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1.
Int J Mol Sci ; 25(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474284

RESUMO

N-retinylidene-N-retinylethanolamine (A2E) has been associated with age-related macular degeneration (AMD) physiopathology by inducing cell death, angiogenesis and inflammation in retinal pigmented epithelial (RPE) cells. It was previously thought that the A2E effects were solely mediated via the retinoic acid receptor (RAR)-α activation. However, this conclusion was based on experiments using the RAR "specific" antagonist RO-41-5253, which was found to also be a ligand and partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ. Moreover, we previously reported that inhibiting PPAR and retinoid X receptor (RXR) transactivation with norbixin also modulated inflammation and angiogenesis in RPE cells challenged in the presence of A2E. Here, using several RAR inhibitors, we deciphered the respective roles of RAR, PPAR and RXR transactivations in an in vitro model of AMD. We showed that BMS 195614 (a selective RAR-α antagonist) displayed photoprotective properties against toxic blue light exposure in the presence of A2E. BMS 195614 also significantly reduced the AP-1 transactivation and mRNA expression of the inflammatory interleukin (IL)-6 and vascular endothelial growth factor (VEGF) induced by A2E in RPE cells in vitro, suggesting a major role of RAR in these processes. Surprisingly, however, we showed that (1) Norbixin increased the RAR transactivation and (2) AGN 193109 (a high affinity pan-RAR antagonist) and BMS 493 (a pan-RAR inverse agonist), which are photoprotective against toxic blue light exposure in the presence of A2E, also inhibited PPARs transactivation and RXR transactivation, respectively. Therefore, in our in vitro model of AMD, several commercialized RAR inhibitors appear to be non-specific, and we propose that the phototoxicity and expression of IL-6 and VEGF induced by A2E in RPE cells operates through the activation of PPAR or RXR rather than by RAR transactivation.


Assuntos
Carotenoides , Degeneração Macular , Receptores Ativados por Proliferador de Peroxissomo , Quinolinas , para-Aminobenzoatos , Anti-Inflamatórios , Agonismo Inverso de Drogas , Inflamação , Degeneração Macular/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo , Receptores X de Retinoides/metabolismo , Retinoides/metabolismo , Ativação Transcricional , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
PLoS One ; 19(3): e0300892, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38512959

RESUMO

Inflammatory bowel diseases (IBD) result from uncontrolled inflammation in the intestinal mucosa leading to damage and loss of function. Both innate and adaptive immunity contribute to the inflammation of IBD and innate and adaptive immune cells reciprocally activate each other in a forward feedback loop. In order to better understand innate immune contributions to IBD, we developed a model of spontaneous 100% penetrant, early onset colitis that occurs in the absence of adaptive immunity by crossing villin-TNFAIP3 mice to RAG1-/- mice (TRAG mice). This model is driven by microbes and features increased levels of innate lymphoid cells in the intestinal mucosa. To investigate the role of type 3 innate lymphoid cells (ILC3) in the innate colitis of TRAG mice, we crossed them to retinoid orphan receptor gamma t deficient (Rorγt-/-) mice. Rorγt-/- x TRAG mice exhibited markedly reduced eosinophilia in the colonic mucosa, but colitis persisted in these mice. Colitis in Rorγt-/- x TRAG mice was characterized by increased infiltration of the intestinal mucosa by neutrophils, inflammatory monocytes, macrophages and other innate cells. RNA and cellular profiles of Rorγt-/- x TRAG mice were consistent with a lack of ILC3 and ILC3 derived cytokines, reduced antimicrobial factors, increased activation oof epithelial repair processes and reduced activation of epithelial cell STAT3. The colitis in Rorγt-/- x TRAG mice was ameliorated by antibiotic treatment indicating that microbes contribute to the ILC3-independent colitis of these mice. Together, these gene expression and cell signaling signatures reflect the double-edged sword of ILC3 in the intestine, inducing both proinflammatory and antimicrobial protective responses. Thus, Rorγt promotes eosinophilia but Rorγt and Rorγt-dependent ILC3 are dispensable for the innate colitis in TRAG mice.


Assuntos
Anti-Infecciosos , Colite , Eosinofilia , Doenças Inflamatórias Intestinais , Camundongos , Animais , Imunidade Inata , Linfócitos/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Eosinofilia/metabolismo , Anti-Infecciosos/metabolismo , Retinoides , Camundongos Endogâmicos C57BL
3.
FASEB J ; 38(5): e23522, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38445789

RESUMO

Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age-related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)-containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non-invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic depletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor-associated cholesterol deposits, and photoreceptor cell death, and loss of rod but not cone function. RPE-specific reduction in Mttp had no significant effect on plasma lipids and lipoproteins. While APOB was decreased in the RPE, most ocular retinoids remained unchanged, with the exception of the storage form of retinoid, retinyl ester. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but is not directly involved in plasma lipoprotein metabolism. These studies demonstrate that RPE-specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.


Assuntos
Proteínas de Transporte , Retina , Epitélio Pigmentado da Retina , Animais , Camundongos , Retinoides , Apolipoproteínas B/genética , Homeostase
4.
Commun Biol ; 7(1): 190, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365890

RESUMO

Enzymatic dissociation of human pluripotent stem cells (hPSCs) into single cells during routine passage leads to massive cell death. Although the Rho-associated protein kinase inhibitor, Y-27632 can enhance hPSC survival and proliferation at high seeding density, dissociated single cells undergo apoptosis at clonal density. This presents a major hurdle when deriving genetically modified hPSC lines since transfection and genome editing efficiencies are not satisfactory. As a result, colonies tend to contain heterogeneous mixtures of both modified and unmodified cells, making it difficult to isolate the desired clone buried within the colony. In this study, we report improved clonal expansion of hPSCs using a retinoic acid analogue, TTNPB. When combined with Y-27632, TTNPB synergistically increased hPSC cloning efficiency by more than 2 orders of magnitude (0.2% to 20%), whereas TTNPB itself increased more than double cell number expansion compared to Y-27632. Furthermore, TTNPB-treated cells showed two times higher aggregate formation and cell proliferation compared to Y-27632 in suspension culture. TTNPB-treated cells displayed a normal karyotype, pluripotency and were able to stochastically differentiate into all three germ layers both in vitro and in vivo. TTNBP acts, in part, by promoting cellular adhesion and self-renewal through the upregulation of Claudin 2 and HoxA1. By promoting clonal expansion, TTNPB provides a new approach for isolating and expanding pure hPSCs for future cell therapy applications.


Assuntos
Benzoatos , Células-Tronco Pluripotentes , Piridinas , Humanos , Amidas/farmacologia , Claudinas/metabolismo , Células-Tronco Pluripotentes/efeitos dos fármacos , Retinoides/farmacologia , Retinoides/metabolismo
5.
Curr Protoc ; 4(2): e989, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38363064

RESUMO

Acne vulgaris (acne) effects nearly 90% of all Western teenagers, and the only pharmaceutical class of agents to treat severe forms of this skin condition are the retinoids, which are well-described teratogens. Yet about 50% of the patients receiving this class of therapeutics are women of child-bearing age, in their peak years of reproductive potential. On this basis, there is a significant unmet medical need for agents to treat severe forms of acne that do not carry this liability. As a means to assess potential agents of this type, here we describe methods for estimating the relative amount of sebum that a mouse produces based on the water retention on fur following a thorough wetting procedure. We have shown that a compound that is clinically effective in reducing sebum production demonstrates activity in this model. The method is therefore useful for evaluating therapeutic candidates for reducing sebum production, which would in turn be useful for treating acne. We have broken the entire procedure down into two phases/two protocols, as listed below. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Pre-wash wet weight measurement Basic Protocol 2: Post-wash wet-weight measurement.


Assuntos
Acne Vulgar , Sebo , Adolescente , Humanos , Feminino , Camundongos , Animais , Masculino , Modelos Animais de Doenças , Acne Vulgar/tratamento farmacológico , Retinoides/uso terapêutico , Equilíbrio Hidroeletrolítico
6.
Skin Res Technol ; 30(2): e13573, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38303407

RESUMO

BACKGROUND: Facial acne scars are a prevalent concern, leading to the development of various treatment modalities. OBJECTIVES: This review aims to explore the latest advancements in the treatment of facial acne scars, focusing on both surgical and non-surgical methods. METHODS: The non-surgical treatments reviewed include topical medications (such as retinoids and alpha hydroxy acids) and non-invasive procedures (like microdermabrasion and chemical peels). Surgical options discussed are punch excision, subcision, and fractional laser treatments. RESULTS: Combination therapy, integrating both surgical and non-surgical approaches, is frequently utilized to achieve optimal results in scar improvement. CONCLUSION: Recent advancements in the treatment of facial acne scars provide promising options for individuals seeking improvement. However, these treatments have associated risks and potential adverse effects, highlighting the importance of consulting a dermatologist before beginning any treatment regimen.


Assuntos
Acne Vulgar , Abrasão Química , Humanos , Cicatriz/etiologia , Cicatriz/terapia , Cicatriz/patologia , Acne Vulgar/terapia , Acne Vulgar/cirurgia , Dermabrasão , Retinoides/uso terapêutico , Resultado do Tratamento
7.
Methods Mol Biol ; 2770: 113-121, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38351450

RESUMO

Spermatogonial stem cells (SSCs) produce haploid sperm via mitosis and meiosis in vivo. Although the technique to culture mouse SSCs has been well established, induction of meiosis in vitro has remained a challenge. Retinoic acid (RA) is required for meiosis in vivo; however, RA alone is not sufficient to induce meiosis in vitro. Here, we describe a method in which nutrient restriction and RA synergistically induce meiotic initiation into meiotic prophase I in cultured mouse SSCs.


Assuntos
Meiose , Retinoides , Masculino , Camundongos , Animais , Sêmen , Tretinoína/farmacologia , Células-Tronco , Nutrientes , Espermatogônias , Espermatogênese , Diferenciação Celular
8.
Ann Med ; 56(1): 2315224, 2024 12.
Artigo em Inglês | MEDLINE | ID: mdl-38353210

RESUMO

BACKGROUND: Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection is associated with significant gut damage, similar to that observed in patients with inflammatory bowel disease (IBD). This pathology includes loss of epithelial integrity, microbial translocation, dysbiosis, and resultant chronic immune activation. Additionally, the levels of all-trans-retinoic acid (atRA) are dramatically attenuated. Data on the therapeutic use of anti-α4ß7 antibodies has shown promise in patients with ulcerative colitis and Crohn's disease. Recent evidence has suggested that the microbiome and short-chain fatty acid (SCFA) metabolites it generates may be critical for anti-α4ß7 efficacy and maintaining intestinal homeostasis. MATERIALS AND METHODS: To determine whether the microbiome contributes to gut homeostasis after anti-α4ß7 antibody administered to SIV-infected rhesus macaques, faecal SCFA concentrations were determined, 16S rRNA sequencing was performed, plasma viral loads were determined, plasma retinoids were measured longitudinally, and gut retinoid synthesis/response gene expression was quantified. RESULTS: Our results suggest that anti-α4ß7 antibody facilitates the return of retinoid metabolism to baseline levels after SIV infection. Furthermore, faecal SCFAs were shown to be associated with retinoid synthesis gene expression and rebound viral loads after therapy interruption. CONCLUSIONS: Taken together, these data demonstrate the therapeutic advantages of anti-α4ß7 antibody administration during HIV/SIV infection and that the efficacy of anti-α4ß7 antibody may depend on microbiome composition and SCFA generation.


Assuntos
Infecções por HIV , Vírus da Imunodeficiência Símia , Animais , Humanos , Vírus da Imunodeficiência Símia/genética , Macaca mulatta/genética , Macaca mulatta/metabolismo , RNA Ribossômico 16S/genética , Integrinas/metabolismo , Integrinas/uso terapêutico , Retinoides/uso terapêutico
9.
Sci Rep ; 14(1): 2696, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302538

RESUMO

Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but is still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development (referred to as the RAPID-E protocol). Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II, but additionally expressed Collagen X, indicative of hypertrophy. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans.


Assuntos
Benzoatos , Cartilagem Articular , Osteoartrite , Células-Tronco Pluripotentes , Retinoides , Humanos , Condrócitos/metabolismo , Tretinoína/farmacologia , Condrogênese/genética , Diferenciação Celular , Cartilagem Articular/metabolismo , Colágeno/metabolismo , Osteoartrite/metabolismo
10.
Bioorg Chem ; 145: 107227, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38387400

RESUMO

Multidrug-resistant (MDR) pathogens are severely impacting our ability to successfully treat common infections. Here we report the synthesis of a panel of adarotene-related retinoids showing potent antimicrobial activity on Staphylococcus aureus strains (including multidrug-resistant ones). Fluorescence and molecular dynamic studies confirmed that the adarotene analogues were able to induce conformational changes and disfunctions to the cell membrane, perturbing the permeability of the phospholipid bilayer. Since the major obstacle for developing retinoids is their potential cytotoxicity, a selected candidate was further investigated to evaluate its activity on a panel of human cell lines. The compound was found to be well tolerated, with IC50 5-15-fold higher than the MIC on S. aureus strains. Furthermore, the adarotene analogue had a good pharmacokinetic profile, reaching a plasma concentration of about 6 µM after 0.5 h after administration (150 mg/kg), at least twice the MIC observed against various bacterial strains. Moreover, it was demonstrated that the compound potentiated the growth-inhibitory effect of the poorly bioavailable rifaximin, when used in combination. Overall, the collected data pave the way for the development of synthetic retinoids as potential therapeutics for hard-to-treat infectious diseases caused by antibiotic-resistant Gram-positive pathogens.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Staphylococcus aureus , Antibacterianos , Retinoides/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Testes de Sensibilidade Microbiana
11.
Toxicol Sci ; 198(2): 246-259, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38237923

RESUMO

Early developmental exposure to environmental toxicants may play a role in the risk for developing autism. A variety of pesticides have direct effects on retinoic acid (RA) signaling and as RA signaling has important roles in neurodevelopment, such compounds may cause developmental neurotoxicity through an overlapping adverse outcome pathway. It is hypothesized that a pesticide's embryonic effects on retinoid function may correspond with neurobehavioral disruption later in development. In the current studies, we determined the effects of RA-acting pesticides on neurobehavioral development in zebrafish. Buprofezin and imazalil caused generalized hypoactivity in the larval motility test, whereas chlorothalonil and endosulfan I led to selective hypoactivity and hyperactivity, respectively. With buprofezin, chlorothalonil, and imazalil, hypoactivity and/or novel anxiety-like behaviors persisted in adulthood and buprofezin additionally decreased social attraction responses in adulthood. Endosulfan I did not produce significant adult behavioral effects. Using qPCR analyses of adult brain tissue, we observed treatment-induced alterations in RA synthesis or catabolic genes, indicating persistent changes in RA homeostasis. These changes were compound-specific, with respect to expression directionality, and potential patterns of homeostatic disruption. Results suggest the likely persistence of disruptions in RA signaling well into adulthood and may represent compensatory mechanisms following early life stage exposures. This study demonstrates that early developmental exposure to environmental toxicants that interfere with RA signaling causes short as well as long-term behavioral disruption in a well-established zebrafish behavioral model and expand upon the meaning of the RA adverse outcome pathway, indicating that observed effects likely correspond with the nature of underlying homeostatic effects.


Assuntos
Nitrilas , Praguicidas , Tiadiazinas , Peixe-Zebra , Animais , Tretinoína/toxicidade , Retinoides/farmacologia , Praguicidas/metabolismo , Endossulfano , Comportamento Animal
12.
PLoS One ; 19(1): e0295897, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38198446

RESUMO

OBJECTIVE: Describe the trends of exposure to harmful drugs during pregnancy over recent years in France. DESIGN: Nationwide cohort study. SETTING: The French National administrative health Data System (SNDS). POPULATION: Pregnancies starting between 2013 and 2019 and outcomes corresponding to live births, medical terminations of pregnancy, and stillbirths. METHODS: Each pregnancy was divided into a preconceptional period of 90 days before conception and three trimesters from conception to birth. Harmful drugs were defined according to their risks to the fetus: teratogenicity or fetotoxicity. Exposure was defined using the critical period during pregnancy for each type of harmful drug: preconceptional period or first trimester for teratogenic drugs and second or third trimesters for fetotoxic drugs. MAIN OUTCOME MEASURES: Prevalence of pregnancies exposed to at least one harmful drug. RESULTS: Among 5,253,284 pregnancies, 204,402 (389 per 10,000) pregnancies were exposed to at least one harmful drug during the critical periods: 48,326 (92 per 10,000) pregnancies were exposed to teratogenic drugs during the preconceptional period or the first trimester, and 155,514 (299 per 10,000) pregnancies were exposed to fetotoxic drugs during the second or third trimesters. Teratogenic drugs were mainly retinoids for topical use (44 per 10,000 pregnancies), antiepileptics (13 per 10,000 pregnancies) and statins (13 per 10,000 pregnancies). Fetotoxic drugs were mainly non-steroidal anti-inflammatory drugs (NSAIDs), for systemic (128 per 10,000 pregnancies) and topical use (122 per 10,000 pregnancies). Exposure to teratogenic drugs decreased from the preconceptional period to the first trimester. Exposure to fetotoxic drugs decreased from the second to the third trimester. Between 2013 and 2019, we found a decrease in harmful drug exposure overall, mainly for topical and systemic NSAIDs and for topical retinoids. CONCLUSIONS: In this nationwide study, about one in 25 pregnancies was exposed to at least one harmful drug, mainly NSAIDs and topical retinoids. Although the prevalence of harmful drug exposure decreased over the study period, NSAID exposure in the second and third trimester remains of concern.


Assuntos
Anti-Inflamatórios não Esteroides , Anticonvulsivantes , Feminino , Gravidez , Humanos , Estudos de Coortes , França/epidemiologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Retinoides , Teratógenos
15.
Toxicol Lett ; 391: 39-44, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38070836

RESUMO

Cyanobacterial blooms are increasing in frequency and intensity globally, and impacting recreational waters as well as waters used for drinking water provisioning. They are sources of bioactive metabolites including retinoids and the neurotoxin anatoxin-a. Here, we investigated the effects of anatoxin-a on a differentiating in vitro human neural stem cell model previously characterised with retinoic acids. Effects on protein and gene expression upon exposure for 9 or 18 days to anatoxin-a alone or in co-exposure with all-trans retinoic acid were evaluated using a panel of neural and glial differentiation biomarkers. Anatoxin-a did not cause distinct developmental neurotoxicity alone, or in co-exposure with retinoic acid. However, in line with its excitotoxicity, in co-exposure with 200 nM all-trans retinoic acid it reduced the differentiation of acetylcholinergic neuron subtypes in the culture at 1000 nM (highest tested concentration). While this could have substantial functional implications for the developing nervous system, there is no indication for developmental neurotoxicity beyond its (excito-)toxicity to acetylcholinergic neurons, which only occurred in co-exposure to all-trans retinoic acid.


Assuntos
Cianobactérias , Síndromes Neurotóxicas , Tropanos , Humanos , Tretinoína/toxicidade , Toxinas de Cianobactérias , Retinoides/metabolismo , Síndromes Neurotóxicas/etiologia , Expressão Gênica
16.
J Cosmet Dermatol ; 23(2): 496-501, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38158455

RESUMO

BACKGROUND: Retinoids and alpha- and beta hydroxy acids are common components utilized in regimens for blemish-prone skin. However, balancing efficacy and tolerability is often challenging. PATIENTS/METHODS: This pilot study evaluated a double-conjugated retinoid serum specifically formulated for blemish-prone skin (AHARet-SA) in combination with exfoliating peel pads (double-conjugated retinoid, glycolic, lactic, and salicylic acids), a cleanser, mineral-based sunscreen, and a lightweight moisturizer in female participants with mild-to-moderate blemish-prone skin. Fifty-five percent of participants were Fitzpatrick Skin Type (FST) IV and 27% were FST V. Participants used the exfoliating peel pads (3x/week for 8 weeks; 2x/week for 4 weeks) followed by nightly AHARet-SA and a moisturizer (as needed). Improvements in skin were assessed using the 5-point Investigator Global Assessment Scale, and participant satisfaction and tolerability were assessed over 12 weeks. RESULTS: Significant mean improvement from baseline in skin clarity occurred after 4 weeks (14%; p = 0.04) with progressive improvements through week 12 (52%; p = 0.004). Eighty-eight percent of participants reported improvements in the appearance and texture of their skin and fewer blemishes/breakouts. Mild, transient adverse events were reported. CONCLUSIONS: A regimen comprised of a double-conjugated serum and exfoliating peel pads formulated for blemish-prone skin led to significant improvements from baseline in skin clarity after 12 weeks in participants with predominately darker skin tones and mild-to-moderate blemish-prone skin.


Assuntos
Acne Vulgar , Retinoides , Humanos , Feminino , Projetos Piloto , Resultado do Tratamento , Pele , Protetores Solares
17.
Neoplasma ; 70(5): 683-696, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38053380

RESUMO

Retinal G protein-coupled receptor (RGR) serves a retinal photoisomerase function to mediate retinoid metabolism and visual chromophore regeneration in the human eyes. Retinoids display critical functions in cell proliferation, differentiation, and apoptosis. Abnormal retinoid metabolism may contribute to tumor development. However, in human tumor tissues, the expression of RGR remains uncharacterized. Herein, we performed the analysis of RGR expression in 620 samples from 24 types of tumors by immunohistochemistry (IHC) and 33 cancer types from the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases by bioinformatic analyses. Furthermore, the biological role of RGR in glioma cells was investigated using molecular biology approaches in vitro. Notably, we found that brain lower grade glioma (LGG), in contrast to other tumor types, had the highest median score of IHC and RNA level of RGR expression. Survival analysis showed that low RGR expression was associated with worse overall survival in LGG (p<0.0001). RGR expression levels in glioma were also associated with pathological subtypes, grades, and isocitrate dehydrogenase (IDH) mutations. Moreover, its molecular function was closely associated with cadherin-related family member 1 (CDHR1), a tumor suppressive protein in glioma, suggesting that RGR might negatively regulate the tumorigenesis and progression of LGG through interacting with CDHR1. Our findings provide new insight into the role of RGR in human cancer, especially in glioma.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/patologia , Proteínas Relacionadas a Caderinas , Regulação para Baixo , Glioma/patologia , Proteínas do Tecido Nervoso/genética , Opsinas/genética , Opsinas/metabolismo , Prognóstico , Retinoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
18.
Int J Mol Sci ; 24(23)2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38069372

RESUMO

A comparative in vivo study of the effects of ionizing radiation (accelerated protons) and visible light (400-700 nm) on the retina and retinal pigment epithelium (RPE) of the mouse eye was carried out. Using the methods of fluorescence spectroscopy and high-performance liquid chromatography (HPLC), we analyzed the relative composition of retinoids in chloroform extracts obtained from the retinas and RPEs immediately after exposure of animals to various types of radiation and 4.5 months after they were exposed and maintained under standard conditions throughout the period. The fluorescent properties of chloroform extracts were shown to change upon exposure to various types of radiation. This fact indicates the accumulation of retinoid oxidation and degradation products in the retina and RPE. The data from fluorescence and HPLC analyses of retinoids indicate that when exposed to ionizing radiation, retinoid oxidation processes similar to photooxidation occur. Both ionizing radiation and high-intensity visible light have been shown to be characterized by long-term effects. The action of any type of radiation is assumed to activate the mechanism of enhanced reactive oxygen species production, resulting in a long-term damaging effect.


Assuntos
Clorofórmio , Epitélio Pigmentado da Retina , Camundongos , Animais , Epitélio Pigmentado da Retina/metabolismo , Retina/metabolismo , Retinoides/metabolismo , Luz , Radiação Ionizante
19.
Cell Rep ; 42(11): 113369, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-37922311

RESUMO

The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Netrina-1 , Retinoides , Células Estreladas do Fígado/metabolismo , Linhagem Celular Tumoral , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias Hepáticas/metabolismo , Receptores de Netrina , Proteínas de Ligação a DNA , Fatores de Transcrição , Proteínas Proto-Oncogênicas c-ets
20.
J Drugs Dermatol ; 22(11): 1094, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37943275

RESUMO

Gold microparticles are indicated as an accessory to 1064 nm lasers to facilitate photo-thermal heating of sebaceous glands for treating mild-to-moderate inflammatory acne vulgaris (Sebacia Microparticles, Coronado Aesthetics LLC, Southlake, TX). The following study assessed the safety and clinical benefit of gold microparticles/laser therapy when used together with commercially available topical acne products. Healthy patients, 12 to 45 years old with mild-to-moderate inflammatory facial acne were prescribed a topical pre-treatment retinoid for 3 to 4 weeks. The gold microparticle suspension was then applied to the entire face and massaged into the skin. The laser procedure was performed with commercially available 1064 nm Nd:YAG lasers with fluence in the 20 to 35 J/cm2 range, a 30 ms pulse duration, and direct cooling. Among participants completing the study (N=52), the mean percent change in inflammatory lesion counts (ILC) was -55% at month 2, reaching -68% at month 12. At that time, 86% of participants achieved a 40% decrease in ILC and 75% achieved a 60% decrease in ILC. Mean Investigator's Global Assessment (IGA) Scale scores decreased by 41.6% from 2.4 at day 0 to 1.4 at month 12. The percentage of participants with clear or almost clear skin increased from 7% at day 0 to 59% at month 12. Acne therapy with topically applied gold microparticles followed by 1064 nm laser irradiation is an effective treatment for moderate to moderately severe acne. The treatment was well-tolerated with a high degree of participant satisfaction. J Drugs Dermatol. 2023;22(11):1088-1094     doi:10.36849/JDD.7744.


Assuntos
Acne Vulgar , Retinoides , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Estudos Prospectivos , Acne Vulgar/diagnóstico , Acne Vulgar/tratamento farmacológico , Lasers , Ouro
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