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1.
Mol Ther ; 32(2): 313-324, 2024 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-38093516

RESUMEN

Renal fibrosis is a characteristic hallmark of chronic kidney disease (CKD) that ultimately results in renal failure, leaving patients with few therapeutic options. TGF-ß is a master regulator of renal fibrosis and mediates progressive renal fibrosis via both canonical and noncanonical signaling pathways. In the canonical Smad signaling, Smad3 is a key mediator in tissue fibrosis and mediates renal fibrosis via a number of noncoding RNAs (ncRNAs). In this regard, targeting Smad3-dependent ncRNAs may offer a specific therapy for renal fibrosis. This review highlights the significance and innovation of TGF-ß/Smad3-associated ncRNAs as biomarkers and therapeutic targets in renal fibrogenesis. In addition, the underlying mechanisms of these ncRNAs and their future perspectives in the treatment of renal fibrosis are discussed.


Asunto(s)
Riñón , Insuficiencia Renal Crónica , Humanos , Fibrosis , Riñón/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/metabolismo , ARN no Traducido/genética , ARN no Traducido/metabolismo , Proteína smad3/genética , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo
2.
Mol Ther ; 32(5): 1526-1539, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38414248

RESUMEN

The Hippo/YAP pathway plays a critical role in tissue homeostasis. Our previous work demonstrated that renal tubular YAP activation induced by double knockout (dKO) of the upstream Hippo kinases Mst1 and Mst2 promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Here, we show that tubular YAP was already activated 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell overproliferation, tubular injury, and renal inflammation induced by UUO or cisplatin. YAP promoted the transcription of the transcription factor KLF5. Consistent with this, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell overproliferation, tubular injury, and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, where tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell overproliferation, tubular injury, and renal inflammation.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Túbulos Renales , Factores de Transcripción de Tipo Kruppel , Proteínas Señalizadoras YAP , Animales , Ratones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proliferación Celular , Cisplatino/farmacología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Túbulos Renales/metabolismo , Túbulos Renales/patología , Túbulos Renales/citología , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Ratones Noqueados , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Serina-Treonina Quinasa 3 , Transducción de Señal , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patología , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética
3.
Cell Mol Life Sci ; 81(1): 262, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38878186

RESUMEN

Through Smad3-dependent signalings, transforming growth factor-ß (TGF-ß) suppresses the development, maturation, cytokine productions and cytolytic functions of NK cells in cancer. Silencing Smad3 remarkably restores the cytotoxicity of NK-92 against cancer in TGF-ß-rich microenvironment, but its effects on the immunoregulatory functions of NK cells remain obscure. In this study, we identified Smad3 functioned as a transcriptional repressor for CSF2 (GM-CSF) in NK cells. Therefore, disrupting Smad3 largely mitigated TGF-ß-mediated suppression on GM-CSF production by NK cells. Furthermore, silencing GM-CSF in Smad3 knockout NK cells substantially impaired their anti-lung carcinoma effects. In-depth study demonstrated that NK-derived GM-CSF strengthened T cell immune responses by stimulating dendritic cell differentiation and M1 macrophage polarization. Meanwhile, NK-derived GM-CSF promoted the survival of neutrophils, which in turn facilitated the terminal maturation of NK cells, and subsequently boosted NK-cell mediated cytotoxicity against lung carcinoma. Thus, Smad3-silenced NK-92 (NK-92-S3KD) may serve as a promising immunoadjuvant therapy with clinical translational value given its robust cytotoxicity against malignant cells and immunostimulatory functions to reinforce the therapeutic effects of other immunotherapies.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos , Células Asesinas Naturales , Neoplasias Pulmonares , Proteína smad3 , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Proteína smad3/metabolismo , Proteína smad3/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Diferenciación Celular , Macrófagos/metabolismo , Macrófagos/inmunología , Transducción de Señal
4.
Diabetologia ; 67(5): 837-849, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38413437

RESUMEN

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Insuficiencia Renal Crónica , Humanos , Nefropatías Diabéticas/metabolismo , Enfermedades Cardiovasculares/complicaciones , Estudios Prospectivos , Hong Kong/epidemiología , Albuminuria , Bancos de Muestras Biológicas , Tasa de Filtración Glomerular , Biomarcadores , Albúminas
5.
J Gen Virol ; 105(1)2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38189334

RESUMEN

Phosphorylation and dephosphorylation of viral movement proteins plays a crucial role in regulating virus movement. Our study focused on investigating the movement protein TGBp1 of Bamboo mosaic virus (BaMV), which is a single-stranded positive-sense RNA virus. Specifically, we examined four potential phosphorylation sites (S15, S18, T58, and S247) within the TGBp1 protein. To study the impact of phosphorylation, we introduced amino acid substitutions at the selected sites. Alanine substitutions were used to prevent phosphorylation, while aspartate substitutions were employed to mimic phosphorylation. Our findings suggest that mimicking phosphorylation at S15, S18 and T58 of TGBp1 might be linked to silencing suppressor activities. The phosphorylated form at these sites exhibits a loss of silencing suppressor activity, leading to reduced viral accumulation in the inoculated leaves. Furthermore, mimicking phosphorylation at residues S15 and S18 could diminish viral accumulation at the single-cell level, while doing so at residue T58 could influence virus movement. However, mimicking phosphorylation at residue S247 does not appear to be relevant to both functions of TGBp1. Overall, our study provides insights into the functional significance of specific phosphorylation sites in BaMV TGBp1, illuminating the regulatory mechanisms involved in virus movement and silencing suppression.


Asunto(s)
Potexvirus , Fosforilación , Potexvirus/genética , Alanina , Sustitución de Aminoácidos
6.
Mol Ther ; 31(2): 344-361, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36514292

RESUMEN

Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which COVID-19 induces AKI are largely unknown, and treatment remains ineffective. Here, we report that kidney-specific overexpressing SARS-CoV-2 N gene can cause AKI, including tubular necrosis and elevated levels of serum creatinine and BUN in 8-week-old diabetic db/db mice, which become worse in those with older age (16 weeks) and underlying diabetic kidney disease (DKD). Treatment with quercetin, a purified product from traditional Chinese medicine (TCM) that shows effective treatment of COVID-19 patients, can significantly inhibit SARS-CoV-2 N protein-induced AKI in diabetic mice with or without underlying DKD. Mechanistically, quercetin can block the binding of SARS-CoV-2 N protein to Smad3, thereby inhibiting Smad3 signaling and Smad3-mediated cell death via the p16-dependent G1 cell-cycle arrest mechanism in vivo and in vitro. In conclusion, SARS-CoV-2 N protein is pathogenic and can cause severe AKI in diabetic mice, particularly in those with older age and pre-existing DKD, via the Smad3-dependent G1 cell-cycle arrest mechanism. Importantly, we identify that quercetin may be an effective TCM compound capable of inhibiting COVID-19 AKI by blocking SARS-CoV-2 N-Smad3-mediated cell death pathway.


Asunto(s)
Lesión Renal Aguda , COVID-19 , Diabetes Mellitus Experimental , Ratones , Animales , SARS-CoV-2 , COVID-19/complicaciones , Quercetina/farmacología , Diabetes Mellitus Experimental/complicaciones , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Lesión Renal Aguda/patología , Ratones Endogámicos , Puntos de Control del Ciclo Celular
7.
Mol Ther ; 31(9): 2734-2754, 2023 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-37415332

RESUMEN

Gastrin-releasing peptide (GRP) binds to its receptor (GRP receptor [GRPR]) to regulate multiple biological processes, but the function of GRP/GRPR axis in acute kidney injury (AKI) remains unknown. In the present study, GRPR is highly expressed by tubular epithelial cells (TECs) in patients or mice with AKI, while histone deacetylase 8 may lead to the transcriptional activation of GRPR. Functionally, we uncovered that GRPR was pathogenic in AKI, as genetic deletion of GRPR was able to protect mice from cisplatin- and ischemia-induced AKI. This was further confirmed by specifically deleting the GRPR gene from TECs in GRPRFlox/Flox//KspCre mice. Mechanistically, we uncovered that GRPR was able to interact with Toll-like receptor 4 to activate STAT1 that bound the promoter of MLKL and CCL2 to induce TEC necroptosis, necroinflammation, and macrophages recruitment. This was further confirmed by overexpressing STAT1 to restore renal injury in GRPRFlox/Flox/KspCre mice. Concurrently, STAT1 induced GRP synthesis to enforce the GRP/GRPR/STAT1 positive feedback loop. Importantly, targeting GRPR by lentivirus-packaged small hairpin RNA or by treatment with a novel GRPR antagonist RH-1402 was able to inhibit cisplatin-induced AKI. In conclusion, GRPR is pathogenic in AKI and mediates AKI via the STAT1-dependent mechanism. Thus, targeting GRPR may be a novel therapeutic strategy for AKI.


Asunto(s)
Lesión Renal Aguda , Cisplatino , Animales , Ratones , Cisplatino/efectos adversos , Necroptosis , Lesión Renal Aguda/metabolismo , Riñón/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BL
8.
BMC Pregnancy Childbirth ; 24(1): 414, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38849756

RESUMEN

CircRNAs are a class of endogenous non-coding RNAs implicated in the pathogenesis of many pregnancy related diseases, one of which is pre-eclampsia (PE). This study aims to investigate the role of CircPAPPA2 (circbase ID: hsa_circ_0015382) in regulating the migration and invasion of trophoblast cells. RNA sequencing was used to identify the differentially expressed circRNAs in placenta of PE and normal pregnant women. Quantitative polymerase chain reaction (qRT-PCR) was used to verify the expression of circPAPPA2 and two miRNAs (miR-942-5p, 5006-3p) in placenta of PE and normal pregnant women. CCK8 and transwell experiments were performed to assess the function of circPAPPA2 in PE development.The interaction between circPAPPA2 and miR-942-5p/miR-5006-3p was verified by dual-luciferase reporter assay. Finally, bioinformatics analyzed with gene ontology, Kyoto Encyclopedia of the target genes. The results showed that the expression of circPAPPA2 was increased in placenta of PE pregnant women. Also, circPAPPA2 impedes trophoblasts cell proliferation and invasion. Moreover, the expression of circPAPPA2 was positively correlated with systolic blood pressure and urine protein. In addition, circPAPPA2 serves as a sponge of miR-942-5p and miR-5006-3p. In conclusion, CircPAPPA2 regulates trophoblasts cell proliferation and invasion by mediating the miR-942/miR-5006-3p.


Asunto(s)
MicroARNs , Placenta , Preeclampsia , ARN Circular , Trofoblastos , Humanos , Preeclampsia/genética , Preeclampsia/metabolismo , Femenino , MicroARNs/genética , MicroARNs/metabolismo , Embarazo , ARN Circular/genética , Trofoblastos/metabolismo , Placenta/metabolismo , Adulto , Movimiento Celular/genética , Proliferación Celular/genética , Estudios de Casos y Controles
9.
Altern Ther Health Med ; 30(1): 414-418, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37820668

RESUMEN

Objective: To analyze the association between persistent human papillomavirus (HPV) infection and vaginal microecological imbalance after surgical treatment of cervical high-grade squamous intraepithelial lesion (HSIL). Methods: This is a retrospective study, 180 cervical HSIL patients admitted to our hospital from May 2019 to May 2021 were selected, of these, 84 were treated with loop electrosurgical excision procedure (LEEP) and 96 with cold knife conization (CKC). Patients were followed up for HPV infection 1 year after surgery. There is a division into a persistent infection group (positive group) and a negative group based on the presence or absence of HPV, the detection technique was PCR amplification. The two groups were compared regarding preoperative HPV infection, vaginal micro-ecological indicators 1 year after surgery, and the correlation between persistent HPV infection and vaginal microecological imbalance. Results: At 1 year after surgery, among 180 cervical HSIL patients, 64 (35.56%) were persistently infected with HPV, with an age of (40.20 ± 4.85) years, including 36 (56.25%) with cervical intraepithelial neoplasia (CIN) grade II, 28 (43.75%) with cervical intraepithelial neoplasia (CIN) grade III, 116 (64.44%) with HPV negative, with an age of (40.22 ± 5.15) years, including 67 (57.76%) with CIN grade II and 49 (42.24%) with CIN grade III, the differences in age and CIN classification between the two groups were not statistically significant (P > .05). Preoperatively, 53 people (82.81%) with HPV viral load >100 RLU/CO in the HPV persistent infection group and 76 people (65.52%) with HPV viral load >100 RLU/CO in the HPV negative group, with statistically significant differences between the two groups (P < .05); The difference in HPV virus typing and HPV infection type between the two groups was not statistically significant (P > .05). At 1 year after surgery, the composition ratio of flora density class IV and flora diversity class IV were significantly higher in the HPV persistent infection group than in the HPV negative group, and the dominant bacteria were mainly gram-positive large bacillus, accounting for 83.33%, the difference between the two groups was statistically significant (P < .05); The differences in Nugent scores and pH values between the two groups were not statistically significant (P > .05). Logistic regression analysis showed that flora density, flora diversity, and dominant bacteria were all independent risk factors for persistent HPV infection after treatment in patients with HSIL (P < .05). Conclusion: After treatment of HSIL patients, clinical attention should be paid to monitoring of HPV infection but also to the changes in vaginal microecology, as timely correction of vaginal microecology can facilitate HPV regression and improve the patient's prognosis.


Asunto(s)
Infecciones por Papillomavirus , Lesiones Intraepiteliales Escamosas , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Neoplasias del Cuello Uterino/cirugía , Neoplasias del Cuello Uterino/patología , Estudios Retrospectivos , Infección Persistente , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/cirugía , Lesiones Intraepiteliales Escamosas/cirugía
10.
J Biol Chem ; 298(7): 102010, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35525270

RESUMEN

Follistatin (FS)-like 1 (FSTL1) is a member of the FS-SPARC (secreted protein, acidic and rich in cysteine) family of secreted and extracellular matrix proteins. The functions of FSTL1 have been studied in heart and lung injury as well as in wound healing; however, the role of FSTL1 in the kidney is largely unknown. Here, we show using single-cell RNA-Seq that Fstl1 was enriched in stromal cells in obstructed mouse kidneys. In addition, immunofluorescence demonstrated that FSTL1 expression was induced in fibroblasts during kidney fibrogenesis in mice and human patients. We demonstrate that FSTL1 overexpression increased renal fibrosis and activated the Wnt/ß-catenin signaling pathway, known to promote kidney fibrosis, but not the transforming growth factor ß (TGF-ß), Notch, Hedgehog, or Yes-associated protein (YAP) signaling pathways in obstructed mouse kidneys, whereas inhibition of FSTL1 lowered Wnt/ß-catenin signaling. Importantly, we show that FSTL1 interacted with Wnt ligands and the Frizzled (FZD) receptors but not the coreceptor lipoprotein receptor-related protein 6 (LRP6). Specifically, we found FSTL1 interacted with Wnt3a through its extracellular calcium-binding (EC) domain and von Willebrand factor type C-like (VWC) domain, and with FZD4 through its EC domain. Furthermore, we show that FSTL1 increased the association of Wnt3a with FZD4 and promoted Wnt/ß-catenin signaling and fibrogenesis. The EC domain interacting with both Wnt3a and FZD4 also enhanced Wnt3a signaling. Therefore, we conclude that FSTL1 is a novel extracellular enhancer of the Wnt/ß-catenin pathway.


Asunto(s)
Proteínas Relacionadas con la Folistatina , Receptores Frizzled , Riñón , Vía de Señalización Wnt , Animales , Proteínas Relacionadas con la Folistatina/genética , Proteínas Relacionadas con la Folistatina/metabolismo , Receptores Frizzled/metabolismo , Humanos , Riñón/metabolismo , Riñón/fisiopatología , Ligandos , Ratones , Proteína Wnt3A
11.
Kidney Int ; 103(3): 501-513, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36328098

RESUMEN

Final urine volume and concentration are defined by water reabsorption through the water channel proteins aquaporin (AQP)-2, -3 and -4 in the collecting duct. However, the transcriptional regulation of these AQPs is not well understood. The Hippo/Yes-associated protein 1 (YAP) pathway plays an important role in organ size control and tissue homeostasis. When the Hippo pathway including the Mst1/Mst2 kinases is inhibited, YAP is activated and functions as a transcription co-activator. Our previous work revealed a pathological role of tubular YAP activation in chronic kidney disease, but the physiological role of YAP in the kidney remains to be established. Here, we found that tubule-specific Yap knockout mice showed increased urine output and decreased urinary osmolality. Decreases in Aqp2, -3 and -4 mRNA and protein abundance in the kidney were evident in Yap knockout mice. Analysis of Mst1/Mst2 double knockout and Mst1/Mst2/Yap triple knockout mice showed that expression of Aqp2 and Aqp4 but not Aqp3 was dependent on YAP. Furthermore, YAP was recruited to the promoters of the Aqp2 and Aqp4 genes and stimulated their transcription. Interestingly, YAP was found to interact with transcription factors GATA2, GATA3 and NFATc1. These three factors promoted Aqp2 transcription in a YAP dependent manner in collecting duct cells. These three factors also promoted Aqp4 transcription whereas only GATA2 and GATA3 enhanced Aqp3 transcription. Thus, our results suggest that YAP promotes Aqp2 and Aqp4 transcription, interacts with GATA2, GATA3 and NFATc1 to control Aqp2 expression, while Aqp-2, -3 and -4 exploit overlapping mechanisms for their baseline transcriptional regulation.


Asunto(s)
Acuaporina 2 , Túbulos Renales Colectores , Ratones , Animales , Acuaporina 2/metabolismo , Proteínas Señalizadoras YAP , Riñón/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Factores de Transcripción/metabolismo , Ratones Noqueados , Agua/metabolismo , Homeostasis , Túbulos Renales Colectores/metabolismo
12.
Clin Sci (Lond) ; 137(5): 317-331, 2023 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-36705251

RESUMEN

Kidney inflammation contributes to the progression of chronic kidney disease (CKD). Modulation of Toll-like receptor 4 (TLR4) signaling is a potential therapeutic strategy for this pathology, but the regulatory mechanisms of TLR4 signaling in kidney tubular inflammation remains unclear. Here, we demonstrated that tubule-specific deletion of TLR4 in mice conferred protection against obstruction-induced kidney injury, with reduction in inflammatory cytokine production, macrophage infiltration and kidney fibrosis. Transcriptome analysis revealed a marked down-regulation of long noncoding RNA (lncRNA) Meg3 in the obstructed kidney from tubule-specific TLR4 knockout mice compared with wild-type control. Meg3 was also induced by lipopolysaccharide in tubular epithelial cells via a p53-dependent signaling pathway. Silencing of Meg3 suppressed LPS-induced cytokine production of CCL-2 and CXCL-2 and the activation of p38 MAPK pathway in vitro and ameliorated kidney fibrosis in mice with obstructive nephropathy. Together, these findings identify a proinflammatory role of lncRNA Meg3 in CKD and suggest a novel regulatory pathway in TLR4-driven inflammatory responses in tubular epithelial cells.


Asunto(s)
ARN Largo no Codificante , Insuficiencia Renal Crónica , Animales , Ratones , Citocinas/metabolismo , Fibrosis , Inflamación/patología , Insuficiencia Renal Crónica/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo
13.
Mol Ther ; 30(9): 3017-3033, 2022 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-35791881

RESUMEN

Clopidogrel, a P2Y12 inhibitor, is a novel anti-fibrosis agent for chronic kidney disease (CKD), but its mechanisms remain unclear, which we investigated by silencing P2Y12 or treating unilateral ureteral obstruction (UUO) in LysM-Cre/Rosa Tomato mice with clopidogrel in vivo and in vitro. We found that P2Y12 was significantly increased and correlated with progressive renal fibrosis in CKD patients and UUO mice. Phenotypically, up to 82% of P2Y12-expressing cells within the fibrosing kidney were of macrophage origin, identified by co-expressing CD68/F4/80 antigens or a macrophage-lineage-tracing marker Tomato. Unexpectedly, more than 90% of P2Y12-expressing macrophages were undergoing macrophage-to-myofibroblast transition (MMT) by co-expressing alpha smooth muscle actin (α-SMA), which was also confirmed by single-cell RNA sequencing. Functionally, clopidogrel improved the decline rate of the estimated glomerular filtration rate (eGFR) in patients with CKD and significantly inhibited renal fibrosis in UUO mice. Mechanistically, P2Y12 expression was induced by transforming growth factor ß1 (TGF-ß1) and promoted MMT via the Smad3-dependent mechanism. Thus, silencing or pharmacological inhibition of P2Y12 was capable of inhibiting TGF-ß/Smad3-mediated MMT and progressive renal fibrosis in vivo and in vitro. In conclusion, P2Y12 is highly expressed by macrophages in fibrosing kidneys and mediates renal fibrosis by promoting MMT via TGF-ß/Smad3 signaling. Thus, P2Y12 inhibitor maybe a novel and effective anti-fibrosis agent for CKD.


Asunto(s)
Enfermedades Renales , Insuficiencia Renal Crónica , Obstrucción Ureteral , Animales , Clopidogrel/metabolismo , Clopidogrel/farmacología , Clopidogrel/uso terapéutico , Fibrosis , Riñón , Enfermedades Renales/etiología , Enfermedades Renales/genética , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Transducción de Señal , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/genética
14.
Mol Ther ; 30(2): 881-897, 2022 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-34628054

RESUMEN

Plasma levels of neuropeptide Y (NPY) are elevated in patients with acute myocardial infarction (AMI), but its role in AMI remains unclear, which was examined here in NPY wild-type/knockout (WT/KO) mice treated with/without exogenous NPY and its Y1 receptor antagonist (Y1Ra) BIBP 3226. We found that AMI mice lacking NPY developed more severe AMI than WT mice with worse cardiac dysfunction, progressive cardiac inflammation and fibrosis, and excessive apoptosis but impairing angiogenesis. All of these changes were reversed when the NPY KO mice were treated with exogenous NPY in a dose-dependent manner. Interestingly, treatment with NPY also dose dependently attenuated AMI in WT mice, which was blocked by BIBP 3226. Phenotypically, cardiac NPY was de novo expressed by infiltrating macrophages during the repairing or fibrosing process in heart-failure patients and AMI mice. Mechanistically, NPY was induced by transforming growth factor (TGF)-ß1 in bone marrow-derived macrophages and signaled through its Y1R to exert its pathophysiological activities by inhibiting p38/nuclear factor κB (NF-κB)-mediated M1 macrophage activation while promoting the reparative M2 phenotype in vivo and in vitro. In conclusion, NPY can attenuate AMI in mice. Inhibition of cardiac inflammation and fibrosis while enhancing angiogenesis but reducing apoptosis may be the underlying mechanisms through which NPY attenuates cardiac remodeling and deterioration of function following AMI.


Asunto(s)
Infarto del Miocardio , Neuropéptido Y , Animales , Humanos , Ratones , Ratones Noqueados , Infarto del Miocardio/sangre , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Neuropéptido Y/sangre , Neuropéptido Y/genética , Remodelación Ventricular
15.
Proc Natl Acad Sci U S A ; 117(34): 20741-20752, 2020 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-32788346

RESUMEN

Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage-myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, α-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-ß1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-ß1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.


Asunto(s)
Proteína smad3/metabolismo , Factor de Transcripción Brn-3A/genética , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Femenino , Fibrosis/fisiopatología , Redes Reguladoras de Genes , Humanos , Inflamación/patología , Riñón/patología , Enfermedades Renales/genética , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/metabolismo , Transducción de Señal/genética , Factor de Transcripción Brn-3A/metabolismo , Factor de Transcripción Brn-3A/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Sistema Urinario/metabolismo
16.
Altern Ther Health Med ; 29(5): 293-297, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37083650

RESUMEN

Objective: To explore the changes in college students' awareness of health protection under the normalization of COVID-19, and to seek its connection with the epidemic management in colleges and universities, so as to provide reference information for continuous health education activities and the cultivation of college students' health emergency literacy in colleges and universities. Methods: Qualitative interviews were used to understand the extent of health emergency literacy among college students enrolled in the context of a normalized epidemic and the factors associated with it that cause changes around a question outline. Results: The interviewees generally had a lax mentality in the late stage of the interview, the importance they attached to epidemic prevention and control decreased significantly, and the way to know about epidemic protection measures and other knowledge was mainly through the mass news media. All respondents affirm the importance of social software for outbreak prevention and control. All 17 interviewees were able to mention basic outbreak protection methods, but 15 of them showed inconsistent behavior in words and actions later. Conclusion: The vast majority of respondents' health emergency literacy appears to weaken in the late stages of epidemic normalization, and the effect of traditional approaches used by universities to improve college students' health emergency literacy is weak.


Asunto(s)
COVID-19 , Alfabetización en Salud , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Encuestas y Cuestionarios , Estudiantes , Alfabetización en Salud/métodos , Investigación Cualitativa
17.
Pestic Biochem Physiol ; 192: 105382, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37105642

RESUMEN

Genetic engineering technology is an ideal method to improve insecticidal efficiency by combining the advantages of different pathogenic microorganisms. Thus, six ascovirus genes were introduced into the genomic DNA of Autographa californica nucleopolyhedrovirus (AcMNPV) to possibly transfer the intrinsically valuable insecticidal properties from ascovirus to baculovirus. The viral budded virus (BV) production and viral DNA replication ability of AcMNPV-111 and AcMNPV-165 were significantly stronger than that of AcMNPV-Egfp (used as the wild-type virus in this study), whereas AcMNPV-33 had reduced ones. AcMNPV-111 and AcMNPV-165 also exhibited excellent insecticidal efficiency in the in vivo bioassays: AcMNPV-111 showed a 24.1% decrease in the LT50 value and AcMNPV-165 exhibited a 56.3% decrease in the LD50 value compared with AcMNPV-Egfp against the 3rd instar of Spodoptera exigua larvae, respectively. Furthermore, the size of the occlusion bodies (OBs) of AcMNPV-33, AcMNPV-111, and AcMNPV-165 were significantly increased compared to that of AcMNPV-Egfp. AcMNPV-111 and AcMNPV-165 had stable virulence against the 2nd to 4th instars tested larvae and higher OB yield than AcMNPV-Egfp in the 3rd and 4th instar larvae. Correlation and regression analyses indicated that it is better to use 5 OBs/larva virus to infect the 2nd instar larvae to produce AcMNPV-111 and 50 OBs/larva virus to infect the 3rd instar larvae to produce AcMNPV-165. The results of this study obtained recombinant viruses with enhanced virulence and exhibited a diversity of ascovirus gene function based on the baculovirus platform, which provided a novel strategy for the improvement of baculovirus as a biological insecticide.


Asunto(s)
Ascoviridae , Replicación Viral , Animales , Replicación Viral/genética , Ascoviridae/genética , Replicación del ADN , Virulencia/genética , ADN Viral/genética , Baculoviridae , Spodoptera/genética , Larva/genética , Ingeniería Genética
18.
Am J Kidney Dis ; 80(2): 196-206.e1, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-34999159

RESUMEN

RATIONALE & OBJECTIVE: Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing DKD phenotype. We compared the risks of adverse outcomes among patients with this phenotype compared with other DKD phenotypes. STUDY DESIGN: Multicenter prospective cohort study. SETTINGS & PARTICIPANTS: 19,025 Chinese adults with type 2 diabetes enrolled in the Hong Kong Diabetes Biobank. EXPOSURES: DKD phenotypes defined by baseline estimated glomerular filtration rate (eGFR) and albuminuria: no DKD (no decreased eGFR or albuminuria), albuminuria without decreased eGFR, decreased eGFR without albuminuria, and albuminuria with decreased eGFR. OUTCOMES: All-cause mortality, cardiovascular disease (CVD) events, hospitalization for heart failure (HF), and chronic kidney disease (CKD) progression (incident kidney failure or sustained eGFR reduction ≥40%). ANALYTICAL APPROACH: Multivariable Cox proportional or cause-specific hazards models to estimate the relative risks of death, CVD, hospitalization for HF, and CKD progression. Multiple imputation was used for missing covariates. RESULTS: Mean participant age was 61.1 years, 58.3% were male, and mean diabetes duration was 11.1 years. During 54,260 person-years of follow-up, 438 deaths, 1,076 CVD events, 298 hospitalizations for HF, and 1,161 episodes of CKD progression occurred. Compared with the no-DKD subgroup, the subgroup with decreased eGFR without albuminuria had higher risks of all-cause mortality (hazard ratio [HR], 1.59 [95% CI, 1.04-2.44]), hospitalization for HF (HR, 3.08 [95% CI, 1.82-5.21]), and CKD progression (HR, 2.37 [95% CI, 1.63-3.43]), but the risk of CVD was not significantly greater (HR, 1.14 [95% CI, 0.88-1.48]). The risks of death, CVD, hospitalization for HF, and CKD progression were higher in the setting of albuminuria with or without decreased eGFR. A sensitivity analysis that excluded participants with baseline eGFR <30 mL/min/1.73 m2 yielded similar findings. LIMITATIONS: Potential misclassification because of drug use. CONCLUSIONS: Nonalbuminuric DKD was associated with higher risks of hospitalization for HF and of CKD progression than no DKD, regardless of baseline eGFR.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Insuficiencia Cardíaca , Insuficiencia Renal Crónica , Albuminuria/epidemiología , Bancos de Muestras Biológicas , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Nefropatías Diabéticas/complicaciones , Femenino , Tasa de Filtración Glomerular , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/epidemiología , Hong Kong/epidemiología , Humanos , Riñón , Masculino , Estudios Prospectivos , Insuficiencia Renal Crónica/complicaciones
19.
Cardiovasc Diabetol ; 21(1): 293, 2022 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-36587202

RESUMEN

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Adulto , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Bancos de Muestras Biológicas , Hong Kong/epidemiología , Factores de Riesgo , Lipoproteínas HDL , HDL-Colesterol
20.
J Org Chem ; 87(6): 3978-3988, 2022 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-35254832

RESUMEN

Nitrogen, phosphorus, and oxygen codoped carbon catalysts were successfully synthesized using dried yeast powder as a pyrolysis precursor. The yeast-derived heteroatom-doped carbon (yeast@C) catalysts exhibited outstanding performance in the oxidation of Csp3-H bonds to ketones and esters, giving excellent product yields (of up to 98% yield) without organic solvents at low O2 pressure (0.1 MPa). The catalytic oxidation protocol exhibited a broad range of substrates (38 examples) with good functional group tolerance, excellent regioselectivity, and synthetic utility. The yeast-derived heteroatom-doped carbon catalysts showed good reusability and stability after recycling six times without any significant loss of activity. Experimental results and DFT calculations proved the important role of N-oxide (N+-O-) on the surface of yeast@C and a reasonable carbon radical mechanism.


Asunto(s)
Nitrógeno , Levadura Seca , Carbono/química , Catálisis , Nitrógeno/química , Oxígeno , Fósforo , Saccharomyces cerevisiae
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