Curcumin-containing Silver Nanoparticles prevent carbon tetrachlorideinduced hepatotoxicity in mice

2020 ◽  
Vol 23 ◽  
Author(s):  
Hossam Ebaid ◽  
Mohamed Habila ◽  
Iftekhar Hassan ◽  
Jameel Al-Tamimi ◽  
Mohamed S. Omar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Silver Nanoparticles ◽  
Nuclear Dna ◽  
Liquid Paraffin ◽  
Tail Length ◽  
Hepatic Tissue ◽  
Tissue Destruction ◽  
Group 2 ◽  
The Impact

Background: Hepatotoxicity remains an important clinical challenge. Hepatotoxicity observed in response to toxins and hazardous chemicals may be alleviated by delivery of the curcumin in silver nanoparticles (AgNPs-curcumin). In this study, we examined the impact of AgNPs-curcumin in a mouse model of carbon tetrachloride (CCl4)-induced hepatic injury. Methods: Male C57BL/6 mice were divided into three groups (n=8 per group). Mice in group 1 were treated with vehicle control alone, while mice in Group 2 received a single intraperitoneal injection of 1 ml/kg CCl4 in liquid paraffin (1:1 v/v). Mice in group 3 were treated with 2.5 mg/kg AgNPs-curcumin twice per week for three weeks after the CCl4 challenge. Results: Administration of CCL4 resulted in oxidative dysregulation, including significant reductions in reduced glutathione and concomitant elevations in the level of malondialdehyde (MDA). CCL4 challenge also resulted in elevated levels of serum aspartate transaminase (AST) and alanine transaminase (ALT); these findings were associated with the destruction of hepatic tissues. Treatment with AgNPs-curcumin prevented oxidative imbalance, hepatic dysfunction, and tissue destruction. A comet assay revealed that CCl4 challenge resulted in significant DNA damage as documented by a 70% increase in nuclear DNA tail-length; treatment with AgNPs-curcumin inhibited the CCL4-mediated increase in nuclear DNA tail-length by 34%. Conclusion: Administration of AgNPs-curcumin resulted in significant antioxidant activity in vivo. This agent has the potential to prevent the hepatic tissue destruction and DNA damage that results from direct exposure to CCL4.

The impact of in vivo and in vitro exposure to base analogue 5-FU on the level of DNA damage in haemocytes of freshwater mussels Unio pictorum and Unio tumidus

2014 ◽  
Vol 191 ◽  
pp. 145-150 ◽  
Author(s):  
Zoran Gačić ◽  
Stoimir Kolarević ◽  
Karolina Sunjog ◽  
Margareta Kračun-Kolarević ◽  
Momir Paunović ◽  
...  
Keyword(s):  
Dna Damage ◽  
Freshwater Mussels ◽  
In Vitro Exposure ◽  
Unio Tumidus ◽  
The Impact ◽  
Unio Pictorum

scholarly journals Morphological comparative assessment of in vivo 2-week oral exposure of silver nanoparticles and silver sulfate on the mice liver

2019 ◽  
Vol 95 (9) ◽  
pp. 899-902
Author(s):  
Natalia N. Belyaeva ◽  
L. P. Sycheva
Keyword(s):  
Silver Nanoparticles ◽  
Comparative Evaluation ◽  
Comparative Assessment ◽  
Oral Exposure ◽  
Silver Sulfate ◽  
Mice Liver ◽  
The Impact ◽  
Functional Indices ◽  
Different Doses

Currently the problem of the impact of nanoparticles and nanomaterials on human health remains to be poorly understood. As in our studies of the impact of silver nanoparticles on rats liver as well in works of other researchers there were investigated morphofunctional indices under peroral exposure. Although all researchers took different sizes, doses and concentrations of silver nanoparticles, various exposure time and different stabilizers, the same effects had been obtained, which, however, were occurred under both different doses and time of exposure. However, it was interesting to compare the impact of silver nanoparticles with reference substance - silver sulfate on the mice liver with the previously evaluated effect produced on the rats ’ liver. By ourselves there was executed the morphological comparative evaluation of in vivo oral 2-weeks exposure of 4 concentrations (0.1; 5; 50 and 500 mg/l) of silver nanoparticles with size of 14 nm, stable arabian gum 1:7 by weight, and of 4 similar concentrations of silver sulfate on the liver of male mice СВАхС57В1/6 weighing 25-35g. 2 groups were considered as control: intact mice and mice received gum in water. Results of the exposure were assessed according to 10 morphological and functional indices. The impact of nanosilver was shown to initiate from its concentration of 50 mg/l and to express in the gain of the index of alteration of the cytoplasm of hepatocytes with the increasing in both severity of steatosis and the number of micronecroses, persisting at the same level at concentrations of 500 mg/l and with the elevation of the index of alteration of nuclei of hepatocytes, while the similar effect develops under the influence of silver sulfate at a concentration of 500 mg/l only. The remaining investigated morphofunctional indices did not differ significantly in all groups of mice. Unlike previously executed studies on rats, mice appeared to be sensitive to the effects of nano-silver more than to silver sulfate.

scholarly journals PTEN mutant NSCLC require ATM to suppress pro-apoptotic signalling and evade radiotherapy

2021 ◽  
Author(s):  
Thomas Fischer ◽  
Oliver Hartmann ◽  
Michaela Reissland ◽  
Cristian Prieto-Garcia ◽  
Kevin Klann ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Western Blot ◽  
Colony Formation ◽  
Ex Vivo ◽  
Radiation Sensitivity ◽  
Genetic Alterations ◽  
Altered Expression ◽  
The Impact

Background: Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. Methods: Using CRISPR genome editing, we deleted PTEN in a human tracheal stem cell-like cell line as well generated primary murine NSCLC, proficient or deficient for Pten, in vivo. These models were used to verify the impact of PTEN loss in vitro and in vivo by immunohistochemical staining, western blot and RNA-Sequencing. Radiation sensitivity was assessed by colony formation and growth assays. To elucidate putative treatment options, identified via the molecular characterisation, PTEN pro- and deficient cells were treated with PI3K/mTOR/DNA-PK-inhibitor PI-103 or the ATM-inhibitors KU-60019 und AZD 1390. Changes in radiation sensitivity were assessed by colony-formation assay, FACS, western-blot, phospho-proteomic mass spectrometry and ex vivo lung slice cultures. Results: We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. Conclusion: PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.

Cellular Senescence Contributes to the Outcome of Lymphoma Chemotherapy by Cell-Autonomous and Paracrine Immune Mechanisms

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3617-3617
Author(s):  
Jan Dörr ◽  
Yong Yu ◽  
Bernd Dörken ◽  
Clemens A. Schmitt
Keyword(s):  
Dna Damage ◽  
Immune Cell ◽  
Genetic Alterations ◽  
Cell Interactions ◽  
Brdu Incorporation ◽  
Tumor Site ◽  
Immune Cell Subsets ◽  
The Impact

Abstract Introduction: Premature senescence reflects an acutely inducible, irreversible growth arrest as a cellular response to stresses such as oncogenic activation and DNA damage, including chemotherapeutic anticancer agents. Senescence complements apoptosis as a tumor suppressive and therapeutic effector principle, but whether a selective disruption of the senescence machinery impairs treatment outcome is unknown. Moreover, function and fate of senescent tumor cells within the tumor site remain unclear. Here, we analyze the impact of defined genetic alterations, i.e. Bcl2 overexpression (blocking apoptosis), deletion of the histone H3 lysine 9 methyltransferase Suv39h1 (controlling senescence), and conditional expression of p53 (mediating both apoptosis and senescence), on therapy-induced senescence (TIS) in the Eμ-myc mouse lymphoma model with specific emphasis on immunological tumor-host and growth-modulating senescent/non-senescent cell interactions as a consequence of TIS in vitro and in vivo. Methods: Lymphoma cells (LCs) of various genetic backgrounds were retrovirally transduced with the bcl2 gene to study TIS in the absence of drug-induced apoptosis. Bcl2-protected LCs were treated with the DNA damaging anticancer agent adriamycin in vitro, or were exposed to the alkylating agent cyclophosphamide upon lymphoma formation in normal immunocompetent mice in vivo. TIS was detected by staining for senescence-associated β-galactosidase activity (SA-β-gal) and other senescence-related markers, including Ki67 and BrdU incorporation. To study tumor-host cell interactions, isolated normal splenocytes were co-incubated with proliferating or senescent LCs in vitro. Immunophenotyping was carried out with antibodies specific for macrophages, granulocytes, natural killer cells and T-lymphocytes. Cytokine production was measured by protein arrays. Results: Senescent LCs engage in cell-cell interactions with different immune cell subsets, in particular macrophages, granulocytes and T-cells in vitro. Fluorescence microscopy reveals that macrophages engulf LCs after they entered TIS. In vivo, TIS correlates with the quantitative attraction of immune cell populations to the tumor site and subsequent clearing of senescent cells. Ongoing mechanistic studies on underlying ligand/receptor interactions will be reported at the meeting. TIS cells exhibit a specific pro-inflammatory secretory profile whose functional impact on tumor and bystander cells is currently being investigated. Importantly, this profile is distinguishable from cytokine profiles of senescence-compromised Suv39h1- or p53-deficient lymphomas, and, thus, reflects a senescence - rather than a DNA damage-associated secretory response. Discussion: The study unveils a functional interaction of senescent LCs with different immune cell subsets in vitro and in vivo. The cytokine arrays show that senescent cells produce a specific secretory profile, which might stimulate immune cell attraction. Therefore, immune cells could be recruited to lymphomas in vivo specifically after TIS with the potential to clear senescent – and possibly non-senescent – cells from the tumor site. The data demonstrate genetically that senescence is a beneficial effector principle of DNA damaging chemotherapy and encourage further exploration of this program to limit cancer expansion in vivo.

scholarly journals Depletion of the 110-Kilodalton Isoform of Poly(ADP-Ribose) Glycohydrolase Increases Sensitivity to Genotoxic and Endotoxic Stress in Mice

2004 ◽  
Vol 24 (16) ◽  
pp. 7163-7178 ◽  
Author(s):  
Ulrich Cortes ◽  
Wei-Min Tong ◽  
Donna L. Coyle ◽  
Mirella L. Meyer-Ficca ◽  
Ralph G. Meyer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Alkylating Agents ◽  
Endotoxic Shock ◽  
Embryonic Stem ◽  
Cellular Processes ◽  
Streptozotocin Induced Diabetes ◽  
The Impact ◽  
Parp 1

ABSTRACT Poly(ADP-ribosylation) is rapidly stimulated in cells following DNA damage. This posttranslational modification is regulated by the synthesizing enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and the degrading enzyme poly(ADP-ribose) glycohydrolase (PARG). Although the role of PARP-1 in response to DNA damage has been studied extensively, the function of PARG and the impact of poly(ADP-ribose) homeostasis in various cellular processes are largely unknown. Here we show that by gene targeting in embryonic stem cells and mice, we specifically deleted the 110-kDa PARG protein (PARG110) normally found in the nucleus and that depletion of PARG110 severely compromised the automodification of PARP-1 in vivo. PARG110-deficient mice were viable and fertile, but these mice were hypersensitive to alkylating agents and ionizing radiation. In addition, these mice were susceptible to streptozotocin-induced diabetes and endotoxic shock. These data indicate that PARG110 plays an important role in DNA damage responses and in pathological processes.

scholarly journals miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression

2020 ◽  
Vol 21 (22) ◽  
pp. 8675
Author(s):  
Asier Benito-Vicente ◽  
Kepa B. Uribe ◽  
Noemi Rotllan ◽  
Cristina M. Ramírez ◽  
Shifa Jebari-Benslaiman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Receptor Expression ◽  
Hepatic Insulin Resistance ◽  
Hepatic Tissue ◽  
Special Importance ◽  
The Impact

Insulin resistance (IR) is one of the key contributing factors in the development of type 2 diabetes mellitus (T2DM). However, the molecular mechanisms leading to IR are still unclear. The implication of microRNAs (miRNAs) in the pathophysiology of multiple cardiometabolic pathologies, including obesity, atherosclerotic heart failure and IR, has emerged as a major focus of interest in recent years. Indeed, upregulation of several miRNAs has been associated with obesity and IR. Among them, miR-27b is overexpressed in the liver in patients with obesity, but its role in IR has not yet been thoroughly explored. In this study, we investigated the role of miR-27b in regulating insulin signaling in hepatocytes, both in vitro and in vivo. Therefore, assessment of the impact of miR-27b on insulin resistance through the hepatic tissue is of special importance due to the high expression of miR-27b in the liver together with its known role in regulating lipid metabolism. Notably, we found that miR-27b controls post-transcriptional expression of numerous components of the insulin signaling pathway including the insulin receptor (INSR) and insulin receptor substrate 1 (IRS1) in human hepatoma cells. These results were further confirmed in vivo showing that overexpression and inhibition of hepatic miR-27 enhances and suppresses hepatic INSR expression and insulin sensitivity, respectively. This study identified a novel role for miR-27 in regulating insulin signaling, and this finding suggests that elevated miR-27 levels may contribute to early development of hepatic insulin resistance.

scholarly journals The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro

2019 ◽  
Vol 93 (11) ◽  
pp. 3345-3366 ◽  
Author(s):  
Mateja Sborchia ◽  
Eric G. De Prez ◽  
Marie-Hélène Antoine ◽  
Lucie Bienfait ◽  
Radek Indra ◽  
...  
Keyword(s):  
Dna Damage ◽  
Renal Injury ◽  
Aristolochic Acid ◽  
Underlying Mechanism ◽  
Dna Adduct ◽  
Gas Chromatography Mass Spectrometry ◽  
Primary Mouse ◽  
The Impact

Abstract Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. The tumour suppressor TP53 is a critical gene in carcinogenesis and frequently mutated in AA-induced urothelial tumours. We investigated the impact of p53 on AAI-induced nephrotoxicity and DNA damage in vivo by treating Trp53(+/+), Trp53(+/−) and Trp53(−/−) mice with 3.5 mg/kg body weight (bw) AAI daily for 2 or 6 days. Renal histopathology showed a gradient of intensity in proximal tubular injury from Trp53(+/+) to Trp53(−/−) mice, especially after 6 days. The observed renal injury was supported by nuclear magnetic resonance (NMR)-based metabonomic measurements, where a consistent Trp53 genotype-dependent trend was observed for urinary metabolites that indicate aminoaciduria (i.e. alanine), lactic aciduria (i.e. lactate) and glycosuria (i.e. glucose). However, Trp53 genotype had no impact on AAI-DNA adduct levels, as measured by 32P-postlabelling, in either target (kidney and bladder) or non-target (liver) tissues, indicating that the underlying mechanisms of p53-related AAI-induced nephrotoxicity cannot be explained by differences in AAI genotoxicity. Performing gas chromatography–mass spectrometry (GC–MS) on kidney tissues showed metabolic pathways affected by AAI treatment, but again Trp53 status did not clearly impact on such metabolic profiles. We also cultured primary mouse embryonic fibroblasts (MEFs) derived from Trp53(+/+), Trp53(+/−) and Trp53(−/−) mice and exposed them to AAI in vitro (50 µM for up to 48 h). We found that Trp53 genotype impacted on the expression of NAD(P)H:quinone oxidoreductase (Nqo1), a key enzyme involved in AAI bioactivation. Nqo1 induction was highest in Trp53(+/+) MEFs and lowest in Trp53(−/−) MEFs; and it correlated with AAI-DNA adduct formation, with lowest adduct levels being observed in AAI-exposed Trp53(−/−) MEFs. Overall, our results clearly demonstrate that p53 status impacts on AAI-induced renal injury, but the underlying mechanism(s) involved remain to be further explored. Despite the impact of p53 on AAI bioactivation and DNA damage in vitro, such effects were not observed in vivo.

scholarly journals Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

2015 ◽  
Vol 112 (26) ◽  
pp. E3421-E3430 ◽  
Author(s):  
Prashant Rai ◽  
Marcus Parrish ◽  
Ian Jun Jie Tay ◽  
Na Li ◽  
Shelley Ackerman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Critical Role ◽  
Alveolar Epithelial Cells ◽  
Dna Double Strand Breaks ◽  
Histone H2ax ◽  
Alveolar Epithelial ◽  
Time Required ◽  
The Impact

Streptococcus pneumoniaeis a leading cause of pneumonia and one of the most common causes of death globally. The impact ofS. pneumoniaeon host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show thatS. pneumoniaeinduces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H2O2, plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H2O2, greatly suppressesS. pneumoniae-induced DNA damage and apoptosis. Importantly,S. pneumoniaeinduces DSBs in the lungs of animals with acute pneumonia, and H2O2production byS. pneumoniaein vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventingS. pneumoniae-induced genotoxicity. Taken together, this study shows thatS. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia.

Leveraging the DNA damage and transcriptional-regulatory roles of PARP-1 as a means to improve prostate cancer therapy.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 179-179
Author(s):  
Matthew Joseph Schiewer ◽  
Jamin Steffen ◽  
Renee Tholey ◽  
Jonathan Robert Brody ◽  
John Pascal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Dna Damage ◽  
Cell Growth ◽  
Target Gene ◽  
Parp Inhibitors ◽  
Transcriptional Regulatory ◽  
The Impact ◽  
Parp 1

179 Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of androgen receptor (AR) function in models of prostatic adenocarcinoma (PCa), and is recruited to regulatory sites of select AR target genes. Pharmacological inhibition of PARP-1 enzymatic activity results in diminished AR and PARP-1 residency at AR target gene regulatory loci, reduced AR target gene expression (more than 50%), and reduced AR-driven, PCa-associated phenotypes, including castrate-resistant PCa (CRPC) AR function, tumor cell growth, and transition to CRPC. These data, in part, served as critical rationale for current clinical trials combining PARP inhibition and abiraterone for patients with metastatic CRPC NCT01576172 . Given the clinical importance of targeting AR function in PCa, preclinical studies were performed to assess the impact of leveraging the dual roles of PARP-1 as a means to improve therapy for advanced disease. Methods: In vitro and in vivo model systems were utilized to assess impact on AR and tumor growth. Multiple PARP inhibitors were used for additional studies. The impact of PARP-1 on gene expression was also assessed using unbiased analyses. PARP-1 mutants were also utilized to segregate the DNA damage and transcriptional regulatory roles of PARP-1. Results: Critically, PARP-1 inhibitors cooperated with castration to elicit an enhanced therapeutic response, and PARP-1 inhibitors were effective at suppressing CRPC growth in vivo. Multiple PARP inhibitors diminished AR chromatin occupancy, altered AR transcriptional output and reduction in PCa and CRPC cell growth. Conclusions: These data identify PARP-1 as a feasible therapeutic target for advanced prostate cancer. Multiple PARP inhibitors show pre-clinical efficacy in models of PCa and CRPC and merit consideration for clinical trial, and a concept will be presented.

Standardization of the Alkaline Elution Procedure Using X-Ray-Damaged Nuclear DNA

1979 ◽  
Vol 65 (5) ◽  
pp. 511-516 ◽  
Author(s):  
Claudia Bolognesi ◽  
Carmelo Federico Cesarone ◽  
Leonardo Santi
Keyword(s):  
Dna Damage ◽  
Nuclear Dna ◽  
Quantitative Assay ◽  
Alkaline Elution ◽  
X Ray ◽  
Structural Modifications ◽  
X Irradiation ◽  
In Vivo Administration

Structural modifications of DNA were induced by X-irradiation of crude hepatic nuclei at various dose ranges to standardize DNA damage evaluated by the alkaline elution technique. This quantitative assay can be used as reference for DNA damage induced by the in vivo administration of mutagens and/or carcinogens involved in the environment.

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