Estrogen restores disordered lipid metabolism in visceral fat of prediabetic mice.

BACKGROUND: Visceral obesity is increasingly prevalent among adolescents and young adults and is commonly recognized as a risk factor for type 2 diabetes. Estrogen [17ß-estradiol (E2)] is known to offer protection against obesity via diverse me-chanisms, while its specific effects on visceral adipose tissue (VAT) remain to be fully elucidated. AIM: To investigate the impact of E2 on the gene expression profile within VAT of a mouse model of prediabetes. METHODS: Metabolic parameters were collected, encompassing body weight, weights of visceral and subcutaneous adipose tissues (VAT and SAT), random blood glucose levels, glucose tolerance, insulin tolerance, and overall body composition. The gene expression profiles of VAT were quantified utilizing the Whole Mouse Genome Oligo Microarray and subsequently analyzed through Agilent Feature Extraction software. Functional and pathway analyses were conducted employing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. RESULTS: Feeding a high-fat diet (HFD) moderately increased the weights of both VAT and SAT, but this increase was mitigated by the protective effect of endogenous E2. Conversely, ovariectomy (OVX) led to a significant increase in VAT weight and the VAT/SAT weight ratio, and this increase was also reversed with E2 treatment. Notably, OVX diminished the expression of genes involved in lipid metabolism compared to HFD feeding alone, signaling a widespread reduction in lipid metabolic activity, which was completely counteracted by E2 administration. This study provides a comprehensive insight into E2's local and direct protective effects against visceral adiposity in VAT at the gene level. CONCLUSION: In conclusion, the present study demonstrated that the HFD-induced over-nutritional challenge disrupted the gene expression profile of visceral fat, leading to a universally decreased lipid metabolic status in E2 deficient mice. E2 treatment effectively reversed this condition, shedding light on the mechanistic role and therapeutic potential of E2 in combating visceral obesity.

Berberine-loaded solid lipid nanoparticles are concentrated in the liver and ameliorate hepatosteatosis in db/db mice.

Berberine (BBR) shows very low plasma levels after oral administration due to its poor absorption by the gastrointestinal tract. We have previously demonstrated that BBR showed increased gastrointestinal absorption and enhanced antidiabetic effects in db/db mice after being entrapped into solid lipid nanoparticles (SLNs). However, whether BBR-loaded SLNs (BBR-SLNs) also have beneficial effects on hepatosteatosis is not clear. We investigated the effects of BBR-SLNs on lipid metabolism in the liver using histological staining and reverse transcription polymerase chain reaction analysis. The results showed that oral administration of BBR-SLNs inhibited the increase of body weight and decreased liver weight in parallel with the reduction of serum alanine transaminase and liver triglyceride levels in db/db mice. The maximum drug concentration in the liver was 20-fold higher than that in the blood. BBR-SLNs reduced fat accumulation and lipid droplet sizes significantly in the liver, as indicated by hematoxylin and eosin and Oil Red O staining. The expression of lipogenic genes, including fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD1), and sterol regulatory element-binding protein 1c (SREBP1c) were downregulated, while lipolytic gene carnitine palmitoyltransferase-1 (CPT1) was upregulated in BBR-SLN-treated livers. In summary, we have uncovered an unexpected effect of BBR-SLNs on hepatosteatosis treatment through the inhibition of lipogenesis and the induction of lipolysis in the liver of db/db mice.

Characterization, pharmacokinetics, and hypoglycemic effect of berberine loaded solid lipid nanoparticles.

The high aqueous solubility, poor permeability, and absorption of berberine (BBR) result in its low plasma level after oral administration, which greatly limits its clinical application. BBR solid lipid nanoparticles (SLNs) were prepared to achieve improved bioavailability and prolonged effect. Developed SLNs showed homogeneous spherical shapes, small size (76.8 nm), zeta potential (7.87 mV), encapsulation efficiency (58%), and drug loading (4.2%). The power of X-ray diffraction combined with (1)H nuclear magnetic resonance spectroscopy was employed to analyze chemical functional groups and the microstructure of BBR-SLNs, and indicated that the drug was wrapped in a lipid carrier. Single dose (50 mg/kg) oral pharmacokinetic studies in rats showed significant improvement (P<0.05) in the peak plasma concentration, area under the curve, and variance of mean residence time of BBR-SLNs when compared to BBR alone (P<0.05), suggesting improved bioavailability. Furthermore, oral administration of both BBR and BBR-SLNs significantly suppressed body weight gain, fasting blood glucose levels, and homeostasis assessment of insulin resistance, and ameliorated impaired glucose tolerance and insulin tolerance in db/db diabetic mice. BBR-SLNs at high dose (100 mg/kg) showed more potent effects when compared to an equivalent dose of BBR. Morphologic analysis demonstrated that BBR-SLNs potentially promoted islet function and protected the islet from regeneration. In conclusion, our study demonstrates that by entrapping BBR into SLNs the absorption of BBR and its anti-diabetic action were effectively enhanced.

Comparison of toxicokinetic and tissue distribution of triptolide-loaded solid lipid nanoparticles vs free triptolide in rats.

The traditional Chinese medicine Tripterygium wilfordii Hook F (TWHF) is used clinically to treat some autoimmune and inflammatory disorders including rheumatoid arthritis, systemic lupus erythematosus, and skin diseases. However TWHF has a high potential for toxicity, so its clinical use is limited. Solid lipid nanoparticle (SLN) delivery systems are reported to have remarkable advantages over conventional formulations of bioactive plant extracts, such as enhancing solubility and bioavailability, offering protection from toxicity, and enhancing pharmacological activity. We reported previously that a tripterygium glycoside (TG) solid lipid nanoparticle (TG-SLN) delivery system had a protective effect against TG-induced male reproductive toxicity. To better understand this issue, we used triptolide (TP) as a model drug in a comparative study of the toxicokinetic and tissue distribution of TP-SLN and free TP in rats, allowing us to observing the in vivo behavior of this nanoformulation and to assess mechanisms of SLN-related toxicity. A fast and sensitive HPLC-APCI-MS/MS method was developed for the determination of triptolide in rat plasma. Fourteen rats were divided randomly into two groups of 7 rats each for toxicokinetic analysis, with one group receiving free TP (450µg/kg) and the other receiving the TP-SLN formulation (450µg/kg). Blood was obtained before dosing and 0.083, 0.17, 0.25, 0.33, 0.5, 0.75, 1, 1.5, 2, 3 and 4h after drug administration. Thirty-six rats were divided randomly into six equal groups for a tissue-distribution study. Half of the rats received intragastric administration of TP (450µg/kg) and the other half received TP-SLN (450µg/kg). At 15, 45, and 90min after dosing, samples of blood, liver, kidney, spleen, lung, and testicular tissue were taken. TP concentration in the samples was determined by LC-APCI-MS-MS. The toxicokinetic results for the nanoformulation showed a significant increase the area under the curve (AUC) (P<0.05), significantly longer T(max) and mean retention times (MRTs) (0-t) (P<0.05), significantly decreased C(max) (P<0.05). The nanoformulation promoted absorption with a slow release character, indicating that toxicokinetic changes may be the most important mechanism for the enhanced efficacy of nanoformulations. Tissue-distribution results suggest a tendency for TP concentrations in the lung and spleen to increase, while TP concentrations in plasma, liver, kidney, and testes tended to decrease in the TP-SLN group. At multiple time points, testicular tissue TP concentrations were lower in the TP-SLN group than in free TP group. This provides an important clue for the decreased reproductive toxicity observed with TP-SLN.

[Study on the expression of androgen receptor in testis, epididymis and prostate of adult rats with diabetes].

OBJECTIVE: To investigate if there is abnormal expression of androgen receptor (AR) in adult diabetic rats. METHODS: The diabetic model rats were induced by using streptozotocin (STZ), which were divided into three groups: control (group C), diabetes (group D) and diabetes with insulin replacement group (group ID). The mRNA and protein expressions of androgen receptor in testis, epididymis and prostate were detected by Northern blot and radioimmunoassay, respectively. RESULTS: Serum testosterone levels and AR mRNA in epididymis of group D or Group ID were lower than those of group C (P <0.05) , respectively, and the protein expression of AR in testis and prostate of group D was lower than that of group C (P <0.05). CONCLUSION: The expression of androgen receptor decreased in testis, epididymis and prostate of diabetic rats, which weakened the biological effects of AR, and it might be one of the causes that resulted in the sexual and productive dysfunction in diabetic rats.

[Changes of 5 alpha-reductase type II activity in sexual gland of diabetic male rats].

OBJECTIVES: To study the changes of sexual gland 5 alpha-reductase type II activity in pubertal and adult rats with diabetes. METHODS: We selected 40 and 90 days old male Wistar rats as pubertal and adult animal model respectively, 30 rats in each group. The rats were randomly divided into three groups: control group (C), diabetic group (D) and diabetes with insulin replacement group (ID). The activity of 5 alpha-reductase type II was measured with thin layer chromatography in the epididymis, prostate and testis. RESULTS: 1. In all sexual glands of pubertal rats, the activity of 5 alpha-reductase type II in D group is significantly lower than that in C and ID groups. 2. In all sexual glands of adult rats. there is no difference in the activity of 5 alpha-reductase type II among these groups. CONCLUSIONS: The activity of 5 alpha-reductase type II is likely to be influenced by metabolic environment, hormonal levels and local specific factors in pubertal rats, but it is relatively stable in adult rats.