Search Results (1,210)

(1) Background: Perfluorodecanoic acid (PFDA), a persistent perfluoroalkyl obesogen, promotes adipogenesis, yet whether its effects can be pharmacologically opposed remains unknown. (2) Methods: We examined the interaction between PFDA (50, 75 μM) and the dietary polyphenol curcumin (20, 30 μM) throughout the 8-day 3T3-L1 preadipocyte differentiation protocol, using cell-viability (WST-1) assays with a two-factor interaction analysis, Oil Red O lipid quantification and mRNA profiling of Pparg, Cebpa, Srebf1, and Fasn. (3) Results: PFDA alone increased lipid accumulation and upregulated Pparg, Cebpa, and Fasn, whereas Srebf1 was induced only weakly and only at the higher dose, a pattern compatible with preferential engagement of the PPARγ/C/EBPα program over the SREBP-1c lipogenic pathway at the mRNA level, although the transcripts were not formally compared and no protein-level data were obtained. At two sub-cytotoxic concentrations, curcumin preserved potent antiadipogenic activity, reducing lipid accumulation by up to 67.3% and reversing PFDA-induced gene upregulation. At the viability endpoint the two compounds acted independently: curcumin significantly reduced viability and PFDA significantly increased it, with no statistically detectable interaction between them (two-way ANOVA, interaction p = 0.85). (4) Conclusions: This dissociation shows that a chemical interaction defined at one biological endpoint does not predict its outcome at another, a principle with broad implications for mixture toxicology—and it establishes curcumin as a candidate dietary intervention that intercepts an obesogen’s transcriptional program against environmentally driven metabolic disruption. Full article

Pathological aggregation of α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD), but increasing evidence indicates that αSyn deposits extend beyond the central nervous system to peripheral tissues, including the skin. In PD patients, cutaneous αSyn accumulation has been associated with seborrheic dermatitis (SD), a chronic inflammatory condition linked to sebocyte dysfunction and altered sebum production. Marked differences in sebum composition between PD patients and healthy controls have been described. We aimed to investigate whether pathological αSyn could contribute to dysregulated sebum production and composition by assessing key markers of sebocyte differentiation and lipogenesis in human sebaceous gland cells and skin biopsies from PD patients (n = 5) and matched controls (n = 5) without clinically recorded SD. O-αSyn exposure of immortalized sebaceous gland cells (SZ95) altered the transcriptional programs related to sebocyte differentiation, inflammation, metabolism, and lipogenesis. Consistently, protein markers of mid-to-late sebocyte differentiation were increased. Upregulation of PLIN2, together with elevated PPARγ, SREBP1, SCD1, and FADS2, indicated progression toward a mature and lipid-producing phenotype characterized by enhanced accumulation of neutral lipids within lipid droplets. Lipidomic profiling revealed remodeling of multiple lipid classes, with increases in triglycerides, ceramides, and selected phospholipids. Increased expression of PLIN2 and PPARγ was also observed in sebaceous glands from PD skin biopsies compared to controls. Collectively, our findings indicate that O-αSyn exposure is associated with molecular changes consistent with altered sebocyte differentiation and lipid remodeling. These results support a potential association between αSyn and lipid dysregulation in sebocytes and suggest that these cells may represent unrecognized peripheral targets of αSyn. Full article

Homeodomain-interacting protein kinase 2 (HIPK2) is an important regulator of various transcription factors and cofactors, which are involved in cell growth, cell death, and embryonic development. Previously, it has been reported that HIPK2 is upregulated during white fat development. However, the expression and functional role of HIPK2 during adipogenesis remain unclear. Here, we investigated the expression and biological function of HIPK2 during the adipogenesis of 3T3-L1 cells. Importantly, protein and mRNA expression of HIPK2 were significantly upregulated in a time-dependent manner during 3T3-L1 preadipocyte differentiation. Notably, distinct pharmacological inhibitors revealed the pivotal roles of p38 MAPK and PKC in the induction of HIPK2 expression during differentiation of 3T3-L1 cells. Moreover, knockdown of HIPK2 significantly reduced lipid storage and triglyceride (TG) levels without cytotoxicity during 3T3-L1 preadipocyte differentiation. At the mechanistic level, HIPK2 knockdown reduced the expression of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FAS), perilipin A, leptin, and resistin, as well as the phosphorylation of signal transducer and activator of transcription-3 (STAT-3) during 3T3-L1 preadipocyte differentiation. Taken together, these results revealed that HIPK2 expression is significantly upregulated in p38 MAPK- and PKC-dependent manners, and this upregulation of HIPK2 plays a critical role in lipid accumulation during differentiation of 3T3-L1 cells, which is mediated by control of the expression and phosphorylation levels of C/EBP-α, PPAR-γ, STAT-3, FAS, and perilipin A. Full article

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are chronic cholestatic liver diseases with limited therapeutic options. First-line therapy for PBC is ursodeoxycholic acid, although up to 40% of patients respond incompletely, and there is no effective therapy for PSC. Newer peroxisome proliferator-activated receptor (PPAR) agonists, e.g., seladelpar and elafibranor, received accelerated FDA approval as second-line treatments for PBC, and additional studies of PPAR agonists for PSC are underway. PPAR agonists have varying affinities for the PPAR isoforms (α, δ, γ), and the functional effects of isoform activation in humans are less known. Interindividual PPAR isoform expression varies across diseases and traditionally required invasive tissue biopsies for evaluation. Newer experimental approaches, such as extracellular vesicles (EVs) from liquid biopsies, can be used to characterize individual gene expression as an alternative (to tissue biopsy). The transcriptomic profiling of EVs uniquely allows for the quantification of coding and non-coding RNA transcripts, which may be used to study pathways relevant to PPAR expression and regulation and to identify biomarkers of treatment response to PPAR agonists in cholestasis. This review explores the application(s) of liquid biopsy-derived EVs for the identification of PPAR regulated pathways and its potential role in the treatment of PBC and PSC. Full article

RARγ is expressed during embryogenesis by stem/primitive progenitor cells, indicating a role in controlling their development. Supporting this view is that a physiological level of 10 nM of the RARγ agonist AGN205327 blocked stem/progenitor cell differentiation during zebrafish embryogenesis, mouse gastruloid development, and adult chondro- and osteogenesis. Similarly, transgene expression of RARγ or the use of the RARγ agonist CD437 enhanced the generation of induced pluripotent stem cells (iPSCs) from human and mouse somatic cells. RARγ regulates many events that control the behavior of stem/progenitor cells regarding whether they develop to give rise to mature cells. RARγ positively regulates the expressions of NOTCH ligands and their receptors, transforming growth factors (TGFs), and molecules pertaining to cell identity, extracellular matrix communication, and all-trans retinoic acid synthesis and catabolism. The genes that are repressed by RARγ include RARγ, PPARγ, and RXRα. RARγ integrates into Wnt/β-catenin and TGFβ signaling by acting as a co-factor to the gene co-activator β-catenin and transcription factor Smad3, respectively. Within the cytoplasm, RARγ regulates Akt/NF-κB signaling. As a model, we propose that ATRA ligand-activated RARγ acts as a gatekeeper to stem cell developmental progression during embryogenesis and that this role extends to stem/progenitor cell homeostasis within adult tissues. Full article

Background/Objectives: The clinical efficacy of cyclophosphamide, a commonly used chemotherapeutic drug, is often restricted by off-target neurotoxicity, which is primarily caused by oxidative stress, neuroinflammation, and apoptosis. With the aim of finding natural neuroprotective agents, pterostilbene was investigated in this study, either in conventional form or when solubilized as a nanoemulsion, for its neuroprotective potential against cyclophosphamide-induced neurotoxicity. Methods: Female Wistar rats were orally administered pterostilbene, either in its conventional form (50 mg/kg p.o) or nanoemulsion form (25 and 50 mg/kg p.o), for 15 days. Cyclophosphamide was injected once on day 14 (200 mg/kg ip). Results: Our findings revealed that administering pterostilbene as a nanoemulsion or in its conventional powder form managed to counteract the cyclophosphamide-induced intoxication features via disrupting the oxidative stress–inflammasome–cytokine axis; by upregulating cortical and hippocampal PPAR-γ, Nrf2, HO-1, BCL2 levels and the BCL2/Bax ratio; and downregulating NLRP3, IL-1β, COX-2, Bax and GFAP levels. Further histopathological and immunohistochemical evaluation confirmed the improved neuronal morphology, reduced degeneration and apoptosis, restoration of cortical and hippocampal architecture, and normalization of GFAP expression levels, approaching those of the control group upon treatment with either conventional or nanoformulated pterostilbene. Conclusions: The promising nature of the nanoemulsion formulation, particularly when administered at the high dose level, was evidenced, hence emphasizing the important role of proper formulation of natural bioactives such as pterostilbene in maximizing their therapeutic potential. Full article

Obesity and its associated metabolic disorders drive the search for natural compounds with anti-adipogenic properties. This study evaluated Vitis vinifera seed extract (GE), rich in oligomeric proanthocyanidins (OPCs), and Allium sativum bulb extract (ALL), rich in thiosulfinates, for their effects on adipogenesis and COX-related prostanoid modulation in 3T3-L1 cells. Differentiating preadipocytes were treated with non-cytotoxic concentrations of GE, ALL, or their combination (AGE) at a 1:600 dilution (approximately 23 μg/mL allicin and 0.05% OPCs). Lipid accumulation was assessed by Oil Red O staining, prostanoid levels (PGE₂, TXA₂, and PGI₂) were quantified by enzyme immunoassay, and adipogenic gene expression (PPARγ, CEBPα and GLUT4) was analyzed by RT-qPCR. All treatments reduced lipid accumulation, with GE showing the most potent inhibition (68.0% of control), followed by ALL (81.6%) and AGE (78.0%). Distinct prostanoid patterns emerged: GE increased both PGE₂ and PGI₂ and decreased TXA₂, while ALL increased PGE₂ and reduced both TXA₂ and PGI₂. The combination (AGE) did not enhance the anti-adipogenic effects. At the molecular level, GE downregulated PPARγ, CEBPα, and GLUT4, whereas ALL did not affect their transcription, indicating distinct mechanisms. These findings demonstrate that GE and ALL inhibit adipogenesis through differential modulation of the COX pathway and gene expression, highlighting their potential as functional ingredients for obesity management. The lack of synergy in the combination warrants further investigation. Full article

Background: Minor phytocannabinoids engage CB₁ and CB₂ receptors, as well as broader receptors and ion-channel targets. However, fragmented evidence limits translation into central nervous system (CNS) therapeutics. This review introduces pharmacological switching, defined as a dose-, state-, or model-dependent shift in the dominant determinant of a compound’s net effect that reverses the direction, rather than merely the magnitude, of that effect on a defined functional endpoint, as a framework for compound–indication matching. Unlike biased agonism, which redistributes downstream coupling without reversing direction, switching requires directional reversal between or within receptor systems. Methods: This narrative review integrates receptor pharmacology, preclinical CNS disease-model data, early-phase clinical evidence, and pharmacokinetics identified through a structured literature search. Results: Three mechanistic axes recurred: PPARγ/CB₂/Nrf2-linked neuroinflammatory modulation; TRP/GABA_A/5-HT₁A-linked control of neuronal excitability; and low-efficacy CB₁ antagonism with 5-HT₁A potentiation. Their expression was context-dependent: tetrahydrocannabivarin is reported to shift from CB₁ antagonism toward partial agonism as receptor occupancy rises, cannabidiolic acid shows stress-conditional anxiolytic and antiemetic activity, and cannabigerolic acid displays seizure-model-dependent bidirectionality. No instance yet meets all five defining criteria; each is graded provisional or proposed pending systematic testing. Human evidence remains limited: inconclusive cannabidivarin efficacy in epilepsy and neuropathic pain, proof-of-mechanism neuroimaging in autism, and early tetrahydrocannabivarin safety data. Conclusions: Minor phytocannabinoids are pharmacologically diverse but clinically underdeveloped. A tiered, biomarker-guided framework is proposed to match compound–indication pairs to the doses, formulations, and subgroups most likely to express their therapeutic pharmacology. Full article

Background: Doxorubicin-induced cardiotoxicity (DIC) is a major limitation of anthracycline chemotherapy and is characterized by oxidative stress, apoptosis, and myocardial remodeling. Dysregulation of AMP-activated protein kinase (AMPK) and its downstream effector sirtuin-1 (SIRT1) has been implicated in the molecular pathogenesis of DIC. Vardenafil (Var), a selective phosphodiesterase-5 inhibitor, has shown cardiovascular benefits; however, its impact on AMPK/SIRT1 signaling during DIC remains unclear. Methods: DIC was induced in rats by cumulative doxorubicin administration. Cardiac function, serum injury biomarkers, oxidative stress indices, histopathological alterations, apoptosis, fibrosis, and molecular markers associated with the AMPK/SIRT1 pathway were evaluated. In addition, molecular docking was performed to assess the potential interaction of Var with AMPK. Results: Var significantly improved cardiac function and reduced serum levels of lactate dehydrogenase, creatine kinase, and blood urea nitrogen. Treatment attenuated myocardial oxidative stress, restored glutathione content, reduced lipid peroxidation, and alleviated histopathological damage. Furthermore, Var suppressed caspase-3 and TGF-β1 expression while enhancing HO-1 levels. Var treatment was associated with restoration of cardiac phosphorylated AMPK (p-AMPK) expression and increased SIRT1, Nrf2, and PPARγ levels in doxorubicin-treated rats, consistent with modulation of an AMPK/SIRT1-associated cytoprotective network. Molecular docking demonstrated favorable interactions between Var and AMPK, providing supportive in silico evidence for the observed molecular findings. Conclusions: These findings demonstrate that Var attenuates doxorubicin-induced cardiotoxicity, and its cardioprotective effects are associated with restoration of the p-AMPK/SIRT1/Nrf2/PPARγ signaling pathway, together with reductions in oxidative stress, apoptosis, and fibrosis. Collectively, these findings suggest that Var attenuates early Dox-induced cardiac injury, potentially through modulation of the AMPK/SIRT1 signaling pathway, warranting further validation in long-term and dose–response studies. Full article

Background: Metabolic dysfunction-associated steatohepatitis (MASH), the progressive stage of metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by hepatic steatosis, inflammation, and fibrosis, yet no specific therapy has been established. This study evaluated the therapeutic potential of Andrias davidianus liver-derived peptides (ALPs) in a mouse model of MASH. Methods: ALPs were prepared by enzymatic hydrolysis of fresh Andrias davidianus liver. A MASH model was induced in mice using a methionine- and choline-deficient diet (MRCD). ALP was administered via oral gavage, and its effects were assessed through histological staining (H&E, Oil Red O, and Sirius Red), immunofluorescence (Ki67), apoptosis detection (TUNEL), serum biochemistry, and RNA-sequencing of liver tissues. Gut microbiota composition was also analyzed. Results: ALP treatment significantly alleviated hepatic histopathological features, including steatosis, inflammation, and fibrosis. It reduced aberrant proliferation and apoptosis of hepatocyte-like cells, and markedly improved serum biochemical markers of liver function. RNA-seq analysis revealed that ALP modulated the expression of lipid metabolism-related genes, an effect associated with suppression of the PPARγ signaling pathway. Furthermore, ALP selectively modulated MRCD-induced gut microbiota dysbiosis, particularly by reducing the Firmicutes-to-Bacteroidota (F/B) ratio and enriching Akkermansia. No overt toxicity was observed in other organs. Conclusions: Our findings demonstrate that ALP exerts protective effects against MASH by improving lipid metabolism, partially through suppression of the PPARγ signaling pathway, and by selectively modulating specific gut microbial taxa. ALP represents a promising natural therapeutic candidate for MASH. Full article

Excessive adipose tissue expansion contributes to metabolic dysfunction, highlighting the need to identify compounds that restrain adipocyte differentiation without causing nonspecific cytotoxicity. This study investigated whether 2-O-methylhonokiol suppresses adipogenesis in 3T3-L1 preadipocytes and examined its effects on adipogenic transcription, metabolic signaling, ER stress-related responses, kinase activity, and early cell cycle progression. 3T3-L1 cells were induced to differentiate with an MDI cocktail and treated with 25 or 50 µM 2-O-methylhonokiol during differentiation. Lipid accumulation was evaluated by Oil Red O staining, protein expression and phosphorylation were analyzed by immunoblotting, cell cycle distribution was assessed 24 h after MDI induction, and basal viability was measured using the CCK-8 assay. 2-O-methylhonokiol markedly reduced neutral lipid accumulation and suppressed key adipogenic regulators and maturation markers, including C/EBPβ, PPARγ, C/EBPα, FABP4, and FASN. At the signaling level, 2-O-methylhonokiol increased AMPKα phosphorylation without altering total AMPKα and reduced FASN expression, whereas mTOR phosphorylation was reduced at 50 µM. These findings suggest that 2-O-methylhonokiol is associated with metabolic and lipogenic signaling remodeling during adipocyte differentiation. 2-O-methylhonokiol also modified kinase-associated responses, increasing AKT and JNK phosphorylation while reducing the detectable phosphorylated ERK signal, with total AKT, ERK, and JNK remaining largely unchanged. ER stress-related signaling displayed a selective profile, characterized by increased IRE1α expression, XBP1s induction, elevated p-eIF2α, unchanged total eIF2α, and no compensatory increase in GRP78. During early adipogenesis, 2-O-methylhonokiol attenuated MDI-induced cell cycle redistribution by preserving a larger G0/G1 population and limiting progression toward later cell cycle phases, consistent with impaired mitotic clonal expansion. These effects occurred at concentrations that did not significantly reduce basal cell viability. Overall, 2-O-methylhonokiol suppresses 3T3-L1 adipogenesis by reducing adipogenic and lipogenic execution, accompanied by AMPK-associated metabolic remodeling, kinase signaling changes, selective ER stress-related responses, and restriction of early cell cycle progression. Further pathway-specific studies are required to define the causal contribution of each signaling axis. Full article

Obesity is a major metabolic disorder characterized by excessive lipid accumulation and adipocyte differentiation. The mitogen-activated protein kinase kinase 5 (MEK5) signaling pathway has been implicated in diverse cellular processes; however, its role in adipogenesis remains incompletely understood. In this study, we investigated the anti-adipogenic effects of BIX02189, a selective MEK5 inhibitor, using 3T3-L1 adipocytes, human adipose-derived stem cells (hASCs), and zebrafish models. Treatment with BIX02189 significantly reduced lipid accumulation and triglyceride content during adipocyte differentiation in a dose-dependent manner without marked cytotoxicity. BIX02189 effectively suppressed MEK5 phosphorylation and downregulated the expression of key adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT/enhancer-binding protein alpha (C/EBP-α). In addition, BIX02189 decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and STAT5, as well as the expression of lipogenic markers such as fatty acid synthase (FAS), perilipin A, and leptin. Conversely, BIX02189 enhanced AMP-activated protein kinase (AMPK) phosphorylation and markedly reduced the protein and mRNA expression of acetyl-CoA carboxylase (ACC), a key enzyme involved in fatty acid synthesis. Similar anti-adipogenic effects were observed in hASCs. Furthermore, BIX02189 significantly attenuated lipid accumulation in a zebrafish obesity model without affecting body length or causing overt toxicity. Collectively, these findings demonstrate that pharmacological inhibition of MEK5 suppresses adipogenesis and lipid accumulation through regulation of the STAT3/STAT5–PPAR-γ axis and activation of AMPK signaling. These findings provide the first evidence that MEK5 inhibition exerts anti-adipogenic effects in adipocytes and zebrafish, highlighting the MEK5 signaling pathway as a previously unrecognized regulator of adipogenesis and lipid metabolism. Full article

Obesity is an escalating global health challenge, driven by adipose tissue dysfunction characterized by adipocyte hypertrophy, chronic low-grade inflammation and impaired insulin signaling, which together promote insulin resistance, dyslipidemia, hepatic steatosis and cardiovascular disease. Chlorogenic acid (CGA), a dietary phenolic phytochemical abundant in coffee, tea, fruits and vegetables, has attracted considerable interest as a modulator of adipocyte biology and metabolism. This review summarizes in vitro and in vivo evidence of the effects of CGA on adipogenesis, lipid metabolism, thermogenesis, inflammation and glucose homeostasis. In vitro studies employing murine and human adipocyte and progenitor cell models demonstrate that CGA attenuates adipocyte differentiation and lipid accumulation via downregulation of adipogenic transcription factors (PPARγ, C/EBPα) and lipogenic enzymes (FASN, ACC, SREBP 1c), alongside activation of AMPK, Shp2–Erk1/2 and Wnt–β catenin signaling. Several reports further show that CGA promotes browning of white adipocytes and enhances thermogenic and mitochondrial gene expression. Complementary in vivo studies in diet-induced obesity and diabetes models reveal that CGA reduces body weight gain, adiposity, adipocyte size and hepatic steatosis, improves lipid profiles, glucose tolerance and insulin sensitivity, and exerts anti-inflammatory and antioxidant effects in metabolic tissues. Collectively, current preclinical evidence supports CGA as a multifaceted modulator of adipose tissue function and whole-body metabolic homeostasis; however, rigorously designed, long-term clinical trials are required to establish its efficacy and safety in humans. Full article

Background: Mung bean soup (MBS), as a common form of mung bean consumption, is widely consumed in folk to relieve summer heat. However, MBS is prone to red discoloration during cooking and storage. Furthermore, how this color change affects its phenolic compounds composition and bioactivity remains poorly understood. Objectives: Herein, this study systematically compared the phenolic profiles and heat stress (HS)-alleviating effects of normal mung bean soup (NMBS) and reddened mung bean soup (RMBS). Methods: Male C57BL/6J mice (six-week-old) were randomly assigned to four groups: control (no HS), HS, HS-NMBS, and HS-RMBS. HS was induced at 40 °C for 2 h/day for 7 days, with NMBS or RMBS provided ad libitum throughout the experiment. Phenolic analysis, oxidative stress markers, inflammatory cytokines, and gut microbiota were evaluated. Results: The results showed that reddening significantly reduced the total phenolic and flavonoid contents by 18.28% and 16.77%, respectively, accompanied by the loss of key bioactive compounds (vitexin and isovitexin). NMBS and RMBS could effectively alleviate HS-induced physiological damages in mice to varying degrees, including reduced weight loss, improved hepatic and intestinal histopathology, and lower levels of oxidative stress and inflammation (p < 0.05). However, NMBS provided superior overall protection by downregulating the expression of HS-associated genes (PPAR-γ) and pro-inflammatory cytokines (IL-1β), while upregulating the anti-inflammatory cytokine IL-10. Furthermore, supplementation with NMBS or RMBS restored the gut microbiota dysbiosis induced by HS. Especially, NMBS was more effective in restoring microbial diversity, modulating the F/B ratio, and enriching beneficial bacteria including Lactobacillus, Dubosiella, and norank_f_Muribaculaceae. Conclusions: These results highlight the importance of avoiding the occurrence of redness in MBS to maximize its efficacy. Full article

Insulin resistance (IR) is the underlying pathogenic mechanism for Type 2 Diabetes Mellitus, which is interconnected with Fatty Liver Disease. To investigate the molecular mechanisms by which different metabolic triggers contribute to hepatic IR onset, we exposed human HepG₂ hepatocytes to varying glucose concentrations (25–50 mM), and/or insulin (1 nM), and a free fatty acid mixture (0.3 mM), mimicking moderate or severe hyperglycemia, hyperinsulinemia, and steatosis. Glucose consumption, glycogen and lipid droplet (LD) accumulation, gene expression, oxidative stress, and insulin signaling were assessed. Under severe hyperglycemia, both insulin and fatty acids decreased glucose consumption, whereas under moderate hyperglycemia, only insulin had this effect. Glycogen accumulation was increased across all treated conditions. Both insulin and fatty acids triggered steatosis and downregulated PPARγ and SIRT1 mRNA, with insulin increasing LD number, while FFAs increased both LD number and size. All conditions enhanced ROS production, resulting in oxidative stress, but with differences in antioxidant enzyme response. Insulin receptor expression was reduced by insulin and FFAs under moderate hyperglycemia but increased by these stimuli under severe hyperglycemia. Both stimuli enhanced AKT phosphorylation under both hyperglycemic conditions. We conclude that different triggers cooperate in promoting hepatic IR through distinct molecular and signaling mechanisms, suggesting that effective treatments may need to target multiple pathways simultaneously. Full article