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Psoriasis, an immune-mediated inflammatory skin disorder characterized by a chronically relapsing-remitting course, continues to be primarily managed through topical therapy. While oral administration of tyrosine kinase 2 inhibitors (TYK2i) stands as an effective approach for psoriasis treatment, the potential efficacy of topical application of TYK2i remains unexplored. Herein, the carbomer/alginic acid hydrogel is embedded with borneol (BO) as a new topical carrier of TYK2i for achieving enhanced transdermal permeation and anti-psoriasis efficacy. The hydrogel system, i.e., TYK2i-BO-gel, exhibits significantly improved preventative and therapeutic effects in mice models of psoriasiform dermatitis, as evidenced by phenotypical images, psoriasis severity score index (PSI), histology, immunohistochemical staining, and PCR analysis. Remarkably, TYK2i-BO-gel outperforms conventional topical corticosteroid therapy by significantly preventing psoriatic lesion recurrence as measured by a nearly 50 % reduction in ear thickness changes (p < 0.0001), PSI (p < 0.0001) and epidermal thickness (p < 0.05). Moreover, a strengthened anti-inflammatory effect caused by TYK2i-BO-gel is seen in a human skin explant model, implying its potential application for human patients. With the addition of BO, the TYK2i-BO-gel not only increases skin permeability but also inhibits the expression of antimicrobial peptides in keratinocytes and facilitates the anti-Th17 response of TYK2i with suppressed activation of STAT3. Therefore, this work represents the accessibility and effectiveness of TYK2i-BO-hydrogel as a new topical formulation for anti-psoriasis management and shows great potential for clinical application.
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Acute guttate psoriasis (AGP) is considered an uncommon variant of psoriasis (PsO), characterized as a widespread eruption of erythematous, psoriasiform papules, and plaques on the trunk, extremities, and scalp. Predisposing factors include a family history of PsO, variation in the main PsO susceptibility gene HLA-Cw*0602, and previous infection with viruses or acute ß-hemolytic Streptococcus A program focused on controversies and recent advances in understanding AGP was presented at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2022 annual meeting. Topics included an overview of clinical presentation and natural history, predisposing genetic and environmental factors, and the recent molecular profiling that supports classification of AGP as a form of PsO. Early molecular profiling studies using proteomic signatures have suggested similarities between AGP and contact dermatitis, but recent studies using gene expression profiling and gene set enrichment scores demonstrate that AGP is more similar to chronic PsO. The expression of regulatory immune pathways seen with AGP suggests potential for early and sustained remission if the disease is suppressed by targeted treatments. Published case reports documenting clinical improvement of AGP with biologics that antagonize interleukin (IL)-12/23, IL-23, and IL-17 support the role of the IL-23/IL-17 axis in AGP, similar to that in PsO. Data supporting the use of antibiotics and other therapeutic agents for AGP are lacking, and randomized controlled trials are needed. Trial design for AGP is challenged by the low incidence, tendency for spontaneous remission, lack of validated end points, and the need for long-term follow up.
Asunto(s)
Artritis Psoriásica , Exantema , Psoriasis , Humanos , Interleucina-17 , Proteómica , Psoriasis/tratamiento farmacológico , Antibacterianos/uso terapéutico , Interleucina-23 , Artritis Psoriásica/tratamiento farmacológicoRESUMEN
There is growing evidence that supports a role of gut dysbiosis in the pathogenesis of psoriasis (Pso). Thus, probiotic supplementation and fecal microbiota transplantation may serve as promising preventive and therapeutic strategies for patients with Pso. One of the basic mechanisms through which the gut microbiota interacts with the host is through bacteria-derived metabolites, usually intermediate or end products produced by microbial metabolism. In this study, we provide an up-to-date review of the most recent literature on microbial-derived metabolites and highlight their roles in the immune system, with a special focus on Pso and one of its most common comorbidities, psoriatic arthritis.
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Artritis Psoriásica , Microbioma Gastrointestinal , Psoriasis , Humanos , Psoriasis/terapia , Psoriasis/microbiología , Trasplante de Microbiota Fecal , Disbiosis/microbiologíaRESUMEN
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphomas (CTCLs). Most cases of MF display an indolent course during its early stage. However, in some patients, it can progress to the tumor stage with potential systematic involvement and a poor prognosis. SS is defined as an erythrodermic CTCL with leukemic involvements. The pathogenesis of MF and SS is still not fully understood, but recent data have found that the development of MF and SS is related to genetic alterations and possibly to environmental influences. In CTCL, many components interacting with tumor cells, such as tumor-associated macrophages, fibroblasts, dendritic cells, mast cells, and myeloid-derived suppressor cells, as well as with chemokines, cytokines and other key players, establish the tumor microenvironment (TME). In turn, the TME regulates tumor cell migration and proliferation directly and indirectly and may play a critical role in the progression of MF and SS. The TME of MF and SS appear to show features of a Th2 phenotype, thus dampening tumor-related immune responses. Recently, several studies have been published on the immunological characteristics of MF and SS, but a full understanding of the CTCL-related TME remains to be determined. This review focuses on the role of the TME in MF and SS, aiming to further demonstrate the pathogenesis of the disease and to provide new ideas for potential treatments targeted at the microenvironment components of the tumor.
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Psoriasis is a common inflammatory skin disease resulting from an interplay of keratinocytes and immune cells. Previous studies have identified an essential role of autophagy in the maintenance of epidermal homeostasis including proliferation and differentiation. However, much less is known about the role of autophagy-related proteins in the cutaneous immune response. Herein, we showed that ULK1, the key autophagic initiator, and its phosphorylation at Ser556 were distinctively decreased in the epidermis from lesional skin of psoriasis patients. Topical application of SBI0206965, a selective ULK1 inhibitor, significantly attenuated epidermal hyperplasia, infiltration of neutrophils, and transcripts of the psoriasis-related markers in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD). In vitro, ULK1 impairment by siRNA and SBI0206965 arrested cell proliferation and promoted apoptosis of keratinocytes but had a marginal effect on the expression of proinflammatory mediators under steady status. Surprisingly, SBI0206965 blocked the production of chemokines and cytokines in keratinocytes stimulated by neutrophils. Of interest, the pro-apoptotic and anti-inflammatory effects of ULK1 inhibition cannot be fully replicated by autophagic inhibitors. Our findings suggest a self-regulatory process by downregulating ULK1 to maintain the immune homeostasis of psoriatic skin via regulating keratinocytes and their crosstalk with neutrophils, possibly through both autophagy-dependent and independent mechanisms. ULK1 might be a potential target for preventing or treating psoriasis.
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Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Psoriasis/etiología , Psoriasis/metabolismo , Animales , Autofagia/efectos de los fármacos , Biomarcadores , Comunicación Celular/inmunología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Humanos , Inmunohistoquímica , Queratinocitos/inmunología , Ratones , Terapia Molecular Dirigida , Infiltración Neutrófila , Neutrófilos/inmunología , Psoriasis/patología , Psoriasis/terapiaRESUMEN
A summary of the research conducted by the recipients of the 2019 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Research Awards is presented. Dr. Alla Ishchenko's project was "Role of Metabolomics in Diagnosis, Disease Severity, and Progression in Psoriasis and Psoriatic Arthritis: A 2-year Prospective Pilot Study" and Dr. Zhenrui Shi's project was "Preclinical Analysis of CCR6 and CCL20 in Mouse and Human Joints, Respectively, as Targets of Therapeutic Intervention in Psoriatic Arthritis."
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Artritis Psoriásica , Distinciones y Premios , Psoriasis , Reumatología , Animales , Ratones , Proyectos Piloto , Estudios ProspectivosRESUMEN
OBJECTIVE: To assess the involvement of the CCR6/CCL20 axis in psoriatic arthritis (PsA) and psoriasis (PsO) and to evaluate its potential as a therapeutic target. METHODS: First, we quantified CCL20 levels in peripheral blood and synovial fluid from PsA patients and examined the presence of CCR6+ cells in synovial and tendon tissue. Utilizing an interleukin-23 minicircle DNA (IL-23 MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression as well as the preventive and therapeutic effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL-1ß to assess the production of CCL20 by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated using a Transwell system. RESULTS: We observed an up-regulation of both CCR6 and CCL20 in the enthesis of IL-23 MC-treated mice, which was confirmed in human biopsy specimens. Specific targeting of the CCR6/CCL20 axis with a CCL20 locked dimer (CCL20LD) blocked entheseal inflammation, leading to profound reductions in clinical and proinflammatory markers in the joints and skin of IL-23 MC-treated mice. The stromal compartment in the tendon was the main source of CCL20 in this model and, accordingly, in vitro activated human tendon cells were able to produce this chemokine and to induce CCR6+ T cell migration, the latter of which could be blocked by CCL20LD. CONCLUSION: Our study highlights the pathogenic role of the CCR6/CCL20 axis in enthesitis and introduces the prospect of a novel therapeutic approach for treating patients with PsO and PsA.
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Artritis Psoriásica/metabolismo , Quimiocina CCL20/sangre , Inflamación/metabolismo , Líquido Sinovial/metabolismo , Animales , Artritis Psoriásica/sangre , Humanos , Inflamación/sangre , Interleucina-1beta/farmacología , Interleucina-23/farmacología , Ratones , Piel/metabolismo , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Membrana Sinovial/metabolismo , Tendones/efectos de los fármacos , Tendones/metabolismoRESUMEN
Previously, we found that rosmarinic acid (RA) exerted anti-inflammatory activities in a dextran sulfate sodium (DSS)-induced colitis model. Here, we investigated the anti-tumor effects of RA on colitis-associated colon cancer (CAC) and the underlying molecular mechanisms. We established an azoxymethane (AOM)/DSS-induced CAC murine model for in vivo studies and used a conditioned media (CM) culture system in vitro. H&E staining, immunohistochemistry, western blot assay, enzyme-linked immunosorbent assay, molecular docking, co-immunoprecipitation, and immunofluorescence assay were utilized to investigate how RA prevented colorectal cancer. In the AOM/DSS-induced CAC murine model, RA significantly reduced colitis severity, inflammation-related protein expression, tumor incidence, and colorectal adenoma development. It significantly modulated toll-like receptor-4 (TLR4)-mediated nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, thus attenuating the expression of anti-apoptotic factors, which mediate transcription factor-dependent tumor growth. In vitro, RA inhibited CM-induced TLR4 overexpression and competitively inhibited TLR4-myeloid differentiation factor 2 complex in an inflammatory microenvironment. Thus, RA suppressed NF-κB and STAT3 activation in colon cancer cells in an inflammatory microenvironment. Therefore, RA suppressed colitis-associated tumorigenesis in the AOM/DSS-induced CAC murine model and abrogated human colon cancer progression in an inflammatory microenvironment by propitiating TLR4-mediated NF-κB and STAT3 activation, pleiotropically.
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Cinamatos/farmacología , Neoplasias Asociadas a Colitis/etiología , Neoplasias Asociadas a Colitis/metabolismo , Depsidos/farmacología , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Biomarcadores , Línea Celular Tumoral , Cinamatos/química , Neoplasias Asociadas a Colitis/tratamiento farmacológico , Neoplasias Asociadas a Colitis/patología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/etiología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Depsidos/química , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , Masculino , Ratones , Modelos Moleculares , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Ácido RosmarínicoRESUMEN
A summary of the research conducted by the recipients of the 2019 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Research Awards is presented. Dr. Alla Ishchenko's project was "Role of Metabolomics in Diagnosis, Disease Severity, and Progression in Psoriasis and Psoriatic Arthritis: A 2-year Prospective Pilot Study" and Dr. Zhenrui Shi's project was "Preclinical Analysis of CCR6 and CCL20 in Mouse and Human Joints, Respectively, as Targets of Therapeutic Intervention in Psoriatic Arthritis."
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The therapy of advanced mycosis fungoides (MF) presents a therapeutic challenge, and the search for new therapeutic targets is ongoing. Poly(ADP-ribose) polymerase 1 was shown to be upregulated in patients with advanced MF and could be druggable by a new class of chemotherapeutic agents, PARP-1 inhibitors, which are already in clinical trials for other malignancies; however, the role of PARP-1 inhibitors in MF has never been established. We examined the efficacy of talazoparib in the murine model of cutaneous T-cell lymphoma. The cytotoxic effect of talazoparib on Moloney MuLV-induced T-cell lymphoma (MBL2) cells was a result of G2/M cell cycle arrest via the upregulation of p53. The in vivo experiments confirmed the clinical impact of talazoparib on MF tumors. When talazoparib was combined with the histone deacetylase (HDAC) inhibitor, romidepsin, the cytotoxic effect was synergized via downregulation of the DNA-repair genes Fanconianemia complementation group A (FANCA), Fanconi anemia complementation group D2 (FANCD2), and DNA topoisomerase II binding protein 1(TOPBP1)and stimulation of apoptosis via Blimp-1 (PRDM1)/Bax axis. Romidepsin increased the expression of IRF8 and Bcl-6, leading to upregulation of Blimp1and Bax; whereas talazoparib upregulated Blimp-1 and Bax via upregulation of interferon regulatory factor 4 (IRF4), leading to cleavage of caspases 6 and 7. Thus, a combination of talazoparib with romidepsin demonstrated the synergistic antilymphoma effect and warranted further investigation in a clinical trial.
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Linfoma Cutáneo de Células T , Lectina de Unión a Manosa , Animales , Apoptosis , Histona Desacetilasas/farmacología , Humanos , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/genética , Lectina de Unión a Manosa/farmacología , Ratones , Ftalazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacologíaRESUMEN
BACKGROUND: Bromodomain and extra-terminal (BET) proteins perform key roles in epigenetic control of gene expression that is involved in inflammatory conditions, including psoriasiform dermatitis (PsD). Predicting which (of many potential available BET inhibitors) will be effective in vivo is challenging. OBJECTIVE: We determine if a novel in vitro assay that includes two critical cell types involved in human psoriasis can predict the therapeutic potential of specific BET inhibitors in vivo. METHODS: An in vitro model consisting of U-937 and HaCaT cell co-culture was created to screen small molecule BET antagonists for inhibition of cutaneous inflammatory genes. Efficacious BET inhibitors were tested in a mouse imiquimod (IMQ)-induced PsD model. RESULTS: In the co-culture system, HaCaT cells exhibited a marked increase in the secretion of a characteristic set of proinflammatory and Th17-associated cytokines. Of the ten commercially-available small molecules targeting BET proteins assayed, most compounds exhibited inhibitory functions at 1 µM against inflammatory activation, but responded variably at lower concentrations. OTX015, a typical representative for most of the compounds, barely inhibited the inflammatory reactions at 0.1 µM. By contrast, ABBV075 was effective in concentrations as low as 0.01 µM. While oral administration OTX015 in IMQ-treated mice reduced disease severity, ABBV075 equally decreased the symptoms and molecular and cellular severity markers at one-tenth of the minimal dosing required for OTX015. CONCLUSION: In vitro screening system combined with an in vivo animal model, can serve as a convenient pre-clinical screening tool for the selection of BET inhibitors (and possibly other drugs) that may have clinical potential in psoriasis therapy.
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Acetanilidas/farmacología , Epigénesis Genética/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Psoriasis/tratamiento farmacológico , Piridonas/farmacología , Piel/efectos de los fármacos , Sulfonamidas/farmacología , Acetanilidas/uso terapéutico , Administración Oral , Animales , Línea Celular Tumoral , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Epigénesis Genética/inmunología , Femenino , Células HaCaT , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Imiquimod/administración & dosificación , Imiquimod/inmunología , Mediadores de Inflamación/metabolismo , Ratones , Monocitos , Psoriasis/inducido químicamente , Psoriasis/inmunología , Psoriasis/patología , Piridonas/uso terapéutico , Piel/inmunología , Piel/patología , Sulfonamidas/uso terapéuticoRESUMEN
Tumor-associated macrophages (TAMs) recruited from blood monocytes are key in establishing an immunosuppressive tumor microenvironment (TME) for the support of tumor growth. We hypothesize that blocking monocyte trafficking (through the inhibition of specific chemokine receptors) into skin can positively affect tumor development. Herein, the authors examined the effects of oral administration of a small molecule inhibitor for CCR2, CCR2i, which blocks CCR2-mediated chemotaxis of monocytes in a syngeneic mouse T-cell lymphoma in skin. Following CCR2i administration, the depletion of macrophages was achieved as early as 2 days after tumor initiation in ear TME. Quantitative real-time PCR detected an increase in the levels of immune stimulatory inflammatory cytokines, for example, IFN-γ and IL-12, in CCR2i- versus vehicle-treated mice. Within 2 weeks, the tumors from the control groups attained the maximum size, whereas CCR2i-treated mice exhibited much smaller tumor sizes and weights. Immunohistochemistry revealed that CCR2i-treated tumors possessed considerably more CD8+ T cells, which demonstrated their essential role in CCR2i-induced tumor inhibition. Finally, the combination of anti-programmed cell death protein 1 with CCR2i considerably increased the efficacy of tumor eradication related to the activation of IFN-γ-producing CD8 T cells. Our findings provide strong evidence that the CCR2i, particularly in combination with an immune checkpoint inhibitor, reduces tumor growth and is a potential future treatment option for cutaneous T-cell lymphomas.
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Linfoma Cutáneo de Células T/metabolismo , Macrófagos/metabolismo , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptores CCR2/antagonistas & inhibidores , Microambiente Tumoral , Administración Oral , Animales , Biomarcadores de Tumor/metabolismo , Linfocitos T CD8-positivos/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Inflamación , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismo , Neoplasias/metabolismo , Neutrófilos/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Receptores CCR2/metabolismoAsunto(s)
Receptores CCR6/metabolismo , Piel/lesiones , Linfocitos T/inmunología , Cicatrización de Heridas/inmunología , Traslado Adoptivo , Animales , Quimiocina CCL20/inmunología , Quimiocina CCL20/metabolismo , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores CCR6/genética , Receptores CCR6/inmunología , Piel/inmunología , Linfocitos T/metabolismo , Linfocitos T/trasplanteRESUMEN
A crucial question pertains to a role of IL-10 as a tumorigenic factor, or just a marker of advanced disease in cutaneous T-cell lymphoma (CTCL). Herein, we measured significantly elevated IL-10 mRNA in a cohort of skin samples of patients with CTCL. Increased IL-10 was also detected in the tumor microenvironment of an established inflammation-dependent murine model of using MBL2 T lymphoma cells. Conditioned media from MBL2 cells was able to stimulate IL-10 production in bone marrow-derived macrophages in an IL-4-dependent manner. Implanted MBL2 T-cell lymphomas in IL-10KO mice were 50% smaller, accompanied by decreased numbers of infiltrating macrophages and reduced efficiency of M2-polarization compared with wild-type mice. With anti-IL-10R mAb treatment, both wild-type tumor-bearing mice and IL-10KO mice exhibited a further growth inhibition. Our data indicate that targeting IL-10 signaling with neutralizing antibodies to IL-10 or its receptor may have a great potential for advanced CTCL therapy.
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Expresión Génica , Interleucina-10/genética , Linfoma Cutáneo de Células T/genética , Animales , Biopsia , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-10/metabolismo , Linfoma Cutáneo de Células T/metabolismo , Linfoma Cutáneo de Células T/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Estadificación de Neoplasias , Transducción de Señal , Carga Tumoral , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chemokine-chemokine receptor (CKR) interactions are traditionally described by a two-step/two-site mechanism that details the major contact points between chemokine ligands and CKRs leading to ligand recognition and receptor activation. Chemokine recognition site 1 (CRS1) encompasses interactions between the CKR N-terminus and the globular chemokine core. Chemokine recognition site 2 (CRS2) includes interactions between the unstructured chemokine N-terminus and the binding pocket of the receptor. The two-step/two-site paradigm has been an adequate framework to study the intricacies of chemokine:CKR interactions, but emerging studies highlight the limitations of this model. Here, we present studies of CRS2 interactions between the chemokine CCL20 and its cognate receptor CCR6 driven by the hypothesis that CCL20 interacts with CCR6 as described by the two-step/two-site model. CCL20 is a chemokine with an unusually short N-terminus of 5 residues (NH2 -ASNFD), compared to the average length of 10 residues for chemokine ligands. We have investigated how well CCL20 tolerates manipulation of the N-terminus by monitoring binding affinity of variants and their ability to activate the receptor. We show the CCL20 N-terminus tolerates truncation of up to 3 residues, extension by up to 5 additional residues, and point mutations at 4 of 5 positions with minimal loss of binding affinity and minimal impairment in ability to stimulate calcium mobilization, inositol triphosphate accumulation, chemotaxis, and ß-arrestin-2 recruitment. Mutation of the fifth residue, aspartate, to alanine or lysine has a dramatic impact on binding affinity for CCR6 and ligand potency. We postulate CCL20 does not activate CCR6 through the canonical two-step/two-site mechanism of CKR activation.
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Quimiocina CCL20/química , Quimiocina CCL20/metabolismo , Receptores CCR6/metabolismo , Secuencia de Aminoácidos , Análisis Mutacional de ADN , Humanos , Células Jurkat , Unión Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMEN
Herein, we report the synthesis of two novel ionic Ti complexes possessing three [N,O]-type bidentate ligands from the reaction of Fe metallascorpionate ligands possessing extended alcohol groups and TiCl4. The reaction of substituted hydroxyphenyl tetrazole and Fe(ClO4)3 in a molar ratio of 3:1 afforded iron scorpionate metalloligands possessing extended arms, which were characterized by IR spectroscopy and ESI-TOF-MS spectrometry. Their molecular structures were also confirmed as neutral Fe-centered scorpionate complexes by X-ray crystallography, in which the extended alcohol groups adopted a tripodal geometry. Moreover, two different crystals of iron scorpionate metalloligand grown from CH2Cl2 and CH3OH were studied, revealing that, in the latter crystal, the tripod arms are folded and aligned toward the C3-rotational axis of the molecule, whereas the tripod arms are unfolded and spread outward from the rotational axis in the former crystal. These metalloligands are solvatochromatic; a bathochromic shift was observed as the solvent polarity increased. From the reaction, the aforesaid Fe complexes were further reacted with TiCl4 in a molar ratio of 1:1 to produce ionic [TiL3]+[FeCl4]- (L = substituted hydroxyphenyl tetrazole) complexes from the transmetalation of Ti and Fe. The complexes were characterized by various analytical methods including UV/vis and IR spectroscopies, electrospray time-of-flight mass spectrometry (ESI-TOF-MS), and X-ray crystallography.
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Ulcerative colitis (UC), a type of inflammatory bowel disease (IBD), is a chronic inflammatory disorder of the colon. Although UC is generally treated with anti-inflammatory drugs or immunosuppressants, most of these treatments often prove to be inadequate. Rosmarinic acid (RA) is a phenolic ester included in various medicinal herbs such as Salvia miltiorrhiz and Perilla frutescens. Although RA has many biological and pharmacological activities, the anti-inflammatory effect of RA in colonic tissue remains unclear. In this study, we investigated the anti-inflammatory effects and underlying molecular mechanism of RA in mice with dextran sulphate sodium (DSS)-induced colitis. In the DSS-induced colitis model, RA significantly reduced the severity of colitis, as assessed by disease activity index (DAI) scores, colonic damage, and colon length. In addition, RA resulted in the reduction of the inflammatory-related cytokines, such as IL-6, IL-1ß, and IL-22, and protein levels of COX-2 and iNOS in mice with DSS-induced colitis. Furthermore, RA effectively and pleiotropically inhibited nuclear factor-kappa B and signal transducer and activator of transcription 3 activation, and subsequently reduced the activity of pro-survival genes that depend on these transcription factors. These results demonstrate that RA has an ameliorative effect on colonic inflammation and thus a potential therapeutic role in colitis.
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Cinamatos/uso terapéutico , Colon/patología , Depsidos/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Cinamatos/farmacología , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/enzimología , Colitis/patología , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Depsidos/farmacología , Sulfato de Dextran , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/genética , Inflamación/patología , Mediadores de Inflamación/metabolismo , Masculino , Ratones Endogámicos ICR , Óxido Nítrico Sintasa de Tipo II/metabolismo , Peroxidasa/metabolismo , Bazo/patología , Ácido RosmarínicoRESUMEN
The flavonoids mosloflavone, oroxylin A, and norwogonin, which were purified from Scutellaria baicalensis Georgi, significantly protected Vero cells against Coxsackievirus B3 (CVB3)-induced cell death. To investigate the in vivo antiviral activity of oroxylin A, we intraperitoneally inoculated CVB3 into 4-week-old BALB/c mice. Body weights and blood glucose levels of the mice were decreased after CVB3 infection, and these changes were attenuated by the administration of oroxylin A. Importantly, treatment of mice with oroxylin A reduced viral titers in the pancreas and decreased the serum levels of the inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α. Additionally, the administration of oroxylin A mitigated the histological pancreatic lesions and apoptotic cell death induced by CVB3 infection and increased the levels of phospho-eIF2α in infected pancreata. The results suggest that oroxylin A may represent a potent antiviral agent against CVB3 infection.