Abstract 16791: Oral Administration of Synthetic Prostacyclin Agonist Ono-1301 Prevents Deterioration of Cardiac Performance by Preserving Cardiac Structural Proteins in the Delta-sarcoglycan-deficient Hamster: Promising Treatment for Patients With DCM

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Shigeru Miyagawa ◽  
Yoshiki Sakai ◽  
Satsuki Fukushima ◽  
Shigeo Masuda ◽  
Atsuhiro Saito ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Oral Administration ◽  
Systolic Function ◽  
Cardiac Performance ◽  
Structural Proteins ◽  
Control Group ◽  
Dependent Manner ◽  
Significant Deterioration

Background: Although drugs such as beta blockers are reported to be effective for dilated cardiomyopathy (DCM), they are only effective in selected patients, and new therapeutics based on different mechanisms are still needed. We hypothesized that synthetic prostacyclin agonist (ONO-1301) would preserve the structural proteins in distressed cardiomyocytes, thus attenuating the deterioration of cardiac performance in the delta sarcoglycan-deficient hamster. Methods and Results: In an in vitro study, ONO-1301 was added to the culture medium of non-myocyte cells and the expression of several cytokines including VEGF was examined by ELISA. For the in vivo study, ONO-1301 (A: 3, n=5, B: 1, n=6, C: 0.3, n=7, D: 0.1 mg/kg/dose, n=7) was orally administered to delta-sarcoglycan-deficient hamsters every day from 8 to 20 weeks after birth. The control group (n=6) was untreated. Functional performance was evaluated by US before, 2, 4, 6, and 8 weeks after administration of ONO-1301. A histological analysis focusing on basement-membrane structural proteins, such as α-sarcoglycan, β-sarcoglycan, and α-dystroglycan, fibrosis, and hypertrophy was performed. In vitro, ONO-1301 enhanced the cytokine expressions dose dependently. In vivo, systolic function (EF) was gradually increased in the ONO-1301-treated groups, while it showed significant deterioration in the control group (45.7±2.9, 42.0±2.6, 32.3±1.0, 30.3±2.5, 26.3±2.7%, in groups A, B, C, D, and control, respectively, P<0.05). ONO-1301 also significantly attenuated the LV dilatation in a dose-dependent manner. Immunostaining revealed that all the cardiac structural proteins were preserved in the basement membrane of cardiomyocytes in the 3.0 mg/kg ONO-1301 treatment group, while they disappeared in the control. The % fibrosis and cell hypertrophy were significantly attenuated in the ONO-1301-treated group compared with the control. Conclusions: Oral administration of synthetic prostacyclin agonists, which can enhance cytokine expressions in non-myocyte cells, may preserve cardiac structural proteins in the delta sarcoglycan-deficient hamster, to maintain cardiac performance. This promising drug may inhibit the progression of the disease pathology in DCM, prolonging their life.

scholarly journals Persimmon-derived tannin has antiviral effects and reduces the severity of infection and transmission of SARS-CoV-2 in a Syrian hamster model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryutaro Furukawa ◽  
Masahiro Kitabatake ◽  
Noriko Ouji-Sageshima ◽  
Yuki Suzuki ◽  
Akiyo Nakano ◽  
...  
Keyword(s):  
Oral Administration ◽  
Syrian Hamster ◽  
Carboxymethyl Cellulose ◽  
Plaque Assay ◽  
Control Group ◽  
Dependent Manner ◽  
Hamster Model ◽  
Antiviral Effects

AbstractCoronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread across the world. Inactivating the virus in saliva and the oral cavity represents a reasonable approach to prevent human-to-human transmission because the virus is easily transmitted through oral routes by dispersed saliva. Persimmon-derived tannin is a condensed type of tannin that has strong antioxidant and antimicrobial activity. In this study, we investigated the antiviral effects of persimmon-derived tannin against SARS-CoV-2 in both in vitro and in vivo models. We found that persimmon-derived tannin suppressed SARS-CoV-2 titers measured by plaque assay in vitro in a dose- and time-dependent manner. We then created a Syrian hamster model by inoculating SARS-CoV-2 into hamsters’ mouths. Oral administration of persimmon-derived tannin dissolved in carboxymethyl cellulose before virus inoculation dramatically reduced the severity of pneumonia with lower virus titers compared with a control group inoculated with carboxymethyl cellulose alone. In addition, pre-administration of tannin to uninfected hamsters reduced hamster-to-hamster transmission of SARS-CoV-2 from a cohoused, infected donor cage mate. These data suggest that oral administration of persimmon-derived tannin may help reduce the severity of SARS-CoV-2 infection and transmission of the virus.

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

scholarly journals In Vivo and In Vitro Evaluation of the Protective Effects of Hesperidin in Lipopolysaccharide-Induced Inflammation and Cytotoxicity of Cell

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 478 ◽  
Author(s):  
Rasha Al-Rikabi ◽  
Hanady Al-Shmgani ◽  
Yaser Hassan Dewir ◽  
Salah El-Hendawy
Keyword(s):  
Breast Cancer ◽  
Chromatin Condensation ◽  
Control Group ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Protective Effects ◽  
Mcf7 Cells ◽  
Tnf Α

(1) Background: Plant flavonoids are efficient in preventing and treating various diseases. This study aimed to evaluate the ability of hesperidin, a flavonoid found in citrus fruits, in inhibiting lipopolysaccharide (LPS) induced inflammation, which induced lethal toxicity in vivo, and to evaluate its importance as an antitumor agent in breast cancer. The in vivo experiments revealed the protective effects of hesperidin against the negative LPS effects on the liver and spleen of male mice. (2) Methods: In the liver, the antioxidant activity was measured by estimating the concentration of glutathione (GSH) and catalase (CAT), whereas in spleen, the concentration of cytokines including IL-33 and TNF-α was measured. The in vitro experiments including MTT assay, clonogenity test, and sulforhodamine 101 stain with DAPI (4′, 6-diamidino-2-phenylindole) were used to assess the morphological apoptosis in breast cancer cells. (3) Results: The results of this study revealed a significant increase in the IL-33 and TNF-α cytokine levels in LPS challenged mice along with a considerable elevation in glutathione (GSH); moreover, the catalase (CAT) level was higher compared to that of the control group. Cytotoxicity of the MCF-7 cell line revealed significant differences among the groups treated with different concentrations when compared to the control groups, in a concentration-dependent manner. Hesperidin significantly inhibited the colony formation of MCF7 cells when compared to that of control. Clear changes were observed in the cell shape, including cell shrinkage and chromatin condensation, which were associated with a later apoptotic stage. (4) Conclusion: The results indicate that hesperidin might be a potential candidate in preventing diseases.

Inhibition Effects of baicalin on Lymphoma Cell Line CA46 in Vitro and in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5053-5053
Author(s):  
Jian Da Hu ◽  
Yi Huang ◽  
Yingyu Chen ◽  
Tiannan Wei ◽  
Tingbo Liu ◽  
...  
Keyword(s):  
Cell Line ◽  
Biological Effects ◽  
Annexin V ◽  
Lymphoma Cell ◽  
Control Group ◽  
Dependent Manner ◽  
Lymphoma Cell Line ◽  
Proliferation Inhibition

Abstract Baicalin is a traditional Chinese medicine with multiple biological effects. Some researches showed baicalin has anti-tumor effects in solid tumor, such as prostate cancer. In order to investigate its effects on proliferation inhibition and apoptosis induction in human lymphoma cell, we treated Burkitt lymphoma cell line CA46 with baicalin in vitro and in vivo of CA46 xenograft. Baicalin remarkably inhibited the cell proliferation, with an IC50 value of 10μM. Apoptosis was remarkably induced by baicalin in a dose-dependent manner, which was detected by Annexin V FITC/PI double staining analysis, TUNEL labeling method and DNA fragmentation respectively. Furthermore, RT-PCR showed that the mRNA expressions of c-myc and bcl-2 in treated CA46 cell decreased in a time-dependent manner. Western-Blot showed that the protein expressions of c-myc, bcl-2, procaspase-3 and PARP(116KD) in baicalin treated CA46 cell were down-regulated, while the expression of PARP(85KD) increased. Based on the results in vitro, we investigated in vivo efficacy of baicalin, alone or in combination with cytotoxic drug VP16, for treatment in CA46 nude mice xenograft. Baicalin with the dosage of 40mg/kg/d and 80kg/mg/d could remarkably inhibit the growth of the tumor compared with control group. Combination of baicalin and VP16 had better anti-tumor effects. Histological examination of tumor samples showed more necrotic cells in treated groups. And obvious apoptosis could be observed by electron microscope. No adverse events were found in treated groups. From above we could conclude that baicalin could efficiently induce proliferation inhibition and apoptosis of CA46 cells in vitro and in vivo, which may be related with the down-regulation of c-myc and bcl-2 expressions, as well as the up-regulation of caspase-3 activity.

The human renin infused rat: use as an in vivo model for the biological evaluation of human renin inhibitors

1999 ◽  
Vol 77 (11) ◽  
pp. 886-895 ◽  
Author(s):  
Gordon Bolger ◽  
Jean-Claude Vigeant ◽  
Francine Liard ◽  
Bruno Simoneau ◽  
Diane Thibeault ◽  
...  
Keyword(s):  
Oral Administration ◽  
Pressor Response ◽  
Biological Evaluation ◽  
In Vivo Model ◽  
Dependent Manner ◽  
Renin Inhibitors ◽  
Human Renin ◽  
Dose Dependent

The human renin infused rat model (HRIRM) was used as an in vivo small-animal model for evaluating the efficacy of a collection of inhibitors of human renin. The intravenous infusion of recombinant human renin (2.4 µg·kg-1·min-1) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47 ± 3 mmHg (1 mmHg = 133.3 Pa), which was reduced by captopril, enalkiren, and losartan in a dose-dependent manner following oral administration, with ED50 values of 0.3 ± 0.1, 2.5 ± 0.9, and 5.2 ± 1.6 mg/kg, respectively. A series of peptidomimetic P2-P3 butanediamide renin inhibitors inhibited purified recombinant human renin in vitro in a concentration-dependent manner, with IC50 values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values (0.8-80 nM) observed at pH 7.4. Following i.v. administration of renin inhibitors, the pressor response to infused human renin in the HRIRM was inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600 µg/kg. The in vivo inhibition of human renin following i.v. administration in the rat correlated significantly better with the in vitro inhibition of human renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5). Oral administration of renin inhibitors also resulted in a dose-dependent inhibition of the pressor response to infused human renin, with ED50 values ranging from 0.4 to 6.0 mg/kg and the identification of six renin inhibitors with an oral potency of <1 mg/kg. The ED50 of renin inhibitors for inhibition of angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor response. These results demonstrate the high potency, dose dependence, and availability following oral administration of the butanediamide series of renin inhibitors.Key words: renin-angiotensin system, recombinant human renin, rat, renin inhibitors.

Scutellarin Attenuates Human-Neutrophil-Elastase-Induced Mucus Production by Inhibiting the PKC-ERK Signaling Pathway in Vitro and in Vivo

2011 ◽  
Vol 39 (06) ◽  
pp. 1193-1206 ◽  
Author(s):  
De-Peng Jiang ◽  
Qi Li ◽  
Jie Yang ◽  
Juliy M. Perelman ◽  
Victor P. Kolosov ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Erk Signaling ◽  
Control Group ◽  
Human Neutrophil Elastase ◽  
Dependent Manner ◽  
Mucus Production

The aim of this study was to investigate the influence of scutellarin on mucus production induced by human neutrophil elastase (HNE) and the possible in vitro and in vivo mechanisms. To this purpose, cells were incubated with saline, scutellarin or gefitinib for 60 min and exposed to 0.1 μM HNE for 24 h. After being pretreated respectively with saline, scutellarin or gefitinib, rats were challenged intratracheally with HNE by means of nebulization for 30 days. The expression of mucin (MUC) 5AC, protein kinase C (PKC), and extracellular signal-regulated kinase 1/2 (ERK1/2) was assessed by ELISA, RT-PCR or Western blotting. The results showed that scutellarin inhibited MUC5AC mRNA and protein expressions induced by HNE in a concentration-dependent manner in vitro. In the in vivo model, scutellarin significantly attenuated MUC5AC mRNA expression and goblet cell hyperplasia in rats treated with HNE for 30 days, as well as decreased the phosporylation of PKC and ERK1/2 compared to the HNE control group. Therefore, our study showed that scutellarin could prevent mucus hypersecretion by inhibiting the PKC-ERK signaling pathway. Inhalation scutellarin may be valuable in the treatment of chronic inflammatory lung disease.

scholarly journals Aqueous Extract of Perilla frutescens var. acuta Relaxes the Ciliary Smooth Muscle by Increasing NO/cGMP Content In Vitro and In Vivo

Molecules ◽  
2018 ◽  
Vol 23 (7) ◽  
pp. 1777 ◽  
Author(s):  
Jaeyong Kim ◽  
Huwon Kang ◽  
Hakjoon Choi ◽  
Ara Jo ◽  
Dooi-Ri Oh ◽  
...  
Keyword(s):  
Aqueous Extract ◽  
Perilla Frutescens ◽  
Ciliary Muscle ◽  
Control Group ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Eye Fatigue ◽  
Freeze Dried

The leaves of Perilla frutescens var. acuta (PFA) are commonly used as a traditional medicine in Korea, Japan, and China. We previously showed that PFA attenuates eye fatigue by improving visual accommodation through a clinical study. However, detailed mechanisms and chemical compounds have not been studied. In this study, we analyzed the active compounds in an aqueous extract of PFA involved in ciliary muscle relaxation in vitro and in vivo. NMR and MS analyses showed that the PFA extract contained mainly luteolin-7-O-diglucuronide and apigenin-7-O-diglucuronide. The composition after freeze-drying and spray-drying was similar. Freeze-dried PFA (50 µg/mL, 100 µg/mL, and 200 µg/mL) increased nitric oxide and cGMP levels in ciliary muscle cells isolated from the eyes of rats. [Ca2+]i decreased in a dose-dependent manner. Furthermore, Sprague-Dawley rats treated with freeze-dried PFA (200 mg/kg, orally) showed significantly increased cGMP levels compared with the control group and irradiated with white light. Our results suggest that PFA extract has the potential to reduce eye fatigue by relaxing ciliary muscles.

scholarly journals In VitroCytotoxicity andIn VivoAntimammary Tumor Effects of the Hydroethanolic Extract ofAcacia seyal(Mimosaceae) Stem Bark

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Stephane Zingue ◽  
Amstrong Nang Njuh ◽  
Alain Brice Tueche ◽  
Jeremie Tamsa ◽  
Edwige Nana Tchoupang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Tumors ◽  
Stem Bark ◽  
Control Group ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Hydroethanolic Extract ◽  
Acacia Seyal

The present study was designed to evaluate thein vitroandin vivoantitumor effects ofA. seyalhydroethanolic extract on breast cancer. The cytotoxicity ofA. seyalextract was evaluated using resazurin reduction assay in 9 cell lines. Further, the protective effect of the hydroethanolic extract ofA. seyalstem barks was evaluated on 7,12-dimethylbenz(a)anthracene- (DMBA-) induced breast cancer rat model. Incidence, burden, volume, and histological analysis of mammary tumors were measured. TheAcacia seyalextract exhibited CC50of 100 in MCF-7 cells after 24 h.In vivo, no tumors were detected in rats from the control group, while 11 rats out of 12 (91.66%) developed mammary tumors in the DMBA-exposed group receiving only the vehicle.Acacia seyalextract significantly (p<0.01) and in the dose-dependent manner reduced tumor incidence (3 rats out of 12 at the dose of 300 mg/kg), burden [62.1% (150 mg/kg) and 65.8% (300 mg/kg)], and mass. It protected rats against DMBA-induced breast hyperplasia, with an optimal effect at the dose of 300 mg/kg. Taken altogether, these results suggest that the hydroethanolic extract ofAcacia seyalmight contain phytoconstituents endowed with antitumoral properties, which could protect against the breast cancer induced in rats.

Anti-Proliferative Efficacy of Icariin on HepG2 Hepatoma and Its Possible Mechanism of Action

2009 ◽  
Vol 37 (06) ◽  
pp. 1153-1165 ◽  
Author(s):  
Jin-Xia Yang ◽  
Iduna Fichtner ◽  
Monika Becker ◽  
Margit Lemm ◽  
Xue-Mei Wang
Keyword(s):  
Bone Marrow ◽  
Mechanism Of Action ◽  
Mtt Assay ◽  
Control Group ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Anticancer Efficacy ◽  
Cd8 Cells

The aim of the present work was to explore the anti-hepatoma effects of icariin both in vitro and in vivo and to elucidate its potential mechanism of action. The MTT assay was applied to test the anti-proliferative effects of icariin in vitro. HepG2 bearing NMRI nu/nu mice were used to test the anticancer effects of icariin in vivo. Immunohistochemical assay and flow cytometry assay (FACS) were applied to detect the possible mechanisms of action of icariin. MTT assay illustrated that icariin inhibited the proliferation of HepG2 cells in a concentration dependent manner; meanwhile, icariin inhibited the tumor growth in HepG2 bearing NMRI nu/nu mice. The tumor weight was inhibited by 55.6% and tumor volume was inhibited by 47.2%. Icariin did not influence the spleen and body weights or blood parameters. Immunohistochemical analysis indicated that the expressions of both CD31 and Ki67 in the icariin treated group were significantly lower than those in the control group (p < 0.01). FACS assay showed that icariin dramatically decreased the percentage of CD4+ and CD8+ cells in bone marrow and CD19+ cells in blood on day 8. On day 17, the percentage of CD8+ cells in blood was lower than those in the control group. CD4/CD8 ratio in icariin group was significantly elevated in bone marrow on day 17. Icariin showed anticancer efficacy both in vitro and in vivo. The possible mechanism of action could be related to its anti-angiogenesis and anti-proliferative effects in tumors.

scholarly journals Aspartame induces angiogenesis in vitro and in vivo models

2014 ◽  
Vol 34 (3) ◽  
pp. 260-265 ◽  
Author(s):  
F Yesildal ◽  
FN Aydin ◽  
S Deveci ◽  
S Tekin ◽  
I Aydin ◽  
...  
Keyword(s):  
Wound Healing ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Control Group ◽  
Dependent Manner ◽  
Xtt Assay ◽  
Skin Wound Healing ◽  
In Vivo Models

Angiogenesis is the process of generating new blood vessels from preexisting vessels and is considered essential in many pathological conditions. The purpose of the present study is to evaluate the effect of aspartame on angiogenesis in vivo chick chorioallantoic membrane (CAM) and wound-healing models as well as in vitro 2,3-bis-2 H-tetrazolium-5-carboxanilide (XTT) and tube formation assays. In CAM assay, aspartame increased angiogenesis in a concentration-dependent manner. Compared with the control group, aspartame has significantly increased vessel proliferation ( p < 0.001). In addition, in vivo rat model of skin wound-healing study showed that aspartame group had better healing than control group, and this was statistically significant at p < 0.05. There was a slight proliferative effect of aspartame on human umbilical vein endothelial cells on XTT assay in vitro, but it was not statistically significant; and there was no antiangiogenic effect of aspartame on tube formation assay in vitro. These results provide evidence that aspartame induces angiogenesis in vitro and in vivo; so regular use may have undesirable effect on susceptible cases.

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