Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARβ/δ activation. Here, we assessed the impact of central leptin administration and PPARβ/δ inhibition on cardiac function. Various cardiac properties, including QRS duration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARβ/δ protein content and decreased HR, QRS duration, and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricular wall growth, which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARβ/δ activity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ventricular atrophy and improving heart function when PPARβ/δ signaling is intact. The protective effects of leptin are lost by PPARβ/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARβ/δ pathways to combat cardiac alterations and heart failure, particularly in the context of obesity.

The role of peroxisome proliferator-activated receptor (PPAR)β/δ in hepatic fibrosis remains a subject of debate. Here, we examined the effects of a PPARβ/δ agonist on the pathogenesis of liver fibrosis and the activation of hepatic stellate cells (HSCs), the main effector cells in liver fibrosis, in response to the pro-fibrotic stimulus transforming growth factor-β (TGF-β). The PPARβ/δ agonist GW501516 completely prevented glucose intolerance and peripheral insulin resistance, blocked the accumulation of collagen in the liver, and attenuated the expression of inflammatory and fibrogenic genes in mice fed a choline-deficient high-fat diet (CD-HFD). The antifibrogenic effect of GW501516 observed in the livers CD-HFD-fed mice could occur through an action on HSCs since primary HSCs isolated from Ppard-/- mice showed increased mRNA levels of the profibrotic gene Col1a1. Moreover, PPARβ/δ activation abrogated TGF-β1-mediated cell migration (an indicator of cell activation) in LX-2 cells (immortalized activated human HSCs). Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-β1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARβ/δ agonist reduces TGF-β1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels.

Inflammation in the reproductive tract has become a serious threat to animal fertility. Recently, the role of peroxisome proliferator-activated receptor gamma (PPARγ) in the context of reproduction and the inflammatory response has been highlighted, but the role of PPARβ/δ has not been fully elucidated. The aim of the present study was to investigate the in vitro effect of PPARβ/δ ligands (agonist: L-165,041 and antagonist: GSK 3787) on the transcriptome profile of porcine endometrium during LPS-induced inflammation in the mid-luteal and follicular phases of the oestrous cycle (days 10-12 and 18-20, respectively) using the RNA-Seq method. During the mid-luteal phase of the oestrous cycle, the current study identified 145 and 143 differentially expressed genes (DEGs) after treatment with an agonist or antagonist, respectively. During the follicular phase of the oestrous cycle, 55 and 207 DEGs were detected after treatment with an agonist or antagonist, respectively. The detected DEGs are engaged in the regulation of various processes, such as the complement and coagulation cascade, NF-κB signalling pathway, or the pathway of 15-eicosatetraenoic acid derivatives synthesis. The results of the current study indicate that PPARβ/δ ligands are involved in the control of the endometrial inflammatory response.

Bladder cancer aggressiveness is correlated with abnormal N-cadherin transmembrane glycoprotein expression. This protein is cleaved by the metalloprotease ADAM10 and the γ-secretase complex releasing a pro-angiogenic N-terminal fragment (NTF) and a proliferation-activating soluble C-terminal fragment (CTF2). Tetraspanin 15 (Tspan15) is identified as an ADAM10-interacting protein to induce selective N-cadherin cleavage. We first demonstrated, in invasive T24 bladder cancer cells, that N-cadherin was cleaved by ADAM10 generating NTF in the extracellular environment and leaving a membrane-anchored CTF1 fragment and that Tspan15 is required for ADAM10 to induce the selective N-cadherin cleavage. Targeting N-cadherin function in cancer is relevant to preventing tumor progression and metastases. For antitumor molecules to inhibit N-cadherin function, they should be complete and not cleaved. We first showed that the GW501516, an agonist of the nuclear receptor PPARβ/δ, decreased Tspan15 and prevented N-cadherin cleavage thus decreasing NTF. Interestingly, the drug did not modify ADAM10 expression, which was important because it could limit side effects since ADAM10 cleaves numerous substrates. By targeting Tspan15 to block ADAM10 activity on N-cadherin, GW501516 could prevent NTF pro-tumoral effects and be a promising molecule to treat bladder cancer. More interestingly, it could optimize the effects of the N-cadherin antagonists those such as ADH-1 that target the N-cadherin ectodomain.

To probe the functions of Aster glehni (AG) extract containing various caffeoylquinic acids on dyslipidemia, obesity, and skeletal muscle-related diseases focused on the roles of skeletal muscle, we measured the levels of biomarkers involved in oxidative phosphorylation and type change of skeletal muscle in C2C12 cells and skeletal muscle tissues from apolipoprotein E knockout (ApoE KO) mice. After AG extract treatment in cell and animal experiments, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were used to estimate the levels of proteins that participated in skeletal muscle type change and oxidative phosphorylation. AG extract elevated protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), phosphorylated 5\'-AMP-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), myoblast determination protein 1 (MyoD), and myoglobin in skeletal muscle tissues. Furthermore, it elevated the ATP concentration. However, protein expression of myostatin was decreased by AG treatment. In C2C12 cells, increments of MyoD, myoglobin, myosin, ATP-producing pathway, and differentiation degree by AG were dependent on PPARβ/δ and caffeoylquinic acids. AG extract can contribute to the amelioration of skeletal muscle inactivity and sarcopenia through myogenesis in skeletal muscle tissues from ApoE KO mice, and function of AG extract may be dependent on PPARβ/δ, and the main functional constituents of AG are trans-5-O-caffeoylquinic acid and 3,5-O-dicaffeoylquinic acid. In addition, in skeletal muscle, AG has potent efficacies against dyslipidemia and obesity through the increase of the type 1 muscle fiber content to produce more ATP by oxidative phosphorylation in skeletal muscle tissues from ApoE KO mice.

Various liver diseases pose great threats to humans. Although the etiologies of these liver diseases are quite diverse, they share similar pathologic phenotypes and molecular mechanisms such as oxidative stress, lipid and glucose metabolism disturbance, hepatic Kupffer cell (KC) proinflammatory polarization and inflammation, insulin resistance, and hepatic stellate cell (HSC) activation and proliferation. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is expressed in various types of liver cells with relatively higher expression in KCs and HSCs. Accumulating evidence has revealed the versatile functions of PPARβ/δ such as controlling lipid homeostasis, inhibiting inflammation, regulating glucose metabolism, and restoring insulin sensitivity, suggesting that PPARβ/δ may serve as a potential molecular drug target for various liver diseases. This article aims to provide a concise review of the structure, expression pattern and biological functions of PPARβ/δ in the liver and its roles in various liver diseases, and to discuss potential future research perspectives.

OBJECTIVE: Myelodysplastic syndromes (MDS) are clinically heterogeneous hematological malignancies with an increased risk of transformation to acute myeloid leukemia, emphasizing the importance of identifying new diagnostic and prognostic markers. This study sought to investigate the predictive ability of all-trans retinoic acid (ATRA)-dependent nuclear transcription factors RARα and PPARβ/δ gene expression in MDS patients.
METHODS: Peripheral blood specimens were collected from 49 MDS patients and 15 healthy volunteers. The specimens were further separated in Ficoll density gradient to obtain the mononuclear cells fractions. Gene expression analysis was carried out using quantitative real-time polymerase chain reaction (qRT-PCR) technique.
RESULTS: In the mononuclear cell fractions of MDS patients, RARα expression was increased (p<0.05) and PPARβ/δ expression was decreased (p<0.01) compared to healthy volunteers. When RARα and PPARβ/δ expression was compared in groups of MDS patients with different risks of disease progression, no statistically significant difference was found for RARα expression, while PPARβ/δ expression was significantly lower in the high-risk group of patients compared to the low-risk group (p<0.05). The expression of RARα was significantly associated with overall survival (p<0.05). ROC analysis showed that the expression of PPARβ/δ, rather than RARα expression, could have potential diagnostic value for MDS patients (AUC=0.75, p=0.003 and AUC=0.65, p=0.081, respectively).
CONCLUSIONS: RARα and PPARβ/δ genes are putative biomarkers that may be associated with the diagnosis and prognosis of MDS.

Peroxisome proliferator-activated receptors (PPARs) are a superfamily of nuclear transcription receptors, consisting of PPARα, PPARγ, and PPARβ/δ, which are highly expressed in the liver. They control and modulate the expression of a large number of genes involved in metabolism and energy homeostasis, oxidative stress, inflammation, and even apoptosis in the liver. Therefore, they have critical roles in the pathophysiology of hepatic diseases. This review provides a general insight into the role of PPARs in liver diseases and some of their agonists in the clinic.

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and β/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARβ/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program.

UNASSIGNED: Puerarin is the main isoflavone extracted from Radix Puerariae lobata (Willd.) and exerts a strong protective effect on endothelial cells. This isoflavone also exerts proven angiogenic effects; however, the potential underlying mechanism has not been fully explored. Here in this work, we aimed to determine the proangiogenesis effect of a puerarin-attached lignin nanoparticle-incorporated hydrogel and explore the underlying mechanism.
UNASSIGNED: Puerarin-attached lignin nanoparticles were fabricated and mixed with the GelMA hydrogel. After the hydrogel was characterized, the angiogenic effect was evaluated in a mouse hind-limb ischemia model. To further explore the mechanism of angiogenesis, human endothelial cell line EA.hy926 was exposure to different concentrations of puerarin. Wound healing assays and tube formation assays were used to investigate the effects of puerarin on cell migration and angiogenesis. qPCR and Western blotting were performed to determine the changes in the levels of angiogenesis indicators, autophagy indicators and PPARβ/δ. 3-MA was used to assess the role of autophagy in the puerarin-mediated angiogenesis effect in vivo and in vitro.
UNASSIGNED: The hydrogel significantly improved blood flow restoration in mice with hind-limb ischemia. This effect was mainly due to puerarin-mediated increases in the angiogenic capacity of endothelial cells and the promotion of autophagy activation. A potential underlying mechanism might be that puerarin-mediated activation of autophagy could induce an increase in PPARβ/δ expression.
UNASSIGNED: The puerarin-attached lignin nanoparticle-incorporated hydrogel effectively alleviated blood perfusion in mice with hind-limb ischemia. Puerarin has a prominent proangiogenic effect. The potential mechanisms might be that puerarin-mediated autophagy activation and increase in PPARβ/δ.