scholarly journals Precise let-7 expression levels balance organ regeneration against tumor suppression

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Linwei Wu ◽  
Liem H Nguyen ◽  
Kejin Zhou ◽  
T Yvanka de Soysa ◽  
Lin Li ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Mouse Models ◽  
Liver Damage ◽  
Tissue Damage ◽  
Tissue Repair ◽  
High Dose ◽  
Organ Regeneration ◽  
Microrna Family ◽  
Dose Dependent

The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics.

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).

The New CXCR4 Inhibitor MDX-1338 Exerts Anti-Tumor Activity in Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1844-1844 ◽  
Author(s):  
Aldo M Roccaro ◽  
Antonio Sacco ◽  
Michelle Kuhne ◽  
AbdelKareem Azab ◽  
Patricia Maiso ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Mouse Models ◽  
Research Funding ◽  
Therapeutic Agents ◽  
Dependent Manner ◽  
Apoptotic Pathways ◽  
Dose Dependent

Abstract Abstract 1844 Background. We have previously shown the SDF1/CXCR4 axis plays a major role in homing and trafficking of multiple myeloma (MM) to the bone marrow (BM), and disruption of the interaction of tumor cells with the BM leads to enhanced sensitivity to therapeutic agents. We hypothesize that the novel anti-CXCR4 antibody, BMS936564/MDX-1338, may prevent the homing and adhesion of MM cells to the BM and will sensitize them to therapeutic agents. Methods. Primary MM cells (CD138+); MM cell lines (MM.1S, RPMI.8226); and primary MM bone marrow stromal cells (BMSCs) were used. Migration towards SDF-1 and BMSCs has been evaluated. Cytotoxicity and DNA synthesis were measured by MTT and thymidine uptake, respectively. Cell signaling and apoptotic pathways were studied by Western Blot. Synergism was calculated using the Chou-Talalay method. In vivo MM tumor growth was evaluated with xenograft mouse models. Results. MDX-1338 inhibited migration of MM cells toward SDF-1a and primary MM BMSCs, in a dose-dependent manner. Adhesion of primary MM cells to BMSCs was also inhibited by BMS936564/MDX-1338 in a dose-dependent manner, while also inducing cytotoxicity on primary BM-derived CD138+ cells. BMS936564/MDX-1338 targeted MM cells in the context of BM milieu by overcoming BMSC-induced proliferation of tumor cells. In addition, BMS936564/MDX-1338 synergistically enhanced bortezomib-induced cytotoxicity in MM cells. BMS936564/MDX-1338-dependent activation of apoptotic pathways in MM cells was documented, as shown by cleavage of caspase-9 and PARP. SDF-1a-induced ERK-, Akt-, and Src-phosphorilation was inhibited by BMS936564/MDX-1338 in a dose-dependent manner. Importantly, BMS936564/MDX-1338 inhibited MM cell proliferation in vivo in xenograft mouse models. Conclusion. These studies therefore show that targeting CXCR-4 in MM by using BMS936564/MDX-1338 represents a valid therapeutic strategy in this disease. Disclosures: Roccaro: Roche:. Kuhne:BMS: Employment. Pan:Bristol-Myers Squibb: Employment. Cardarelli:Bristol-Myers Squibb: Employment. Ghobrial:Noxxon: Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Research Funding; Noxxon:; Millennium:; Celegene:; Novartis:.

scholarly journals Dose-Dependent Differential Effect of Neurotrophic Factors on In Vitro and In Vivo Regeneration of Motor and Sensory Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Daniel Santos ◽  
Francisco Gonzalez-Perez ◽  
Xavier Navarro ◽  
Jaume del Valle
Keyword(s):  
Neurite Outgrowth ◽  
Functional Recovery ◽  
Neurotrophic Factors ◽  
Collagen Matrix ◽  
High Dose ◽  
Organotypic Cultures ◽  
High Doses ◽  
Dose Dependent

Although peripheral axons can regenerate after nerve transection and repair, functional recovery is usually poor due to inaccurate reinnervation. Neurotrophic factors promote directional guidance to regenerating axons and their selective application may help to improve functional recovery. Hence, we have characterized in organotypic cultures of spinal cord and dorsal root ganglia the effect of GDNF, FGF-2, NGF, NT-3, and BDNF at different concentrations on motor and sensory neurite outgrowth. In vitro results show that GDNF and FGF-2 enhanced both motor and sensory neurite outgrowth, NGF and NT-3 were the most selective to enhance sensory neurite outgrowth, and high doses of BDNF selectively enhanced motor neurite outgrowth. Then, NGF, NT-3, and BDNF (as the most selective factors) were delivered in a collagen matrix within a silicone tube to repair the severed sciatic nerve of rats. Quantification of Fluorogold retrolabeled neurons showed that NGF and NT-3 did not show preferential effect on sensory regeneration whereas BDNF preferentially promoted motor axons regeneration. Therefore, the selective effects of NGF and NT-3 shown in vitro are lost when they are applied in vivo, but a high dose of BDNF is able to selectively enhance motor neuron regeneration both in vitro and in vivo.

scholarly journals Ammonia-Induced Energy Metabolism Disorder and Autophagy via AMPK/mTOR/ULK1 Pathway in Chicken Livers

2020 ◽  
Author(s):  
Zhuo Li ◽  
Zhiying Miao ◽  
Linlin Ding ◽  
Jun Bao ◽  
Xiaohua Teng
Keyword(s):  
Energy Metabolism ◽  
Liver Damage ◽  
Respiratory System ◽  
Tissue Damage ◽  
Digestive System ◽  
Chicken Liver ◽  
Time Dependent ◽  
Metabolism Disorder ◽  
Dose Dependent ◽  
Energy Metabolism Disorder

Abstract BackgroundAmmonia (NH3) is a well-known environmental pollution gas, threatening human health. NH3 is also the most harmful gas to poultry for many years. Some studies have found NH3 can damage eyes, respiratory system, and digestive system. However, molecular mechanism of NH3 toxicity on chicken livers remains unclear. MethodsIn this study, we selected chicken liver as research object and successfully duplicated NH3 poisoning model of chickens. The ultrastructure of chicken livers was observed. The activities of ATPases (Na+K+-ATPase, Mg++-ATPase, Ca++-ATPase, and Ca++Mg++-ATPase) and the expression of energy metabolism-related genes (HK1, HK2, PK, PFK, PDHX, CS, LDHA, LDHB, AMPK, SDHA, SDHB, and avUCP) and autophagy-related genes (PI3K, LC3I, LC3II, Beclin1, SQSTM1, mTOR, ULK1, ATG5, ATG12, and ATG13) were measured to explore the effect of NH3 on energy metabolism and autophagy in chicken livers.ResultsOur results showed that excess NH3 caused liver tissue damage. Meanwhile, ATPases activities were inhibited during NH3 treatment. Moreover, we found that NH3 exposure altered the expression of energy metabolism-related and autophagy-related genes. NH3-induced compensatory increase of AMPK activated autophagy process through inhibiting mTOR and promoting ULK1. In addition. there was dose-dependent and time-dependent effects on all detected indexes in NH3-caused chicken liver damage. ConclusionExcess NH3 induced energy metabolism disorder and autophagy via AMPK/mTOR/ULK1 pathway in chicken livers.

scholarly journals A Titanium (IV)–Dithiophenolate Complex and Its Chitosan Nanocomposite: Their Roles towards Rat Liver Injuries In Vivo and against Human Liver Cancer Cell Lines

2021 ◽  
Vol 22 (20) ◽  
pp. 11219
Author(s):  
Nadia Z. Shaban ◽  
Salah A. Yehia ◽  
Doaa Awad ◽  
Shaban Y. Shaban ◽  
Samar R. Saleh
Keyword(s):  
Oxidative Stress ◽  
Liver Cancer ◽  
Cell Lines ◽  
Rat Liver ◽  
Liver Damage ◽  
Human Liver ◽  
Therapeutic Effects ◽  
Liver Injuries ◽  
Human Liver Cancer

Titanium (IV)–dithiophenolate complex chitosan nanocomposites (DBT–CSNPs) are featured by their antibacterial activities, cytotoxicity, and capacity to bind with DNA helixes. In this study, their therapeutic effects against rat liver damage induced by carbon tetrachloride (CCl4) and their anti-proliferative activity against human liver cancer (HepG2) cell lines were determined. Results of treatment were compared with cisplatin treatment. Markers of apoptosis, oxidative stress, liver functions, and liver histopathology were determined. The results showed that DBT–CSNPs and DBT treatments abolished liver damage induced by CCl4 and improved liver architecture and functions. DNA fragmentation, Bax, and caspase-8 were reduced, but Bcl-2 and the Bcl-2/Bax ratios were increased. However, there was a non-significant change in the oxidative stress markers. DBT–CSNPs and DBT inhibited the proliferation of HepG2 cells by arresting cells in the G2/M phase and inducing cell death. DBT–CSNPs were more efficient than DBT. Low doses of DBT and DBT–CSNPs applied to healthy rats for 14 days had no adverse effect. DBT and DBT–CSNP treatment gave preferable results than the treatment with cisplatin. In conclusion, DBT–CSNPs and DBT have anti-apoptotic activities against liver injuries and have anti-neoplastic impacts. DBT–CSNPs are more efficient. Both compounds can be used in pharmacological fields.

Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumour-propagating cells and their dynamic cellular transition during liver cancer progression

Gut ◽  
2021 ◽  
pp. gutjnl-2021-324321
Author(s):  
Lei Zhou ◽  
Ken HO Yu ◽  
Tin Lok Wong ◽  
Zhao Zhang ◽  
Chun Ho Chan ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Single Cell ◽  
Mouse Models ◽  
Cancer Progression ◽  
3D Culture ◽  
Lineage Tracing ◽  
Protective Mechanism ◽  
Intact Mouse ◽  
Hcc Cells

ObjectiveHepatocellular carcinoma (HCC) has high intratumoral heterogeneity, which contributes to therapeutic resistance and tumour recurrence. We previously identified Prominin-1 (PROM1)/CD133 as an important liver cancer stem cell (CSC) marker in human HCC. The aim of this study was to investigate the heterogeneity and properties of Prom1+ cells in HCC in intact mouse models.DesignWe established two mouse models representing chronic fibrotic HCC and rapid steatosis-related HCC. We performed lineage tracing post-HCC induction using Prom1C-L/+; Rosa26tdTomato/+ mice, and targeted depletion using Prom1C-L/+; Rosa26DTA/+ mice. Single-cell RNA sequencing (scRNA-seq) was carried out to analyse the transcriptomic profile of traced Prom1+ cells.ResultsProm1 in HCC tumours marks proliferative tumour-propagating cells with CSC-like properties. Lineage tracing demonstrated that these cells display clonal expansion in situ in primary tumours. Labelled Prom1+ cells exhibit increasing tumourigenicity in 3D culture and allotransplantation, as well as potential to form cancers of differential lineages on transplantation. Depletion of Prom1+ cells impedes tumour growth and reduces malignant cancer hallmarks in both HCC models. scRNA-seq analysis highlighted the heterogeneity of Prom1+ HCC cells, which follow a trajectory to the dedifferentiated status with high proliferation and stem cells traits. Conserved gene signature of Prom1 linage predicts poor prognosis in human HCC. The activated oxidant detoxification underlies the protective mechanism of dedifferentiated transition and lineage propagation.ConclusionOur study combines in vivo lineage tracing and scRNA-seq to reveal the heterogeneity and dynamics of Prom1+ HCC cells, providing insights into the mechanistic role of malignant CSC-like cells in HCC progression.

scholarly journals In Vivo Exposure to Bisphenol-A Altered the Reproductive Functionality in Male Coturnix Coturnix Japonica

2020 ◽  
Author(s):  
SUTHAN PERMUAL ◽  
GAUTHAM KOLLURI ◽  
JAG MOHAN ◽  
RAM SINGH ◽  
JAGBIR TYAGI
Keyword(s):  
Bisphenol A ◽  
Sperm Quality ◽  
Quality Attributes ◽  
High Dose ◽  
Japanese Quails ◽  
High Doses ◽  
Dose Dependent

Abstract Bisphenol-A, is one of the most characterized endocrine disruptors on the reproductive functions in humans and animals. We have previously reported in vitro and in vivo effects of bisphenol-A on functional role of sperm in chicken. Here, the effects of 1 and 5 mg/kg bisphenol-A daily administered by gavage for 3 wk to adult male Japanese quails on reproductive functionality was investigated. Cloacal index and foam frequency were greatly reduced at high dose. Sperm quality attributes were affected at both doses. Sperm quality attributes were affected at both doses. Alkaline phosphatase showed most significant reduction among seminal enzymes. Dose dependent response (P < 0.01) of bisphenol-A was noticed with modulating testosterone concentrations at low and high doses. Disturbances regarding fertility and hatchability traits were prominent in high and low dose groups. The current study confirms the compromising actions of bisphenol-A on reproductive success in male Japanese quails at lower doses that are considered to be safe (50 mg/kg BW/d) under in vivo exposure module. These results indicate higher sensitivity of quails to bisphenol-A toxicity and explores the possibility of using quail subjects as an accurate toxic indicators.

scholarly journals Circulating Microvesicle-Associated Inducible Nitric Oxide Synthase Is a Novel Therapeutic Target to Treat Sepsis: Current Status and Future Considerations

2021 ◽  
Author(s):  
Robert J Webber ◽  
Richard M Sweet ◽  
Douglas S Webber
Keyword(s):  
Nitric Oxide ◽  
Mouse Models ◽  
Therapeutic Target ◽  
Current Status ◽  
High Dose ◽  
Genetically Engineer ◽  
Dose Dependent ◽  
Harmful Effects ◽  
Novel Therapeutic ◽  
Inducible Nitric Oxide

Objective: To determine if mitigating the harmful effects of circulating microvesicle-associated inducible nitric oxide (MV-A iNOS) in vivo increases the survival of challenged mice in three different mouse models of sepsis. Design: The ability of anti-MV-A iNOS monoclonal antibodies (mAbs) to rescue challenged mice was assessed using three different mouse models of sepsis. Setting: The vivarium of a research laboratory. Subjects: Balb/c mice. Interventions: Mice were challenged with an LD80 dose of either lipopolysaccharide (LPS / endotoxin), TNFα, or MV-A iNOS and then treated at various times after the challenge with saline as control or with an anti-MV-A iNOS mAb as a potential immunotherapeutic to treat sepsis. Measurement and Main Results: Each group of mice was checked daily for survivors, and Kaplan-Meier survival curves were constructed. Five different murine anti-MV-A iNOS mAbs from our panel of 24 murine anti-MV-A iNOS mAbs (1) were found to rescue some of the challenged mice. All five murine mAbs were used to genetically engineer humanized anti-MV-A iNOS mAbs by inserting the murine complementarity-determining regions (CDRs) into a human IgG1,kappa scaffold and expressing the humanized mAbs in CHO cells. Three humanized anti-MV-A iNOS mAbs were effective at rescuing mice from sepsis in three different animal models of sepsis. The effectiveness of the treatment was both time and dose dependent. Humanized anti-MV-A iNOS rHJ mAb could rescue up to 80% of the challenged animal if administered early and at a high dose. Conclusions: Our conclusions are MV-A iNOS is a novel therapeutic target to treat sepsis; anti-MV-A iNOS mAbs can mitigate the harmful effects of MV-A iNOS; the neutralizing mAb's efficacy is both time and dose dependent; and a specifically targeted immunotherapeutic for MV-A iNOS could potentially save tens-of-thousands of lives annually and could result in improved antibiotic stewardship.

High-Dose Calcitriol Modulates the Expression and Activity of Tissue Factor and Thrombomodulin in Tumor Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 921-921
Author(s):  
Enriqueta Coll-Sangrona ◽  
Ali Amirkhosravi ◽  
Alshad S. Lalani ◽  
Liza Robles ◽  
Hina Desai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Endothelial Cells ◽  
Tumor Cells ◽  
High Dose ◽  
Dependent Manner ◽  
High Concentrations ◽  
Dose Dependent ◽  
A549 Lung

Abstract Calcitriol, the hormonally-active metabolite of Vitamin D3, plays critical roles in calcium homeostasis, cell growth and differentiation, and immunoregulation. The anti-tumor activities of high-dose calcitriol have been demonstrated in a variety of preclinical models of solid tumors, leukemias and lymphomas. Recently, a new dose-intense formulation of calcitriol, termed DN-101 (Asentar™), was developed specifically for cancer therapy which allows for supraphysiological concentrations of calcitriol to be safely delivered in vivo to patients with cancer. In a recent Phase 2 clinical trial, DN-101 significantly increased overall survival and also reduced the incidence of thromboembolic events in men with androgen-independent prostate cancer receiving docetaxel-based chemotherapy. Based on previous observations we hypothesized that calcitriol’s anti-thrombotic effects in vivo may be due to the downregulation of Tissue Factor (TF) antigen and activity and/or upregulation of Thrombomodulin (TM). To test this hypothesis, we incubated A549 lung carcinoma, A375-C15 metastatic melanoma, THP-1 monocytic leukemia, and Eahy926 endothelial cells with increasing concentrations of calcitriol for 24 hrs. For TF induction, tumor cells were stimulated with TNFα for 5 hrs and activity was measured by a clotting assay and a thrombin generation assay (TGA). TM activity was measured by a chromogenic assay. TF and TM surface antigen were assessed by flow cytometry. Calcitriol prevented the induction of TF in TNFα-stimulated THP-1 cells in a dose-dependent manner (from 33% at 1 nM to 94% at 100 nM) as evidenced by a prolongation of plasma clotting time, a decrease in endogenous thrombin potential (ETP), and a reduction of surface TF antigen. In addition, the activity and surface expression of TM on THP-1 cells was increased significantly (40% and 3-fold respectively, P < 0.01) following 100 nM calcitriol treatment. Similarly, in TNFα-stimulated melanoma cells, calcitriol prevented the induction of TF activity (from 26% at 1 nM to 60% at 1 μM) and expression in a dose-dependent manner. High-dose calcitriol treatment also increased melanoma cell TM activity between 8% and 62%. In contrast, constitutively expressed TF activity and antigen were less affected by calcitriol in A549 lung carcinoma cells (12 to 28% reduction at concentrations between 1–100 nM) whilst TM activity and antigen were unaffected. In comparison to the tumor cells, calcitriol had no significant effect on TM or TF activity or antigen in TNFα-stimulated EAhy926 endothelial cells. In conclusion, we have demonstrated that high concentrations of calcitriol inhibit the induction of surface TF expression and upregulates TM in multiple tumor cell lines in vitro. The degree of the inhibition is proportional to the extent of TF induction by TNF-α. These in vitro results provide further support for the anticoagulant properties associated with high concentrations of calcitriol and may provide a rationale for understanding the lower incidence of thromboembolic complications observed in patients with metastatic prostate cancer treated with DN-101.

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