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1.
Exp Neurol ; 377: 114805, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38729552

RESUMEN

Staufen-1 (STAU1) is a double-stranded RNA-binding protein (RBP) involved in a variety of pathological conditions. In this study, we investigated the potential role of STAU1 in Alzheimer's disease (AD), in which two hallmarks are well-established as cerebral ß-amyloid protein (Aß) deposition and Tau-centered neurofibrillary tangles. We found that STAU1 protein level was significantly increased in cells that stably express full-length APP and the brain of APP/PS1 mice, an animal model of AD. STAU1 knockdown, as opposed to overexpression, significantly decreased the protein levels of ß-amyloid converting enzyme 1 (BACE1) and Aß. We further found that STAU1 extended the half-life of the BACE1 mRNA through binding to the 3' untranslated region (3'UTR). Transcriptome analysis revealed that STAU1 enhanced the expression of growth arrest and DNA damage 45 ß (GADD45B) upstream of P38 MAPK signaling, which contributed to STAU1-induced regulation of Tau phosphorylation at Ser396 and Thr181. Together, STAU1 promoted amyloidogenesis by inhibiting BACE1 mRNA decay, and augmented Tau phosphorylation through activating GADD45B in relation to P38 MAPK. Targeting STAU1 that acts on both amyloidogenesis and tauopathy may serve as an optimistic approach for AD treatment.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Proteínas de Unión al ARN , Proteínas tau , Animales , Proteínas tau/metabolismo , Proteínas tau/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Ratones , Fosforilación , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Ácido Aspártico Endopeptidasas/metabolismo , Ácido Aspártico Endopeptidasas/genética , Humanos , Ratones Transgénicos , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Células Cultivadas , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/genética
2.
Genes Dis ; 11(3): 101009, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38292192

RESUMEN

Furin is a pro-protein convertase that moves between the trans-Golgi network and cell surface in the secretory pathway. We have previously reported that cerebral overexpression of furin promotes cognitive functions in mice. Here, by generating the brain-specific furin conditional knockout (cKO) mice, we investigated the role of furin in brain development. We found that furin deficiency caused early death and growth retardation. Magnetic resonance imaging showed severe hydrocephalus. In the brain of furin cKO mice, impaired ciliogenesis and the derangement of microtubule structures appeared along with the down-regulated expression of RAB28, a ciliary vesicle protein. In line with the widespread neuronal loss, ependymal cell layers were damaged. Further proteomics analysis revealed that cell adhesion molecules including astrocyte-enriched ITGB8 and BCAR1 were altered in furin cKO mice; and astrocyte overgrowth was accompanied by the reduced expression of SOX9, indicating a disrupted differentiation into ependymal cells. Together, whereas alteration of RAB28 expression correlated with the role of vesicle trafficking in ciliogenesis, dysfunctional astrocytes might be involved in ependymal damage contributing to hydrocephalus in furin cKO mice. The structural and molecular alterations provided a clue for further studying the potential mechanisms of furin.

3.
Adv Sci (Weinh) ; 11(11): e2305260, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38183387

RESUMEN

It is long been suggested that one-carbon metabolism (OCM) is associated with Alzheimer's disease (AD), whereas the potential mechanisms remain poorly understood. Taking advantage of chemical biology, that mitochondrial serine hydroxymethyltransferase (SHMT2) directly regulated the translation of ADAM metallopeptidase domain 10 (ADAM10), a therapeutic target for AD is reported. That the small-molecule kenpaullone (KEN) promoted ADAM10 translation via the 5' untranslated region (5'UTR) and improved cognitive functions in APP/PS1 mice is found. SHMT2, which is identified as a target gene of KEN and the 5'UTR-interacting RNA binding protein (RBP), mediated KEN-induced ADAM10 translation in vitro and in vivo. SHMT2 controls AD signaling pathways through binding to a large number of RNAs and enhances the 5'UTR activity of ADAM10 by direct interaction with GAGGG motif, whereas this motif affected ribosomal scanning of eukaryotic initiation factor 2 (eIF2) in the 5'UTR. Together, KEN exhibits therapeutic potential for AD by linking OCM with RNA processing, in which the metabolic enzyme SHMT2 "moonlighted" as RBP by binding to GAGGG motif and promoting the 5'UTR-dependent ADAM10 translation initiation.


Asunto(s)
Enfermedad de Alzheimer , Glicina Hidroximetiltransferasa , Animales , Ratones , Regiones no Traducidas 5' , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Glicina Hidroximetiltransferasa/genética , ARN Mensajero/genética
4.
Biomed Pharmacother ; 170: 116057, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38159373

RESUMEN

In the 21st century, cardiovascular disease (CVD) has become one of the leading causes of death worldwide. The prevention and treatment of CVD remain pressing scientific issues. Several recent studies have suggested that ferroptosis may play a key role in CVD. Most studies conducted thus far on ferroptosis and CVD have supported the link. Ferroptosis mediated by different signaling and metabolic pathways can lead to ischemic heart disease, myocarditis, heart failure, ischemia-reperfusion injury, and cardiomyopathy. Still, the specific mechanism of ferroptosis in CVD, the particular organ areas affected, and the stage of disease involved need to be further studied. Therefore, understanding the mechanisms regulating ferroptosis in CVD may improve disease management. Throughout this review, we summarized the mechanism of ferroptosis and its effect on the pathogenesis of CVD. We also predicted and discussed future research directions, aiming to provide new ideas and strategies for preventing and treating CVD.


Asunto(s)
Enfermedades Cardiovasculares , Ferroptosis , Insuficiencia Cardíaca , Isquemia Miocárdica , Humanos , Manejo de la Enfermedad
5.
Environ Toxicol Pharmacol ; 105: 104345, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38103811

RESUMEN

Mercury (Hg) pollution is threatening the health of endangered Tachypleus tridentatus whereas the toxic mechanism is still unclear. This study combined transcriptomic and metabolomics technology to reveal the toxic mechanisms of mercury (Hg 2+, 0.025 mg/L) exposing to T. tridentatus larvae for 15 days. Mercury induced cellular toxicity and cardiovascular dysfunction by dysregulating the genes related to endocrine system, such as polyubiquitin-A, cathepsin B, atrial natriuretic peptide, etc. Mercury induced lipid metabolic disorder with the abnormal increase of lysoPC, leukotriene D4, and prostaglandin E2. Cytochrome P450 pathway was activated to produce anti-inflammatory substances to reconstruct the homeostasis. Mercury also inhibited arginine generation, which may affect the development of T. tridentatus by disrupting the crucial signaling pathway. The mercury methylation caused enhancement of S-adenosylmethionine to meet the need of methyl donor. The mechanisms described in present study provide new insight into the risk assessment of mercury exposure to T. tridentatus.


Asunto(s)
Cangrejos Herradura , Mercurio , Animales , Cangrejos Herradura/química , Cangrejos Herradura/genética , Especies en Peligro de Extinción , Perfilación de la Expresión Génica , Transcriptoma
6.
Brain Sci ; 13(5)2023 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-37239217

RESUMEN

Amyloidogenesis is one of the key pathophysiological changes in Alzheimer's disease (AD). Accumulation of the toxic Aß results from the catalytic processing of ß-amyloid precursor protein (APP) associated ß-amyloid converting enzyme 1 (BACE1) activity. It is reported that dead-box helicase 17 (DDX17) controls RNA metabolism and is involved in the development of multiple diseases. However, whether DDX17 might play a role in amyloidogenesis has not been documented. In the present study, we found that DDX17 protein level was significantly increased in HEK and SH-SY5Y cells that stably express full-length APP (HEK-APP and Y5Y-APP) and in the brain of APP/PS1 mice, an animal model of AD. DDX17 knockdown, as opposed to DDX17 overexpression, markedly reduced the protein levels of BACE1 and the ß-amyloid peptide (Aß) in Y5Y-APP cells. We further found that DDX17-mediated enhancement of BACE1 was selectively attenuated by translation inhibitors. Specifically, DDX17 selectively interacted with the 5' untranslated region (5'UTR) of BACE1 mRNA, and deletion of the 5'UTR abolished the effect of DDX17 on luciferase activity or protein level of BACE1. Here, we show that the enhanced expression of DDX17 in AD was associated with amyloidogenesis; through the 5'UTR-dependent BACE1 translation, DDX17 might serve as an important mediator contributing to the progression of AD.

7.
Proc Natl Acad Sci U S A ; 120(22): e2220148120, 2023 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-37216506

RESUMEN

Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD.


Asunto(s)
Enfermedad de Alzheimer , Animales , Ratones , Regiones no Traducidas 5' , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Cromatografía Liquida , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Biosíntesis de Proteínas , Espectrometría de Masas en Tándem
8.
Neurosci Lett ; 808: 137265, 2023 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-37085111

RESUMEN

TNFAIP3-interacting protein 2 (TNIP2) is known as a negative regulator of NF-κB signaling and inhibit inflammatory response and apoptosis, and is also involved in RNA metabolism. In this study, we investigated the potential role of TNIP2 in amyloidogenesis critically associated with Alzheimer's disease (AD). We found a significant decline of TNIP2 protein level in both mouse and cell model of AD. In SH-SY5Y and HEK cells that stably express human full-length APP695 (SY5Y-APP and HEK-APP), TNIP2 overexpression decreased the protein levels of ß-secretase (BACE1) and C99, as well as Aß peptides (including Aß40 and Aß42), while those of α-secretase (ADAM10) and the related C83 remained unchanged. We further found that TNIP2 promoted the degradation of BACE1 mRNA and was able to bound to the 3' untranslated region (3'UTR) with the reduced luciferase activity. These results indicated that TNIP2 effectively inhibited amyloidogenic processing by regulating the 3'UTR-associated mRNA decay of BACE1.


Asunto(s)
Enfermedad de Alzheimer , Neuroblastoma , Ratones , Humanos , Animales , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Regiones no Traducidas 3' , Péptidos beta-Amiloides/metabolismo , Ratones Transgénicos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo
9.
Mar Pollut Bull ; 188: 114726, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36860019

RESUMEN

The booming coastal zone economy poses increasing anthropogenic threats to marine life and habitats. Using the endangered living fossil horseshoe crab (HSC) as an example, we quantified the intensity of various anthropogenic pressures along the coast of Hainan Island, China, and for the first time assessed their impact on the distribution of juvenile HSCs through a field survey, remote sensing, spatial geographic modeling, and machine learning methods. The results indicate that the Danzhou Bay needs to be protected as a priority based on species and anthropogenic pressure information. Aquaculture and port activities dramatically impact the density of HSCs and therefore be managed priority. Finally, a threshold effect between total, coastal residential, and beach pressure and the density of juvenile HSCs were detected, which indicates the need for a balance between development and conservation as well as the designation of suitable sites for the construction of marine protected areas.


Asunto(s)
Cangrejos Herradura , Actividades Humanas , Humanos , Animales , China , Efectos Antropogénicos , Acuicultura
10.
Ecotoxicol Environ Saf ; 252: 114585, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36724710

RESUMEN

Marine and intertidal heavy metal pollution has been a major concern in recent years. Tachypleus tridentatus has existed on earth for more than 430 million years. It has suffered a sharp decline in population numbers caused by environmental pollution and anthropogenic disturbance for almost 40 years. However, the effects of heavy metal pollution on juvenile T. tridentatus have not been reported. Here we show the mechanism of cadmium (Cd) detoxification in juvenile T. tridentatus using integrated antioxidant indexes and transcriptomic and metabolomic analysis. High Cd2+ concentration caused oxidative stress in juvenile T. tridentatus. The hazards increase with increasing Cd2+ concentration in juvenile T. tridentatus. Transcriptomics and metabolomics analyses concluded that high Cd2+ concentration resulted in the imbalance of glycerophospholipid metabolism in juvenile T. tridentatus to detoxify Cd. Our results offer a rationale for protective measures and further studies of heavy metal stress in T. tridentatus.


Asunto(s)
Cadmio , Cangrejos Herradura , Animales , Cangrejos Herradura/genética , Cadmio/toxicidad , Transcriptoma , Perfilación de la Expresión Génica
11.
CNS Neurosci Ther ; 29(5): 1300-1311, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36708130

RESUMEN

AIMS: Amyloid beta (Aß) is an important pathological feature of Alzheimer's disease (AD). A disintegrin and metalloproteinase 10 (ADAM10) can reduce the production of toxic Aß by activating the nonamyloidogenic pathway of amyloid precursor protein (APP). We previously found that apicidin, which is a histone deacetylase (HDAC) inhibitor, can promote the expression of ADAM10 and reduce the production of Aß in vitro. This study was designed to determine the potential of apicidin treatment to reverse learning and memory impairments in an AD mouse model and the possible correlation of these effects with ADAM10. METHODS: Nine-month-old APP/PS1 mice and C57 mice received intraperitoneal injections of apicidin or vehicle for 2 months. At 11 months of age, we evaluated the memory performance of mice with Morris water maze (MWM) and context fear conditioning tests. The Aß levels were assessed in mouse brain using the immunohistochemical method and ELISA. The expression of corresponding protein involved in proteolytic processing of APP and the phosphorylation of tau were assessed by Western blotting. RESULTS: Apicidin reversed the deficits of spatial reference memory and contextual fear memory, attenuated the formation of Aß-enriched plaques, and decreased the levels of soluble and insoluble Aß40/42 in APP/PS1 mice. Moreover, apicidin significantly increased the expression of ADAM10, improved the level of sAPPα, and reduced the production of sAPPß, but did not affect the levels of phosphorylated tau in APP/PS1 mice. CONCLUSION: Apicidin significantly improves the AD symptoms of APP/PS1 mice by regulating the expression of ADAM10, which may contribute to decreasing the levels of Aß rather than decreasing the phosphorylation of tau.


Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Ratones , Animales , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Ratones Transgénicos , Enfermedad de Alzheimer/metabolismo , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismo , Memoria Espacial , Modelos Animales de Enfermedad , Presenilina-1/genética , Presenilina-1/metabolismo
12.
Traffic ; 24(1): 20-33, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36412210

RESUMEN

AP2S1 is the sigma 2 subunit of adaptor protein 2 (AP2) that is essential for endocytosis. In this study, we investigated the potential role of AP2S1 in intracellular processing of amyloid precursor protein (APP), which contributes to the pathogenesis of Alzheimer disease (AD) by generating the toxic ß-amyloid peptide (Aß). We found that knockdown or overexpression of AP2S1 decreased or increased the protein levels of APP and Aß in cells stably expressing human full-length APP695, respectively. This effect was unrelated to endocytosis but involved lysosomal degradation. Morphological studies revealed that silencing of AP2S1 promoted the translocalization of APP from RAB9-positive late endosomes (LE) to LAMP1-positive lysosomes, which was paralleled by the enhanced LE-lysosome fusion. In support, silencing of vacuolar protein sorting-associated protein 41 (VPS41) that is implicated in LE-lyso fusion prevented AP2S1-mediated regulation of APP degradation and translocalization. In APP/PS1 mice, an animal model of AD, AAV-mediated delivery of AP2S1 shRNA in the hippocampus significantly reduced the protein levels of APP and Aß, with the concomitant APP translocalization, LE-lyso fusion and the improved cognitive functions. Taken together, these data uncover a LE-lyso fusion mechanism in APP degradation and suggest a novel role for AP2S1 in the pathophysiology of AD.


Asunto(s)
Subunidades sigma de Complejo de Proteína Adaptadora , Enfermedad de Alzheimer , Ratones , Humanos , Animales , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/metabolismo , Endosomas/metabolismo , Lisosomas/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Complejo 2 de Proteína Adaptadora/metabolismo , Subunidades sigma de Complejo de Proteína Adaptadora/metabolismo , Proteínas de Unión al GTP rab/metabolismo
13.
J Alzheimers Dis ; 91(1): 407-426, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36442191

RESUMEN

BACKGROUND: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer's disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-ß protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive. OBJECTIVE: The present study was to investigate the role of HMGCS2 in Tau/p degradation. METHODS: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy. RESULTS: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or ß-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau. CONCLUSION: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role.


Asunto(s)
Enfermedad de Alzheimer , Proteínas tau , Humanos , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Cuerpos Cetónicos , Sirolimus/farmacología , Autofagia/fisiología , Hidroximetilglutaril-CoA Sintasa/genética , Hidroximetilglutaril-CoA Sintasa/metabolismo
14.
J Ocean Univ China ; 21(3): 541-548, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35582546

RESUMEN

Effective culture and management of adult tri-spine horseshoe crab, Tachypleus tridentatus can ensure that stock enhancement programs and aquaculture systems are maintained. To explore suitable feed for animals during the breeding season, Pacific oyster (Ostrea gigas) (oyster group; OG) and frozen sharpbelly fish (Hemiculter leucisculus) (frozen fish group; FG) were selected to feed 20 T. tridentatus male and female pairs, respectively. At the end of the experiment, intestinal samples were obtained to measure digestive enzymes activities. The intestinal flora were determined by 16S rDNA sequencing. No eggs were observed in the FG and one T. tridentatus adult died. No animals died in the OG, and 9.7 × 104 eggs were obtained. These results show that oysters are more suitable for the development and reproduction of adult T. tridentatus than frozen fish. Additionally, the digestive enzyme activity analysis revealed that animals in the OG exhibited higher protein digestibility than those in the FG, but no significant differences in lipid and carbohydrate uptake were observed between the groups. Furthermore, the intestinal flora analysis showed that operational taxonomic units (OTUs) and the Chao1 index were significantly higher in the OG than in the FG, but no significant difference was observed in the Shannon or Simpson indices between the groups. Our data indicate that the oyster diet improved the intestinal microbial diversity of T. tridentatus. We hypothesize that nutrients, such as oyster-based taurine, proteins, and highly unsaturated fatty acids, improve protease activity in the T. tridentatus digestive tract, alter the intestinal floral structure, and improve the reproductive performance of T. tridentatus.

15.
Front Immunol ; 13: 794779, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35401525

RESUMEN

Humoral immunity is the first line of defense in the invertebrate immune system, and antimicrobial peptides play an important role in this biological process. A novel antimicrobial peptide, termed Tatritin, was identified and characterized in hemolymph of Chinese horseshoe crab, Tachypleus tridentatus, infected with Gram-negative bacteria via transcriptome analysis. Tatritin was significantly induced by bacterial infection in hemolymph and gill. The preprotein of Tatritin consists of a signal peptide (21 aa) and a mature peptide (47 aa) enriched by cysteine. The putative mature peptide was 5.6 kDa with a theoretical isoelectric point (pI) of 9.99 and showed a α-helix structure in the N-terminal and an anti-parallel ß-sheet structure in the cysteine-stabilized C-terminal region. The chemically synthesized peptide of Tatritin exhibited a broad spectrum of antimicrobial activity against Gram-negative and Gram-positive bacteria and fungi. Furthermore, Tatritin may recognize and inhibit pathogenic microorganisms by directly binding to LPS, DNA, and chitin. In addition, administration of Tatritin reduced the mortality of zebrafish after bacterial infection. Due to its broad-spectrum antimicrobial activity in vivo and in vitro and the sensitivity to drug-resistant bacterial strains, Tatritin peptide can be used as a new type of drug for infection treatment or as an immune enhancer in animals.


Asunto(s)
Antiinfecciosos , Cangrejos Herradura , Animales , Antiinfecciosos/farmacología , Péptidos Antimicrobianos , China , Cisteína , Péptidos , Pez Cebra
16.
Atherosclerosis ; 347: 28-38, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35299058

RESUMEN

BACKGROUND AND AIMS: Activated innate immune cells infiltrating the valve and their secreted cytokines drive the differentiation of valve interstitial cells into myofibroblastic and osteoblastic phenotypes in calcified aortic valve stenosis (CAVS). In this study, we investigated how NLRP3 inhibition with CY-09 reduces aortic valve stenosis and calcification. METHODS: ApoE-/- mice were fed a high-fat diet for 24 weeks with or without intraperitoneal injection of 2.5 mg/kg/day NLRP3 inhibitor CY-09 for 42 consecutive days, while the control group mice were fed a normal diet. The valve function was monitored by echocardiography; calcified nodules were assessed by Von Kossa staining; and calcification-related molecules, inflammatory factors, and white leucocyte influx into the valve were assessed by immunohistochemistry, TUNEL assay, and PCR. RESULTS: Mice treated with CY-09 exhibited improved aortic valve function and reduced valve calcification deposition. CY-09 intervention significantly downregulated the elevated expression of the NLRP3 inflammasome pathway molecules NLRP3, caspase-1, and IL-1ß and the osteogenic calcification markers RUNX2, SPARC, and BMP2 in stenotic valves, while the number of apoptotic cells and dystrophic calcification markers CDH11 and α- SMA did not change significantly. Inhibition of NLRP3 activity also reduced the ratio of M1/M2 macrophages, prevented the shift of macrophages towards the M1 phenotype, and downregulated the levels of the proinflammatory factors IL-6 and TNF-α. CONCLUSIONS: This study provides a proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a feasible strategy for alleviating aortic valve calcification and stenosis.


Asunto(s)
Estenosis de la Válvula Aórtica , Válvula Aórtica , Macrófagos , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Válvula Aórtica/metabolismo , Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/patología , Calcinosis , Polaridad Celular , Células Cultivadas , Constricción Patológica , Modelos Animales de Enfermedad , Inflamasomas/metabolismo , Macrófagos/metabolismo , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo
17.
Respir Res ; 22(1): 308, 2021 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-34863181

RESUMEN

BACKGROUND: Tracheal injury is a common clinical condition that still lacks an effective therapy at present. Stimulation of epithelial sodium channel (ENaC) increases Na+ transport, which is a driving force to keep tracheal mucosa free edema fluid during tracheal injury. Ferulic acid (FA) has been proved to be effective in many respiratory diseases through exerting anti-oxidant, anti-inflammatory, and anti-thrombotic effects. However, these studies rarely involve the level of ion transport, especially ENaC. METHODS: C57BL/J male mice were treated intraperitoneally with normal saline or FA (100 mg/kg) 12 h before, and 12 h after intratracheal administration of lipopolysaccharide (LPS, 5 mg/kg), respectively. The effects of FA on tracheal injury were not only assessed through HE staining, immunofluorescence assay, and protein/mRNA expressions of ENaC located on tracheas, but also evaluated by the function of ENaC in mouse tracheal epithelial cells (MTECs). Besides, to explore the detailed mechanism about FA involved in LPS-induced tracheal injury, the content of cyclic guanosine monophosphate (cGMP) was measured, and Rp-cGMP (cGMP inhibitor) or cGMP-dependent protein kinase II (PKGII)-siRNA (siPKGII) were applied in primary MTECs, respectively. RESULTS: Histological examination results demonstrated that tracheal injury was obviously attenuated by pretreatment of FA. Meanwhile, FA could reverse LPS-induced reduction of both protein/mRNA expressions and ENaC activity. ELISA assay verified cGMP content was increased by FA, and administration of Rp-cGMP or transfection of siPKGII could reverse the FA up-regulated ENaC protein expression in MTECs. CONCLUSIONS: Ferulic acid can attenuate LPS-induced tracheal injury through up-regulation of ENaC at least partially via the cGMP/PKGII pathway, which may provide a promising new direction for preventive and therapeutic strategy in tracheal injury.


Asunto(s)
Lesión Pulmonar Aguda/genética , Ácidos Cumáricos/farmacología , Proteína Quinasa Dependiente de GMP Cíclico Tipo II/genética , Canales Epiteliales de Sodio/genética , Regulación de la Expresión Génica , Tráquea/efectos de los fármacos , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Células Cultivadas , Proteína Quinasa Dependiente de GMP Cíclico Tipo II/biosíntesis , Ensayo de Inmunoadsorción Enzimática , Canales Epiteliales de Sodio/biosíntesis , Depuradores de Radicales Libres/farmacología , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , ARN/genética , Transducción de Señal , Tráquea/metabolismo , Tráquea/patología
18.
J Mol Cell Cardiol ; 159: 80-90, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34097926

RESUMEN

Circular RNAs (circRNAs) are essential regulators associated with many cardiac conditions, including myocardial infarction (MI). This study aimed to explore circRNA expression during MI development in an animal model and in hypoxia/reoxygenation (H/R)-treated cardiomyocytes. Microarray and real-time quantitative PCR showed that the circRNA PVT1 (circPVT1) was expressed at high levels in MI tissues and H/R-triggered cardiomyocytes. Loss-of-function assays were utilized for examining the influence of circPVT1 on cardiac function and cardiomyocyte properties. Cardiac function was measured by echocardiography at 7 d after MI. Reduced circPVT1 expression significantly decreased MI-triggered myocardial infarct size by 60% and prevented MI-triggered reductions in fractional shortening (%FS) and ejection fraction (EF%). Results of LDH, CCK-8, EdU staining, colony formation assays, and flow cytometry showed that circPVT1 silencing restored cell viability and proliferation while decreased apoptosis. Mechanistic experiments indicated that microRNAs (miR)-125b and miR-200a associated with circPVT1. We demonstrated that circPVT1 functioned as a competitive endogenous RNA (ceRNA) to sponge both miR-125b and miR-200a. Gain-of-function assays showed that miR-125b and miR-200a upregulation partially eliminated the effects of circPVT1 on cardiomyocyte properties. In addition, we found that the previously reported p53/TRAF6, SIRT7, Keap1/Nrf2, and PDCD4 pathways were regulated by the circPVT1/miR-125b/miR-200a axis. In conclusion, our study suggests that circPVT1 protects the myocardium from MI and H/R injury by preventing miR-125b- and miR-200a-mediated apoptotic signaling.


Asunto(s)
MicroARNs/genética , Interferencia de ARN/fisiología , ARN Circular/genética , ARN Largo no Codificante/genética , Daño por Reperfusión/genética , Animales , Apoptosis/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Ratas , Transducción de Señal/genética , Regulación hacia Arriba/genética
19.
Curr Pharm Des ; 27(3): 415-422, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32867648

RESUMEN

MicroRNA (miRNA/miR) is a class of small evolutionarily conserved non-coding RNA, which can inhibit the target gene expression at the post-transcriptional level and serve as significant roles in cell differentiation, proliferation, migration and apoptosis. Of note, the aberrant miR-21 has been involved in the generation and development of multiple lung diseases, and identified as a candidate of biomarker, therapeutic target, or indicator of prognosis. MiR-21 relieves acute lung injury via depressing the PTEN/Foxo1-TLR4/NF-κB signaling cascade, whereas promotes lung cancer cell growth, metastasis, and chemo/radio-resistance by decreasing the expression of PTEN and PDCD4 and promoting the PI3K/AKT transduction. The purpose of this review is to elucidate the potential mechanisms of miR-21 associated lung diseases, with an emphasis on its dual regulating effects, which will trigger novel paradigms in molecular therapy.


Asunto(s)
Enfermedades Pulmonares , MicroARNs , Apoptosis , Proteínas Reguladoras de la Apoptosis , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/genética , MicroARNs/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de Unión al ARN/genética
20.
Curr Pharm Des ; 26(41): 5310-5316, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32842936

RESUMEN

A steady and continuous supply of oxygen is important for humans, since an excess or deficiency in oxygen levels may result in the death of cells, tissues, or organisms. As a mechanical barrier against pathogens, the respiratory epithelium is always exposed to hypoxia in some detrimental external environments and/or pathologic states. The barrier function is accordingly impaired as a result of the disrupted cell composition ratio, ion transport, and tight junctions in a hypoxia-inducible factor-dependent or independent way. Hypoxia has been identified as an element of the primary or secondary pathogenic factors of many respiratory diseases. Still, the relationship between hypoxia and epithelial barrier dysfunction is not fully understood. Thus, we summarized recent researches on epithelial barrier dysfunction induced by hypoxia in the respiratory system, aiming to explore the possible therapeutic targets in hypoxia-related respiratory system diseases.


Asunto(s)
Hipoxia , Uniones Estrechas , Células Epiteliales , Humanos , Oxígeno , Sistema Respiratorio
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