RESUMO
Pomegranate (Punica granatum L.) is a polyphenol-rich food and medicinal plant containing flavonols, anthocyanins, and tannins. Ellagitannins (ETs) are the most abundant polyphenols in pomegranate. A growing body of research shows that polyphenol-rich pomegranate extracts and their metabolites target multiple types of brain cell and support their redox balance, proliferation and survival, as well as cell signaling. Independent studies have demonstrated that the significant neuroprotective effects of ETs are mediated by their antioxidant and anti-inflammatory effects, their chelating properties, by their ability to activate various signaling pathways, as well as the ability to influence mitochondrial damage, thus regulating autophagy, apoptosis and neurotransmitter signaling. The multitude of in vitro and in vivo studies summarized in the present review suggest that pomegranate polyphenols act on both neuronal and glial cells directly, and also affect blood-brain barrier function, restoring redox balance in the blood and brain and increasing blood flow to the brain.
Assuntos
Lythraceae , Punica granatum , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Antocianinas , Taninos/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Taninos Hidrolisáveis/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêuticoRESUMO
Pomegranate (Punica granatum L.) is a rich source of polyphenols, including ellagitannins and ellagic acid. The plant is used in traditional medicine, and its purified components can provide anti-inflammatory and antioxidant activity and support of host defenses during viral infection and recovery from disease. Current data show that pomegranate polyphenol extract and its ellagitannin components and metabolites exert their beneficial effects by controlling immune cell infiltration, regulating the cytokine secretion and reactive oxygen and nitrogen species production, and by modulating the activity of the NFκB pathway. In vitro, pomegranate extracts and ellagitannins interact with and inhibit the infectivity of a range of viruses, including SARS-CoV-2. In silico docking studies show that ellagitannins bind to several SARS-CoV-2 and human proteins, including a number of proteases. This warrants further exploration of polyphenol-viral and polyphenol-host interactions in in vitro and in vivo studies. Pomegranate extracts, ellagitannins and ellagic acid are promising agents to target the SARS-CoV-2 virus and to restrict the host inflammatory response to viral infections, as well as to supplement the depleted host antioxidant levels during the stage of recovery from COVID-19.
Assuntos
COVID-19 , Lythraceae , Punica granatum , Humanos , Polifenóis/farmacologia , Taninos Hidrolisáveis/farmacologia , Ácido Elágico/farmacologia , Extratos Vegetais/farmacologia , SARS-CoV-2RESUMO
Discoid Lupus Erythematosus (DLE) is a chronic cutaneous disease of unknown etiology and of immunoinflammatory origin that is characterized by inflammatory plaques and may lead to disfiguring scarring and skin atrophy. Current treatments are limited, with a large proportion of patients either poorly or not responsive, which makes DLE an unmet medical need. Macrophage migration inhibitory factor (MIF) is the prototype of a pleiotropic family of cytokine that also includes the recently discovered homologue D-dopachrome tautomerase (DDT) or MIF2. MIF and DDT/MIF-2 exert several biological properties, primarily, but not exclusively of a proinflammatory nature. MIF and DDT have been suggested to play a key role in the pathogenesis of several autoimmune diseases, such as multiple sclerosis and type 1 diabetes, as well as in the development and progression of certain forms of cancers. In the present study, we have performed an immunohistochemistry analysis for the evaluation of MIF in DLE lesions and normal skin. We found high levels of MIF in the basal layer of the epidermis as well as in the cutaneous appendage (eccrine glands and sebocytes) of normal skin. In DLE lesions, we observed a significant negative correlation between the expression of MIF and the severity of inflammation. In addition, we performed an analysis of MIF and DDT expression levels in the skin of DLE patients in a publicly available microarray dataset. Interestingly, while these in silico data only evidenced a trend toward reduced levels of MIF, they demonstrated a significant pattern of expression and correlation of DDT with inflammatory infiltrates in DLE skins. Overall, our data support a protective role for endogenous MIF and possibly DDT in the regulation of homeostasis and inflammation in the skin and open up novel avenues for the treatment of DLE.
Assuntos
Epiderme/metabolismo , Oxirredutases Intramoleculares/metabolismo , Lúpus Eritematoso Discoide/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Epiderme/patologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Lúpus Eritematoso Discoide/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
3,3-Disubstituted oxindole derivatives bearing a nitrogen atom at the C-3 position have been synthesized starting from 3-alkyl oxindole through a metal free pathway. These derivatives have been tested in five human tumor cell lines (PC3, MCF7, SW620, MiaPaca2 and A375) and on primary cells (PBMCs) from healthy donors providing compound 6d showing a strong anticancer effect in all cancer lines on the low micromolar range.
Assuntos
Oxindóis/síntese química , Proliferação de Células , Humanos , Estrutura Molecular , Oxindóis/química , Relação Estrutura-AtividadeRESUMO
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients' survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches.
Assuntos
Suscetibilidade a Doenças , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Animais , Biomarcadores , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Estudos Clínicos como Assunto , Gerenciamento Clínico , Modelos Animais de Doenças , Humanos , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/terapiaRESUMO
At least since March 2020, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic and the multi-organ coronavirus disease 2019 (COVID-19) are keeping a firm grip on the world. Although most cases are mild, older patients and those with co-morbidities are at increased risk of developing a cytokine storm, characterized by a systemic inflammatory response leading to acute respiratory distress syndrome and organ failure. The present paper focuses on the small molecule MP1032, describes its mode of action, and gives rationale why it is a promising option for the prevention/treatment of the SARS-CoV-2-induced cytokine storm. MP1032 is a phase-pure anhydrous polymorph of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt that exhibits good stability and bioavailability. The physiological action of MP1032 is based on a multi-target mechanism including localized, self-limiting reactive oxygen species (ROS) scavenging activities that were demonstrated in a model of lipopolysaccharide (LPS)-induced joint inflammation. Furthermore, its immune-regulatory and PARP-1-modulating properties, coupled with antiviral effects against SARS-CoV-2, have been demonstrated in various cell models. Preclinical efficacy was elucidated in LPS-induced endotoxemia, a model with heightened innate immune responses that shares many similarities to COVID-19. So far, during oral clinical development with three-month daily administrations, no serious adverse drug reactions occurred, highlighting the outstanding safety profile of MP1032.
Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Luminol/análogos & derivados , Pneumonia Viral/tratamento farmacológico , Aminação , Animais , Antivirais/química , Betacoronavirus/imunologia , COVID-19 , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Feminino , Humanos , Fatores Imunológicos/química , Inflamação/imunologia , Luminol/química , Luminol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Pneumonia Viral/imunologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/imunologia , Espécies Reativas de Oxigênio/imunologia , SARS-CoV-2 , Células VeroRESUMO
Neuroblastoma (NB) is the most frequent extracranial pediatric tumor. Despite the current available multiple therapeutic options, the prognosis for high-risk NB patients remains unsatisfactory and makes the disease a clear unmet medical need. Thus, more tailored therapeutic approaches are warranted to improve both the quality of life and the survival of the patients. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that plays a key role in several diseases, including cancer. Preclinical and clinical studies in NB patients convergently indicate that MIF exerts pro-tumorigenic properties in NB. MIF is upregulated in NB tumor tissues and cell lines and it contributes to NB aggressiveness and immune-escape. To date, there are only a few data about the role of the second member of the MIF family, the MIF homolog d-dopachrome tautomerase (DDT), in NB. Here, we review the preclinical and clinical studies on the role of the MIF family of cytokines in NB and suggest that MIF and possibly DDT inhibitors may be promising novel prognostic and therapeutic targets in NB management.
Assuntos
Citocinas/genética , Citocinas/metabolismo , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Família Multigênica , Neuroblastoma/etiologia , Neuroblastoma/metabolismo , Animais , Biomarcadores Tumorais , Citocinas/antagonistas & inibidores , Gerenciamento Clínico , Suscetibilidade a Doenças , Descoberta de Drogas , Reposicionamento de Medicamentos , Humanos , Oxirredutases Intramoleculares/antagonistas & inibidores , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Terapia de Alvo Molecular , Neuroblastoma/tratamento farmacológico , Neuroblastoma/patologiaRESUMO
Recent preclinical and clinical observations have offered relevant insights on the etiopathogenesis of late onset Alzheimer's disease (AD) and upregulated immunoinflammatory events have been described as underlying mechanisms involved in the development of AD. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by several cells of the innate and adaptive immune system, as well as non-immune cells. In the present review, we highlight experimental, genetic, and clinical studies on MIF in rodent models of AD and AD patients, and we discuss emerging therapeutic opportunities for tailored modulation of the activity of MIF, that may potentially be applied to AD patients. Dismantling the exact role of MIF and its receptors in AD may offer novel diagnostic and therapeutic opportunities in AD.
Assuntos
Doença de Alzheimer , Oxirredutases Intramoleculares , Fatores Inibidores da Migração de Macrófagos , Receptores Imunológicos , Regulação para Cima/imunologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/imunologia , Macrófagos , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , RoedoresRESUMO
Liver fibrosis is defined as excessive extracellular matrix deposition in the hepatic parenchyma as a consequence of complex interactions among matrix-producing hepatic stellate cells (HSCs) and liver-resident and infiltrating cells. In addition to the liver, the process of fibrosis may represent end-stage disease of several diseases including kidneys, lungs, spleens, heart, muscles and at certain extent, the central nervous system and the peripheral nerves. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development. The aim of the present study was to test the efficacy of a new drug combination for the treatment of hepatic fibrosis in order to provide a proof-of-concept for the use of therapeutic agents in clinical practice. For this purpose, we have studied the effects of the PDGF inhibitor imatinib and the angiogenesis inhibitor sorafenib, administered alone or in combination, in reducing the progression of the fibrogenetic process in a pre-clinical model of liver damage induced in mice by repeated administration of Concanavalin A (ConA), resembling long-tern autoimmune hepatitis. Our results suggest that treatments with imatinib and sorafenib can modulate potently and, in a superimposable fashion, the fibrinogenic process when administered alone. However, and in agreement with the computational data presently generated, they only exert partial overlapping antifibrotic effects in modulating the main pathways involved in the process of liver fibrosis, without significant additive or synergist effects, when administered in combination.
Assuntos
Inibidores da Angiogênese/farmacologia , Mesilato de Imatinib/farmacologia , Cirrose Hepática/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Sorafenibe/farmacologia , Animais , Simulação por Computador , Concanavalina A/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Células Estreladas do Fígado , Humanos , Fígado/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Camundongos , Camundongos Endogâmicos BALB CRESUMO
The main focus of this study is exploring the effect and mechanism of two HIV-protease inhibitors: Ritonavir and Ritonavir-nitric oxide (Ritonavir-NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir-NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of ß-galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir-NO treatment only in metastatic B16F10 cells, ranking it as a late-response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton-as we observed diminished expression of vinculin, α-actin, and ß-tubulin. Permanent inhibition of S6 protein by Ritonavir-NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO-modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells.
Assuntos
Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Inibidores da Protease de HIV/farmacologia , Melanoma/tratamento farmacológico , Ritonavir/farmacologia , Actinas/biossíntese , Linhagem Celular Tumoral , Humanos , Lipofuscina/metabolismo , Melanoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Tubulina (Proteína)/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Vinculina/biossíntese , beta-Galactosidase/metabolismoRESUMO
Tetraspanins are a conserved family of proteins involved in a number of biological processes including, cell-cell interactions, fertility, cancer metastasis and immune responses. It has previously been shown that TSPAN32 knockout mice have normal hemopoiesis and B-cell responses, but hyperproliferative T cells. Here, we show that TSPAN32 is expressed at higher levels in the lymphoid lineage as compared to myeloid cells. In vitro activation of T helper cells via anti-CD3/CD28 is associated with a significant downregulation of TSPAN32. Interestingly, engagement of CD3 is sufficient to modulate TSPAN32 expression, and its effect is potentiated by costimulation with anti-CD28, but not anti-CTLA4, -ICOS nor -PD1. Accordingly, we measured the transcriptomic levels of TSPAN32 in polarized T cells under Th1 and Th2 conditions and TSPAN32 resulted significantly reduced as compared with unstimulated cells. On the other hand, in Treg cells, TSPAN32 underwent minor changes upon activation. The in vitro data were finally translated into the context of multiple sclerosis (MS). Encephalitogenic T cells from Myelin Oligodendrocyte Glycoprotein (MOG)-Induced Experimental Autoimmune Encephalomyelitis (EAE) mice showed significantly lower levels of TSPAN32 and increased levels of CD9, CD53, CD82 and CD151. Similarly, in vitro-activated circulating CD4 T cells from MS patients showed lower levels of TSPAN32 as compared with cells from healthy donors. Overall, these data suggest an immunoregulatory role for TSPAN32 in T helper immune response and may represent a target of future immunoregulatory therapies for T cell-mediated autoimmune diseases.
Assuntos
Esclerose Múltipla/imunologia , Subpopulações de Linfócitos T/imunologia , Tetraspaninas/genética , Animais , Células Cultivadas , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Humanos , Células Jurkat , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/genética , Tetraspaninas/metabolismoRESUMO
Background and objectives: Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT) are two pleiotropic and primarily, but not exclusively, proinflammatory cytokines belonging to the MIF family of cytokines that have recently been shown to be implicated in the pathogenesis of progressive forms of human progressive Multiple Sclerosis (MS) and the experimental model counterpart in rodents. Materials and Methods: We have presently evaluated a transcriptomic analysis of the expression of MIF, DDT, their receptors CD74 and CD44, and MIF co-receptors CXCR2, CXCR4, and CXCR7 in peripheral blood of patients with Clinically Isolated Syndrome (CIS), with rapid progression to clinical defined MS. Results: Our analysis reveals that MIF, DDT, and CD44 are overexpressed in CD4+ T cells from patients with CIS, as compared to healthy controls. Accordingly, a significant overlap was observed between the genes overexpressed in CD4+ T cells from patients with CIS and the genes belonging to the MIF regulatory network. This upregulated expression appeared to be unique for CD4+T cells, as other immune cells including CD8+ T cells, B cells, and monocytes from these patients exhibited expression levels of these molecules that were superimposable to those observed in healthy controls. Conclusions: Overall, our data suggest that the overexpression MIF cytokine family signature may occur in CD4+ T cells from patients with CIS, and that this phenomenon may be implicated in the pathogenesis of the disease, offering the possibility to represent both a diagnostic marker and a therapeutic target.
Assuntos
Receptores de Hialuronatos/metabolismo , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Esclerose Múltipla/metabolismo , Regulação para Cima , Adolescente , Adulto , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Feminino , Humanos , Masculino , Esclerose Múltipla/sangue , Adulto JovemRESUMO
Concanavalin A (ConA)-induced hepatitis is an experimental model of human autoimmune hepatitis induced in rodents by i.v. injection of Con A. The disease is characterized by increase in serum levels of transaminases and massive immune infiltration of the livers. Type 1, type 2, and type 17 cytokines play a pathogenic role in the development of ConA-induced hepatitis. To understand further the immunoregulatory mechanisms operating in the development and regulation of ConA-induced hepatitis, we have evaluated the role of the anti-inflammatory pathway Nrf2/HO-1/CO (Nuclear Factor E2-related Factor 2/Heme Oxygenase-1/Carbon Monoxide) in this condition and determined whether the in vivo administration of CO via the CO-releasing molecule (CORM) CORM-A1, influences serological and histological development of Con-A-induced hepatitis. We have firstly evaluated in silico the genes belonging to the Nrf2/HO-1/CO pathway that are involved in the pathogenesis of autoimmune hepatitis (AIH). The data obtained from the in silico study demonstrate that a significant number of genes modulated in the liver of ConA-challenged mice belong to the Nrf2 pathway; on the other hand, the administration of CORM-A1 determines an improvement in several sero-immunological and histological parameters, and it is able to modulate genes identified by the in silico analysis. Collectively, our data indicate that the Nrf2/HO-1/CO pathway is fundamental for the regulation of the immune responses, and that therapeutic intervention aimed at its modulation by CORM-A1 may represent a valuable strategy to be considered for the treatment of autoimmune hepatitis in humans.
Assuntos
Heme Oxigenase-1/genética , Hepatite Autoimune/genética , Inflamação/genética , Proteínas de Membrana/genética , Fator 2 Relacionado a NF-E2/genética , Animais , Boranos/administração & dosagem , Monóxido de Carbono/metabolismo , Carbonatos/administração & dosagem , Concanavalina A/toxicidade , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatite Autoimune/etiologia , Hepatite Autoimune/fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Fígado/metabolismo , Fígado/fisiopatologia , Camundongos , Transdução de Sinais , Fator de Necrose Tumoral alfaRESUMO
Uveitis is a sight-threatening inflammatory disease of the eye which represents the third leading cause of blindness in the developed countries. The conventional pharmacological treatment includes corticosteroids and immunosuppressive agents, which are limited by their side effects. New therapeutic strategies are thus strongly needed. Exogenously-administered carbon monoxide (CO) may represent an effective treatment for conditions characterized by a dysregulated inflammatory response. Carbon monoxide-releasing molecules (CORMs) are a novel group of compounds capable of carrying and liberating controlled quantities of CO. Among CORMs, CORM-A1 represents the first example of water soluble CO releaser. We show here that CORM-A1 under a late prophylactic regime is able to significantly ameliorate the natural course of experimental autoimmune uveoretinitis, a rodent model of immunoinflammatory posterior uveitis. The present study strongly supports the development of CORM-A1 as a potential new drug for treatment of patients with non-infectious posterior uveitis.
Assuntos
Doenças Autoimunes/imunologia , Boranos/farmacologia , Carbonatos/farmacologia , RNA Mensageiro/efeitos dos fármacos , Retina/efeitos dos fármacos , Retinite/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Úvea/efeitos dos fármacos , Uveíte/imunologia , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/patologia , Citocinas/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Lew , Retina/imunologia , Retina/patologia , Retinite/induzido quimicamente , Retinite/patologia , Proteínas de Ligação ao Retinol/toxicidade , Baço/efeitos dos fármacos , Baço/metabolismo , Linfócitos T Reguladores/imunologia , Úvea/imunologia , Úvea/patologia , Uveíte/induzido quimicamente , Uveíte/patologiaRESUMO
AIMS/HYPOTHESIS: Recent studies have identified carbon monoxide (CO) as a potential therapeutic molecule for the treatment of autoimmune diseases owing to its anti-inflammatory and anti-apoptotic properties. We explored the efficacy and the mechanisms of action of the CO-releasing molecule (CORM)-A1 in preclinical models of type 1 diabetes. METHODS: The impact of CORM-A1 on diabetes development was evaluated in models of spontaneous diabetes in NOD mice and in diabetes induced in C57BL/6 mice by multiple low-dose streptozotocin (MLDS). Ex vivo analysis was performed to determine the impact of CORM-A1 both on T helper (Th) cell and macrophage differentiation and on their production of soluble mediators in peripheral tissues and in infiltrates of pancreatic islets. The potential effect of CORM-A1 on cytokine-induced apoptosis in pancreatic islets or beta cells was evaluated in vitro. RESULTS: CORM-A1 conferred protection from diabetes in MLDS-induced mice and reduced diabetes incidence in NOD mice as confirmed by preserved insulin secretion and improved histological signs of the disease. In MLDS-challenged mice, CORM-A1 attenuated Th1, Th17, and M1 macrophage response and facilitated Th2 cell differentiation. In addition, CORM-A1 treatment in NOD mice upregulated the regulatory arm of the immune response (M2 macrophages and FoxP3(+) regulatory T cells). Importantly, CORM-A1 interfered with in vitro cytokine-induced beta cell apoptosis through the reduction of cytochrome c and caspase 3 levels. CONCLUSIONS/INTERPRETATION: The ability of CORM-A1 to protect mice from developing type 1 diabetes provides a valuable proof of concept for the potential exploitation of controlled CO delivery in clinical settings for the treatment of autoimmune diabetes.
Assuntos
Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Autoimunidade/imunologia , Monóxido de Carbono/administração & dosagem , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ilhotas Pancreáticas/efeitos dos fármacos , Animais , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Experimental , Feminino , Insulina/sangue , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Estresse Oxidativo , Linfócitos T Auxiliares-Indutores/citologiaRESUMO
Increasing evidence supports the role of epigenetics in the development of autoimmune disorders and the possibility of using epigenetic modifying drugs in the context of MS has not yet been investigated. We have explored the effect of the hypomethylating agent 5-aza-2'-deoxycytidine (DAC) in two murine models of experimental allergic encephalomyelitis (EAE). DAC treatment was associated with a significant amelioration of the clinical and histological hallmarks of EAE in both models. These effects were observed both in prophylactic and therapeutic regimens. The milder course of the disease was associated with a reduction in the number of spinal cord infiltrating lymphocytes and amelioration of the histopathological signs associated with EAE. In addition, increased transcript levels of anti-inflammatory cytokines and decreased mRNA expression of pro-inflammatory mediators were also observed. Finally, DAC treatment increased the percentage of circulating regulatory T cells by inducing Foxp3 expression via demethylation of a CpG island in Foxp3.
Assuntos
Anti-Inflamatórios/efeitos adversos , Azacitidina/análogos & derivados , Encefalomielite Autoimune Experimental/genética , Esclerose Múltipla/genética , Animais , Anti-Inflamatórios/administração & dosagem , Azacitidina/administração & dosagem , Citocinas/metabolismo , Decitabina , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Camundongos , Esclerose Múltipla/patologia , Linfócitos T ReguladoresRESUMO
VGX-1027 [(S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid] is a small molecule compound with immunomodulatory properties, which favourably influences the development of immuno-inflammatory and autoimmune diseases in different animal models such as type 1 diabetes mellitus, pleurisy, rheumatoid arthritis and inflammatory bowel disease. However, the precise mechanism of action of VGX-1027 remains to be ascertained. With this aim, we have studied the immunomodulatory effects of VGX-1027 in vitro, using a genome-wide oligonucleotide microarray approach, and in vivo, using the NZB/NZW F1 model of systemic lupus erythematosus. Microarray data revealed that the administration of VGX-1027 profoundly affected the immune response to exogenous antigens, by modulating the expression of genes that are primarily involved in antigen processing and presentation as well as genes that regulate immune activation. When administered in vivo VGX-1027 ameliorated the course of the disease in the NZB/NZW F1 mice, which correlated with higher per cent survival and improved clinical and histopathological signs. The data presented herein support the theory that VGX-1027 modulates immunity, probably by inhibiting inflammatory antigen presentation and so limiting immune cell expansion.
Assuntos
Acetatos/farmacologia , Fatores Imunológicos/farmacologia , Lipopolissacarídeos/toxicidade , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Oxazóis/farmacologia , Receptor 4 Toll-Like/imunologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Masculino , CamundongosRESUMO
Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate compared to other breast cancer subtypes. Our study aimed to explore the prognostic significance of 83 immune-related genes, by using transcriptomic data from the TCGA database. Our analysis identified the Poliovirus Receptor-Like 3 protein (PVRL3) as a critical negative prognostic marker in TNBC patients. Furthermore, we found that the Enhancer of Zeste Homolog 2 (EZH2), a well-known epigenetic regulator, plays a pivotal role in modulating PVRL3 levels in TNBC cancer cell lines expressing EZH2 along with high levels of PVRL3. The elucidation of the EZH2-PVRL3 regulatory axis provides valuable insights into the molecular mechanisms underlying TNBC aggressiveness and opens up potential pathways for personalized therapeutic intervention.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste , Regulação Neoplásica da Expressão Gênica , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Prognóstico , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Linhagem Celular Tumoral , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Nectinas/metabolismo , Nectinas/genéticaRESUMO
In the present study, we have explored the involvement of Toll-like Receptor 4 (TLR4) in atrial fibrillation (AF), by using a meta-analysis of publicly available human transcriptomic data. The meta-analysis revealed 565 upregulated and 267 downregulated differentially expressed genes associated with AF. Pathway enrichment analysis highlighted a significant overrepresentation in immune-related pathways for the upregulated genes. A significant overlap between AF differentially expressed genes and TLR4-modulated genes was also identified, suggesting the potential role of TLR4 in AF-related transcriptional changes. Additionally, the analysis of other Toll-like receptors (TLRs) revealed a significant association with TLR2 and TLR3 in AF-related gene expression patterns. The examination of MYD88 and TICAM1, genes associated with TLR4 signalling pathways, indicated a significant yet nonspecific enrichment of AF differentially expressed genes. In summary, this study offers novel insights into the molecular aspects of AF, suggesting a pathophysiological role of TLR4 and other TLRs. By targeting these specific receptors, new treatments might be designed to better manage AF, offering hope for improved outcomes in affected patients.
Assuntos
Fibrilação Atrial , Receptor 4 Toll-Like , Humanos , Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Transcriptoma , Transdução de Sinais/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Proteínas Adaptadoras de Transporte VesicularRESUMO
The existing literature supports the anti-inflammatory, antioxidant, and antiviral capacities of the polyphenol extracts derived from Geranium sanguineum L. These extracts exhibit potential in hindering viral replication by inhibiting enzymes like DNA polymerase and reverse transcriptase. The antiviral properties of G. sanguineum L. seem to complement its immunomodulatory effects, contributing to infection resolution. While preclinical studies on G. sanguineum L. suggest its potential effectiveness against COVID-19, there is still a lack of clinical evidence. Therefore, the polyphenols extracted from this herb warrant further investigation as a potential alternative for preventing and treating COVID-19 infections.