Antitumor Effects of Intra-Arterial Delivery of Albumin-Doxorubicin Nanoparticle Conjugated Microbubbles Combined with Ultrasound-Targeted Microbubble Activation on VX2 Rabbit Liver Tumors

Image-guided intra-arterial therapies play a key role in the management of hepatic malignancies. However, limited clinical outcomes suggest the need for new multifunctional drug delivery systems to enhance local drug concentration while reducing systemic adverse reactions. Therefore, we developed the albumin-doxorubicin nanoparticle conjugated microbubble (ADMB) to enhance therapeutic efficiency by sonoporation under exposure to ultrasound. ADMB demonstrated a size distribution of 2.33 ± 1.34 µm and a doxorubicin loading efficiency of 82.7%. The echogenicity of ADMBs was sufficiently generated in the 2–9 MHz frequency range and cavitation depended on the strength of the irradiating ultrasound. In the VX2 rabbit tumor model, ADMB enhanced the therapeutic efficiency under ultrasound exposure, compared to free doxorubicin. The intra-arterial administration of ADMBs sufficiently reduced tumor growth by five times, compared to the control group. Changes in the ADC values and viable tumor fraction supported the fact that the antitumor effect of ADMBs were enhanced by evidence of necrosis ratio (over 70%) and survival tumor cell fraction (20%). Liver toxicity was comparable to that of conventional therapies. In conclusion, this study shows that tumor suppression can be sufficiently maximized by combining ultrasound exposure with intra-arterial ADMB administration.

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PL-019 Effect of early exercise on autophagy of liver tumor in mice

Exercise Biochemistry Review ◽

10.14428/ebr.v1i1.8223 ◽

2018 ◽

Vol 1 (1) ◽

Author(s):

Ning Jiang ◽

Zhe Wang ◽

Jing Li ◽

Xinghao Wang

Keyword(s):

Exercise Training ◽

Liver Tumor ◽

Liver Tumors ◽

Hepatoma Cell ◽

Tumor Model ◽

Inflammatory Cells ◽

Exercise Group ◽

Control Group ◽

Early Exercise ◽

Tumor Group

Objective To investigate whether the liver autophagy level can be altered by pre exercise training in mice liver tumors. Methods 40 Male C57BL/6J mice aged 7 months were randomly divided into 2 groups: control group (YC) and exercise group (YE). YE were exercised on a treadmill for 12 weeks (12m/min). After12 weeks each group was randomly divided into two groups. The tumor model was constructed by injection of HEPA1- 6 mouse hepatoma cell into liver tissue.Then the groups were control group (YC), exercise group (YE), tumor group (YCT), exercise tumor group (YET).The experimental samples were prepared on the 13 day after the tumor model was constructed. the hematoxylin and eosin stain of the liver was observed.The expression of autophagy related protein BECLIN1, LC3-II and ATG5 in liver tissues of mice was detected by Western blot. Results Compared with YCT group,the boundary of inflammatory cells and tumor cells in YET group was clear with normal cells.Compared with YCT group, the expression levels of BECLIN1, LC3-II and ATG5 in liver tissue of YET group were significantly higher (p < 0.01, P < 0.01, P < 0.05). Conclusions Early exercise can help the 7 month old mice to resist the occurrence and development of the liver tumor. It's probably associated with increased level of autophagy in the liver by early exercise training.

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Liver Damage After Radiofrequency Ablation Combined with Transcatheter Therapy in Treating Rabbit VX2 Liver Tumors

10.21203/rs.3.rs-36292/v1 ◽

2020 ◽

Author(s):

Xu-Hua Duan ◽

Wen-Hui Wang ◽

Xinwei Han ◽

Jian-Zhuang Ren ◽

Hao Li ◽

...

Keyword(s):

Radiofrequency Ablation ◽

Liver Injury ◽

Liver Tumors ◽

Tumor Model ◽

Arterial Embolization ◽

Hepatocyte Proliferation ◽

Control Group ◽

Tumor Control ◽

Hepatocellular Necrosis ◽

Vx2 Tumor

Abstract Background: To evaluate the effect of transcatheter therapies combining with radiofrequency ablation (RFA) treatment on hepatocellular necrosis, apoptosis and proliferation by using the rabbit VX2 tumor model. Methods: Ninety six models were randomly divided into 4 groups: transcatheter arterial chemoembolization group (TACE), radiofrequency ablation group (RFA), TACE+RFA group and transcatheter arterial embolization (TAE) + RFA group. The above groups were further divided into two subgroups, A (15 rabbits) and B (9 rabbits). The subgroup B (control group) was followed up until animal death. Results: The high expression of heat shock protein 70 (HSP70) was observed in the adjacent liver tissue in TACE and TACE+RFA. The highest increase of transaminase levels and serum HSP70 were detected in TACE+RFA group. TAE+RFA group had a low apoptotic rate and more hepatocyte proliferation as compared to TACE and TACE+RFA groups; and it had the longest end-point survival among these groups. Conclusions: The TAE+RFA treatment had a better outcome than RFA, including a better liver tumor control, a less liver injury, and a longer survival than TACE+RFA. Compared to TACE and TACE+RFA procedures, TAE+RFA significantly decreased the liver injury, hepatocellular necrosis, apoptosis and systemic proinflammatory cytokine release caused by anticancer drugs application.

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MODIFICATING ACTION OF DICLOFENAC ON EFFECTS OF PHOTODYNAMIC THERAPY – IN VIVO STUDY

Problems in oncology ◽

10.37469/0507-3758-2019-65-3-447-453 ◽

2019 ◽

Vol 65 (3) ◽

pp. 447-453

Author(s):

Galina Kireeva ◽

Stepan Kruglov ◽

A. Tarasov ◽

Ye. Plakhov ◽

Yekaterina Gubareva ◽

...

Keyword(s):

Photodynamic Therapy ◽

Tumor Model ◽

Significant Inhibition ◽

Ehrlich Carcinoma ◽

Control Group ◽

Ehrlich Tumor ◽

Antitumor Effects ◽

Modifying Effect ◽

Effective Treatment Regimen

Introduction. Non-steroidal anti-inflammatory drugs and, in particular, diclofenac, are considered as drugs with a potentially anticarcinogenic effect and can be used to enhance the effects of antitumor therapy. Aim. To evaluate the effectiveness of diclofenac as a potential modifier of photodynamic therapy (PDT) in vivo in Ehrlich tumor model in mice. Materials and methods. The study was conducted on male mice of BALB/C strain with intradermally grafted Ehrlich carcinoma. Experimental procedures were performed on day 7 after tumor inoculation. The control group did not receive treatment, in one group only diclofenac was administered, photosensitizer was administered in three groups (photoditazin, 5 mg / kg, intravenously once), tumor was irradiated with a laser (ALOD, 662 nm) or PDT was performed, respectively, and in three groups the procedures indicated above in each case were combined with the administration of diclofenac. 2 series of experiments were conducted to assess the reproducibility of the results. The size of the tumor was recorded after exposure. Results. In the first series of the experiment, in all groups with the administration of diclofenac (45 mg/kg/day), a high animal mortality was unexpectedly observed, associated with the toxic effect of diclofenac, which required a change in its administration regime and dose (15 mg/kg) in the second series of the experiment. The administration of diclofenac did not significantly affect the efficacy of PDT, and also did not have a modifying effect in other groups (with the introduction of a photosensitizer or laser irradiation) compared with similar groups without diclofenac. PDT with photoditazine turned out to be the most effective treatment regimen: in 8 out of 10 mice in the group from the 21th day after procedure the tumors were not recorded, the animals were alive until the end of the observation for 60 days. The introduction of a photosensitizer and radiation without a photosensitizer did not lead to a significant inhibition of tumor growth. Conclusion. In vivo on a model of intradermally grafted Ehrlich tumor in mice, diclofenac does not have a modifying effect on the antitumor effects of PDT.

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Antitumor Potential of Lippia citriodora Essential Oil in Breast Tumor-Bearing Mice

Antioxidants ◽

10.3390/antiox10060875 ◽

2021 ◽

Vol 10 (6) ◽

pp. 875

Author(s):

Katerina Spyridopoulou ◽

Tamara Aravidou ◽

Evangeli Lampri ◽

Eleni Effraimidou ◽

Aglaia Pappa ◽

...

Keyword(s):

Breast Cancer ◽

Antiproliferative Activity ◽

Folk Medicine ◽

Tumor Model ◽

Flowering Plant ◽

Antitumor Effects ◽

Lippia Citriodora ◽

Antitumor Potential ◽

Apoptotic Marker

Lippia citriodora is a flowering plant cultivated for its lemon-scented leaves and used in folk medicine for the preparation of tea for the alleviation of symptoms of gastrointestinal disorders, cold, and asthma. The oil extracted from the plant leaves was shown to possess antioxidant potential and to exert antiproliferative activity against breast cancer. The aim of this study was to further investigate potential antitumor effects of L. citriodora oil (LCO) on breast cancer. The in vitro antiproliferative activity of LCO was examined against murine DA3 breast cancer cells by the sulforhodamine B assay. We further explored the LCO’s pro-apoptotic potential with the Annexin-PI method. The LCO’s anti-migratory effect was assessed by the wound-healing assay. LCO was found to inhibit the growth of DA3 cells in vitro, attenuate their migration, and induce apoptosis. Finally, oral administration of LCO for 14 days in mice inhibited by 55% the size of developing tumors in the DA3 murine tumor model. Noteworthy, in the tumor tissue of LCO-treated mice the apoptotic marker cleaved caspase-3 was elevated, while a reduced protein expression of survivin was observed. These results indicate that LCO, as a source of bioactive compounds, has a very interesting nutraceutical potential.

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Hepatoprotective effect of galangin on carbon tetrachloride-induced hepatotoxicity via the LKB1/AMPK pathway

European Journal of Inflammation ◽

10.1177/20587392211000896 ◽

2021 ◽

Vol 19 ◽

pp. 205873922110008

Author(s):

Meng Chen ◽

Xinyan Song ◽

Jifang Jiang ◽

Lei Xing ◽

Pengfei Wang

Keyword(s):

Carbon Tetrachloride ◽

Liver Toxicity ◽

Corn Oil ◽

Histopathological Examination ◽

Hepatoprotective Effect ◽

Control Group ◽

Group Model ◽

Protective Effects ◽

Model Group ◽

Expression Levels

To investigate the protective effects of galangin on liver toxicity induced by carbon tetrachloride (CCl4) in mice. Mouse hepatotoxicity model was established by intraperitoneal injection (i.p.) of 10 ml/kg body weight CCl4 that diluted with corn oil to a proportion of 1:500 on Kunming mice. The mice were randomly divided into five groups named control group, model group, and 1, 5, and 10 mg/kg galangin group. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed by ELISA. Liver histopathological examination was observed via optical microscopy. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), and glutathion (GSSG) were analyzed to assess oxidative stress. Finally, western blot assay was carried out to analyse the expression levels of total AMP-activated protein kinase (AMPK), phospho-AMPK (p-AMPK), total liver kinase B1 (LKB1), and phospho-LKB1 (p-LKB1). Compared with the control group, in the model group, the levels of AST, ALT, MDA, and GSSG increased significantly ( p < 0.01); the activity of SOD and GSH decreased significantly ( p < 0.01); and the histopathological examination revealed liver necrosis. However, treatment with galangin (5 and 10 mg/kg) significantly reversed these CCl4-induced liver damage indicators. Furthermore, treatment with galangin (10 mg/kg) significantly increased the p-AMPK and p-LKB1 expression levels ( p < 0.01). This study supports the hepatoprotective effect of galangin against hepatotoxicity, perhaps occurring mainly through the LKB1/AMPK-mediated pathway.

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Murine hepatoma treatment with mature dendritic cells stimulated by Trichinella spiralis excretory/secretory products

Parasite ◽

10.1051/parasite/2020045 ◽

2020 ◽

Vol 27 ◽

pp. 47

Author(s):

Jing Ding ◽

Xiaolei Liu ◽

Bin Tang ◽

Xue Bai ◽

Yang Wang ◽

...

Keyword(s):

Dendritic Cells ◽

Tumor Growth ◽

Antitumor Effect ◽

Trichinella Spiralis ◽

Critical Role ◽

Tumor Model ◽

Control Group ◽

Tumor Inhibition ◽

Significant Difference ◽

Secretory Products

Excretory/Secretory Products (ESPs) of the nematode Trichinella spiralis contain antitumor-active substances that inhibit tumor growth. Mature dendritic cells (DCs) play a critical role in the antitumor immunity of the organism. As pathogen-derived products, it ought to be discussed whether T. spiralis ESPs will reduce the antitumor effect of mature DCs from the host before it is applied to patients’ tumors. Therefore, the aim of this work was to evaluate the immunological effect of DCs stimulated by T. spiralis ESPs in H22 tumor-bearing mice. H22 tumor model mice in this study were randomly divided into four groups according to the treatment: PBS control group, ESP group, DCs group, and DCs stimulated with T. spiralis ESP (ESP+DCs group). The antitumor effect was evaluated by tumor inhibition rate and cytokine detection using ELISA. The results showed significant inhibition in tumor growth in the ESP+DCs, DCs and ESP groups when compared with the PBS control group (p < 0.01, p < 0.01, and p < 0.05, respectively). However, no significant difference was observed on tumor inhibition rates between the ESP+DCs and DCs groups. The decrease in IL-4, IL-6, and IL-10, and the increase in IFN-γ between the DCs and ESP+DCs groups were also not significant. Therefore, DCs stimulated by ESP did not reduce the antitumor effect of mature DCs, which demonstrated that the T. spiralis ESP would not affect the antitumor effect of mature DCs by modulating the immune response of the host, and that ESPs are safe in antitumor immunology when applied in a tumor model mice.

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A novel brainstem tumor model: guide screw technology with functional, radiological, and histopathological characterization

Neurosurgical FOCUS ◽

10.3171/foc.2005.18.6.12 ◽

2005 ◽

Vol 18 (6) ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

James Lee ◽

George I. Jallo ◽

Michael Guarnieri ◽

Benjamin S. Carson ◽

Margret B. Penno

Keyword(s):

Fdg Pet ◽

Survival Rates ◽

Tumor Model ◽

Neurological Deficits ◽

Ct Scans ◽

Rank Test ◽

Control Group ◽

Brainstem Tumor ◽

Positron Emission ◽

Brainstem Tumors

Object Survival rates for high-grade brainstem tumors are approximately 10% and optimal therapy has yet to be determined. Development of a satisfactory brainstem tumor model is necessary for testing new therapeutic paradigms that may prolong survival. The authors report the technique, functional progression, radiological appearance, and histopathological features of a novel brainstem tumor model in rats. Methods Thirty female Fischer 344 rats were randomized (10 animals/group) to receive an injection of either 3 μl of 9L gliosarcoma cells (100,000 cells), 3 μl of F98 glioma cells (100,000 cells), or 3 μl of medium (Dulbecco modified Eagle medium) into the pontine tegmentum of the brainstem. Using a cannulated guide screw system implanted in the skull of the animal, rats in each group were injected at coordinates 1.4 mm to the right of the sagittal and 1 mm anterior to the lambdoid sutures, at a depth of 7 mm from the dura mater. The angle of the syringe during injection was anteflexed 5° from the vertical. Postoperatively, the rats were evaluated for neurological deficits by using an automated rotarod test. High-resolution [18F]fluorodeoxyglucose–positron emission tomography (FDG-PET) fused with computerized tomography (CT) scans were acquired pre- and postoperatively through the onset of hemiparesis and correlated accordingly. Kaplan–Meier curves were generated for survival and disease progression, and brains were processed postmortem for histopathological investigation. The 9L and F98 tumor cells grew in 95% of the animals in which they were injected and resulted in a statistically significant mean onset of hemiparesis of 16.5 ± 0.56 days (p = 0.001, log-rank test), compared with animals in the control group, which had no neurological deficits by Day 45. The FDG-PET studies coregistered with CT scans demonstrated space-occupying brainstem lesions, and this finding was confirmed by histological studies. Animals in the control group showed no functional, radiological, or pathological signs of tumor. Conclusions Progression to hemiparesis was consistent in all tumor-injected animals, with predictable onset of symptoms occurring approximately 17 days postsurgery. The histopathological and radiological characteristics of the 9L and F98 brainstem tumors were comparable to those of aggressive primary human brainstem tumors. Establishment of this animal tumor model will facilitate the testing of new therapeutic paradigms for the treatment of these lesions.

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Perfluorooctanoic Acid Exposure in Early Pregnancy Induces Oxidative Stress in The Uterus and Liver in Mice

10.21203/rs.3.rs-160447/v1 ◽

2021 ◽

Author(s):

Yan Zhang ◽

Linchao Zhang ◽

JiaLu Bao ◽

LianTao Liu ◽

Xiaodan Wang

Keyword(s):

Early Pregnancy ◽

Caspase 3 ◽

Liver Toxicity ◽

Liver Weight ◽

Perfluorooctanoic Acid ◽

Control Group ◽

Dependent Manner ◽

Subsequent Increase ◽

Decidual Cells ◽

Pregnant Mice

Abstract To investigate the mechanism perfluorooctanoic acid (PFOA)’s toxicity on the uterus and liver of the mice during early pregnancy, pregnant mice were given 0, 1, 5, 10, 20, 40 mg/kg PFOA daily by gavage from gestational day (GD) 1-7, and sacrificed on GD 9. Uterus and liver weight were recorded, liver and uterine indexes were calculated, histopathological changes of the liver and uterus were examined, and levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) in liver were detected by spectrophotometric method. Expression of FAS, FASL, Bax, Bcl-2, and Caspase-3 in decidual cells were detected by immunohistochemistry and the TUNEL method was used to detect apoptotic uterine cells. Results showed that liver weight increased, and the uterus index was significantly reduced at 40 mg/kg compared with the control group. With increasing doses of PFOA, levels of SOD and GSH-PX were significantly decreased, and MDA significantly increased in liver tissue. 20 mg/kg and 40 mg/kg of PFOA caused greater harm to the uterus and congestion and resorption may occur. Expression of FAS, FASL, Bax, and Caspase-3 in decidual cells of the uterus in PFOA treatment groups significantly increased in a dose-dependent manner. The expression of Bcl-2 was down-regulated, which decreased the ratio of Bcl-2/Bax. It is therefore proposed that oxidative damage may be one of the mechanisms by which PFOA induces liver toxicity, and a subsequent increase in uterine cell apoptosis may induce embryo loss or damage.

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Incidence of Second Primary Malignancies and Peripheral Sensory Neuropathy in Patients with Multiple Myeloma Receiving Daratumumab Containing Regimen

Blood ◽

10.1182/blood-2019-123156 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5550-5550 ◽

Cited By ~ 1

Author(s):

Thura Win Htut ◽

Donald P. Quick ◽

Myint Aung Win ◽

Sriman Swarup ◽

Anita Sultan ◽

...

Keyword(s):

Multiple Myeloma ◽

Sensory Neuropathy ◽

Phase Iii ◽

Control Group ◽

Second Primary ◽

Peripheral Sensory Neuropathy ◽

Antitumor Effects ◽

Refractory Multiple Myeloma ◽

Second Primary Malignancies ◽

Peripheral Sensory

Introduction: Proteasome inhibitors-based regimens are the mainstay of initial therapy for most patients with multiple myeloma. Daratumumab is a human IgGκ monoclonal antibody that targets CD38 with direct antitumor effects and has an immunomodulatory component. Recent studies have demonstrated that addition of daratumumab to standard regimens enhance direct cytotoxicity on myeloma cells and have shown survival benefits. Yet, there are notable safety concerns. We performed a combined analysis of randomized controlled trials (RCT) to determine the risk of second primary malignancies (SPM) and peripheral sensory neuropathy (PSN) with newer daratumumab combination regimens. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma that mention SPM and PSN as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,547 patients with multiple myeloma from 5 phase III RCTs were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 25, suggesting some heterogeneity among RCT. The SPM incidence was 76 (4.29%) in study group vs 77 (4.34%) in control group. The RR for SPM was 1.12 (95% CI: 0.74 - 1.69; P = 0.58) and RD was 0.01 (95% CI: -0.01 to 0.02; P = 0.34). The RR for SPM was noted at 2.56 (95% CI: 0.26 - 25.46; P = 0.42) in a subset of relapsed and refractory multiple myeloma. Any-grade PSN was reported in 527 (46.84%) in daratumumab arm vs 550 (48.72%) in control arm with the RR of 0.98 (95% CI: 0.80 -1.21; P = 0.88). High-grade PSN was noted in 63 (5.6%) vs 76 (6.73%) in control group with the RR of 0.73 (95% CI: 0.42 -1.27; P = 0.27). Conclusions: Our meta-analysis depicted that there was no significant increase in the risk of second primary malignancies and peripheral sensory neuropathy in patients on daratumumab combination regimen, in newly diagnosed and relapsed refractory multiple myeloma, compared to control arm. However, long-term follow-up of these patients is required to determine the actual relation with second primary malignancies. Disclosures No relevant conflicts of interest to declare.

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Enhancement of Liver Toxicity on Diabetes Mellitus by a Universal Chemical Pollutant (Acrylonitrile) in Rats

Journal of King Abdulaziz University-Medical Sciences ◽

10.4197/med.26-2.2 ◽

2019 ◽

Vol 26 (2) ◽

pp. 9-17

Author(s):

Sameer E. Alharthi

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Aqueous Solution ◽

Liver Toxicity ◽

Elevated Serum ◽

Diabetic Rat ◽

Control Group ◽

Distilled Water ◽

Serum Aminotransferase ◽

Cyp2e1 Activity

The present study was designed to investigate potential liver damage due to acrylonitrile in Streptozotocin induced diabetes in rats. Twenty-four rats were divided into 4 treatment groups. Nondiabetic control rat receiving distilled water, non-diabetic rat receiving acrylonitrile aqueous solution (10 mg/kg/day), diabetic control rat receiving distilled water and diabetic rat receiving acrylonitrile aqueous solution. All groups received the treatment for 4 weeks. The animals were assessed for hepatoxicity markers in serum, oxidative stress markers, CYP2E1 activity and cyanide formation in tissues. Acrylonitrile significantly elevated serum aminotransferase, alanine aminotransferase, total bilirubin levels, triglycerides and total cholesterol in diabetic groups as compared to normal control group. Antioxidant markers like glutathione showed significant decline while a significant increase in malondialdehyde, superoxide dismutase and catalase in diabetic rats treated with acrylonitrile. CYP2E1 activity was observed in acrylonitrile – exposed nondiabetic and diabetic groups as compared to control. Cyanide formation was raised in both the nondiabetic and diabetic groups as compared to control group. Acrylonitriles can produce acute hepatic injury, induction of diabetes mellitus type II, and accomplish the CYP2E1 enzyme which sequentially leads to generation of oxidative stress and its metabolic product–cyanide that may potentiate the oxidative stress posing more deleterious effect.

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