RESUMEN
The increasing frequency of methicillin-resistant (MR) staphylococci in humans and animals need special attention for their difficult treatment and zoonotic character, therefore novel antimicrobial compounds on a natural base against antibiotic-resistant bacteria are requested. Currently, bacteriocins/enterocins present a new promising way to overcome this problem, both in prevention and treatment. Therefore, the preventive and medicinal effect of dipeptide enterocin EntA/P was evaluated against MR Staphylococcus epidermidis SEP3/Tr2a strain in a rabbit model, testing their influence on growth performance, glutathione-peroxidase (GPx) enzyme activity, phagocytic activity (PA), secretory (s)IgA, and jejunal morphometry (JM). Eighty-eight rabbits (aged 35 days, meat line M91, both sexes) were divided into experimental groups S (SEP3/Tr2a strain; 1.0 × 105 CFU/mL; dose 500µL/animal/day for 7 days, between days 14 and 21 to simulate the pathogen attack), E (EntA/P; 50 µL/animal/day, 25,600 AU/mL in two intervals, for preventive effect between days 0 and 14; for medicinal effect between days 28 and 42), E + S (EntA/P + SEP3/Tr2a; preventive effect; SEP3/Tr2a + EntA/P; medicinal effect) and control group (C; without additives). Higher body weight was recorded in all experimental groups (p < 0.001) compared to control data. The negative influence/attack of the SEP3Tra2 strain on the intestinal immunity and environment was reflected as decreased GPx activity, worse JM parameters and higher sIgA concentration in infected rabbits. These results suggest the promising preventive use of EntA/P to improve the immunity and growth of rabbits, as well as its therapeutic potential and protective role against staphylococcal infections in rabbit breeding.
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Bacteriocinas , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Humanos , Masculino , Femenino , Conejos , Animales , Staphylococcus epidermidis , Resistencia a la Meticilina , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacteriocinas/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/veterinaria , Infecciones Estafilocócicas/microbiología , Glutatión/farmacología , Glutatión/uso terapéutico , Peroxidasas/farmacología , Peroxidasas/uso terapéutico , Inmunoglobulina A/farmacología , Inmunoglobulina A/uso terapéuticoRESUMEN
Nanoprobes for efficient tumor-targeted imaging and therapy are urgently needed for clinical tumor theranostics. Herein, inspired by the heterogeneity of the tumor microenvironment, we report a covalent organic framework (COF)-derived biomimetic nanozyme for precise tumor-targeted imaging and NIR-II photothermal-catalysis-enhanced chemotherapy (PTCEC). Using a crystalline nanoscale COF as the precursor, a peroxidase-like porous N-doped carbonous nanozyme (PNC) was obtained, which was cloaked with an M1 macrophage cell membrane (M1m) to create a multifunctional biomimetic nanoprobe for tumor-targeted imaging and therapy. The M1m coating enabled the nanoprobe to target cancer cells and tumor tissues for highly efficient tumor imaging and drug delivery. The peroxidase-like activity of the PNC allowed for the conversion of intratumoral H2O2 into toxic ËOH that synergized with its NIR-II photothermal effect to strengthen the chemotherapy. Therefore, highly efficient tumor-targeted imaging and NIR-II PTCEC were realized with an M1 macrophage mimic nanoprobe. This work provides a feasible tactic for a biomimetic theranostic nanoprobe and will inspire the development of new bioactive nanomaterials for clinical tumor theranostic applications.
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Estructuras Metalorgánicas , Nanopartículas , Neoplasias , Humanos , Peróxido de Hidrógeno , Nanomedicina Teranóstica/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Peroxidasas/uso terapéutico , Línea Celular Tumoral , Nanopartículas/química , Microambiente TumoralRESUMEN
The antioxidant system of tumor cells severely impairs reactive oxygen species (ROS)-mediated tumor therapy. Despite extensive attempts to attenuate the antioxidant capacity by eliminating ROS scavengers such as glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) over-expressed in the tumor microenvironment can regenerate GSH from glutathione disulfide (GSSG), hence weakening ROS-induced oxidative damage. Therefore, engineering a nanoplatform capable of depleting both NADPH and GSH is extremely significant for improving ROS-mediated tumor treatment. Herein, a synergetic antioxidant inhibition strategy is proposed to attenuate intracellular antioxidant capacity for hypoxic tumor therapy. In this context, both porous Prussian blue nanoparticles (PPB NPs) and cisplatin prodrug [cis-Pt (IV)] in the nanoplatform can oxidize GSH to directly reduce GSH levels, while PPB NPs also enable NADPH depletion by peroxidase-mimicking to impair GSH regeneration. Furthermore, PPB NPs with catalase-mimicking activity catalyze H2O2 decomposition to alleviate tumor hypoxia, thus reducing the generation of GSH and boosting singlet oxygen (1O2) production by Chlorin e6 (Ce6) for enhancing oxidative damage. Experimental results prove that the nanoplatform, denoted as PPB-Ce6-Pt, can induce remarkable tumor cells apoptosis and ferroptosis. Importantly, a simple loading method and the use of Food Drug Administration (FDA)-approved materials make PPB-Ce6-Pt have great potential for practical applications. STATEMENT OF SIGNIFICANCE: The antioxidant system in tumor cells disables ROS-mediated tumor therapy. Besides, extensive attempts aim at depleting GSH without considering their regeneration. Therefore, we developed a synergetic strategy to attenuate intracellular antioxidant capacity for hypoxic tumor therapy. PPB-Ce6-Pt nanoplatform could not only directly reduce GSH levels but also deplete NADPH by peroxidase-mimicking to impair GSH regeneration. In addition, PPB-Ce6-Pt nanoplatform could catalyze H2O2 decomposition to alleviate tumor hypoxia, thus reducing the generation of GSH and boosting 1O2 production by Chlorin e6 (Ce6) for increasing oxidative damage. Then, intracellular ROS boost and redox dyshomeostasis induced remarkable tumor cells apoptosis and ferroptosis. Importantly, a simple loading method and the use of biosafety materials made the nanoplatform have great potential for practical applications.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Antioxidantes/farmacología , Fotoquimioterapia/métodos , Especies Reactivas de Oxígeno , Peróxido de Hidrógeno/química , NADP/farmacología , NADP/uso terapéutico , Estrés Oxidativo , Neoplasias/tratamiento farmacológico , Glutatión/metabolismo , Nanopartículas/química , Peroxidasas/farmacología , Peroxidasas/uso terapéutico , Línea Celular Tumoral , Fármacos Fotosensibilizantes/química , Microambiente TumoralRESUMEN
OBJECTIVES: The purpose of this study was to evaluate the incidence of primary headache and potential biomarkers in patients diagnosed with Hashimoto thyroiditis. METHODS: Patients with Hashimoto thyroiditis referred to the outpatient endocrinology clinic were included in the study. The demographic data, thyroid function test results, and autoantibody titers were recorded. The headache's clinical characteristics were also determined. The same researcher used the visual analog scale for headache severity rating in all patients. RESULTS: 155 patients with Hashimoto thyroiditis were included the study. There were 95 (61.3%) cases diagnosed with headache consisting of 20 (21.1%) migraine cases, 17 (17.9%) tension type headaches (TTHs), and 20 (21.1%) new daily persistent headaches (NDPHs). 38 of 155 (24.5%) had hypothyroidism related headaches (HRHs). There was no statistically significant relationship between the headache type and a high blood antibody level anti thyroid peroxidase antibody (p=0.135), while a positive correlation was found with thyroid stimulating hormone (TSH) (p<0.001). Hashimoto patients with migraine (n=14, 70.0%) were found to have higher blood antibody levels, while these ratios were found as 86.8% (n=33) in HRH-patients, 76.5% (n=13) in TTH-patients, and 60.0% (n=12) in NDPH-patients. 86 of 155 (55.5%) patients reported new onset headaches after a Hashimoto's thyroiditis diagnosis, and the headaches persisted without hormone therapy in 48 (84.2%) of these patients. These patients diagnosed with primary headache and this was interpreted as demonstrating comorbidity between Hashimoto's disease and primary headaches. CONCLUSION: Detection of only the relationship between TSH level and headache suggested that different mechanisms play a role in the pathophysiology. In the diagnosis of primary headache, it is important to look into secondary reasons.
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Enfermedad de Hashimoto , Trastornos Migrañosos , Humanos , Enfermedad de Hashimoto/complicaciones , Enfermedad de Hashimoto/epidemiología , Enfermedad de Hashimoto/diagnóstico , Cefalea/etiología , Cefalea/complicaciones , Tirotropina/uso terapéutico , Biomarcadores , Trastornos Migrañosos/complicaciones , Peroxidasas/uso terapéuticoRESUMEN
BACKGROUND: Small-cell lung cancer (SCLC) molecular subtypes have been primarily characterized based on the expression pattern of the following key transcription regulators: ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P) and YAP1 (SCLC-Y). Here, we investigated the proteomic landscape of these molecular subsets with the aim to identify novel subtype-specific proteins of diagnostic and therapeutic relevance. METHODS: Pellets and cell media of 26 human SCLC cell lines were subjected to label-free shotgun proteomics for large-scale protein identification and quantitation, followed by in-depth bioinformatic analyses. Proteomic data were correlated with the cell lines' phenotypic characteristics and with public transcriptomic data of SCLC cell lines and tissues. RESULTS: Our quantitative proteomic data highlighted that four molecular subtypes are clearly distinguishable at the protein level. The cell lines exhibited diverse neuroendocrine and epithelial-mesenchymal characteristics that varied by subtype. A total of 367 proteins were identified in the cell pellet and 34 in the culture media that showed significant up- or downregulation in one subtype, including known druggable proteins and potential blood-based markers. Pathway enrichment analysis and parallel investigation of transcriptomics from SCLC cell lines outlined unique signatures for each subtype, such as upregulated oxidative phosphorylation in SCLC-A, DNA replication in SCLC-N, neurotrophin signalling in SCLC-P and epithelial-mesenchymal transition in SCLC-Y. Importantly, we identified the YAP1-driven subtype as the most distinct SCLC subgroup. Using sparse partial least squares discriminant analysis, we identified proteins that clearly distinguish four SCLC subtypes based on their expression pattern, including potential diagnostic markers for SCLC-Y (e.g. GPX8, PKD2 and UFO). CONCLUSIONS: We report for the first time, the protein expression differences among SCLC subtypes. By shedding light on potential subtype-specific therapeutic vulnerabilities and diagnostic biomarkers, our results may contribute to a better understanding of SCLC biology and the development of novel therapies.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Biomarcadores , Línea Celular Tumoral , Medios de Cultivo , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/uso terapéutico , Peroxidasas/genética , Peroxidasas/metabolismo , Peroxidasas/uso terapéutico , Proteómica , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismoRESUMEN
Photodynamic therapy (PDT) has become a promising cancer treatment due to in situ generation of cytotoxic reactive oxygen (ROS); however, it remains limited by the hypoxia of tumor microenvironment (TME) and penetration depth of laser. Herein, we developed a kind of GSH-/H2O2-responsive copper-encapsulating magnetic nanoassemblies (MNSs) for switchable T1-weighted magnetic resonance imaging (MRI) and enzyme-like activity potentiating PDT of cancer. MNSs were rationally constructed using the chelation effect of copper ions (Cu2+) with polyacrylic acid-coated ultrasmall iron oxide nanoparticles (UIONPs). After uptake by tumor cells, the incorporated Cu2+ of MNSs was reduced to Cu+ through the intracellular GSH, which resulted in the disassembly of MNSs accompanied by the "silenced" MR signal shifting to a positive state. Sequentially, the generated Cu+ manifested peroxidase-like activity, catalyzing local H2O2 in TME to cytotoxic ·OH for chemodynamic therapy. Furthermore, Cu2+ and UIONPs could decompose H2O2 to O2, thus providing extra oxygen necessary for enhancing the PDT effect of photosensitizer IR-780. Finally, IR-780-loading MNSs (MNSs@IR-780) under laser irradiation significantly inhibited tumor growth and prolonged the survival of gastric MGC-803 tumor-bearing mice. Therefore, this study provides a versatile nanoplatform as a tumor-responsive theragnostic agent. STATEMENT OF SIGNIFICANCE: Tumor hypoxia and penetration depth of laser severely hindered the PDT of cancer. Valence-convertible metal ions (VCMI, e.g., Cu2+/Cu+, Fe3+/Fe2+) have been reported as Fenton-like agents disintegrating H2O2 to O2 to enhance PDT. Tumor-delivery of VCMI is of essential importance for in situ triggering of a Fenton-like reaction. We thereby developed magnetic nanoassemblies (MNSs) to encapsulate Cu2+ and load photosensitizer (IR-780). Stimulated by GSH and H2O2, MNSs performed catalase/peroxidase-like activity that provided extra O2 for PDT and catalyzed H2O2 to ·OH for CDT. Consequently, IR-780-loading MNSs under laser irradiation significantly inhibit the tumor growth due to effective tumor delivery of Cu2+ and IR-780. This study might offer a feasible nanoplatform for tumor-delivery of metal ions and drugs.
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Antineoplásicos , Neoplasias , Fotoquimioterapia , Ratones , Animales , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Cobre/farmacología , Peróxido de Hidrógeno/farmacología , Línea Celular Tumoral , Fotoquimioterapia/métodos , Microambiente Tumoral , Antineoplásicos/farmacología , Neoplasias/patología , Imagen por Resonancia Magnética , Oxígeno/farmacología , Peroxidasas/farmacología , Peroxidasas/uso terapéuticoRESUMEN
The depletion of reactive oxygen species (ROS) by glutathione (GSH) and oxidative stress induced protective autophagy severely impaired the therapeutic effect of chemodynamic therapy (CDT). Therefore, how to construct a CDT treatment nanosystem with high yield and full utilization of ROS in tumor site is the main issue of CDT. Herein, a multifunctional cascade bioreactor based on mesoporous Mo-doped Cu9S5 (m-MCS) nanozymes loaded with L-Arginine (LA), abbreviated as m-MCS@LA, is constructed for realizing enhanced CDT promoted by ultrasound (US) triggered gas therapy. The m-MCS based on the catalytic performance of multivalent metal ions, which were served as nanozymes, exhibit enhanced Fenton-like and glutathione (GSH) peroxidase-like activities in comparison to Cu9S5 nanoparticles without Mo-doping. Once placed in tumor microenvironment (TME), the existence of redox couples (Cu+/Cu2+ and Mo4+/Mo6+) in m-MCS enabled it to react with hydrogen peroxide (H2O2) to generate ·OH for achieving CDT effect via Fenton-like reaction. Meanwhile, m-MCS could consume overexpressed GSH in tumor microenvironment (TME) to alleviate antioxidant capability for enhancing CDT effect. Moreover, m-MCS with mesoporous structure could be employed as the carrier to load natural nitric oxide (NO) donor LA. US as the excitation source with high tissue penetration can trigger m-MCS@LA to produce NO. As the gas transmitter with physiological functions, NO could play dual roles to kill cancer cells through gas therapy directly, and enhance CDT effect by inhibiting protective autophagy simultaneously. As a result, this US-triggered and NO-mediated synergetic cancer chemodynamic/gas therapy based on m-MCS@LA NPs can effectively eliminate primary tumor and achieved tumor-specific treatment, which provide a possible strategy for developing more effective CDT in future practical applications. STATEMENT OF SIGNIFICANCE: The depletion of reactive oxygen species (ROS) by glutathione (GSH) and oxidative stress induced protective autophagy severely impaired the therapeutic effect of chemodynamic therapy (CDT). Herein, a multifunctional cascade bioreactor based on mesoporous Mo-doped Cu9S5 (m-MCS) nanozymes loaded with L-Arginine (m-MCS@LA) is constructed for realizing enhanced CDT promoted by ultrasound (US) triggered gas therapy. The m-MCS with double redox couples presents the enhanced enzyme-like activities to perform cascade reactions for reducing GSH and generating ROS. LA loaded by m-MCS can produce NO triggered by US to inhibit the mitochondria protective autophagy for reactivating mitochondria involved apoptosis pathway. The US-triggered and NO-mediated CDT based on m-MCS@LA can effectively eliminate primary tumor through the high yield and full utilization of ROS.
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Peróxido de Hidrógeno , Neoplasias , Antioxidantes/farmacología , Arginina/farmacología , Autofagia , Línea Celular Tumoral , Glutatión/farmacología , Humanos , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología , Mitocondrias/metabolismo , Neoplasias/tratamiento farmacológico , Óxido Nítrico/farmacología , Peroxidasas/farmacología , Peroxidasas/uso terapéutico , Especies Reactivas de Oxígeno , Microambiente TumoralRESUMEN
Chemodynamic therapy (CDT), an emerging tumor-specific therapeutic modality, is frequently restrained by insufficient intratumoral Fenton catalysts and increasingly inefficient catalysis caused by the continuous consumption of limited H2O2 within tumors. Herein, we engineered a pH-responsive bortezomib (BTZ) polymer prodrug catalytic nanoreactor (HeZn@HA-BTZ) capable of self-supplying Fenton catalyst and H2O2. It is aimed for tumor-specific chemo/chemodynamic therapy via oxidative stress and endoplasmic reticulum (ER) stress dual-amplification and macrophage repolarization. A catecholboronate bond-based hyaluronic acid-BTZ prodrug HA-DA-BTZ was modified on Hemin and Zn2+ coordination nanoscale framework (HeZn), an innovative CDT inducer, to construct He-Zn@HA-BTZ. He-Zn@HA-BTZ with good stability and superior peroxidase-like activity preferentially accumulated at tumor sites and be actively internalized by tumor cells. Under the cleavage of catecholboronate bond in acidic endo/lysosomes, pre-masked BTZ was rapidly released to induce ubiquitinated protein aggregation, robust ER stress and elevated H2O2 levels. The amplified H2O2 was further catalyzed by HeZn via Fenton-catalytic reactions to produce hypertoxic â¢OH, enabling cascaded oxidative stress amplification and long-lasting effective CDT, which in turn aggravated BTZ-induced ER stress. Eventually, a dual-amplification of oxidative stress and ER stress was achieved to initiate cell apoptosis/necrosis with reduced BTZ toxicity. Intriguingly, He-Zn@HA-BTZ could repolarize macrophages from M2 to antitumor M1 phenotype for potential tumor therapy. This "all in one" prodrug nanocatalytic reactor not only enriches the CDT inducer library, but provides inspirational strategy for simultaneous oxidative stress and ER stress based excellent cancer therapy.
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Neoplasias , Profármacos , Bortezomib/farmacología , Catálisis , Catecoles , Hemina/uso terapéutico , Humanos , Ácido Hialurónico/química , Peróxido de Hidrógeno/metabolismo , Macrófagos/metabolismo , Nanotecnología , Neoplasias/tratamiento farmacológico , Peroxidasas/uso terapéutico , Polímeros/uso terapéutico , Profármacos/uso terapéutico , Agregado de ProteínasRESUMEN
INTRODUCTION: Alzheimer's disease (AD) is a progressive, neurodegenerative disease that severely affects individuals' cognitive abilities, memory, and quality of life. It affects the elderly population, and there is no permanent prevention or cures available to date, treatments mainly aiming to alleviate the symptoms as and when they appear. Alternate therapeutic approaches are being researched constantly, and there is a growing focus on phytomedicine, herbal medicine, organic compounds, and ayurvedic compounds for the treatment of AD. METHODS: The current study aims to provide an extensive review of these plants against AD from the currently existing literature. Most relevant keywords like Alzheimer's Disease, phytomedicines, ethnic medicines, the role of phytomedicine in neuroprotection, common phytomedicines against AD, etc., were used to select the plants and their metabolites effective in treating AD. The study focuses on six plants: Panax ginseng, Ginkgo biloba, Bacopa monnieri, Withania somnifera, Curcuma longa, and Lavandula angustifolia. Their active components have been studied along with neuroprotective properties, and evidence of in-vitro, pre-clinical, and clinical studies conducted to prove their therapeutic potential against the disease have been presented. RESULTS: All plants envisaged in the study show potential for fighting against AD to varying degrees. Their compounds have shown therapeutic effects by reversing the neurological changes such as clearing Aß plaque and neurofibrillary tangle formation, and ameliorative effects against neurodegeneration through processes including improving concentration, memory, cognition and learning, higher working and cue memory, improved spatial memory, inhibition of NF-κB expression, inhibiting the release of pro-inflammatory cytokines, inhibition of AChE and lipid peroxidase enzymes, and reduction of interleukin levels and tumor necrosis factor-alpha. CONCLUSION: The present review is a comprehensive and up-to-date analysis supported by the evidentiary proofs from pre-clinical studies, meta-analyses, and review papers related to natural phytochemicals' impact on neurodegenerative disorders like AD.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Anciano , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , FN-kappa B , Factor de Necrosis Tumoral alfa , Calidad de Vida , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Peroxidasas/uso terapéutico , LípidosRESUMEN
BACKGROUND: Delayed pressure urticaria (DPU) is a rare form of chronic inducible urticaria (CIndU) when it manifests alone. Treatment of DPU is disappointing owing to the lack of response to antihistamines, even when up-dosing. In addition, the absence of randomized clinical trials and the low number of patients included in the studies mean that there is little scientific evidence for the validity of omalizumab in DPU. OBJECTIVE: Objectives of the study were to perform a real-world study of the effectiveness and safety of omalizumab in DPU patients without chronic spontaneous urticaria or other forms of CIndU and to describe their clinical and diagnostic features. METHOD: We performed an ambispective observational study of 14 patients with DPU who did not respond to 2 or more second-generation H1-antihistamines in an up-dosing regimen and/or corticosteroids, montelukast, or cyclosporine. Treatment was initiated with omalizumab 300 mg every 4 weeks. We recorded the following: age, time to diagnosis, previous treatment, diagnostic testing (mean time threshold after removing the stimulus and duration of the lesions), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D dimer, total IgE, antithyroid peroxidase (anti-TPO) antibodies, and the Urticaria Control Test (UCT) score before and after the first dose. We evaluated the efficacy of omalizumab according to the Urticaria Control Test score. We analyzed the time to complete or satisfactory response after the first dose (superfast) and its adverse effects. RESULTS: Women accounted for 64.28% patients. The mean age at diagnosis was 43.64 (±13.78) years. The time to diagnosis was 4.53 (±5.54) years. The mean time threshold after removing the stimulus was 4.18 h (±2.75). The mean duration of lesions after testing was 32.42 (±13.8) hours. High ERS values (>20.0 mm/h) were detected in 50% of patients. CRP was >0.5 mg/dL in 42.85% and D dimer levels were high (>500.0 ng/mL) in 3/10 patients. Anti-TPO level was normal in 100% of patients. Total IgE was >100 IU/mL in 6/8 patients. Medium UCT levels before treatment with omalizumab were 3.07 (±2.40), reaching 15.28/16 (±1.72) after the first dose of omalizumab. All 14 patients responded superfast, and none experienced an adverse reaction. CONCLUSIONS: Despite the limitation of a low sample size in this real-life study, our findings suggest that omalizumab is a rapid, effective, and safe treatment for patients with DPU refractory to antihistamines in an up-dosing regimen. We recommend omalizumab for patients who do not respond to up-dosing antihistamines and montelukast.
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Antialérgicos , Urticaria Crónica , Ciclosporinas , Urticaria , Acetatos , Corticoesteroides/uso terapéutico , Adulto , Proteína C-Reactiva , Enfermedad Crónica , Urticaria Crónica/diagnóstico , Urticaria Crónica/tratamiento farmacológico , Ciclopropanos , Ciclosporinas/uso terapéutico , Femenino , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Inmunoglobulina E , Persona de Mediana Edad , Omalizumab/uso terapéutico , Peroxidasas/uso terapéutico , Quinolinas , Sulfuros , Resultado del Tratamiento , Urticaria/diagnóstico , Urticaria/tratamiento farmacológicoRESUMEN
Glutathione peroxidase 8 (GPx8) belongs to a family of enzymes that have a critical role in controlling levels of reactive oxygen species (ROS). GPX family members have been associated with several cancers. Here, we examined the role of GPx8 in esophageal squamous cell carcinoma (ESCC). Immunohistochemical staining and western blot analysis were used to study the clinical significance of GPx8 in ESCC tissue. GPx8 was further evaluated in cells by MTT assay and colony formation. RT-PCR, western blot, immunofluorescence staining, TUNEL assay, TEM, and flow cytometry were used to assess the molecular mechanism underlying endoplasmic reticulum (ER) stress associated with GPx8 in ESCC cells. Xenografted tumor growth was used to assess the in vivo role of GPx8. We found that GPx8 was overexpressed in both ESCC cell lines and tumor tissue. GPx8 knockdown significantly suppressed ESCC proliferation and induced autophagy and apoptosis in ESCC cell lines, whereas GPx8 overexpression led to increased proliferation and inhibition of apoptosis. GPx8-mediated inhibition of apoptosis was associated with the ER stress pathway through inositol-requiring enzyme 1 (IRE1) and Jun N-terminal kinase (JNK). Knockdown of GPx8 in xenograft models of ESCC resulted in a significant reduction in tumor weight and volume, which was further reduced with IRE1 or JNK inhibitors. Our study suggests that GPx8 regulates apoptosis and autophagy in ESCC through the IRE1/JNK pathway in response to ER stress. Targeting this pathway might be a potential therapeutic strategy for ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Apoptosis , Autofagia , Línea Celular Tumoral , Proliferación Celular , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas , Peroxidasas/metabolismo , Peroxidasas/uso terapéutico , Proteínas Serina-Treonina QuinasasRESUMEN
Sialoperoxidase and myeloperoxidase are the two main peroxidase enzymes found in the oral cavity. Sialoperoxidase is present in salivary secretions and in the biofilms that line the oral surfaces, while myeloperoxidase is abundant in the dentogingival sulcus area. In the presence of hydrogen peroxide (H2O2), oral peroxidases catalyze the oxidation of the pseudohalide anion thiocyanate (SCN) to hypothiocyanite (OSCN), a strong oxidant that serves an antimicrobial role. Furthermore, oral peroxidases consume bacteriaproduced H2O2 and could help inactivate toxic carcinogenic and genotoxic substances. Numerous in vitro studies have reported the antibacterial, antimycotic and antiviral role of peroxidases, suggesting possible applications in oral therapy. However, the use of oral hygiene products incorporating peroxidase systems has not yet been shown to be beneficial for the treatment or prevention of oral infections. This paradox reflects our incomplete knowledge of the physiological role of peroxidases in a complex environment, such as the oral region. While hygiene is crucial for restoring oral microbiota to a symbiotic state, there are no data to suggest that the addition of a peroxidase per se can create a dysbiotic state. Recent investigations have associated the presence of peroxidase activity with grampositive cocci microbial flora, and its insufficiency with dysbiosis has been linked to pathologies, such as caries, periodontitis or infections of the oral mucosa. Therefore, oxidants generated by oral peroxidases appear to be an essential ecological determinant for oral health through the selection of a symbiotic microbiota capable of resisting oxidative stress. The objective of the present review was to update the current knowledge of the physiological aspects and applications of oral peroxidases in clinical practice.
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Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Boca/enzimología , Boca/microbiología , Higiene Bucal/métodos , Peroxidasas/farmacología , Peroxidasas/uso terapéutico , Animales , Mimetismo Biológico , Humanos , Oxidantes/metabolismoRESUMEN
BACKGROUND: Neuroinflammation is the major pathogenesis of cerebral ischemia. Microglia are activated and polarized to either the pro-inflammatory M1 phenotype or anti-inflammatory M2 phenotype, which act as a critical mediator of neuroinflammation. Sestrin2 has pro-survival properties against ischemic brain injury. However, whether sestrin2 has an anti-inflammatory function by shifting microglia polarization and its underlying mechanism is unknown. METHODS: Adult male C57BL/6 mice (N = 108) underwent transient middle cerebral artery occlusion (tMCAO) and were treated with exogenous sestrin2. Neurological deficit scores and infarct volume were determined. Cell apoptosis was examined by TUNEL staining and Western blotting. The expression of inflammatory mediators, M1/M2-specific markers, and signaling pathways were detected by reverse transcription-polymerase chain reaction, immunostaining, and Western blotting. To explore the underlying mechanism, primary neurons were subjected to oxygen-glucose deprivation (OGD) and then treated with oxygenated condition medium of BV2 cells incubated with different doses of sestrin2. RESULTS: Sestrin2 attenuated the neurological deficits, infarction volume, and cell apoptosis after tMCAO compared to those in the control (p < 0.05). Sestrin2 had an anti-inflammatory effect and could suppress M1 microglia polarization and promote M2 microglia polarization. Condition medium from BV2 cells cultured with sestrin2 reduced neuronal apoptosis after OGD in vitro. Furthermore, we demonstrated that sestrin2 drives microglia to the M2 phenotype by inhibiting the mammalian target of rapamycin (mTOR) signaling pathway and restoring autophagic flux. CONCLUSIONS: Sestrin2 exhibited neuroprotection by shifting microglia polarization from the M1 to M2 phenotype in ischemic mouse brain, which may be due to suppression of the mTOR signaling pathway and the restoration of autophagic flux.
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Autofagia/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Polaridad Celular/efectos de los fármacos , Inflamación/tratamiento farmacológico , Microglía/efectos de los fármacos , Peroxidasas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Autofagia/fisiología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Línea Celular , Polaridad Celular/fisiología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Inflamación/metabolismo , Inflamación/patología , Ratones , Microglía/metabolismo , Microglía/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Peroxidasas/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Lignin peroxidase is a cosmetic skin-lightening alternative that breaks down plant cell walls and melanin. OBJECTIVE: This research examined the topical efficacy of lignin peroxidase in pigment lightening. METHODS: Sixty women aged 18 to 65 years with mild to moderate facial dyspigmentation were enrolled for 12 weeks in 2 cohorts. Cohort 1 applied lignin peroxidase to 1 randomized side of the face and nothing to the opposite side. Cohort 2 applied lignin peroxidase to 1 facial side and generic hydroquinone to the other. Investigator, subject, and dermospectrophotometer measurements were obtained. RESULTS: In cohort 1, improved skin texture (P < .001), roughness (P < .001), and overall appearance (P = .002) was noted at week 2 with lignin peroxidase versus no treatment. By week 12, there was a decrease in spot size with lignin peroxidase versus no treatment (P = .014). This was confirmed by a statistically significant reduction in melanin scores with the dermospectrophotometer on lignin peroxidase-treated side at weeks 4, 8, and 12 (P = .003) and a similar reduction in Melasma Area Severity Index score. Cohort 2 demonstrated parity between lignin peroxidase and hydroquinone, but lignin peroxidase was statistically superior in skin texture and roughness. LIMITATIONS: The sample size was limited. CONCLUSIONS: Lignin peroxidase might be an over-the-counter skin-lightening preparation with efficacy parity to hydroquinone.
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Hidroquinonas/uso terapéutico , Hiperpigmentación/tratamiento farmacológico , Peroxidasas/uso terapéutico , Preparaciones para Aclaramiento de la Piel/uso terapéutico , Adolescente , Adulto , Anciano , Cara , Femenino , Humanos , Hidroquinonas/farmacología , Persona de Mediana Edad , Peroxidasas/farmacología , Método Simple Ciego , Preparaciones para Aclaramiento de la Piel/farmacología , Pigmentación de la Piel/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND: Historically, the most effective treatments for skin lightening have contained hydroquinone. However, there is a need for an effective alternative. AIMS: The purpose of this study was to evaluate the skin-lightening efficacy and safety of lignin peroxidase (LIP) creams using a regimen of both day and night products compared with twice-daily application of 2% hydroquinone cream and placebo in Asian women. PATIENTS/METHODS: This was a randomized, double-blind, placebo-controlled, split-face, single-center study of 51 patients. Patients were randomized to receive day and night LIP cream on one randomly selected side of their face and either 2% hydroquinone cream or placebo on the other. RESULTS: A statistically significant change from baseline in the melanin index was observed in LIP-treated skin, with a mean reduction of 7.6% (P < 0.001) on Day 31. Conversely, hydroquinone and placebo did not provide a statistically significant lightening effect when instrumentally measured. Dermatologist scoring demonstrated a significant improvement in overall fairness as early as 8 days after treatment initiation in the LIP-treated group, which was not observed in the other groups. Overall, patients preferred the LIP creams. CONCLUSIONS: The application of day/night LIP cream provided a significantly more rapid and observable skin-lightening effect than hydroquinone 2% cream or placebo.
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Antioxidantes/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Hidroquinonas/uso terapéutico , Peroxidasas/uso terapéutico , Trastornos de la Pigmentación/tratamiento farmacológico , Administración Cutánea , Adulto , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Pueblo Asiatico , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Hidroquinonas/administración & dosificación , Hidroquinonas/efectos adversos , Persona de Mediana Edad , Prioridad del Paciente , Peroxidasas/administración & dosificación , Peroxidasas/efectos adversos , Estadísticas no Paramétricas , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Carbamide peroxide and hydrogen peroxide have been used as tooth whitening agents. The aim of this paper was to determine the efficiency of several enzyme-containing whitening systems. A method to determine the rate of 'in vitro' tetracycline whitening was also developed. METHODS: We determined the tetracycline whitening ability of carbamide peroxide and hydrogen peroxide, and the influence of peroxidase and lactoperoxidase on this tetracycline whitening rate. RESULTS: High peroxidase and lactoperoxidase concentrations increased the rate of tetracycline decoloration obtained with carbamide peroxide or hydrogen peroxide. The decoloration rate observed was lower when the glucose/glucose oxidase system was used to generate hydrogen peroxide 'in situ'. The presence of peroxidase increased the decoloration rate of extracted teeth obtained with carbamide. CONCLUSIONS: Enzymes such as peroxidase could be used as whitening catalysts to increase the rate of tetracycline decoloration.
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Antibacterianos/efectos adversos , Peroxidasas/uso terapéutico , Tetraciclina/efectos adversos , Blanqueamiento de Dientes/métodos , Decoloración de Dientes/terapia , Análisis de Varianza , Peróxido de Carbamida , Combinación de Medicamentos , Interacciones Farmacológicas , Glucosa Oxidasa/uso terapéutico , Humanos , Peróxido de Hidrógeno/uso terapéutico , Peróxidos/uso terapéutico , Decoloración de Dientes/inducido químicamente , Urea/análogos & derivados , Urea/uso terapéuticoRESUMEN
Increasing evidence has shown that reactive oxygen species (ROS) are important mediators in liver ischemia/reperfusion injury(IRI). ROS include hydrogen peroxide (H(2)O(2)), superoxide anion (O(-2)), and hydroxyl radical (HO(-)), which may be generated by activated Kupffer cells in the liver, contributing to reperfusion injury. Hepatic IRI is a multistep process that damages liver graft function. To establish a series of therapeutic strategies to improve the outcome of liver transplantation, a good understanding of the mechanisms of IRI is essential. However, the detail mechanisms of how ROS lead to hepatocyte damage in IRI remains unclear. The aim of this review was to describe recent developments in the field of oxidative stress research. The first part of this review focused on the key roles and possible mechanisms of ROS in hepatic IRI. The second part of this review summarizes some findings including novel and classic antioxidant methods to ameliorate the hepatocyte damage during IRI.
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Antioxidantes/uso terapéutico , Precondicionamiento Isquémico/métodos , Circulación Hepática , Trasplante de Hígado/fisiología , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/fisiopatología , Ácido Ascórbico/uso terapéutico , Depuradores de Radicales Libres/análisis , Depuradores de Radicales Libres/metabolismo , Glutatión Peroxidasa/uso terapéutico , Humanos , Fallo Hepático/cirugía , Trasplante de Hígado/métodos , Peroxidasas/uso terapéutico , Peroxirredoxinas , Especies Reactivas de Oxígeno/análisis , Daño por Reperfusión/prevención & control , Tiorredoxinas/uso terapéuticoRESUMEN
H(2)O(2) is a reactive oxygen species that has drawn much interest because of its role as a second messenger in receptor-mediated signaling. Mammalian 2-Cys peroxiredoxins have been shown to eliminate efficiently the H(2)O(2) generated in response to receptor stimulation. 2-Cys peroxiredoxins are members of a novel peroxidase family that catalyze the H(2)O(2) reduction reaction in the presence of thioredoxin, thioredoxin reductase and NADPH. Several lines of evidence suggest that 2-Cys peroxiredoxins have dual roles as regulators of the H(2)O(2) signal and as defenders of oxidative stress. In particular, 2-Cys peroxiredoxin appears to provide selective, specific and localized control of receptor-mediated signal transduction. Thus, the therapeutic potential of 2-Cys peroxiredoxins is clear for diseases, such as cancer and cardiovascular diseases, that involve reactive oxygen species.
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Modelos Biológicos , Estrés Oxidativo/fisiología , Peroxidasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiología , Secuencia de Aminoácidos , Humanos , Datos de Secuencia Molecular , Peroxidasas/genética , Peroxidasas/uso terapéutico , Peroxirredoxinas , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Alineación de SecuenciaRESUMEN
Human peroxiredoxin II (Prx II) has been known to function as an antioxidant enzyme in cells. Using head-and-neck cancer cell lines, we investigated whether Prx II expression is related to the resistance of cells to radiation therapy in vivo and in vitro, and whether a Prx II antisense serves as a radiosensitizer. Increased expression of Prx II was observed in tissues isolated from the patients who did not respond to radiation therapy, whereas Prx II expression was weak in tissues from the patients with regressed tumors. Enhanced expression of Prx II in UMSCC-11A (11A) cells was also observed after treatment with gamma radiation. This increased expression conferred radiation resistance to cancer cells because overexpression of Prx II protected 11A cells from radiation-induced cell death, suggesting that blocking Prx II expression could enhance radiation sensitivity. Treatment of 11A cells with a Prx II antisense decreased induction of Prx II, enhancing the radiation sensitivity. From these results, we suggest that stress-induced overexpression of Prx II increases radiation resistance via protection of cancer cells from radiation-induced oxidative cytolysis and that a Prx II antisense can be used as a radiosensitizer.