Crocin Ameliorates Diabetic Nephropathy through Regulating Metabolism, CYP4A11/PPARγ, and TGF-ß/Smad Pathways in Mice.

INTRODUCTION: Crocin is one of the main components of Crocus sativus L. and can alleviate oxidative stress and inflammation in diabetic nephropathy (DN). However, the specific mechanism by which crocin treats DN still needs to be further elucidated. METHOD: In the present study, a mouse model of DN was first established to investigate the therapeutic effect of crocin on DN mice. Subsequently, non-targeted metabolomics techniques were used to analyze the mechanisms of action of crocin in the treatment of DN. The effects of crocin on CYP4A11/PPARγ and TGF-ß/Smad pathway were also investigated. RESULT: Results showed that crocin exhibited significant therapeutic and anti-inflammatory, and anti-oxidative effects on DN mice. In addition, the non-targeted metabolomics results indicated that crocin treatment affected several metabolites in kidney. These metabolites were mainly associated with biotin metabolism, riboflavin metabolism, and arachidonic acid metabolism. Furthermore, crocin treatment upregulated the decreased levels of CYP4A11 and phosphorylated PPARγ, and reduced the increased levels of TGF-ß1 and phosphorylated Smad2/3 in the kidneys of DN mice. CONCLUSION: In conclusion, our study validated the considerable therapeutic, anti-inflammatory, and antioxidative impacts of crocin on DN mice. The mechanism of crocin treatment may be related to the regulation of biotin riboflavin and arachidonic acid metabolism, the activation of CYP4A11/PPARγ pathway, and the inhibition of TGF-ß/Smad pathway in the kidney.

Evaluation of antiobesity and hepatorenal protective activities of Salvia officinalis extracts pre-treatment in high-fat diet-induced obese rats.

The present study evaluated the effects of Hail Salvia officinalis total extract (SOTE) and its high flavonoid fraction (SOHFF) on the high-fat diet (HFD)-induced obesity and hepatorenal damage in rats. Salvia officinalis plants were collected from Hail region, Saudi Arabia. Rats were fed HFD and supplemented orally with SOTE (250 mg kg-1) or SOHFF (100 mg kg-1) or simvastatin (SVS; 10 mg kg-1) every day for 8 weeks. Compared to the controls, HFD-induced obesity led to significant increases in body weight, body weight gained, blood insulin, leptin, cardiac enzymes (LDH and CPK) activity, and atherogenic index (AI). HFD rats also showed higher levels of hepatic and renal function biomarkers (ALT, urea, and creatinine), as well as lower levels of PPARγ and Nrf2-gene expression and a disrupted lipid profile. Moreover, HFD rats had lower levels of hepatic and renal antioxidant biomarkers (CAT, GPx, SOD, GR, and GSH), accompanied by higher levels of hepatic and renal lipid peroxidation (LPO), nitric oxide (NO), and inflammatory mediators (interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α)). In addition, histological examination of hepatic and renal tissues revealed histopathological changes that validated the biochemical findings. Compared to HFD group, SOTE and SOHFF treatment led to marked amelioration of all the aforementioned parameters. Collectively, supplementation with SOTE and SOHFF effectively reversed HFD-induced alterations through its antioxidant, hypolipidemic, and anti-inflammatory properties. Hence, SOTE and SOHFF have therapeutic potential in controlling obesity and related pathologies.

PPARγ receptors are involved in the effects of cannabidiol on orofacial dyskinesia and cognitive dysfunction induced by typical antipsychotic in mice.

Tardive dyskinesia (TD) is a movement disorder that appears after chronic use of drugs that block dopaminergic receptors such as antipsychotics. Besides the motor symptoms, patients with TD also present cognitive deficits. Neuroinflammatory mechanisms could be involved in the development of these symptoms. A previous study showed that cannabidiol (CBD), the major non-psychotomimetic compound of Cannabis sativa plant, prevents orofacial dyskinesia induced by typical antipsychotics by activating peroxisome proliferator-activated receptors gamma (PPARγ). Here, we investigated if CBD would also reverse haloperidol-induced orofacial dyskinesia and associated cognitive deficits. We also verified if these effects depend on PPARγ receptor activation. Daily treatment with haloperidol (3 mg/kg, 21 days) increased the frequency of vacuous chewing movements (VCM) and decreased the discrimination index in the novel object recognition test in male Swiss mice. CBD (60 mg/kg/daily) administered in the last 7 days of haloperidol treatment attenuated both behavioral effects. Furthermore, haloperidol increased IL-1ß and TNF-α levels in the striatum and hippocampus while CBD reverted these effects. The striatal and hippocampal levels of proinflammatory cytokines correlated with VCM frequency and discrimination index, respectively. Pretreatment with the PPARγ antagonist GW9662 (2 mg/kg/daily) blocked the behavioral effects of CBD. In conclusion, these results indicated that CBD could attenuate haloperidol-induced orofacial dyskinesia and improve non-motor symptoms associated with TD by activating PPARγ receptors.

B-ring-homo-tonghaosu, isolated from Chrysanthemum morifolium capitulum, acts as a peroxisome proliferator-activated receptor-γ agonist.

The capitula of Chrysanthemum morifolium and C. indicum are used to prepare Chrysanthemi Flos in traditional Japanese Kampo medicine. In our previous study, we reported on the agonistic effect of methanol extract of C. indicum capitulum on peroxisome proliferator-activated receptor (PPAR)-γ. We further isolated (E)-tonghaosu from C. indicum capitulum as one of the active ingredients. In the present study, we aimed to evaluate the PPAR-γ agonistic activity of a methanol extract of C. morifolium capitulum (MCM) in which (E)-tonghaosu could not be detected. MCM exhibited PPAR-γ agonistic activity in a concentration-dependent manner, and at a dose of 100 µg/ml, it showed similar activity to pioglitazone (30 µM), a standard PPAR-γ agonist. Through activity-guided fractionation, we isolated two geometric isomers, (E)- (1) and (Z)-B-ring-homo-tonghaosu (2), as the active ingredients of MCM. Both compounds exerted concentration-dependent PPAR-γ agonistic effects, and 1 had higher activity than 2. At 1.4 µM, 1 had similar activity to pioglitazone (30 µM), which was achieved by 2 at a concentration of 140 µM. Thus, 1 has the potential to become a lead compound for the drug discovery of PPAR-γ agonists. We compared the activities and the contents of (E)-, (Z)-tonghaosu, 1, and 2 among 13 commercial samples of Chrysanthemi Flos, including those derived from both C. morifolium and C. indicum. Their PPAR-γ agonistic activities were not related to the contents of these compounds. 1 and 2 were detected in the samples derived from both species but (E)- and (Z)-tonghaosu were not detected in the samples derived from C. morifolium; hence (E)- and (Z)-tonghaosu can serve as marker compounds to identify the capitula of C. indicum in Chrysanthemi Flos samples.

5,4'-Dihydroxy-7,8-dimethoxyflavanone and Aliarin from Dodonaea viscosa Are Activators of PPARγ.

PPARγ agonists are widely used medications in diabetes mellitus therapy. Their role in improving adipose tissue function contributes to antidiabetic effects. The extracts of Dodonaea viscosa have been reported to exert antidiabetic activity. However, the effective mediators and the underlying mechanisms were largely unknown. In this study, we investigated the action on PPARγ transactivation and adipocyte modulation of two typical flavonoid constituents from D. viscosa, 5,4'-dihydroxy-7,8-dimethoxyflavanone and aliarin. Our results showed that 5,4'-dihydroxy-7,8-dimethoxyflavanone and aliarin were potential partial PPARγ agonists. The compounds induced adipogenesis in 3T3-L1 cells, with an upregulated adiponectin mRNA level and enhanced insulin sensitivity. The favorable effects of 5,4'-dihydroxy-7,8-dimethoxyflavanone, aliarin, and other flavonoid constituents on adipocytes might contribute to the antidiabetic efficacy of D. viscosa.

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling leading to right ventricular hypertrophy (RVH) and failure. Peroxisome proliferator-activated receptor γ (PPARγ), a member of nuclear receptors, has been proved to ameliorate PAH. However, its effect on PAH-induced right ventricular failure (RVF) remains unknown. Therefore, we investigated the therapeutic potential of PPARγ in preventing monocrotaline (MCT)-induced RV dysfunction. The PAH model was induced by MCT administration. Male rats were administered with MCT to develop PAH and RVF formed by approximately day 30. Significant increase in RV area, RVAW resulted in an ascending RV index. However, the LV function including EF, FS, and LVID did not change significantly. PPARγ agonist prevented PAH-induced RVF by preserving RV index and preventing RVH. PPARγ's beneficial effects seem to result from various factors, including anti-apoptosis, preservation RV index, reversal of inflammation, improvement of glucolipid metabolism, reduction of ROS. In a word, PPARγ agonist prevents the development of RVF.

Adenovirus-mediated peroxisome proliferator activated receptor gamma overexpression prevents nutritional fibrotic steatohepatitis in mice.

OBJECTIVE: The pathogenesis of non-alcoholic steatohepatitis is still unclear. We have demonstrated previously that peroxisome proliferator activated receptor gamma (PPARγ) ligand protects against inflammation and fibrogenesis in experimental non-alcoholic steatohepatitis. We aim to elucidate the effect and the mechanism of PPARγ itself on nutritional fibrotic steatohepatitis in mice. METHODS: C57BL/6J mice were fed with methionine-choline deficient (MCD) diet for 8 weeks to induce fibrotic steatohepatitis. Mice fed the MCD diet were treated with adenovirus carrying PPARγ (Ad-PPARγ), Ad-PPARγ plus PPARγ agonist rosiglitazone, or PPARγ antagonist 2-chloro-5-nitrobenzaniliden (GW9662), respectively. The effects of up-regulation of PPARγ in the presence or absence of its agonist/or antagonist were assessed by comparing the severity of hepatic injury, activation of hepatic stellate cells and the expression of adiponectin, heme oxygenase-1, and fibrogenic related genes. RESULTS: Mice fed with MCD diet for 8 weeks showed severe hepatic injury including hepatic steatosis, inflammatory infiltration, and fibrosis. Administration of Ad-PPARγ significantly lowered serum alanine aminotransferase level and ameliorated hepatic steatosis, necroinflammation, and fibrosis. These effects were associated with enhanced expression of PPARγ, up-regulated expression of adiponectin and heme oxygenase-1, and down-regulated expression of tumor necrosis factor alpha, interleukin-6, α-smooth muscle actin, transforming growth factor beta 1, matrix metallopeptidase-2, and -9. Administration of GW9662 promoted the severity of liver histology. CONCLUSIONS: The present study provided evidences for the protective role of overexpressing PPARγ in ameliorating hepatic fibrosing steatohepatitis in mice. Modulation of PPARγ expression might serve as a therapeutic approach for fibrotic steatohepatitis.