scholarly journals Antiangiogenesis Roles of Exosomes with Fei-Liu-Ping Ointment Treatment are Involved in the Lung Carcinoma with the Lewis Xenograft Mouse Model

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Qi Zheng ◽  
Haolong Liu ◽  
Huiting Fan ◽  
Ying Zhang ◽  
Wei Hou
Keyword(s):  
Mouse Model ◽  
Lung Carcinoma ◽  
Animal Studies ◽  
Xenograft Model ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Model Group ◽  
Xenograft Mouse Model ◽  
Lung Cancer Patients ◽  
Serum Tumour

Exosomes display efficient biocompatibility and represent valuable vehicles for drug or effective material delivery in a tumour-therapeutic approach. Following treatment with Fei-Liu-Ping (FLP) ointment, a traditional Chinese herbal formula, which is used for treating lung cancer patients, could inhibit lung carcinoma growth in clinical and animal studies. In the present study, the values of VEGF and PDGF, which were closely related to angiogenesis, were estimated in serum and carcinoma tissue exosomes to unveil the FLP effects on angiogenesis. The common inflammatory factors of IL-6, IL-1β, TNF-α, and TGF-β in serum exosomes were also detected with the Lewis xenograft model. Methods. Male C57BL/6 mice were randomly divided into four groups, namely, normal, model, cyclophosphamide (CTX), and FLP treatment groups. Histological structures were observed and imaged by H&E. CD31 expressions in tumour tissues were detected by immunofluorescence (IF) and western blot (WB). VEGF, PDGF, and PDGFR levels in exosomes, serum, tumour, and lung tissues were detected by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), and WB, respectively. IL-6, IL-1β, TNF-α, and TGF-β levels in exosomes were measured by multiplex immunoassay panels. Results. The results showed that FLP had tumour growth inhibition rate (39.31%). CD31 protein expression was obviously decreased in tumour tissues of CTX- and FLP-treated MO mice, compared to that of MO mice (P<0.05 or P<0.001). VEGF, PDGF, and PDGFR expression levels with FLP treatment were downregulated in exosomes, serum, tumour, and lung tissues compared to model group (P<0.05 or P<0.01). The expressions of IL-6, IL-1β, and TNF-α were downregulated in exosomes compared to the model group (P<0.05 or P<0.01). Conclusions. This study suggested that FLP had the ability of inhibiting tumourigenesis in a Lewis lung xenograft mouse model, whose therapeutic mechanisms might relate with the downregulation of angiogenesis factor and tumour inflammatory cytokines levels.

scholarly journals Effects of Shugan-Jianpi Recipe on the Expression of the p38 MAPK/NF-κB Signaling Pathway in the Hepatocytes of NAFLD Rats

Medicines ◽  
2018 ◽  
Vol 5 (3) ◽  
pp. 106 ◽  
Author(s):  
Yuanjun Deng ◽  
Kairui Tang ◽  
Runsen Chen ◽  
Yajie Liu ◽  
Huan Nie ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
P38 Mapk ◽  
Low Dose ◽  
Serum Levels ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
High Dose ◽  
Model Group ◽  
Necrosis Factor Alpha ◽  
Tnf Α

Background: In traditional Chinese medicine, the Shugan-Jianpi recipe is often used in the treatment of nonalcoholic fatty liver disease (NAFLD). This study aimed to explore the mechanism of the Shugan-Jianpi recipe in relation to rats with NAFLD induced by a high-fat diet. Methods: Rats were randomly divided into eight groups: normal group (NG), model group (MG), low-dose Chaihu–Shugan–San group (L-CG), high-dose Chaihu–Shugan–San group (H-CG), low-dose Shenling–Baizhu–San group (L-SG), high-dose Shenling–Baizhu–San group (H-SG), low dose of integrated-recipes group (L-IG), and high dose of integrated-recipes group (H-IG). After 26 weeks, a lipid profile, aspartate, and alanine aminotransferases in serum were detected. The serum levels of inflammatory factors including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) were analyzed using the enzyme linked immunosorbent assay (ELISA) method. Hepatic pathological changes were observed with hematoxylin-eosin (HE) and oil red O staining. The expression of the p38 mitogen-activated protein kinases (MAPK)/nuclear factor-κB (NF-κB) pathway was detected by quantitative real-time PCR and Western blotting. Results: A pathological section revealed that NAFLD rats have been successfully reproduced. Compared with the model group, each treatment group had different degrees of improvement. The Shugan-Jianpi recipe can inhibit the serum levels of IL-1β, IL-6, and TNF-α in NAFLD rats. The expression of mRNA and a protein related to the p38 MAPK/NF-κB signaling pathway were markedly decreased as a result of the Shugan-Jianpi recipe. Conclusions: The Shugan-Jianpi recipe could attenuate NAFLD progression, and its mechanism may be related to the suppression of the p38 MAPK/NF-κB signaling pathway in hepatocytes.

scholarly journals Targeting cyclooxygenase by indomethacin decelerates progression of acute lymphoblastic leukemia in a xenograft model

2019 ◽  
Vol 3 (21) ◽  
pp. 3181-3190 ◽  
Author(s):  
Nina Richartz ◽  
Eva Duthil ◽  
Anthony Ford ◽  
Elin Hallan Naderi ◽  
Sampada Bhagwat ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mouse Model ◽  
Lymphoblastic Leukemia ◽  
Xenograft Model ◽  
Xenograft Mouse Model ◽  
Cox Inhibitor ◽  
Key Points

Key Points The COX inhibitor indomethacin delays progression of ALL in a human xenograft mouse model. The xenograft-derived ALL cells treated with indomethacin express elevated levels of p53.

scholarly journals Effect of Huagantongluofang, a Chinese Traditional Medicine, in Hepatic Fibrogenesis in a Mouse Model of Biliary Cirrhosis

2017 ◽  
Vol 44 (1) ◽  
pp. 368-376 ◽  
Author(s):  
Ji Xuan ◽  
Wei Wen ◽  
Yong Wang ◽  
Feng Wang ◽  
Hua-bing Xu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mouse Model ◽  
Traditional Medicine ◽  
Hepatic Fibrosis ◽  
Therapeutic Effect ◽  
Enzyme Linked Immunosorbent Assay ◽  
Chinese Traditional Medicine ◽  
Cholestatic Liver Disease ◽  
Biliary Cirrhosis ◽  
Model Group

Background: Biliary cirrhosis (BC) is a chronic cholestatic liver disease, in which hepatic fibrosis is an early symptom. This study aimed to identify the biological function and the therapeutic effect of a Chinese traditional medicine, HuaGanTongLuoFang (HGTLF), in a mouse model of BC. Methods: The mice (n = 72) were randomly divided into a sham group (n =12) and BC group (n = 60). The animals in the BC group were then randomly divided into five groups (n = 12 in each) and treated with three different doses of HGTLF, ureodeoxycholic acid (UDCA), or normal saline (the model group). Four weeks later, serum and liver tissues were obtained from all the animals for analyses. Hematoxylin and eosin (H&E) staining was used to quantify the hepatic morphology, while real-time PCR and Enzyme-linked immunosorbent assay (ELISA) were used to determine the level of hepatic fibrosis-related genes. Results: Compared with the model group, all three doses of HGTLF improved hepatic function, as well as reducing inflammation and fibrogenesis. The best therapeutic effect was observed in the high-dose HGTLF group. Furthermore, HGTLF contributed to down-regulation of hepatic fibrosis-related genes (platelet-derived growth factor [PDGF], transforming growth factor-β [TGF-β], p38, nuclear factor-κB [NF-kB], intercellular adhesion molecular-1 [ICAM-1], and tissue inhibitor of metalloproteinase-1 [TIMP-1]). Conclusion: The data suggested that HGTLF effectively improved liver function and the morphology of the liver tissue in a mouse model of BC, possibly via suppression of hepatic fibrosis-related signals.

Evaluation of Pharmacokinetic-Pharmacodynamic (PKPD) Relationship of an Oral, Selective, First-in-Class, Potent IDH2 Inhibitor, AG-221, from a Phase 1 Trial in Patients with Advanced IDH2 Mutant Positive Hematologic Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3737-3737 ◽  
Author(s):  
Bin Fan ◽  
Yue Chen ◽  
Fang Wang ◽  
Katharine Yen ◽  
Luke Utley ◽  
...  
Keyword(s):  
Mouse Model ◽  
Phase I ◽  
Half Life ◽  
Phase I Study ◽  
Xenograft Model ◽  
Hematologic Malignancies ◽  
Plasma Exposure ◽  
Xenograft Mouse Model

Abstract Introduction: Isocitrate dehydrogenase (IDH) is a critical enzyme in the citric acid cycle, catalyzing the oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate (a-KG). The mutant IDH are not catalytically inactive enzymes, but rather possess novel enzymatic activities, catalyzing the reduction of α-KG to the ‘oncometabolite' 2-hydroxyglutarate (2-HG), which has been found to be elevated in patients with several tumor types, including acute myelogenous leukemia (AML). AG-221 is an oral, selective, first-in class, potent inhibitor of the IDH2 mutant protein. The compound has been demonstrated to reduce 2-HG levels by >90% and reverse histone and DNA hypermethylation in vitro, and to induce differentiation in leukemia cell models. In vivo pharmacokinetic/pharmacodynamic (PK/PD) studies in a U87MG IDH2 (R140Q) xenograft mouse model demonstrated robust plasma 2-HG lowering, and the correlation between PK (AG-221 exposure) and PD (the inhibition of 2-HG production) was used for human efficacious exposure projection. The PK/PD correlation was further confirmed in a primary human AML xenograft model in mice. These results are compared to early PK/PD results from the ongoing first-in-human Phase I study of AG-221 in patients with advanced IDH2 mutant positive hematologic malignancies [NCT01915498]. Methods: This first-in-man Phase I study of oral AG-221 was designed to evaluate the safety, PK, and PD, including 2-HG levels, as well as clinical activity. AG-221 was administered orally once (QD) or twice (BID) per day in continuous 28-day cycles. Sequential cohorts of patients were enrolled at higher dose levels. Patients included in this analysis were enrolled to doses of 30, 50, 75 mg BID and 100 mg QD (total N=21). Patients bearing the two dominant IDH2 mutations, R140Q (85.7%) or R172K (14.3%), were enrolled in the Phase I study. Blood was collected at multiple time points for determination of the PK and PD effects of AG-221. The concentrations of AG-221and 2-HG in plasma samples were determined using a qualified LC-MS/MS based method. PK and PK/PD analyses were performed using WinNonLin®. In addition, PK/PD relationships and efficacy of AG-221 was evaluated in a U87MG IDH2-R140Q xenograft mouse model and a primary human AML xenograft mouse model carrying the IDH2-R140Q mutation following oral doses. Results: Preliminary analysis of PK demonstrated excellent oral AG-221 exposure in humans. The mean plasma half-life is greater than 40 hours. Plasma 2-HG concentrations decreased rapidly; substantial and constant plasma 2-HG inhibition was achieved following multiple AG-221 doses in patients, and the inhibition was dose and drug exposure dependent. Based on exposure-response analyses with R140Q patients, the AG-221 AUC0-10hr value of 47.1 hr•ug/mL is estimated to result in sustained 90% plasma 2-HG inhibition in human (Figure1) which is associated with IC90 of 66 ng/mL. This is consistent with an in vivo IC90 in an AML xenograft model, U87MG IDH2-R140Q. In addition, up to 50% plasma 2-HG inhibition was observed in limited number of patients with R172K mutation. Figure 1. AG-221 plasma exposure and 2-HG inhibition correlation in patients with IDH2-R140Q mutation Figure 1. AG-221 plasma exposure and 2-HG inhibition correlation in patients with IDH2-R140Q mutation Conclusions: The pharmacokinetic profile for AG-221 supports QD dosing based on the high plasma exposure and long half-life observed in this study. AG 221 suppressed the production of 2-HG in plasma to the normal range found in healthy volunteers. 2-HG inhibition in R140Q mutation was translated well from mice to humans as well as from in vitro to in vivo. Disclosures Fan: Agios Pharmaceuticals: Employment, Stockholder Other. Chen:Agios Pharmaceuticals: Employment, Stockholder Other. Wang:Agios Pharmaceuticals: Employment, Stockholder Other. Yen:Agios: Employment. Utley:Agios Pharmaceuticals: Employment, Stockholder Other. Almon:Agios Pharmaceuticals: Employment, Stockholder Other. Biller:Agios Pharmaceuticals: Employment, Stockholder Other. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other. Yang:Agios Pharmaceuticals: Employment, Stockholder Other.

scholarly journals Effect of berberine on hyperandrogenemia, ovulation dysfunction and inflammation in a mouse model of polycystic ovary syndrome

2020 ◽  
Vol 19 (9) ◽  
pp. 1963-1968
Author(s):  
Kena Lu ◽  
Hanmei Lin
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Inflammatory Factors ◽  
Control Group ◽  
High Dose ◽  
Model Group ◽  
Blank Control Group ◽  
Ovary Syndrome ◽  
Stage Of Development

Purpose: To study the effect of berberine (BBR) on hyperandrogenemia (HA), ovulation dysfunction and inflammation in a mouse model of polycystic ovary syndrome (PCOS).Methods: Forty-five female Kunming mice were randomly divided into control group (9 mice), and mice injected with dehydroepiandrosterone (n = 36) for establishment of PCOS model. The PCOS mice were randomly divided into model group, low-dose BBR (0.25 g/kg), medium-dose BBR (0.5 g/kg) and highdose (1.0 g/kg) groups, with 9 mice in each group. Changes in ovarian morphology were monitored, and sex hormone levels i.e. testosterone (T) and luteinizing hormone (LH)), and inflammatory factors were determined.Results: The model group levels of T and LH were significantly higher than those of the blank control group (p < 0.05), but T and LH levels were significantly lower in middle- and high-dose BBR groups than in the model mice. There were marked increases in IL-6 and TNF-α levels in model mice, when compared to blank control mice, but reduced in the mice treated at the 3 doses of BBR, relative to model mice (p < 0.05). In contrast, the number of follicles was higher at each stage of development in mice for each BBR dose than in the model mice, with increase in corpus luteum.Conclusion: Berberine lowers the weight of PCOS mice, mitigates hyperandrogenemia and inflammatory state, and enhances recovery of ovulation. However, there is need for further studies on its clinic applicability. Keywords: Berberine, Polycystic ovary syndrome, Hyperandrogenemia, Ovulation dysfunction, Inflammatory

scholarly journals Shexiang-Wulong Pills Attenuate Rheumatoid Arthritis by Alleviating Inflammation in a Mouse Model of Collagen-Induced Arthritis

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Zhihui Zhang ◽  
Ying Cao ◽  
Qiang Yuan ◽  
Aiguo Zhang ◽  
Kaiqi Zhang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Song Dynasty ◽  
Bone Destruction ◽  
Serum Levels ◽  
Treated Group ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Group Model ◽  
Model Group ◽  
Collagen Induced Arthritis

Shexiang-Wulong Pill (SWP) is derived from “Moschus Yuan,” first formulated during the Song Dynasty for the treatment of joint pain. The aim of this study was to evaluate the therapeutic effect of SWP in a mouse model of collagen-induced arthritis (CIA). Forty-five DBA/1 mice were randomly divided into control group, model group, and SWP-treated group. SWP was administered by oral gavage for 22 days after the booster immunization. The clinical arthritic scores and joint histopathology, including synovial hyperplasia and hypoxic regions, cartilage erosion, and bone destruction, were evaluated. Microcomputed tomography (micro-CT) was used to assess microstructural changes in the bone. Serum levels of TNF-a, IL-6, and IFN-γ were measured by enzyme-linked immunosorbent assay (ELISA). The results showed a statistically significant improvement in joint pathological changes in the SWP-treated group. Imaging assessment confirmed that SWP protected the bone tissue from CIA-induced erosion and increased the bone density. In addition, the serum levels of TNF-a, IL-6, and IFN-γ in SWP-treated mice were significantly lower than those in the model group (P<0.05). Taken together, Shexiang-Wulong Pill can effectively alleviate joint swelling in CIA mice, inhibit synovial tissue hyperplasia, reduce inflammatory cell infiltration, and delay bone destruction. These results indicate that Shexiang-Wulong Pills could be an efficient medication for the treatment of RA.

scholarly journals Allicin Attenuates Inflammation and Suppresses HLA-B27 Protein Expression in Ankylosing Spondylitis Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Xin Gu ◽  
Haishan Wu ◽  
Peiliang Fu
Keyword(s):  
Ankylosing Spondylitis ◽  
Mouse Model ◽  
Protein Translation ◽  
Inflammatory Factors ◽  
High Dose ◽  
Hla B27 ◽  
Wild Type ◽  
Model Group ◽  
Rt Pcr ◽  
Protein Expressions

Here we aimed to determine the therapeutic effect of allicin on ankylosing spondylitis (AS) and explore the mechanism(s) of action. AS mouse model was constructed by transferring the HLA-B2704 gene into Kunming mice and verified by RT-PCR and CT imaging. Verified AS mice were randomly divided into model group (n=6) and allicin-treated groups (50, 100, and 200 mg/kg, resp.,n=6, p.o., for 2 months). Wild type mice were used as control (n=6). The levels of AS-related inflammatory factors were measured by ELISA. mRNA and protein expressions of HLA-B27 were checked by RT-PCR and western blotting. As the results, the mouse model of AS was successfully established, and high-dose allicin could markedly alleviate spine inflammatory injury possibly via reducing the secretion of the inflammatory factors (IL-6, IL-8, and TNF-α) sharply in AS mice. Moreover, allicin significantly inhibited HLA-B27 protein translation but failed to suppress HLA-B27 gene transcription in AS mice, indicating a posttranscriptional mechanism of this modulation. In conclusion, allicin has potential to be used for AS treatment as an anti-inflammatory nutraceutical.

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