RESUMEN
Our study proposes a pharmacological strategy to target cancerous mitochondria via redox-cycling "mitocans" such as quinone/ascorbate (Q/A) redox-pairs, which makes cancer cells fragile and sensitive without adverse effects on normal cells and tissues. Eleven Q/A redox-pairs were tested on cultured cells and cancer-bearing mice. The following parameters were analyzed: cell proliferation/viability, mitochondrial superoxide, steady-state ATP, tissue redox-state, tumor-associated NADH oxidase (tNOX) expression, tumor growth, and survival. Q/A redox-pairs containing unprenylated quinones exhibited strong dose-dependent antiproliferative and cytotoxic effects on cancer cells, accompanied by overproduction of mitochondrial superoxide and accelerated ATP depletion. In normal cells, the same redox-pairs did not significantly affect the viability and energy homeostasis, but induced mild mitochondrial oxidative stress, which is well tolerated. Benzoquinone/ascorbate redox-pairs were more effective than naphthoquinone/ascorbate, with coenzyme Q0/ascorbate exhibiting the most pronounced anticancer effects in vitro and in vivo. Targeted anticancer effects of Q/A redox-pairs and their tolerance to normal cells and tissues are attributed to: (i) downregulation of quinone prenylation in cancer, leading to increased mitochondrial production of semiquinone and, consequently, superoxide; (ii) specific and accelerated redox-cycling of unprenylated quinones and ascorbate mainly in the impaired cancerous mitochondria due to their redox imbalance; and (iii) downregulation of tNOX.
Asunto(s)
Neoplasias , Superóxidos , Ratones , Animales , Superóxidos/metabolismo , Oxidación-Reducción , Ácido Ascórbico/metabolismo , Quinonas/metabolismo , Neoplasias/metabolismo , Adenosina Trifosfato/metabolismoRESUMEN
The impact of radiation-induced hydrogen peroxide (H2O2) on the biological effects of X-rays and carbon-ion beams was investigated using a selenium-deficient (SeD) mouse model. Selenium is the active center of glutathione peroxidase (GSH-Px), and SeD mice lack the ability to degrade H2O2. Male and female SeD mice were prepared by feeding a torula yeast-based SeD diet and ultrapure water. Thirty-day survival rates after whole-body irradiation, radiation-induced leg contracture, and MRI-based redox imaging of the brain were assessed and compared between SeD and normal mice. Thirty-day lethality after whole-body 5.6â Gy irradiation with X-rays or carbon-ion beams was higher in the SeD mice than in the normal mice, while SeD did not give the notable difference between X-rays and carbon-ion beams. SeD also did not affect the maximum leg contracture level after irradiation with carbon-ion beams, but delayed the leg contraction rate. In addition, no marked effects of SeD were observed on variations in the redox status of the brain after irradiation. Collectively, the present results indicate that SeD slightly altered the biological effects of X-rays and/or carbon-ion beams. GSH-Px processes endogenous H2O2 generated through mitochondrial respiration, but does not have the capacity to degrade H2O2 produced by irradiation.
RESUMEN
Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, TLR2 deficiency unexpectedly exacerbated psoriasiform skin inflammation. Importantly, messenger RNA (mRNA) levels of Foxp-3 and IL-10 in the lesional skin were significantly decreased in TLR2 KO mice compared with wild-type mice. Furthermore, flow cytometric analysis of the lymph nodes revealed that the frequency of regulatory T cells (Tregs) among CD4-positive cells was decreased. Notably, stimulation with Pam3CSK4 (TLR2/1 ligand) or Pam2CSK4 (TLR2/6 ligand) increased IL-10 production from Tregs and DCs and the proliferation of Tregs. Finally, adoptive transfer of Tregs from wild-type mice reduced imiquimod-induced skin inflammation in TLR2 KO mice. Taken together, our results suggest that TLR2 signaling directly enhances Treg proliferation and IL-10 production by Tregs and DCs, suppressing imiquimod-induced psoriasis-like skin inflammation. Enhancement of TLR2 signaling may be a new therapeutic strategy for psoriasis.
Asunto(s)
Imiquimod/efectos adversos , Interleucina-10 , Psoriasis , Piel , Linfocitos T Reguladores , Receptor Toll-Like 2/deficiencia , Animales , Imiquimod/farmacología , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-10/genética , Interleucina-10/inmunología , Ratones , Ratones Noqueados , Psoriasis/inducido químicamente , Psoriasis/genética , Psoriasis/inmunología , Psoriasis/patología , Piel/inmunología , Piel/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Receptor Toll-Like 2/inmunologíaRESUMEN
Cryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most needy populations of malnourished children and HIV-infected persons. We describe here the discovery and early optimization of a class of imidazopyridine-containing compounds with potential for treating Cryptosporidium infections. The compounds target the Cryptosporidium methionyl-tRNA synthetase (MetRS), an enzyme that is essential for protein synthesis. The most potent compounds inhibited the enzyme with Ki values in the low picomolar range. Cryptosporidium cells in culture were potently inhibited with 50% effective concentrations as low as 7 nM and >1,000-fold selectivity over mammalian cells. A parasite persistence assay indicates that the compounds act by a parasiticidal mechanism. Several compounds were demonstrated to control infection in two murine models of cryptosporidiosis without evidence of toxicity. Pharmacological and physicochemical characteristics of compounds were investigated to determine properties that were associated with higher efficacy. The results indicate that MetRS inhibitors are excellent candidates for development for anticryptosporidiosis therapy.
Asunto(s)
Antiprotozoarios/farmacología , Criptosporidiosis/tratamiento farmacológico , Cryptosporidium parvum/efectos de los fármacos , Imidazoles/farmacología , Metionina-ARNt Ligasa/antagonistas & inhibidores , Piridinas/farmacología , Animales , Cryptosporidium parvum/genética , Ciclooxigenasa 1/efectos de los fármacos , Modelos Animales de Enfermedad , Descubrimiento de Drogas/métodos , Femenino , Células Hep G2 , Humanos , Imidazoles/química , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piridinas/químicaAsunto(s)
Interleucinas , Pénfigo , Pénfigo/sangre , Pénfigo/inmunología , Humanos , Interleucinas/sangre , Femenino , Masculino , Persona de Mediana Edad , Adulto , Estudios de Casos y Controles , AncianoRESUMEN
CXCL17 is expressed in a variety of cancers and promotes tumor progression by recruiting myeloid-derived suppressor cells (MDSCs). MDSCs suppress tumor immunity by attracting regulatory T cells (Tregs) into tumor sites through CCL5. In this study, we examined the role of CXCL17 in skin disorders. CXCL17 mRNA levels in psoriasis skin, but not in lesional skin of atopic dermatitis or cutaneous T cell lymphoma, were significantly higher than those in normal skin. CXCL17 was mainly expressed in the epidermis, and IFN-γ dose-dependently increased CXCL17 expression by human keratinocytes in vitro. As CXCL17 mRNA expression was increased by treatment with imiquimod (IMQ), we examined the effects of CXCL17 in IMQ-induced psoriasis-like skin inflammation. Injection of recombinant CXCL17 into the ear before and during IMQ application decreased ear thickness, inflammatory cytokine expression, and the number of infiltrating cells compared with PBS injection. Flow cytometric analysis and immunofluorescent staining revealed that the numbers of MDSCs, which are CD11b+Gr-1+, and that of Tregs, which are CD4+CD25+, were higher in the ear of the CXCL17-injected mice than in PBS-injected mice. MDSCs, but not Tregs, showed chemotaxis to CXCL17 in vitro. When mice were injected with anti-CCL5 Ab or anti-CCL4 Ab simultaneously with recombinant CXCL17, ear thickness and cytokine expression increased to a similar level of mice treated with PBS and control IgG, suggesting that these chemokines were important for anti-inflammatory effects. Taken together, CXCL17 attenuates IMQ-induced psoriasis-like skin inflammation by recruiting MDSCs and Tregs, which may be important for regulating excessive inflammation in psoriasis skin.
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Aminoquinolinas/farmacología , Quimiocinas CXC/inmunología , Quimiocinas/inmunología , Células Supresoras de Origen Mieloide/fisiología , Piel/efectos de los fármacos , Piel/inmunología , Linfocitos T Reguladores/inmunología , Animales , Quimiocina CCL4/inmunología , Quimiocina CCL5/inmunología , Quimiocinas/genética , Quimiotaxis , Citocinas/genética , Citocinas/inmunología , Dermatitis/tratamiento farmacológico , Dermatitis/inmunología , Epidermis/efectos de los fármacos , Epidermis/inmunología , Humanos , Imiquimod , Queratinocitos/efectos de los fármacos , Queratinocitos/inmunología , Ratones , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Piel/patología , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
This study reports a non-invasive magnetic resonance imaging (MRI) of kidney dysfunction in mice, based on the induction of redox-imbalance and oxidative stress in the renal tissues, using mito-TEMPO as redox-sensitive contrast probe. Kidney dysfunction was triggered by hypercholesterolemia. The mice were divided in three groups: (i) on normal diet (ND); (ii) on cholesterol diet (CD); (iii) on cholesterol plus cholestyramine diet (CC). After 15 weeks feeding, the mice were subjected to the following analyses: plasma cholesterol levels; serum test for renal functionality; nitroxide-enhanced MRI of tissue redox-status in vivo; histochemical staining of tissue section to visualize renal damage; evaluation of total antioxidant capacity and oxidative stress on isolated tissue specimens. MRI signal of mito-TEMPO in the kidney was characterized by: high intensity and long life-time in CD mice, indicating a high oxidative capacity of renal tissues; poor intensity and short life-time in ND mice, indicating a high reducing capacity; moderate intensity and relatively short life-time in CC mice, indicating a protective effect of lipid-lowering drug. The data were confirmed on isolated tissue specimens, using conventional tests. They suggest that hypercholesterolemia induces redox-imbalance in kidney and this process could be visualized using MRI and mito-TEMPO as a redox-sensitive contrast.
Asunto(s)
Medios de Contraste , Riñón/diagnóstico por imagen , Riñón/fisiopatología , Imagen por Resonancia Magnética/métodos , Compuestos Organofosforados , Estrés Oxidativo , Piperidinas , Animales , Ratones , Oxidación-ReducciónRESUMEN
The enhanced permeability and retention (EPR) effect is variable depending on nanoparticle properties and tumor/vessel conditions. Thus, intratumoral evaluations of the vasculature and nanoparticle distribution are important for predicting the therapeutic efficacy and the intractability of tumors. We aimed to develop a tumor vasculature evaluation method and high-resolution nanoparticle delivery imaging using magnetic resonance (MR) micro-imaging technology with a gadolinium (Gd)-dendron assembled liposomal contrast agent. Using the Gd-liposome and a cryogenic receiving coil, we achieved 50-µm isotropic MR angiography with clear visualization of tumor micro-vessel structure. The Gd-liposome-enhanced MR micro-imaging revealed differences in the vascular structures between Colon26- and SU-DHL6-grafted mice models. The vessel volumes and diameters measured for both tumors were significantly correlated with histological observations. The MR micro-imaging methods facilitate the evaluation of intratumoral vascularization patterns, the quantitative assessment of vascular-properties that alter tumor malignancy, particle retentivity, and the effects of treatment.
Asunto(s)
Dendrímeros/química , Gadolinio/química , Liposomas/química , Imagen por Resonancia Magnética/métodos , Nanopartículas/química , Animales , Medios de Contraste/química , Angiografía por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
Antibiotic-resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to address this challenge. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis, and the type found in Gram-positive bacteria is substantially different from its counterpart found in the mammalian cytoplasm. Both previously published and new selective inhibitors were shown to be highly active against Gram-positive bacteria with MICs of ≤1.3 µg/ml against Staphylococcus, Enterococcus, and Streptococcus strains. Incorporation of radioactive precursors demonstrated that the mechanism of activity was due to the inhibition of protein synthesis. Little activity against Gram-negative bacteria was observed, consistent with the fact that Gram-negative bacterial species contain a different type of MetRS enzyme. The ratio of the MIC to the minimum bactericidal concentration (MBC) was consistent with a bacteriostatic mechanism. The level of protein binding of the compounds was high (>95%), and this translated to a substantial increase in MICs when the compounds were tested in the presence of serum. Despite this, the compounds were very active when they were tested in a Staphylococcus aureus murine thigh infection model. Compounds 1717 and 2144, given by oral gavage, resulted in 3- to 4-log decreases in the bacterial load compared to that in vehicle-treated mice, which was comparable to the results observed with the comparator drugs, vancomycin and linezolid. In summary, the research describes MetRS inhibitors with oral bioavailability that represent a class of compounds acting by a novel mechanism with excellent potential for clinical development.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Metionina-ARNt Ligasa/antagonistas & inhibidores , Animales , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Proteínas Sanguíneas/metabolismo , Farmacorresistencia Bacteriana/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Escherichia coli/efectos de los fármacos , Femenino , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Inactivación Metabólica , Ratones , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos , Staphylococcus aureus/efectos de los fármacosRESUMEN
Potent inhibitors of Trypanosoma brucei methionyl-tRNA synthetase were previously designed using a structure-guided approach. Compounds 1 and 2 were the most active compounds in the cyclic and linear linker series, respectively. To further improve cellular potency, SAR investigation of a binding fragment targeting the "enlarged methionine pocket" (EMP) was performed. The optimization led to the identification of a 6,8-dichloro-tetrahydroquinoline ring as a favorable fragment to bind the EMP. Replacement of 3,5-dichloro-benzyl group (the EMP binding fragment) of inhibitor 2 using this tetrahydroquinoline fragment resulted in compound 13, that exhibited an EC50 of 4nM.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Metionina-ARNt Ligasa/antagonistas & inhibidores , Metionina/farmacología , Trypanosoma brucei brucei/enzimología , Animales , Sitios de Unión/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Células Hep G2 , Humanos , Metionina/administración & dosificación , Metionina/química , Metionina-ARNt Ligasa/metabolismo , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
To assess the role of inter-cellular adhesion molecule (ICAM)-1 and L-selectin in psoriasis pathogenic process, we examined the psoriasiform skin inflammation triggered by imiquimod, a toll-like receptor 7/8 agonist, in mice lacking ICAM-1 (ICAM-1(-/-)), L-selectin (L-selectin(-/-)), or both (L-selectin/ICAM-1(-/-)). Disease severity was significantly reduced in ICAM-1(-/-) and L-selectin(-/-) mice compared with wild type mice, while it was exacerbated in L-selectin/ICAM-1(-/-) mice. Cutaneous interleukin (IL)-17A, IL-23, and tumor necrosis factor (TNF)-α expression was increased in L-selectin/ICAM-1(-/-) mice compared with wild type mice. Furthermore, only L-selectin/ICAM-1(-/-) mice was refractory to anti-TNF-α antibody treatment. The skin lesion from L-selectin/ICAM-1(-/-) mice showed augmented E-selectin expression compared with ICAM-1(-/-) and L-selectin(-/-) mice, and augmented E-selectin ligand-1 expression compared with wild type mice. The current study demonstrates that although ICAM-1 and L-selectin regulate psoriasiform inflammation, deleting both L-selectin and ICAM-1 simultaneously would rather induce refractory skin inflammation, due to compensatory up-regulation of other adhesion molecules.
Asunto(s)
Aminoquinolinas , Células Presentadoras de Antígenos/inmunología , Molécula 1 de Adhesión Intercelular/genética , Selectina L/genética , Psoriasis/inducido químicamente , Psoriasis/fisiopatología , Piel/fisiopatología , Animales , Movimiento Celular , Imiquimod , Inflamación/inducido químicamente , Inflamación/inmunología , Molécula 1 de Adhesión Intercelular/inmunología , Interleucina-17/metabolismo , Selectina L/inmunología , Ratones , Ratones Noqueados , Psoriasis/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Índice de Severidad de la EnfermedadRESUMEN
The methionyl-tRNA synthetase (MetRS) is a novel drug target for the protozoan pathogen Giardia intestinalis. This protist contains a single MetRS that is distinct from the human cytoplasmic MetRS. A panel of MetRS inhibitors was tested against recombinant Giardia MetRS, Giardia trophozoites, and mammalian cell lines. The best compounds inhibited trophozoite growth at 500 nM (metronidazole did so at â¼5,000 nM) and had low cytotoxicity against mammalian cells, indicating excellent potential for further development as anti-Giardia drugs.
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Antiprotozoarios/farmacología , Giardia lamblia/efectos de los fármacos , Metionina-ARNt Ligasa/antagonistas & inhibidores , Trofozoítos/efectos de los fármacos , Giardia lamblia/enzimología , Metronidazol/farmacología , Trofozoítos/enzimologíaRESUMEN
Psoriasis, a chronic inflammatory dermatosis, is frequently associated with metabolic disorders, suggesting that adipokines are involved in its pathogenesis. We recently reported that the adipokine visfatin activates NF-κB and STAT3 in keratinocytes. Antimicrobial peptide expression is enhanced in psoriatic lesions and may promote disease development. Here, we investigated the effects of visfatin on antimicrobial peptide expression. In vitro, visfatin enhanced basal and tumor necrosis factor-α (TNF-α)-induced mRNA expression and secretion of cathelicidin antimicrobial peptide (CAMP), and enhanced TNF-α-induced human ß-defensin-2 (hBD-2), hBD-3, and S100A7 mRNA expression and secretion in human keratinocytes. siRNAs targeting CCAAT/enhancer-binding protein-α (C/EBPα) suppressed visfatin-induced and visfatin plus TNF-α-induced CAMP production. siRNAs targeting NF-κB p65 and STAT3 suppressed visfatin plus TNF-α-induced hBD-2 and S100A7 production. siRNAs targeting c-Jun and STAT3 suppressed visfatin plus TNF-α-induced hBD-3 production. Visfatin and/or TNF-α enhanced C/EBP transcriptional activity and C/EBPα phosphorylation, which were suppressed by p38 mitogen-activated protein kinase (MAPK) inhibition. Visfatin and/or TNF-α induced p38 MAPK phosphorylation. Visfatin increased mRNA and protein expression of CAMP, hBD-2, hBD-3, and S100A7 orthologs in murine imiquimod-treated skin, mimicking psoriasis. In conclusion, visfatin enhances CAMP, hBD-2, hBD-3, and S100A7 production in human keratinocytes and their orthologs in murine imiquimod-treated psoriatic skin. Visfatin may potentiate the development of psoriasis via antimicrobial peptides.
Asunto(s)
Catelicidinas/biosíntesis , Queratinocitos/metabolismo , Nicotinamida Fosforribosiltransferasa/farmacología , Psoriasis/patología , Proteínas S100/metabolismo , Piel/metabolismo , beta-Defensinas/metabolismo , Aminoquinolinas , Animales , Péptidos Catiónicos Antimicrobianos , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Humanos , Imiquimod , Ratones , Ratones Endogámicos BALB C , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Receptor de Insulina/metabolismo , Proteína A7 de Unión a Calcio de la Familia S100 , Factor de Transcripción STAT3/metabolismo , Piel/patología , Receptores Toll-Like/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Propionibacterium acnes has been implicated as one of the suggested causative antigens for sarcoidosis, a systemic granulomatous disease. By injecting heat-killed P. acnes into the dorsal skin of C57BL/6J mice on days 1, 3, 5, and 14, sarcoid-like granulomatosis was induced in skin and lungs of these mice on day 28. To clarify the role of cell adhesion molecules in cutaneous sarcoidosis, we induced sarcoid-like granulomatosis in mice deficient of intercellular adhesion molecule (ICAM)-1, L-selectin, P-selectin, or E-selectin via repeated P. acnes injection. Histopathologic analysis revealed that granuloma formation was aggravated in the skin and lungs of ICAM-1-deficient mice compared with wild-type mice. Within skin granulomas of ICAM-1-deficient mice, P. acnes immunization up-regulated mRNA expression of tumor necrosis factor-α, although it failed to induce IL-10 mRNA expression in contrast to wild-type mice. Infiltration of regulatory T cells into skin granuloma was similar between wild-type mice and ICAM-1-deficient mice. P. acnes immunization induced IL-10 production by CD4(+)CD25(+)Foxp3(+) regulatory T cells in lymph nodes of wild-type mice in vivo, which was absent in regulatory T cells of ICAM-1-deficient mice. Our results indicate that ICAM-1 is imperative for inducing regulatory T cells to produce IL-10 in vivo, which would prevent granuloma formation.
Asunto(s)
Granuloma del Sistema Respiratorio , Molécula 1 de Adhesión Intercelular , Interleucina-10 , Propionibacterium acnes/inmunología , Enfermedades Cutáneas Bacterianas , Linfocitos T Reguladores , Animales , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Granuloma del Sistema Respiratorio/genética , Granuloma del Sistema Respiratorio/inmunología , Granuloma del Sistema Respiratorio/metabolismo , Granuloma del Sistema Respiratorio/patología , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/inmunología , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-10/biosíntesis , Interleucina-10/genética , Interleucina-10/inmunología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Noqueados , ARN Mensajero/biosíntesis , ARN Mensajero/inmunología , Piel/inmunología , Piel/metabolismo , Piel/patología , Enfermedades Cutáneas Bacterianas/genética , Enfermedades Cutáneas Bacterianas/inmunología , Enfermedades Cutáneas Bacterianas/metabolismo , Enfermedades Cutáneas Bacterianas/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patologíaRESUMEN
Diabetic patients are at high risk of developing delayed cutaneous wound healing. Adiponectin plays a pivotal role in the pathogenesis of diabetes and is considered to be involved in various pathological conditions associated with diabetes; however, its role in wound repair is unknown. In this study, we elucidated the involvement of adiponectin in cutaneous wound healing in vitro and in vivo. Normal human keratinocytes expressed adiponectin receptors, and adiponectin enhanced proliferation and migration of keratinocytes in vitro. This proliferative and migratory effect of adiponectin was mediated via AdipoR1/AdipoR2 and the ERK signaling pathway. Consistent with in vitro results, wound closure was significantly delayed in adiponectin-deficient mice compared with wild-type mice, and more importantly, keratinocyte proliferation and migration during wound repair were also impaired in adiponectin-deficient mice. Furthermore, both systemic and topical administration of adiponectin ameliorated impaired wound healing in adiponectin-deficient and diabetic db/db mice, respectively. Collectively, these results indicate that adiponectin is a potent mediator in the regulation of cutaneous wound healing. We propose that upregulation of systemic and/or local adiponectin levels is a potential and very promising therapeutic approach for dealing with diabetic wounds.
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Adiponectina/fisiología , Movimiento Celular/inmunología , Proliferación Celular , Queratinocitos/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Piel/inmunología , Cicatrización de Heridas/inmunología , Adiponectina/biosíntesis , Adiponectina/deficiencia , Animales , Movimiento Celular/genética , Células Cultivadas , Diabetes Mellitus/enzimología , Diabetes Mellitus/inmunología , Diabetes Mellitus/patología , Humanos , Queratinocitos/enzimología , Queratinocitos/patología , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Noqueados , Ratones Obesos , Receptores de Adiponectina/biosíntesis , Receptores de Adiponectina/fisiología , Piel/enzimología , Piel/patología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Cicatrización de Heridas/genéticaRESUMEN
Atopic dermatitis (AD) is often characterized by chronic skin changes of dermal fibrosis, typically regulated by inflammatory and angiogenic factors. However, the significance of angiogenesis inhibitory factors in the development of AD is poorly understood. The present study investigated the potential role of an angiogenesis inhibitory factor, vasohibin-1 (VASH1), in AD by evaluating serum and skin VASH1 levels and their correlation with clinical features. The results showed that VASH1 expression levels in both the serum and skin of patients with AD were significantly elevated compared to healthy controls. Immunohistochemical staining of AD skin showed increased VASH1 expression in dermal vascular endothelial cells. Notably, there was a significant correlation between serum VASH1 levels and disease duration as well as VASH1 and vascular endothelial growth factor A expression levels in the skin tissue of patients with AD. These results may suggest a pathogenesis of increased angiogenesis and associated elevated inhibitory processes accompanying inflammation in the chronic phase of AD.
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Psoriasis is a chronic inflammatory disease that sometimes necessitates therapeutic intervention with biologics. Autoantibody production during treatment with tumor necrosis factor (TNF) inhibitors is a recognized phenomenon, however, the production of autoantibodies associated with antiphospholipid syndrome (APS) has not been comprehensively evaluated in patients with psoriasis. This study was conducted to assess the prevalence of APS-associated autoantibodies in patients with psoriasis treated with different biologics and to investigate the potential associations between autoantibody production and clinical or serological parameters. Patients with psoriasis undergoing biologics treatments were enrolled in this study, and were categorized based on the type of biologics administered, TNF, interleukin (IL)-17, or IL-23 inhibitors. Clinical and serological data were collected and analyzed in conjunction with data on APS autoantibodies. TNF inhibitors were associated with a higher frequency of APS autoantibodies compared to IL-17 and IL-23 inhibitors. Notably, the presence of APS autoantibodies correlated with concurrent arthritis and higher disease severity at treatment initiation in patients treated with TNF inhibitors. Elevated Psoriasis Area and Severity Index scores and anti-nuclear antibody titers higher than × 320 were predictors of APS autoantibody production. Despite the higher autoantibody rates, clinical symptoms of APS were absent in these patients. This study provides the first comprehensive evidence of an increased frequency of APS autoantibodies associated with TNF inhibitor treatment in patients with psoriasis. The observed association between APS autoantibody positivity and TNF inhibitor treatment or clinical parameters suggests a potential immunomodulatory interplay between autoimmunity and inflammation in the pathogenesis of psoriasis.
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Anticuerpos Antifosfolípidos , Síndrome Antifosfolípido , Productos Biológicos , Psoriasis , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Femenino , Masculino , Persona de Mediana Edad , Productos Biológicos/uso terapéutico , Productos Biológicos/efectos adversos , Adulto , Anticuerpos Antifosfolípidos/sangre , Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/inmunología , Síndrome Antifosfolípido/tratamiento farmacológico , Interleucina-17/antagonistas & inhibidores , Interleucina-17/inmunología , Interleucina-23/inmunología , Interleucina-23/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología , Prevalencia , Anciano , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Índice de Severidad de la Enfermedad , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/efectos adversosRESUMEN
Duplication of chromosome 15q11-13 has been reported to be one of the most frequent cytogenetic copy number variations in autism spectrum disorder (ASD), and a mouse model of paternal 15q11-13 duplication was generated, termed 15q dup mice. While previous studies have replicated some of the behavioral and brain structural phenotypes of ASD separately, the relationship between brain structure and behavior has rarely been examined. In this study, we performed behavioral experiments related to anxiety and social behaviors and magnetic resonance imaging (MRI) using the same set of 15q dup and wild-type mice. 15q dup mice showed increased anxiety and a tendency toward alterations in social behaviors, as reported previously, as well as variability in terms of sociability. MRI analysis revealed that a lower sociability index was correlated with a smaller gray matter volume in the right medial entorhinal cortex. These results may help to understand how variability in behavioral phenotypes of ASD arises even in individuals with the same genetic background and to determine the individual differences in neurodevelopmental trajectory correlated with specific brain structures that underlie these phenotypes.
RESUMEN
Brentuximab vedotin (BV), a conjugate of anti-CD30 antibody and monomethyl auristatin E, has emerged as a promising treatment option for refractory CD30+ mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL). BV has been shown to be safe and effective in treating Hodgkin's lymphoma and peripheral T-cell lymphoma. This multicenter, prospective, single-arm phase I/II study evaluated the efficacy of BV in Japanese patients with CD30+ cutaneous lymphomas, namely CD30+ cutaneous T-cell lymphoma. Participants were divided into two groups: those with CD30+ MF or pcALCL (cohort 1, n = 13) and those with CD30+ lymphoproliferative disorders other than those in cohort 1 (cohort 2, n = 3). The studied population included the full analysis set (FAS), modified FAS (mFAS), and safety analysis set (SAF). These sets were identified in cohorts 1 and 1 + 2 and labeled FAS1 and FAS2, mFAS1 and mFAS2, and SAF1 and SAF2, respectively. Each treatment cycle lasted 3 weeks, and BV was continued for up to 16 cycles after the third cycle based on treatment response. The primary endpoint was the 4-month objective response rate (ORR4) determined by the Independent Review Forum (IRF). ORR4 was 69.2% for FAS1 and 62.5% for FAS2 (P < 0.0001). Secondary endpoints of ORR, assessed using the global response score (53.8% in FAS1) and modified severity-weighted assessment tool (62.5% in FAS1), using the IRF, provided results comparable to the primary findings. The incidence of ≥grade 3 adverse events (≥15%) in SAF1 was peripheral neuropathy in three patients (23%) and fever and eosinophilia in two patients (15%). In conclusion, BV showed favorable efficacy, tolerability, and safety profile in Japanese patients with relapsed or refractory CD30+ primary cutaneous T-cell lymphoma. The trial was registered with University Hospital Medical Information Network Clinical Trials Registry, Japan (protocol ID: UMIN000034205).
Asunto(s)
Brentuximab Vedotina , Antígeno Ki-1 , Neoplasias Cutáneas , Humanos , Brentuximab Vedotina/administración & dosificación , Brentuximab Vedotina/uso terapéutico , Masculino , Persona de Mediana Edad , Antígeno Ki-1/inmunología , Antígeno Ki-1/análisis , Femenino , Anciano , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Estudios Prospectivos , Japón , Adulto , Anciano de 80 o más Años , Micosis Fungoide/tratamiento farmacológico , Micosis Fungoide/patología , Micosis Fungoide/inmunología , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/uso terapéutico , Inmunoconjugados/efectos adversos , Resultado del Tratamiento , Pueblos del Este de AsiaRESUMEN
New classes of antiparasitic drugs active against Trypanosoma brucei are needed to combat human African trypanosomiasis. Inhibitors of methionyl-tRNA synthetase (MetRS) have excellent potential to be developed for this purpose (S. Shibata, J. R. Gillespie, A. M. Kelley, A. J. Napuli, Z. Zhang, K. V. Kovzun, R. M. Pefley, J. Lam, F. H. Zucker, W. C. Van Voorhis, E. A. Merritt, W. G. Hol, C. L. Verlinde, E. Fan, and F. S. Buckner, Antimicrob. Agents Chemother. 55:1982-1989, 2011). In order to assess the potential for resistance to develop against this new class of inhibitors, T. brucei cultures were grown in the presence of MetRS inhibitors or comparison drugs. Resistance up to â¼50 times the baseline 50% inhibitory concentration (IC50) was induced against a MetRS inhibitor after â¼120 days. A similar level of resistance to the clinical drug eflornithine was induced after â¼50 days and for pentamidine after â¼80 days. Thus, resistance was induced more slowly against MetRS inhibitors than against clinically used drugs. The parasites resistant to the MetRS inhibitor were shown to overexpress MetRS mRNA by a factor of 35 over the parental strain. Southern analysis indicated that the MetRS gene was amplified in the genome by nearly 8-fold. When injected into mice, the MetRS inhibitor-resistant parasites caused a reduced level of infection, indicating that the changes associated with resistance attenuated their virulence. This finding and the fact that resistance to MetRS inhibitors developed relatively slowly are encouraging for further development of this class of compounds. Published studies on other antitrypanosomal drugs have primarily shown that alterations in membrane transporters were the mechanisms responsible for resistance. This is the first published report of induced drug resistance in the African trypanosome due to overexpression of the target enzyme.