Lower serum insulin-like growth factor-1 levels are independently associated with anemia in patients undergoing maintenance hemodialysis.

The relationship between serum insulin-like growth factor-1 (IGF-1) levels and anemia in patients undergoing maintenance hemodialysis (MHD) remains unclear. This cross-sectional study included patients who underwent MHD treatment for >3 months at our dialysis center in March 2021. Demographic and clinical data were recorded. Blood samples were collected before the hemodialysis sessions, and general serum biochemical parameters, routine blood markers, and serum IGF-1 levels were measured. Patients were divided into a group without anemia (hemoglobin ≥110 g/L) and a group with anemia (hemoglobin <110 g/L), and multivariable linear and binary logistic regression analyses were performed to study the relationship between the levels of serum IGF-1 and anemia. A total of 165 patients (male/female = 99:66) with MHD were enrolled in the study, with a median age of 66.0 (58.0, 75.0) years and a median dialysis vintage of 27.0 (12.0, 55.0) months. The mean hemoglobin level was 96.38 ± 16.72 g/L, and 126 patients had anemia (76.4%). Compared to patients without anemia, patients with anemia had lower serum IGF-1 and triglyceride levels and higher intravenous iron supplementation on dialysis (all p < 0.05). After adjusting for confounding factors in different models, the nine-model multivariate binary logistic regression analyses also confirmed that lower serum IGF-1 levels and serum IGF-1 < 197.03 ng/ml were both independently associated with anemia in patients undergoing MHD. However, further multicenter studies with larger sample sizes are required to confirm these findings.

Indirubin-3'-oxime promotes the efficacy of GnRHa in obese-induced central precocious puberty and maintains normal bone growth and body weight via the ERK-Sp1-KISS-1/GPR54 axis.

Central precocious puberty (CPP) is a widespread developmental abnormality. The application of gonadotrophin-releasing hormone agonist (GnRHa) is widely useful for the medical therapy of CPP. This study aimed to investigate the combination effect and mechanism of indirubin-3'-oxime (I3O), an active ingredient analogue of traditional Chinese medicine, and GnRHa treatment on the progression of CPP. First, female C57BL/6 mice were fed with a high-fat diet (HFD) for the induction of precocious puberty and treated with GnRHa and I3O alone or in combination. Development of sexual maturation, bone growth and obesity were determined by vaginal opening detection, H&E staining and ELISA. The protein and mRNA expression levels of related genes were evaluated via western blotting, immunohistochemical method and RT-qPCR. Subsequently, tBHQ, an inhibitor of ERK, was applied to verify whether the mechanism of I3O was associated with this signaling. The results showed that the treatment of I3O alone or in combination with GnRHa could alleviate the HFD-induced earlier vaginal opening and serum levels of the gonadal hormone in mice. And, I3O could significantly eliminate the role of growth deceleration of GnRHa in bone development and reversed the side effect of GnRHa on body weight. More importantly, we found that I3O decreased the expression of KISS-1 and GPR54 by suppressing the phosphorylation of ERK1/2 and Sp1 in the hypothalamus in mice. In summary, these data indicated that I3O could promote the efficacy of GnRHa in HFD-induced precocious puberty, and maintain bone growth and body weight in mice via the ERK-Sp1-KISS-1/GPR54 axis.

1,25-Dihydroxyvitamin D attenuates diabetic cardiac autophagy and damage by vitamin D receptor-mediated suppression of FoxO1 translocation.

Cardiovascular abnormalities are one of the most important complications associated with diabetes. However, the effect of 1, 25-dihydroxyvitamin D (1,25D) on the diabetic heart and the associated regulatory mechanisms are not well appreciated. Here, we report that activation of the vitamin D receptor (VDR) by 1,25D depresses autophagic activity by inhibiting nuclear FoxO1 translocation to attenuate diabetic heart damage. Treatment with 1,25D improved oral glucose tolerance test outcomes, fasting blood glucose levels and CK-MB release in Zucker diabetic fatty (ZDF, fa/fa) rats. Moreover, 1,25D intervention decreased the expression of Bcl-2, Bax, cleaved caspase-3, nuclear FoxO1, LC3II/LC3I and Beclin1 in the hearts of ZDF rats. However, VDR was noticeably up-regulated by 1,25D, which was inhibited in diabetic hearts. In the cardiomyocyte cell line H9c2, further accumulation of LC3II and the augmentation of p62 after treatment with high glucose and chloroquine confirmed increased autophagic activity in diabetic hearts. Moreover, increased Bcl-2 and Bax levels were observed after treatment with an agonist (rapamycin) and antagonist (3MA) of autophagy in high-glucose-cultured cells. The knockdown of VDR with siRNA further induced the expression of LC3II and FoxO1 translocation and altered the Bax/Bcl-2 ratio in high-glucose-exposed cells, and these effects were suppressed by treatment with 1,25D or an inhibitor of FoxO1 transcriptional activity. In summary, 1,25D supplementation attenuated diabetic heart-related cardiac autophagy and damage by activating the VDR to inhibit the nuclear translocation of FoxO1.

Impaired ferritinophagy flux induced by high fat diet mediates hepatic insulin resistance via endoplasmic reticulum stress.

Although iron disequilibrium has been observed frequently in high-fat diet (HFD) related insulin resistance (IR) the exact mechanism still obscure. Herein, we explore the potential mechanism, focusing on hepatic ferritinophagy flow. Male C57/6J mice were administered with HFD or low-fat diet (LFD) for 10 weeks, and HepG2 cells were treated with palmitate (PA, 200 mM) for 24 h. HFD led to abnormal hepatic steatosis and decline p-AKT and p-GSK3ß by 67.1% and 66.3%, respectively. Also, not only decreased iron level but increased endoplasmic reticulum stress (ERS) were observed in the liver of HFD mice and that both them impaired glucose uptake and reduced the expression of p-AKT. However, ferric ammonium citrate (FAC) supplementation improved hepatic IR, as well as ERS. What's more, HFD/PA depleted the labile iron pool (LIP), accumulated p62 and disturbed the expression of nuclear receptor coactivator 4 (NCOA4) and ferritin. While NCOA4 overexpression or rapamycin improved the ERS and impaired glucose uptake in PA incubated HepG2 cells, which was abolished by NCOA4 knockdown or bafilomycin A1. Taken together, these findings suggest that HFD could restrict ferritinophagy flux and interfere with iron metabolism, which resulting in hepatic IR via ERS.

Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes.

Overnutrition disrupts circadian metabolic rhythms by mechanisms that are not well understood. Here, we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity in mouse liver, triggering synchronous high-amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. SREBP expression was rhythmically induced by DIO, leading to circadian FA synthesis and, surprisingly, FA oxidation (FAO). DIO similarly caused a high-amplitude circadian rhythm of PPARα, which was also required for FAO. Provision of a pharmacological activator of PPARα abrogated the requirement of SREBP for FAO (but not FA synthesis), suggesting that SREBP indirectly controls FAO via production of endogenous PPARα ligands. The high-amplitude rhythm of PPARα imparted time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for non-core clock components PPARα and SREBP1 remodels metabolic gene transcription in response to overnutrition and enables a chronopharmacological approach to metabolic disorders.

Biosynthesis of SnO2 Nanoparticles Based on Response Surface Methodology and the Study of Their Dye Removal.

Litsea cubeba is an evergreen tree from the Lauraceae family, with the common name of mountain pepper in Taiwan. The extracts from different parts such as the bark, leaf, root and fruit have various medicinal properties and have been extensively used in traditional Chinese medicine. SnO2 nanoparticles (NPs) were synthesized using an extract of Litsea cubeba fruit based on response surface methodology (RSM). The phytochemicals present in the extract of Litsea cubeba fruit played a crucial role in the NP formation, which could be confirmed by Fourier-Transform Infrared Spectrometer (FTIR). Analysis of variance (ANOVA) was used to evaluate the validation of the RSM models and indicated that the quadratic model was highly significant and suitable to represent the response of the NP formation yield. The optimum parameters were determined using the Design Expert Program and were as follows: extract volume ratio 30.0%, pH 6.3 and reaction temperature 44.4 °C. Using the optimal reaction conditions from the central composite design (CCD) of RSM, the SnO2 NPs were prepared and characterized by field-emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM) and X-ray diffraction (XRD). The FE-SEM results showed that the SnO2 NPs were spherical, and XRD results showed that the NPs had a tetragonal crystal structure. Furthermore, the photodegradation kinetics of malachite green by the SnO2 NPs was represented well with a pseudo first-order model.

Comparative pharmacokinetics of arctigenin in normal and type 2 diabetic rats after oral and intravenous administration.

Arctigenin is the main active ingredient of Fructus Arctii for the treatment of type 2 diabetes. In this study, the pharmacokinetics of arctigenin in normal and type 2 diabetic rats following oral and intravenous administration was investigated. As compared to normal rats, Cmax and AUC(0-10h) values of oral arctigenin in diabetic rats increased by 356.8% and 223.4%, respectively. In contrast, after intravenous injection, the Cmax and AUC(0-10h) values of arctigenin showed no significant difference between diabetic and normal rats. In order to explore how the bioavailability of oral arctigenin increased under diabetic condition, the absorption behavior of arctigenin was evaluated by in situ single-pass intestinal perfusion (SPIP). The results indicated that arctigenin was a substrate of P-glycoprotein (P-gp). The absorption difference of arctigenin in the normal and diabetic rats could be eliminated by the pretreatment of classic P-gp inhibitor verapamil, suggesting that P-gp might be the key factor causing the absorption enhancement of arctigenin in diabetic rats. Further studies revealed that the uptake of rhodamine 123 (Rho123) in diabetic rats was significantly higher, indicating that diabetes mellitus might impair P-gp function. Consistently, a lower mRNA level of P-gp in the intestine of diabetic rats was found. In conclusion, the absorption of arctigenin after oral administration was promoted in diabetic rats, which might be partially attribute to the decreased expression and impaired function of P-gp in intestines.

A LC-ESI-MS method for the simultaneous determination of madecassoside and its metabolite madecassic acid in rat plasma: comparison pharmacokinetics in normal and collagen-induced arthritic rats.

To develop a simple and highly sensitive high performance liquid chromatography with electrospray ionization mass spectrometric (LC-ESI-MS) method for the simultaneous determination of madecassoside and its major metabolite madecassic acid in rat plasma, and compare the pharmacokinetics of the two compounds in normal and collagen-induced arthritis (CIA) rats. Glycyrrhetinic acid was used as the internal standard (IS). Chromatographic separation was accomplished on an Inertsil ODS-3 column, using a gradient elution with the mobile phase composed of acetonitrile and water acidified with 0.1% (V/V) formic acid. Detection was achieved by ESI-MS under the negative selected ion monitoring (SIM) mode. In normal and CIA rats, madecassoside (30 mg·kg(-1)) was orally administered for 21 consecutive days from the day of arthritis onset. For madecassoside, the linear range was 10-1 000 ng·mL(-1) with the square regression coefficient (r) of 0.998 9, while for madecassic acid, the linear range was 10-500 ng·mL(-1) with the square regression coefficient (r) of 0.996 1. The lower limit of quantification was 10 ng·mL(-1) for both analytes. The intra- and inter-day precision ranged from 1.78% to 13.42% for madecassoside and 2.30% to 14.90% for madecassic acid, and the accuracy was between -0.95% and 6.30% for madecassoside and between -1.48% and 5.34% for madecassic acid. The average recoveries of madecassoside, madecassic acid and IS from spiked plasma samples were > 81%. The developed method was successfully applied to the pharmacokinetic study of madecassoside and madecassic acid in rats after an oral administration of madecassoside. During initial 7 days of dosing, the cmax and AUC of madecassoside were greatly decreased and Vd/F was markedly increased in CIA rats, and no significant difference was observed on the first day of dosing. In contrast, the T1/2, cmax and AUC of madecassic acid were significantly increased, and Ke of madecassic acid was greatly decreased in CIA rats compared with normal rats. Along with repeated administration of madecassoside, the differences of pharmacokinetic parameters of both madecassoside and madecassic acid between CIA and normal rats gradually subsided. The pharmacokinetic characteristics of both madecassoside and madecassic acid in rats were significantly altered by arthritis status, and the differences of pharmacokinetic parameters between arthritis and normal rats coincide with the severity of arthritis.