Hepatocyte-derived extracellular vesicles regulate liver regeneration through a negative feedback mechanism.

While significant progress has been made in understanding various aspects of liver regeneration, the molecular mechanisms responsible for the initiation and termination of cell proliferation in the liver following massive tissue loss or injury of liver remain unknown. As it was previously shown, the loss of liver mass affects putative hepatocyte-specific mitogenic inhibitors in the blood. Although the presence of these putative inhibitors regulating precise liver regeneration has been described in numerous publications, they have never been identified.

Hepatocyte-derived extracellular vesicles regulate liver regeneration after partial hepatectomy.

While significant progress has been made in understanding different aspects of liver regeneration, the molecular mechanisms responsible for the initiation and termination of cell proliferation in the liver after massive loss or injury of liver tissue remain unknown. The loss of liver mass affects tissue-specific mitogenic inhibitors in the blood, which in turn regulate the proliferation of remaining hepatocytes and liver regeneration. Although well described in a number of publications, which inhibitory substances or "sensor molecules" control the regeneration mechanisms to properly maintain liver size remain unknown.

Neuron enriched extracellular vesicles' MicroRNA expression profiles as a marker of early life alcohol consumption.

Alcohol consumption may impact and shape brain development through perturbed biological pathways and impaired molecular functions. We investigated the relationship between alcohol consumption rates and neuron-enriched extracellular vesicles' (EVs') microRNA (miRNA) expression to better understand the impact of alcohol use on early life brain biology. Neuron-enriched EVs' miRNA expression was measured from plasma samples collected from young people using a commercially available microarray platform while alcohol consumption was measured using the Alcohol Use Disorders Identification Test.

Regulatory miRNAs in cancer cell recovery from therapy exposure and its implications as a novel therapeutic strategy for preventing disease recurrence.

The desired outcome of cancer therapies is the eradication of disease. This can be achieved when therapy exposure leads to therapy-induced cancer cell death as the dominant outcome. Theoretically, a permanent therapy-induced growth arrest could also contribute to a complete response, which has the potential to lead to remission.

Neuron Enriched Exosomal MicroRNA Expression Profiles as a Marker of Early Life Alcohol Consumption.

Background: Alcohol consumption may impact and shape brain development through perturbed biological pathways and impaired molecular functions. We investigated the relationship between alcohol consumption rates and neuron-enriched exosomal microRNA (miRNA) expression to better understand the impact of alcohol use on early life brain biology.

Methods: Neuron-enriched exosomal miRNA expression was measured from plasma samples collected from young people using a commercially available microarray platform while alcohol consumption was measured using the Alcohol Use Disorders Identification Test.

Uncoupled nitric oxide synthase activity promotes colorectal cancer progression.

Increased levels of reactive oxygen/nitrogen species are one hallmark of chronic inflammation contributing to the activation of pro-inflammatory/proliferative pathways. In the cancers analyzed, the tetrahydrobiopterin:dihydrobiopterin ratio is lower than that of the corresponding normal tissue, leading to an uncoupled nitric oxide synthase activity and increased generation of reactive oxygen/nitrogen species. Previously, we demonstrated that prophylactic treatment with sepiapterin, a salvage pathway precursor of tetrahydrobiopterin, prevents dextran sodium sulfate-induced colitis in mice and associated azoxymethane-induced colorectal cancer.

PARP inhibitors in the treatment of ARID1A mutant ovarian clear cell cancer: PI3K/Akt1-dependent mechanism of synthetic lethality.

Introduction: Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme involved in the repair of DNA single-strand breaks (SSB). The recent development of poly(ADP-ribose) polymerase inhibitors (PARPi) results from over 45 years of studies. When the activity of PARP1 or PARP2 is compromised, DNA SSB lesions are unresolved and can be converted to DNA double-strand breaks (DSBs) by the cellular transcription mechanisms.

Mitigation of Radiation-Induced Lung and Heart Injuries in Mice by Oral Sepiapterin after Irradiation.

After radiation exposure, endothelium-dependent vasorelaxation is impaired due to impaired nitric oxide production. Endothelial dysfunction is characterized by uncoupled endothelial nitric oxide synthase activity, oxidation of the reduced cofactor tetrahydrobiopterin to dihydrobiopterin as one well recognized mechanism. Oral treatment with sepiapterin, a tetrahydrobiopterin precursor, decreased infiltrating inflammatory cells and cytokine levels in mice with colitis.

Nitric oxide-donor/PARP-inhibitor combination: A new approach for sensitization to ionizing radiation.

Recently, clinical development of PARP inhibitors (PARPi) expanded from using them as a single agent to combining them with DNA-damaging therapy to derive additional therapeutic benefit from stimulated DNA damage. Furthermore, inhibiting PARP in cancers with BRCA1/2 mutations has been shown to be an effective synthetic lethality approach either as a single agent or in combination with the different DNA damaging agents: chemotherapy or ionizing radiation (IR). However, inherited BRCA1/2 mutations account only for 5-10% of breast cancers, 10-15% of ovarian cancers, and lesser for the other cancers.

DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169.

Human Dual-specificity tyrosine (Y) Regulated Kinase 1A (DYRK1A) is encoded by a dosage dependent gene whereby either trisomy or haploinsufficiency result in developmental abnormalities. However, the function and regulation of this important protein kinase are not fully understood. Here, we report proteomic analysis of DYRK1A in human cells that revealed a novel role of DYRK1A in DNA double-strand breaks (DSBs) repair, mediated in part by its interaction with the ubiquitin-binding protein RNF169 that accumulates at the DSB sites and promotes homologous recombination repair (HRR) by displacing 53BP1, a key mediator of non-homologous end joining (NHEJ).

Tumor cell escape from therapy-induced senescence.

H460 non-small cell lung, HCT116 colon and 4T1 breast tumor cell lines induced into senescence by exposure to either etoposide or doxorubicin were able to recover proliferative capacity both in mass culture and when enriched for the senescence-like phenotype by flow cytometry (based on β-galactosidase staining and cell size, and a senescence-associated reporter, BTG1-RFP). Recovery was further established using both real-time microscopy and High-Speed Live-Cell Interferometry (HSLCI) and was shown to be accompanied by the attenuation of the Senescence-Associated Secretory Phenotype (SASP). Cells enriched for the senescence-like phenotype were also capable of forming tumors when implanted in both immunodeficient and immunocompetent mice.

Cells redox environment modulates BRCA1 expression and DNA homologous recombination repair.

Cancer development and progression have been linked to oxidative stress, a condition characterized by unbalanced increase in ROS and RNS production. The main endogenous initiators of the redox imbalance in cancer cells are defective mitochondria, elevated NOX activity, and uncoupled NOS3. Traditionally, most attention has been paid to direct oxidative damage to DNA by certain ROS.

Tumor Cell Recovery from Senescence Induced by Radiation with PARP Inhibition.

Inhibitors of poly(ADP-ribose) polymerase (PARP) are clinically used as single-agent therapy for tumors with BRCA1 or BRCA2 mutations. One approach to expanding the use of PARP inhibitors to a wider range of tumors is to combine them with cytotoxic chemotherapy or radiotherapy. Preclinical studies in experimental animals and tumor cells in culture indicate that PARP inhibition modestly sensitizes most tumor cells to ionizing radiation.

Role of nitric oxide in the radiation-induced bystander effect.

Cells that are not irradiated but are affected by "stress signal factors" released from irradiated cells are called bystander cells. These cells, as well as directly irradiated ones, express DNA damage-related proteins and display excess DNA damage, chromosome aberrations, mutations, and malignant transformation. This phenomenon has been studied widely in the past 20 years, since its first description by Nagasawa and Little in 1992, and is known as the radiation-induced bystander effect (RIBE).

A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGFβ1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity.

Purpose: This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets.

Methods And Materials: This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3, and TGFβ1). DNA from blood samples of 179 patients (∼ 80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis.

Nitric Oxide: Genomic Instability And Synthetic Lethality.

Regardless of etiology, inflammatory conditions are characterized by overexpression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide and reactive nitrogen species (NO/RNS) in epithelial and inflammatory cells at the site of carcinogenesis. NO/RNS produced in inflamed tissues can contribute to the process of carcinogenesis by different mechanisms. One of these mechanisms is NO-dependent stimulation of genomic instability by inhibiting of Breast Cancer type 1 Susceptibility protein (BRCA1) expression.

The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression.

Unlabelled: Here, evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast with normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on high-performance liquid chromatography analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin:dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid, and head and neck tumors compared with normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling, including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression, and TCF4 promoter activity, and reduced NF-κB promoter activity.

Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727.

Signal transducer and activator of transcription 3 (Stat3) is a key mediator in the development of many cancers. For 20 years, it has been assumed that Stat3 mediates its biological activities as a nuclear localized transcription factor activated by many cytokines. However, recent studies from this laboratory and others indicate that Stat3 has an independent function in the mitochondria (mitoStat3) where it controls the activity of the electron transport chain (ETC) and mediates Ras-induced transformation of mouse embryo fibroblasts.

Nitric oxide-dependent downregulation of BRCA1 expression promotes genetic instability.

Elevated levels of nitric oxide (NO) and reactive nitrogen species (RNS) may link inflammation to the initiation, promotion, and progression of cancer. Traditionally, this link has been thought to be mediated by the effects of NO/RNS in generating DNA damage. However, this damage also stimulates DNA repair responses with subsequent blocks to cell proliferation and apoptosis, thereby preventing accumulation of NO/RNS-generated mutations.

Factors influencing protein tyrosine nitration--structure-based predictive models.

Models for exploring tyrosine nitration in proteins have been created based on 3D structural features of 20 proteins for which high-resolution X-ray crystallographic or NMR data are available and for which nitration of 35 total tyrosines has been experimentally proven under oxidative stress. Factors suggested in previous work to enhance nitration were examined with quantitative structural descriptors. The role of neighboring acidic and basic residues is complex: for the majority of tyrosines that are nitrated the distance to the heteroatom of the closest charged side chain corresponds to the distance needed for suspected nitrating species to form hydrogen bond bridges between the tyrosine and that charged amino acid.

Protein tyrosine nitration in cellular signal transduction pathways.

How specificity and reversibility in tyrosine nitration are defined biologically in cellular systems is poorly understood. As more investigations identify proteins involved in cell regulatory pathways in which only a small fraction of that protein pool is modified by nitration to affect cell function, the mechanisms of biological specificity and reversal should come into focus. In this review experimental evidence has been summarized to suggest that tyrosine nitration is a highly selective modification and under certain physiological conditions fulfills the criteria of a physiologically relevant signal.

Proteomic analysis of radiation-induced changes in rat lung: Modulation by the superoxide dismutase mimetic MnTE-2-PyP(5+).

Purpose: To identify temporal changes in protein expression in the irradiated rat lung and generate putative mechanisms underlying the radioprotective effect of the manganese superoxide dismutase mimetic MnTE-2-PyP(5+).

Methods And Materials: Female Fischer 344 rats were irradiated to the right hemithorax with a single dose of 28 Gy and killed from day 1 to 20 weeks after irradiation. Proteomic profiling was performed to identify proteins that underwent significant changes in abundance.

Nitration of the tumor suppressor protein p53 at tyrosine 327 promotes p53 oligomerization and activation.

Previous studies demonstrate that nitric oxide (NO) promotes p53 transcriptional activity by a classical DNA damage responsive mechanism involving activation of ATM/ATR and phosphorylation of p53. These studies intentionally used high doses of NO donors to achieve the maximum DNA damage. However, lower concentrations of NO donors also stimulate rapid and unequivocal nuclear retention of p53 but apparently do not require ATM/ATR-dependent p53 phosphorylation or total p53 protein accumulation.

Tyrosine nitration of IkappaBalpha: a novel mechanism for NF-kappaB activation.

The NF-kappaB family of transcription factors is an important component of stress-activated cytoprotective signal transduction pathways. Previous studies demonstrated that some activation mechanisms require phosphorylation, ubiquitination, and degradation of the inhibitor protein, IkappaBalpha. Herein, it is demonstrated that ionizing radiation in the therapeutic dose range stimulates NF-kappaB activity by a mechanism in which IkappaBalpha tyrosine 181 is nitrated as a consequence of constitutive NO* synthase activation, leading to dissociation of intact IkappaBalpha from NF-kappaB.