RESUMO
Exposure to the non-protein amino acid cyanotoxin ß-N-methylamino-L-alanine (BMAA), released by cyanobacteria found in many water reservoirs has been associated with neurodegenerative diseases. We previously demonstrated that BMAA induced cell death in both retina photoreceptors (PHRs) and amacrine neurons by triggering different molecular pathways, as activation of NMDA receptors and formation of carbamate-adducts was only observed in amacrine cell death. We established that activation of Retinoid X Receptors (RXR) protects retinal cells, including retina pigment epithelial (RPE) cells from oxidative stress-induced apoptosis. We now investigated the mechanisms underlying BMAA toxicity in these cells and those involved in RXR protection. BMAA addition to rat retinal neurons during early development in vitro increased reactive oxygen species (ROS) generation and polyADP ribose polymers (PAR) formation, while pre-treatment with serine (Ser) before BMAA addition decreased PHR death. Notably, RXR activation with the HX630 agonist prevented BMAA-induced death in both neuronal types, reducing ROS generation, preserving mitochondrial potential, and decreasing TUNEL-positive cells and PAR formation. This suggests that BMAA promoted PHR death by substituting Ser in polypeptide chains and by inducing polyADP ribose polymerase activation. BMAA induced cell death in ARPE-19 cells, a human epithelial cell line; RXR activation prevented this death, decreasing ROS generation and caspase 3/7 activity. These findings suggest that RXR activation prevents BMAA harmful effects on retinal neurons and RPE cells, supporting this activation as a broad-spectrum strategy for treating retina degenerations.
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Treatment with bexarotene, a selective retinoid X receptor (RXR) agonist, significantly improves behavioral dysfunctions in various neurodegenerative animal models. Additionally, it activates neurodevelopmental and plasticity pathways in the brains of adult mice. Our objective was to investigate the impact of RXR activation by bexarotene on adult neural stem cells (aNSC) and their cell lineages. To achieve this, we treated NSCs isolated from the subventricular zone (SVZ) of adult rat brains from the proliferative stage to the differentiated status. The results showed that bexarotene-treated aNSC exhibited increased BrdU incorporation, SOX2+ dividing cell pairs, and cell migration from neurospheres, revealing that the treatment promotes self-renewing proliferation and cell motility in SVZ-aNCS. Furthermore, bexarotene induced a cell fate shift characterized by a significant increase in GFAP+/S100B+ differentiated astrocytes, which uncovers the participation of activated-RXR in astrogenesis. In the neuronal lineage, the fate shift was counteracted by bexarotene-induced enhancement of NeuN+ nuclei together with neurite network outgrowth, indicating that the RXR agonist stimulates SVZ-aNCS neuronal differentiation at later stages. These findings establish new connections between RXR activation, astro- and neurogenesis in the adult brain, and contribute to the development of therapeutic strategies targeting nuclear receptors for neural repair.
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Pseudomyxoma peritonei (PMP) refers to a growth disorder characterized by glycoprotein neoplasm in the peritoneum, where mucin oversecretion occurs. The tumors of the appendix region are well associated with PMP; however, ovarian, colon, stomach, pancreas, and urachus tumors have also been linked to PMP. Other mucinous tumors in the pelvis, paracolic gutters, greater omentum, retrohepatic space, and Treitz ligament can be the reason for PMP. Despite being rare and having a slow growth rate, PMP can be lethal without treatment. It is treated with neoadjuvant chemotherapy with the option of cytoreductive surgery and intraperitoneal chemotherapy. In the current study, we hypothesize that there may be novel gentle ways to inhibit or eliminate the mucin. Dr. David Morris has used mucolytics - such as bromelain and N-acetyl cysteine to solubilize mucin. In the present review, we aimed to study the regulation of mucin expression by promoter methylation, and drugs that can inhibit mucin, such as boldine, amiloride, naltrexone, dexamethasone, and retinoid acid receptors antagonist. This review also explored some possible pathways, such as inhibition of Na + , Ca2+ channels and induction of DNA methyltransferase along with inhibition of ten-eleven translocation enzymes, which can be good targets to control mucin. Mucins are strong adhesive molecules that play great roles in clinging to cells or cell to cell. Besides, they have been greatly involved in metastasis and also act as disease markers for cancers. Diagnostic markers may have exclusive roles in disease initiation and progression. Therefore, the present review explores various drugs to control and target mucin in various diseases, specifically cancers. (AU)
Assuntos
Pseudomixoma Peritoneal/tratamento farmacológico , Aporfinas/uso terapêutico , Retinoides/uso terapêutico , Dexametasona/uso terapêutico , Cálcio , Amilorida/uso terapêutico , Metilação/efeitos dos fármacos , Mucinas/efeitos dos fármacos , Naltrexona/uso terapêuticoRESUMO
INTRODUCTION AND OBJECTIVES: Liver fibrosis is a common pathological change in many chronic liver diseases. Activation of hepatic stellate cells (HSCs) is the core event in liver fibrosis. This study aimed to investigate the role of testicular orphan receptor 4 (TR4) in the activation of HSCs. MATERIALS AND METHODS: In vivo, bile duct ligation (BDL)-induced rat liver fibrosis model was established, and the expressions of TR4 and α-smooth muscle actin (α-SMA) in liver tissues were detected. In vitro, TR4 knockdown and overexpression in JS-1 cells using lentiviral vectors were constructed, and the expressions of TR4, α-SMA, Col-I, and TGF-ß1/smads and retinoid X receptor (RXR) pathway-related genes were detected. RESULTS: TR4 was highly expressed in BDL-induced fibrotic liver, accompanied by increased expression of α-SMA. Knockdown of TR4 significantly inhibited the expressions of α-SMA, Col-I, p-TßRI, and p-Smad2/3, and up-regulated the expression of RXRα in HSCs in vitro. In contrast, TR4 overexpression significantly increased the expressions of α-SMA, Col-I, p-TßRI, and p-Smad2/3, and inhibited the expression of RXRα. CONCLUSIONS: TR4 may promote the activation of HSCs by up-regulating TßR I/Smad2/3 signaling pathway and down-regulating RXRα signaling, thereby promoting the progression of liver fibrosis. Our findings may provide a new therapeutic target against hepatic fibrosis.
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Células Estreladas do Fígado , Fator de Crescimento Transformador beta1 , Ratos , Animais , Células Estreladas do Fígado/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Cirrose Hepática/metabolismo , Transdução de Sinais , Fígado/patologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismoRESUMO
1,25(OH)2 D3 , the active form of vitamin D, has been extensively studied for its putative protective activities against tumors. It does biological work by connecting to a nuclear receptor called VDR, which heterodimerizes itself to another nuclear receptor, RXR. The study observed differences in VDR and RXR expression in non-melanoma skin cancer a actinic keratosis and compared it with normal skin. We performed VDR and RXR immunohistochemistry of 76 controls (normal skin), 49 actinic keratosis, 99 basal cell carcinomas and 96 squamous cell carcinomas from formalin-fixed paraffin-embedded, resulting from surgical procedures. There was a clear pattern in the control group (p < 0.001), with the positivity of both receptors, VDR and RXR. Actinic keratosis differed from the basal cell carcinoma and control groups concerning RXR expression (p < 0.001). SCC was negative for both receptors, differing in all groups (p < 0.001). The site of positivity (nuclear, cytoplasmatic or both) of VDR differed between all groups (p < 0.001). To date, our series is the largest of VDR and RXR immunohistochemistry concerning non-melanoma skin cancer. Our findings reinforce the need to understand the pathways involving VDR and RXR to direct therapies and prevention manoeuvres.
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Carcinoma Basocelular , Ceratose Actínica , Neoplasias Cutâneas , Proteínas de Transporte , Humanos , Receptores de Calcitriol/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores X de Retinoides/metabolismoRESUMO
Herein, we developed an ethosomal hydrogel based on three types of ethosomes: simple, mixed (surfactant-based micelles and lipid vesicles) or binary (comprising two type of alcohols). Ethanol injection was employed for vesicles preparation, and sodium alginate, as gelling agent. We purposed the local-transdermal administration of the off-the-shelf retinoid fenretinide (FENR) for chemoprevention of breast cancer. Rheograms and flow index values for alginate dispersion (without ethosomes) and hydrogels containing simple, mixed or binary ethosomes suggested pseudoplastic behavior. An increase in the apparent viscosity was observed upon ethosome incorporation. The ethosomal hydrogel displayed increased bioadhesion compared to the alginate dispersion, suggesting that the lipid vesicles contribute to the gelling and bioadhesion processes. In the Hen's Egg Test-Chorioallantoic Membrane model, few spots of lysis and hemorrhage were observed for formulations containing simple (score of 2) and mixed vesicles (score 4), but not for the hydrogel based on the binary system, indicating its lower irritation potential. The binary ethosomal hydrogel provided a slower FENR in vitro release and delivered 2.6-fold less drug into viable skin layers compared to the ethosome dispersion, supporting the ability of the gel matrix to slow down drug release. The ethosomal hydrogel decreased by ~ five-fold the IC50 values of FENR in MCF-7 cells. In conclusion, binary ethosomal gels presented technological advantages, provided sustained drug release and skin penetration, and did not preclude drug cytotoxic effects, supporting their potential applicability as topical chemopreventive systems.
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Neoplasias da Mama , Fenretinida , Administração Cutânea , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/prevenção & controle , Galinhas/metabolismo , Sistemas de Liberação de Medicamentos , Feminino , Fenretinida/metabolismo , Fenretinida/farmacologia , Humanos , Hidrogéis/metabolismo , Lipossomos/metabolismo , Pele/metabolismo , Absorção CutâneaRESUMO
Herein, we developed an ethosomal hydrogel based on three types of ethosomes: simple, mixed (surfactant-based micelles and lipid vesicles) or binary (comprising two type of alcohols). Ethanol injection was employed for vesicles preparation, and sodium alginate, as gelling agent. We purposed the local-transdermal administration of the off-the-shelf retinoid fenretinide (FENR) for chemoprevention of breast cancer. Rheograms and flow index values for alginate dispersion (without ethosomes) and hydrogels containing simple, mixed or binary ethosomes suggested pseudoplastic behavior. An increase in the apparent viscosity was observed upon ethosome incorporation. The ethosomal hydrogel displayed increased bioadhesion compared to the alginate dispersion, suggesting that the lipid vesicles contribute to the gelling and bioadhesion processes. In the Hen’s Egg Test–Chorioallantoic Membrane model, few spots of lysis and hemorrhage were observed for formulations containing simple (score of 2) and mixed vesicles (score 4), but not for the hydrogel based on the binary system, indicating its lower irritation potential. The binary ethosomal hydrogel provided a slower FENR in vitro release and delivered 2.6-fold less drug into viable skin layers compared to the ethosome dispersion, supporting the ability of the gel matrix to slow down drug release. The ethosomal hydrogel decreased by ~ five-fold the IC50 values of FENR in MCF-7 cells. In conclusion, binary ethosomal gels presented technological advantages, provided sustained drug release and skin penetration, and did not preclude drug cytotoxic effects, supporting their potential applicability as topical chemopreventive systems.
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Photoreceptor cell (PHR) death is a hallmark of most retinal neurodegenerative diseases, in which inflammation plays a critical role. Activation of retinoid X receptors (RXR) modulates and integrates multiple cell functions, and has beneficial effects in animal models of chronic inflammatory diseases. Nonetheless, the mechanisms involved and their role in retina neuroprotection are poorly understood. In this work we assessed whether RXR activation prevents inflammation and/or PHR death in retinitis pigmentosa, an inherited retina neurodegeneration, using as an ex vivo model, retinas from the rd1 mice, a murine model of this disease. We demonstrated that rd1 retinas had lower levels of RXR alpha isoform than their wt counterparts at early developmental times, whereas its distribution pattern remained similar. In mixed neuro-glial cultures obtained from either rd1 or wt retinas, both PHR and Müller glial cells (MGC) expressed RXRalpha, and RXR activation by its synthetic pan-agonist PA024 selectively increased mRNA levels of RXRgamma isoform. PA024 decreased PHR death in rd1 mixed cultures; it reduced the amount of non-viable neurons, delayed the onset of PHR apoptosis, and decreased Bax mRNA levels. PA024 also reduced MGC reactivity in vitro before and at the onset of degeneration, decreasing GFAP expression, increasing glutamine synthetase mRNA levels, and promoting the transcription of the anti-inflammatory cytokine, Il-10. These results suggest that RXR activation rescues rd1 PHR and decreases MGC reactivity, promoting an anti-inflammatory environment in the rd1 retina, thus supporting the potential of RXR agonists as pharmacological tools for treating retina degenerative diseases.
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Modelos Animais de Doenças , Inflamação/metabolismo , Células Fotorreceptoras/metabolismo , Retinose Pigmentar/metabolismo , Receptores X de Retinoides/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Alzheimer's disease (AD) is the main cause of dementia in the world. Studies of human AD brains show abnormalities in the white matter and reduction of myelin and oligodendrocyte markers. It has been proposed that oligodendrocyte progenitor cells (OPCs) present in the adult brain are a potential source for re-myelination, through proliferation and differentiation into mature oligodendrocytes. Bexarotene, a Retinoid X Receptor agonist, has been demonstrated to reverse behavioral deficits and to improved synaptic transmission and plasticity in murine models of AD, which was associated with the reduction of soluble Aß peptides. In the present study, we analyzed changes in the expression of oligodendrocyte lineage markers following oral administration of Bexarotene in a very old (24-month-old) triple transgenic mouse model of AD (3xTg-AD), for which early demyelination changes have been previously described. Bexarotene increased the expression of OPCs and intermediate oligodendrocyte progenitors (Olig2+ and O4+), and increased the number of mitotic (O4+) and myelinating mature (MBP+) oligodendrocytes. We clearly show that Bexarotene promotes re-myelination which might be important for the previously observed cognitive improvement of 3xTg-AD mice treated with this drug.
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Doença de Alzheimer/metabolismo , Bexaroteno/farmacologia , Bainha de Mielina/metabolismo , Fármacos Neuroprotetores/farmacologia , Oligodendroglia/efeitos dos fármacos , Receptores X de Retinoides/agonistas , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Proliferação de Células , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligodendroglia/metabolismo , Oligodendroglia/fisiologia , Presenilina-1/genética , Proteínas tau/genéticaRESUMO
Nuclear receptors are ligand-activated transcription factors that can modulated cellular processes involved in the development, homeostasis, cell proliferation, metabolism, and reproduction through the control of the specific genetic and molecular program. In the central nervous system, they are key regulators of neural stem cell fate decisions and can modulate the physiology of different brain cells. Over the past decades, a large body of evidence has supported that nuclear receptors are potential therapeutic targets for the treatment of neurodegenerative disorders such as Alzheimer's disease, the most common dementia worldwide, and the main cause of disability in later life. This disease is characterized by the progressive accumulation of amyloid-beta peptides and hyperphosphorylated tau protein that can explain alterations in synaptic transmission and plasticity; loss of dendritic spines; increased in reactive microglia and inflammation; reduction of neuronal stem cells number; myelin and vascular alterations that finally leads to increased neuronal death. Here, we present a review of type II no steroidal nuclear receptors that form obligatory heterodimers with the Retinoid X Receptor (RXR) and its potential in the therapeutic of AD. Activation of type II nuclear receptor by synthetic agonist leads to transcriptional regulation of specific genes that acts counteracting against the detrimental effects of amyloid-beta peptides and hyperphosphorylated tau in neuronal cells recovering the functionality of the synapses. But also, activation of type II nuclear receptor leads to modifications in APP metabolism, repression of inflammatory cascade and inductors of the generation of neuronal stem cells and progenitor cells supporting its potential therapeutics role for Alzheimer's disease.