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1.
Infect Immun ; 89(3)2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33257536

RESUMEN

Schistosomiasis is a parasitic helminth disease that can cause organ lesions leading to health damage. During a schistosome infection, schistosome eggs can flow into the liver along the portal vein. Numerous inflammatory cells gather around the eggs, causing granulomas and fibrosis in the liver. In this process, many molecules are involved in the initiation and regulation of the fibrous scar formation. However, the precise molecular mechanisms responsible for the progression of granuloma formation and fibrosis initiation caused by schistosome infection have not been extensively studied. In this study, C57BL/6 wild-type mice and Stat3flox/flox Alb-Cre mice were infected with cercariae of Schistosoma japonicum Liver injury, effector molecule levels, and RNA transcriptome resequencing of liver tissue were detected at 4, 5, and 6 weeks postinfection. We investigated the role of STAT3 (signal transducer and activator of transcription 3) in Schistosoma-induced liver injury in mice. After 6 weeks postinfection, there was obvious liver fibrosis. A sustained pathological process (inflammation, oxidative stress, proliferation, and apoptosis) occurred in S. japonicum-induced liver fibrosis initiation. Meanwhile, we observed activation of the STAT3 pathway in hepatic injury during S. japonicum infection by RNA transcriptome resequencing. Liver deficiency of phospho-STAT3 alleviated infection-induced liver dysfunction, hepatic granuloma formation, and fibrosis initiation. It also promoted STAT3-dependent apoptosis and reduced liver inflammation, oxidative stress, and proliferation. Our results suggest that STAT3 signal pathway and its mediating inflammation, oxidative stress, proliferation, and apoptosis are involved in S. japonicum-induced liver injury and may be a new potential guideline for the treatment of schistosomiasis.


Asunto(s)
Apoptosis/genética , Proliferación Celular/genética , Inflamación/genética , Cirrosis Hepática/genética , Estrés Oxidativo/genética , Factor de Transcripción STAT3/genética , Esquistosomiasis Japónica/genética , Animales , Inflamación/parasitología , Cirrosis Hepática/parasitología , Schistosoma japonicum/genética , Esquistosomiasis Japónica/patología
2.
Ann Hepatol ; 21: 100224, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32702499

RESUMEN

Janus protein tyrosine kinase (JAK) has the ability to activate signal transducer and activator of transcription (STAT). STAT3 is a valued member of the JAK/STAT signaling pathway. In recent years, several studies have documented that STAT3 is closely related to the occurrence and development of liver fibrosis caused by various factors. Activation of STAT3 can play anti- or pro-inflammatory roles in the pathogenesis of liver fibrosis. This article reviewed the recent studies on STAT3 in the development of various liver fibrosis to find a more effective method to relieve and cure liver diseases, such as hepatitis B virus (HBV), non-alcoholic fatty liver disease (NAFLD), schistosomiasis, and chemical liver injury.


Asunto(s)
ADN/genética , Regulación de la Expresión Génica , Cirrosis Hepática/genética , Factor de Transcripción STAT3/genética , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/metabolismo , Factor de Transcripción STAT3/biosíntesis , Transducción de Señal
3.
Cancer Cell Int ; 20: 470, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33005103

RESUMEN

BACKGROUND: Dysfunction of microRNAs (miRNAs) is a major cause of aberrant expression of inflammatory cytokines and contributes to macrophage polarization. Proinflammatory M1 macrophages promote T helper (Th) 1 responses and show tumoricidal activity, whereas M2 macrophages display regulatory functions in tissue repair and remodeling and promote Th2 immune responses. Previous studies have shown that miRNA let-7 is associated with cellular differentiation and that the expression of let-7b-5p is significantly augmented in M2 macrophages. However, the mechanism by which let-7b-5p regulates macrophage differentiation in prostate cancer (PCa) remains largely unknown. METHODS: Human macrophages were induced by blood monocytes from healthy male donors, and M1 macrophages were polarized by stimulating them overnight with 100 ng/ml of lipopolysaccharides and 100 ng/ml of IFN-γ. Conditioned medium from PC-3 cells was used to induce prostatic macrophages (M-CMs) in vitro, and we then transfected let-7b-5p mimics or inhibitors into M1 and M-CMs for 72 h. The expression of cluster of differentiation 206 (CD206) in each group was detected with the High-Throughput Connotation of Imaging System. We used quantitative real-time polymerase chain reaction (qRT-PCR) to examine the expression of the inflammatory cytokines IL-10, IL-12, IL-13, TNF-alpha, and let-7b in macrophages. SOCS1 protein levels were evaluated by ELISA, and the phosphorylation difference in STAT family member proteins was analyzed using CST signal-pathway chip. Phagocytosis by macrophages and the effect of macrophages on the proliferation of prostate cancer PC-3 cells were evaluated with phagocytosis assay or the Cell Counting Kit-8 (CCK-8) and colony formation assay. The relationship between SOCS1 and let-7b-5p was confirmed with a dual-luciferase reporter. RESULTS: The expression of cluster of differentiation 206 (CD206, a M2-like macrophage surface molecule) was significantly increased in M1 macrophages treated with let-7b-5p mimics, while CD206 expression was decreased in M-CMs treated with let-7b-5p inhibitors. Overexpression or knockdown of let-7b-5p significantly affected the expression of inflammatory factors in macrophages-including interleukin 10 (IL-10), IL-12, IL-13, and tumor necrosis factor alpha. Let-7b-5p downregulated the expression of suppressor of cytokine signaling 1 (SOCS1) and increased the phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5a proteins in M-CMs and M1 macrophages with let-7b-5p mimics relative to the other groups. In addition, with the elevated expression of let-7b-5p, the phagocytosis by macrophages showed a commensurate and significant decrease. As a result, M-CMs treated with let-7b-5p inhibitors reduced the proliferation of PC-3 PCa cells. CONCLUSIONS: Collectively, these data indicated that let-7b-5p may regulate M2 polarization through the SOCS1/STAT pathway and that reversal of M2 differentiation by let-7b-5p inhibitors enhanced macrophage phagocytosis, ultimately inhibiting the proliferation of PCa cells.

4.
Pharmacol Res ; 159: 104926, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32502636

RESUMEN

Cardiac remodeling is accompanied by cardiac hypertrophy, fibrosis, dysfunction, and eventually leading to heart failure. Intermedin (IMD), as a paracrine/autocrine peptide, has a protective effect in cardiovascular diseases. In this study, we elucidated the role and the underlying mechanism of IMD in pathological remodeling. Pathological remodeling mouse models were induced by abdominal aorta constriction for 4 weeks or angiotensin II (Ang II) infusion for 2 weeks in wildtype, IMD-overexpression, IMD-knockout and klotho-knockdown mice. Western blot, real-time PCR, histological staining, echocardiography and hemodynamics were used to detect the role of IMD in cardiac remodeling. Cardiac hypertrophy, fibrosis and dysfunction were significantly aggravated in IMD-knockout mice versus wildtype mice, and the expression of klotho was downregulated. Conversely, cardiac remodeling was alleviated in IMD-overexpression mice, and the expression of klotho was upregulated. Hypertension induced by Ang II infusion rather than abdominal aorta constriction was mitigated by IMD. However, the cardioprotective effect of IMD was blocked in klotho-knockdown mice. Similar results were found in cultured neonatal rat cardiomyocytes, which was pretreated with IMD before Ang II stimulation. Mechanistically, IMD inhibited the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the activity of calcineurin to protect against cardiac hypertrophy through upregulating klotho in vivo and in vitro. Furthermore, peroxisome proliferator-activated receptor γ (PPARγ) might mediate IMD upregulating klotho. In conclusion, pathological remodeling may be alleviated by endogenous IMD, which inhibits the expression of calcineurin and p-CaMKII by upregulating klotho via the PPARγ pathway. It suggested that IMD might be a therapeutic target for heart disease.


Asunto(s)
Glucuronidasa/metabolismo , Hipertrofia Ventricular Izquierda/prevención & control , Miocitos Cardíacos/metabolismo , Neuropéptidos/metabolismo , Disfunción Ventricular Izquierda/prevención & control , Función Ventricular Izquierda , Remodelación Ventricular , Angiotensina II , Animales , Aorta Abdominal/fisiopatología , Aorta Abdominal/cirugía , Calcineurina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Células Cultivadas , Constricción , Modelos Animales de Enfermedad , Fibrosis , Glucuronidasa/genética , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Proteínas Klotho , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Neuropéptidos/genética , PPAR gamma/metabolismo , Hormonas Peptídicas/farmacología , Fosforilación , Ratas Sprague-Dawley , Transducción de Señal , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología
5.
Infect Immun ; 87(12)2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31570558

RESUMEN

Schistosomiasis is a parasitic helminth disease that can cause severe inflammatory pathology, leading to organ damage, in humans. During a schistosomal infection, the eggs are trapped in the host liver, and products derived from eggs induce a polarized Th2 cell response, resulting in granuloma formation and eventually fibrosis. Previous studies indicated that the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is involved in schistosomiasis-associated liver fibrosis and that taurine could ameliorate hepatic granulomas and fibrosis caused by Schistosoma japonicum infection. Nevertheless, the precise role and molecular mechanism of the NLRP3 inflammasome and the protective effects of taurine in S. japonicum infection have not been extensively studied. In this study, we investigated the role of the NLRP3 inflammasome and the hepatoprotective mechanism of taurine in schistosoma-induced liver injury in mice. NLRP3 deficiency ameliorated S. japonicum-infection-induced hepatosplenomegaly, liver dysfunction, and hepatic granulomas and fibrosis; it also reduced NLRP3-dependent liver pyroptosis. Furthermore, taurine suppressed hepatic thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in mice with S. japonicum infections, thereby inhibiting the activation of downstream inflammatory mediators such as interleukin-1ß and subsequent pyroptosis. Our results suggest that the TXNIP/NLRP3 inflammasome pathway and mediating pyroptosis are involved in S. japonicum-induced liver injury and may be a potential therapeutic target for schistosomiasis treatment. In addition, taurine may be useful to alleviate or to prevent the occurrence of schistosomiasis-associated liver fibrosis.


Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Inflamasomas/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Schistosoma japonicum/inmunología , Esquistosomiasis Japónica/inmunología , Taurina/farmacología , Tiorredoxinas/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Hígado/lesiones , Hígado/parasitología , Cirrosis Hepática/parasitología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Piroptosis/inmunología , Esquistosomiasis Japónica/parasitología , Transducción de Señal/inmunología
6.
Microb Pathog ; 130: 204-212, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30885749

RESUMEN

A proliferation of studies have demonstrated that the toll-like receptor 2 (TLR2) pathway affects the chemotaxis, phagocytosis, and cytokine release of neutrophils when pathogens invade. Our previous studies have demonstrated that pretreatment with high doses of Pam3CSK4 (>25 µg/ml) improves the antimicrobial activity of neutrophils, however, short-lived neutrophils limit their therapeutic functions. Here, we used granulocyte macrophage-colony stimulating factor (GM-CSF) to generate neutrophils from murine bone marrow, and assessed their effect on the immune response against methicillin-resistant Staphylococcus aureus. As comparing with classical method of generating neutrophils directly from murine bone marrow, our findings show that pretreatment with Pam3CSK4 enhanced the phagocytic and killing activities against MRSA by the GM-CSF induced neutrophils (GM-CSF neutrophils). Chemotaxis of GM-CSF induced neutrophils was significantly increased after the pretreatment with Pam3CSK4. Furthermore, Pam3CSK4 pretreatment enhanced iNOS, CRAMP, TNF-α, IL-1ß, IL-10, and IL-6 expression. Finally, we observed that p38MAPK and Akt phosphorylation kinases were increased significantly in GM-CSF neutrophils pretreatment with Pam3CSK4 in a dose- and time-dependent manner, whereas p38MAPK inhibitor (SB2021190) and PI3K inhibitor (LY294002) attenuated the antimicrobial activities including phagocytosis, killing activity, respiratory burst, and the release of lactoferrin(LTF) by the GM-CSF induced neutrophils. Together, these findings suggest that pretreatment with Pam3CSK4 enhances the antibacterial function of GM-CSF neutrophils against MRSA, and this could be related to the p38MAPK and PI3K signaling pathways.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Lipopéptidos/metabolismo , Staphylococcus aureus Resistente a Meticilina/inmunología , Neutrófilos/inmunología , Receptor Toll-Like 2/metabolismo , Animales , Células Cultivadas , Quimiotaxis/efectos de los fármacos , Ratones , Neutrófilos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Estallido Respiratorio/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
7.
Int J Cancer ; 143(8): 2039-2052, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-29752722

RESUMEN

The activity of negative immune regulatory molecules, such as indoleamine 2,3-oxygenase (IDO), significantly attenuates DC (Dendritic cells)-mediated immunotherapy. We have previously reported that knockdown of IDO using siRNA can reinstall anti-tumor immunity. However, a DC-targeted siRNA delivery system for in vivo mobilized DCs remains to be developed, while gene silencing in mobilized DCs for cancer immunotherapy has never been explored. In our study, we developed a novel DC-targeted siRNA delivery system, man-GNR-siIDO, using as a nanocarrier of siRNA specific for IDO (siIDO) and mannose (man) as a guide molecule for targeting DCs. We explored the immunostimulatory man-GNR-siIDO nano-construct in DCs mobilized by Flt3-L, a receptor-type tyrosine kinase ligand, for lung cancer immunotherapy. In vivo DC-targeted gene silencing of IDO resulted in robust anti-tumor immunity as evidenced by promoting DC maturation, up-regulating tumor antigen-specific T-cell proliferation and enhancing tumor-specific cytotoxicity. A combinatorial treatment for Lewis Lung Carcinoma (LLC)-bearing mice, with man-GNR-siIDO and Flt3-L, significantly attenuated tumor growth and delayed tumor formation, suggesting the treatment feasibility of the man-GNR-siIDO system in Flt3-L mobilized DCs in the immunotherapy of lung cancer. Therefore, our study highlights a clinical potential for a first-in-class anti-cancer immunotherapy through simultaneous DC-mobilization and DC-targeted gene silencing of IDO with man-GNR-siIDO and Flt3-L treatments.


Asunto(s)
Carcinoma Pulmonar de Lewis/terapia , Células Dendríticas/inmunología , Silenciador del Gen/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Animales , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/inmunología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/genética , Humanos , Inmunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/inmunología
8.
Nanomedicine ; 14(5): 1679-1693, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29684526

RESUMEN

Melanoma is significantly associated with mutant BRAF gene, a suitable target for siRNA-based anti-melanoma therapy. However, a tumor-specific delivery system is a major hurdle for clinical applications. Here, we developed a novel nano-carrier, FA-GNR-siBRAF for safe topical application, which consists of folic acid (FA) as the tumor-targeting moiety, golden nanorods (GNR) providing photothermal capability to kill tumor cells under laser irradiation, and siRNA specifically silencing BRAF (siBRAF). The in vitro and in vivo results revealed that FA-GNR-siBRAF displayed high transfection rates, and subsequently induced remarkable gene knockdown of BRAF, resulting in suppression of melanoma growth due to the interruption of the MEK/ERK pathway. Combinatorial photothermal effects and BRAF knockdown by FA-GNR-siBRAF effectively killed tumor cells through apoptosis, with enhanced efficiency than individual treatments. Therefore, the FA-GNR-siBRAF simultaneously induced BRAF gene silencing and photothermal effects which achieved synergistic efficacy in the treatment of melanoma, paving a new path for developing clinical treatment methods for melanoma.


Asunto(s)
Ácido Fólico/química , Silenciador del Gen , Hipertermia Inducida , Melanoma Experimental/terapia , Nanotubos/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , ARN Interferente Pequeño/genética , Animales , Apoptosis , Terapia Combinada , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/genética , Femenino , Oro/química , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 1/genética , Ratones , Ratones Endogámicos C57BL , Fototerapia , Proteínas Proto-Oncogénicas B-raf/genética , Células Tumorales Cultivadas
9.
Arterioscler Thromb Vasc Biol ; 36(11): 2176-2190, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27634835

RESUMEN

OBJECTIVE: Oxidative stress plays a critical role in the development of abdominal aortic aneurysm (AAA). Intermedin (IMD) is a regulator of oxidative stress. Here, we investigated whether IMD reduces AAA by inhibiting oxidative stress. APPROACH AND RESULTS: In angiotensin II-induced ApoE-/- mouse and CaCl2-induced C57BL/6J mouse model of AAA, IMD1-53 significantly reduced the incidence of AAA and maximal aortic diameter. Ultrasonography, hematoxylin, and eosin staining and Verhoeff-van Gieson staining showed that IMD1-53 significantly decreased the enlarged aortas and elastic lamina degradation induced by angiotensin II or CaCl2. Mechanistically, IMD1-53 attenuated oxidative stress, inflammation, vascular smooth muscle cell apoptosis, and matrix metalloproteinase activation. IMD1-53 inhibited the activation of redox-sensitive signaling pathways, decreased the mRNA and protein expression of nicotinamide adenine dinucleotide phosphate oxidase subunits, and reduced the activity of nicotinamide adenine dinucleotide phosphate oxidase in AAA mice. Expression of Nox4 was upregulated in human AAA segments and in angiotensin II-treated mouse aortas and was markedly decreased by IMD1-53. In vitro, vascular smooth muscle cells with small-interfering RNA knockdown of IMD showed significantly increased angiotensin II-induced reactive oxygen species, and small-interfering RNA knockdown of Nox4 markedly inhibited the reactive oxygen species. IMD knockdown further increased the apoptosis of vascular smooth muscle cells and inflammation, which was reversed by Nox4 knockdown. Preincubation with IMD17-47 and protein kinase A inhibitor H89 inhibited the effect of IMD1-53, reducing Nox4 protein levels. CONCLUSIONS: IMD1-53 could have a protective effect on AAA by inhibiting oxidative stress.


Asunto(s)
Antioxidantes/farmacología , Aorta Abdominal/efectos de los fármacos , Aneurisma de la Aorta Abdominal/prevención & control , Estrés Oxidativo/efectos de los fármacos , Hormonas Peptídicas/farmacología , Adrenomedulina/metabolismo , Angiotensina II , Animales , Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Apoptosis/efectos de los fármacos , Cloruro de Calcio , Células Cultivadas , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Dilatación Patológica , Modelos Animales de Enfermedad , Genotipo , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , NADPH Oxidasas/metabolismo , Neuropéptidos/metabolismo , Hormonas Peptídicas/metabolismo , Fenotipo , Interferencia de ARN , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transfección
10.
J Cardiovasc Pharmacol ; 67(6): 519-25, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26859198

RESUMEN

Adhesion of monocytes to the vascular endothelium is crucial in atherosclerosis development. Connexins (Cxs) which form hemichannels or gap junctions, modulate monocyte-endothelium interaction. We previously found that rutaecarpine, an active ingredient of the Chinese herbal medicine Evodia, reversed the altered Cx expression induced by oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells, and consequently decreases the adhesive properties of endothelial cells to monocytes. This study further investigated the effect of rutaecarpine on Cx expression in monocytes exposed to ox-LDL. In cultured human monocytic cell line THP-1, ox-LDL rapidly reduced the level of atheroprotective Cx37 but enhanced that of atherogenic Cx43, thereby inhibiting adenosine triphosphate release through hemichannels. Pretreatment with rutaecarpine recovered the expression of Cx37 but inhibited the upregulation of Cx43 induced by ox-LDL, thereby improving adenosine triphosphate-dependent hemichannel activity and preventing monocyte adhesion. These effects of rutaecarpine were attenuated by capsazepine, an antagonist of transient receptor potential vanilloid subtype 1. The antiadhesive effects of rutaecarpine were also attenuated by hemichannel blocker 18α-GA. This study provides additional evidence that rutaecarpine can modulate Cx expression through transient receptor potential vanilloid subtype 1 activation in monocytes, which contributes to the antiadhesive properties of rutaecarpine.


Asunto(s)
Conexinas/efectos de los fármacos , Endotelio Vascular/metabolismo , Alcaloides Indólicos/farmacología , Lipoproteínas LDL/metabolismo , Monocitos/metabolismo , Quinazolinas/farmacología , Adenosina Trifosfato/metabolismo , Aterosclerosis/fisiopatología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Factores de Tiempo
11.
Calcif Tissue Int ; 96(1): 80-7, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25416842

RESUMEN

Thyroid hormones (THs) including thyroxine (T4) and triiodothyronine (T3) play critical roles in bone remodeling. However, the role and mechanism of THs in vascular calcification (VC) have been unclear. To explore the pathophysiological roles of T3 on VC, we investigated the changes in plasma and aortas of THs concentrations and the effect of T3 on rat VC induced by vitamin D3 plus nicotine (VDN). VDN-treated rat showed decreased plasma T3 content, increased vascular calcium deposition, and alkaline phosphatase (ALP) activity. Administration of T3 (0.2 mg/kg body weight IP) for 10 days greatly reduced vascular calcium deposition and ALP activity in calcified rat aortas when compared with controls. Concurrently, the loss of smooth muscle lineage markers α-actin and SM22a was restored, and the increased bone-associated molecules, such as runt-related transcription factor2 (Runx2), Osterix, and osteopontin (OPN) levels in calcified aorta, were reduced by administration of T3. The suppression of klotho in calcified rat aorta was restored by T3. Methimazole (400 mg/L) blocked the beneficial effect of T3 on VC. These results suggested that T3 can inhibit VC development.


Asunto(s)
Remodelación Ósea/efectos de los fármacos , Colecalciferol/farmacología , Nicotina/farmacología , Hormonas Tiroideas/farmacología , Calcificación Vascular/tratamiento farmacológico , Animales , Huesos/irrigación sanguínea , Modelos Animales de Enfermedad , Masculino , Osteopontina/metabolismo , Ratas Sprague-Dawley , Hormonas Tiroideas/metabolismo , Calcificación Vascular/inducido químicamente
12.
Chemistry ; 20(23): 7160-7, 2014 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-24771671

RESUMEN

The development of magnetic nanoparticles (MNPs) with functional groups has been intensively pursued in recent years. Herein, a simple, versatile, and cost-effective strategy to synthesize water-soluble and amino-functionalized MNPs, based on the thermal decomposition of phthalimide-protected metal-organic precursors followed by deprotection, was developed. The resulting amino-functionalized Fe3O4, MnFe2O4, and Mn3O4 MNPs with particle sizes of about 14.3, 7.5, and 6.6 nm, respectively, had narrow size distributions and good dispersibility in water. These MNPs also exhibited high magnetism and relaxivities of r2 = 107.25 mM(-1) s(-1) for Fe3O4, r2 = 245.75 mM(-1) s(-1) for MnFe2O4, and r1 = 2.74 mM(-1) s(-1) for Mn3O4. The amino-functionalized MNPs were further conjugated with a fluorescent dye (rhodamine B) and a targeting ligand (folic acid: FA) and used as multifunctional probes. Magnetic resonance imaging and flow-cytometric studies showed that these probes could specifically target cancer cells overexpressing FA receptors. This new protocol opens a new way for the synthesis and design of water-soluble and amino-functionalized MNPs by an easy and versatile route.


Asunto(s)
Nanopartículas de Magnetita/química , Metales/química , Ftalimidas/química , Apoptosis/efectos de los fármacos , Compuestos Férricos/química , Óxido Ferrosoférrico/química , Citometría de Flujo , Colorantes Fluorescentes/química , Ácido Fólico/química , Células HeLa , Humanos , Células MCF-7 , Imagen por Resonancia Magnética , Nanopartículas de Magnetita/toxicidad , Compuestos de Manganeso/química , Óxidos/química , Tamaño de la Partícula , Rodaminas/química
13.
Exp Parasitol ; 145: 1-6, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24996067

RESUMEN

Gastrointestinal helminth infection, including Trichinella spiralis, initiates a series of intestinal structural, cellular and physiological changes. Intestinal invasion is an important stage of trichinellosis because it determines the development and subsequent course of the disease and its consequences. Apoptosis mediated by endoplasmic reticulum stress (ERS) plays a key role in infectious diseases, but the effect of T. spiralis infection on inducing apoptosis in the small intestine has been neglected. We investigated apoptosis and changes in ERS-associated apoptosis molecules in the intestine of mice with T. spiralis infection. TUNEL staining and detection of the apoptotic marker cleaved caspase 3 revealed that apoptosis occurred in the mouse intestine at days 3 and 7 post-infection. The ER chaperone 78-kDa glucose-regulated protein (GRP78) was upregulated at days 3 and 7 post-infection. The ERS-associated apoptosis molecules C/EBP homologous protein, cleaved caspase 12 and c-Jun NH2-terminal kinase were upregulated at days 3 and 7, days 3, 7 and 10 and days 7 and 10 post-infection, respectively. Thus, apoptosis occurred in the intestine of mice with T. spiralis infection, and the ERS-mediated apoptosis pathway was activated by infection with this small intestine dwelling nematode.


Asunto(s)
Apoptosis , Estrés del Retículo Endoplásmico/fisiología , Yeyuno/patología , Trichinella spiralis/fisiología , Triquinelosis/patología , Animales , Caspasa 12/metabolismo , Chaperón BiP del Retículo Endoplásmico , Femenino , Proteínas de Choque Térmico/metabolismo , Yeyuno/parasitología , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Ratones Endogámicos ICR , Conejos , Factor de Transcripción CHOP/metabolismo , Regulación hacia Arriba
14.
Heliyon ; 10(11): e32229, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38868006

RESUMEN

Recent studies have underscored the cardioprotective properties of liraglutide. This research explores its impact on cardiac hypertrophy and heart failure following transverse aortic constriction (TAC). We found that liraglutide administration markedly ameliorated cardiac hypertrophy, fibrosis, and function. These benefits correlated with increased ANP expression and reduced activity in the calcineurin A/NFATc3 signaling pathway. Moreover, liraglutide mitigated ER stress and cardiomyocyte apoptosis, and enhanced autophagy. Notably, the positive effects of liraglutide diminished when co-administered with A71915, an ANP inhibitor, suggesting that ANP upregulation is critical to its cardioprotective mechanism.

15.
Stem Cells Transl Med ; 13(2): 151-165, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-37936499

RESUMEN

Hepatocyte-like cells (HLCs) that are differentiated from mesenchymal stem cells (MSCs) provide a valuable resource for drug screening and cell-based regeneration therapy. Differentiating HLCs into 3D spheroids enhances their phenotypes and functions. However, the molecular mechanisms underlying MSCs hepatogenic differentiation are not fully understood. In this study, we generated HLCs from human adipose-derived mesenchymal stem cells (hADMSCs) in both 2D and 3D cultures. We performed an acetyl-proteomics assay on the HLCs derived from both 2D and 3D differentiation and identified a differential change in H3K56 acetylation between the 2 differentiated cells. Our findings revealed that 3D differentiation activated ALB gene transcription by increasing the acetylation level of H3K56, thereby enhancing the phenotypes and functions of HLCs and further promoting their maturation. Notably, inhibiting p300 reduced the acetylation level of H3K56 during hepatogenic differentiation, leading to decreased phenotypes and functions of HLCs, whereas activation of p300 promoted hepatogenic differentiation, suggesting that p300 plays a critical role in this process. In summary, our study demonstrates a potential mechanism through which 3D spheroids differentiation facilitates hADMSCs differentiation into HLCs by promoting p300-mediated H3K56 acetylation, which could have significant clinical applications in liver regeneration and disease modeling.


Asunto(s)
Hepatocitos , Células Madre Mesenquimatosas , Humanos , Acetilación , Diferenciación Celular , Células Cultivadas
16.
Biomaterials ; 304: 122408, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38041911

RESUMEN

The limitations of traditional two-dimensional (2D) cultures and animal testing, when it comes to precisely foreseeing the toxicity and clinical effectiveness of potential drug candidates, have resulted in a notable increase in the rate of failure during the process of drug discovery and development. Three-dimensional (3D) in-vitro models have arisen as substitute platforms with the capacity to accurately depict in-vivo conditions and increasing the predictivity of clinical effects and toxicity of drug candidates. It has been found that 3D models can accurately represent complex tissue structure of human body and can be used for a wide range of disease modeling purposes. Recently, substantial progress in biomedicine, materials and engineering have been made to fabricate various 3D in-vitro models, which have been exhibited better disease progression predictivity and drug effects than convention models, suggesting a promising direction in pharmaceutics. This comprehensive review highlights the recent developments in 3D in-vitro tissue models for preclinical applications including drug screening and disease modeling targeting multiple organs and tissues, like liver, bone, gastrointestinal tract, kidney, heart, brain, and cartilage. We discuss current strategies for fabricating 3D models for specific organs with their strengths and pitfalls. We expand future considerations for establishing a physiologically-relevant microenvironment for growing 3D models and also provide readers with a perspective on intellectual property, industry, and regulatory landscape.


Asunto(s)
Bioimpresión , Ingeniería de Tejidos , Animales , Humanos , Ingeniería de Tejidos/métodos , Bioimpresión/métodos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Impresión Tridimensional
17.
Pharmaceuticals (Basel) ; 17(9)2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39338366

RESUMEN

Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with myocardial fatty acid metabolism. Carnitine palmitoyltransferase-1ß (CPT-1ß) is the rate-limiting enzyme responsible for ß-oxidation of long-chain fatty acids. Intermedin (IMD) is a pivotal bioactive small molecule peptide, participating in the protection of various cardiovascular diseases. However, the role and underlying mechanisms of IMD in DCM are still unclear. In this study, we investigated whether IMD alleviates DCM via regulating CPT-1ß. A rat DCM model was established by having rats to drink fructose water for 12 weeks. A mouse DCM model was induced by feeding mice a high-fat diet for 16 weeks. We showed that IMD and its receptor complexes levels were significantly down-regulated in the cardiac tissues of DCM rats and mice. Reduced expression of IMD was also observed in neonatal rat cardiomyocytes treated with palmitic acid (PA, 300 µM) in vitro. Exogenous and endogenous IMD mitigated cardiac hypertrophy, fibrosis, dysfunction, and lipid accumulation in DCM rats and IMD-transgenic DCM mice, whereas knockout of IMD worsened these pathological processes in IMD-knockout DCM mice. In vitro, IMD alleviated PA-induced cardiomyocyte hypertrophy and cardiac fibroblast activation. We found that CPT-1ß enzyme activity, mRNA and protein levels, and acetyl-CoA content were increased in T2DM patients, rats and mice. IMD up-regulated the CPT-1ß levels and acetyl-CoA content in T2DM rats and mice. Knockdown of CPT-1ß blocked the effects of IMD on increasing acetyl-CoA content and on inhibiting cardiomyocyte hypertrophy and cardiac fibroblast activation. IMD receptor antagonist IMD17-47 and the phosphatidyl inositol 3 kinase (PI3K)/protein kinase B (Akt) inhibitor LY294002 reversed the effects of IMD on up-regulating CPT-1ß and acetyl-CoA expression and on inhibiting cardiomyocyte hypertrophy and cardiac fibroblast activation. We revealed that IMD alleviates DCM by up-regulating CPT-1ß via calcitonin receptor-like receptor/receptor activity-modifying protein (CRLR/RAMP) receptor complexes and PI3K/Akt signaling. IMD may serve as a potent therapeutic target for the treatment of DCM.

18.
Exp Parasitol ; 134(1): 92-101, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23466989

RESUMEN

Parasitic helminth and their products can suppress or modulate the host immune response for long-term survival and continued infection. Commonly, helminth can induce conditional T helper cell type 2 (Th2) response, regulatory T cell and cytokines, and altered function of antigen presentation cells by modulating toll-like receptors (TLRs). The helminth Trichinella spiralis establishes chronic infection in skeletal muscles of a wide range of mammalian hosts. We infected mice with T. spiralis and investigated Th1/Th2/Th17 cytokine profiles in serum and expression of TLRs and related signal molecules in spleen at various times post-infection. The infection evoked a mixed Th1/Th2 and inhibited Th17 immune response, with initial predominance of a Th1 response in intestine stage and subsequent predominance of a Th2 response in muscle stage. Different stages of infection had different impacts on the expression of TLRs and related signaling molecules. In the adult stage of infection, TLR1 and TLR4 were upregulated and the MyD88-dependent signal pathway was activated. The muscle larvae inhibited TLR4 and TRIF-dependent signal pathway. Our results implied that T. spiralis infection may regulate Th1/Th2/Th17 cytokine production through TLRs.


Asunto(s)
Citocinas/sangre , Bazo/metabolismo , Receptores Toll-Like/metabolismo , Trichinella spiralis/inmunología , Triquinelosis/inmunología , Animales , Citocinas/metabolismo , Regulación hacia Abajo , Femenino , Intestinos/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Músculo Esquelético/parasitología , Bazo/inmunología , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología , Regulación hacia Arriba
19.
Parasitol Res ; 112(10): 3457-63, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23832642

RESUMEN

The parasitic nematode Trichinella spiralis can cause trichinellosis, which leads to pathological processes in the intestine and muscle. The intestinal invasion determines the development, subsequent course, and consequences of the disease. Gastrointestinal nematode infection, including with T. spiralis, is accompanied by a rapid and reversible expansion of mucosal mast cell and goblet cell in the intestinal epithelium, which play important roles in the host immune response to parasite and worm expulsion from the intestine. Taurine and its derivatives have anti-infection and anti-inflammatory properties. We investigated whether taurine supplementation in mice could influence the development and pathological processes of infection with T. spiralis. Supplementing 1% taurine in drinking water in mice infected with T. spiralis could alleviate the burden of intestinal adult worms on days 7 and 10 postinfection (all p < 0.01) and the formation of infective muscle larvae in striated muscle during T. spiralis infection (p < 0.01). As compared with T. spiralis infection alone, taurine treatment increased the number of goblet cells on days 7, 10, and 15 (p < 0.01 and p < 0.05) and alleviated intestinal mucosal mast cell hyperplasia on days 10 and 15 (all p < 0.01). So taurine supplementation in drinking water increased infection-induced intestinal goblet cell hyperplasia and ameliorated mucosal mastocytosis. Thus, taurine can ameliorate the pathological processes of trichinellosis and may be of great value for the treatment and prevention of infection with T. spiralis and other gastrointestinal nematodes.


Asunto(s)
Agua Potable/química , Parasitosis Intestinales/tratamiento farmacológico , Taurina/farmacología , Triquinelosis/tratamiento farmacológico , Animales , Femenino , Parasitosis Intestinales/parasitología , Intestinos/citología , Intestinos/patología , Mastocitos/citología , Mastocitos/patología , Mastocitosis/tratamiento farmacológico , Ratones , Ratones Endogámicos ICR , Músculo Esquelético/parasitología , Taurina/administración & dosificación , Taurina/química , Trichinella spiralis , Triquinelosis/parasitología
20.
Gland Surg ; 12(2): 197-207, 2023 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-36915815

RESUMEN

Background: Human epidermal growth factor receptor 2 (HER2) is a landmark protein in determining the targeted treatment of breast cancer (BC). However, the latest research shows that different intensity of HER2 protein expression levels in BC leads to different clinical characteristics, treatment, and prognosis, especially in HER2 low expression patients. Therefore, this study intends to analyze and compare the clinicopathologic features and prognosis of BC patients with low and zero HER2 expression from The Cancer Genome Atlas (TCGA) database and the data collected by our center. Methods: First, the BC dataset was downloaded from TCGA database, including 345 eligible and with complete clinical information BC patients, to compare the difference between HER2 low expression groups and HER2 zero expression groups and their correlation with estrogen receptor (ER) and progesterone receptor (PR) expression. Then, the clinicopathological data and follow-up of 405 patients with HER2 low expression and HER2 zero expression diagnosed with BC admitted to the Affiliated Hospital of Youjiang Medical University for Nationalities (YJMU) from January 2017 to December 2021 were collected to verify the consistency of the results of the two data sets. Results: Both the clinical samples and the TCGA data showed that the ER and PR rates were higher in the HER2 low expression group compared with the HER2 zero expression group. There were no significant differences in tumor size, lymph node metastasis, distant metastasis, and disease-free survival (DFS). In addition, the data analysis of 405 clinical samples also showed that the HER2 low expression group had a lower 3-year recurrence or metastasis rate compared with the HER2 zero expression group. Conclusions: Compared with HER2 zero expression, HER2 low patients express more ER and PR, and have less short-term recurrence and metastasis, but there is no obvious difference in DFS between the two groups.

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