2L2, in addition to TNF, non-alcoholic fatty liver, NF-κB, PPAR, and WNT signaling, as contributing to steatohepatitis pathogenesis. The docking revealed a strong affinity between OEA and Wnt3a, β-catenin, and PGC-1α. Therefore, we postulated that the hepatoprotective effect of OEA may be due to Wnt3a/β-catenin-mediated inactivation of PGC1-α pathway. In vivo, OEA inhibited Wnt3a/β-catenin and increased PGC1-α by activating PPAR-α. Hence, PGC1-α reduced fat cell β-oxidation and NF-κB-mediated inflammation. OEA lessened MDA and raised TAC to mitigate oxidative damage. OEA additionally reduced apoptosis by lowering Bax/Bcl-2 ratio and caspase-3. In summary, PPAR-α involvement in the protective effects of OEA against VPA-induced steatohepatitis can be confirmed by suppressing Wnt3a/β-catenin and activating PGC-1α signaling.

Lifestyle and Pharmacologic Approaches to Prevention of Metabolic Dysfunction-associated Steatotic Liver Disease-related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major concern for public health. Fatty liver disease, related to alcohol misuse or metabolic syndrome, has become the leading cause of chronic liver disease and HCC. The strong association between type 2 diabetes mellitus and HCC can be partly attributed to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). There is a strong interest in strategies that may mitigate HCC risk and reduce HCC incidence in this growing population of at-risk individuals. In this review, we describe the pathogenesis of HCC in patients with MASLD and discuss potential emerging pharmacological and lifestyle interventions for MASLD-related HCC. HCC risk has been observed to be lower with healthy lifestyle behaviors, such as healthy dietary patterns (eg, high consumption of vegetables, whole grains, fish and poultry, yogurt, and olive oil, and low consumption of red and processed meats and dietary sugar) and increased physical activity. Selecting an appropriate anti-diabetic therapy for individuals with liver disease and diabetes may also decrease the occurrence of HCC. Metformin, PPAR activators, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, aspirin, and statins have all shown promise to reduce the risk of HCC, although guidelines do not recommend their use for the sole purpose of chemoprevention at this time, given a dearth of data defining their risk-benefit ratio.

Betulinic acid from Inonotus obliquus ameliorates T2DM by modulating short-chain fatty acids producing bacteria and amino acids metabolism in db/db mice.

Inonotus obliquus has also been used as a traditional folk medicine in Europe and Northeastern China to treat metabolic diseases. Betulinic acid (BA) is a major ingredient with anti-diabetic property derived from I. obliquus, however, its bioavailability is limited. Whether the beneficial effects of BA on type 2 diabetic mellitus (T2DM) referring to modulation of gut microbiota and associated metabolites remain unclear. This work aims to investigate the alleviating effect of BA on T2DM in db/db mice and elucidate the mechanism from perspective of network pharmacology, gut microbiome and fecal metabolome. BA was orally administered to db/db mice for 45 days, and the related biochemical parameters were evaluated. The associated mechanism was explored using network pharmacology analysis, 16S rRNA sequencing and UHPLC-MS metabolomics comprehensively. Additionally, Spearman analysis was performed to assess the correlation between gut microbes, metabolites, and T2DM-related biochemical parameters. BA ameliorated T2DM symptoms by reducing body weight gain, regulating serum glucose and lipid levels, and mitigating T2DM-associated liver injury in db/db mice. Network pharmacology analysis indicated the ameliorative effect was via targeting at PPAR activity. BA intervention increased the relative abundance of short-chain fatty acids (SCFAs) producing bacteria including Lactobacillus and Eubacterium_xylanophilum group, and enhanced the production of SCFAs. Moreover, BA primarily regulates arginine and proline metabolism, D-glutamine and D-glutamate metabolism, and alanine, aspartate and glutamate metabolism. Spearman analysis indicated a negative correlation between SCFAs-producing bacteria and amino acids, as well as serum glucose and lipid levels. Apart from PPAR signaling pathway, BA modulated gut microbiota composition and associated metabolites in db/db mice. This study provided novel insights into the therapeutic potential of BA for alleviating T2DM symptoms.

Citronellic Acid Improves Skin Barrier Function by Activation of PPAR-α

Citronellic Acid Improves Skin Barrier Function by Activation of PPAR-α

P73 Fatty acid rewiring via PPARα-FADS2 axis in keratinocytes contributes to skin inflammation in psoriasis through NF-κB pathway

Abstract Psoriasis is a chronic inflammatory skin disease characterized by excessive keratinocyte proliferation, accompanied by significant alterations in immune homeostasis. Dysregulation of fatty acid metabolism, particularly involving polyunsaturated fatty acids (PUFAs), has been implicated in the pathogenesis of psoriasis; however, the precise relationship between metabolic dysregulation and inflammatory responses in psoriasis remains poorly understood. In this study, we investigated the role of Δ6 desaturase/fatty acid desaturase 2 (FADS2), the first and rate-limiting enzyme in PUFA synthesis, in psoriasis and its underlying mechanisms. We first demonstrate that the expression of FADS2 was significantly decreased in the epidermis of the skin lesions from psoriasis patients and imiquimod (IMQ)-induced psoriasis mouse model. Treatment with IL-23 inhibitor Guselkumab restored FADS2 expression in the epidermis of lesional skin of psoriasis patients. Furthermore, silencing FADS2 in cultured human keratinocytes resulted in the upregulation of multiple chemokines and antimicrobial peptides under M5 condition (a psoriasis-like inflammatory condition). Mechanically, suppression of FADS2 disrupted PUFA metabolism with an inhibition of the desaturation of omega-3 fatty acids to the anti-inflammatory metabolite docosahexaenoic acid (DHA), thereby contributing to the inflammatory processes through the NF-κB pathway. Additionally, we found that FADS2 expression in keratinocytes was dependent on peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor involved in lipid metabolism across various tissues. A reduction in the PPARα-FADS2 axis was observed in the lesional skin of psoriasis patients and IMQ-induced psoriasis mouse model. In vivo experiments revealed that silencing FADS2 via the topical application of small interfering RNA (siRNA) exacerbated IMQ-induced psoriasis-like dermatitis, whereas enhancing FADS2 expression through PPARα activation with its agonist WY14643 led to a significant attenuation of psoriasis inflammation. These findings identify PPARα as a critical regulator of FADS2 expression in psoriasis and elucidate the contribution of FADS2 to fatty acid reprogramming and inflammatory responses in psoriasis. Therefore, FADS2 and PPARα emerge as promising therapeutic targets for managing psoriasis.

Antinociceptive, antineuropathic, and antimigraine-like activities ofFritillariaimperialis L. rich in verticinone on rats: Mechanisms of action

Ethnopharmacological relevanceFritillaria imperialis L. (Fabaceae), commonly known as “Laleh vazhgon”, ethnomedicinally utilized in Iranian traditional medicine to treat joint pain, chronic daily headaches, and back pain. Aim of the studyTo investigate the antinociceptive, anti-neuropathic, and anti-migraine activities of Fritillaria imperialis bulbs essential oil (FIEO) as well as to uncover the potential mechanisms of action involved. Materials and methodsThe antinociceptive activity of FIEO and its main constituent, Verticinone (Vt), was assessed using the formalin-induced paw licking assay. The potential mechanisms of antinociception were investigated through various antagonists. Additionally, their antineuropathic activity was examined using the cervical spinal cord contusion (CCS) technique and the possible role of Stat3 was evaluated using Western blot analysis. The nitroglycerin-induced model (NTG) was also employed for the evaluation of migraine. ResultsFIEO demonstrated significant antinociceptive activity in both phases of the formalin-induced test. However, the FIEO activity was more pronounced effect observed in the second phase. Modulators of the NO-cGMP-K+ channel pathway significantly reversed the antinociceptive activity of FIEO (P < 0.05). Additionally, antagonists of TRPV1, PPARα, dopamine D1, GABAA, and δ-opioid receptors also significantly reversed the antinociceptive effects of FIEO (P < 0.05). In a separate study, both FIEO and Vt were found to attenuate hyperalgesia and mechanical allodynia (P < 0.01) when evaluated using the CCS-induced pain model. Furthermore, FIEO may alleviate migraine behaviors, likely related to the regulation of NO and CGRP levels. ConclusionFIEO exerts an antineuropathic effect through the phosphorylation of Stat3. Furthermore, the antinociceptive activity is partially modulated via the NO-cGMP-K+ channel pathway, as well as the activation of TRPV, PPAR, opioid, and GABA receptors. Vt may be involved in the antinociceptive, antineuropathic, and antimigraine activities induced by FIEO.

ASSESSMENT OF THE COMBINATION OF FENOFIBRATE AND SILDENAFIL IN ALZHEIMER’S DISEASE

The purpose of the study was to evaluate the effectiveness of fenofibrate and sildenafil at various dosages in the treatment of Alzheimer’s disease. Sildenafil is an up-regulator of brain-derived neurotrophic factor (BDNF), whereas fenofibrate is a powerful PPAR-α activator. The typical medication was rivastigmine, while the inducer was AlCl3 . The tests of spatial working memory included the MWM, Y-Maze, and NOR. Moreover, the levels of Aβ, PPAR-α, BDNF, TNF-α, and IL-1β in the brain were measured using ELISA kits. During the probing session, the MWM displayed a decline in escape latency and rise in the target quadrant entry. The results of the Y-maze and the NOR demonstrated the emergence of spontaneous changes in the discrimination and recognition index scores. The therapy groups showed decline in the levels of TNF-α, IL-1β, and Aβ. The brain histology of the treated group showed moderate neurodegeneration. From this study, we can conclude that fenofibrate and sildenafil when used in combination could be a successful treatment for AD.

Integrated multi-omics analyses combined with western blotting discovered that cis-TSG alleviated liver injury via modulating lipid metabolism.

Background: Polygonum multiflorum shows dual hepatoprotective and hepatotoxic effects. The bioactive components responsible for these effects are unknown. This study investigates whether cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (cis-TSG), a stilbene glycoside, has hepatoprotective and/or hepatotoxic effects in a liver injury model. Methods: C57BL/6J mice were administered α-naphthylisothiocyanate (ANIT) to induce cholestasis, followed by treatment with cis-TSG. Hepatoprotective and hepatotoxic effects were assessed using serum biomarkers, liver histology, and metabolomic and lipidomic profiling. Transcriptomic analysis were conducted to explore gene expression changes associated with lipid and bile acid metabolism, inflammation, and oxidative stress. Results and Discussion: ANIT administration caused significant liver injury, evident from elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and dysregulated lipid metabolism. cis-TSG treatment markedly reduced ALT and AST levels, normalized lipid profiles, and ameliorated liver damage, as seen histologically. Metabolomic and lipidomic analyses revealed that cis-TSG influenced key pathways, notably glycerophospholipid metabolism, sphingolipid metabolism, and bile acid biosynthesis. The treatment with cis-TSG increased monounsaturated and polyunsaturated fatty acids (MUFAs and PUFAs), enhancing peroxisome proliferator-activated receptor alpha (PPARα) activity. Transcriptomic data confirmed these findings, showing the downregulation of genes linked to lipid metabolism, inflammation, and oxidative stress in the cis-TSG-treated group. The findings suggest that cis-TSG has a hepatoprotective effect through modulation of lipid metabolism and PPARα activation.

E2F3a activates Gadd45b gene expression through PPARα-mediated transcriptional regulation in hepatic cells

Growth arrest and DNA damage-inducible beta (GADD45b) plays a critical role in intracellular events such as cell growth and apoptosis. Although the functional study of GADD45b has been conducted, the mechanism for the transcriptional regulation of GADD45b is largely unknown. Due to the drastic induction of hepatic GADD45b mRNA by peroxisome proliferator-activated receptor alpha (PPARα) activation in wild-type mice, we investigated a key factor that affects the upregulation of GADD45b mRNA. Interestingly, we found that GADD45b-promoter luciferase activity was dramatically increased as the 5’-flanking regions were closer to the transcription start site (TSS) in Hepa1c1c7 cells. Additionally, we found two E2F (E2F-myc activator/cell cycle regulator) binding motifs in the region (-150/-1) of the GADD45b promoter. Notably, E2F3 mRNA was significantly increased only in wild-type mice treated with WY-14643, a PPARα agonist, followed by the induction of GADD45b mRNA. Furthermore, gene functional studies and Chromatin Immunoprecipitation (ChIP) assays revealed that E2F3 could regulate the GADD45b gene via the E2F binding motif. Thus, we suggest that E2F3 may play a key role in regulating the GADD45b gene as a positive transcription factor.

Magnolol preserves the integrity of the intestinal epithelial barrier and mitigates intestinal injury through activation of PPAR γ in COPD rat

Ethnopharmacological relevanceMagnolia officinalis Rehder & E.H. Wilson is traditionally used in the treatment of gastrointestinal disorders, diarrhea, and cough. Its main active ingredient, magnolol, exhibits protective effects on the lungs and gastrointestinal tract, including the inhibition of inflammation in these organs. Aim of the studyThis work aims to explore the molecular mechanism by which magnolol suppressed Chronic obstructive pulmonary disease (COPD) intestinal damage by improving the intestinal epithelial barrier. Materials and methodsThe study focused on investigating the mitigation effect of magnolol on intestinal injury and epithelial barrier in a COPD rat. Caco-2 cells were induced with TNF-α or IL-1β to establish the barrier injury model in order to explore the direct protective effect of magnolol on the intestinal barrier and elucidate the molecular mechanism by which it activates peroxisome proliferators-activated receptors-γ (PPARγ). ResultsMagnolol significantly improves pulmonary function and tissue damage in COPD rats by inhibiting inflammation, protease imbalance, and oxidative stress. It also suppresses colon tissue damage and inflammation, and protects colon epithelial barrier function by suppressing the decline of tight junction proteins, reducing colon epithelial permeability. In Caco-2 cells, magnolol directly reduces monolayer permeability, increases TEER, and upregulates tight junction protein expression induced by TNF-α or IL-1β. Drug Affinity Responsive Target Stability (DARTS) and thermal shift assays show that magnolol effectively binds to SRC, activating PPARγ signaling in Caco-2 cells and colon tissues of COPD rats. Furthermore, magnolol enhances the binding of PPARγ and RXRα, promoting their activation and entry into the nucleus. The PPARγ inhibitor GW9662 can reverse the effects of magnolol on PPARγ activation and tight junction protein upregulation in IL-1β or TNF-α induced Caco-2 cells. ConclusionsThis work demonstrates that magnolol enhances lung and intestinal functions in COPD rats, and elucidates its mechanism of action in protecting the intestinal epithelial barrier by activating PPARγ.

Potential mechanism of perillaldehyde in the treatment of nonalcoholic fatty liver disease based on network pharmacology and molecular docking

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic metabolic liver diseases worldwide. Perillaldehyde (4-propyl-1-en-2-ylcyclohexene-1-aldehyde, PA) is a terpenoid compound extracted from Perilla, which has effective pharmacological activities such as anti-inflammatory, antidepressant, and anticancer. This study aimed to explore the pharmacological effects of PA in intervening with NAFLD and reveal its potential mechanisms. Firstly, we identified the core targets of PA intervention therapy for NAFLD through network pharmacology and molecular docking techniques. After that, in vitro animal experiments such as H&E and Masson staining, immunofluorescence, immunohistochemistry, and Western blot were conducted to validate the results network effectively pharmacology predicted. Network pharmacology analysis suggested that PPAR-α may be the core target of PA intervention in NAFLD. H&E and Masson staining showed that after low-dose (50 mg/kg) PA administration, there was a noticeable improvement in fat deposition in the livers of NAFLD mice, and liver tissue fibrosis was alleviated. Immunohistochemical and immunofluorescence analysis showed that low dose (50 mg/kg) PA could reduce hepatocyte apoptosis, decrease the content of pro-apoptosis protein Bax, and increase the expression of anti-apoptosis protein Bcl-2 in NAFLD mice. Western blot results confirmed that low-dose (50 mg/kg) PA could increase the expression of PPAR-α and inhibit the expression of NF-κB in NAFLD mice. Our study indicated that PA could enhance the activity of PPAR-α and reduce the level of NF-κB in NAFLD mice, which may positively affect the prevention of NAFLD.

Lipotoxicity of palmitic acid is associated with DGAT1 downregulation and abolished by PPARα activation in liver cells

Lipotoxicity refers to the harmful effects of excess fatty acids on metabolic health, and it can vary depending on the type of fatty acids involved. Saturated and unsaturated fatty acids exhibit distinct effects, though the precise mechanisms behind these differences remain unclear. Here, we investigated the lipotoxicity of palmitic acid (PA), a saturated fatty acid, compared with oleic acid (OA), a monounsaturated fatty acid, in the hepatic cell line HuH7. Our results demonstrated that PA, unlike OA, induces lipotoxicity, endoplasmic reticulum (ER) stress, and autophagy inhibition. Compared with OA, PA treatment leads to less lipid droplet (LD) accumulation and a significant reduction in the mRNA and protein level of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme of triacylglycerol synthesis. Using modulators of ER stress and autophagy, we established that DGAT1 downregulation by PA is closely linked to these cellular pathways. Notably, the ER stress inhibitor 4-phenylbutyrate can suppress PA-induced DGAT1 downregulation. Furthermore, knockdown of DGAT1 by siRNA or with A922500, a specific DGAT1 inhibitor, resulted in cell death, even with OA. Both PA and OA increased the oxygen consumption rate; however, the increase associated with PA was only partially coupled to ATP synthesis. Importantly, treatment with GW7647 a specific PPARα agonist mitigated the lipotoxic effects of PA, restoring PA-induced ER stress, autophagy block, and DGAT1 suppression. In conclusion, our study highlights the crucial role of DGAT1 in PA-induced lipotoxicity, broadening the knowledge of the mechanisms underlying hepatic lipotoxicity and providing the basis for potential therapeutic interventions.

Golden Tomato Juice Enhances Hepatic PPAR-α Expression, Mitigates Metabolic Dysfunctions and Influences Redox Balance in a High-Fat-Diet Rat Model.

Golden tomato (GT), harvested at the veraison stage, has gained attention due to its rich content of bioactive compounds and potential health benefits. Previous studies have highlighted GT's antioxidant properties and its positive effects on metabolic syndrome (MetS), a condition characterized by obesity, dyslipidemia, and oxidative stress. This study investigates for the first time a derivative from GT, i.e., the juice (GTJ), which could be a potential candidate for development as a functional food. We first characterized GT juice, identifying 9-oxo-10(E),12(E)-octadecadienoic (9-oxo-10(E),12(E)-ODA) fatty acid, a known peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, using High-Performance Liquid Chromatography (HPLC)-mass spectrometry. Then, using a high-fat-diet (HFD) rat model, we assessed the impact of daily GT juice supplementation in addressing MetS. We outlined that GTJ improved body weight and leptin-mediated food intake. Moreover, it ameliorated glucose tolerance, lipid profile, systemic redox homeostasis, hepatic oxidative stress, and steatosis in HFD rats. Furthermore, GT juice enhances the hepatic transcription of PPAR-α, thus putatively promoting fatty acid oxidation and lipid metabolism. These findings suggest that GT juice mitigates lipidic accumulation and putatively halters oxidative species at the hepatic level through PPAR-α activation. Our study underscores the protective effects of GT juice against MetS, highlighting its future potential as a nutraceutical for improving dysmetabolism and associated alterations.

Burnt Plastic (Pyroplastic) from the M/V X-Press Pearl Ship Fire and Plastic Spill Contain Compounds That Activate Endocrine and Metabolism-Related Human and Fish Transcription Factors.

In May 2021, the M/V X-Press Pearl ship fire disaster led to the largest maritime spill of resin pellets (nurdles) and burnt plastic (pyroplastic). Field samples collected from beaches in Sri Lanka nearest to the ship comprised nurdles and pieces of pyroplastic. Three years later, the toxicity of the spilled material remains unresolved. To begin understanding its potential toxicity, solvent extracts of the nurdles and pyroplastic were screened for their bioactivity by several Attagene FACTORIAL bioassays (TF, NR, and AquaTox), which measured the activity of a combined 70 human transcription factor response elements and nuclear receptors and 6 to 7 nuclear receptors for each of three phylogenetically distinct fish species. Extracts of the pyroplastics robustly activated end points for the human aryl hydrocarbon receptor (AhR), estrogen receptor (ER), pregnane X receptor (PXR), peroxisome proliferator-activated receptor (PPAR), retinoid X receptor (RXR), and oxidative stress (NRF2) and had the potential for activation of several others. The bioactivity profile of the pyroplastics was most similar (similarity score = 0.96) to that of probable human carcinogens benzo[b]fluoranthene and benzo[k]fluoranthene despite the extracts being a complex mixture of thousands of compounds. The activity diminished only slightly for extracts of pyroplastic collected eight months after the spill. The AquaTox FACTORIAL bioassay measured the activation of ERα, ERβ, androgen receptor (AR), PPARα, PPARγ, and RXRβ for human, zebrafish (Danio rerio), Japanese medaka (Oryzias latipes), and rainbow trout (Oncorhynchus mykiss), revealing species-specific sensitivities to the chemicals associated with the pyroplastics. These findings provide needed information to guide long-term monitoring efforts, make hazard assessments of the spilled material, and direct further research on pyroplastic, an emerging global contaminant.