The pharmacological effects of pomegranates have been described considering metabolic aspects such as hypoglycemic and hypolipidemic activities. The pomegranate extract has activity on the central nervous system (CNS) as a natural antidepressant and anxiolytic. The chemical composition of pomegranates is complex since the bioactive compounds are multiple secondary metabolites that have been identified in the extracts derived from the peel, seed, flowers, leaves, or in their combination; so, it has not been easy to identify an individual compound as responsible for its observed pharmacological properties. From this point of view, the present review analyzes the effects of crude extracts or fractions of pomegranates and their possible mechanisms of action concerning antidepressant- and anxiolytic-like effects in animal models. Serotonin receptors, estrogen receptors, the peroxisome proliferator-activated receptor gamma (PPARγ), or monoamine oxidase enzymes, as well as potent antioxidant and neuroplasticity properties, have been described as possible mediators involved in the antidepressant- and anxiolytic-like behaviors after pomegranate treatment. The pharmacological effects observed on the CNS in experimental models associated with a specific stress level suggest that pomegranates could simultaneously modulate the stress response by activating several targets. For the present review, scientific evidence was gathered to integrate it and suggest a possible pathway for mediators to be involved in the mechanisms of action of the pomegranate\'s antidepressant- and anxiolytic-like effects. Furthermore, the potential benefits are discussed on comorbid conditions with anxiety and depression, such as perimenopause transition and pain.

BACKGROUND: This study presents the clinical and genetic mutation characteristics of an unusual case of adult-onset diabetes mellitus occurring in adolescence, featuring a unique mutation in the peroxisome proliferator-activated receptor gamma (PPARG) gene. Data Access Statement: Research data supporting this publication are available from the NN repository at www.NNN.org/download/.
METHODS: The methodology employed entailed meticulous collection of comprehensive clinical data from the probands and their respective family members. Additionally, high-throughput sequencing was conducted to analyze the PPARG genes of the patient, her siblings, and their offspring. The results of this investigation revealed that the patient initially exhibited elevated blood glucose levels during pregnancy, accompanied by insulin resistance and hypertriglyceridemia. Furthermore, these strains displayed increased susceptibility to diabetic kidney disease without any discernible aggregation patterns. The results from the gene detection process demonstrated a heterozygous mutation of guanine (G) at position 284 in the coding region of exon 2 of PPARG, which replaced the base adenine (A) (exon2c.284A>Gp.Tyr95Cys). This missense mutation resulted in the substitution of tyrosine with cysteine at the 95th position of the translated protein. Notably, both of her siblings harbored a nucleotide heterozygous variation at the same site, and both were diagnosed with diabetes.
CONCLUSIONS: The PPARG gene mutation, particularly the p.Tyr95Cys mutation, may represent a newly identified subtype of maturity-onset diabetes of the young. This subtype is characterized by insulin resistance and lipid metabolism disorders.

Postnatal hippocampal neurogenesis is essential for learning and memory. Hippocampal neural precursor cells (NPCs) can be induced to proliferate and differentiate into either glial cells or dentate granule cells. Notably, hippocampal neurogenesis decreases dramatically with age, partly due to a reduction in the NPC pool and a decrease in their proliferative activity. Alpha-melanocyte-stimulating hormone (α-MSH) improves learning, memory, neuronal survival and plasticity. Here, we used postnatally-isolated hippocampal NPCs from Wistar rat pups (male and female combined) to determine the role of the melanocortin analog [Nle4, D-Phe7]-α-MSH (NDP-MSH) in proliferation and fate acquisition of NPCs. Incubation of growth-factor deprived NPCs with 10 nM NDP-MSH for 6 days increased the proportion of Ki-67- and 5-bromo-2\'-deoxyuridine (BrdU)-positive cells, compared to the control group, and these effects were blocked by the MC4R antagonist JKC-363. NDP-MSH also increased the proportion of glial fibrillar acidic protein (GFAP)/Ki-67, GFAP/sex-determining region Y-box2 (SOX2) and neuroepithelial stem cell protein (NESTIN)/Ki-67-double positive cells (type-1 and type-2 precursors). Finally, NDP-MSH induced peroxisome proliferator-activated receptor (PPAR)-γ protein expression, and co-incubation with the PPAR-γ inhibitor GW9662 prevented the effect of NDP-MSH on NPC proliferation and differentiation. Our results indicate that in vitro activation of MC4R in growth-factor-deprived postnatal hippocampal NPCs induces proliferation and promotes the relative expansion of the type-1 and type-2 NPC pool through a PPAR-γ-dependent mechanism. These results shed new light on the mechanisms underlying the beneficial effects of melanocortins in hippocampal plasticity and provide evidence linking the MC4R and PPAR-γ pathways in modulation of hippocampal NPC proliferation and differentiation.

Bisphenol A (BPA) and bisphenol B (BPB) are widely used in the production of plastics, and their potential adverse health effects, particularly on endocrine disruption and metabolic health, have raised concern. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a pivotal role in metabolic regulation and adipogenesis, making it a target of interest in understanding the development of obesity and associated health impacts. In this study, we employ X-ray crystallography and molecular dynamics (MD) simulations to study the interaction of PPARγ with BPA and BPB. Crystallographic structures reveal the binding of BPA and BPB to the ligand binding domain of PPARγ, next to C285, where binding of partial agonists as well as antagonists and inverse agonists of PPARγ signaling has been previously observed. However, no interaction of BPA and BPB with Y437 in the activation function 2 site is observed, showing that these ligands cannot stabilize the active conformation of helix 12 directly. Furthermore, free energy analyses of the MD simulations revealed that I341 has a large energetic contribution to the BPA and BPB binding modes characterized in this study.

BACKGROUND: Meibomian gland dysfunction (MGD), complicated by type 2 diabetes, is associated with a high incidence of ocular surface disease, and no effective drug treatment exists. Diabetes mellitus (DM) MGD shows a notable disturbance in lipid metabolism. Er-Dong-Xiao-Ke decoction (EDXKD) has important functions in nourishing yin, clearing heat, and removing blood stasis, which are effective in the treatment of DM MGD.
OBJECTIVE: To observe the therapeutic effect of EDXKD on DM MGD and its underlying molecular mechanism.
METHODS: After establishing a type 2 DM (T2DM)-induced MGD rat model, different doses of EDXKD and T0070907 were administered. The chemical constituents of EDXKD were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the molecular mechanism of EDXKD in treating DM MGD was predicted using network pharmacology. Lipid metabolism in DM meibomian glands (MGs) was analyzed using LC-MS/MS, and lipid biomarkers were screened and identified. Histological changes and lipid accumulation in MGs were detected by staining, and Peroxisome proliferator-activated receptor gamma (PPARG) expression in MG acinar cells was detected by immunofluorescence. The expression of lipid metabolism-related factors was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or western blotting.
RESULTS: EDXKD reduced lipid accumulation in the MGs and improved the ocular surface index in DM MGD rats. The main active components of EDXKD had advantages in lipid regulation. Additionally, the PPARG signaling pathway was the key pathway of EDXKD in the treatment of DM MGD. Twelve lipid metabolites were biomarkers of EDXKD in the treatment of DM MGD, and glycerophospholipid metabolism was the main pathway of lipid regulation. Moreover, EDXKD improved lipid deposition in the acini and upregulated the expression of PPARG. Further, EDXKD regulated the PPARG-mediated UCP2/AMPK signaling network, inhibited lipid production, and promoted lipid transport.
CONCLUSIONS: EDXKD is an effective treatment for MGD in patients with T2DM. EDXKD can regulate lipids by regulating the PPARG-mediated UCP2/AMPK signaling network, as it reduced lipid accumulation in the MGs of DM MGD rats, promoted lipid metabolism, and improved MG function and ocular surface indices.

Chronic pain often coincides with changes in gut microbiota composition. Yet, the role of gut microbiota in bone cancer pain (BCP) is still not fully understood. This study investigated the role of gut microbiota in BCP and the effect of oxymatrine (OMT) on gut microbiota in BCP. A BCP mice model was developed to assess gut microbiota composition, serum and brain tissue butyric acid levels, and blood-brain barrier (BBB) permeability. Microbiota transplantation was used to restore gut microbiota, and the effect of Clostridium butyricum or sodium butyrate (NaB) supplementation on pain-related behaviors and BBB integrity was evaluated. The potential benefits of OMT on gut microbiota composition, peroxisome proliferator-activated receptor gamma (PPARγ)/cyclooxygenase-2 (COX-2) signaling, BBB integrity, and pain-related behaviors were also explored. BCP significantly altered gut microbiota composition and reduced serum and brain tissue butyric acid levels. Additionally, BBB permeability increased considerably in the BCP group compared with sham and control mice. Microbiota transplantation, as well as C butyricum or NaB supplementation, ameliorated pain-related behaviors and BBB integrity; the supplementation of C butyricum or NaB boosted brain-tight-junction protein expression, potentially through modulating PPARγ/COX-2 signaling. OMT influenced gut microbiota composition and regulated PPARγ/COX-2 signaling in the BCP model, improving pain-related behaviors and BBB integrity. BCP affects gut microbiota composition and butyric acid levels. Modulating gut microbiota and butyric acid levels through transplantation or supplementation may alleviate BCP. OMT shows potential as a treatment by altering gut microbiota composition and regulating PPARγ/COX-2 signaling. These findings provide new insights into BCP pathophysiology and possible treatments. PERSPECTIVE: This study explores the impact of gut microbiota on BCP. Microbiota transplantation alleviates BCP and enhances BBB integrity. Also, C butyricum or NaB improves BBB via PPARγ/COX-2. OMT, a BCP treatment, modifies microbiota by regulating PPARγ/COX-2, in turn improving pain and BBB integrity. These findings suggest a therapeutic approach, emphasizing clinical relevance in targeting gut microbiota and restoring butyric acid levels.

Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is widely used in many commercial products. The United States Environmental Protection Agency has listed TPhP as a priority compound that requires health risk assessment. We previously found that TPhP could accumulate in the placentae of mice and impair birth outcomes by activating peroxisome proliferator-activated receptor gamma (PPARγ) in the placental trophoblast. However, the underlying mechanism remains unknown. In this study, we used a mouse intrauterine exposure model and found that TPhP induced preeclampsia (PE)-like symptoms, including new on-set gestational hypertension and proteinuria. Immunofluorescence analysis showed that during placentation, PPARγ was mainly expressed in the labyrinth layer and decidua of the placenta. TPhP significantly decreased placental implantation depth and impeded uterine spiral artery remodeling by activating PPARγ. The results of the in vitro experiments confirmed that TPhP inhibited extravillous trophoblast (EVT) cell migration and invasion by activating PPARγ and inhibiting the PI3K-AKT signaling pathway. Overall, our data demonstrated that TPhP could activate PPARγ in EVT cells, inhibit cell migration and invasion, impede placental implantation and uterine spiral artery remodeling, then induce PE-like symptom and impair birth outcomes. Although the exposure doses used in this study was several orders of magnitude higher than human daily intake, our study highlights the placenta as a potential target organ of TPhP worthy of further research.

Lung cancer is one of the most lethal malignancies worldwide. Peroxisome proliferator-activated receptor gamma (PPARγ, NR1C3) is a ligand-activated transcriptional factor that governs the expression of genes involved in glucolipid metabolism, energy homeostasis, cell differentiation, and inflammation. Multiple studies have demonstrated that PPARγ activation exerts anti-tumor effects in lung cancer through regulation of lipid metabolism, induction of apoptosis, and cell cycle arrest, as well as inhibition of invasion and migration. Interestingly, PPARγ activation may have pro-tumor effects on cells of the tumor microenvironment, especially myeloid cells. Recent clinical data has substantiated the potential of PPARγ agonists as therapeutic agents for lung cancer. Additionally, PPARγ agonists also show synergistic effects with traditional chemotherapy and radiotherapy. However, the clinical application of PPARγ agonists remains limited due to the presence of adverse side effects. Thus, further research and clinical trials are necessary to comprehensively explore the actions of PPARγ in both tumor and stromal cells and to evaluate the in vivo toxicity. This review aims to consolidate the molecular mechanism of PPARγ modulators and to discuss their clinical prospects and challenges in tackling lung cancer.

Liver can sense the nutrient status and send signals to other organs to regulate overall metabolic homoeostasis. Herein, we demonstrate that ketone bodies act as signals released from the liver that specifically determine the distribution of excess lipid in epididymal white adipose tissue (eWAT) when exposed to a ketogenic diet (KD). An acute KD can immediately result in excess lipid deposition in the liver. Subsequently, the liver sends the ketone body β-hydroxybutyrate (BHB) to regulate white adipose expansion, including adipogenesis and lipogenesis, to alleviate hepatic lipid accumulation. When ketone bodies are depleted by deleting 3-hydroxy-3-methylglutaryl-CoA synthase 2 gene in the liver, the enhanced lipid deposition in eWAT but not in inguinal white adipose tissue is preferentially blocked, while lipid accumulation in liver is not alleviated. Mechanistically, ketone body BHB can significantly decrease lysine acetylation of peroxisome proliferator-activated receptor gamma in eWAT, causing enhanced activity of peroxisome proliferator-activated receptor gamma, the key adipogenic transcription factor. These observations suggest that the liver senses metabolic stress first and sends a corresponding signal, that is, ketone body BHB, to specifically promote eWAT expansion to adapt to metabolic challenges.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Riboflavin, one of water soluble vitamins, plays a role in lipid metabolism and antioxidant function. However, the effects of riboflavin deficiency on NAFLD development have not yet to be fully explored.
METHODS: In the present study, an animal model of NAFLD was induced by high fat diet feeding in mice and a cellular model of NAFLD was developed in HepG2 cells by palmitic acid (PA) exposure. The effects of riboflavin deficiency on lipid metabolism and antioxidant function were investigated both in vivo and in vitro. In addition, the possible role of peroxisome proliferator-activated receptor gamma (PPARγ) was studied in HepG2 cells using gene silencing technique.
RESULTS: The results showed that riboflavin deficiency led to hepatic lipid accumulation in mice fed high fat diet. The expressions of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1) were up-regulated, whereas that of adipose triglyceride lipase (ATGL) down-regulated. Similar changes in response to riboflavin deficiency were demonstrated in HepG2 cells treated with PA. Factorial analysis revealed a significant interaction between riboflavin deficiency and high dietary fat or PA load in the development of NAFLD. Hepatic PPARγ expression was significantly upregulated in mice fed riboflavin deficient and high fat diet or in HepG2 cells treated with riboflavin deficiency and PA load. Knockdown of PPARγ gene resulted in a significant reduction of lipid accumulation in HepG2 cells exposed to riboflavin deficiency and PA load.
CONCLUSIONS: There is a synergetic action between riboflavin deficiency and high dietary fat on the development of NAFLD, in which PPARγ may play an important role.