Non-alcoholic fatty liver disease (NAFLD) has been considered a main health concern worldwide, and Platycodon grandiflorum (PG) has been traditionally employed in ethnopharmacology for managing hepatic metabolic disorders. This study aimed to elucidate the potential effect of PG on NAFLD in rats, and furthermore, the mechanism was explored. PG supplementation significantly increased body weight, serum total cholesterol, triglycerides, and LDL-cholesterol levels in HFD-induced obese rats (p < 0.05). In addition, HFD-induced lipid accumulation and inflammatory response in the liver were also suppressed. Then, the factors contributing to the regulating effect of PG on NAFLD were estimated by using network pharmacology and RNA sequencing. Moreover, western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) suggested that PG treatment obviously downregulated the expression levels of nuclear factor-κB (NF-κB), Toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), and inhibitor I kappa B alpha (IκBα), whereas it upregulated the expression of peroxisome proliferator-activated receptor-gamma (PPARγ). Taken together, these findings corroborated the modulatory capacity of PG on NAFLD rats through regulating inflammatory response via PPARγ and TLR4/NF-κB pathway.

Advanced glycation end products/receptor for AGEs (AGE/RAGE) signaling has a well-established role in the etiology of diabetic-related cardiovascular disorders. The purpose of the study was to elucidate the role of chrysin, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, against ischemia/reperfusion (IR) injury in diabetic rats and its functional interaction with the AGE/RAGE signaling pathway.

A single intraperitoneal injection of streptozotocin (STZ, 70 mg/kg) was administered to rats for induction of diabetes. Rats having blood glucose levels more than 300 mg/dl following a 72 hr STZ injection were classified as diabetic. PPAR-γ antagonist GW9662 (1 mg/kg, i.p.), chrysin (60 mg/kg, p.o.), or both were administered to diabetic rats for 4 weeks. On the 29th day, rats were given ischemia for 45 min and then reperfusion for 1 hr to induce myocardial infarction (MI).

Pretreatment with chrysin significantly improved hemodynamic status, ventricular functions, and cardiac injury markers in diabetic myocardium. Increased PPAR-γ/Nrf2 and decreased RAGE protein expressions were linked to this improvement. Chrysin pretreatment resulted in the upregulation of endogenous antioxidants and reduced TBARS levels. Moreover, chrysin significantly decreased inflammation and apoptosis in diabetic myocardium.

PPAR-γ/Nrf2 co-activation by chrysin ameliorated IR-induced MI in diabetic rats, possibly via modulating AGE/RAGE signaling.

Childhood obesity, especially in girls, often correlates with advanced puberty and long-term comorbidities. Among the central circuits controlling energy homeostasis, hypothalamic lipid sensing pathways, involving free fatty-acid receptors (FFARs), peroxisome proliferator-activated receptors (PPARs), and the bile-acid (BA) receptor, Takeda G protein-coupled receptor 5 (TGR5), have been recognized as major players, with putative pathogenic roles in obesity and its complications. However, their contribution to pubertal regulation and obesity-induced pubertal alterations remains largely unexplored. We describe herein changes in the hypothalamic profiles of specific lipid species, including certain fatty-acyls, BA derivatives, and several glycerolphospholipids, during the juvenile-pubertal transition and conditions of overweight linked to precocious puberty in female rats. Hypothalamic expression of the FFAR, Gpr84, as well as Ppar-γ and Tgr5 gradually increased during the infantile-prepubertal transition, whereas early overfeeding increased hypothalamic mRNA levels of the FFARs, Gpr43, and Gpr84. Expression of Gpr84, Ppar-α, and Tgr5 was documented in FACS-isolated Kiss1 neurons from juvenile and pubertal female mice. Central pharmacological gain- and loss-of-function manipulations of GPR84-, PPAR-, or TGR5-signaling in prepubertal lean and early overfed female rats resulted in specific changes in pubertal timing. In lean rats, central blockade of PPAR-γ/α delayed puberty onset, whereas in early overfed rats, central stimulation of TGR5 signaling partially prevented obesity-induced advanced puberty; effects that were also marginally observed after GPR84 inhibition. Our results disclose the role of brain lipid-sensing pathways in the control of puberty, with a variable contribution of central FFAR-, PPAR-, and TGR5-signaling depending on the maturational and nutritional status.NEW & NOTEWORTHY Puberty is highly sensitive to body energy status, and child obesity is often linked to perturbed puberty. However, whether this comes from excessive energy stores or specific nutrient signals altered in obesity remains largely unexplored. Using suitable preclinical models of early obesity and accelerated puberty, we disclose herein conclusive evidence for altered hypothalamic lipid profiles and the roles of specific lipid-sensing pathways in pubertal control, with a variable contribution depending on the maturational and nutritional status.

Background: This study investigates the effects of cadmium chloride (CdCl2) on hippocampal peroxisome proliferator-activated receptor gamma (PPARγ) expression and examines whether PPARγ activation mediates the neuroprotective effects of quercetin (QUR). Methods: Sixty adult male rats were included in this study, separated into 12 rats per group as follows: control, CdCl2 (0.5 mg/kg), CdCl2 + PPARγ agonist (Pioglitazone, 10 mg/kg), CdCl2 + QUR (25 mg/kg), and CdCl2 + QUR + PPARγ antagonist (GW9662, 1 mg/kg). Treatments were administered orally for 30 days. At the end of the experiment, behavioral memory tests, hippocampal histology, markers of cholinergic function, neuroplasticity, oxidative stress, inflammation, and apoptosis, as well as transcription levels of some genes were carried out. Results: CdCl2 exposure significantly reduced hippocampal PPARγ mRNA and DNA binding potential and nuclear levels. Additionally, CdCl2 impaired spatial, short-term, and recognition memory, decreased granular cell density in the dentate gyrus (DG), and reduced levels of neuroprotective factors, including Nrf2, brain-derived neurotrophic factor (BDNF), acetylcholine (ACh), and several antioxidant enzymes including heme-oxygenase-1 (HO-1) and superoxide dismutase (SOD), as well as reduced glutathione (GSH). Conversely, CdCl2 elevated levels of oxidative stress, inflammation, and apoptosis markers such as interleukin-6 (IL-6), malondialdehyde (MDA), Bax, tumor necrosis factor-α (TNF-α), and cleaved caspase-3. QUR and Pioglitazone reversed these effects, restoring expression and PPARγ activation, improving memory, and modulating antioxidant and anti-inflammatory pathways. In contrast, blocking PPARγ with GW9662 negated the neuroprotective effects of QUR, exacerbating oxidative stress and inflammation by reversing all their beneficial effects. Conclusions: Activation of PPARγ by QUR or Pioglitazone offers a promising therapeutic strategy for mitigating CdCl2-induced neurotoxicity.

Changes in skin pigmentation, like hyperpigmentation or moles, can affect appearance and social life. Unlike locally containable moles, malignant melanomas are aggressive and can spread rapidly, disproportionately affecting younger individuals with a high potential for metastasis. Research has shown that the peroxisome proliferator-activated receptor gamma (PPAR-γ) and its ligands exhibit protective effects against melanoma. As a transcription factor, PPAR-γ is crucial in functions like fatty acid storage and glucose metabolism. Activation of PPAR-γ promotes lipid uptake and enhances sensitivity to insulin. In many cases, it also inhibits the growth of cancer cell lines, like breast, gastric, lung, and prostate cancer. In melanoma, PPAR-γ regulates cell proliferation, differentiation, apoptosis, and survival. During tumorigenesis, it controls metabolic changes and the immunogenicity of stromal cells. PPAR-γ agonists can target hypoxia-induced angiogenesis in tumor therapy, but their effects on tumors can be suppressive or promotional, depending on the tumor environment. Published data show that PPAR-γ-targeting agents can be effective in specific groups of patients, but further studies are needed to understand lesser-known biological effects of PPAR-γ and address the existing safety concerns. This review provides a summary of the current understanding of PPAR-γ and its involvement in melanoma.

High-fat diets (HFDs) have become increasingly prevalent in modern societies, driving rising rates of obesity and metabolic syndrome. Concurrently, radiation exposure from medical treatments and environmental sources poses health risks shaped by both biological and environmental factors. This review explores the intersection between HFDs and radiation sensitivity/susceptibility, focusing on how diet-induced metabolic alterations influence the body's response to radiation. Evidence from preclinical and clinical studies indicates that HFDs significantly alter metabolism, leading to increased oxidative stress and immune system dysregulation. These metabolic changes can exacerbate radiation-induced oxidative stress, inflammation, and DNA damage, potentially increasing radiation sensitivity in normal tissues. Conversely, obesity and HFD-induced metabolic disruptions may activate cellular pathways involved in DNA repair, cell survival, and inflammatory responses, fostering tumor resistance and modifying the tumor microenvironment, which may impair the efficacy of radiation therapy in cancer treatment. Understanding the interplay between diet and radiation exposure is critical for optimizing public health guidelines and improving therapeutic outcomes. These findings underscore the need for further research into dietary interventions that may mitigate radiation-associated risks.

Harnessing cross-species regenerative cues to direct human regenerative potential is increasingly recognized as an excellent strategy in regenerative medicine, particularly for addressing the challenges of impaired wound healing in aging populations. The skin mucus of Andrias davidianus plays a critical role in self-protection and tissue repair, yet the fundamental regenerative factors and mechanisms involved remain elusive. Here, this work presents evidence that glycosaminoglycans (GAGs) derived from the skin secretion of Andrias davidianus (SAGs) serve as potent mediators of angiogenesis and inflammatory remodeling, facilitating efficient healing of diabetic wounds. Mechanistic studies reveal that SAGs promote macrophage polarization toward an anti-inflammatory and pro-regenerative phenotype (CD206+/Arg1+) via glucolipid metabolic reprogramming. This process suppresses excessive inflammation and enhances the expression of VEGF and IL-10 to create a facilitative microenvironment for tissue regeneration. Additionally, this work develops SAGs-GelMA composite microspheres that address multiple stages of wound healing, including rapid hemostasis, exudate control, and activation of endogenous regenerative processes. This engineered approach significantly improves the scarless healing of diabetic wounds by facilitating the recruitment and activation of reparative macrophages. The findings offer new insights into the regenerative mechanisms of Andrias davidianus and highlight the potential therapeutic application of SAGs in tissue repair.

Sepsis is the leading cause of death among critically ill patients in clinical practice, making it urgent to reduce its incidence and mortality rates. In sepsis, macrophage dysfunction often worsens and complicates the condition. M1 and M2 macrophages, two distinct types, contribute to pro-inflammatory and anti-inflammatory effects, respectively. An imbalance between them is a major cause of sepsis. The aim of this study was to explore the potential of a differential metabolite between M1 and M2 macrophages in mitigating septic colonic injury via multiomics in combination with clinical data and animal experiments. Using nontargeted metabolomics analysis, we found that Kynurenic acid (KYNA), a metabolite of tryptophan metabolism, was significantly upregulated in the supernatant of M2 macrophages. Furthermore, we discovered that the level of KYNA was significantly decreased in sepsis in both human and mouse serum and was negatively correlated with inflammatory factor levels. In vivo experiments demonstrated that KYNA can effectively alleviate septic colon injury and reduce inflammatory factor levels in mice, indicating that KYNA plays a very important protective role in sepsis. Mechanistically, KYNA promotes the transition of M1 macrophages to M2 macrophages by inhibiting the NF-κB signaling pathway and alleviates septic colonic injury through the PPARγ/NF-κB axis. This article reveals that KYNA, a differentially abundant metabolite between M1 and M2 macrophages, can become a new strategy for alleviating septic colon injury.

PPARγ functions as a master ligand-dependent transcription factor that regulates the expressions of a variety of key genes related to metabolic homeostasis and inflammatory immunity. It has been recognized as a popular and druggable target in modern drug discovery. Similar to other nuclear receptors, PPARγ is a phosphoprotein, and its biological functions are regulated by phosphorylation, especially at Ser273 site which is mediated by CDK5 or ERK. In the past decade, the excessive level of PPARγ-Ser273 phosphorylation has been confirmed to be a crucial factor in promoting the occurrence and development of some major diseases. Ligands capable of inhibiting PPARγ-Ser273 phosphorylation have shown great potentials for treatment. Despite these achievements, to our knowledge, no related review focusing on this topic has been conducted so far. Therefore, we herein summarize the basic knowledge of PPARγ and CDK5/ERK-mediated PPARγ-Ser273 phosphorylation as well as its physiopathological role in representative diseases. We also review the developments and therapeutic applications of PPARγ-targeted ligands based on this mechanism. Finally, we suggest several directions for future investigations. We expect that this review can evoke more inspiration of scientific communities, ultimately facilitating the promotion of the PPARγ-Ser273 phosphorylation-involved mechanism as a promising breakthrough point for addressing the clinical treatment of human diseases.

Triphenyl phosphate (TPhP) is a widely used organophosphate flame retardant, the health risks of TPhP are a global concern. In this study, we found that prenatal TPhP exposure at human relevant concentration induced hyperlipidemia in male offspring, it increased serum levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol. Placental trophoblast-derived extracellular vesicles (T-EVs) could transport to the fetus through maternal-fetal circulation. TPhP significantly upregulated the protein level of peroxisome proliferator activated receptor γ (PPARγ) in T-EVs. Similar to TPhP, gestational exposure to T-EVs isolated from TPhP exposed mice placentae induced the same effects. While, gestational intervention with GW9662 (PPARγ inhibitor) or GW4869 (EVs secretion inhibitor) would alleviate the disturbed lipid metabolism induced by TPhP. Meanwhile, in vitro experiments verified that TPhP upregulated PPARγ in HTR8/SVneo cells derived EVs, and these EVs promoted adipogenesis in preadipocyte 3T3-L1 cells. Knock down of PPARγ in HTR8/SVneo could alleviate the adipogenensis effects of EVs derived from TPhP exposed HTR8/SVneo cells. These results demonstrate that TPhP exposure induces hyperlipidemia in male offspring by upregulating PPARγ in T-EVs. Our study provides new insights into the metabolic disruptive effects of TPhP, and emphasizes the mediating effects of placental T-EVs on gestational environmental stress in fetal development.

Flavanones, a class of flavonoids, are abundant in fruits, vegetables, and herbs. They are known to have several biological activities, such as anti-inflammatory and anti-cancer activities, but their effects on obesity remain unclear. Obesity is closely associated with adipocyte differentiation and lipid accumulation in adipose tissue. Therefore, in this study, we examined the effects of flavanone derivatives on adipocyte differentiation and lipid accumulation by using 3T3-L1 cells. Among the 15 flavanone derivatives studied, 4'-phenylflavanone (4PF), with a biphenyl structure, significantly inhibited adipocyte differentiation-related lipid accumulation in 3T3-L1 cells; this inhibition of lipid accumulation was dose-dependent. Gene expression analysis showed that 4PF suppressed the expression of adipogenic marker genes. Although the induction of peroxisome proliferator activator γ2 (Pparγ2), a master regulator of adipocyte differentiation, and its target genes during adipocyte differentiation was attenuated in 4PF-treated cells, 4PF did not directly regulate Pparγ2 gene expression and its activation. In contrast, 4PF suppressed mitotic clonal expansion (MCE), which is associated with changes in the expression of proliferation-related genes at the early stages of adipocyte differentiation. Taken together, these results suggest that 4PF inhibits lipid accumulation because it suppresses MCE during adipocyte differentiation. Thus, our findings may help in the development of anti-obesity drugs.

Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.

Antioxidant-rich supplementation plays an essential role in the function of mammals' central nervous system. However, no research has documented the effect of berberine (BER) supplementation on the cerebrocerebellar function of prepubertal rats. The present study was designed to investigate the impact of BER supplementation on neurochemical and behavioural changes in prepubertal male rats. Five groups (90 ± 5 g, n = 7 each) of experimental rats were orally treated with corn oil or different doses of BER (25, 50, 100, and 200 mg/kg bw) from the 28th at 68 post-natal days. On the 69 days of life, animals underwent behavioural assessment in the open field, hanging wire, and negative geotaxis tests. The result revealed that BER administration improved locomotive and motor behaviour by increasing distance travelled, line crossings, average speed, time mobile, and absolute turn angle in open field test and decrease in time to re-orient on an incline plane, a decrease in immobility time relative to the untreated control. Furthermore, BER supplementation increased (p < 0.05) antioxidant enzyme activities such as SOD, CAT, GPx, GSH, and TSH and prevented increases (p < 0.05) in oxidative and inflammatory levels as indicated by decreases in RONS, LPO, XO, carbonyl protein, NO, MPO, and TNF-α compared to the untreated control. BER-treated animals a lessened number of dark-stained Nissl cells compared to the untreated control rats. Our findings revealed that BER minimised neuronal degeneration and lesions, improved animal behaviour, and suppressed oxidative and inflammatory mediators, which may probably occur through its agonistic effect on PPAR-α, PPAR-δ, and PPAR-γ - essential proteins known to resolve inflammation and modulate redox signalling towards antioxidant function.

Obstructive sleep apnea (OSA), a common sleep-disordered breathing condition, is characterized by intermittent hypoxia (IH) and sleep fragmentation and has been implicated in the pathogenesis and severity of nonalcoholic fatty liver disease (NAFLD). Abnormal molecular changes mediated by IH, such as high expression of hypoxia-inducible factors, are reportedly involved in abnormal pathophysiological states, including insulin resistance, abnormal lipid metabolism, cell death, and inflammation, which mediate the development of NAFLD. However, the relationship between IH and NAFLD remains to be fully elucidated. In this review, we discuss the clinical correlation between OSA and NAFLD, focusing on the molecular mechanisms of IH in NAFLD progression. We meticulously summarize clinical studies evaluating the therapeutic efficacy of continuous positive airway pressure treatment for NAFLD in OSA. Additionally, we compile potential molecular biomarkers for the co-occurrence of OSA and NAFLD. Finally, we discuss the current research progress and challenges in the field of OSA and NAFLD and propose future directions and prospects.

Accurate simulation of different cell type interactions is crucial for physiological and precisein vitrodrug testing. Human tissue-resident macrophages are critical for modulating disease conditions and drug-induced injuries in various tissues; however, their limited availability has hindered their use inin vitromodeling. Therefore, this study aimed to create macrophage-containing organoid co-culture models by directly incorporating human-induced pluripotent stem cell (hiPSC)-derived pre-macrophages into organoid and scaffold cell models. The fully differentiated cells in these organoids exhibited functional characteristics of tissue-resident macrophages with enriched pan-macrophage markers and the potential for M1/M2 subtype specialization upon cytokine stimulation. In a hepatic organoid model, the integrated macrophages replicated typical intrinsic properties, including cytokine release, polarization, and phagocytosis, and the co-culture model was more responsive to drug-induced liver injury than a macrophage-free model. Furthermore, alveolar organoid models containing these hiPSC-derived macrophages also showed increased drug and chemical sensitivity to pulmonary toxicants. Moreover, 3D adipocyte scaffold models incorporating macrophages effectively simulated in vivo insulin resistance observed in adipose tissue and showed improved insulin sensitivity on exposure to anti-diabetic drugs. Overall, the findings demonstrated that incorporating hiPSC-derived macrophages into organoid culture models resulted in more physiological and sensitivein vitrodrug evaluation and screening systems.

Oral squamous cell carcinoma (OSCC) stands as a prevalent subtype of head and neck squamous cell carcinoma, leading to disease recurrence and low survival rates. PPARγ, a ligand-dependent nuclear transcription factor, holds significance in tumor development. However, the role of PPARγ in the development of OSCC has not been fully elucidated. Through transcriptome sequencing analysis, we discovered a notable enrichment of ferroptosis-related molecules upon treatment with PPARγ antagonist. We subsequently confirmed the occurrence of ferroptosis through transmission electron microscopy, iron detection, etc. Notably, ferroptosis inhibitors could not completely rescue the cell death caused by PPARγ inhibitors, and the rescue effect was the greatest when disulfidptosis and ferroptosis inhibitors coexisted. We confirmed that the disulfidptosis phenotype indeed existed. Mechanistically, through qPCR and Western blotting, we observed that the inhibition of PPARγ resulted in the upregulation of heme oxygenase 1 (HMOX1), thereby promoting ferroptosis, while solute carrier family 7 member 11 (SLC7A11) was also upregulated to promote disulfidptosis in OSCC. Finally, a flow cytometry analysis of flight and multiplex immunohistochemical staining was used to characterize the immune status of PPARγ antagonist-treated OSCC tissues in a mouse tongue orthotopic transplantation tumor model, and the results showed that the inhibition of PPARγ led to ferroptosis and disulfidptosis, promoted the aggregation of cDCs and CD8+ T cells, and inhibited the progression of OSCC. Overall, our findings reveal that PPARγ plays a key role in regulating cell death in OSCC and that targeting PPARγ may be a potential therapeutic approach for OSCC.

Cardiac remodeling is the primary pathological feature of chronic heart failure (HF). Exploring the characteristics of cardiac remodeling in the very early stages of HF and identifying targets for intervention are essential for discovering novel mechanisms and therapeutic strategies. Silent mating type information regulation 2 homolog 3 (SIRT3), as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolism. However, whether SIRT3 plays a role in cardiac remodeling by regulating the biosynthesis of mitochondrial cardiolipin (CL) is unknown. In this study, we induced pressure overload in wild-type (WT) and SIRT3 knockout (SIRT3-/-) mice via transverse aortic constriction (TAC). Compared with WT mouse hearts, the hearts of SIRT3-/- mice exhibited more-pronounced cardiac remodeling and fibrosis, greater reactive oxygen species (ROS) production, decreased mitochondrial-membrane potential (ΔΨm), and abnormal mitochondrial morphology after TAC. Furthermore, SIRT3 deletion aggravated TAC-induced decrease in total CL content, which might be associated with the downregulation of the CL synthesis related enzymes cardiolipin synthase 1 (CRLS1) and phospholipid-lysophospholipid transacylase (TAFAZZIN). In our in vitro experiments, SIRT3 overexpression prevented angiotensin II (AngII)- induced aberrant mitochondrial function, CL biosynthesis disorder, and peroxisome proliferator-activated receptor gamma (PPARγ) downregulation in cardiomyocytes; meanwhile, SIRT3 knockdown exacerbated these effects. Moreover, the addition of GW9662, a PPARγ antagonist, partially counteracted the beneficial effects of SIRT3 overexpression. In conclusion, SIRT3 regulated PPARγ-mediated CL biosynthesis, maintained the structure and function of mitochondria, and thereby protected the myocardium against cardiac remodeling.

Therapeutic resistance is a major obstacle to successful treatment or effective containment of cancer. Peroxisome proliferator-activated receptors (PPARs) play an essential role in regulating energy homeostasis and determining cell fate. Despite of the pleiotropic roles of PPARs in cancer, numerous studies have suggested their intricate relationship with therapeutic resistance in cancer. In this review, we provided an overview of the roles of excessively activated PPARs in promoting resistance to modern anti-cancer treatments, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The mechanisms through which activated PPARs contribute to therapeutic resistance in most cases include metabolic reprogramming, anti-oxidant defense, anti-apoptosis signaling, proliferation-promoting pathways, and induction of an immunosuppressive tumor microenvironment. In addition, we discussed the mechanisms through which activated PPARs lead to multidrug resistance in cancer, including drug efflux, epithelial-to-mesenchymal transition, and acquisition and maintenance of the cancer stem cell phenotype. Preliminary studies investigating the effect of combination therapies with PPAR antagonists have suggested the potential of these antagonists in reversing resistance and facilitating sustained cancer management. These findings will provide a valuable reference for further research on and clinical translation of PPAR-targeting treatment strategies.

Changes in phosphatidylcholine levels in the liver have been associated with the development of metabolic dysfunction-associated steatotic liver disease. Here, the effects of supplementing phosphatidylcholine on the development of early signs of metabolic dysfunction-associated steatohepatitis were assessed.

Male and female C57BL/6J mice were fed a liquid control or a fructose-, fat-, and/or cholesterol-rich diet for 7 or 8 weeks. The diets of female mice were fortified ± phosphatidylcholine (12.5 mg/g diet). In liver tissue and portal blood, indices of liver damage, inflammation, and bacterial endotoxemia were measured. J774A.1 cells and human monocytes preincubated with phosphatidylcholine (0.38 mmol/L) were challenged with lipopolysaccharide (50-100 ng/mL) ± the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (10 μmol/L) or ± a liver receptor homolog 1 (LRH-1) antagonist 1-(3'-[1-(2-[4-morpholinyl]ethyl)-1H-pyrazol-3-yl]-3-biphenylyl)ethanon (1-10 μmol/L).

In fructose-, fat-, and/or cholesterol-rich diet-fed mice the development of fatty liver and the beginning of inflammation were associated with significantly lower hepatic phosphatidylcholine levels when compared with controls. Supplementing phosphatidylcholine significantly attenuated the development of fatty liver and inflammation, being associated with protection against the induction of PPARγ2, and activation of nuclear factor of κ light polypeptide gene enhancer in B-cell inhibitor α whereas Lrh1 expression was unchanged. The protective effects of phosphatidylcholine on the lipopolysaccharide-induced activation of J774A.1 cells and human monocytes were attenuated significantly by the PPARγ activator pioglitazone and the LRH-1 antagonist.

Our data suggest that phosphatidylcholine levels in the liver are lower in early metabolic dysfunction-associated steatohepatitis in mice and that supplementation of phosphatidylcholine can diminish the development of metabolic dysfunction-associated steatotic liver disease through mechanisms involving LRH-1/PPARγ2/ nuclear factor κ-light-chain enhancer of activated B-cell signaling.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing. Obesity, insulin resistance, and lipid metabolic dysfunction are always accompanied by NAFLD. Celastrol modulates the Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) signaling pathways, thereby promoting lipolysis in 3T3-L1 adipocytes. In the present study, oleic-acid-induced NAFLD and differentiated 3T3-L1 preadipocytes were used as models of NAFLD and obesity to investigate the protective effect of celastrol. We investigated the impact of celastrol on hepatic steatosis caused by oleic acid (OA), as well as the associated underlying molecular pathways. To address the aforementioned questions, we used a cellular approach to analyze the signaling effects of celastrol on various aspects. These factors include the improvement in fatty liver in HepG2 cells, the differentiation of 3T3-L1 preadipocytes, glucose uptake, and the modulation of key transcriptional pathways associated with PPARγ. The administration of celastrol effectively mitigated lipid accumulation caused by OA in HepG2 cells, thereby ameliorating fatty liver conditions. Furthermore, celastrol suppressed the impacts on adipocyte differentiation in 3T3-L1 adipocytes. Additionally, celastrol exhibited the ability to bind to PPARγ and modulate its transcriptional activity. Notably, the ameliorative effects of celastrol on hepatic steatosis were reversed by rosiglitazone. According to our preliminary findings from in vitro celastrol signaling studies, PPARγ is likely to be the direct target of celastrol in regulating hepatic steatosis in HepG2 cells and adipocyte differentiation in 3T3-L1 cells.

As the most prevalent chronic liver disease globally, NAFLD encompasses a pathological process that ranges from simple steatosis to NASH, fibrosis, cirrhosis, and HCC, closely associated with numerous extrahepatic diseases. While the initial etiology was believed to be hepatocyte injury caused by lipid toxicity from accumulated triglycerides, recent studies suggest that an imbalance of cholesterol homeostasis is of greater significance. The role of nuclear receptors in regulating liver cholesterol homeostasis has been demonstrated to be crucial. This review summarizes the roles and regulatory mechanisms of nuclear receptors in the 3 main aspects of cholesterol production, excretion, and storage in the liver, as well as their cross talk in reverse cholesterol transport. It is hoped that this review will offer new insights and theoretical foundations for the study of the pathogenesis and progression of NAFLD and provide new research directions for extrahepatic diseases associated with NAFLD.

Peroxisome proliferator-activated receptors (PPARs) are currently among the most focused-on therapeutic targets for non-alcoholic steatohepatitis (NASH), although no clinical transformation has been achieved to date. In this study, we aimed to evaluate the effects of GW9662 on choline-deficient, L-amino acid-defined high-fat diet (CDAA-HFD)-induced NASH mice and reveal the mechanism underlying this effect.

GW9662 (1 mg/kg) was administered in CDAA-HFD mouse model of NASH. The effect of GW9662 on hepatic lipid metabolism was investigated using liver RNA-seq and HepG2 cells induced by oleic acid and palmitic acid. In addition, 16S rRNA gene sequencing was performed to analyze the effects of GW9662 on the composition and function of the fecal microbiota.

GW9662 improved the CDAA-HFD caused elevation in the levels of ALT, AST, hepatic free fatty acids and triglycerides. The liver pathological analysis indicated that GW9662 alleviated the hepatic steatosis and fibrosis. The NAFLD activity score and RNA-Seq revealed that GW9662 mainly regulated the fatty acids transport and lipid synthesis by inhibiting PPARγ, CD36, FABP1, FASN, and SCD1, and through the up-regulation of PPARα. Moreover, GW9662 reduced the epididymal fat weight. GW9662 reversed the gut microbiota disorder by increasing the abundance of the beneficial bacteria Dubosiella and Lactobacillus and decreasing the abundance of harmful bacteria Lachnospiraceae_NK4A136_group, Helicobacteraceae, Desulfovibriaceae, and Rickenaceae.

GW9662 ameliorated lipid metabolism by inhibiting the PPARγ/CD36 pathway and altering the composition of the gut microbiota in NASH mice. Therefore, the PPARγ antagonist GW9662 deserves more attention as a potential therapeutic agent for NASH.

Multiple sclerosis (MS) is a debilitating, inflammatory, and demyelinating disease of the central nervous system influenced by environmental and genetic factors. Around 2.8 million people worldwide are affected by MS due to its challenging diagnosis and treatment. Our study investigates the role of the JAK/STAT and PPAR-gamma signaling pathways in the progression of multiple sclerosis. Inflammation and demyelination can be caused by dysregulation of these pathways. Modulating the STAT-3, mTOR, and PPAR-gamma signaling pathways may offer therapeutic potential for multiple sclerosis. Matrine (40 and 80 mg/kg, i.p.), a quinolizidine alkaloid derived from Sophora flavescens, has been investigated for its therapeutic potential in our laboratory. Matrine has been studied for its neuroprotective effect in neurodegenerative diseases. It inhibits inflammatory responses and promotes regeneration of damaged myelin sheaths, indicating its potential efficacy in treating multiple sclerosis. Matrine exerts its neuroprotective effect by inhibiting STAT-3 and mTOR and promoting PPAR-gamma expression.GW9662, a PPAR-gamma antagonist (2 mg/kg, i.p.), was administered to evaluate the involvement of PPAR-gamma and to compare the efficacy of matrine's potential neuroprotective effect. Matrine's interaction with the STAT-3, mTOR, and PPAR-gamma pathways in multiple Sclerosis was also validated and confirmed through insilico investigation. In addition, matrine altered the CBC profile, intensifying the clinical presentation of multiple sclerosis. In addition, we evaluated the diagnostic potential of various biological samples, including CSF, blood plasma, and brain homogenates (striatum, cortex, hippocampus, and midbrain). These samples were used to evaluate the neurochemical changes caused by neurobehavioral alterations during the progression of multiple sclerosis. These results indicate that matrine treatment ameliorated multiple sclerosis and that the mechanism underlying these effects may be closely related to the modulation of the STAT-3/mTOR/PPAR-gamma signaling pathway.

L-Citrulline (L-Cit) is discussed to possess a protective effect on intestinal barrier dysfunction but also to diminish aging-associated degenerative processes. Here, the effects of L-Cit on lifespan were assessed in C. elegans, while the effects of L-Cit on aging-associated decline were determined in C57BL/6J mice. For lifespan analysis, C. elegans were treated with ±5 mM L-Cit. Twelve-month-old male C57BL/6J mice (n = 8-10/group) fed a standard chow diet received drinking water ± 2.5 g/kg/d L-Cit or 5 g/kg/d hydrolyzed soy protein (Iso-N-control) for 16 or 32 weeks. Additionally, 4-month-old C57BL/6J mice were treated accordingly for 8 weeks. Markers of senescence, glucose tolerance, intestinal barrier function, and intestinal microbiota composition were analyzed in mice. L-Cit treatment significantly extended the lifespan of C. elegans. The significant increase in markers of senescence and signs of impaired glucose tolerance found in 16- and 20-month-old control mice was attenuated in L-Cit-fed mice, which was associated with protection from intestinal barrier dysfunction and a decrease in NO2- levels in the small intestine, while no marked differences in intestinal microbiota composition were found when comparing age-matched groups. Our results suggest that pharmacological doses of L-Cit may have beneficial effects on lifespan in C. elegans and aging-associated decline in mice.

Menin is a scaffold protein encoded by the Men1 gene, which interacts with various transcriptional proteins to activate or repress cellular processes and is a key mediator in multiple organs. Both liver-specific and hepatocyte-specific Menin deficiency promotes high-fat diet-induced liver steatosis in mice, as well as insulin resistance and type 2 diabetic phenotype. The potential link between Menin and hepatic metabolism homeostasis may provide new insights into the mechanism of fatty liver disease.

Disturbance of hepatic Menin expression impacts metabolic pathways associated with non-alcoholic fatty liver disease (NAFLD), including the FoxO signaling pathway, which is similar to that observed in both oleic acid-induced fatty hepatocytes model and biopsied fatty liver tissues, but with elevated hepatic Menin expression and inhibited FABP1. Higher levels of Menin facilitate glucose uptake while restraining fatty acid uptake. Menin targets the expression of FABP3/4/5 and also CD36 or GK, PCK by binding to their promoter regions, while recruiting and deploying the cellular localization of PPARγ and SIRT1 in the nucleus and cytoplasm. Accordingly, Menin binds to PPARγ and/or FoxO1 in hepatocytes, and orchestrates hepatic glucose and fatty acid uptake by recruiting SIRT1.

Menin plays an orchestration role as a transcriptional activator and/or repressor to target downstream gene expression levels involved in hepatic energy uptake by interacting with the cellular energy sensor SIRT1, PPARγ, and/or FoxO1 and deploying their translocations between the cytoplasm and nucleus, thereby maintaining metabolic homeostasis. These findings provide more evidence suggesting Menin could be targeted for the treatment of hepatic steatosis, NAFLD or metabolic dysfunction-associated fatty liver disease (MAFLD), and even other hepatic diseases.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high invasion and metastasis rates. Xian-Ling-Lian-Xia formula (XLLX) is a traditional Chinese medicine prescription widely used in China for treating TNBC. Clinical studies have shown that XLLX significantly reduces the recurrence and metastasis rate of TNBC and improves disease-free survival. However, the potential molecular mechanisms of XLLX on TNBC are not clear yet. Here, we investigated the effects of XLLX on TNBC using a mouse model and tumor cell lines. The results showed that XLLX significantly inhibited the proliferation, migration, and invasion abilities of TNBC cell lines MDA-MB-231 and 4T1 in vitro, induced apoptosis, and regulated the expression of proliferation, apoptosis, and EMT marker proteins in tumor cells. In in vivo experiments, XLLX treatment significantly reduced the progression of TNBC tumors and lung metastasis. Transcriptomics reveals that XLLX treatment significantly enriched differentially expressed genes in the peroxisome proliferator-activated receptor gamma (PPARγ) and AMP-dependent protein kinase (AMPK) signaling pathways. The western blot results confirmed that XLLX significantly upregulated the protein expression of PPARγ and p-AMPK in TNBC cells, tumors, and lung tissues. It is noteworthy that GW9662 (a PPARγ inhibitor) and Compound C (an AMPK inhibitor) partially reversed the anti-proliferation and anti-metastasis effects of XLLX in TNBC cells. Therefore, XLLX may effectively inhibit the growth and metastasis of TNBC by activating the PPARγ/AMPK signaling pathway.

Patients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates underlying these deficits remain unclear. Here, we show that prenatal and lactation alcohol exposure (PLAE) in mice induces FASD-like memory impairments. This is accompanied by a reduction of N-acylethanolamines (NAEs) and peroxisome proliferator-activated receptor gamma (PPAR-γ) in the hippocampus specifically in a childhood-like period (at post-natal day (PD) 25). To determine their role in memory deficits, two pharmacological approaches were performed during this specific period of early life. Thus, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase NAEs, with GW9662, a PPAR-γ antagonist; ii) pioglitazone, a PPAR-γ agonist. We observed that URB597 suppresses PLAE-induced memory deficits through a PPAR-γ dependent mechanism, since its effects are prevented by GW9662. Direct PPAR-γ activation, using pioglitazone, also ameliorates memory impairments. Lastly, to further investigate the region and cellular specificity, we demonstrate that an early overexpression of PPAR-γ, by means of a viral vector, in hippocampal astrocytes mitigates memory deficits induced by PLAE. Together, our data reveal that disruptions of PPAR-γ signaling during neurodevelopment contribute to PLAE-induced memory dysfunction. In turn, PPAR-γ activation during a childhood-like period is a promising therapeutic approach for memory deficits in the context of early alcohol exposure. Thus, these findings contribute to the gaining insight into the mechanisms that might underlie memory impairments in FASD patients.

p-coumaric acid (p-CA), a common plant phenolic acid with multiple bioactivities, has a lipid-lowering effect. As a dietary polyphenol, its low toxicity, with the advantages of prophylactic and long-term administration, makes it a potential drug for prophylaxis and the treatment of nonalcoholic fatty liver disease (NAFLD). However, the mechanism by which it regulates lipid metabolism is still unclear. In this study, we studied the effect of p-CA on the down-regulation of accumulated lipids in vivo and in vitro. p-CA increased a number of lipase expressions, including hormone-sensitive lipase (HSL), monoacylglycerol lipase (MGL) and hepatic triglyceride lipase (HTGL), as well as the expression of genes related to fatty acid oxidation, including long-chain fatty acyl-CoA synthetase 1 (ACSL1), carnitine palmitoyltransferase-1 (CPT1), by activating peroxisome proliferator-activated receptor α, and γ (PPARα and γ). Furthermore, p-CA promoted adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and enhanced the expression of the mammalian suppressor of Sec4 (MSS4), a critical protein that can inhibit lipid droplet growth. Thus, p-CA can decrease lipid accumulation and inhibit lipid droplet fusion, which are correlated with the enhancement of liver lipases and genes related to fatty acid oxidation as an activator of PPARs. Therefore, p-CA is capable of regulating lipid metabolism and is a potential therapeutic drug or health care product for hyperlipidemia and fatty liver.

Atherosclerosis, a chief pathogenic factor of cardiovascular disease, is associated with many factors including inflammation, dyslipidemia, and oxidative stress. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are widely expressed with tissue- and cell-specificity. They control multiple genes that are involved in lipid metabolism, inflammatory response, and redox homeostasis. Given the diverse biological functions of PPARs, they have been extensively studied since their discovery in 1990s. Although controversies exist, accumulating evidence have demonstrated that PPAR activation attenuates atherosclerosis. Recent advances are valuable for understanding the mechanisms of action of PPAR activation. This article reviews the recent findings, mainly from the year of 2018 to present, including endogenous molecules in regulation of PPARs, roles of PPARs in atherosclerosis by focusing on lipid metabolism, inflammation, and oxidative stress, and synthesized PPAR modulators. This article provides information valuable for researchers in the field of basic cardiovascular research, for pharmacologists that are interested in developing novel PPAR agonists and antagonists with lower side effects as well as for clinicians.

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.

Long-term high-fat diet (HFD) causes insulin resistance, which is a primary etiological factor in the development of obesity and type 2 diabetes mellitus. Impaired insulin clearance is not only a consequence but also a cause of insulin resistance. The kidney is a major site of insulin clearance, where the insulin-degrading enzyme (IDE) plays a vital role in the proximal tubule. Thus, the study investigates the role of renal IDE in the regulation of insulin resistance in HFD-induced obese mice.

Twenty four-weeks of HFD in C57BL/6 mice causes insulin resistance and impaires insulin clearance, accompanied by a decrease in renal IDE expression and activity. Palmitic acid decreases IDE mRNA and protein expressions in HK-2 cells. RNA-Seq analysis found that the PPAR pathway is involved. 24-weeks of HFD decreases renal PPARγ, but not PPARα or PPARβ/δ mRNA expression. The inhibition of IDE expression by palmitic acid is prevented by the PPARγ agonist rosiglitazone. The amount of PPARγ bound to the promoters of IDE is decreased in palmitic acid-treated cells. Rosiglitazone improves insulin clearance and insulin resistance and increases renal IDE expression in HFD fed-mice.

Long-term HFD decreases renal IDE expression and activity, and causes insulin resistance, which involves PPARγ.

Chronic liver disease (CLD) is a continuous process that causes a reduction of liver function lasting more than six months. CLD includes alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), chronic viral infection, and autoimmune hepatitis, which can lead to liver fibrosis, cirrhosis, and cancer. Liver inflammation and oxidative stress are commonly associated with the development and progression of CLD. Molecular signaling pathways such as AMP-activated protein kinase (AMPK), C-Jun N-terminal kinase, and peroxisome proliferator-activated receptors (PPARs) are implicated in the pathogenesis of CLD. Therefore, antioxidant and anti-inflammatory agents from natural products are new potent therapies for ALD, NAFLD, and hepatocellular carcinoma (HCC). In this review, we summarize some powerful products that can be potential applied in all the stages of CLD, from ALD/NAFLD to HCC. The selected agents such as β-sitosterol, curcumin, genistein, and silymarin can regulate the activation of several important molecules, including AMPK, Farnesoid X receptor, nuclear factor erythroid 2-related factor-2, PPARs, phosphatidylinositol-3-kinase, and lysyl oxidase-like proteins. In addition, clinical trials are undergoing to evaluate their efficacy and safety.