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1.
ACS Appl Mater Interfaces ; 13(1): 186-195, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33351580

RESUMO

In virtue of uniform mesopores and core-shell nanoarchitectures, metallic nanodot-encapsulated hollow mesoporous nanostructures have shown promising potential in various applications. However, their fabrication with versatile tunability of the encapsulated metallic content has been a challenge. Herein, we have prepared metallic nanodot-encapsulated hollow mesoporous silica nanoparticles (M-HMSNPs) with adjustable inner metallic components. The sacrificial template of polystyrene (PS) nanoparticles precoated with metals (Au/Ag/Pt) is fully wrapped with mesoporous silica (mSiO2). The metallic nanodots are formed during the template removal process by calcination. The type and content of the encapsulated nanodots can be readily and precisely controlled by the initially deposited metallic layers. We demonstrate the application of the gold (Au) nanodot-loaded HMSNPs (denoted Au-HMSNPs) as smart surface-enhanced Raman spectroscopy (SERS) probes, which can screen between big molecules and small analytes. With the aid of a Raman reporter, the SERS probe can successfully quantify H2O2, which is used to distinguish cancer cells in vitro. Further integrated with enzymes, the SERS chips of specificity are prepared and used to detect corresponding substrates of glucose and uric acid, responsively. Besides SERS sensing, the current strategy can inspire future development of many other M-HMSNPs for various applications such as catalysis, energy storage, theranostics, etc.

2.
Front Oncol ; 10: 598256, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33262952

RESUMO

Circular RNAs (circRNAs) have important regulatory roles in the development of various cancers. However, the biological functions and potential molecular mechanisms of circRNAs in hepatocellular carcinoma (HCC) are still unclear. In this study, we investigated the role of a new circRNA-circGSK3B (hsa_circ_0003763) and its molecular mechanism in HCC. We found that circGSK3B was highly expressed in HCC tissues and HCC cell lines. Additionally, the expression level of circGSK3B significantly correlated with HCC tumor size and vascular invasion. Functionally, we confirmed that circGSK3B can promote the proliferation, migration, and invasion of HCC cells in vivo and in vitro. In terms of mechanism, we demonstrated that circGSK3B acts as a miR-1265 sponge, positively regulates the target gene CAB39, and promotes the reprogramming of glutamine metabolism, thereby promoting the progression of HCC. Finally, the classic RNA binding protein QKI was observed to participate in the biogenesis of circGSK3B. In summary, we proved that the circGSK3B-miR-1265-CAB39 axis can promote the proliferation, migration, invasion of HCC cells, indicating that circGSKB may serve as a promising diagnostic and prognostic marker in HCC.

3.
Biomed Res Int ; 2020: 3796792, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33313313

RESUMO

Objective: To investigate the predictive factors associated with rapid progressive chronic kidney disease (CKD) in patients with primary glomerular disease (PGD). Methods: Baseline data, clinical biochemistry, laboratory data, and imaging data were collected from 112 PGD patients in CKD stages 3 and 4 who were hospitalized at the Third Xiangya Hospital. Patients were divided into rapid progression group (Group R) and no rapid progression group (NR) according to the definition of rapid progression of CKD. Results: The age, systolic blood pressure (SBP), serum ß2-microglobulin (sß2-MG), urinary α1-microglobulin (uα1-MG), and cardiothoracic ratio (CTR) of the R group were significantly higher than the NR group. However, the size of the kidney, high-dense lipoprotein (HDL), hemoglobin (Hb), and hematocrit of the R group were significantly lower than the NR group (P < 0.05). Binary logistic regression analysis showed that baseline CTR, SBP, size of the kidney, and HDL were independent risk factors for rapid progression of PGD. At the end of follow-up, CTR and SBP of group R were higher than the NR group, and the size of the kidney and HDL of group R were lower than the NR group. Conclusion: Increased baseline CTR and SBP and decreased baseline HDL and renal volume could be the predictors of rapid progression in patients of PGD at the CKD stages 3 and 4.

4.
Curr Med Chem ; 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33138745

RESUMO

Kidney disease is a serious health problem that burdens our healthcare system. It is crucial to find the accurate pathogenesis of various types of kidney disease to provide guidance for precise therapies for patients suffered from these diseases. However,the exact molecular mechanisms underlying these diseases have not been fully understood. Disturbance of calcium homeostasis in renal cells plays a fundamental role in the development of various types of kidney disease,such as primary glomerular disease, diabetic nephropathy, acute kidney injury and polycystic kidney disease,through promoting cell proliferation,stimulating extracellular matrix accumulation, aggravating podocyte injury, disrupting cellular energetics as well as disregulating cell survival and death dynamics.As a result, preventing the disturbance of calcium homeostasis in specific renal cells(such as tubular cells, podocytes and mesangial cells) is becoming one of the most promosing therapeutic stratergies in the treatment of kidney disease.The endoplasmic reticulum and mitochondria are two vital organelles in this process. Calcium ions cycle between the endoplasmic reticulum and mitochondria at the conjugation of these two organelles known as the mitochondria-associated endoplasmic reticulum membrane, maintaining calcium homeostasis. The pharmacologic modulation of cellular calcium homeostasis can be viewed as a novel therapeutic method to renal diseases. Here, we will introduce the calcium homeostasis under physiological conditions and the disturbance of calcium homeostasis in kidney diseases. We will focus on the calcium homeostasis regulation in renal cells (including tubular cells, podocytes and mesangial cells), especially that in the mitochondria-associated endoplasmic reticulum membranes of these renal cells.

5.
Redox Biol ; 37: 101745, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33099216

RESUMO

Nogo-B is an endoplasmic reticulum-residential protein with distinctive functions in different diseases. However, it remains unclear the role of Nogo-B in liver sterile inflammatory injury. This study aims to elucidate the functions and mechanisms in liver ischemia and reperfusion injury (IRI). The Nogo-B expression and liver function were analyzed in biopsy/serum specimens from 36 patients undergoing ischemia-related hepatectomy and in a mouse model of liver IRI. Human specimens were harvested prior to ischemia and post-reperfusion. The Nogo-B knockout (Nogo-BKO) and myeloid-specific Nogo-B knockout (Nogo-BMKO) mice were used to analyze the function and mechanism of Nogo-B in a mouse model of liver IRI. In human specimens, the Nogo-B expression was positively correlated with higher levels of serum transaminase (sALT) and severe histopathological injury at one day post-hepatectomy. Moreover, Nogo-B is mainly expressed on macrophages in normal and ischemic liver tissues from human and mice. Unlike in controls, the Nogo-BKO or Nogo-BMKO livers was protected against IRI, with reduced reactive oxygen species (ROS) production and liver inflammation in ischemic livers. In parallel in vitro studies, Nogo-B deficiency reduced M1 macrophage polarization and inhibited proinflammatory cytokines (TNF-α, IL-6, MCP-1 and iNOS) in response to LPS or HMGB-1 stimulation. Mechanistic studies showed that Nogo-B bound to MST1/2, increased MST1/2, LAST1, and YAP phosphorylation, leading to reduced YAP activity. Interestingly, disruption of macrophage YAP abolished Nogo-B deficiency-mediated cytoprotective effects in vitro and in vivo. Thus, YAP is crucial for the regulation of macrophage Nogo-B-triggered liver inflammation. Nogo-B promotes macrophage-related innate inflammation and contributes to IR-induced liver injury by activating the MST-mediated Hippo/YAP pathway, which provides a potential therapeutic target for clinical management in liver IRI.

6.
Curr Med Chem ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023427

RESUMO

Diabetic nephropathy (DN) is a common microvascular complication of diabetes and one of the leading causes of end-stage renal disease. Tubular damage is an early change and characteristic of DN, and mitochondrial dysfunction plays an important role in the development of DN. Therefore, the timely removal of damaged mitochondria in tubular cells is an effective treatment strategy for DN. Mitophagy is a type of selective autophagy that ensures the timely elimination of damaged mitochondria to protect cells from oxidative stress. In this review, we summarize our understanding of mitochondrial dysfunction and dynamic disorders in tubular cells in DN and the molecular mechanism of mitophagy. Finally, the role of mitophagy in DN and its feasibility as a therapeutic target for DN are discussed.

7.
Sci Rep ; 10(1): 15636, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973230

RESUMO

Acute kidney disease (AKD) is a state between acute kidney injury (AKI) and chronic kidney disease (CKD), but the prognosis of AKD is unclear and there are no risk-prediction tools to identify high-risk patients. 2,556 AKI patients were selected from 277,898 inpatients of three affiliated hospitals of Central South University from January 2015 to December 2015. The primary point was whether AKI patients developed AKD. The endpoint was death or end stage renal disease (ESRD) 90 days after AKI diagnosis. Multivariable Cox regression was used for 90-day mortality and two prediction models were established by using multivariable logistic regression. Our study found that the incidence of AKD was 53.17% (1,359/2,556), while the mortality rate and incidence of ESRD in AKD cohort was 19.13% (260/1,359) and 3.02% (41/1,359), respectively. Furthermore, adjusted hazard ratio of mortality for AKD versus no AKD was 1.980 (95% CI 1.427-2.747). In scoring model 1, age, gender, hepatorenal syndromes, organic kidney diseases, oliguria or anuria, respiratory failure, blood urea nitrogen (BUN) and acute kidney injury stage were independently associated with AKI progression into AKD. In addition, oliguria or anuria, respiratory failure, shock, central nervous system failure, malignancy, RDW-CV ≥ 13.7% were independent risk factors for death or ESRD in AKD patients in scoring model 2 (goodness-of fit, P1 = 0.930, P2 = 0.105; AUROC1 = 0.879 (95% CI 0.862-0.896), AUROC2 = 0.845 (95% CI 0.813-0.877), respectively). Thus, our study demonstrated AKD was independently associated with increased 90-day mortality in hospitalized AKI patients. A new prediction model system was able to predict AKD following AKI and 90-day prognosis of AKD patients to identify high-risk patients.

8.
Clin Exp Nephrol ; 24(12): 1103-1121, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32767135

RESUMO

MiRNAs play essential roles in processes of physiological status and disease conditions including in renal diseases, while extracellular vesicles (EVs) serve as important mediators for cell-cell communication. In body fluid or extracellular spaces, miRNAs are packaged into EVs and transferred to targeted cells to perform their bioeffects under particular conditions. In the present review, we aim to summarize and update the known and verified EV-carrying miRNAs (EV-miRNAs) and their general roles in kidney diseases. In addition to performing a systemic analysis, we try to provide some clues and perspectives for the future study of EV-miRNAs in renal diseases.

9.
Front Cell Dev Biol ; 8: 595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32766245

RESUMO

Autophagy is a process of intracellular self-recycling and degradation that plays an important role in maintaining cell homeostasis. However, the molecular mechanism of autophagy remains to be further studied. Mitochondria-associated endoplasmic reticulum membranes (MAMs) are the region of the ER that mediate communication between the ER and mitochondria. MAMs have been demonstrated to be involved in autophagy, Ca2+ transport and lipid metabolism. Here, we discuss the composition and function of MAMs, more specifically, to emphasize the role of MAMs in regulating autophagy. Finally, some key information that may be useful for future research is summarized.

10.
Biomed Pharmacother ; 129: 110398, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32603889

RESUMO

Hepatic ischemia reperfusion (I/R) injury (HIRI) HIRI is a complex, multifactorial pathophysiological process and in liver surgery has been known to significantly affect disease prognosis, surgical success rates, and patient survival. Ginsenoside Rgl (Rgl) monomer is one of the main active ingredients of ginseng. Previous studies have demonstrated that Rgl exerts various pharmacological effects through several mechanisms including suppression of apoptosis-related proteins levels, downregulation of inflammatory mediators and as well as antioxidant, which effectively exerts an organ protective effect I/R-induced damage. However, the exact mechanisms of Rg1 on HIRI remain to be elucidated. In the present study, we investigated the protective effect of Rg1 on hepatic ischemia-reperfusion (I/R) injury (HIRI) and explored its underlying molecular mechanism. A rat warm I/R injury model in vivo and an oxygen-glucose deprivation/reperfusion (OGD/R)-treated BRL-3A cell model in vitro were established after pretreating with Rg1(20 mg/kg). The results showed that Rg1 reduced the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). TUNEL staining showed that pretreated with Rg1 inhibited the apoptosis rate compared with the I/R group. Moreover, pretreated with Rg1 significantly reduced the expression of Cyt-C, Caspase-9 and Caspase-3 to inhibit the cell apoptosis. Flow cytometry analysis showed the MMP in the I/R group was significantly increased, whereas pretreated with Rg1 effectively stabilized the MMP compared with the I/R group. in vitro, the proliferation of BRL-3A cells was significantly decreased by the OGD/R treatment, while Rg1 effectively reversed this phenomenon. In addition, western blotting showed that the increase of Cyt-C, Caspase-9 and Caspase-3 was inhibited by H2O2. These observations suggest that Rg1 exerts the protective effect by inhibiting the CypD protein-mediated mitochondrial apoptotic pathway.

11.
Am J Chin Med ; 48(5): 1159-1178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32668973

RESUMO

Hepatic ischemia-reperfusion (IR) injury remains the major cause of liver damage post-liver surgery or transplantation. Diminishing oxidative stress and inflammatory responses is a powerful channel to reduce the rate of morbidity and mortality. Gastrodin (GSTD), a bioactive compound extracted from the traditional Chinese herbal agent with a long history of clinical application in nervous system diseases, is suggested to possess anti-oxidative effects on liver diseases, such as nonalcoholic fatty liver disease. However, the therapeutic potential of GSTD in liver IR injury remains unclear. In this paper, we performed surgery to set up the 70% hepatic IR injury models in mice after a three-day pretreatment of GSTD. We found the administration of GSTD reduced liver damage, which correlated with lower histological Suzuki's score, lower serum alanine transaminase (AST) and alanine transaminase (ALT) levels, less oxidative stress, and cell apoptosis in a dose-responsive manner, as compared to the parallel control. Meanwhile, we observed a great induction of heme oxygenase-1 (HO-1) and an activation of the p38 mitogen-activated protein kinases/nuclear factor erythroid 2-related factor 2 (p38MAPK/Nrf2) pathway in response to the GSTD pretreatment, while the protective effects upon GSTD diminished in mice with HO-1 heterozygous mutation. In addition, GSTD inhibited IR induced toll-like receptor (TLR) 4, but not TLR2 in a HO-1 dependent manner, leading to a down-regulation of cytokines, such as interleukin (IL)-6 and TNF-[Formula: see text]. Collectively, our findings revealed GSTD attenuated liver IR injury via activation of the HO-1 pathway, providing a novel therapeutic strategy to minimize the IR induced oxidative stress in the process of liver transplantation.


Assuntos
Antioxidantes , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/farmacologia , Glucosídeos/administração & dosagem , Glucosídeos/farmacologia , Fígado , Fator 2 Relacionado a NF-E2/metabolismo , Fitoterapia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas , Heme Oxigenase-1/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Cuidados Pré-Operatórios , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Biomed Pharmacother ; 130: 110521, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32717631

RESUMO

OBJECTIVE: This study aimed to assess the effect and mechanism of SS31 on cisplatin-induced acute kidney injury (CP-AKI) both in vivo and in vitro. METHOD: Male mices and HK-2 cells were treated using cisplatin to establish models of CP-AKI. 32 C57BL/6 mices were randomly divided into four groups (control group, CP group, CP + normal saline group, CP + SS-31 group). Cisplatin was intraperitoneally injected once to the mice (25 mg/kg). SS31 was administrated for 10 days at dosages of 10 mg/kg per day. Kidney histological changes and level of reactive oxygen species(ROS) were detected. In vitro studies, HK-2 cells were incubated with cisplatin (50 u M) or combimed with SS-31(100 u M), the level of mitochondrial ROS, apoptosis rate and the the expression of NLRP3, Caspase-1 and IL-1ß were tested. RESULTS: Renal tubulointerstitial apoptosis and oxidative stress were significantly increased in CP-AKI mice. Cisplatin caused elevation of serum creatinine (Scr), blood urea nitrogen (BUN) levels and enhanced IL-1ß, caspase1 and NLRP3 expression, the electron microscopy examination showed mitochondria cristae swelling, mitochondrial spheres and partial ridge breakdown in renal tubular cell of CP-AKI mice. SS31 treatment could effectively suppress mitochondrial ROS, ameliorate these lesions and decrease the expression of NLRP3, IL-1ß and Caspase1. In vitro studies, SS31 could restored the level of mitochondrial ROS and downregulate apoptosis rate in HK-2 cells, moreover, the elevated expression of NLRP3, IL-1ß and Caspase-1were restored. CONCLUSION: SS31 could protect CP-AKI in mices, which might be due to an anti-oxidative and anti-apoptotic action via regulating mitochondrial ROS-NLRP3 pathway. NLRP3 inflammasome might be considered as a novel therapeutic target of CP-AKI.

13.
Ann Transl Med ; 8(6): 399, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32355843

RESUMO

A large number of immune cells are present in the tumour microenvironment (TME), of which, tumour-associated macrophages (TAMs) are among the most important and highly infiltrated cells, and mainly include the M1 type classically activated and M2 type alternatively activated TAMs. Both cell types are known to play an important role in tumour initiation and proliferation. It has recently been confirmed that the TAMs in tumours tend to be dominated by the M2 type. However, the precise mechanism underlying TAM recruitment and polarization in the immune microenvironment remains to be elucidated. The Hippo-Yes-associated protein (YAP) signalling pathway is one of the most extensively discussed mechanism for the regulation of tumour proliferation, migration, angiogenesis, and invasion in recent years. To date, several studies have revealed that YAP is involved in the interrelating interactions between tumour and immune cells, particularly the TAMs. In this review, we have summarized the mechanism by which the YAP regulates the activity of TAMs and its impact on the TME.

14.
ACS Omega ; 5(19): 10878-10890, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32455208

RESUMO

To establish the molecular mechanism of ginsenoside Rg1 in nonalcoholic fatty liver disease (NAFLD), Sprague Dawley (SD) rats (180-220 g) were randomly divided into a control group, model group, ginsenoside Rg1 low-dose group (30 mg/(kg day)), high-dose (60 mg/(kg day)) group, and simvastatin group (1 mg/(kg day)), with 10 SD rats in each group. The control group was given a normal diet. The model group rats were given high-sugar and high-fat diets for 14 weeks. After the model of NAFLD was established successfully, ginsenoside Rg1 was administered orally for 4 or 8 weeks. The results showed that ginsenoside Rg1 decreased the levels of glucose (GLU), insulin (INS), triglyceride (TG), and total cholesterol (TC) and improved liver function. Meanwhile, ginsenoside Rg1 inhibited the secretion of interleukin-1 (IL-1), IL-6, IL-8, IL-18, and tumor necrosis factor-α (TNF-α) and improved hepatocyte morphology and lipid accumulation in the liver. Furthermore, ginsenoside Rg1 promoted the expression of peroxisome proliferator-activated receptor-α (PPAR-α), carnitine palmitoyl transferase 1α (CPT1A), carnitine palmitoyl transferase 2 (CPT2), and cholesterol 7α-hydroxylase (CYP-7A) and inhibited the expression of sterol regulatory element binding proteins-1C (SREBP-1C). In conclusion, ginsenoside Rg1 can inhibit inflammatory reaction, regulate lipid metabolism, and alleviate liver injury in NAFLD model rats.

15.
BMC Nephrol ; 21(1): 52, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059699

RESUMO

BACKGROUND: Flurbiprofen axetil (FA) is a commonly prescribed agent to relieve perioperative pain, but the relationship between FA and postoperative acute kidney injury (AKI) remains unclear. This study attempted to evaluate the effects of different dose of perioperative FA on postoperative AKI. METHODS: A total of 9915 patients were enrolled for this retrospective study. The clinical characteristics and the prevalence of postoperative AKI among patients non-using, using low dose (50-100 mg), middle dose (100-250 mg) and large dose (≧250 mg) of FA were analyzed respectively. The impact of different dose of FA on postoperative AKI was analyzed using univariable and multivariate logistic regression analysis. RESULTS: The prevalence of postoperative AKI was 6.7% in the overall subjects and 5.1% in 2446 cases who used FA. The incidence of AKI in low dose group was significantly less than that of non use group (4.5% vs 7.2%, P < 0.001), but the incidence of AKI in large dose group was significantly higher than that in the non-use group (18.8% vs 7.2%, P < 0.001). However, there was no significant difference between patients without using FA and subjects using middle dose of FA (7.2% vs 5.6%, p = 0.355). Multivariate logistic regression analysis showed that low dose of FA was a protective factor for postoperative AKI (OR = 0.75, p = 0.0188), and large dose of FA was a risk factor for postoperative AKI (OR = 4.8, p < 0.0001). CONCLUSIONS: The impact of FA on postoperative AKI was dose-dependent, using of low dose FA (50-100 mg) perioperatively may effectively reduce the incidence of postoperative AKI.

16.
Artif Cells Nanomed Biotechnol ; 48(1): 435-442, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31916466

RESUMO

Non-coding RNAs play an important role in the pathogenesis of prostate cancer (PC). This study aims to characterize the role of GAS5 rs145204276 and HOTAIR rs4759314 polymorphisms in the pathogenesis of PC. Both INS allele of GAS5 rs145204276 and A allele of HOTAIR rs4759314 were identified to increase the survival of PC patients. And patients carrying DEL/DEL + AG genotypes tend to present higher levels of HMGB1, GAS5, HOTAIR and lower levels of miR-1284 and miR-22. In addition, the transcription activity of GAS5 promoter was increased by the deletion allele of rs145204276 polymorphism, while the G allele of rs4759314 polymorphism increased the transcription activity of HOTAIR promoter. GAS5 and HOTAIR could bind to miR-1284 and miR-22, respectively, while miR-1284 and miR-22 could bind to the 3'UTR of HMGB1. Compared with the control group, the expressions of miR-1284 or miR-22 were decreased with the presence of GAS5 or HOTAIR, and the expression of HMGB1 was the highest in the GAS5 + HOTAIR group. In summary, the findings of this study demonstrated that both GAS5 rs145204276 and HOTAIR rs4759314 polymorphisms could affect the prognosis of PC by modulating the expression of HMGB1 via modulating the GAS5/miR-1284/HMGB1 and HOTAIR/miR-22/HMGB1 signalling pathways.


Assuntos
Proteína HMGB1 , MicroRNAs , Proteínas de Neoplasias , Polimorfismo Genético , Neoplasias da Próstata , RNA Longo não Codificante , RNA Neoplásico , Transdução de Sinais/genética , Idoso , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células PC-3 , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo
17.
Cell Death Dis ; 11(1): 73, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996668

RESUMO

Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently reported to be involved in AKI. Here in this study, we investigated the internal relation between ferroptosis and the protective effect of VDR in cisplatin induced AKI. By using ferroptosis inhibitor ferrostatin-1 and measurement of ferroptotic cell death phenotype in both in vivo and in vitro cisplatin induced AKI model, we observed the decreased blood urea nitrogen, creatinine, and tissue injury by ferrostatin-1, hence validated the essential involvement of ferroptosis in cisplatin induced AKI. VDR agonist paricalcitol could both functionally and histologically attenuate cisplatin induced AKI by decreasing lipid peroxidation (featured phenotype of ferroptosis), biomarker 4-hydroxynonenal (4HNE), and malondialdehyde (MDA), while reversing glutathione peroxidase 4 (GPX4, key regulator of ferroptosis) downregulation. VDR knockout mouse exhibited much more ferroptotic cell death and worsen kidney injury than wild type mice. And VDR deficiency remarkably decreased the expression of GPX4 under cisplatin stress in both in vivo and in vitro, further luciferase reporter gene assay showed that GPX4 were target gene of transcription factor VDR. In addition, in vitro study showed that GPX4 inhibition by siRNA largely abolished the protective effect of paricalcitol against cisplatin induced tubular cell injury. Besides, pretreatment of paricalcitol could also alleviated Erastin (an inducer of ferroptosis) induced cell death in HK-2 cell. These data suggested that ferroptosis plays an important role in cisplatin induced AKI. VDR activation can protect against cisplatin induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4.


Assuntos
Lesão Renal Aguda/metabolismo , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Ferroptose/genética , Mitocôndrias/metabolismo , Receptores de Calcitriol/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/genética , Aldeídos/metabolismo , Animais , Morte Celular/genética , Linhagem Celular , Creatinina/metabolismo , Cicloexilaminas/farmacologia , Ergocalciferóis/farmacologia , Ferroptose/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão e Varredura , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Fenilenodiaminas/farmacologia , Piperazinas/metabolismo , RNA Interferente Pequeno , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética
18.
Nucl Med Commun ; 41(3): 219-227, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31895760

RESUMO

BACKGROUND: To compare the accuracy of various equations for estimating glomerular filtration rate. METHODS: Chronic kidney disease was classified by Tc-DTPA scintigraphy (reference glomerular filtration rate), estimating glomerular filtration rate was estimated using various formulas. The similarity to reference glomerular filtration rate decide the accuracy of estimating glomerular filtration rate. RESULTS: Overall, the Fengscr-cys equation had significantly higher accuracy and correct proportion in chronic kidney disease stage classification than other equations. The subgroup analysis showed that Fengscr-cys equation was slightly more precise than other equations both in the male and female patients. Moreover, in patients older than 60 years or whose reference glomerular filtration rate was above 60 ml/min, Fengscr-cys equation also showed better accuracy. CONCLUSION: Our data suggest that estimating glomerular filtration rate equations evaluated by serum cystatin C were better than serum creatinine-based equations, estimating glomerular filtration rate equations evaluated by both serum creatinine and cystatin C were better than those evaluated by serum creatinine or cystatin C alone. Among all enrolled equations, Fengscr-cys equation might be the best one to evaluate glomerular filtration rate in general Chinese paticipants.

19.
Int Immunol ; 32(5): 321-334, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31930324

RESUMO

Intrahepatic cholestasis induced by drug toxicity may cause cholestatic hepatic injury (CHI) leading to liver fibrosis and cirrhosis. The G protein-coupled bile acid receptor 1 (TGR5) is a membrane receptor with well-known roles in the regulation of glucose metabolism and energy homeostasis. However, the role and mechanism of TGR5 in the context of inflammation during CHI remains unclear. Wild-type (WT) and TGR5 knockout (TGR5-/-) mice with CHI induced by bile duct ligation (BDL) were involved in vivo, and WT and TGR5-/- bone marrow-derived macrophages (BMDMs) were used in vitro. TGR5 deficiency significantly exacerbated BDL-induced liver injury, inflammatory responses and hepatic fibrosis compared with WT mice in vivo. TGR5-/- macrophages were more susceptible to lipopolysaccharide (LPS) stimulation than WT macrophages. TGR5 activation by its ligand suppressed LPS-induced pro-inflammatory responses in WT but not TGR5-/- BMDMs. Notably, expression of ß-catenin was effectively inhibited by TGR5 deficiency. Furthermore, TGR5 directly interacted with Gsk3ß to repress the interaction between Gsk3ß and ß-catenin, thus disrupting the ß-catenin destruction complex. The pro-inflammatory nature of TGR5-knockout was almost abolished by lentivirus-mediated ß-catenin overexpression in BMDMs. BMDM migration in vitro was accelerated under TGR5-deficient conditions or supernatant from LPS-stimulated TGR5-/- BMDMs. From a therapeutic perspective, TGR5-/- BMDM administration aggravated BDL-induced CHI, which was effectively rescued by ß-catenin overexpression. Our findings reveal that TGR5 plays a crucial role as a novel regulator of immune-mediated CHI by destabilizing the ß-catenin destruction complex, with therapeutic implications for the management of human CHI.

20.
Curr Med Chem ; 27(20): 3346-3361, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30479205

RESUMO

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a polysystem autoimmune disease that adversely affects human health. Various organs can be affected, including the kidney or brain. Traditional treatment methods for SLE primarily rely on glucocorticoids and immunosuppressors. Unfortunately, these therapeutic agents cannot prevent a high recurrence rate after SLE remission. Therefore, novel therapeutic targets are urgently required. METHODS: A systematic search of the published literature regarding the abnormal structure and function of mitochondria in SLE and therapies targeting mitochondria was performed in several databases. RESULTS: Accumulating evidence indicates that mitochondrial dysfunction plays important roles in the pathogenesis of SLE, including influencing mitochondrial DNA damage, mitochondrial dynamics change, abnormal mitochondrial biogenesis and energy metabolism, mitophagy, oxidative stress, inflammatory reactions, apoptosis and NETosis. Further investigation of mitochondrial pathophysiological roles will result in further clarification of SLE. Specific lupus-induced organ damage also exhibits characteristic mitochondrial changes. CONCLUSION: This review aimed to summarize the current research on the role of mitochondrial dysfunction in SLE, which will necessarily provide potential novel therapeutic targets for SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Mitocôndrias , Humanos , Mitofagia , Biogênese de Organelas , Estresse Oxidativo
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