Icariin alleviates high-fat diet-induced nonalcoholic fatty liver disease via up-regulating miR-206 to mediate NF-κB and MAPK pathways.

Nonalcoholic fatty liver disease (NAFLD) is an abnormal lipid accumulation disease in hepatocytes. The existing drugs for NAFLD have some side effects, so new therapeutic agents are required to be explored. In this study, the effect and mechanism of icariin (ICA) on high-fat diet-induced NAFLD were investigated. Firstly, a high-fat diet was used to construct a NAFLD rat model and HepG2 cells were treated with 1 mM free fatty acid (FFA). After ICA treatment, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured; liver injury and lipid deposition were observed by H&E and Oil Red O staining; interleukin-1ß (IL-1ß), IL-12, and IL-6 were measured by enzyme-linked immunosorbent assay. Additionally, qRT-PCR and western blot were performed to detect miR-206 expression and NF-κB/MAPK pathway-related protein expression in liver tissues and cells. After a variety of trials, we discovered that compared with the NAFLD group, ICA significantly reduced ALT, AST, TBil, TG, TC, and LDL-C levels and increased HDL-C levels, and improved liver tissue injury and lipid deposition. Moreover, ICA reduced IL-1ß, IL-12, and IL-6 levels in liver tissues and cells as well as inhibited MAPK and NF-κB-related protein expression in the liver tissues. Notably, ICA could significantly increase miR-206 expression in liver tissues and cells. Further experiments confirmed that inhibition of miR-206 was able to reverse the effect of ICA on NAFLD. In conclusion, ICA can alleviate NAFLD by upregulating miR-206 to mediate NF-κB and MAPK pathways.

Population attributable fractions of fatty liver disease for type 2 diabetes Mellitus.

PURPOSE: To determine the population attributable fraction (PAF) of fatty liver disease (FLD) for type 2 diabetes mellitus (T2DM) and compare it to the PAFs of other metabolic abnormalities. METHODS: We conducted a 10-year retrospective cohort study of 33,346 individuals in Karamay Central Hospital of Xinjiang. Individuals were followed up for T2DM occurrence based on FBS. The PAFs of FLD were calculated generally and respectively in different sex and age groups. A comparison of the PAF of FLD and that of other metabolic abnormalities, as well as the PAFs of FLD in different groups classified based on age and sex, was performed using Cox regression. RESULTS: During an average follow-up period of 3.71 years, 1486 T2DM were diagnosed. The incidence density of T2DM was 1.2/100 person-years, and cumulative incidence rate was 4456.31/100,000 person-years. Partial PAF (PAFp) of FLD in the entire population was 23.11%. In the male population, PAFp was higher at 30-40 years old. In the female population, it was higher when age ≥ 60 years old. In multivariable Cox regression model, FLD, male sex, age ≥ 45 years old, overweight, hypertriglyceridaemia, and systolic hypertension were independent risk factors for T2DM, with corresponding PAFp of 25.00%, 24.99%, 36.47%, 24.96%, 5.71%, and 6.76%, respectively. Age ≥ 45 years old showed the highest PAFp and adjusted hazard ratio, followed by FLD. CONCLUSIONS: FLD contributes more to T2DM incidence than other metabolic disorders. Particular attention should be given to male populations of 30-40 and female populations above 60 for FLD prevention and treatment.

Piezotronic and Piezo-Phototronic Effects-Enhanced Core-Shell Structure-Based Nanowire Field-Effect Transistors.

Piezotronic and piezo-phototronic effects have been extensively applied to modulate the performance of advanced electronics and optoelectronics. In this study, to systematically investigate the piezotronic and piezo-phototronic effects in field-effect transistors (FETs), a core-shell structure-based Si/ZnO nanowire heterojunction FET (HJFET) model was established using the finite element method. We performed a sweep analysis of several parameters of the model. The results show that the channel current increases with the channel radial thickness and channel doping concentration, while it decreases with the channel length, gate doping concentration, and gate voltage. Under a tensile strain of 0.39‱, the saturation current change rate can reach 38%. Finally, another core-shell structure-based ZnO/Si nanowire HJFET model with the same parameters was established. The simulation results show that at a compressive strain of -0.39‱, the saturation current change rate is about 18%, which is smaller than that of the Si/ZnO case. Piezoelectric potential and photogenerated electromotive force jointly regulate the carrier distribution in the channel, change the width of the channel depletion layer and the channel conductivity, and thus regulate the channel current. The research results provide a certain degree of reference for the subsequent experimental design of Zn-based HJFETs and are applicable to other kinds of FETs.

Urolithin C reveals anti-NAFLD potential via AMPK-ferroptosis axis and modulating gut microbiota.

The pharmacology of urolithin C (UroC) on non-alcoholic fatty liver disease (NAFLD) is largely undetermined. We sought to investigate the potential for NAFLD improvement by administration of UroC and the underlying mechanisms. We verified the therapeutic effect of UroC on choline-deficient amino acid-defined high fat diet (CDAHFD) induced NAFLD mice via evaluating NAFLD activity score (NAS), AST, ALT, hepatic phosphorylated AMPK, and 4-hydroxynonenal. Oleic acid-induced AML12 cell was appraised by oil red staining and western blotting to explore the effect and mechanism of UroC in vitro. Transcriptional regulation of UroC was explored by liver RNA sequencing, gut microbiota composition was explored by 16SrRNA sequencing, and colorectal tight junctional proteins were detected by western blotting and immunohistochemistry. The detrimental effects of CDAHFD included the increased liver index, AST, ALT, hepatic 4-hydroxynonenal, impaired intestinal mucosal barrier, and most importantly, pathological damage in liver. Oral administration of UroC largely protected against these harmful alterations. Remarkably, both RNA sequencing and western blotting results indicated an activation in hepatic AMPK signaling pathway which was thought to inhibit ferroptosis response to UroC in vivo, while no change were found in AMPK-ferroptosis axis response to UroC in oleic acid-induced AML12 cells, hinted an indispensable linkage between UroC and hepatic AMPK, presumably the gut-liver axis. Furthermore, UroC could neither alleviate lipid deposition nor inhibit ferroptosis in vitro. The 16SrRNA showed UroC partially counteracted the dysbiosis induced by CDAHFD. Specifically, UroC reversed the elevated proportion of Firmicutes/Bacteroidota and enhanced the level of Parabacteroides goldsteinii and Lactobacillus vaginalis, which played a beneficial role in metabolic disorders. Oral administration of Urolithin C protected against the detrimental impact of CDAHFD via regulating AMPK-ferroptosis axis, maintaining intestinal mucosal barrier and counteracting gut dysbiosis.

Hyperoside Ameliorates Renal Tubular Oxidative Damage and Calcium Oxalate Deposition in Rats through AMPK/Nrf2 Signaling Axis.

Background: Nephrolithiasis is a common disease that seriously affects the health and life quality of patients. Despite the reported effect of hyperoside (Hyp) against nephrolithiasis, the specific mechanism has not been clarified. Therefore, this study is aimed at investigating the effect and potential mechanism of Hyp on renal injury and calcium oxalate (CaOx) crystal deposition. Methods: Rat and cell models of renal calculi were constructed by ethylene glycol (EG) and CaOx induction, respectively. The renal histopathological damage, CaOx crystal deposition, and renal function damage of rats were assessed by HE staining, Pizzolato staining, and biochemical detection of blood and urine parameters. MTT and crystal-cell adhesion assays were utilized to determine the activity of HK-2 cells and crystal adhesion ability, biochemical detection and enzyme-linked immunosorbent assay (ELISA) to measure the levels of oxidative stress-related substances and inflammatory factors, and western blot to test the expression levels of proteins related to the AMPK/Nrf2 signaling pathway. Results: Briefly speaking, Hyp could improve the renal histopathological injury and impaired renal function, reduce the deposition of CaOx crystals in the renal tissue of rats with renal calculi, and decrease the adhesion of crystals to CaOx-treated HK-2 cells. Besides, Hyp also significantly inhibited oxidative stress response. Furthermore, Hyp was associated with the downregulation of malondialdehyde, lactate dehydrogenase, and reactive oxygen species and upregulation of superoxide dismutase activity. Additionally, Hyp treatment also suppressed inflammatory response and had a correlation with declined levels of interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor. Further exploration of mechanism manifested that Hyp might play a protective role through promoting AMPK phosphorylation and nuclear translation of Nrf2 to activate the AMPK/Nrf2 signaling pathway. Conclusion: Hyp can improve renal pathological and functional damage, decrease CaOx crystal deposition, and inhibit oxidative stress and inflammatory response. Such effects may be achieved by activating the AMPK/Nrf2 signaling pathway.

Exosomal CXCL14 Contributes to M2 Macrophage Polarization through NF-κB Signaling in Prostate Cancer.

Chemokine (C-X-C motif) ligand 14 (CXCL14) plays a critical role in maintaining homeostasis and inflammation in the local cell environment and regulating cancer progression. However, the role of CXCL14 in prostate cancer (PC) has not been fully investigated. In this study, the expression of CXCL14 was determined in PC tumor tissues by qRT-PCR and immunohistochemistry assay. Wound healing, invasion, colony formation, cell proliferation, and apoptosis assays were performed to evaluate the role of CXCL14 in PC progression. Exosomes were isolated from PC cell-condition medium by using ultracentrifugation assay and identified by using transmission electron microscopy and nanoparticle tracking analysis. M2 macrophage polarization-associated genes were measured by using qRT-PCR and Western blot assays. A PC xenograft mouse model was used to assess the role of CXCL14 in tumor growth in vivo. The results showed that CXCL14 was significantly upregulated in PC tissues and was positively correlated with pathological stages, lymph node metastasis, and angiolymphatic invasion. The positive correlations were also observed between CXCL14 and PD-L1 and IL-10. Knockdown CXCL14 dramatically inhibited PC cell proliferation, invasion, and colony formation, but not apoptosis. CXCL14 promoted M2 macrophage polarization through the NF-κB signaling pathway and exosome-mediated mechanism. Moreover, CXCL14 knockdown inhibited tumor growth in vivo. Taken together, exosomal CXCL14 promoted M2 macrophage polarization through the NF-κB signaling pathway and contributed to PC progression.

The role of C/EBP homologous protein (CHOP) in regulating macrophage polarization in RAW264.7 cells.

Schistosomiasis is a zoonotic parasitic disease that is endemic in Asia. Macrophages are mainly involved in the inflammatory response of late schistosoma infection. Our previous study found that C/EBP homologous protein (CHOP) expression is significantly increased, and M2 macrophages are activated in schistosome-induced liver fibrosis mice. However, the role of CHOP in the regulation of macrophage polarization remains to be further studied. Western blotting or quantitative PCR revealed that IL-4 increased the expression of arginase-1, macrophage mannose receptor 1, phosphorylation signal transducer and activator of transcription 6 (p-STAT6), Krüppel-like factor 4 (KLF4), CHOP, and IL-13 receptor alpha (IL-13Rα) and induced M2 polarization in RAW264.7 as measured by flow cytometry. Inhibiting STAT6 phosphorylation (AS1517499) reduced the IL-4-induced expression of KLF4, CHOP, and IL-13Rα and also the number of M2 macrophages. The overexpression of CHOP stimulated M2 polarization, but AS1517499 inhibited this effect. CHOP increased the protein expression of KLF4 but did not change the expression of p-STAT6. Soluble egg antigen (SEA) could promote the IL-4-induced protein expression of p-STAT6, CHOP, and KLF4. Overall, the findings show that SEA can promote the activation of M2 macrophages by causing increased CHOP-induced KLF4 levels and activation of STAT6 phosphorylation.

lncRNA ROR promotes the proliferation of renal cancer and is negatively associated with favorable prognosis.

Renal cell carcinoma (RCC) is one of the third most common types of urological cancer worldwide. Long non­coding RNA (lncRNA) ROR has been reported to be important in regulating the malignant activities of different types of cancer, however, the function of lncRNA ROR in RCC remains to be fully elucidated. In order to investigate the function of lncRNA ROR in RCC, reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analysis was used to detect the expression of lncRNA ROR in renal cancer tissues and adjacent tissues. Cell proliferation and apoptosis were determined using Cell Counting Kit-8 and apoptosis assays. Western blot analysis was used to measure the expression levels of c­Myc and p53 following the suppression of lncRNA ROR in RCC cell lines. According to the results of the RT­qPCR analysis, lncRNA ROR was found to be expressed at high levels in RCC tissues and cell lines. Patients with RCC exhibiting high expression levels of lncRNA ROR had shorter survival rates, compared with those with low expression levels of lncRNA ROR. The knockdown of lncRNA ROR resulted in a decrease of cell proliferation and increase of apoptosis in vitro. The suppression of lncRNA ROR also induced an increase in the expression of p53 and a decrease in the expression of c­Myc in vitro. Taken together, these results demonstrated that lncRNA ROR was expressed at high levels in RCC tissue and cell lines, and was associated with the proliferation ability of RCC cells. These findings indicate that lncRNA ROR may be a promising therapeutic target for treating RCC.