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Replacement of miR-155 Elicits Tumor Suppressive Activity and Antagonizes Bortezomib Resistance in Multiple Myeloma.

Aberrant expression of microRNAs (miRNAs) has been associated to the pathogenesis of multiple myeloma (MM). While miR-155 is considered a therapeutic target in several malignancies, its role in MM is still unclear. The analysis of miR-155 expression indicates its down-regulation in MM patient-derived as compared to healthy plasma cells, thus pointing to a tumor suppressor role in this malignancy. On this finding, we investigated miR-155 replacement as a potential anti-tumor strategy in MM. The miR-155 enforced expression triggered anti-proliferative and pro-apoptotic effects in vitro. Given th

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… Using WST-8 and Bromodeoxyuridine(BrdU) uptake assays, we observed significant inhibition of cell viability and S-phase DNA synthesis induced by miR-155 mimics ( Figure 2 A,B). …

Bone morphogenic protein signaling is a major determinant of dentate development.

To understand life-long neurogenesis in the dentate gyrus (DG), characterizing dentate neural stem cells and the signals controlling their development are crucial. In the present study, we show that bone morphogenic protein (Bmp) signaling is a critical regulator of embryonic dentate development, required for initiating neurogenesis in embryonic DG progenitors and required for the establishment of dentate neural stem cells postnatally. We tested the hypothesis that Bmp signaling regulates dentate development in part by controlling the expression of Lef1, a Wnt responsive transcription factor e

Microglial inhibitory factor (MIF/TKP) mitigates secondary damage following spinal cord injury.

Spinal cord injury (SCI) induces an immune response during which microglia, the resident immunocompetent cells of the central nervous system, become activated and migrate to the site of damage. Depending on their state of activation, microglia secrete neurotoxic or neurotrophic factors that influence the surrounding environment and have a detrimental or restorative effect following SCI, including causing or protecting bystander damage to nearby undamaged tissue. Subsequent infiltration of macrophages contributes to the SCI outcome. We show here that suppressing microglia/macrophage activation

Requirement for DNA ligase IV during embryonic neuronal development.

The embryonic ventricular and subventricular zones (VZ/SVZ) contain the neuronal stem and progenitor cells and undergo rapid proliferation. The intermediate zone (IZ) contains nonreplicating, differentiated cells. The VZ/SVZ is hypersensitive to radiation-induced apoptosis. Ablation of DNA non-homologous end-joining (NHEJ) proteins, XRCC4 or DNA ligase IV (LigIV), confers ataxia telangiectasia mutated (ATM)-dependent apoptosis predominantly in the IZ. We examine the mechanistic basis underlying these distinct sensitivities using a viable LigIV (Lig4(Y288C)) mouse, which permits an examination

Growth inhibition of head and neck squamous cell carcinoma cells by sgRNA targeting the cyclin D1 mRNA based on TRUE gene silencing.

Head and neck squamous cell carcinoma (HNSCC) exhibits increased expression of cyclin D1 (CCND1). Previous studies have shown a correlation between poor prognosis of HNSCC and cyclin D1 overexpression. tRNase ZL-utilizing efficacious gene silencing (TRUE gene silencing) is one of the RNA-mediated gene expression control technologies that have therapeutic potential. This technology is based on a unique enzymatic property of mammalian tRNase ZL, which is that it can cleave any target RNA at any desired site by recognizing a pre-tRNA-like complex formed between the target RNA and an artificial sm

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… Detection of DNA synthesis by chemiluminescent bromodeoxyuridine (BrdU) ELISA To measure cell proliferation, newly synthesized DNA of replicating cells was assayed by BrdU incorporation using a BrdU labeling and detection ELISA-kit (Cell Proliferation Biotrak ELISA System version 2, GE Healthcare) according …

The exon junction complex component Magoh controls brain size by regulating neural stem cell division.

Brain structure and size require precise division of neural stem cells (NSCs), which self-renew and generate intermediate neural progenitors (INPs) and neurons. The factors that regulate NSCs remain poorly understood, and mechanistic explanations of how aberrant NSC division causes the reduced brain size seen in microcephaly are lacking. Here we show that Magoh, a component of the exon junction complex (EJC) that binds RNA, controls mouse cerebral cortical size by regulating NSC division. Magoh haploinsufficiency causes microcephaly because of INP depletion and neuronal apoptosis. Defective mi

Alpha2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment.

Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. alpha(2)-Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of alpha(2)-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that alpha(2)-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selec

Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved.

The insulin receptor (IR) and the insulin-like growth factor I receptor (IGF-IR) have a highly homologous structure, but different biological effects. Insulin and IGF-I half-receptors can heterodimerize, leading to the formation of insulin/IGF-I hybrid receptors (Hybrid-Rs) that bind IGF-I with high affinity. As the IR exists in two isoforms (IR-A and IR-B), we evaluated whether the assembly of the IGF-IR with either IR-A or IR-B moieties may differently affect Hybrid-R signaling and biological role. Three different models were studied: (a) 3T3-like mouse fibroblasts with a disrupted IGF-IR ge

Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells.

Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient-derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monoc

Intranasal administration of aTf protects and repairs the neonatal white matter after a cerebral hypoxic-ischemic event.

Our previous studies showed that the intracerebral injection of apotransferrin (aTf) attenuates white matter damage and accelerates the remyelination process in a neonatal rat model of cerebral hypoxia-ischemia (HI) injury. However, the intracerebral injection of aTf might not be practical for clinical treatments. Therefore, the development of less invasive techniques capable of delivering aTf to the central nervous system would clearly aid in its effective clinical use. In this work, we have determined whether intranasal (iN) administration of human aTf provides neuroprotection to the neonata

Астроцитизированный PTN уменьшает дефицит гиппокампального неврогенеза и когниции в моделях множественного склероза.

Множественный склероз (MS) — аутоиммунное воспалительное заболевание, которое приводит к моторным, сенсорным, когнитивным и эффективным расстройствам. Гиппокампальное обезвоживание, обычное явление в MS, связано с нарушенной когнитивной функцией и настроением. Несмотря на это, точные механизмы, лежащие в основе когнитивных нарушений в MS, по-прежнему остаются труднодостижимыми. Плейотропхин (PTN), скрытый нейронными стволовыми клетками и астроцитами, играет решающую роль в регулировании когниции. В этом исследовании изучается роль PTN на основе астроцитов. Мы обнаружили, что генетическое удале

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… For NSC differentiation analysis, bromodeoxyuridine (BrdU) was injected into control and demyelinated mice. …

Canine Multicentric Lymphoma: Diagnostic, Treatment, and Prognostic Insights.

Lymphoma accounts for 24% of all documented canine neoplasms and 85% of hematological malignancies, while multicentric lymphoma corresponds to 84% of all canine lymphomas. Canine lymphomas of B-cell origin account for 60% to 80% of lymphomas. Similar to humans, the histologic grade, architecture, as well as immunophenotype determination, are crucial. These lesions are the most prevalent spontaneous tumors in dogs and this species may be a valuable animal model for the study of human non-Hodgkin's lymphoma. Therefore, it is important to investigate and assess therapeutic responses and to seek p

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… Assays evaluating proliferation, including the analysis of bromodeoxyuridine (BrdU) uptake, reactivity to Ki67 antibody, and argyrophilic nucleolar organizer region (AgNOR) indices, have been used to assess the proliferative activity of tumor cells in dogs undergoing combination chemotherapy, providing …

NTP Hepatotoxicity Studies of the Liver Carcinogen Methapyrilene Hydrochloride (CAS No. 135-23-9) Administered in Feed to Male F344/N Rats.

Methapyrilene hydrochloride is a histamine H(1)-receptor antagonist that was an active ingredient in many over-the-counter cold and allergy … ive control), or 50 ppm Wy-14,643 ( positive control) in feed. Rats in all groups were administered bromodeoxyuridine (BrdU) by osmotic minipump for the assessment of hepatocyte proliferation. Ten rats from each group were evaluated on days 15, 29, and 43 and at 14 weeks. At these times, samples of liver tissue were analyzed for evidence of cell proliferation via B …

Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury.

Spinal cord injury leads to acute local ischemia, which may contribute to secondary degeneration. Hypoxia stimulates angiogenesis through a cascade of events, involving angiogenesis stimulatory substances, such as vascular endothelial growth factor (VEGF). To test the importance of angiogenesis for functional outcome and wound healing in spinal cord injury VEGF165 (proangiogenic), Ringer's (control) or angiostatin (antiangiogenic) were delivered locally immediately after a contusion injury produced using the NYU impactor and a 25 mm weight-drop. Rats treated with VEGF showed significantly impr

Advanced Diagnostic Techniques

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Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools.

Chronic kidney disease (CKD) is an increasing health burden (affecting approximately 13.4% of the population). Currently, no curative treatment options are available and treatment is focused on limiting the disease progression. The accumulation of senescent cells has been implicated in the development of kidney fibrosis by limiting tissue rejuvenation and through the secretion of pro-fibrotic and pro-inflammatory mediators termed as the senescence-associated secretory phenotype. The clearance of senescent cells in aging models results in improved kidney function, which shows promise for the op

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… Abbreviations: BrdU, bromodeoxyuridine. Senescence is an important driver of fibrosis. Senescent cells acquire a senescence-associated secretory phenotype (SASP) characterized by the expression and secretion of pro-fibrotic and pro-inflammatory factors. …

Utilization of redox modulating small molecules that selectively act as pro-oxidants in cancer cells to open a therapeutic window for improving cancer therapy.

There is a rapidly growing body of literature supporting the notion that differential oxidative metabolism in cancer versus normal cells represents a metabolic frailty that can be exploited to open a therapeutic window into cancer therapy. These cancer cell-specific metabolic frailties may be amenable to manipulation with non-toxic small molecule redox active compounds traditionally thought to be antioxidants. In this review we describe the potential mechanisms and clinical applicability in cancer therapy of four small molecule redox active agents: melatonin, vitamin E, selenium, and vitamin C

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… Somatostatin analogue octreotide and melatonin inhibit bromodeoxyuridine incorporation into cell nuclei and enhance apoptosis in the transplantable murine colon 38 cancer. Anticanc. Res. 1998;18(5A):3615–3619. 37. Kadoma Y., Fujisawa S. …

Insights into Endothelial Progenitor Cells: Origin, Classification, Potentials, and Prospects.

With the discovery of endothelial progenitor cells (EPCs) in the late 1990s, a paradigm shift in the concept of neoangiogenesis occurred. The identification of circulating EPCs in peripheral blood marked the beginning of a new era with enormous potential in the rapidly transforming regenerative field. Overwhelmed with the revelation, researchers across the globe focused on isolating, defining, and interpreting the role of EPCs in various physiological and pathological conditions. Consequently, controversies emerged regarding the isolation techniques and classification of EPCs. Nevertheless, th

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… During the first two hours after injecting BrdU- (bromodeoxyuridine-) labelled nonmitotic cells into the hippocampus of adult rats, approximately 37% of these cells exhibited endothelial markers, which gradually decreased to 9% after one month when more than 90% of the transplanted cells exhibited neural …

Animal models of chemotherapy-induced cognitive decline in preclinical drug development.

RationaleChemotherapy-induced cognitive impairment (CICI), chemobrain, and chemofog are the common terms for mental dysfunction in a cancer patient/survivor under the influence of chemotherapeutics. CICI is manifested as short/long term memory problems and delayed mental processing, which interferes with a person's day-to-day activities. Understanding CICI mechanisms help in developing therapeutic interventions that may alleviate the disease condition. Animal models facilitate critical evaluation to elucidate the underlying mechanisms and form an integral part of verifying different treatment

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… MTX impaired hippocampal neurogenesis by reducing different immunohistochemical markers like Ki67, BrdU (bromodeoxyuridine), and DCX. This was supported by administering two doses of MTX (75 mg/kg, i.v ) in male Lister hooded rats, given a week apart. …

Hematopoietic Tumors

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… Recently, proliferative assays (e.g., analysis of bromodeoxyuridine [BrdU] uptake, Ki-67 antibody reactivity, and AgNOR indices) to measure the proliferative activity of tumor cells have been shown to provide significant prognostic information in dogs treated with combination chemotherapy. 60 , 163 , …