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1.
Theranostics ; 13(13): 4333-4355, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37649609

RESUMEN

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor, with extremely low survival rates. Identifying key signaling pathways driving PDAC progression is crucial for the development of therapies to improve patient response rates. Kindlin-2, a multi-functional protein, is involved in numerous biological processes including cell proliferation, apoptosis and migration. However, little is known about the functions of Kindlin-2 in pancreatic cancer progression in vivo. Methods: In this study, we employ an in vivo PDAC mouse model to directly investigate the role of Kindlin-2 in PDAC progression. Then, we utilized RNA-sequencing, the molecular and cellular assays to determine the molecular mechanisms by which Kindlin-2 promotes PDAC progression. Results: We show that loss of Kindlin-2 markedly inhibits KrasG12D-driven pancreatic cancer progression in vivo as well as in vitro. Furthermore, we provide new mechanistic insight into how Kindlin-2 functions in this process, A fraction of Kindlin-2 was localized to the endoplasmic reticulum and associated with the RNA helicase DDX3X, a key regulator of mRNA translation. Loss of Kindlin-2 blocked DDX3X from binding to the 5'-untranslated region of c-Myc and inhibited DDX3X-mediated c-Myc translation, leading to reduced c-Myc-mediated glucose metabolism and tumor growth. Importantly, restoration of the expression of either the full-length Kindlin-2 or c-Myc, but not that of a DDX3X-binding-defective mutant of Kindlin-2, in Kindlin-2 deficient PDAC cells, reversed the inhibition of glycolysis and pancreatic cancer progression induced by the loss of Kindlin-2. Conclusion: Our studies reveal a novel Kindlin-2-DDX3X-c-Myc signaling axis in PDAC progression and suggest that inhibition of this signaling axis may provide a promising therapeutic approach to alleviate PDAC progression.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Ratones , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas c-myc , Transducción de Señal , Neoplasias Pancreáticas
2.
Cell Mol Life Sci ; 80(1): 18, 2022 Dec 24.
Artículo en Inglés | MEDLINE | ID: mdl-36564652

RESUMEN

Glomerular diseases afflict millions of people and impose an enormous burden on public healthcare costs worldwide. Identification of potential therapeutic targets for preventing glomerular diseases is of considerable clinical importance. CHILKBP is a focal adhesion protein and modulates a wide array of biological functions. However, little is known about the role of CHILKBP in glomerular diseases. To investigate the function of CHILKBP in maintaining the structure and function of podocytes in a physiologic setting, a mouse model (CHILKBP cKO) was generated in which CHILKBP gene was conditionally deleted in podocytes using the Cre-LoxP system. Ablation of CHILKBP in podocytes resulted in massive proteinuria and kidney failure in mice. Histologically, typical podocyte injury including podocyte loss, foot process effacement, and glomerulosclerosis was observed in CHILKBP cKO mice. Mechanistically, we identified ZO-1 as a key junctional protein that interacted with CHILKBP. Loss of CHILKBP in podocytes exhibited a significant reduction of ZO-1 expression, leading to abnormal actin organization, aberrant slit diaphragm protein expression and compromised podocyte filtration capacity. Restoration of CHILKBP or ZO-1 in CHILKBP-deficient podocytes effectively alleviated podocyte injury induced by the loss of CHILKBP in vitro and in vivo. Finally, we showed the glomerular expression of CHILKBP and ZO-1 was decreased in patients with proteinuric kidney diseases. Our findings reveal a novel signaling pathway consisting of CHILKBP and ZO-1 that plays an essential role in maintaining podocyte homeostasis and suggest novel therapeutic approaches to alleviate glomerular diseases.


Asunto(s)
Enfermedades Renales , Podocitos , Ratones , Animales , Podocitos/metabolismo , Glomérulos Renales/metabolismo , Enfermedades Renales/metabolismo , Transducción de Señal , Proteinuria/metabolismo
3.
Cell Death Dis ; 13(5): 482, 2022 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-35595729

RESUMEN

Androgen receptor (AR) signaling plays important roles in breast cancer progression. We show here that Kindlin-2, a focal adhesion protein, is critically involved in the promotion of AR signaling and breast cancer progression. Kindlin-2 physically associates with AR and Src through its two neighboring domains, namely F1 and F0 domains, resulting in formation of a Kindlin-2-AR-Src supramolecular complex and consequently facilitating Src-mediated AR Tyr-534 phosphorylation and signaling. Depletion of Kindlin-2 was sufficient to suppress Src-mediated AR Tyr-534 phosphorylation and signaling, resulting in diminished breast cancer cell proliferation and migration. Re-expression of wild-type Kindlin-2, but not AR-binding-defective or Src-binding-defective mutant forms of Kindlin-2, in Kindlin-2-deficient cells restored AR Tyr-534 phosphorylation, signaling, breast cancer cell proliferation and migration. Furthermore, re-introduction of phosphor-mimic mutant AR-Y534D, but not wild-type AR reversed Kindlin-2 deficiency-induced inhibition of AR signaling and breast cancer progression. Finally, using a genetic knockout strategy, we show that ablation of Kindlin-2 from mammary tumors in mouse significantly reduced AR Tyr-534 phosphorylation, breast tumor progression and metastasis in vivo. Our results suggest a critical role of Kindlin-2 in promoting breast cancer progression and shed light on the molecular mechanism through which it functions in this process.


Asunto(s)
Neoplasias de la Mama , Proteínas del Citoesqueleto , Proteínas Musculares , Receptores Androgénicos , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Femenino , Humanos , Proteínas de la Membrana , Ratones , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Proteínas de Neoplasias , Fosforilación , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Transducción de Señal , Tirosina/metabolismo
4.
Front Pharmacol ; 13: 872912, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35370728

RESUMEN

Capsaicin, a major ingredient in chili pepper, has broad pharmaceutical applications, including relieving pain, anti-inflammation, and treating psoriasis. In dermatological biology, capsaicin has been shown to prevent the ultraviolet (UV)-induced melanogenesis via TRPV1 receptor. To strengthen the roles of capsaicin in skin function, the damaged skin, triggered by exposure to UV, was reversed by capsaicin in both in vitro and in vivo models. In cultured dermal fibroblasts, the exposure to UV induced a decrease of collagen synthesis and increases expression of matrix metalloproteinases (MMPs), generation of reactive oxygen species (ROS), and phosphorylation of Erk and c-Jun, and these events subsequently led to skin damage. However, the UV-mediated damages could be reversed by pre-treatment with capsaicin in a dose-dependent manner. The effect of capsaicin in blocking the UV-mediated collagen synthesis was mediated by reducing generation of ROS in dermal fibroblasts, instead of the receptor for capsaicin. Hence, capsaicin has high potential value in applying as an agent for anti-skin aging in dermatology.

5.
J Cosmet Dermatol ; 20(10): 3278-3288, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33896085

RESUMEN

BACKGROUND: During melanogenesis, melanocytes produce melanin through enzymatic reactions. Microphthalmia-associated transcription factor (MITF) is a major regulator in controlling the expressions of melanogenic enzymes tyrosinase (TYR), tyrosine-related protein-1 (TRP1), and dopachrome tautomerase (DCT). Self-Growth Colony (SGC) is prepared from human platelet-rich plasma (PRP) having an enrichment of growth factors, and which has claimed skin regeneration function. AIM: In this study, we aim to identify and investigate the novel role of SGC in skin melanogenesis. METHODS: MTT assay was performed to determine the cytotoxicity of applied SGC. Melanin assay was adopted to quantify the intracellular melanin after SGC treatment. Promoter-driven luciferase assay, real-time PCR, and Western blotting were performed to determine the expressions of melanogenic enzymes and MITF in SGC-treated cultured Melan-A cells, being treated with or without UV induction. Ex vivo mouse skin was treated with SGC, and then was subjected to Western blotting and histochemical staining. RESULTS: We identified that SGC inhibited melanogenesis in cultured melanocytes and ex vivo mouse skin. The phenomena were attributed to a reduction of MITF expression, which subsequently down-regulated the melanogenic enzymes, that is, TYR, TRP1, and DCT. Moreover, ERK signaling was activated in the SGC-inhibited melanogenesis. CONCLUSIONS: The findings suggest that SGC extracting from human blood can be a safe and potential agent in promoting skin whitening.


Asunto(s)
Factor de Transcripción Asociado a Microftalmía , Plasma Rico en Plaquetas , Animales , Melaninas , Melanocitos , Ratones , Factor de Transcripción Asociado a Microftalmía/genética , Extractos Vegetales
6.
J Agric Food Chem ; 68(50): 14863-14873, 2020 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-33280383

RESUMEN

Chili pepper belongs to the genus Capsicum of Solanaceae family. Capsaicin is the primary capsaicinoid in placenta and flesh of chili pepper fruit, which has been shown to have various pharmacological functions, including gastric protection, anti-inflammation, and obesity treatment. Here, we revealed that capsaicin as well as chilli extract was able to inhibit synthesis of melanin in melanocytes. In cultured melanocytes, the melanin content was reduced to 54 ± 6.55% and 42 ± 7.41% with p < 0.001 under treatment of 50 µM capsaicin for 24 and 72 h, respectively. In parallel, the protein levels of tyrosinase and tyrosinase-related protein-1 were reduced to 62 ± 8.35% and 48 ± 8.92% with p < 0.001. Such an inhibitory effect of capsaicin was mediated by activation of transient receptor potential vanilloid 1-induced phosphorylation of extracellular signal-regulated kinase. This resulted in a degradation of microphthalmia-associated transcription factor, leading to reduction of melanogenic enzymes and melanin. These results revealed that capsaicin could be an effective inhibitor for skin melanogenesis. Hence, chili pepper, as our daily food, has potential in dermatological application, and capsaicin should be considered as a safe agent in treating hyperpigmentation problems.


Asunto(s)
Capsaicina/farmacología , Melaninas/biosíntesis , Melanocitos/efectos de los fármacos , Extractos Vegetales/farmacología , Canales Catiónicos TRPV/metabolismo , Animales , Capsicum/química , Línea Celular , Frutas/química , Humanos , Melanocitos/enzimología , Melanocitos/metabolismo , Ratones , Monofenol Monooxigenasa/genética , Monofenol Monooxigenasa/metabolismo , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Fosforilación , Piel/efectos de los fármacos , Piel/enzimología , Piel/metabolismo , Canales Catiónicos TRPV/genética
7.
Neurochem Int ; 141: 104861, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33038610

RESUMEN

Acetylcholinesterase (AChE) hydrolyses acetylcholine to choline and acetate, playing an important role in terminating the neurotransmission in brain and muscle. Recently, the non-neuronal functions of AChE have been proposed in different tissues, in which there are various factors to regulate the expression of AChE. In mammalian skin, AChE was identified in melanocytes and keratinocytes. Our previous study has indicated that AChE in keratinocyte affects the process of solar light-induced skin pigmentation; however, the expression of AChE in keratinocytes in responding to sunlight remains unknown. Here, we provided several lines of evidence to support a notion that AChE could be upregulated at transcriptional and translational levels in keratinocytes when exposed to solar light. The light-mediated AChE expression was triggered by Ca2+, supported by an induction of Ca2+ ionophore A23187 and a blockage by Ca2+ chelator BAPTA-AM. In addition, this increase on AChE transcriptional expression was eliminated by mutagenesis on the activating protein 1 (AP1) site in ACHE gene. Hence, the solar light-induced AChE expression is mediated by Ca2+ signalling through AP1 site. This finding supports the role of solar light in affecting the cholinergic system in skin cells, and which may further influence the dermatological function.


Asunto(s)
Acetilcolinesterasa/biosíntesis , Factor de Transcripción Activador 1/genética , Queratinocitos/enzimología , Queratinocitos/efectos de la radiación , Piel/enzimología , Piel/efectos de la radiación , Luz Solar , Acetilcolinesterasa/genética , Factor de Transcripción Activador 1/metabolismo , Animales , Calcimicina/farmacología , Calcio/metabolismo , Línea Celular , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Proteínas Ligadas a GPI/biosíntesis , Proteínas Ligadas a GPI/genética , Regulación Enzimológica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mutagénesis
8.
FASEB J ; 34(7): 8941-8958, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32519787

RESUMEN

Cholinergic system conducts signal transmission in brain and muscle. Besides nervous system, the nonneuronal functions of cholinergic system have been proposed in various tissues. The expression of cholinergic proteins and release of acetylcholine in human skin have been reported, but its mechanism and influence on dermatological functions is not elucidated. Here, the expression profile of cholinergic markers was further investigated in skin and keratinocyte. The expression levels of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), vesicular acetylcholine transporter (VAChT), and synaptophysin, were upregulated during differentiation of keratinocytes. In cultured keratinocytes, a transient exposure of solar light induced the release of acetylcholine, which was mediated by intracellular Ca2+ mobilization. The light-induced acetylcholine release was mediated by the present of opsin. The light-induced melanogenesis was inhibited by acetylcholine or AChE inhibitor in melanocyte in vitro and mouse skin ex vivo. These results indicated that the potential role of cholinergic system could be a negative regulator in skin pigmentation.


Asunto(s)
Acetilcolina/metabolismo , Acetilcolinesterasa/metabolismo , Queratinocitos/metabolismo , Melanocitos/metabolismo , Piel/metabolismo , Luz Solar , Acetilcolinesterasa/química , Animales , Humanos , Queratinocitos/citología , Queratinocitos/efectos de la radiación , Masculino , Melanocitos/citología , Melanocitos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Piel/citología , Piel/efectos de la radiación
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