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Thioredoxin-interacting protein (TXNIP) is an important regulatory protein for thioredoxin (TRX) that elicits the generation of reactive oxygen species (ROS) by inhibiting the redox function of TRX. Abundant evidence suggests that TXNIP is involved in the fibrotic process of diabetic kidney disease (DKD). However, the potential mechanism of TXNIP in DKD is not yet well understood. In this study, we found that TXNIP knockout suppressed renal fibrosis and activation of mammalian target of rapamycin complex 1 (mTORC1) and restored transcription factor EB (TFEB) and autophagy activation in diabetic kidneys. Simultaneously, TXNIP interference inhibited epithelial-to-mesenchymal transformation (EMT), collagen I and fibronectin expression, and mTORC1 activation, increased TFEB nuclear translocation, and promoted autophagy restoration in HK-2 cells exposed to high glucose (HG). Rapamycin, an inhibitor of mTORC1, increased TFEB nuclear translocation and autophagy in HK-2 cells under HG conditions. Moreover, the TFEB activators, curcumin analog C1 and trehalose, effectively restored HG-induced autophagy, and abrogated HG-induced EMT and collagen I and fibronectin expression in HK-2 cells. Taken together, these findings suggest that TXNIP deficiency ameliorates renal fibrosis by regulating mTORC1/TFEB-mediated autophagy in diabetic kidney diseases.
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Nefropatías Diabéticas , Humanos , Autofagia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Proteínas Portadoras/genética , Colágeno Tipo I , Nefropatías Diabéticas/etiología , Fibronectinas , Fibrosis , Diana Mecanicista del Complejo 1 de la Rapamicina , TiorredoxinasRESUMEN
BACKGROUND: Ferroptosis has been implicated in the pathological process of type 2 diabetic osteoporosis (T2DOP), although the specific underlying mechanisms remain largely unknown. This study aimed to clarify the role and possible mechanism of acid sphingomyelinase (ASM)-mediated osteoblast ferroptosis in T2DOP. METHODS: We treated hFob1.19 cells with normal glucose (NG) and different concentrations of high glucose (HG, 26.25 mM, 35 mM, or 43.75 mM) for 48 h. We then measured cell viability and osteogenic function, quantified ferroptosis and autophagy levels, and measured the levels of ASM and ceramide in the cells. To further investigate the specific mechanism, we examined these indicators by knocking down ASM expression, hydroxychloroquine (HCQ) treatment, or N-acetylcysteine (NAC) treatment. Moreover, a T2DOP rat model was induced and microcomputed tomography was used to observe the bone microstructure. We also evaluated the serum levels of iron metabolism-associated factors, ceramide and lipid peroxidation (LPO) and measured the expression of ASM, LC3 and GPX4 in bone tissues. RESULTS: HG inhibited the viability and osteogenic function of osteoblasts by inducing ferroptosis in a concentration-dependent manner. Furthermore, the expression of ASM and ceramide and autophagy levels were increased by HG treatment, and these factors were required for the HG-induced reactive oxygen species (ROS) generation and LPO. Similarly, inhibiting intracellular ROS also reduced HG-induced ASM activation and autophagy. ASM-mediated activation of autophagy was crucial for HG-induced degradation of GPX4, and inhibiting ASM improved osteogenic function by decreasing HG-induced autophagy, GPX4 degradation, LPO and subsequent ferroptosis. We also found that inhibiting ASM could alleviated ferroptosis and autophagy and improved osteogenic function in a T2DOP rat model. CONCLUSION: ASM-mediated autophagy activation induces osteoblast ferroptosis under HG conditions through the degradation of GPX4, providing a novel mechanistic insight into the treatment and prevention of T2DOP.
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Diabetes Mellitus Tipo 2 , Ferroptosis , Osteoporosis , Animales , Ratas , Autofagia , Ceramidas , Glucosa , Osteoporosis/tratamiento farmacológico , Osteoporosis/etiología , Especies Reactivas de Oxígeno , Esfingomielina Fosfodiesterasa/genética , Microtomografía por Rayos XRESUMEN
BACKGROUND: Sepsis is a life-threatening disease with a poor prognosis, and metabolic disorders play a crucial role in its development. This study aims to identify key metabolites that may be associated with the accurate diagnosis and prognosis of sepsis. METHODS: Septic patients and healthy individuals were enrolled to investigate metabolic changes using non-targeted liquid chromatography-high-resolution mass spectrometry metabolomics. Machine learning algorithms were subsequently employed to identify key differentially expressed metabolites (DEMs). Prognostic-related DEMs were then identified using univariate and multivariate Cox regression analyses. The septic rat model was established to verify the effect of phenylalanine metabolism-related gene MAOA on survival and mean arterial pressure after sepsis. RESULTS: A total of 532 DEMs were identified between healthy control and septic patients using metabolomics. The main pathways affected by these DEMs were amino acid biosynthesis, phenylalanine metabolism, tyrosine metabolism, glycine, serine and threonine metabolism, and arginine and proline metabolism. To identify sepsis diagnosis-related biomarkers, support vector machine (SVM) and random forest (RF) algorithms were employed, leading to the identification of four biomarkers. Additionally, analysis of transcriptome data from sepsis patients in the GEO database revealed a significant up-regulation of the phenylalanine metabolism-related gene MAOA in sepsis. Further investigation showed that inhibition of MAOA using the inhibitor RS-8359 reduced phenylalanine levels and improved mean arterial pressure and survival rate in septic rats. Finally, using univariate and multivariate cox regression analysis, six DEMs were identified as prognostic markers for sepsis. CONCLUSIONS: This study employed metabolomics and machine learning algorithms to identify differential metabolites that are associated with the diagnosis and prognosis of sepsis patients. Unraveling the relationship between metabolic characteristics and sepsis provides new insights into the underlying biological mechanisms, which could potentially assist in the diagnosis and treatment of sepsis. TRIAL REGISTRATION: This human study was approved by the Ethics Committee of the Research Institute of Surgery (2021-179) and was registered by the Chinese Clinical Trial Registry (Date: 09/12/2021, ChiCTR2200055772).
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Metabolómica , Sepsis , Animales , Humanos , Ratas , Biomarcadores/metabolismo , Metabolómica/métodos , Fenilalanina , Pronóstico , Sepsis/diagnóstico , Sepsis/metabolismoRESUMEN
Water clarity, denoted by the Secchi disk depth (SDD), is one of the most important indicators for monitoring water quality. In the Songhua River basin (SHRB), few studies have used Landsat to monitor long-term (3-4 decades) changes in lake SDD and explore the impact of natural and human factors on SDD interannual variation at the watershed scale. Lakes in the SHRB are of great significance to local populations. Understanding the spatiotemporal dynamics of SDD could help policymakers manage, protect, and predict lake water quality. We utilized the Landsat red/blue band ratio in the Google Earth Engine to estimate the SDD of 77 lakes and generated annual mean SDD maps from 1990 to 2018. The results of the SDD interannual changes showed that the water quality in the SHRB has improved since 2005. Specifically, the SDD in the SHRB displayed a significant increasing trend (p < 0.05) from 0.29 m in 2005 to 0.37 m in 2018. Moreover, the number of lakes displaying a significant increasing trend for SDD increased from 18 between 1990 and 2005 to 31 between 2005 and 2018. We also found that use of chemical fertilizer significantly impacted lakes, followed by wastewater discharge and normalized difference vegetation index. Improvements in the quantity and ability of wastewater discharge treatment and increased vegetation cover have alleviated water pollution; however, the non-point pollution of agriculture still poses a threat to some lakes in the SHRB. Therefore, more efforts should be made to further improve the aquatic ecological environment of SHRBs.
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Ríos , Calidad del Agua , China , Monitoreo del Ambiente , Humanos , Lagos , Agua , Contaminación del AguaRESUMEN
Understanding the spatiotemporal dynamics of total suspended matter (TSM) in waters is necessary to promote efficient water resource management. In our study, we have estimated the spatiotemporal pattern of TSM with the combination of time-series Landsat images and field survey. Among various remote sensing-derived parameters, the red/blue band turns to be robust and the most sensitive to the TSM from field measurements. In Songnen Plain, the mean annual TSM in 60.5% of the water bodies decreased from 1984 to 2018. The decreasing of TSM is likely due to the increasing of vegetation in the area. The TSM concentration in waters declined from April to July, and then increased from September onwards. We also found the TSM in water bodies in Songnen Plain has very high spatial variation. Our results indicated that the meteorological factors such as wind and precipitation may affect the variation of TSM. Our results demonstrate that long-term Landsat data are useful to examine TSM in inland waters. Our findings can support for water resource management under human activities and climate change.
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Monitoreo del Ambiente , Viento , China , Cambio ClimáticoRESUMEN
Nudel is a newly discovered factor related to cell migration. The tubular epithelial-mesenchymal transition (EMT) includes four steps: the loss of the adhesive properties of epithelial cells, the acquisition of a mesenchymal cell phenotype, the destruction of the tubular basal membrane, and the migration into the renal interstitium. The purpose of this study was to investigate the role of Nudel in the high-glucose-induced EMT of tubular epithelial cells. Human renal proximal tubular epithelial cells (HKCs) were treated with Nudel shRNA to clarify the role and mechanism of Nudel in tubular EMT induced by high glucose. We found that Nudel was expressed at a high level in high-glucose-stimulated HKCs, and the expression of Nudel was associated with the activation of signal transducer and activator of transcription 3. After transfection with Nudel shRNA, we detected the expression levels of E-cadherin, α-smooth muscle actin (α-SMA), and the Wiskott-Aldrich syndrome family of proteins (including WASP, N-WASP, WAVE1, WAVE2, and WAVE3) via assay. Cell migration was analyzed by the scratching method. The results showed that high glucose downregulated E-cadherin expression, upregulated α-SMA expression, and promoted the migration of HKCs. The expression levels of N-WASP, WAVE1, and WAVE2 were also elevated in HKCs treated with high glucose. All changes induced by high glucose were ameliorated by Nudel depletion. We conclude that Nudel participates in the transition and the migration of tubular epithelial cells via the regulation of WASP family proteins.
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Proteínas Portadoras/metabolismo , Células Epiteliales/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Glucosa/toxicidad , Túbulos Renales Proximales/efectos de los fármacos , Proteínas Portadoras/genética , Línea Celular , Movimiento Celular/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibrosis , Humanos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Fosforilación , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Familia de Proteínas del Síndrome de Wiskott-Aldrich/genética , Familia de Proteínas del Síndrome de Wiskott-Aldrich/metabolismo , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
Thioredoxin-interacting protein (TXNIP) is associated with inflammation, tubulointerstitial fibrosis, and oxidative stress in diabetic kidney disease, yet the potential role of TXNIP in nondiabetic renal injury is not well known. This study aimed to investigate the effect of TXNIP on renal injury by creating a unilateral ureteral obstruction (UUO) model in TXNIP knockout (TKO) mice. We performed sham or UUO surgery in 8-week-old TXNIP KO male mice and age and sex-matched wild-type (WT) mice. Animals were killed at 3, 5, 7, or 14 days after surgery, and renal tissues were obtained for RNA, protein, and other analysis. Our results show that the expression of TXNIP was increased in a time-dependent manner in the ligated kidneys. TXNIP deletion reduced renal fibrosis, apoptosis, α-SMA, TGF-ß1 and CTGF expression, and activation of Smad3, p38 MAPK, and ERK1/2 in UUO kidneys. We also found UUO-induced renal F4/80+ macrophage infiltration, MCP-1 expression and activation of NF-κB and NLRP3 inflammasome were attenuated in TKO mice. Furthermore, our study revealed that TXNIP deficiency inhibited the expression of 8-OHdG, heme oxygenase-1 (HO-1) and NADPH oxidase 4 (Nox4) in UUO kidney. In summary, our study suggests that TXNIP plays a key role in the renal inflammation and fibrosis induced by UUO. Inhibition of TXNIP may be a strategy to slow the progression of chronic kidney diseases.
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Proteínas Portadoras/metabolismo , Nefritis/etiología , Tiorredoxinas/metabolismo , Obstrucción Ureteral/complicaciones , Actinas/genética , Animales , Apoptosis , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/genética , Factor de Crecimiento del Tejido Conjuntivo/genética , Modelos Animales de Enfermedad , Fibrosis , Riñón/metabolismo , Riñón/patología , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Nefritis/genética , Nefritis/metabolismo , Estrés Oxidativo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Tiorredoxinas/antagonistas & inhibidores , Tiorredoxinas/genética , Factor de Crecimiento Transformador beta1/genética , Obstrucción Ureteral/genética , Obstrucción Ureteral/metabolismoRESUMEN
It is high incidence of tubulointerstitial lesion (TIL) in lupus nephritis (LN) and TIL can affect the prognosis of patients with LN. Signal transducer and activator of transcription (STAT) 3 was activated in LN and STAT3 inhibition could delay the onset of LN. Here, we evaluated the role of a well-known STAT3 inhibitor, S3I-201, on TIL in lupus nephritis. STAT3 was activated in MRL/lpr mice (a mouse model of lupus nephritis), and treatment with S3I-201 inhibited the activation of it. The level of 24-h urine protein and nitrogen urea increased in MRL/lpr mice and adminstration of S3I-201 reduced the level of urinary protein. In addition, S3I-201 attenuated the expression of α-smooth muscle actin (α-SMA), Fibronectin (FN) proteins, as well as the expression of monocyte chemotactic factor-1 (MCP-1) and intercellular adhesion molecule (ICAM-1). However, the expression of E-cadherin improved when treatment with S3I-201. These results revealed that the activation of STAT3 mediates tubulointerstitial lesion in mice with LN. S3I-201, by suppressing STAT3 activity, has therapeutic effect in lupus nephritis.
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Bencenosulfonatos/farmacología , Riñón/efectos de los fármacos , Nefritis Lúpica/tratamiento farmacológico , Nefritis Intersticial/tratamiento farmacológico , Ácidos Aminosalicílicos/farmacología , Animales , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Modelos Animales de Enfermedad , Femenino , Riñón/patología , Riñón/fisiopatología , Nefritis Lúpica/patología , Nefritis Lúpica/fisiopatología , Ratones , Ratones Endogámicos MRL lpr , Nefritis Intersticial/patología , Nefritis Intersticial/fisiopatología , Proteinuria/tratamiento farmacológico , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The purpose of this study was to investigate the role of oncostatin M (OSM) in tubulointerstitial lesion (TIL) in lupus nephritis (LN). We found that OSM was highly expressed in the renal tissue of LN mice. OSM is one of the interleukin-6 cytokine family members. In order to clarify the role and mechanism of OSM in LN, mice with LN were treated with anti-OSM antibody or isotype antibody. We evaluated the tubular epithelial-mesenchymal transdifferentiation (EMT) by detecting the E-cadherin, α-smooth muscle actin (α-SMA), and fibronectin (FN) expression. We analyzed the inflammation by observing the monocyte chemotactic factor-1 (MCP-1) and intercellular adhesion molecule (ICAM-1) expression and calculated the tubulointerstitial fibrosis area by Masson staining. The results showed that anti-OSM antibody, rather than isotype antibody, improved EMT, inflammation, and tubulointerstitial fibrosis. In addition, the signal transducer and activator of transcription (STAT) 1 and STAT3 signaling was activated by tyrosine phosphorylation in LN mouse renal tissue, indicating that the phosphorylated STAT1 (p-STAT1) and p-STAT3 were involved in kidney injury. Moreover, decreased p-STAT3 instead of p-STAT1 has been observed after anti-OSM antibody injection. Thus, we concluded that OSM is associated with TIL in lupus nephritis, which may be connected with the activation of STAT3 rather than that of STAT1.
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Anticuerpos/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Oncostatina M/metabolismo , Animales , Anticuerpos/inmunología , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Femenino , Isotipos de Inmunoglobulinas/inmunología , Isotipos de Inmunoglobulinas/uso terapéutico , Molécula 1 de Adhesión Intercelular/metabolismo , Nefritis Lúpica/metabolismo , Ratones , Oncostatina M/antagonistas & inhibidores , Oncostatina M/inmunología , Fosforilación/efectos de los fármacos , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Osteoporosis (OP) is a highly prevalent disorder characterized by low bone mass that severely reduces patient quality of life. Although numerous treatments for OP have been introduced in clinic, many have side effects and high costs. Therefore, there is still an unmet need for optimal solutions. Here, raw signal analysis was used to identify potential high-risk factors for OP, and the biological functions and possible mechanisms of action (MOAs) of these factors were explored via gene set enrichment analysis (GSEA). Subsequently, molecular biological experiments were performed to verify and analyze the discovered risk factors in vitro and in vivo. PMAIP1 was identified as a potential risk factor for OP and significantly suppressed autophagy in osteoblasts via the AMPK/mTOR pathway, thereby inhibiting the proliferation and differentiation of osteoblasts. Furthermore, we constructed an ovariectomy (OVX) model of OP in rats and simultaneously applied si-PMAIP1 for in vivo interference. si-PMAIP1 upregulated the expression of LC3B and p-AMPK and downregulated the expression of p-mTOR, and these effects were reversed by the autophagy inhibitor. Micro-CT revealed that, si-PMAIP1 significantly inhibited the development of osteoporosis in OVX model rats, and this therapeutic effect was attenuated by treatment with an autophagy inhibitor. This study explored the role and mechanism of PMAIP1 in OP and demonstrated that PMAIP1 may serve as a novel target for OP treatment.
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Proteínas Quinasas Activadas por AMP , Autofagia , Modelos Animales de Enfermedad , Osteoblastos , Osteoporosis , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Femenino , Humanos , Ratas , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/fisiología , Autofagia/genética , Diferenciación Celular/genética , Proliferación Celular/genética , Células Cultivadas , Expresión Génica/genética , Osteoblastos/metabolismo , Osteoporosis/metabolismo , Osteoporosis/genética , Osteoporosis/etiología , Ovariectomía , Ratas Sprague-Dawley , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/fisiologíaRESUMEN
In the context of human activities and climate change, the gradual degradation of coastal water quality seriously threatens the balance of coastal and marine ecosystems. However, the spatiotemporal patterns of coastal water quality and its driving factors were still not well understood. Based on 31 water quality parameters from 2015 to 2020, a new approach of optimizing water quality index (WQI) model was proposed to quantitatively assess the spatial and temporal water quality along tropical Hainan Island, China. In addition, pollution sources were further identified by factor analysis and the effects of pollution source on water quality was finally quantitatively in our study. The results showed that the average water quality was moderate. Water quality at 86.36% of the monitoring stations was good while 13.53% of the monitoring stations has bad or very bad water quality. Besides, the coastal water quality had spatial and seasonal variation, along Hainan Island, China. The water quality at "bad" level was mainly appeared in the coastal waters along large cities (Haikou and Sanya) and some aquaculture regions. Seasonally, the average water quality in March, October and November was worse than in other months. Factor analysis revealed that water quality in this region was mostly affected by urbanization, planting and breeding factor, industrial factor, and they played the different role in different coastal zones. Waters at 10.23% of monitoring stations were at the greatest risk of deterioration due to severe pressure from environmental factors. Our study has significant important references for improving water quality and managing coastal water environment.
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Renal fibrosis is the most common pathway in progressive kidney diseases. The unilateral ureteral obstruction (UUO) model is used to induce progressive renal fibrosis. We evaluated the effects of irisin on renal interstitial fibrosis in UUO mice. The GSE121190, GSE36496, GSE42303, and GSE96101 datasets were downloaded from the Gene Expression Omnibus (GEO) database. In total, 656 differentially expressed genes (DEGs) were identified in normal and UUO mouse renal samples. Periostin and matrix metalloproteinase-2 (MMP-2) were selected to evaluate the effect of irisin on renal fibrosis in UUO mice. In UUO mice, irisin ameliorated renal function, decreased the expression of periostin and MMP-2, and attenuated epithelial-mesenchymal transition and extracellular matrix deposition in renal tissues. In HK-2 cells, irisin treatment markedly attenuated TGF-ß1-induced expression of periostin and MMP-2. Irisin treatment also inhibited TGF-ß1-induced epithelial-mesenchymal transition, extracellular matrix formation, and inflammatory responses. These protective effects of irisin were abolished by the overexpression of periostin and MMP-2. In summary, irisin treatment can improve UUO-induced renal interstitial fibrosis through the TGF-ß1/periostin/MMP-2 signaling pathway, suggesting that irisin may be used for the treatment of renal interstitial fibrosis.
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Moléculas de Adhesión Celular , Transición Epitelial-Mesenquimal , Fibronectinas , Fibrosis , Enfermedades Renales , Metaloproteinasa 2 de la Matriz , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Obstrucción Ureteral , Animales , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/patología , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/tratamiento farmacológico , Fibronectinas/metabolismo , Ratones , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Masculino , Humanos , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/etiología , Enfermedades Renales/tratamiento farmacológico , Riñón/patología , Riñón/metabolismo , Riñón/efectos de los fármacos , Ratones Endogámicos C57BL , Línea Celular , Modelos Animales de Enfermedad , PeriostinaRESUMEN
Background: This study aimed to discover diagnostic and prognostic biomarkers for sepsis immunotherapy through analyzing the novel cellular death process, cuproptosis. Methods: We used transcriptome data from sepsis patients to identify key cuproptosis-related genes (CuRGs). We created a predictive model and used the CIBERSORT algorithm to observe the link between these genes and the septic immune microenvironment. We segregated sepsis patients into three subgroups, comparing immune function, immune cell infiltration, and differential analysis. Single-cell sequencing and real-time quantitative PCR were used to view the regulatory effect of CuRGs on the immune microenvironment and compare the mRNA levels of these genes in sepsis patients and healthy controls. We established a sepsis forecast model adapted to heart rate, body temperature, white blood cell count, and cuproptosis key genes. This was followed by a drug sensitivity analysis of cuproptosis key genes. Results: Our results filtered three key genes (LIAS, PDHB, PDHA1) that impact sepsis prognosis. We noticed that the high-risk group had poorer immune cell function and lesser immune cell infiltration. We also discovered a significant connection between CuRGs and immune cell infiltration in sepsis. Through consensus clustering, sepsis patients were classified into three subgroups. The best immune functionality and prognosis was observed in subgroup B. Single-cell sequencing exposed that the key genes manage the immune microenvironment by affecting T cell activation. The qPCR results highlighted substantial mRNA level reduction of the three key genes in the SP compared to the HC. The prediction model, which combines CuRGs and traditional diagnostic indicators, performed better in accuracy than the other markers. The drug sensitivity analysis listed bisphenol A as highly sensitive to all the key genes. Conclusion: Our study suggests these CuRGs may offer substantial potential for sepsis prognosis prediction and personalized immunotherapy.
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BACKGROUND: Sepsis is a common and critical condition encountered in clinical practice that can lead to multi-organ dysfunction. Sepsis-induced coagulopathy (SIC) significantly affects patient outcomes. However, the precise mechanisms remain unclear, making the identification of effective prognostic and therapeutic targets imperative. METHODS: The analysis of transcriptome data from the whole blood of sepsis patients, facilitated the identification of key genes implicated in coagulation. Then we developed a prognostic model and a nomogram to predict patient survival. Consensus clustering classified sepsis patients into three subgroups for comparative analysis of immune function and immune cell infiltration. Single-cell sequencing elucidated alterations in intercellular communication between platelets and immune cells in sepsis, as well as the role of the coagulation-related gene FYN. Real-time quantitative PCR determined the mRNA levels of critical coagulation genes in septic rats' blood. Finally, administration of a FYN agonist to septic rats was observed for its effects on coagulation functions and survival. RESULTS: This study identified four pivotal genes-CFD, FYN, ITGAM, and VSIG4-as significant predictors of survival in patients with sepsis. Among them, CFD, FYN, and ITGAM were underexpressed, while VSIG4 was upregulated in patients with sepsis. Moreover, a nomogram that incorporates the coagulation-related genes (CoRGs) risk score with clinical features of patients accurately predicted survival probabilities. Subgroup analysis of CoRGs expression delineated three molecular sepsis subtypes, each with distinct prognoses and immune profiles. Single-cell sequencing shed light on heightened communication between platelets and monocytes, T cells, and plasmacytoid dendritic cells, alongside reduced interactions with neutrophils in sepsis. The collagen signaling pathway was found to be essential in this dynamic. FYN may affect platelet function by modulating factors such as ELF1, PTCRA, and RASGRP2. The administration of the FYN agonist can effectively improve coagulation dysfunction and survival in septic rats. CONCLUSIONS: The research identifies CoRGs as crucial prognostic markers for sepsis, highlighting the FYN gene's central role in coagulation disorders associated with the condition and suggesting novel therapeutic intervention strategies.
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Sepsis , Sepsis/complicaciones , Sepsis/sangre , Humanos , Ratas , Animales , Pronóstico , Masculino , Trastornos de la Coagulación Sanguínea/genética , Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/etiología , Femenino , Ratas Sprague-DawleyRESUMEN
Kidney fibrosis is considered to be the ultimate aggregation pathway of chronic kidney disease (CKD), but its underlying mechanism remains elusive. Protein kinase C-delta (PKC-δ) plays critical roles in the control of growth, differentiation, and apoptosis. In this study, we found that PKC-δ was highly upregulated in human biopsy samples and mouse kidneys with fibrosis. Rottlerin, a PKC-δ inhibitor, alleviated unilateral ureteral ligation (UUO)-induced kidney fibrosis, inflammation, VDAC1 expression, and cGAS-STING signaling pathway activation. Adeno-associated virus 9 (AAV9)-mediated VDAC1 silencing or VBIT-12, a VDAC1 inhibitor, attenuated renal injury, inflammation, and activation of cGAS-STING signaling pathway in UUO mouse model. Genetic and pharmacologic inhibition of STING relieved renal fibrosis and inflammation in UUO mice. In vitro, hypoxia resulted in PKC-δ phosphorylation, VDAC1 oligomerization, and activation of cGAS-STING signaling pathway in HK-2 cells. Inhibition of PKC-δ, VDAC1 or STING alleviated hypoxia-induced fibrotic and inflammatory responses in HK-2 cells, respectively. Mechanistically, PKC-δ activation induced mitochondrial membrane VDAC1 oligomerization via direct binding VDAC1, followed by the mitochondrial DNA (mtDNA) release into the cytoplasm, and subsequent activated cGAS-STING signaling pathway, which contributed to the inflammation leading to fibrosis. In conclusion, this study has indicated for the first time that PKC-δ is an important regulator in kidney fibrosis by promoting cGAS-STING signaling pathway which mediated by VDAC1. PKC-δ may be useful for treating renal fibrosis and subsequent CKD.
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Background: Hemorrhagic shock was a leading cause of death worldwide, with myocardial injury being a primary affected organ. As commonly used solutions in fluid resuscitation, acetated Ringer's (AR) and Lactate Ringer's solution (LR) were far from perfect for their adverse reactions such as lactic acidosis and electrolyte imbalances. In previous studies, TPP@PAMAM-MR (TPP-MR), a novel nanocrystal resuscitation fluid has been found to protect against myocardial injury in septic rats. However, its role in myocardial injury in rats with hemorrhagic shock and underlying mechanism is unclear. Methods: The hemorrhagic shock rats and hypoxia-treated cardiomyocytes (H9C2) were utilized to investigate the impact of TPP-MR on cardiac function, mitochondrial function, and lipid peroxidation. The expressions of ferritin-related proteins glutathione peroxidase 4 (GPX4), Acyl CoA Synthase Long Chain Family Member 4 (ACSL4), and Cyclooxygenase-2(COX2) were analyzed through Western blotting to explore the mechanism of TPP-MR on hemorrhagic myocardial injury. Results: TPP-MR, a novel nanocrystalline resuscitation fluid, was synthesized using TPP@PAMAM@MA as a substitute for L-malic acid. We found that TPP-MR resuscitation significantly reduced myocardial injury reflected by enhancing cardiac output, elevating mean arterial pressure (MAP), and improving perfusion. Moreover, TPP-MR substantially prolonged hemorrhagic shock rats' survival time and survival rate. Further investigations indicated that TPP-MR improved the mitochondrial function of myocardial cells, mitigated the production of oxidative stress agents (ROS) and increased the glutathione (GSH) content. Additionally, TPP-MR inhibited the expression of the ferroptosis-associated GPX4 protein, ACSL4 and COX2, thereby enhancing the antioxidant capacity. Conclusion: The results showed that TPP-MR had a protective effect on myocardial injury in rats with hemorrhagic shock, and its mechanism might be related to improving the mitochondrial function of myocardial cells and inhibiting the process of ferroptosis.
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Ferroptosis , Miocitos Cardíacos , Nanopartículas , Choque Hemorrágico , Animales , Choque Hemorrágico/tratamiento farmacológico , Choque Hemorrágico/terapia , Ratas , Ferroptosis/efectos de los fármacos , Masculino , Miocitos Cardíacos/efectos de los fármacos , Nanopartículas/química , Resucitación/métodos , Ratas Sprague-Dawley , Línea Celular , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ciclooxigenasa 2/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
[This corrects the article DOI: 10.3389/fimmu.2023.1181697.].
RESUMEN
Epigenetic research plays an important role in the malignant tumor genotyping and tumor clinical treatment recently. Epigenetics is the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence, including DNA methylation and histone modifications. DNA methylation is one of the most important epigenetic modifications often occurring on the cytosine of CpG islands located in gene promoter regions, which is thought to be closely correlated with tumorigenesis. The inducibility and reversibility of DNA methylation provide us an insight into tumor development and treatment. Aberrant DNA hypermethylation is associated with the progress of myelodysplastic syndrome (MDS). The DNA methyltransferase inhibitors (azacytidine and decitabine) have achieved suc-cess in treating high-and intermediate-risk MDS. This will bring new ideas to understand the cause and develop the treat-ment of MDS. This review mainly introduces the latest progress of the action mechanism of those two medicines, the clini-cal effect and new problems during the clinical application on MDS.
Asunto(s)
Antineoplásicos/uso terapéutico , Metilasas de Modificación del ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/enzimología , Antineoplásicos/farmacología , Metilación de ADN , Inhibidores Enzimáticos/farmacología , Humanos , Síndromes Mielodisplásicos/genéticaRESUMEN
Background: The primary pathophysiology of diabetic kidney disease (DKD) is tubulointerstitial fibrosis (TIF), and an essential contributing element is excessive extracellular matrix deposition. Irisin is a polypeptide formed by splitting fibronectin type III domain containing 5 (FNDC5), which participates in a number of physiological and pathological processes. Methods: The purpose of this article is to examine irisin's function in DKD and analyze both its in vitro and in vivo effects. The Gene Expression Omnibus (GEO) database was used to download GSE30122, GSE104954, and GSE99325. Analysis of renal tubule samples from nondiabetic and diabetic mice identified 94 differentially expressed genes (DEGs). The transforming growth factor beta receptor 2 (TGFBR2), irisin, and TGF-ß1 were utilized as DEGs to examine the impact of irisin on TIF in diabetic kidney tissue, according to the datasets retrieved from the GEO database and Nephroseq database. Additionally, the therapeutic impact of irisin was also examined using Western blot, RT-qPCR, immunofluorescence, immunohistochemistry, and kits for detecting mouse biochemical indices. Results: In vitro, the findings demonstrated that irisin not only down-regulated the expression of Smad4 and ß-catenin but also reduced the expression of proteins linked to fibrosis, the epithelial-mesenchymal transition (EMT), and mitochondrial dysfunction in HK-2 cells maintained in high glucose (HG) environment. In vivo, overexpressed FNDC5 plasmid was injected into diabetic mice to enhance its expression. Our studies found that overexpressed FNDC5 plasmid not only reversed the biochemical parameters and renal morphological characteristics of diabetic mice but also alleviated EMT and TIF by inhibiting Smad4/ß-catenin signaling pathway. Conclusion: The above experimental results revealed that irisin could reduce TIF in diabetic mice via regulating the Smad4/ß-catenin pathway.