Sinapic acid modulates oxidative stress and metabolic disturbances to attenuate ovarian fibrosis in letrozole-induced polycystic ovary syndrome SD rats.

Sinapic acid (SA) is renowned for its many pharmacological activities as a polyphenolic compound. The cause of polycystic ovary syndrome (PCOS), a commonly encountered array of metabolic and hormonal abnormalities in females, has yet to be determined. The present experiment was performed to evaluate the antifibrotic properties of SA in rats with letrozole-induced PCOS-related ovarian fibrosis. SA treatment successfully mitigated the changes induced by letrozole in body weight (BW) (p < .01) and relative ovary weight (p < .05). Histological observation revealed that SA reduced the number of atretic and cystic follicles (AFs) and (CFs) (p < .01), as well as ovarian fibrosis, in PCOS rats. Additionally, SA treatment impacted the serum levels of sex hormones in PCOS rats. Luteinizing hormone (LH) and testosterone (T) levels were decreased (p < .01, p < .05), and follicle-stimulating hormone (FSH) levels were increased (p < .05). SA administration also decreased triglyceride (TG) (p < .01) and total cholesterol (TC) levels (p < .05) and increased high-density lipoprotein cholesterol (HDL-C) levels (p < .01), thereby alleviating letrozole-induced metabolic dysfunction in PCOS rats. Furthermore, SA treatment targeted insulin resistance (IR) and increased the messenger RNA (mRNA) levels of antioxidant enzymes in the ovaries of PCOS rats. Finally, SA treatment enhanced the activity of peroxisome proliferator-activated receptor-γ (PPAR-γ), reduced the activation of transforming growth factor-ß1 (TGF-ß1)/Smads, and decreased collagen I, α-smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF) levels in the ovaries of PCOS rats. These observations suggest that SA significantly ameliorates metabolic dysfunction and oxidative stress and ultimately reduces ovarian fibrosis in rats with letrozole-induced PCOS.

Sinapic Acid Attenuates Chronic DSS-Induced Intestinal Fibrosis in C57BL/6J Mice by Modulating NLRP3 Inflammasome Activation and the Autophagy Pathway.

Ulcerative colitis (UC) is a chronic gastrointestinal disease that results from repeated inflammation and serious complications. Sinapic acid (SA) is a hydroxycinnamic acid present in a variety of plants that has antioxidant, anti-inflammatory, anticancer, and other protective effects. This study investigated the antifibrotic effect of SA on chronic colitis induced by dextran sulfate sodium salt (DSS) in mice. We observed that SA could significantly reduce clinical symptoms (such as improved body weight loss, increased colon length, and decreased disease activity index score) and pathological changes in mice with chronic colitis. SA supplementation has been demonstrated to repair intestinal mucosal barrier function and maintain epithelial homeostasis by inhibiting activation of the NLRP3 inflammasome and decreasing the expression of IL-6, TNF-α, IL-17A, IL-18, and IL-1ß. Furthermore, SA could induce the expression of antioxidant enzymes (Cat, Sod1, Sod2, Mgst1) by activating the Nrf2/keap1 pathway, thus improving antioxidant capacity. Additionally, SA could increase the protein expression of downstream LC3-II/LC3-I and Beclin1 and induce autophagy by regulating the AMPK-Akt/mTOR signaling pathway, thereby reducing the production of intestinal fibrosis-associated proteins Collagen-I and α-SMA. These findings suggest that SA can enhance intestinal antioxidant enzymes, reduce oxidative stress, expedite intestinal epithelial repair, and promote autophagy, thereby ameliorating DSS-induced colitis and intestinal fibrosis.

Anesthesia/surgery-induced learning and memory dysfunction by inhibiting mitophagy-mediated NLRP3 inflammasome inactivation in aged mice.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication, not only affects the quality of life of the elderly and increases the mortality rate, but also brings a greater burden to the family and society. Previous studies demonstrated that Nod-like receptor protein 3 (NLRP3) inflammasome participates in various inflammatory and neurodegenerative diseases. However, possible mitophagy mechanism in anesthesia/surgery-elicited NLRP3 inflammasome activation remains to be elucidated. Hence, this study clarified whether mitophagy dysfunction is related to anesthesia/surgery-elicited NLRP3 inflammasome activation. POCD model was established in aged C57BL/6 J mice by tibial fracture fixation under isoflurane anesthesia. Morris Water Maze (MWM) was used to evaluate learning and memory abilities. We found that in vitro experiments, lipopolysaccharide (LPS) significantly facilitated NLRP3 inflammasome activation and mitophagy inhibition in BV2 cells. Rapamycin restored mitophagy and improved mitochondrial function, and inhibited NLRP3 inflammasome activation induced by LPS. In vivo experiments, anesthesia and surgery caused upregulation of hippocampal NLRP3, caspase recruitment domain (ASC) and interleukin-1ß (IL-1 ß), and downregulation of microtubule-associated protein light chain 3II (LC3II) and Beclin1 in aged mice. Olaparib inhibited anesthesia/surgery-induced NLRP3, ASC, and IL-1ß over-expression in the hippocampus, while upregulated the expression of LC3II and Beclin1. Furthermore, Olaparib improved cognitive impairment in older mice. These results revealed that mitophagy was involved in NLRP3 inflammasome-mediated anesthesia/surgery-induced cognitive deficits in aged mice. Overall, our results suggested that mitophagy was related in NLRP3 inflammasome-induced cognitive deficits after anesthesia and surgery in aged mice. Activating mitophagy may have clinical benefits in the prevention of cognitive impairment induced by anesthesia and surgery in elderly patients.

Multi-omics analysis reveals BDE47 induces depression-like behaviors in mice by interfering with the 2-arachidonoyl glycerol-associated microbiota-gut-brain axis.

2,2',4,4'-tetrabromodiphenyl ether (BDE47) is a foodborne environmental risk factor for depression, but the pathogenic mechanism has yet to be fully characterized. In this study, we clarified the effect of BDE47 on depression in mice. The abnormal regulation of the microbiome-gut-brain axis is evidenced closely associated with the development of depression. Using RNA sequencing, metabolomics, and 16s rDNA amplicon sequencing, the role of the microbiome-gut-brain axis in depression was also explored. The results showed that BDE47 exposure increased depression-like behaviors in mice but inhibited the learning memory ability of mice. The RNA sequencing analysis showed that BDE47 exposure disrupted dopamine transmission in the brain of mice. Meanwhile, BDE47 exposure reduced protein levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT), activated astrocytes and microglia cells, and increased protein levels of NLRP3, IL-6, IL-1ß, and TNF-α in the brain of mice. The 16 s rDNA sequencing analysis showed that BDE47 exposure disrupted microbiota communities in the intestinal contents of mice, and faecalibaculum was the most increased genus. Moreover, BDE47 exposure increased the levels of IL-6, IL-1ß, and TNF-α in the colon and serum of mice but decreased the levels of tight junction protein ZO-1 and Occludin in the colon and brain of mice. In addition, the metabolomic analysis revealed that BDE47 exposure induced metabolic disorders of arachidonic acid and neurotransmitter 2-Arachidonoyl glycerol (2-AG) was one of the most decreased metabolites. Correlation analysis further revealed gut microbial dysbiosis, particularly faecalibaculum, is associated with altered gut metabolites and serum cytokines in response to BDE47 exposure. Our results suggest that BDE47 might induce depression-like behavior in mice through gut microbial dysbiosis. The mechanism might be associated with the inhibited 2-AG signaling and increased inflammatory signaling in the gut-brain axis.

An ultrasensitive bacterial imprinted electrochemical sensor for the determination of Lactobacillus rhamnosus GG.

An ultrasensitive label-free electrochemical sensor based on a homemade imprinted polypyrrole (PPy) polymer film was prepared to achieve quantitative determination of Lactobacillus rhamnosus GG (LGG). The LGG-imprinted polymer (LIP) film was deposited on a portable screen-printed electrode (SPE) via electropolymerization, which constituted an independent integrated system. The main preparation parameters of the LIP sensor were investigated to obtain optimal performance. Under optimized conditions, the peak current response of the LIP sensor showed a linear relationship with the logarithmic value of LGG concentration in the range from 101 to 109 CFU mL-1 and a detection limit of 5 CFU mL-1. The proposed LIP sensor has achieved efficient, ultrasensitive, highly selective, and cost-effective detection of LGG and can be further developed for practical applications in the quality inspection and development of probiotic products.

Organophosphorus flame retardant TDCPP induces neurotoxicity via mitophagy-related ferroptosis in vivo and in vitro.

Tris (1,3-dichloro-2-propyl) phosphate (TDCPP) has neurotoxicity, but its mechanism remains unclear. Evidence recently showed that ferroptosis might be associated with TDCPP-induced neurotoxicity. To explore the role and underlying mechanism of ferroptosis in TDCPP-induced neurotoxicity, the occurrence of ferroptosis was examined in mice and PC12 cells upon TDCPP exposure. The mechanism of TDCPP-induced ferroptosis was clarified in vitro combined with the RNA sequencing assay. The in vivo results showed that orally TDCPP exposure (100 mg/kg, 30 d) inhibited the learning and memory ability of mice, reduced hippocampus neurons, induced malondialdehyde (MDA) accumulation, and decreased glutathione (GSH) and superoxide dismutase (SOD) levels in the hippocampus. Moreover, TDCPP exposure (100 mg/kg, 30 d) altered the ferroptosis and autophagy-related protein abundances in the hippocampus. The in vitro results showed that TDCPP exposure (0, 5, 20, 50, 100, and 200 µM) for 24 h induced dose-dependent cell death in PC12 cells, and the cell death was ameliorated by the co-treatment with ferrostatin-1 (1 µM, 24 h). Similarly, TDCPP exposure (0, 50, 100, and 200 µM) for 24 h increased the levels of MDA and LPO, but decreased the reduced GSH in PC12 cells. Furthermore, TDCPP exposure (0, 50, 100, and 200 µM) for 24 h altered the ferroptosis and autophagy-related protein abundances in PC12 cells. The RNA-sequencing revealed that TDCPP exposure (100 µM, 24 h) induced mitophagy activation in SH-SY5Y cells. Meanwhile, the in vitro experiments confirmed that TDCPP exposure (0, 50, 100, and 200 µM) for 24 h increased abundances of mitophagy-related protein phosphatase and tensin homolog induced kinase 1(PINK1), Parkinson protein 2 E3 ubiquitin-protein ligase (PARKIN), inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), and voltage-dependent anion channel 1 (VDAC1) in PC12 cells. Moreover, TDCPP treatment (100 µM, 24 h) increased the mitochondrial recruitment of PARKIN, decreased the mitochondrial membrane potential (MMP) level, and increased the Fe2+ level in mitochondria. In addition, decreased ATP levels and increased reactive oxygen species (ROS) levels were observed in PC12 cells upon TDCPP exposure (0, 50, 100, and 200 µM) for 24 h. In summary, ferroptosis was associated with TDCPP-induced neurotoxicity, and the mechanism might be related to PINK1/PARKIN-mediated mitophagy initiated by mitochondrial damage.

Rhamnocitrin Attenuates Ovarian Fibrosis in Rats with Letrozole-Induced Experimental Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine-related cause of infertility in women and has an unknown etiology. Studies have shown that rhamnocitrin (Rha) exhibits positive effects on the reproductive system. This study investigated Rha's antifibrotic effects on PCOS rats and revealed its underlying mechanisms. Female SD rats were randomized into 4 groups (n = 8, each); the control group received tea oil by intraperitoneal injection and 1% w/v CMC by oral gavage; the PCOS group received letrozole (1 mg/kg); the PCOS+Rha group received letrozole and Rha (5 mg/kg); the PCOS+Met group received letrozole and Met (265 mg/kg) for 21 days. At the study end, Rha treatment restored letrozole-induced alterations in the relative ovarian weights, body weight, and relative weights of uterine and visceral adipose tissues. Histological observation showed that Rha ameliorates ovarian structure and fibrosis in PCOS. Administration of Rha reduced letrozole-induced metabolic dysfunction by ameliorating the levels of TC, TG, and HDL-C in the PCOS rats. Rha treatment also modulated the serum levels of sex hormones, which decreased T, E2, and LH and increased FSH in PCOS rats. In addition, Rha treatment modulated insulin resistance and increased gene expression of antioxidant enzymes (Cat, Sod2, Gpx3, Mgst1, Prdx3, Gsta4, Gsr, and Sod1) in the ovaries of the PCOS rats. Finally, Rha treatment appeared to increase the activity of PPAR-γ and inhibit the TGF-ß1/Smad pathway in the ovaries of the PCOS rats. Our findings suggest that Rha significantly ameliorated metabolic disturbances and ovarian fibrosis in the PCOS rats. Rha perhaps is an effective compound for preventing ovarian fibrosis in the future.

Dietary sinapic acid attenuated high-fat diet-induced lipid metabolism and oxidative stress in male Syrian hamsters.

The current study investigated the effects of sinapic acid on high-fat diet (HFD)-induced lipid metabolism and oxidative stress in male Syrian hamsters. Sinapic acid treatment significantly reduced body weight, epididymal fat, and perirenal fat mass in HFD hamsters. Sinapic acid also improved dyslipidemia levels (reducing the serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol, and increasing the high-density lipoprotein cholesterol) and increased T-AOC levels to mitigate oxidative stress injury. Moreover, sinapic acid intervention increased the activations of PPAR-γ, CPT-1, and CYP7A1 and decreased the activations of FAS, ACC1, SREBP1, SREBP2, and HMGCR in the livers of HFD hamsters. In addition, sinapic acid intervention also significantly inhibited the intestinal mRNA levels of Srebp2 and Npc1l1 in HFD hamsters. In conclusion, sinapic acid can significantly attenuate abnormal lipid metabolism in the development of HFD-induced obesity and reduce the level of oxidative stress to exert its anti-obesity effect. PRACTICAL APPLICATIONS: Obesity is the main cause of some chronic metabolic syndromes, such as dyslipidemia, nonalcoholic fatty liver disease, diabetes, and hyperuricemia. Searching for new, safe, and effective natural products in weight loss and fat reduction has become one of the hot research topics. As a natural source of simple phenolic acids, sinapic acid is present in fruits, vegetables, and grains and has been indicated to have anti-inflammatory, antioxidant, antihyperuricemic, lipid homeostasis regulation, and anticancer activities. However, the lipid metabolism- and oxidative stress-regulating activities of sinapic acid are not clear. Here, the current study investigated the lipid metabolism and oxidative stress regulating activities of sinapic acid in male Syrian hamsters fed a high-fat diet.

Oral administration of Lactobacillus plantarum CQPC11 attenuated the airway inflammation in an ovalbumin (OVA)-induced Balb/c mouse model of asthma.

This study investigated the antiasthmatic and anti-inflammatory effects of Lactobacillus plantarum-CQPC11 (LP-CQPC11) on ovalbumin (OVA)-induced asthmatic Balb/c mice. Administration of different doses of LP-CQPC11 (105 , 107 , and 109 colony-forming unit [CFU]/mouse) effectively reduced airway hyperresponsiveness (AHR) and the lung W/D ratio in asthmatic mice. LP-CQPC11 treatment reduced the accumulation of inflammatory cells in the BALF and attenuated histologic edema in asthmatic mice. Administration of LP-CQPC11 decreased the serum levels of OVA-specific IgE, IgE, and OVA-specific IgG1. LP-CQPC11 treatment decreased the levels of inflammatory cytokines (TNF-α, IL-4, IL-13, IL-5, and IL-6) in the BALF of asthmatic mice. In addition, LP-CQPC11 also elevated the mRNA levels of Foxp3 and T-bet and decreased the mRNA levels of Gata3 and RORγt in asthmatic mice lungs. Administration of LP-CQPC11 also reduced OVA-induced oxidative stress by improving the activities of GSH-Px, SOD, and catalase in the lungs. Finally, LP-CQPC11 treatment also significantly decreased the activation of the NF-κB pathway to modulate the inflammatory reaction in the lungs of asthmatic mice. The results from this study clearly demonstrated that oral administration of LP-CQPC11 exhibited outstanding activity in attenuating OVA-induced asthma in a mouse model. Furthermore, LP-CQPC11 may be an effective microecologic agent in preventing allergic asthma in the future. PRACTICAL APPLICATIONS: Allergic asthma is a common chronic inflammation-associated respiratory disease. Lactic acid bacteria (LAB) are known as a health product involved in modulating immune tolerance and play important roles in disease prevention and treatment. Many studies have reported that LAB, as probiotics, exhibits great antioxidation, anticancer, and anti-inflammatory activities and have health benefits in gastrointestinal disorders. In fact, human studies have confirmed that Lactobacillus rhamnosus strains have an effective activity to reduce the risk of allergic asthma. LP-CQPC11 was isolated from Sichuan pickled cabbages (a type of LAB-fermented vegetable product, also called Sichuan paocai) and was reported to reduce d-galactose-induced aging in mice in our previous study. However, the antiasthmatic and anti-inflammatory activities of LP-CQPC11 are unclear. The current study investigated the antiasthmatic and anti-inflammatory effects of LP-CQPC11 on OVA-induced asthmatic Balb/c mice.

Effects of Sinapic Acid Combined with Cisplatin on the Apoptosis and Autophagy of the Hepatoma Cells HepG2 and SMMC-7721.

Sinapic acid (Sa) is a small-molecule phenolic acid compound predominant in fruits, vegetables, and grains. This study investigated the antitumor effects of cisplatin (DDP) combined with Sa (Sa/DDP) on the hepatic cancer cells (HCC), HepG2 and SMMC-7721. The HepG2 and SMMC-7721 cells were treated with Sa or Sa/DDP, and the cell proliferation and cell cycle were detected using the MTT assay. The cell migration was detected using the transwell and scratch assays, while apoptosis and autophagy were detected using Hoechst, MDC, and Annexin V-FITC/PI staining. The protein expression was quantitated using the western blot. Sa/DDP was found to not only inhibit cancer cell proliferation and migration but also induce cell apoptosis. Simultaneously, the Sa/DDP combination was found to activate autophagy, and the HCQ autophagy inhibitor enhanced the apoptosis in the Sa/DDP-induced liver cancer cells. The combined use of Sa and DDP makes it an attractive adjuvant therapy strategy for tumors, establishing the prospect of phenolic acid compounds for the adjuvant treatment of hepatocellular carcinoma.

A preliminary study on the mechanism of the neurosteroid-mediated ionotropic receptor dysfunction in neurodevelopmental toxicity induced by decabromodiphenyl ether.

The mechanism of neurodevelopmental toxicity of decabromodiphenyl ether (BDE209) remains unclear. Recent evidence suggests that neurosteroids disorders play a vital role in BDE209 induced-neurodevelopmental toxicity. To explore the mechanism of it, pregnant ICR mice were orally gavaged with 0, 225, and 900 mg kg-1 BDE209 for about 42 days. Spatial learning and memory abilities of offspring were tested on postnatal day (PND) 21. Offspring were euthanized at PND26, the neuronal structure, neurosteroids level, and related proteins including neurosteroids synthase, ionotropic receptors and cAMP-response element binding protein (CREB) pathway were evaluated, as well as Ca2+ concentration and the mitochondrial membrane potential (Mmp). Our results showed that BDE209 impaired learning and memory abilities and disrupted neuronal structure. Meanwhile, BDE209 decreased the pregnenolone (PREG), dehydroepiandrosterone (DHEA), progesterone (PROG) and allopregnanolone (ALLO) levels in the serum and brain, as well as the mRNA and protein levels of cholesterol-side-chain cleavage enzyme (P450scc), steroid 17α-hy-droxylase (P450C17), 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and steroid 5α-reductase of type I (5α-R) in the hippocampi. Also, BDE209 suppressed mRNA and protein levels of NR1, NR2A and NR2B subunits of the N-methyl-D-aspartic acid receptor (NMDAR) and α1 subunit of the Gamma-amino butyric acid A receptor (GABAAR), but increased the levels of ß2 and γ2 subunits of the GABAAR in the hippocampi. Moreover, BDE209 increased the Ca2+ concentration and phosphorylation extracellular regulated protein kinases (P-ERK) 1/2 level, but decreased the P-CREB and Mmp level in the hippocampi. These results indicate that BDE209 exposure during pregnancy and lactation is possible to affect learning and memory formation of offspring by the neurosteroid-mediated ionotropic receptors dysfunction.

Dietary proanthocyanidins alleviated ovarian fibrosis in letrozole-induced polycystic ovary syndrome in rats.

This study investigated the effects of proanthocyanidins (PCs) on ovarian fibrosis in letrozole-induced polycystic ovary syndrome (PCOS) in rats. The administration of PCs effectively reduced the body weight (BW) and relative ovarian weight in PCOS rats. ELISA results revealed that PCs significantly reduced the level of serum T, LH, LH/FSH in the PCOS group. In addition, qRT-PCR results revealed that treatment with PCs significantly increased the main antioxidant enzymes (Cat, Sod2, Gpx3, Mgst1, Gsta4, Sod1 and Prdx3) in PCOS rats. Also, the expression analysis of proteins by Western blotting revealed that PCs significantly decreased the level of TGF-ßR1, p-Smad3, p-Smad2 and Smad4 and reversed the downregulation of Smad7 in PCOS rats. The study suggested that PCs improved ovarian fibrosis in PCOS rats by regulating the serum hormone level, inhibiting oxidative stress and suppressing the activation of the TGF-ß1/Smads signaling pathway. PRACTICAL APPLICATIONS: Currently, plant extracts are being widely used to treat female reproductive and metabolic disorders. Particularly, proanthocyanidins (PCs), the well-known natural polyphenolic compounds, which are a significant source of antioxidants present in many colored fruits, are consumed as fruits as well as a dietary supplement to prevent many disorders. Recent pharmacological studies have reported that PCs have many health beneficial properties, such as antioxidant activity, improving cholesterol homeostasis, blood lipid regulatory properties, microcirculation improvement effect, antitumor activity and anti-aging activity. Despite these properties of PCs, the antifibrosis effect of PCs has not been studied to date. The main purpose of this study was to research the role and the mechanisms of PCs in ovarian fibrosis in PCOS rats.

Ameliorative Effect of Sinapic Acid on Dextran Sodium Sulfate- (DSS-) Induced Ulcerative Colitis in Kunming (KM) Mice.

Ulcerative colitis is a chronic gastrointestinal disease characterized by intestinal inflammation and serious mucosal damage. As a naturally hydroxycinnamic acid, sinapic acid (SA) has antioxidant, anticancer, and neuroprotective activities. We investigated the anticolitic effect and potential mechanisms of SA in DSS-induced colitis in Kunming (KM) mice. SA treatment significantly reduced body weight loss, colon shortening, and intestinal wall thickening in colitis mice. SA treatment also significantly reduced the histological infiltration of inflammatory cells and decreased myeloperoxidase (MPO) activity in the colons of colitis mice. The administration of SA attenuated oxidative damage by enhancing the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase and reduced the serum and colonic mRNA levels of proinflammatory cytokines in colitis mice. We used qRT-PCR and Western blotting assays and demonstrated that SA reduced the activation of the NLRP3 inflammasome and attenuated intestinal permeability by enhancing the expression of ZO-1, occludin, and claudin-1 in colitis mice. Here, we conclude that SA exhibits great anticolitic activity against DSS-induced colitis by enhancing the activity of antioxidant enzymes, reducing intestinal inflammation, and maintaining the intestinal barrier. Finally, we suggest that SA may be a safe adjuvant for the prevention of clinical colitis.

Neurotoxicity and related mechanisms of flame retardant TCEP exposure in mice.

Objective: To explore the neurotoxicity and mechanism of tris(2-chloroethyl) phosphate (TCEP) exposure in mice.Methods: Total 30 adult Kunming mice were randomly divided into normal control group (0 mg/kg·d), low-dose TCEP group (10 mg/kg·d), and high-dose TCEP group (100 mg/kg·d), and administered continuously by gavage for 30 days.Results: Compared with the control group, the water intake of high-dose TCEP group was declined significantly (p < 0.05), and the organ index of liver and spleen were increased significantly (p < 0.05). In addition, the escape latency of TCEP exposed mice were longer than that in the control group in water maze test (p < 0.05), while the total swimming course of high-dose TCEP group was elevated and the swimming time in target quadrant was obviously shortened compared with the control group (p < 0.05). The serum levels of total-triiodothyronine (TT3) and free triiodothyronine (FT3) were significantly higher in the high-dose TCEP group than in the control group (p＜0.05). Compared with the control group, the activities of glutathione transferase (GST) and super oxide dismutase (SOD) in the high-dose TCEP group were increased, and GST in the low-dose TCEP group were decreased, while the content of malonaldehyde (MDA) in both groups was increased (p＜0.05). In the CCK8 assay, the viability of PC12 cells decreased with an increase of TCEP concentration, indicating a concentration dependent neurotoxicity.Conclusion: TCEP exposure can cause neurotoxicity by increasing thyroid hormones and inducing oxidative damage in mice.

Dietary Mixed Cereal Grains Ameliorate the Azoxymethane and Dextran Sodium Sulfate-Induced Colonic Carcinogenesis in C57BL/6J Mice.

The chemopreventive effects of various mixed cereal grain (MCG) samples on azoxymethane (AOM, 10 mg/kg) and dextran sulfate sodium (DSS, 0.02 g/mL)-induced colorectal cancer (CRC) in C57BL/6J mice were studied. The main MCG preparation consisted of fermented brown rice (FBR), glutinous brown rice, glutinous Sorghum bicolor, glutinous Panicum miliaceum, Coix lacryma-jobi, and black soybean at an appropriate mixing ratio. Other MCG preparations contained rice coated with 5% Phellinus linteus and 5% Curcuma longa (MCG-PC) or 10% Phellinus linteus (MCG-P) or 10% Curcuma longa (MCG-C). Consumption of dietary MCG-PC by CRC mice significantly increased colon length, decreased the ratio of colon weight to length, and reduced the number of colon tumors. Similar effects, although to a lower extent, were observed in CRC mice fed with MCG-P, followed by those fed with MCG-C, MCG, FBR, or white rice. MCG-PC significantly suppressed colonic neoplasia and decreased the levels of various cytokines (tumor necrosis factor: Tnf, interleukin 1 beta: Il1b, interleukin 6: Il6, and interferon gamma: Ifnγ) in serum and colon tissue of the CRC mice. In addition, MCG-PC increased the mRNA expressions of tumor suppressor protein p53 (Tp53) and cyclin-dependent kinase inhibitor 1A (Cdkn1a), activated pro-apoptotic caspase 3 (Casp3), and reduced expressions of both mRNA and protein of inducible nitric oxide synthase 2 (Nos2), prostaglandin-endoperoxide synthase 2 (Ptgs2), and cyclin D1 (Ccnd1) in colon tissue. These findings suggest that compared with other cereal grain preparations, MCG-PC had a greater activity against AOM/DSS-induced CRC by reducing intestinal inflammation and modulating the expression of certain carcinogenesis related factors (Nos2, Ptgs2, Tp53, Cdkn1a, Ccnd1, and Casp3) in colon tissue of CRC mice.

Fresh Saengshik Showed a Positive Effect on Mitigating Dextran Sulfate Sodium-Induced Experimental Colitis in Mice.

This study was to compare the anticolitis activity of fresh Saengshik (FSS) with heated Saengshik (HSS) with dextran sulfate sodium (DSS)-induced experimental colitis mouse model. Both FSS- and HSS-fed colitis mice exhibited the effects of the increase in the body weight, the alleviation in the colon shortening, and the reduction of the ratio of colon weight to length. However, FSS-fed colitis mice showed a much more significant decrease in DSS-induced tissue damage by mucosal edema and crypt deficiency than did HSS-fed ones. Besides, FSS contributed to decreasing the serum levels of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta) and inhibiting the colonic mRNA expressions of these cytokines in colitis tissue of the mice. FSS also resulted in the lower colonic mRNA expression level of inflammation-related inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in colitis mice than did HSS. Overall results confirmed Saengshik, especially FSS, inhibits more effectively against DSS-induced inflammation reaction in colitis mice than HSS.

Interaction between HuR and circPABPN1 Modulates Autophagy in the Intestinal Epithelium by Altering ATG16L1 Translation.

Intestinal epithelial autophagy is crucial for host defense against invasive pathogens, and defects in this process occur frequently in patients with inflammatory bowel disease (IBD) and other mucosal disorders, but the exact mechanism that activates autophagy is poorly defined. Here, we investigated the role of RNA-binding protein HuR (human antigen R) in the posttranscriptional control of autophagy-related genes (ATGs) in the intestinal epithelium. We found that targeted deletion of HuR in intestinal epithelial cells (IECs) specifically decreased the levels of ATG16L1 in the intestinal mucosa. Intestinal mucosa from patients with IBD exhibited reduced levels of both HuR and ATG16L1. HuR directly interacted with Atg16l1 mRNA via its 3' untranslated region and enhanced ATG16L1 translation, without affecting Atg16l1 mRNA stability. Circular RNA circPABPN1 blocked HuR binding to Atg16l1 mRNA and lowered ATG16L1 production. HuR silencing in cultured IECs also prevented rapamycin-induced autophagy, which was abolished by overexpressing ATG16L1. These findings indicate that HuR regulates autophagy by modulating ATG16L1 translation via interaction with circPABPN1 in the intestinal epithelium.

Protective activity of mogroside V against ovalbumin-induced experimental allergic asthma in Kunming mice.

We investigated the antiasthmatic effect of mogroside V (Mog V) in mice with ovalbumin (OVA)-induced asthma. Administration of Mog V effectively attenuated OVA-induced airway hyperresponsiveness and reduced the number of inflammatory cells in bronchoalveolar lavage fluid (BALF). Histological examination showed that Mog V reduced the inflammatory infiltration of the lungs in the asthmatic mice. ELISAs suggested that Mog V effectively decreased the levels of IL-4, IL-5, and IL-13 in BALF and serum levels of OVA-specific IgE and IgG1 in the asthmatic mice. A quantitative reverse-transcription PCR assay also indicated that Mog V decreased the mRNA levels of IL-17A, IL-23, and RORγt in the lungs of the asthmatic mice (the opposite effect on Foxp3 mRNA). Furthermore, Mog V significantly reduced the OVA-induced activation of NF-κB in the lungs. This study indicates that Mog V alleviates OVA-induced inflammation in airways, and this effect is associated with a reduction in NF-κB activation. PRACTICAL APPLICATIONS: A traditional Chinese medicine herb has been reported to have a strong curative effect on asthma in clinical practice. Siraitia grosvenorii is known in China as a functional food product with the ability to improve lung function. Mogroside V is a triterpene glycoside isolated from S. grosvenorii. Nonetheless, the antiasthmatic effect of mogroside V has not been evaluated yet. The aim of this study was to investigate the antiasthmatic activity of mogroside V in mice with chemically induced asthma. The data from this study will provide some scientific evidence supporting wider use of S. grosvenorii in functional foods.

Total flavonoids extracted from Nervilia Fordii function in polycystic ovary syndrome through IL-6 mediated JAK2/STAT3 signaling pathway.

Large doses of flavonoids could cure many diseases with no serious side effects. However, the role of flavonoids in the treatment of polycystic ovary syndrome (PCOS) has not been reported. Therefore, total flavonoids extracted from Nervilia Fordii were selected to explore its therapeutic efficiency in PCOS. PCOS rat model was constructed to explore the role of total flavonoids in the treatment of PCOS. ELISA was used to assess the changes of ovulation function under the treatment of total flavonoids with or without exogenous interleukin-6 (IL-6). Western blot, real-time PCR and immunohistochemistry were carried out to assess the related molecular mechanisms. We explored that total flavonoids obviously increased the serum levels of follicle-stimulating hormone (FSH), and sharply decreased the serum levels of luteinizing hormone (LH), testosterone (T) and insulin (INS) in the PCOS-IR rats via partly inhibiting the activation of JAK2/STAT3 pathway, partially up-regulating the IL-6 expression and partially down-regulating the suppressor of cytokine signaling 3 (SOCS3) expression in ovaries of PCOS rats. The effect of total flavonoids on estrous cycles, serum levels of FSH, LH, T and INS were partially attenuated by IL-6 in PCOS rat model. Moreover, IL-6 significantly reversed the effect of total flavonoids on the phosphorylation of JAK2/STAT3, the expression of IL-6 and SOCS3 in ovaries of PCOS rats. Total flavonoids extracted from Nervilia Fordii might induce the expression of IL-6 in ovary and act as a potential therapeutic drug for the treatment of PCOS.

Thymosin ß4 promotes glucose-impaired endothelial progenitor cell function via Akt/endothelial nitric oxide synthesis signaling pathway.

Circulating endothelial progenitor cells (EPCs) are a subtype of hematopoietic stem cells, which can differentiate into endothelial cells and restore endothelial function. However, high glucose decreases the number and impairs the function of EPCs. A previous study showed that thymosin ß4 (Tß4), a pleiotropic peptide beneficial for multiple functions of various types of cells, could promote EPC migration and dose-dependently upregulate the phosphorylation of Akt and endothelial nitric oxide synthesis signaling (eNOS). In present study, the hypothesis that Tß4 can improve glucose-suppressed EPC functions via the Akt/eNOS signaling pathway and restores the production of nitric oxide (NO) is investigated. EPCs were isolated from the peripheral blood of healthy volunteers and formed a cobblestone shape after 3-4 weeks of cultivation. Then, EPCs were treated with high concentrations of glucose (25 mM) for 4 days and administrated with Tß4 for further study. Transwell migration and tube formation assays were performed to access the migratory and angiogenic ability of EPCs. In addition, the quantity of Akt, eNOS and the concentration of nitric oxide (NO) was investigated. Functional studies showed that high concentrations of glucose significantly suppressed EPC function, while this adverse effect was reversed by the administration of Tß4. In addition, Akt small interfering (si)RNA and eNOS siRNA were demonstrated to reduce the protective effect of Tß4 against glucose-impaired EPC functions. These findings suggest that Tß4 improves glucose-impaired EPC functions via the Akt/eNOS signaling pathway.