Induction of developmental toxicity and cardiotoxicity in zebrafish embryos/larvae by acetyl-11-keto-β-boswellic acid (AKBA) through oxidative stress.
Han L1, Xia Q1, Zhang L2, Zhang X1, Li X1, Zhang S1, Wang L1, Liu C3, Liu K1.
Author information
1
Biology Institute, Qilu University of Technology (Shandong Academy of Sciences) , Jinan , People's Republic of China.
2
Biological Science Section, Therapeutic Good Administration , Symonston , Australia.
3
Tianjin Center for New Drug Evaluation and Research, State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research , Tianjin , People's Republic of China.
Abstract
Acetyl-11-keto-β-boswellic acid (AKBA), a triterpenoid from Boswellia serrate, is regarded as an angiogenesis inhibitor. However, its toxicity is unknown. The aim of this study was to examine its developmental toxicity and cardiotoxicity. A developmental toxicity assay in zebrafish embryos/larvae from 4 to 96 hours post-fertilization (hpf) was performed and a cardiotoxicity assay was designed from 48 to 72 hpf. Markers of oxidative stress and related genes were selected to access the possible mechanisms. According to the results, AKBA induced pericardium edema, yolk-sac edema, abnormal melanin, spinal curvature, hatching inhibition and shortened body length. Further, increased SV-BA distance, reduced heart rate, increased pericardium area and decreased blood flow velocity were detected in AKBA treated groups. The inhibition of cardiac progenitor gene expression, such as Nkx2.5 and Gata4, may be related to cardiotoxicity. The activities of antioxidant enzymes were decreased and the content of MDA was increased. In addition, AKBA treatment decreased the expression levels of Mn-Sod, Cat, and Gpx. These results suggested that AKBA induced developmental toxicity and cardiotoxicity through oxidative stress. As far as we know, this is the first report on the toxicity of AKBA. It reminds us to pay attention to developmental toxicity and cardiotoxicity of AKBA.

KEYWORDS:
Acetyl-11-keto-β-boswellic acid; cardiotoxicity; developmental toxicity; oxidative stress; zebrafish

PMID: 31656113 DOI: 10.1080/01480545.2019.1663865
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Select item 31655854
3.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Oct 26. doi: 10.1007/s00210-019-01746-8. [Epub ahead of print]
Chrysophanol exhibits anti-cancer activities in lung cancer cell through regulating ROS/HIF-1a/VEGF signaling pathway.
Zhang J1, Wang Q1,2, Wang Q1, Guo P1, Wang Y1, Xing Y1, Zhang M1, Liu F1, Zeng Q3.
Author information
1
Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021, Shandong, China.
2
Hospital Affiliated to Shandong University of Traditional Chinese Medicine, Jinan, 250011, Shandong, China.
3
Hospital Affiliated to Shandong University of Traditional Chinese Medicine, Jinan, 250011, Shandong, China. qingyunzengjnsd@163.com.
Abstract
In the present study, we explored the anti-tumor and anti-angiogenesis effects of chrysophanol, and to investigate the underlying mechanism of the chrysophanol on anti-tumor and anti-angiogenesis in human lung cancer. The viability of cells was measured by CCK-8 assay, cell apoptosis was measured by Annexin-FITC/PI staining assay, and the cell migration and invasion were analyzed by wound-healing assay and transwell assay. ROS generation and mitochondrial membrane potential were analyzed by DCFH-DA probe and mitochondrial staining kit. Angiogenesis was analyzed by tube formation assay. The expression of CD31 was analyzed by immunofluorescence. The levels of proteins were measured by western blot assay. The anti-tumor effects of chrysophanol in vivo were detected by established xenograft mice model. In this study, we found that the cell proliferation, migration, invasion, tube formation, the mitochondrial membrane potential, and the expression of CD31 were inhibited by chrysophanol in a dose-dependent manner, but cell apoptotic ratios and ROS levels were increased by chrysophanol in a dose-dependent manner. Furthermore, the effects of chrysophanol on A549, H738, and HUVEC cell apoptotic rates were reversed by the ROS inhibitor NAC. Besides, the effects of chrysophanol on HUVEC cell tube formation were reversed by the HIF-1α inhibitor KC7F2 and the VEGF inhibitor axitinib in vitro. Moreover, tumor growth was reduced by chrysophanol, and the expression of CD31, CD34, and angiogenin was suppressed by chrysophanol in vivo. Our finding demonstrated that chrysophanol is a highly effective and low-toxic drug for inhibition of tumor growth especially in high vascularized lung cancer.

KEYWORDS:
Angiogenesis; Invasion; Metastasis; Tube formation

PMID: 31655854 DOI: 10.1007/s00210-019-01746-8
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Select item 31655041
4.
Exp Eye Res. 2019 Oct 23:107851. doi: 10.1016/j.exer.2019.107851. [Epub ahead of print]
RKIP negatively regulates the glucose induced angiogenesis and endothelial-mesenchymal transition in retinal endothelial cells.
Feng L1, Zhang C1, Liu G1, Wang F2.
Author information
1
Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China.
2
Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China. Electronic address: 18917683335@163.com.
Abstract
Diabetic retinopathy (DR), a common microvascular complication of diabetes, is reported to be the leading cause of blindness worldwide. In our previous study, we found that the Raf kinase inhibitor protein (RKIP) is significantly decreased in vitreous humor of proliferative diabetic retinopathy (PDR) patients, which indicated that RKIP might play a role in the development of PDR. To investigate the role of RKIP in PDR, stable overexpression and knockdown of RKIP in Human retinal capillary endothelial cells (HRCECs) were generated by using lentivirus constructs. Then, the glucose-induced cell viability, migration, angiogenesis, and (endothelial to mesenchymal transition) EndMT were determined in the RKIP-wide type (WT), -knocking down (KD) and -overexpression (OE) HRCECs. The results showed that, compared with the RKIP-WT groups, the glucose-induced cell viabilities, migration and angiogenesis were significantly increased in the RKIP-KD groups, while significantly decreased in the RKIP-OE groups. Besides, compared with the control groups, CD31 and vWF were upregulated, while α-SMA was downregulated in the RKIP-KD groups, while CD31 and vWF were downregulated, while α-SMA was upregulated in the RKIP-OE groups induced by glucose. In conclusion, our results showed that RKIP negatively regulates glucose-induced cell viability, migration, angiogenesis, and EndMT in HRCECs, suggesting that the downregulation of RKIP in the vitreous humor of PDR patients might contribute to the development of DR.

Copyright © 2019. Published by Elsevier Ltd.

KEYWORDS:
Angiogenesis; Cell viability; Diabetic retinopathy; Endothelial to mesenchymal transition; Migration; Raf kinase inhibitor protein

PMID: 31655041 DOI: 10.1016/j.exer.2019.107851
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Select item 31652997
5.
Biomolecules. 2019 Oct 24;9(11). pii: E644. doi: 10.3390/biom9110644.
Pharmacology Study of the Multiple Angiogenesis Inhibitor RC28-E on Anti-Fibrosis in a Chemically Induced Lung Injury Model.
Kou X1, Sun Y2, Li S3, Bian W4, Liu Z5, Zhang D6, Jiang J7.
Author information
1
Department of Pharmacology, Binzhou Medical University, Yantai 256603, China. xiangyingkou@sina.com.
2
Department of Pharmacology, Binzhou Medical University, Yantai 256603, China. sunyy21cn@163.com.
3
RemeGen Co., Ltd., Yantai 264006, China. lisj@remegen.cn.
4
Department of Pharmacology, Binzhou Medical University, Yantai 256603, China. bian_1005@163.com.
5
RemeGen Co., Ltd., Yantai 264006, China. liuzhihao@remegen.cn.
6
Department of Pharmacology, Binzhou Medical University, Yantai 256603, China. dlzhang313@163.com.
7
Department of Pharmacology, Binzhou Medical University, Yantai 256603, China. jjiang@bzmc.edu.cn.
Abstract
BACKGROUND:
Disease-related injury in any organ triggers a complex cascade of cellular and molecular responses that culminate in tissue fibrosis, inflammation, and angiogenesis simultaneously. Multiple cell angiogenesis is an essential part of the tissue damage response, which is involved in fibrosis development. RC28-E is a novel recombinant dual decoy receptor lgG1 Fc-fusion protein that can block vascular endothelial growth factor (VEGFA), platelet-derived growth factor (PDGF), and fibroblast growth factor-2 (FGF-2) simultaneously. This protein has stepped into clinical trials (NCT03777254) for the treatment of pathological neovascularization-related diseases. Here, we report on the role of RC28-E during anti-fibrosis and its potential multitarget function in regulating fibrosis.

METHODS:
A bleomycin-induced pulmonary fibrosis C57BL/6 mouse model was established. Hematoxylin and eosin staining (HE) and Masson staining (Masson's) were performed to evaluate the pulmonary fibrosis based on the scoring from, Ashcroft score. Fibrosis related factors and inflammatory cytokines including HYP, α-SMA, procollagen, ICAM, IL-6, IL-1, and TNF-α were also determined at the protein and mRNA levels to characterize the fibrosis. Both mRNA and protein levels of VEGF, FGF, and transforming growth factor (TGF)-β were detected by quantitative real-time PCR (qRT-PCR) and immunohistochemical (IHC) analysis, respectively. Pulmonary fibrosis and related cytokines were re-evaluated in vivo after 3 doses of RC28-E (5 mg/kg, 15 mg/kg, and 50 mg/kg, ip. Tiw × 9) in comparison with a mono-target antagonist treatment (VEGF or FGF blocking). RC28-E attenuated the activation of TGF-β induced fibroblasts in vitro. Expression levels of α-SMA and collagen I, as well as proliferation and migration, were determined with the human skin fibroblast cell line Detroit 551 and primary murine pulmonary fibroblast cells. The mechanism of RC28-E via the TGF-β/Smad pathway was also investigated.

RESULTS:
RC28-E exhibits significant anti-fibrosis effects on Idiopathic pulmonary fibrosis (IPF) in vivo. Moreover, TGF-β induced fibroblast activation in vitro via the inhibition of the TGF-β downstream Smad pathway, thus providing potential therapeutics for clinical disease-related fibrosis-like IPF as well as chemotherapy-induced fibrosis in cancer therapy.

KEYWORDS:
FGF; VEGF; angiogenesis; anti-fibrosis; lung injury; pharmacology study

PMID: 31652997 DOI: 10.3390/biom9110644
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Select item 31652618
6.
Cells. 2019 Oct 22;8(10). pii: E1297. doi: 10.3390/cells8101297.
Inhibition of Non-Small Cell Lung Cancer Cells by Oxy210, an Oxysterol-Derivative that Antagonizes TGFβ and Hedgehog Signaling.
Stappenbeck F1, Wang F2, Tang LY3, Zhang YE4, Parhami F5.
Author information
1
MAX BioPharma, Inc., 2870 Colorado Avenue, Santa Monica, CA 90404, USA. fstappenbeck@maxbiopharma.com.
2
MAX BioPharma, Inc., 2870 Colorado Avenue, Santa Monica, CA 90404, USA. fwang@maxbiopharma.com.
3
Laboratory of Cellular & Molecular Biology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, 37/2056B Bethesda, MD 20892-4256, USA. tangl2@mail.nih.gov.
4
Laboratory of Cellular & Molecular Biology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, 37/2056B Bethesda, MD 20892-4256, USA. zhangyin@mail.nih.gov.
5
MAX BioPharma, Inc., 2870 Colorado Avenue, Santa Monica, CA 90404, USA. fparhami@maxbiopharma.com.
Abstract
Non-Small Cell Lung Cancer (NSCLC) is a common malignancy and leading cause of death by cancer. Metastasis and drug resistance are serious clinical problems encountered in NSCLC therapy. Aberrant activation of the Transforming Growth Factor beta (TGFβ) and Hedgehog (Hh) signal transduction cascades often associate with poor prognosis and aggressive disease progression in NSCLC, as these signals can drive cell proliferation, angiogenesis, metastasis, immune evasion and emergence of drug resistance. Therefore, simultaneous inhibition of TGFβ and Hh signaling, by a single agent, or in combination with other drugs, could yield therapeutic benefits in NSCLC and other cancers. In the current study, we report on the biological and pharmacological evaluation of Oxy210, an oxysterol-based dual inhibitor of TGFβ and Hh signaling. In NSCLC cells, Oxy210 inhibits proliferation, epithelial-mesenchymal transition (EMT) and invasive activity. Combining Oxy210 with Carboplatin (CP) increases the anti-proliferative response to CP and inhibits TGFβ-induced resistance to CP in A549 NSCLC cells. In addition, Oxy210 displays encouraging drug-like properties, including chemical scalability, metabolic stability and oral bioavailability in mice. Unlike other known inhibitors, Oxy210 antagonizes TGFβ and Hh signaling independently of TGFβ receptor kinase inhibition and downstream of Smoothened, respectively.

KEYWORDS:
TGFβ signaling; drug resistance; hedgehog signaling; metastasis; oxysterols

PMID: 31652618 DOI: 10.3390/cells8101297
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Conflict of interest statement
Select item 31651672
7.
J Cardiovasc Pharmacol. 2019 Oct 18. doi: 10.1097/FJC.0000000000000772. [Epub ahead of print]
CD137-CD137L signaling affects angiogenesis by mediating phenotypic conversion of macrophages.
Xu Y1, Yan Y2, Geng T1, Wang C1, Xu Y1, Yang P1, Yan J1.
Author information
1
Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, CHN.
2
Department of Cardiology, Ren Ji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, CHN.
Abstract
BACKGROUND:
Angiogenesis in atherosclerotic plaque is an important factor causing plaque hemorrhage, vulnerability and rupture and different phenotypes of macrophages have different effects on angiogenesis. Our previous study has demonstrated CD137-CD137L signaling, a pair of inflammatory co-stimulatory molecules, can promote angiogenesis in atherosclerotic plaque. Therefore, we aimed to investigate whether this signaling could affect angiogenesis by regulating phenotypic transition of macrophages.

METHODS:
Male mouse primary peritoneal macrophages were extracted by intraperitoneal injection of thioglycollate, and then flow cytometry was used to detect the expression of CD137. Flow cytometry, Western blotting, quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA) were used to assess the phenotypic changes of macrophages after different treatment. Mouse brain microvascular endothelial cells (bEnd.3) were co-cultured with macrophages and tube formation was assessed to examine angiogenesis.

RESULTS:
We found that the number of junctions and branches of bEnd.3 were increased when CD137-CD137L signaling was activated, while such number was further increased when bEnd.3 were co-cultured with macrophages. Flow cytometry showed that CD137 was expressed on almost all primary peritoneal macrophages. The expression of CD86 was decreased in the agonist CD137L group and increased in the agonist CD137L + inhibitory anti-CD137 antibody group after adding the CD137 inhibitor. The expression of CD206 in each group exhibited opposite trend compared with CD86. Moreover, the expression of inducible nitric oxide synthase (iNOS) at the mRNA and protein levels was decreased after stimulating CD137-CD137L signaling, and such downward trend was reversed when CD137-CD137L signaling was inhibited. Furthermore, the expression of arginase-1 was opposite to that of iNOS. ELISA indicated that the content of interleukin-12 (IL-12) in the supernatant of macrophages in the agonist CD137L group was lower than that in the control group, and its content in the inhibited group was higher than that in the activated group. The change of interleukin-10 (IL-10) content in macrophage supernatant was opposite to that of IL-12. When AKT serine/threonine kinase 1 (Akt1) inhibitor was used to inhibit the phenotypic transformation of macrophages induced by CD137-CD137L, the number of junctions and branches formed by bEnd.3 was decreased compared with the co-culture group.

CONCLUSIONS:
These results indicated that CD137-CD137L signaling could promote angiogenesis by regulating phenotypic transition of macrophages of male mice.

PMID: 31651672 DOI: 10.1097/FJC.0000000000000772
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Select item 31650542
8.
J Cell Physiol. 2019 Oct 24. doi: 10.1002/jcp.29350. [Epub ahead of print]
Downregulation of microRNA-103a reduces microvascular endothelial cell injury in a rat model of cerebral ischemia by targeting AXIN2.
Wu Z1,2, Liang Y3, Yu S1.
Author information
1
Department of Encephalopathy, Jiangmen Wuyi Hospital of Traditional Chinese Medicine, Jiangmen, Guangdong, China.
2
Department of Encephalopathy, Hunan University of Chinese Medicine, Changsha, Hunan, China.
3
Department of Rehabilitation, Jiangmen Wuyi Hospital of Traditional Chinese Medicine, Jiangmen, Guangdong, China.
Abstract
Multiple microRNAs (miRNAs) have been found to be linked with cerebral ischemia. Thus, this study was employed to characterize the capabilities of miRNA-103a (miR-103a) on the brain microvascular endothelial cells (BMECs) injury in rat models of middle cerebral artery occlusion (MCAO) by regulating AXIN2. The MCAO rat model was developed by the suture method, where normal saline, miR-103a inhibitors, or its negative control were separately injected into the lateral ventricle to assess the function of miR-103a inhibitors in BMECs apoptosis, microvessel density, as well as angiogenesis. In addition, the oxygen-glucose deprivation model was induced in primarily cultured BMECs to unearth the functions of miR-103a inhibitors on cell viability and apoptosis, lactate dehydrogenase (LDH) release and tube formation ability. Furthermore, the relationship between miR-103a and AXIN2 was verified. The modeled rats of MCAO showed robustly expressed miR-103a, poorly expressed AXIN2, severe neurological deficits, accelerated apoptosis and reduced angiogenesis. miR-103a expression had a negative correlation with AXIN2 messenger RNA expression (r = -0.799; p < .05). In response to the treatment of miR-103a inhibitors, the BMECs apoptosis was suppressed and angiogenesis was restored, corresponding to upregulated Bcl-2, VEGF, and Ang-1, in addition to downregulated caspase-3 and Bax. Meanwhile, AXIN2 was verified to be the miR-103a's target gene. More important, miR-103a inhibitors led to promoted BMEC viability and tube formation and suppressed apoptosis and LDH release rate. This study highlights that miR-103a targets and negatively regulates AXIN2, whereby reducing BMEC injury in cerebral ischemia.

© 2019 Wiley Periodicals, Inc.

KEYWORDS:
AXIN2; angiogenesis; brain microvascular endothelial cells; cerebral ischemia; microRNA-103a

PMID: 31650542 DOI: 10.1002/jcp.29350
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Select item 31649488
9.
Cancer Cell Int. 2019 Oct 21;19:271. doi: 10.1186/s12935-019-0977-9. eCollection 2019.
Inactivation of the Wnt/β-catenin signaling pathway underlies inhibitory role of microRNA-129-5p in epithelial-mesenchymal transition and angiogenesis of prostate cancer by targeting ZIC2.
Jiang Z1, Zhang Y1,2, Chen X3, Wu P1, Chen D4.
Author information
1
1Department of Urology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110001 Liaoning People's Republic of China.
2
Department of Urology, People's Hospital of Datong Hui and Tu Autonomous County, No. 1, Wenhua Road, Qiaotou Town, Datong Hui and Tu Autonomous County, Xining, 810100 Qinghai People's Republic of China.
3
3Department of Pharmacy, The First Hospital of China Medical University, Shenyang, 110001 People's Republic of China.
4
4Central Lab, The First Hospital of China Medical University, Shenyang, 110001 People's Republic of China.
Abstract
BACKGROUND:
Prostate cancer (PCa) is a common disease that often occurs among older men and a frequent cause of malignancy associated death in this group. microRNA (miR)-129-5p has been identified as an essential regulator with a significant role in the prognosis of PC. Therefore, this study aimed to investigate roles of miR-129-5p in PCa.

METHODS:
Microarray analysis was conducted to identify PCa-related genes. The expression of miR-129-5p and ZIC2 in PCa tissues was investigated. To understand the role of miR-129-5p and ZIC2 in PCa, DU145 cells were transfected with mimic or inhibitor of miR-129-5p, or si-ZIC2 and the expression of Wnt, β-catenin, E-cadherin, vimentin, N-cadherin, vascular endothelial growth factor (VEGF), and CD31, as well as the extent of β-catenin phosphorylation was determined. In addition, cell proliferation, migration, invasion, angiogenesis, apoptosis and tumorigenesis were detected.

RESULTS:
miR-129-5p was poorly expressed and ZIC2 was highly expressed in PCa tissues. Down-regulation of ZIC2 or overexpression of miR-129-5p reduced the expression of ZIC2, Wnt, β-catenin, N-cadherin, vimentin, and β-catenin phosphorylation but increased the expression of E-cadherin. Importantly, miR-129-5p overexpression significantly reduced cell migration, invasion, angiogenesis and tumorigenesis while increasing cell apoptosis.

CONCLUSIONS:
The findings of the present study indicated that overexpression of miR-129-5p or silencing of ZIC2 could inhibit epithelial-mesenchymal transition (EMT) and angiogenesis in PCa through blockage of the Wnt/β-catenin signaling pathway.

© The Author(s) 2019.

KEYWORDS:
Angiogenesis; Epithelial–mesenchymal transition; Prostate cancer; Wnt/β-catenin signaling pathway; Zinc-finger protein of the cerebellum 2; microRNA-129-5p

PMID: 31649488 PMCID: PMC6805653 DOI: 10.1186/s12935-019-0977-9
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Conflict of interest statement
Select item 31649116
10.
Biol Open. 2019 Oct 24. pii: bio.044800. doi: 10.1242/bio.044800. [Epub ahead of print]
MiR145-5p inhibits proliferation of PMVECs via PAI-1 in experimental hepatopulmonary syndrome rat pulmonary microvascular hyperplasia.
Chen Y1, Yang C1, Li Y1, Chen L1, Yang Y1, Belguise K2, Wang X2, Lu K3, Yi B3.
Author information
1
Department of Anesthesia, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
2
LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062 Toulouse, France.
3
Department of Anesthesia, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China lukaizhi2010@163.com yibin1974@163.com.
Abstract
BACKGROUND/AIM:
Hepatopulmonary syndrome (HPS) is a triad of advanced liver disease, intrapulmonary vasodilatation (IPVD), and arterial hypoxemia. Increasing evidence show HPS is associated with pulmonary microvascular hyperplasia. The aim of this work was to investigate the underlying mechanism of miR-145 in regulating the proliferation of pulmonary microvascular endothelial cells (PMVECs) and angiogenesis in HPS via PAI-1.

METHODS:
Morphology score and number of pulmonary microvascular were assessed in lung tissues from rats with HPS by hematoxylin and eosin (H&E) staining. Expression levels of PAI-1 were assessed in lung tissues from HPS rats, as well as in PMVECs treated with HPS rat serum. We also selected the putative microRNA binding site on PAI-1 by bioinformatics analysis. Then, miR145-3p and miR145-5p expression levels in the lung and PMVECs of rats were detected by qRT-PCR because miR145-5p is a microRNA binding site on PAI-1. In addition, the effects of miR-145-5p regulation on PAI-1 were examined by upregulation and downregulation of miR-145-5p. And specific lentivirus transfection was used to overexpression and knockdown PAI-1 to assess PAI-1 function on PMVECs proliferation.

RESULTS:
Our data showed that levels of PAI-1 expression in lung tissue of rats increased significantly when rats were treated with common bile duct ligation (CBDL). We found that levels of miR-145-5p were frequently downregulated in HPS tissues and cell lines, and overexpression of miR-145-5p dramatically inhibited PMVECs proliferation. We further verified PAI-1 as a novel and direct target of miR-145-5p in HPS. MiR-145-5p inhibits PAI-1 synthesis. And the expression changes of PAI-1 directly affect the proliferation of PMVECs.

CONCLUSION:
MiR-145-5p negatively regulates PMVECs proliferation through PAI-1 expression. In addition, overexpression of miR-145-5p may prove beneficial as a therapeutic strategy for HPS treatment.

© 2019. Published by The Company of Biologists Ltd.

KEYWORDS:
Hepatopulmonary syndrome (HPS); MiR145-5p; Plasminogen activator inhibitor-1 (PAI-1); Pulmonary microvascular endothelial cells (PMVECs)

PMID: 31649116 DOI: 10.1242/bio.044800
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Select item 31648565
11.
Nutr Cancer. 2019 Oct 25:1-15. doi: 10.1080/01635581.2019.1673451. [Epub ahead of print]
The effects of anticancer medicinal herbs on vascular endothelial growth factor based on pharmacological aspects: a review study.
Fakhri S1, Abbaszadeh F2,3, Jorjani M3,4, Pourgholami MH5.
Author information
1
Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences , Kermanshah , Iran.
2
Department of Neuroscience, Faculty of Advanced Technologies in Medical Sciences, Iran University of Medical Sciences , Tehran , Iran.
3
Neurobiology Research Center, Shahid Beheshti University of Medical Sciences , Tehran , Iran.
4
Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences , Tehran , Iran.
5
Neuroscience Research Center, Shahid Beheshti University of Medical Sciences , Tehran , Iran.
Abstract
As a complicated process of forming new blood vessels from the present vasculature endothelium, angiogenesis plays a critical role in the progression of cancer, through developing new blood vessels in tumor cells. Angiogenesis is regulated by proteins known as inhibitor or activator molecules, affected by different medicinal herbs and small molecules. In the present review, the molecular mechanisms of tumor angiogenesis are outlined, focusing on the pharmacological aspects and molecular mechanisms of natural compounds used in chemotherapy and their effects on angiogenesis, focusing on vascular endothelial growth factor (VEGF). Our findings show that a significant number of drugs used in the treatment of cancer are antiangiogenic small molecules and phytochemicals which inhibit VEGF and angiogenesis. Besides, medicinal herbs are potential multi-target agents with more covering mechanisms, lower costs and lower toxicity to develop novel anticancer drugs through targeting the VEGF signaling pathway and receptor tyrosine kinases (RTKs) in the angiogenesis. For this reason, herbal anti-VEGF agents are considered as imperative targets to be used for cancer treatment in clinical applications. The findings reveal a promising perspective for medicinal herbs and natural compounds acting on VEGF and angiogenesis to find new targets and potential therapeutic use in the treatment of cancer.

PMID: 31648565 DOI: 10.1080/01635581.2019.1673451
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Select item 31648351
12.
Exp Clin Endocrinol Diabetes. 2019 Oct 24. doi: 10.1055/a-1022-9874. [Epub ahead of print]
Thyroid Hormone Effects on Mesenchymal Stem Cell Biology in the Tumour Microenvironment.
Schmohl KA1, Müller AM1, Nelson PJ1, Spitzweg C1.
Author information
1
Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.
Abstract
Non-classical thyroid hormone signalling via cell surface receptor integrin αvβ3, expressed on most cancer cells and proliferating endothelial cells, has been shown to drive tumour cell proliferation and survival, as well as angiogenesis. Tumours develop within a complex microenvironment that is composed of many different cell types, including mesenchymal stem cells. These multipotent progenitor cells actively home to growing tumours where they differentiate into cancer-associated fibroblast-like cells and blood vessel-stabilising pericytes and thus support the tumour's fibrovascular network. Integrin αvβ3 expression on mesenchymal stem cells makes them susceptible to thyroid hormone stimulation. Indeed, our studies demonstrated - for the first time - that thyroid hormones stimulate the differentiation of mesenchymal stem cells towards a carcinoma-associated fibroblast-/pericyte-like and hypoxia-responsive, pro-angiogenic phenotype, characterised by the secretion of numerous paracrine pro-angiogenic factors, in addition to driving their migration, invasion, and recruitment to the tumour microenvironment in an experimental hepatocellular carcinoma model. The deaminated thyroid hormone metabolite tetrac, a specific inhibitor of thyroid hormone action at the integrin site, reverses these effects. The modulation of mesenchymal stem cell signalling and recruitment by thyroid hormones via integrin αvβ3 adds a further layer to the multifaceted effects of thyroid hormones on tumour progression, with important implications for the management of cancer patients and suggests a novel mechanism for the anti-tumour activity of tetrac.

© Georg Thieme Verlag KG Stuttgart · New York.

PMID: 31648351 DOI: 10.1055/a-1022-9874
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Conflict of interest statement
Select item 31648117
13.
Colloids Surf B Biointerfaces. 2019 Oct 15;185:110552. doi: 10.1016/j.colsurfb.2019.110552. [Epub ahead of print]
Encapsulation of an endostatin peptide in liposomes: Stability, release, and cytotoxicity study.
Rezaei N1, Mehrnejad F2, Vaezi Z3, Sedghi M3, Asghari SM4, Naderi-Manesh H5.
Author information
1
Department of Life Sciences Engineering, Faculty of New Sciences & Technologies, University of Tehran, 14395-1561 Tehran, Iran.
2
Department of Life Sciences Engineering, Faculty of New Sciences & Technologies, University of Tehran, 14395-1561 Tehran, Iran. Electronic address: Mehrnejad@ut.ac.ir.
3
Department of Nanobiotechnology/Biophysics, Faculty of Biological Science, Tarbiat Modares University, 14115-154 Tehran, Iran.
4
Department of Biology, Faculty of Sciences, University of Guilan, 41335-19141 Rasht, Iran.
5
Department of Nanobiotechnology/Biophysics, Faculty of Biological Science, Tarbiat Modares University, 14115-154 Tehran, Iran. Electronic address: Naderman@modares.ac.ir.
Abstract
The endostatin protein is a potent inhibitor of angiogenesis and tumor growth. The anti-angiogenic and antitumor properties of full-length endostatin can be mimicked by its N-terminal segment, including residues 1-27. Therefore, our previous studies have shown that a mutant N-terminal peptide which the Zn-binding loop was replaced by a disulfide loop (referred to as the ES-SS peptide) has preserved antiangiogenic and antitumor properties compared to the native peptide. To increase stability and plasma half-life of the ES-SS peptide, the nano-sized liposomal formulations of the peptide with different ratio of phosphocholine (PC) were synthesized. The liposomal peptide formulations possessed an average size of around 100 nm with (-4 to -36 mv) in zeta potential. The encapsulation efficiency of the ES-SS peptide was in the range of 24-54% with different lipid: peptide molar ratios. In vitro release of the peptide from liposomes indicated a complete peptide release after 7 days. Cytotoxicity assay was evaluated using the human umbilical vein endothelial cells (HUVECs) for various concentrations of the liposomal peptide. The results depicted the gradual release of the peptide through liposomes. By comparing with the free peptide, the liposomal peptide formulations have indicated higher cell viability with IC50 value about 0.1 μM. The peptide-liposome interactions, as well as the peptide effect on the liposome structure, were also investigated through coarse-grained molecular dynamics (CG-MD) simulation. The results revealed that the peptides were assembled in the hydrophilic core of the liposome. The peptide behavior in liposome can stabilize the liposome structure and be a response to the observed low peptide release rate. The investigation is promising for designing a liposome-based anti-angiogenesis peptide delivery system.

Copyright © 2019 Elsevier B.V. All rights reserved.

KEYWORDS:
Anticancer activity; Cytotoxicity; Endostatin peptide; Liposome; Peptide delivery

PMID: 31648117 DOI: 10.1016/j.colsurfb.2019.110552
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Select item 31597844
14.
Rinsho Ketsueki. 2019;60(9):1199-1204. doi: 10.11406/rinketsu.60.1199.
New developments in the treatment of follicular lymphoma.
Leonard JP1.
Author information
1
Division of Hematology and Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital.
Abstract
The treatment of follicular lymphoma (FL) continues to evolve. Those patients who present with minimal symptoms often are observed without therapy until significant progression occurs. When treatment is needed, initial options include single agent rituximab (R, anti-CD20), or various forms of chemoimmunotherapy including either R or the newer anti-CD20 monoclonal antibody obinutuzumab (O), with or without maintenance administration. Recent data suggest that the immunomodulatory agent lenalidomide can also be effective in combination with rituximab in both the upfront and relapsed setting. Patients with recurrent disease are frequently treated with chemoimmunotherapy or phosphoinositol-3-kinase (PI3K) inhibitors. Current information suggests that the most important prognostic feature of FL is the presence or absence of early progression (within 2 years of initial treatment/diagnosis). Ongoing efforts are focused on biomarkers to optimally match treatment to patient populations and further improve clinical outcomes.

KEYWORDS:
Chemoimmunotherapy; Follicular lymphoma; Phosphoinositol-3-kinase inhibitors

PMID: 31597844 DOI: 10.11406/rinketsu.60.1199
[Indexed for MEDLINE]
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15.
Cancer Invest. 2019;37(9):501-505. doi: 10.1080/07357907.2019.1662031. Epub 2019 Oct 4.
Leptomeningeal Metastases in Renal Cell Carcinoma at Initial Diagnosis: 2 Case Reports and Literature Review.
Dridi M1, Bouleftour W1, Rivoirard R1, Dal Col P2, Langrand-Escure J3, Vassal C1, Guillot A1.
Author information
1
Department of Medical Oncology, Institut de Cancérologie Lucien Neuwirth , Saint Priest en Jarez , France.
2
Anatomo-pathology Department, CHU de Saint Etienne , Saint-Etienne , France.
3
Department of Radiotherapy, Institut de Cancérologie Lucien Neuwirth , Saint Priest en Jarez , France.
Abstract
Leptomeningeal metastasis (LM) in solid tumors are rare, even more in renal cell carcinoma (RCC). To date there is a lack of consensual treatment modalities of leptomeningeal metastasis. Furthermore, with the improvement of outcomes and more effective systemic targeted therapies, the management of leptomeningeal metastasis becomes a real challenge. We here report two cases of RCC with leptomeningeal metastasis at initial diagnosis. Both patients had concurrent adjacent skull bone metastasis. Therapeutic management of both patients consisted in surgical resection, followed by radiotherapy in one case. Systemic treatment was delayed according to current recommendations for the management of metastatic RCC. The aim of this work is to report the therapeutic approach and related outcomes and also provide a review of the currently available literature on leptomeningeal disease in renal cell carcinoma. Indeed, local treatment with curative outcome of meningeal location in RCC should be performed specially in LM at initial diagnosis.

KEYWORDS:
Renal cell carcinoma; clinical management; leptomeningeal metastasis

PMID: 31583922 DOI: 10.1080/07357907.2019.1662031
[Indexed for MEDLINE]
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Select item 31513439
16.
Expert Opin Investig Drugs. 2019 Oct;28(10):861-869. doi: 10.1080/13543784.2019.1667333. Epub 2019 Sep 26.
Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease.
Hussain RM1, Neiweem AE2, Kansara V3, Harris A2, Ciulla TA2,3,4.
Author information
1
Retina Associates , Elmhurst , IL , USA.
2
Department of Ophthalmology, Indiana University School of Medicine , Indianapolis , IN , USA.
3
Clearside Biomedical, Inc , Alpharetta , GA , USA.
4
Retina Service, Midwest Eye Institute , Indianapolis , IN , USA.
Abstract
Introduction: The Tie-2/Angiopoietin pathway is a therapeutic target for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Activation of Tie-2 receptor via Ang-1 maintains vascular stability to limit exudation. Ang-2, a competitive antagonist to Ang-1, and VE-PTP, an endothelial-specific phosphatase, interfere with the Tie-2-Ang-1 axis, resulting in vascular leakage. Areas covered: Faricimab, a bispecific antibody that inhibits VEGF-A and Ang-2, is in phase 3 trials for nAMD and DME. Nesvacumab is an Ang-2 inhibitor; when coformulated with aflibercept, it failed to show benefit over aflibercept monotherapy in achieving visual gains in phase 2 studies of nAMD and DME. ARP-1536 is an intravitreally administered VE-PTP inhibitor undergoing preclinical studies. AKB-9778 is a subcutaneously administered VE-PTP inhibitor that, when combined with monthly ranibizumab, reduced DME more effectively than ranibizumab monotherapy in a phase 2 study. AKB-9778 monotherapy did not reduce diabetic retinopathy severity score compared to placebo. AXT107, currently in the preclinical phase, promotes conversion of Ang-2 into a Tie-2 agonist and blocks signaling through VEGFR2 and other receptor tyrosine-kinases. Expert opinion: Tie-2/Angiopoietin pathway modulators show promise to reduce treatment burden and improve visual outcomes in nAMD and DME, with potential to treat cases refractory to current treatment modalities.

KEYWORDS:
AKB-9778; ARP-1536; AXT107; Age-related macular degeneration; Tie-2 receptor; angiopoietin; diabetic macular edema; faricimab; nesvacumab; vascular endothelial growth factor

PMID: 31513439 DOI: 10.1080/13543784.2019.1667333
[Indexed for MEDLINE]
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Select item 31479282
17.
Expert Opin Drug Saf. 2019 Nov;18(11):1031-1041. doi: 10.1080/14740338.2019.1663168. Epub 2019 Sep 11.
The safety of anti-interleukins monoclonal antibodies for the treatment of psoriasis.
D'Adamio S1, Silvaggio D1, Lombardo P1, Bianchi L1, Talamonti M1, Galluzzo M1.
Author information
1
Dermatology Unit, University of Rome "Tor Vergata" , Rome , Italy.
Abstract
Introduction: Psoriasis is a chronic inflammatory disease and affects about 10% of the world's population. Psoriasis is associated with a number of comorbidities. Biologic therapies for the treatment of moderate-severe plaque psoriasis include tumor necrosis factor α inhibitors (TNFi), and newer molecules targeting IL-12 and 23, blocking p40 subunit, or targeting subunit p19 of IL-23 and other molecules blocking IL-17A, or directed against the IL-17 receptor. Areas covered: Anti-interleukin drugs show great improvement in disease control and on the other hand are not affected by important adverse reactions of older compounds. Approach to chronic disease affected patients, in particular, and to patients with multiple comorbidities is revolutionized by novel molecules that are safer and more manageable. Expert opinion: A recent work suggests that pro-fibrogenic cytokines, IL-17, might be important player of liver damage and even in regulation of obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Choosing to interfere with IL-23/Il-17 axis, definitely, is like acting against psoriatic march and in a parallel way against its comorbidities.

KEYWORDS:
Biologic therapies; IL-12; IL-17; IL-23; interleukins inhibitors; safety

PMID: 31479282 DOI: 10.1080/14740338.2019.1663168
[Indexed for MEDLINE]
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Select item 31379161
18.
J Agric Food Chem. 2019 Aug 28;67(34):9522-9531. doi: 10.1021/acs.jafc.9b03647. Epub 2019 Aug 16.
Feruloylated Oligosaccharides Alleviate Dextran Sulfate Sodium-Induced Colitis in Vivo.
Xia X1, Zhu L1, Lei Z1,2, Song Y1, Tang F1, Yin Z3, Wang J4, Huang J3.
Author information
1
The First Affiliated Hospital, Biomedical Translational Research Institute and School of Pharmacy , Jinan University , Guangzhou , Guangdong 510632 , China.
2
Department of Basic Medical Research , The Sixth Affiliated Hospital of Guangzhou Medical University, Qing Yuan People's Hospital , Qingyuan , Guangdong 511518 , China.
3
Formula-pattern Research Center, College of Traditional Chinese Medicine , Jinan University , Guangzhou , Guangdong 510632 , China.
4
Beijing Engineering and Technology Research Center of Food Additives , Beijing Technology and Business University , Beijing 100048 , China.
Abstract
The imbalance of T lymphocyte subsets substantially conduces to disturbed intestinal immune system and succeeding colonic tissue damage in inflammatory bowel diseases. It is considered that regulation of phytochemicals on cytokine production potentially provides a broad prospect for the exploitation of immunomodulatory agents. Here, we reported that oral administration of feruloylated oligosaccharides (FOs) effectively alleviated mice colitis disease induced by dextran sulfate sodium (DSS). FOs decreased the percentage of T helper (Th)17 cells and downregulated the production of Th17-specific cytokines. In contrast, FOs increased the percentage of regulatory T (Treg) cells and elevated the production of Treg-specific cytokines in colons of DSS-challenged mice. These results indicated that FOs restored the immunologic equilibrium of Th17 and Treg subsets, hereby ameliorating the deterioration of colitis. Furthermore, FOs diminished the secretion of interleukin (IL)-23 and IL-6 but enhanced the transforming growth factor-β1 (TGF-β1) in dendritic cells in vitro and in vivo, which contributed to the restoration of Th17 and Treg cells immune balance. The mechanistic analysis showed that the regulation of FOs on IL-23 and IL-6 was associated with the nuclear factor-κ-gene binding signaling pathway and TGF-β1 with mitogen-activated protein kinase-activator protein 1 signaling pathway. Taken together, oral administration of FOs exerted potent immunomodulatory effects against mice colitis via restoring the immune balance of Th17 and Treg cells.

KEYWORDS:
Th17 cells; Treg cells; colitis; dendritic cells; feruloylated oligosaccharide

PMID: 31379161 DOI: 10.1021/acs.jafc.9b03647
[Indexed for MEDLINE]
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19.
Cell Prolif. 2019 Sep;52(5):e12662. doi: 10.1111/cpr.12662. Epub 2019 Jul 31.
Potent anti-angiogenesis and anti-tumour activity of pegaptanib-loaded tetrahedral DNA nanostructure.
Xie X1, Zhang Y1, Ma W1, Shao X1, Zhan Y1, Mao C1, Zhu B2,3,4, Zhou Y5, Zhao H6, Cai X1.
Author information
1
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
2
Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
3
Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
4
Department of Forensic Genetics, School of Forensic Medicine, Southern Medical University, Guangzhou, China.
5
College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
6
Department of Restorative Sciences, College of Dentistry, Texas A&M University, Dallas, Texas.
Abstract
OBJECTIVES:
Pegaptanib might be a promising anti-tumour drug targeting VEGF to inhibit tumour vascular endothelial cell proliferation. However, the poor biostability limited its application. In this study, we took tetrahedron DNA nanostructures (TDNs) as drug nanocarrier for pegaptanib to explore the potent anti-angiogenesis and anti-tumour activity of this drug delivery system.

MATERIALS AND METHODS:
The successful synthesis of TDNs and pegaptanib-TDNs was determined by 8% polyacrylamide gel electrophoresis (PAGE), capillary electrophoresis and dynamic light scattering (DLS). The cytotoxicity of pegaptanib alone and pegaptanib-TDNs on HUVECs and Cal27 was evaluated by the cell count kit-8 (CCK-8) assay. The effect of pegaptanib and pegaptanib-TDNs on proliferation, migration and tube formation of HUVECs induced by VEGF was examined by CCK-8 assay, wound healing assay and tubule formation experiment. The cell binding capacity and serum stability were detected by flow cytometry and PAGE, respectively.

RESULTS:
Pegaptanib-TDNs had stronger killing ability than pegaptanib alone, and the inhibiting effect was in a concentration-dependent manner. What's more, pegaptanib-loaded TDNs could effectively enhance the ability of pegaptanib to inhibit proliferation, migration and tube formation of HUVECs induced by VEGF. These might attribute to the stronger binding affinity to the cell membrane and greater serum stability of pegaptanib-TDNs.

CONCLUSIONS:
These results suggested that pegaptanib-TDNs might be a novel strategy to improve anti-angiogenesis and anti-tumour ability of pegaptanib.

© 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.

KEYWORDS:
VEGF; anti-angiogenesis; anti-tumour; pegaptanib; pegaptanib-TDNs

PMID: 31364793 DOI: 10.1111/cpr.12662
[Indexed for MEDLINE]
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Select item 31356114
20.
Expert Opin Investig Drugs. 2019 Sep;28(9):787-797. doi: 10.1080/13543784.2019.1650019. Epub 2019 Aug 20.
The evolving role of antiangiogenic therapies in glioblastoma multiforme: current clinical significance and future potential.
Anthony C1, Mladkova-Suchy N2, Adamson DC1,3.
Author information
1
Department of Neurosurgery, Emory University , Atlanta , GA , USA.
2
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London , UK.
3
Neurosurgery section, Atlanta VA Medical Center , Decatur , GA , USA.
Abstract
Introduction: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, but its prognosis remains poor despite significant advances in our understanding of its molecular biology and investigation of numerous treatment modalities. Despite conventional treatment consisting of surgical resection, radiotherapy, and temozolomide marginally prolonging survival, most GBM patients die within 2 years of initial diagnosis. Bevacizumab (Bev) is the best-studied antiangiogenic agent for GBM and currently the only FDA-approved second-line treatment. Areas covered: Areas covered in this review include the molecular pathways of angiogenesis in glioblastoma, specifically the overexpression of vascular endothelial growth factor (VEGF) and robust formation of tumor neovasculature. In addition, this review covers pharmacological targeting of this process as a longstanding attractive clinical strategy, specifically by Bev. Expert opinion: This review attempts to discuss the history of early studies of antiangiogenic treatment for GBM that eventually failed in subsequent studies and the evolving modern role of Bev in the course of treatment for a variety of indications, including symptom control, reduced glucocorticoid use, and improved quality of life.

KEYWORDS:
GBM; VEGF; anti-angiogenesis; bevacizumab; glioblastoma; malignant glioma; neuro-oncology; personalized medicine

PMID: 31356114 DOI: 10.1080/13543784.2019.1650019