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1.
Breast Cancer Res ; 24(1): 48, 2022 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-35836253

RESUMEN

BACKGROUND: A pro-oxidant enzyme, NADPH oxidase 4 (Nox4) has been reported to be a critical downstream effector of TGFß-induced myofibroblast transformation during fibrosis. While there are a small number of studies suggesting an oncogenic role of Nox4 derived from activated fibroblasts, direct evidence linking this pro-oxidant to the tumor-supporting CAF phenotype and the mechanisms involved are lacking, particularly in breast cancer. METHODS: We targeted Nox4 in breast patient-derived CAFs via siRNA-mediated knockdown or administration of a pharmaceutical inhibitor (GKT137831). We also determine primary tumor growth and metastasis of implanted tumor cells using a stable Nox4-/- syngeneic mouse model. Autophagic flux of CAFs was assessed using a tandem fluorescent-tagged ptfl-LC3 plasmid via confocal microscopy analysis and determination of the expression level of autophagy markers (beclin-1 and LC3B). Nox4 overexpressing CAFs depend on the Nrf2 (nuclear factor-erythroid factor 2-related factor 2) pathway for survival. We then determined the dependency of Nox4-overexpressing CAFs on the Nrf2-mediated adaptive stress response pathway for survival. Furthermore, we investigated the involvement of Birc5 on CAF phenotype (viability and collagen contraction activity) as well as the expression level of CAF markers, FAP and αSMA. CONCLUSIONS: We found that deletion of stroma Nox4 and pharmaceutically targeting its activity with GKT137831 significantly inhibited orthotopic tumor growth and metastasis of implanted E0771 and 4T1 murine mammary carcinoma cell lines in mice. More importantly, we found a significant upregulation of Nox4 expression in CAFs isolated from human breast tumors versus normal mammary fibroblasts (RMFs). Our in situ RNA hybridization analysis for Nox4 transcription on a human breast tumor microarray further support a role of this pro-oxidant in the stroma of breast carcinomas. In addition, we found that Nox4 promotes autophagy in CAFs. Moreover, we found that Nox4 promoted survival of CAFs via activation of Nrf2, a master regulator of oxidative stress response. We have further shown Birc5 is involved as a downstream modulator of Nrf2-mediated pro-survival phenotype. Together these studies indicate a role of redox signaling via the Nox4-Nrf2 pathway in tumorigenesis and metastasis of breast cancer cells by promoting autophagy and survival of CAFs.


Asunto(s)
Neoplasias de la Mama , Fibroblastos Asociados al Cáncer , Animales , Neoplasias de la Mama/patología , Fibroblastos Asociados al Cáncer/patología , Carcinogénesis/metabolismo , Línea Celular Tumoral , Femenino , Fibroblastos/metabolismo , Humanos , Ratones , NADPH Oxidasa 4/genética , NADPH Oxidasa 4/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Survivin/metabolismo , Regulación hacia Arriba
2.
Radiat Environ Biophys ; 59(1): 99-109, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31728622

RESUMEN

Treatment of differentiated thyroid cancer often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. However, there is morbidity associated with I-131 therapy, which can result in both acute and chronic complications. Currently, there are no approved radioprotectors that can be used in conjunction with I-131 to reduce complications in thyroid cancer therapy. It is well known that the damaging effects of ionizing radiation are mediated, in part, by the formation of reactive oxygen species (ROS). A potent scavenger of ROS, Mn(III)meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnTnBuOE-2-PyP), has radioprotective and anti-tumor effects in various cancer models including head and neck, prostate, and brain tumors exposed to external beam radiation therapy. Female C57BL/6 mice were administered I-131 orally at doses of 0.0085-0.01 mCi/g (3.145 × 105 to 3.7 × 105 Bq) of body weight with or without MnTnBuOE-2-PyP. We measured acute external inflammation, blood cell counts, and collected thyroid tissue and salivary glands for histological examination. We found oral administration of I-131 caused an acute decrease in platelets and white blood cells, caused facial swelling, and loss of thyroid and salivary tissues. However, when MnTnBuOE-2-PyP was given during and after I-131 administration, blood cell counts remained in the normal range, less facial inflammation was observed, and the salivary glands were protected from radiation-induced killing. These data indicate that MnTnBuOE-2-PyP may be a potent radioprotector of salivary glands in thyroid cancer patients receiving I-131 therapy.


Asunto(s)
Radioisótopos de Yodo/efectos adversos , Metaloporfirinas/uso terapéutico , Protectores contra Radiación/uso terapéutico , Radiofármacos/efectos adversos , Neoplasias de la Tiroides/radioterapia , Animales , Línea Celular Tumoral , Femenino , Humanos , Metaloporfirinas/farmacología , Ratones Endogámicos C57BL , Protectores contra Radiación/farmacología , Glándulas Salivales/efectos de los fármacos , Glándulas Salivales/patología , Glándulas Salivales/efectos de la radiación , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/patología , Glándula Tiroides/efectos de la radiación , Neoplasias de la Tiroides/patología
3.
Int J Mol Sci ; 21(5)2020 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-32182883

RESUMEN

BACKGROUND: Chemotherapy treatment for breast cancer can induce cognitive impairments often involving oxidative stress. The brain, as a whole, is susceptible to oxidative stress due to its high-energy requirements, limited anaerobic respiration capacities, and limited antioxidant defenses. The goal of the current study was to determine if the manganese porphyrin superoxide dismutase mimetic MnTnBuOE-2-PyP (MnBuOE) could ameliorate the effects of doxorubicin, cyclophosphamide, and paclitaxel (AC-T) on mature dendrite morphology and cognitive function. METHODS: Four-month-old female C57BL/6 mice received intraperitoneal injections of chemotherapy followed by subcutaneous injections of MnBuOE. Four weeks following chemotherapy treatment, mice were tested for hippocampus-dependent cognitive performance in the Morris water maze. After testing, brains were collected for Golgi staining and molecular analyses. RESULTS: MnBuOE treatment preserved spatial memory during the Morris water-maze. MnBuOE/AC-T showed spatial memory retention during all probe trials. AC-T treatment significantly impaired spatial memory retention in the first and third probe trial (no platform). AC-T treatment decreased dendritic length in the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) areas of the hippocampus while AC-T/MnBuOE maintained dendritic length. Comparative proteomic analysis revealed affected protein networks associated with cell morphology and behavior functions in both the AC-T and AC-T/MnBuOE treatment groups.


Asunto(s)
Cognición/efectos de los fármacos , Ciclofosfamida/farmacología , Doxorrubicina/farmacología , Hipocampo/efectos de los fármacos , Metaloporfirinas/farmacología , Oxidación-Reducción/efectos de los fármacos , Paclitaxel/farmacología , Animales , Antioxidantes/farmacología , Región CA1 Hipocampal/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos C57BL , Neurogénesis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Proteómica/métodos , Protectores contra Radiación/farmacología , Memoria Espacial/efectos de los fármacos
4.
Radiat Environ Biophys ; 58(1): 89-98, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30483886

RESUMEN

Radiodermatitis is a painful side effect for cancer patients undergoing radiotherapy. Irradiation of the skin causes inflammation and breakdown of the epidermis and can lead to significant morbidity and mortality in severe cases, as seen in exposure from accidents or weapons such as "dirty bombs" and ultimately leads to tissue fibrosis. However, the pathogenesis of radiodermatitis is not fully understood. Using a mouse model of radiodermatitis, we showed that the Transient Receptor Potential Melastatin 2 (TRPM2) ion channel plays a significant role in the development of dermatitis following exposure to ionizing radiation. Irradiated TRPM2-deficient mice developed less inflammation, fewer severe skin lesions and decreased fibrosis when compared to wild type mice. The TRPM2-deficient mice also showed a faster recovery period as seen by their increased weight gain post irradiation. Finally, TRPM2-deficient mice exhibited lower systemic inflammation with a reduction in inflammatory cytokines present in the serum. These findings suggest that TRPM2 may be a potential therapeutic target for reducing the severity of radiodermatitis.


Asunto(s)
Radiodermatitis/etiología , Radiodermatitis/metabolismo , Canales Catiónicos TRPM/metabolismo , Animales , Relación Dosis-Respuesta en la Radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Radiodermatitis/patología , Piel/patología , Piel/efectos de la radiación
5.
Respirology ; 21(5): 951-7, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27012592

RESUMEN

BACKGROUND AND OBJECTIVE: With the worldwide emergence of highly drug-resistant tuberculosis (TB), novel agents that have direct antimycobacterial effects or that enhance host immunity are urgently needed. Curcumin is a polyphenol responsible for the bright yellow-orange colour of turmeric, a spice derived from the root of the perennial herb Curcuma longa. Curcumin is a potent inducer of apoptosis-an effector mechanism used by macrophages to kill intracellular Mycobacterium tuberculosis (MTB). METHODS: An in vitro human macrophage infection model was used to determine the effects of curcumin on MTB survival. RESULTS: We found that curcumin enhanced the clearance of MTB in differentiated THP-1 human monocytes and in primary human alveolar macrophages. We also found that curcumin was an inducer of caspase-3-dependent apoptosis and autophagy. Curcumin mediated these anti-MTB cellular functions, in part, via inhibition of nuclear factor-kappa B (NFκB) activation. CONCLUSION: Curcumin protects against MTB infection in human macrophages. The host-protective role of curcumin against MTB in macrophages needs confirmation in an animal model; if validated, the immunomodulatory anti-TB effects of curcumin would be less prone to drug resistance development.


Asunto(s)
Apoptosis , Curcumina/farmacología , Macrófagos Alveolares , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Humanos , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/inmunología , Modelos Inmunológicos , Mycobacterium tuberculosis/fisiología , FN-kappa B/metabolismo , Sustancias Protectoras/farmacología , Tuberculosis/inmunología , Tuberculosis/terapia
6.
Redox Biol ; 73: 103219, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-38851001

RESUMEN

Radiation causes damage to normal tissues that leads to increased oxidative stress, inflammation, and fibrosis, highlighting the need for the selective radioprotection of healthy tissues without hindering radiotherapy effectiveness in cancer. This study shows that adiponectin, an adipokine secreted by adipocytes, protects normal tissues from radiation damage invitro and invivo. Specifically, adiponectin (APN) reduces chronic oxidative stress and fibrosis in irradiated mice. Importantly, APN also conferred no protection from radiation to prostate cancer cells. Adipose tissue is the primary source of circulating endogenous adiponectin. However, this study shows that adipose tissue is sensitive to radiation exposure exhibiting morphological changes and persistent oxidative damage. In addition, radiation results in a significant and chronic reduction in blood APN levels from adipose tissue in mice and human prostate cancer patients exposed to pelvic irradiation. APN levels negatively correlated with bowel toxicity and overall toxicities associated with radiotherapy in prostate cancer patients. Thus, protecting, or modulating APN signaling may improve outcomes for prostate cancer patients undergoing radiotherapy.


Asunto(s)
Adiponectina , Fibrosis , Estrés Oxidativo , Neoplasias de la Próstata , Masculino , Animales , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Humanos , Ratones , Estrés Oxidativo/efectos de la radiación , Adiponectina/metabolismo , Adiponectina/sangre , Traumatismos por Radiación/metabolismo , Traumatismos por Radiación/patología , Tejido Adiposo/metabolismo , Tejido Adiposo/efectos de la radiación , Protectores contra Radiación/farmacología , Protectores contra Radiación/uso terapéutico
7.
Am J Physiol Lung Cell Mol Physiol ; 305(1): L64-72, 2013 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-23624787

RESUMEN

The early inflammatory response to influenza A virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which inflammatory cells invade the respiratory tract remain unclear. Uncontrolled inflammation and oxidative stress cause lung damage in response to influenza A infection. We have previously shown that the fatty acid binding protein 5 (FABP5) has anti-inflammatory properties. We speculate that, as a transporter of fatty acids, FABP5 plays an important protective role against oxidative damage to lipids during infection as well. Using FABP5-/- and wild-type (WT) mice infected with influenza A virus, we showed that FABP5-/- mice had increased cell infiltration of macrophages and neutrophils compared with WT mice. FABP5-/- mice presented lower viral burden but lost as much weight as WT mice. The adaptive immune response was also increased in FABP5-/- mice as illustrated by the accumulation of T and B cells in the lung tissues and increased levels of H1N1-specific IgG antibodies. FABP5 deficiency greatly enhanced oxidative damage and lipid peroxidation following influenza A infection and presented with sustained tissue inflammation. Interestingly, FABP5 expression decreased following influenza A infection in WT lung tissues that corresponded to a decrease in the anti-inflammatory molecule PPAR-γ activity. In conclusion, our results demonstrate a previously unknown contribution of FABP5 to influenza A virus pathogenesis by controlling excessive oxidative damage and inflammation. This property could be exploited for therapeutic purposes.


Asunto(s)
Proteínas de Unión a Ácidos Grasos/fisiología , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Gripe Humana/inmunología , Proteínas de Neoplasias/fisiología , Estrés Oxidativo , Neumonía/etiología , Inmunidad Adaptativa , Animales , Western Blotting , Células Cultivadas , Susceptibilidad a Enfermedades , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Humanos , Técnicas para Inmunoenzimas , Inmunoprecipitación , Gripe Humana/complicaciones , Gripe Humana/virología , Peroxidación de Lípido , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , PPAR gamma/metabolismo , Neumonía/metabolismo , Neumonía/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
8.
Radiat Res ; 199(1): 89-111, 2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-36368026

RESUMEN

Increasing utilization of nuclear power enhances the risks associated with industrial accidents, occupational hazards, and the threat of nuclear terrorism. Exposure to ionizing radiation interferes with genomic stability and gene expression resulting in the disruption of normal metabolic processes in cells and organs by inducing complex biological responses. Exposure to high-dose radiation causes acute radiation syndrome, which leads to hematopoietic, gastrointestinal, cerebrovascular, and many other organ-specific injuries. Altered genomic variations, gene expression, metabolite concentrations, and microbiota profiles in blood plasma or tissue samples reflect the whole-body radiation injuries. Hence, multi-omic profiles obtained from high-resolution omics platforms offer a holistic approach for identifying reliable biomarkers to predict the radiation injury of organs and tissues resulting from radiation exposures. In this review, we performed a literature search to systematically catalog the radiation-induced alterations from multi-omic studies and radiation countermeasures. We covered radiation-induced changes in the genomic, transcriptomic, proteomic, metabolomic, lipidomic, and microbiome profiles. Furthermore, we have covered promising multi-omic biomarkers, FDA-approved countermeasure drugs, and other radiation countermeasures that include radioprotectors and radiomitigators. This review presents an overview of radiation-induced alterations of multi-omics profiles and biomarkers, and associated radiation countermeasures.


Asunto(s)
Síndrome de Radiación Aguda , Protectores contra Radiación , Humanos , Protectores contra Radiación/farmacología , Multiómica , Proteómica , Síndrome de Radiación Aguda/diagnóstico , Síndrome de Radiación Aguda/etiología , Biomarcadores
9.
Int Immunol ; 23(11): 679-91, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22033195

RESUMEN

Lung disease due to Mycobacterium avium complex (MAC) organisms is increasing. A greater understanding of the host immune response to MAC organisms will provide a foundation to develop novel therapies for these recalcitrant infections. IL-32 is a newly described pro-inflammatory cytokine that enhances host immunity against various microbial pathogens. Cytokines that induce IL-32 such as interferon-gamma, IL-18, IL-12 and tumor necrosis factor-alpha are of considerable importance to mycobacterial immunity. We performed immunohistochemistry and morphometric analysis to quantify IL-32 expression in the lungs of 11 patients with MAC lung disease and 10 controls with normal lung tissues. After normalizing for basement membrane length, there was a profound increase in IL-32 expression in the airway epithelial cells of the MAC-infected lungs compared with controls. Following normalization for alveolar surface area, there was a trend toward increased IL-32 expression in type II alveolar cells and alveolar macrophages in the lungs of MAC patients. Human airway epithelial cells (BEAS-2B) infected with M. avium produced IL-32 by a nuclear factor-kappa B-dependent mechanism. In both BEAS-2B cells and human monocyte-derived macrophages, exogenous IL-32γ significantly reduced the growth of intracellular M. avium. This finding was corroborated by an increase in the number of intracellular M. avium recovered from THP-1 monocytes silenced for endogenous IL-32 expression. The anti-mycobacterial effect of IL-32 may be due, in part, to increased apoptosis of infected cells. These findings indicate that IL-32 facilitates host defense against MAC organisms but may also contribute to the airway inflammation associated with MAC pulmonary disease.


Asunto(s)
Células Epiteliales/inmunología , Interleucinas/inmunología , Macrófagos Alveolares/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Complejo Mycobacterium avium/inmunología , Infección por Mycobacterium avium-intracellulare/inmunología , Sistema Respiratorio/inmunología , Anciano , Estudios de Casos y Controles , Células Cultivadas , Células Epiteliales/efectos de los fármacos , Células Epiteliales/microbiología , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Interferón gamma/inmunología , Interleucina-12/inmunología , Interleucina-18/inmunología , Interleucinas/genética , Interleucinas/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/microbiología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/microbiología , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Monocitos/microbiología , Complejo Mycobacterium avium/efectos de los fármacos , Complejo Mycobacterium avium/crecimiento & desarrollo , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Infección por Mycobacterium avium-intracellulare/metabolismo , Infección por Mycobacterium avium-intracellulare/microbiología , FN-kappa B/inmunología , Sistema Respiratorio/efectos de los fármacos , Sistema Respiratorio/metabolismo , Sistema Respiratorio/microbiología , Factor de Necrosis Tumoral alfa/inmunología , Estados Unidos
10.
Am J Respir Crit Care Med ; 184(5): 547-60, 2011 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-21471090

RESUMEN

RATIONALE: During acute lung injury (ALI) the macrophage pool expands markedly as inflammatory monocytes migrate from the circulation to the airspaces. As inflammation resolves, macrophage numbers return to preinjury levels and normal tissue structure and function are restored. OBJECTIVES: To determine the fate of resident and recruited macrophages during the resolution of ALI in mice and to elucidate the mechanisms responsible for macrophage removal. METHODS: ALI was induced in mice using influenza A (H1N1; PR8) infection and LPS instillation. Dye labeling techniques, bone marrow transplantation, and surface immunophenotyping were used to distinguish resident and recruited macrophages during inflammation and to study the role of Fas in determining macrophage fate during resolving ALI. MEASUREMENTS AND MAIN RESULTS: During acute and resolving lung injury from influenza A and LPS, a high proportion of the original resident alveolar macrophages persisted. In contrast, recruited macrophages exhibited robust accumulation in early inflammation, followed by a progressive decline in their number. This decline was mediated by apoptosis with local phagocytic clearance. Recruited macrophages expressed high levels of the death receptor Fas and were rapidly depleted from the airspaces by Fas-activating antibodies. In contrast, macrophage depletion was inhibited in mice treated with Fas-blocking antibodies and in chimeras with Fas-deficient bone marrow. Caspase-8 inhibition prevented macrophage apoptosis and delayed the resolution of ALI. CONCLUSIONS: These findings indicate that Fas-induced apoptosis of recruited macrophages is essential for complete resolution of ALI.


Asunto(s)
Lesión Pulmonar Aguda/patología , Apoptosis/inmunología , Macrófagos Alveolares/patología , Receptor fas/inmunología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/terapia , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Caspasa 8/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Inmunohistoquímica , Macrófagos Alveolares/inmunología , Ratones , Ratones Endogámicos C57BL , Receptor fas/metabolismo
11.
Int J Mol Sci ; 13(8): 9785-9797, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22949830

RESUMEN

MnTE-2-PyP, a superoxide dismutase mimetic, inhibited OVA-induced airway inflammation in mice suggesting an effect on Th2 responsiveness. Thus, we hypothesized that MnTE-2-PyP may alter dendritic cell-Th2 interactions. Bone marrow derived dendritic cells (DC) and OVA(323-339)-specific Th2 cells were cultured separately in the presence or absence of MnTE-2-PyP for 3 days prior to the co-culturing of the two cell types in the presence of an OVA(323-339) peptide and in some cases stimulated with CD3/CD28. MnTE-2-PyP-pretreated DC inhibited IL-4, IL-5 and IFNγ production and inhibited Th2 cell proliferation in the DC-Th2 co-culturing system in the presence of the OVA(323-339) peptide. Similar results were obtained using the CD3/CD28 cell-activation system; the addition of MnTE-2-PyP inhibited Th2 cell proliferation. MnTE-2-PyP suppressed CD25 expression on OVA-specific Th2 cells, which implied that MnTE-2-PyP can inhibit the activation of Th2 cells. MnTE-2-PyP also down-regulated co-stimulatory molecules: CD40, CD80 and CD86 on immature DC. Our studies suggest that the major mechanism by which MnTE-2-PyP inhibits airway inflammation is by acting on the DC and suppressing Th2 cell proliferation and activation.


Asunto(s)
Antioxidantes/farmacología , Asma/inmunología , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Metaloporfirinas/farmacología , Células Th2/inmunología , Animales , Asma/tratamiento farmacológico , Asma/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Citometría de Flujo , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/farmacología , Células Th2/efectos de los fármacos , Células Th2/patología
12.
Cell Mol Bioeng ; 15(5): 391-407, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36444349

RESUMEN

Introduction: Oxidative stress due to excess reactive oxygen species (ROS) is related to many chronic illnesses including degenerative disc disease and osteoarthritis. MnTnBuOE-2-PyP5+ (BuOE), a manganese porphyrin analog, is a synthetic superoxide dismutase mimetic that scavenges ROS and has established good treatment efficacy at preventing radiation-induced oxidative damage in healthy cells. BuOE has not been studied in degenerative disc disease applications and only few studies have loaded BuOE into drug delivery systems. The goal of this work is to engineer BuOE microparticles (MPs) as an injectable therapeutic for long-term ROS scavenging. Methods: Methacrylated chondroitin sulfate-A MPs (vehicle) and BuOE MPs were synthesized via water-in-oil polymerization and the size, surface morphology, encapsulation efficiency and release profile were characterized. To assess long term ROS scavenging of BuOE MPs, superoxide scavenging activity was evaluated over an 84-day time course. In vitro cytocompatibility and cellular uptake were assessed on human intervertebral disc cells. Results: BuOE MPs were successfully encapsulated in MACS-A MPs and exhibited a slow-release profile over 84 days. BuOE maintained high potency in superoxide scavenging after encapsulation and after 84 days of incubation at 37 °C as compared to naked BuOE. Vehicle and BuOE MPs (100 µg/mL) were non-cytotoxic on nucleus pulposus cells and MPs up to 23 µm were endocytosed. Conclusions: BuOE MPs can be successfully fabricated and maintain potent superoxide scavenging capabilities up to 84-days. In vitro assessment reveals the vehicle and BuOE MPs are not cytotoxic and can be taken up by cells. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-022-00744-w.

13.
Front Physiol ; 13: 989793, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36213236

RESUMEN

Metabolic alterations are a common survival mechanism for prostate cancer progression and therapy resistance. Oxidative stress in the cellular and tumor microenvironment dictates metabolic switching in the cancer cells to adopt, prosper and escape therapeutic stress. Therefore, regulation of oxidative stress in tumor cells and in the tumor-microenvironment may enhance the action of conventional anticancer therapies. NRF2 is the master regulator for oxidative stress management. However, the overall oxidative stress varies with PCa clinical stage, metabolic state and therapy used for the cancer. In agreement, the blanket use of NRF2 inducers or inhibitors along with anticancer therapies cause adverse effects in some preclinical cancer models. In this review, we have summarized the levels of oxidative stress, metabolic preferences and NRF2 activity in the different stages of prostate cancer. We also propose condition specific ways to use NRF2 inducers or inhibitors along with conventional prostate cancer therapies. The significance of this review is not only to provide a detailed understanding of the mechanism of action of NRF2 to regulate oxidative stress-mediated metabolic switching by prostate cancer cells to escape the radiation, chemo, or hormonal therapies, and to grow aggressively, but also to provide a potential therapeutic method to control aggressive prostate cancer growth by stage specific proper use of NRF2 regulators.

14.
J Orthop Res ; 40(11): 2586-2596, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35148568

RESUMEN

As cancer survivorship increases, so does the number of patients that suffer from the late effects of radiation therapy. This includes arthrofibrosis, the development of stiff joints near the field of radiation. Previous reports have concentrated on skin fibrosis around the joint but largely ignored the deeper tissues of the joint. We hypothesized that fat, muscle, and the joint tissues themselves would play a more significant role in joint contracture after radiation than the skin surrounding the joint. To address this hypothesis, we irradiated the right hind flanks of mice with fractionated and unfractionated dose schedules, then monitored the mice for 3 months postradiotherapy. Mice were euthanized and physiological indications of arthrofibrosis including limb contracture and joint resting position were assessed. Stifle (knee) joints demonstrated significant arthrofibrosis, but none was observed in the hock (ankle) joints. During these studies, we were surprised to find that male and female mice showed a significantly different response to radiation injury. Female mice developed more injuries, had significantly worse contracture, and showed a greater difference in the expression of all markers studied. These results suggest that women undergoing radiation therapy might be at significantly greater risk for developing arthrofibrosis and may require specific adjustments to their care.


Asunto(s)
Contractura , Artropatías , Animales , Articulación del Tobillo , Contractura/etiología , Contractura/patología , Femenino , Fibrosis , Artropatías/tratamiento farmacológico , Articulación de la Rodilla/patología , Masculino , Ratones
15.
Free Radic Biol Med ; 193(Pt 1): 274-291, 2022 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-36265795

RESUMEN

The castration-resistant (CR) prostate cancer (PCa) is lethal and is the second leading cause of cancer-related deaths in U.S. males. To develop effective treatments toward CR PCa, we investigated reactive oxygen species (ROS) signaling pathway for its role involving in CR PCa progression. ROS can regulate both cell growth and apoptosis: a moderate increase of ROS promotes proliferation; its substantial rise results in cell death. p66Shc protein can increase oxidant species production and its elevated level is associated with the androgen-independent (AI) phenotype of CR PCa cells; while heme oxygenase-1 (HO-1) is an antioxidant enzyme and elevated in a sub-group of metastatic PCa cells. In this study, our data revealed that HO-1 and p66Shc protein levels are co-elevated in various AI PCa cell lines as well as p66Shc cDNA-transfected cells. Knockdown and/or inhibition of either p66Shc or HO-1 protein leads to reduced tumorigenicity as well as a reduction of counterpart protein. Knockdown of HO-1 alone results in increased ROS levels, nucleotide and protein oxidation and induction of cell death. Together, our data indicate that elevated HO-1 protein levels protect PCa cells from otherwise apoptotic conditions induced by aberrant p66Shc/ROS production, which thereby promotes PCa progression to the CR phenotype. p66Shc and HO-1 can serve as functional targets for treating CR PCa.


Asunto(s)
Hemo-Oxigenasa 1 , Neoplasias de la Próstata , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src , Humanos , Masculino , Antioxidantes/metabolismo , Hemo-Oxigenasa 1/metabolismo , Neoplasias de la Próstata/patología , Especies Reactivas de Oxígeno/metabolismo , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/genética , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/metabolismo
16.
Redox Biol ; 52: 102301, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35358851

RESUMEN

Radiation is a common anticancer therapy for prostate cancer, which transforms tumor-associated normal fibroblasts to myofibroblasts, resulting in fibrosis. Oxidative stress caused by radiation-mediated mitochondrial damage is one of the major contributors to fibrosis. As diabetics are oxidatively stressed, radiation-mediated reactive oxygen species cause severe treatment failure, treatment-related side effects, and significantly reduced survival for diabetic prostate cancer patients as compared to non-diabetic prostate cancer patients. Hyperglycemia and enhanced mitochondrial damage significantly contribute to oxidative damage and disease progression after radiation therapy among diabetic prostate cancer patients. Therefore, reduction of mitochondrial damage in normal prostate fibroblasts after radiation should improve the overall clinical state of diabetic prostate cancer patients. We previously reported that MnTE-2-PyP, a manganese porphyrin, reduces oxidative damage in irradiated hyperglycemic prostate fibroblasts by scavenging superoxide and activating NRF2. In the current study, we have investigated the potential role of MnTE-2-PyP to protect mitochondrial health in irradiated hyperglycemic prostate fibroblasts. This study revealed that hyperglycemia and radiation increased mitochondrial ROS via blocking the mitochondrial electron transport chain, altered mitochondrial dynamics, and reduced mitochondrial biogenesis. Increased mitochondrial damage preceeded an increase in myofibroblast differentiation. MnTE-2-PyP reduced myofibroblast differentiation, improved mitochondrial health by releasing the block on the mitochondrial electron transport chain, enhanced ATP production efficiency, and restored mitochondrial dynamics and metabolism in the irradiated-hyperglycemic prostate fibroblasts. Therefore, we are proposing that one of the mechanisms that MnTE-2-PyP protects prostate fibroblasts from irradiation and hyperglycemia-mediated damage is by protecting the mitochondrial health in diabetic prostate cancer patients.


Asunto(s)
Diabetes Mellitus , Hiperglucemia , Metaloporfirinas , Neoplasias de la Próstata , Exposición a la Radiación , Diabetes Mellitus/metabolismo , Fibroblastos/metabolismo , Fibrosis , Humanos , Hiperglucemia/metabolismo , Masculino , Mitocondrias/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/radioterapia
17.
Clin Exp Metastasis ; 39(4): 641-659, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35604506

RESUMEN

Bone metastatic prostate cancer (BM-PCa) remains one of the most difficult cancers to treat due to the complex interactions of cancer and stromal cells. We previously showed that bone marrow neutrophils elicit an anti-tumor immune response against BM-PCa. Further, we demonstrated that BM-PCa induces neutrophil oxidative burst, which has previously been identified to promote primary tumor growth of other cancers, and a goal of this study was to define the importance of neutrophil oxidative burst in BM-PCa. To do this, we first examined the impact of depletion of reactive oxygen species (ROS), via systemic deletion of the main source of ROS in phagocytes, NADPH oxidase (Nox)2, which we found to suppress prostate tumor growth in bone. Further, using pharmacologic ROS inhibitors and Nox2-null neutrophils, we found that ROS depletion specifically suppresses growth of androgen-insensitive prostate cancer cells. Upon closer examination using bulk RNA sequencing analysis, we identified that metastatic prostate cancer induces neutrophil transcriptomic changes that activates pathways associated with response to oxidative stress. In tandem, prostate cancer cells resist neutrophil anti-tumor response via extracellular (i.e., regulation of neutrophils) and intracellular alterations of glutathione synthesis, the most potent cellular antioxidant. These findings demonstrate that BM-PCa thrive under oxidative stress conditions and such that regulation of ROS and glutathione programming could be leveraged for targeting of BM-PCa progression.


Asunto(s)
Neoplasias Óseas , Neoplasias de la Próstata , Neoplasias Óseas/secundario , Glutatión/metabolismo , Humanos , Masculino , Neutrófilos/patología , Estrés Oxidativo , Neoplasias de la Próstata/patología , Especies Reactivas de Oxígeno/metabolismo
18.
Histochem Cell Biol ; 135(3): 293-304, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21347610

RESUMEN

Reactive oxygen species (ROS) and antioxidants are essential to maintain a redox balance within tissues and cells. Intracellular ROS regulate key cellular functions such as proliferation, differentiation and apoptosis through cellular signaling, and response to injury. The redox environment is particularly important for stem/progenitor cells, as their self-renewal and differentiation has been shown to be redox sensitive. However, not much is known about ROS and antioxidant protein function in freshly isolated keratinocytes, notably the different keratinocyte subpopulations. Immunostaining of neonatal cutaneous sections revealed that antioxidant enzymes [catalase, SOD2, gluthatione peroxidase-1 (GPx)] and ROS are localized predominantly to the epidermis. We isolated keratinocyte subpopulations and found lower levels of SOD2, catalase and GPx, as well as decreased SOD and catalase activity in an epidermal side population with stem cell-like characteristics (EpSPs) compared to more differentiated (Non-SP) keratinocytes. EpSPs also exhibited less mitochondrial area, fewer peroxisomes and produced lower levels of ROS than Non-SPs. Finally, EpSPs were more resistant to UV radiation than their progeny. Together, our data indicate ROS and antioxidant levels are decreased in stem-like EpSPs.


Asunto(s)
Antioxidantes/metabolismo , Epitelio/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células de Población Lateral/metabolismo , Animales , Catalasa/metabolismo , Células Cultivadas , Glutatión Peroxidasa/metabolismo , Ratones , Ratones Endogámicos C57BL , Células de Población Lateral/citología , Superóxido Dismutasa/metabolismo , Glutatión Peroxidasa GPX1
19.
Adv Redox Res ; 32021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38831957

RESUMEN

The pathogenesis of hypertension has been linked to excessive levels of reactive oxygen species (ROS), particularly superoxide (O2•-), in multiple tissues and organ systems. Overexpression of superoxide dismutase (SOD) to scavenge O2•- has been shown to decrease blood pressure in hypertensive animals. We have previously shown that MnTnBuOE-2-PyP5+ (BuOE), a manganese porphyrin SOD mimic currently in clinical trials as a normal tissue protector for cancer patients undergoing radiation therapy, can scavenge O2•- and acutely decrease normotensive blood pressures. Herein, we hypothesized that BuOE decreases hypertensive blood pressures. Using angiotensin II (AngII)-hypertensive mice, we demonstrate that BuOE administered both intraperitoneally and intravenously (IV) acutely decreases elevated blood pressure. Further investigation using renal sympathetic nerve recordings in spontaneously hypertensive rats (SHRs) reveals that immediately following IV injection of BuOE, blood pressure and renal sympathetic nerve activity (RSNA) decrease. BuOE also induces dose-dependent vasodilation of femoral arteries from AngII-hypertensive mice, a response that is mediated, at least in part, by nitric oxide, as demonstrated by ex vivo video myography. We confirmed this vasodilation in vivo using doppler imaging of the superior mesenteric artery in AngII-hypertensive mice. Together, these data demonstrate that BuOE acutely decreases RSNA and induces vasodilation, which likely contribute to its ability to rapidly decrease hypertensive blood pressure.

20.
Radiat Res ; 195(2): 128-139, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33264413

RESUMEN

Novel synthetic compounds, known as manganese porphyrins (MnPs), have been designed to shift the redox status of both normal cells and cancer cells. When MnPs are coupled with cancer therapies, such as radiation, they have been shown to sensitize tumor cells to treatment and protect normal tissues from damage through the modulation of the redox status of various tissue types. Until now, our preclinical studies have focused on local effects of MnPs and radiation; however, we recognize that successful outcomes for cancer patients involve control of tumor cells throughout the body. In this study, using murine orthotopic mammary tumor models, we investigated how MnPs and radiation influence the development of distant metastasis. We hypothesized that the combination of MnP (MnP/RT), such as MnTnBuOE-2-PyP5+ and radiation treatment (RT) would increase local tumor control via a shift in the intratumoral redox environment, leading to subsequent downregulation of HIF-1 in the primary tumor. Secondarily, we hypothesized that these primary tumor treatment effects would result in a reduction in pulmonary metastatic burden. Balb/c mice with orthotopic 4T1 mammary carcinomas were treated with saline, MnP, RT or MnP/RT. We found MnP/RT did extend local tumor growth delay and overall survival compared to controls and was associated with increased intratumoral oxidative stress. However, the primary tumor growth delay observed with MnP/RT was not associated with a reduced pulmonary metastatic burden. Future directions to investigate the effects of MnP/RT on the development of distant metastasis may include modifications to the radiation dose, the experimental timeline or using a murine mammary carcinoma cell line with a less aggressive metastatic behavior. Clinical trials are underway to investigate the clinical utility of MnTnBuOE-2-PyP5+ for patients undergoing radiotherapy for various tumor types. The promising preclinical data from this study, as well as others, provides support that MnP/RT has the potential to improve local tumor control for these patients.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Carcinoma/radioterapia , Metaloporfirinas/farmacología , Tolerancia a Radiación/efectos de los fármacos , Animales , Neoplasias de la Mama/patología , Carcinoma/tratamiento farmacológico , Carcinoma/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Terapia Combinada , Femenino , Humanos , Manganeso/farmacología , Ratones , Ratones Endogámicos BALB C , Oxidación-Reducción/efectos de los fármacos , Oxidación-Reducción/efectos de la radiación , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Porfirinas/farmacología
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