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Obesity is a global health problem characterized as an increase in the mass of adipose tissue. Adipogenesis is one of the key pathways that increases the mass of adipose tissue, by which preadipocytes mature into adipocytes through cell differentiation. Peroxisome proliferator-activated receptor γ (PPARγ), the chief regulator of adipogenesis, has been acutely investigated as a molecular target for natural products in the development of anti-obesity treatments. In this review, the regulation of PPARγ expression by natural products through inhibition of CCAAT/enhancer-binding protein β (C/EBPβ) and the farnesoid X receptor (FXR), increased expression of GATA-2 and GATA-3 and activation of the Wnt/β-catenin pathway were analyzed. Furthermore, the regulation of PPARγ transcriptional activity associated with natural products through the antagonism of PPARγ and activation of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) were discussed. Lastly, regulation of mitogen-activated protein kinase (MAPK) by natural products, which might regulate both PPARγ expression and PPARγ transcriptional activity, was summarized. Understanding the role natural products play, as well as the mechanisms behind their regulation of PPARγ activity is critical for future research into their therapeutic potential for fighting obesity.

Peroxisome proliferator-activated receptor gamma (PPARγ), belonging to the nuclear receptor superfamily, is a ligand-dependent transcription factor involved in a variety of pathophysiological conditions such as inflammation, metabolic disorders, cardiovascular disease, and cancers. In this latter context, PPARγ is expressed in many tumors including breast cancer, and its function upon binding of ligands has been linked to the tumor development, progression, and metastasis. Over the last decade, much research has focused on the potential of natural agonists for PPARγ including fatty acids and prostanoids that act as weak ligands compared to the strong and synthetic PPARγ agonists such as thiazolidinedione drugs. Both natural and synthetic compounds have been implicated in the negative regulation of breast cancer growth and progression. The aim of the present review is to summarize the role of PPARγ activation in breast cancer focusing on the underlying cellular and molecular mechanisms involved in the regulation of cell proliferation, cell cycle, and cell death, in the modulation of motility and invasion as well as in the cross-talk with other different signaling pathways. Besides, we also provide an overview of the in vivo breast cancer models and clinical studies. The therapeutic effects of natural and synthetic PPARγ ligands, as antineoplastic agents, represent a fascinating and clinically a potential translatable area of research with regards to the battle against cancer.

Daqinjiao decoction (DQJD), an ancient traditional Chinese medicine formula, is clinically used in the treatment of cerebral small vessel disease (CSVD). However, the underlying molecular mechanisms by which DQJD exerts its therapeutic effects on CSVD remain elusive. A Sprague Dawley rat model of chronic cerebral hypoperfusion (CCH) was established using bilateral common carotid artery occlusion (BCCAO) surgery. The effects of DQJD administered via intragastric gavage (i.g.) were evaluated by magnetic resonance imaging (MRI), haematoxylin eosin (HE) staining, and transmission electron microscopy. A combined strategy of transcriptomics and network pharmacology was innovatively applied to study the active ingredients, gene targets, and mechanisms of DQJD in treating CSVD. Molecular docking, real‐time quantitative polymerase chain reaction (RT‐qPCR), and Western blot analysis were applied to confirm the above results further. DQJD improved the pathological damage in cortical and hippocampal tissue by reducing the release of inflammatory factors in CCH rats. RNA‐seq technology identified 46 DEGs between DQJD treatment and the model group. Network pharmacology and pathway analysis of DEGs revealed that the PPAR/VEGF signalling pathway was predicted to be significantly affected. Consistently, validation experiments confirmed that activation of the RXR‐γ/PPAR‐γ/VEGF‐α signalling pathway represents a key mechanism underlying DQJD's therapeutic effects against CSVD. DQJD dampened inflammation and ameliorated pathological damage in the hippocampus and cortex, and these beneficial effects were associated with neurovascular protection via activating the RXR‐γ/PPAR‐γ/VEGF‐α pathway.

Peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ) agonists have anti-inflammatory and anti-neovascularization effects, but few reports have tested the combination of PPARα and PPARγ agonists. In this study, we investigated the therapeutic effects of ophthalmic solutions of agonists of PPARα, PPARγ, and the combination in a rat corneal alkali burn model. After alkali injury, an ophthalmic solution of 0.05% fenofibrate (PPARα group), 0.1% pioglitazone (PPARγ group), 0.05% fenofibrate + 0.1% pioglitazone (PPARα+γ group), or vehicle (vehicle group) was topically instilled onto the rat’s cornea twice a day. After instillation, upregulation was seen of PPAR mRNA corresponding to each agonist group. Administration of agonists for PPARα, PPARγ, and PPARα+γ suppressed inflammatory cells, neovascularization, and fibrotic changes. In addition, the PPARγ agonist upregulated M2 macrophages, which contributed to wound healing, whereas the PPARα agonist suppressed immature blood vessels in the early phase. Administration of PPARα+γ agonists showed therapeutic effects in corneal wound healing, combining the characteristics of both PPARα and PPARγ agonists. The results indicate that the combination of PPARα and γ agonists may be a new therapeutic strategy.

The cytokine storm is an abnormal production of inflammatory cytokines, due to the over-activation of the innate immune response. This mechanism has been recognized as a critical mediator of influenza-induced lung disease, and it could be pivotal for COVID-19 infections. Thus, an immunomodulatory approach targeting the over-production of cytokines could be proposed for viral aggressive pulmonary disease treatment. In this regard, the peroxisome proliferator-activated receptor (PPAR)-γ, a member of the PPAR transcription factor family, could represent a potential target. Beside the well-known regulatory role on lipid and glucose metabolism, PPAR-γ also represses the inflammatory process. Similarly, the PPAR-γ agonist thiazolidinediones (TZDs), like pioglitazone, are anti-inflammatory drugs with ameliorating effects on severe viral pneumonia. In addition to the pharmacological agonists, also nutritional ligands of PPAR-γ, like curcuma, lemongrass, and pomegranate, possess anti-inflammatory properties through PPAR-γ activation. Here, we review the main synthetic and nutritional PPAR-γ ligands, proposing a dual approach based on the strengthening of the immune system using pharmacological and dietary strategies as an attempt to prevent/treat cytokine storm in the case of coronavirus infection.

Purpose: Increasing evidence supported that semaphorin 3A (Sema3A), insulin-like growth factor (IGF)-1 and β-catenin were involved in the development of osteoporosis and diabetes. This study is aimed to evaluate whether Sema3A/IGF-1/β-catenin is directly involved in the alterations of bone microarchitecture and bone strength of diabetic rats. Methods: Diabetic rats were induced by streptozotocin and high fat diet exposure. Bone microarchitecture and strength in the femurs were evaluated by micro-CT scanning, three-point bending examination and the stainings of HE, alizarin red S and safranin O/fast green, respectively. The alterations of lumbar spines microarchitecture were also determined by micro-CT scanning. Western blot and immunohistochemical analyses were used to examine the expression of Sema3A, β-catenin, IGF-1, peroxisome proliferator-activated receptor γ (PPARγ) and cathepsin K in rat tibias. Results: Diabetic rats exhibited decreased trabecular numbers and bone formation, but an increased trabecular separation in the femurs and lumbar spines. Moreover, the increased bone fragility and decreased bone stiffness were evident in the femurs of diabetic rats. Diabetic rats also exhibited a pronounced bone phenotype which manifested by decreased expression of Sema3A, IGF-1 and β-catenin, as well as increased expression of cathepsin K and PPARγ. Conclusions: This study suggests that diabetes could perturb bone loss through the Sema3A/IGF-1/β-catenin pathway. Sema3A deficiency in bone may contribute to upregulation of PPARγ and cathepsin K expression, which further disrupts bone remodeling in diabetic rats.

This study aimed to investigate the protective effects and underlying mechanisms of cistanche on sevoflurane‐induced aged cognitive dysfunction rat model. Aged (24 months) male SD rats were randomly assigned to four groups: control group, sevoflurane group, control + cistanche and sevoflurane + cistanche group. Subsequently, inflammatory cytokine levels were measured by ELISA, and the cognitive dysfunction of rats was evaluated by water maze test, open‐field test and the fear conditioning test. Three days following anaesthesia, the rats were killed and hippocampus was harvested for the analysis of relative biomolecules. The oxidative stress level was indicated as nitrite and MDA concentration, along with the SOD and CAT activity. Finally, PPAR‐γ antagonist was used to explore the mechanism of cistanche in vivo. The results showed that after inhaling the sevoflurane, 24‐ but not 3‐month‐old male SD rats developed obvious cognitive impairments in the behaviour test 3 days after anaesthesia. Intraperitoneal injection of cistanche at the dose of 50 mg/kg for 3 consecutive days before anaesthesia alleviated the sevoflurane‐induced elevation of neuroinflammation levels and significantly attenuated the hippocampus‐dependent memory impairments in 24‐month‐old rats. Cistanche also reduced the oxidative stress by decreasing nitrite and MDA while increasing the SOD and CAT activity. Moreover, such treatment also inhibited the activation of microglia. In addition, we demonstrated that PPAR‐γ inhibition conversely alleviated cistanche‐induced protective effect. Taken together, we demonstrated that cistanche can exert antioxidant, anti‐inflammatory, anti‐apoptosis and anti‐activation of microglia effects on the development of sevoflurane‐induced cognitive dysfunction by activating PPAR‐γ signalling.

Liver fibrosis is a necessary stage in the development of chronic liver diseases to liver cirrhosis. This study aims to investigate the anti‐fibrotic effects of levo‐tetrahydropalmatine (L‐THP) on hepatic fibrosis in mice and cell models and its underlying mechanisms. Two mouse hepatic fibrosis models were generated in male C57 mice by intraperitoneal injection of carbon tetrachloride (CCl4) for 2 months and bile duct ligation (BDL) for 14 days. Levo‐tetrahydropalmatine was administered orally at doses of 20 and 40 mg/kg. An activated LX2 cell model induced by TGF‐β1 was also generated. The results showed that levo‐tetrahydropalmatine alleviated liver fibrosis by inhibiting the formation of extracellular matrix (ECM) and regulating the balance between TIMP1 and MMP2 in the two mice liver fibrosis models and cell model. Levo‐tetrahydropalmatine inhibited activation and autophagy of hepatic stellate cells (HSCs) by modulating PPARγ/NF‐κB and TGF‐β1/Smad pathway in vivo and in vitro. In conclusion, levo‐tetrahydropalmatine attenuated liver fibrosis by inhibiting ECM deposition and HSCs autophagy via modulation of PPARγ/NF‐κB and TGF‐β1/Smad pathway.

Background Neuroinflammation and oxidative stress, mediated by microglial activation, hinder the development of oligodendrocytes (OLs) and delay myelination in preterm infants, leading to white matter injury (WMI) and long‐term neurodevelopmental sequelae. Peroxisome proliferator‐activated receptor gamma (PPAR‐γ) has been reported to inhibit inflammation and oxidative stress via modulating microglial polarization in various central nervous system diseases. However, the relationship between PPAR‐γ and microglial polarization in neonatal WMI is not well understood. Therefore, this study aimed to elucidate the role and mechanisms of PPAR‐γ in preterm infants affected by WMI. Methods In this study, an in vivo hypoxia‐ischemia (HI) induced brain WMI neonatal mouse model was established. The mice were administered intraperitoneally with either RSGI or GW9662 to activate or inhibit PPAR‐γ, respectively. Additionally, an in vitro oxygen–glucose deprivation (OGD) cell model was established and pretreated with pcDNA 3.1‐PPAR‐γ or si‐PPAR‐γ to overexpress or silence PPAR‐γ, respectively. The neuroprotective effects of PPAR‐γ were investigated in vivo. Firstly, open field test, novel object recognization test, and beam‐walking test were employed to assess the effects of PPAR‐γ on neurobehavioral recovery. Furthermore, assessment of OLs loss and OL‐maturation disorder, the number of myelinated axons, myelin thickness, synaptic deficit, activation of microglia and astrocyte, and blood–brain barrier (BBB) were used to evaluate the effects of PPAR‐γ on pathological repair. The mechanisms of PPAR‐γ were explored both in vivo and in vitro. Assessment of microglia polarization, inflammatory mediators, reactive oxygen species (ROS), MDA, and antioxidant enzymes was used to evaluate the anti‐inflammatory and antioxidative effects of PPAR‐γ activation. An assessment of HMGB1/NF‐κB and NRF2/KEAP1 signaling pathway was conducted to clarify the mechanisms by which PPAR‐γ influences HI‐induced WMI in neonatal mice. Results Activation of PPAR‐γ using RSGI significantly mitigated BBB disruption, promoted M2 polarization of microglia, inhibited activation of microglia and astrocytes, promoted OLs development, and enhanced myelination in HI‐induced WMI. Conversely, inhibition of PPAR‐γ using GW9662 further exacerbated the pathologic hallmark of WMI. Neurobehavioral tests revealed that neurological deficits were ameliorated by RSGI, while further aggravated by GW91662. In addition, activation of PPAR‐γ significantly alleviated neuroinflammation and oxidative stress by suppressing HMGB1/NF‐κB signaling pathway and activating NRF2 signaling pathway both in vivo and in vitro. Conversely, inhibition of PPAR‐γ further exacerbated HI or OGD‐induced neuroinflammation, oxidative stress via modulation of the same signaling pathway. Conclusions Our findings suggest that PPAR‐γ regulates microglial activation/polarization as well as subsequent neuroinflammation/oxidative stress via the HMGB1/NF‐κB and NRF2/KEAP1 signaling pathway, thereby contributing to neuroprotection and amelioration of HI‐induced WMI in neonatal mice. Our findings suggest that PPAR‐γ regulates microglial activation/polarization as well as subsequent neuroinflammation/oxidative stress via the HMGB1/NF‐κB and NRF2 signaling pathway, thereby contributing to myelination and amelioration of WMI after HI insult in neonatal mice.

Sirtuins, especially SIRT1, play a significant role in regulating inflammatory response, autophagy, and cell response to oxidative stress. Since their discovery, sirtuins have been regarded as anti-ageing and longevity-promoting enzymes. Sirtuin-regulated processes seem to participate in the most prevalent placental pathologies, such as pre-eclampsia. Furthermore, more and more research studies indicate that SIRT1 may prevent pre-eclampsia development or at least alleviate its manifestations. Having considered this, we reviewed recent studies on the role of sirtuins, especially SIRT1, in processes determining normal or abnormal development and functioning of the placenta.