RESUMO
BACKGROUND: Enterococcus faecalis is a common cause of healthcare-associated infections. Its resistance to linezolid, the antibiotic of last resort for vancomycin-resistant enterococci, has become a growing threat in healthcare settings. METHODS: We analyzed the data of E. faecalis isolates from 26 medical institutions between 2018 and 2020 and performed univariate and multivariate logistic regression analyses to determine the independent predictors for linezolid-resistant E. faecalis (LREFs). Then, we used the artificial neural network (ANN) and logistic regression (LR) to build a prediction model for linezolid resistance and performed a performance evaluation and comparison. RESULTS: Of 12,089 E. faecalis strains, 755 (6.25%) were resistant to linezolid. Among vancomycin-resistant E. faecalis, the linezolid-resistant rate was 24.44%, higher than that of vancomycin-susceptible E. faecalis (p < 0.0001). Univariate and multivariate regression analyses showed that gender, age, specimen type, length of stay before culture, season, region, GDP (gross domestic product), number of beds, and hospital level were predictors of linezolid resistance. Both the ANN and LR models constructed in the study performed well in predicting linezolid resistance in E. faecalis, with AUCs of 0.754 and 0.741 in the validation set, respectively. However, synthetic minority oversampling technique (SMOTE) did not improve the prediction ability of the models. CONCLUSION: E. faecalis linezolid-resistant rates varied by specimen site, geographic region, GDP level, facility level, and the number of beds. At the same time, community-acquired E. faecalis with linezolid resistance should be monitored closely. We can use the prediction model to guide clinical medication and take timely prevention and control measures.
Assuntos
Enterococcus faecium , Infecções por Bactérias Gram-Positivas , Enterococos Resistentes à Vancomicina , Humanos , Linezolida/farmacologia , Linezolida/uso terapêutico , Enterococcus faecalis , Vancomicina/uso terapêutico , Big Data , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Bactérias Gram-Positivas/microbiologia , Testes de Sensibilidade MicrobianaRESUMO
Damage-associated molecular patterns (DAMPs) are a cause of acute kidney injury (AKI). Our knowledge of these DAMPs remains incomplete. Here, we report serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Lipopolysaccharide (LPS) and kidney ischemia/reperfusion injury instigated AKI with concurrent increases in serum Prdx1 and reductions of Prdx1 expression in kidney tubular epithelial cells. Genetic knockout of Prdx1 or use of a Prdx1-neutralizing antibody protected mice from AKI and this protection was impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, lipopolysaccharide increased serum and kidney proinflammatory cytokines, macrophage infiltration, and the content of M1 macrophages. All these events were suppressed in Prdx1-/- mice and renewed upon introduction of rPrdx1. In primary peritoneal macrophages, rPrdx1 induced M1 polarization, activated macrophage-inducible C-type lectin (Mincle) signaling, and enhanced proinflammatory cytokine production. Prdx1 interacted with Mincle to initiate acute kidney inflammation. Of note, rPrdx1 upregulated Mincle and the spleen tyrosine kinase Syk system in the primary peritoneal macrophages, while knockdown of Mincle abolished the increase in activated Syk. Additionally, rPrdx1 treatment enhanced the downstream events of Syk, including transcription factor NF-κB signaling pathways. Furthermore, serum Prdx1 was found to be increased in patients with AKI; the increase of which was associated with kidney function decline and inflammatory biomarkers in patient serum. Thus, kidney-derived serum Prdx1 contributes to AKI at least in part by activating Mincle signaling and downstream pathways.
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Injúria Renal Aguda , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Lipopolissacarídeos , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Inflamação/metabolismo , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Alarminas , Camundongos Endogâmicos C57BLRESUMO
Seizures are a frequent symptom of unruptured brain arteriovenous malformations (bAVMs). However, the brain regions responsible for these seizures remain unclear. To identify the brain regions causally involved in bAVM-related seizures, we retrospectively reviewed 220 patients with unruptured bAVMs. Using voxel-based lesion-symptom mapping (VLSM) analyses, we tested whether individual brain regions were associated with unruptured bAVM-related seizures. The result revealed that unruptured bAVMs causing seizures are anatomically heterogeneous at the voxel level. Subsequently, lesion network mapping (LNM) analyses was performed to determine whether bAVMs causing seizures belonged to a distributed brain network. LNM analyses indicated that these lesions were located in a functional network characterized by connectivity to the left caudate and precuneus. Moreover, the discrimination performance of the identified seizure network was evaluated in discovery set by calculating the individualized network damage score and was tested in validation set. Based on the calculated network damage scores, patients were divided into low-, medium-, and high-risk groups. The prevalence of seizures significantly differed among the three risk categories in both discovery (p = .003) and validation set (p = .004). Finally, we calculated the percentage of voxels in the canonical resting-state networks that overlapped with the seizure-susceptible brain regions to investigate the involvement of resting-state networks. With an involvement percentage over 50%, the frontoparietal control (82.9%), limbic function (76.7%), and default mode network (69.3%) were considered to be impacted in bAVM-related seizures. Our study identified the seizure-susceptible brain regions for unruptured bAVMs, which could be a plausible neuroimaging biomarker in predicting possible seizures.
Assuntos
Malformações Arteriovenosas , Convulsões , Humanos , Estudos Retrospectivos , Convulsões/diagnóstico por imagem , Convulsões/etiologia , Encéfalo/diagnóstico por imagemRESUMO
Mitochondrial metabolism plays an important role in the occurrence and development of cancers. Cytochrome C oxidase assembly factor six (COA6) is essential in mitochondrial metabolism. However, the role of COA6 in lung adenocarcinoma (LUAD) remains unknown. Here we report that the expression of COA6 mRNA and protein were upregulated in LUAD tissues compared with lung normal tissues. We found that COA6 had high sensitivity and specificity to distinguish LUAD tissues from normal lung tissues shown by a receiver operating characteristic (ROC) curve. In addition, our univariate and multivariate Cox regression analysis indicated that COA6 was an independent unfavorable prognostic factor for LUAD patients. Furthermore, our survival analysis and nomogram showed that a high expression of COA6 mRNA was related to the short overall survival (OS) of LUAD patients. Notably, our weighted correlation network analysis (WGCNA) and functional enrichment analysis revealed that COA6 may participate in the development of LUAD by affecting mitochondrial oxidative phosphorylation (OXPHOS). Importantly, we demonstrated that depletion of COA6 could decrease the mitochondrial membrane potential (MMP), nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH), and adenosine triphosphate (ATP) production in LUAD cells (A549 and H1975), hence inhibiting the proliferation of these cells in vitro. Together, our study strongly suggests that COA6 is significantly associated with the prognosis and OXPHOS in LUAD. Hence, COA6 is highly likely a novel prognostic biomarker and therapeutic target of LUAD.
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Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Fosforilação Oxidativa , Adenocarcinoma de Pulmão/genética , RNA Mensageiro , Neoplasias Pulmonares/genética , Proteínas de Transporte , Proteínas MitocondriaisRESUMO
Diabetic kidney disease (DKD) is a major cause of end stage renal diseases worldwide. Despite successive interventions for delaying the progression of DKD, current treatments cannot reverse the pathological progression. Mefunidone (MFD) is a new compound with potent antifibrotic properties, but the effect of MFD on DKD remains unknown. Therefore, we investigated the protective effects of MFD in both models of the db/db type 2 diabetes (T2D) and streptozotocin (STZ)-induced type 1 diabetes (T1D) models. Compared with the model group, MFD treatment significantly reduced pathological changes observed by PAS staining, PASM staining, and Masson staining in vivo. To further elucidate the potential mechanisms, we discovered MFD treatment notably restored podocyte function, alleviated inflammation, abated ROS generation, inhibited the TGF-ß1/SAMD2/3 pathway, suppressed the phosphorylation levels of MAPKs (ERK1/2, JNK, and P38), and reduced epithelial-to-mesenchymal transition(EMT). In conclusion, these findings demonstrate the effectiveness of MFD in diabetic nephropathy and elucidate its possible mechanism.
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Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Piperazinas/farmacologia , Piridonas/farmacologia , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Fluorofenidone (AKF-PD) is a novel pyridone agent that reduces the deposition of extracellular matrix (ECM) in various models of renal fibrosis. However, there are no reports on the effect of AKF-PD in preventing fibrosis in the folic acid nephropathy model. Besides, the mechanisms of action of AKF-PD in preventing renal fibrosis are not fully understood. In the study, we observed that AKF-PD reduced folate-induced kidney injury, ameliorated the deterioration of renal function, and suppressed the deposition of ECM by decreasing the expression of collagen I, collagen III, transforming growth factor-ß (TGF-ß), fibronectin (FN), and alpha smooth muscle actin (α-SMA) in the folic acid nephropathy model. Additionally, AKF-PD suppressed the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the production of caspase-1 and IL-1ß, and alleviated mitochondrial oxidative damage by promoting mitochondrial energy metabolism and reducing the expression of NADPH oxidase 4 (NOX4). The results of in vitro experiments demonstrated that AKF-PD suppressed NLRP3 inflammasome activation in activated peritoneal-derived macrophages (PDMs) and renal tubular epithelial cells (RTECs). AKF-PD increased the intracellular ATP content and decreased the expression of NOX4, while preventing the excessive production of mitochondrial reactive oxygen species (mtROS) in activated PDMs. In conclusion, this study demonstrated that AKF-PD inhibited renal fibrosis by suppressing the mtROS-NLRP3 pathway in the folic acid nephropathy model. These findings provide new evidence in support of the clinical use of AKF-PD in the treatment of diseases related to renal fibrosis.
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Nefropatias/tratamento farmacológico , Rim/patologia , Piridonas/farmacologia , Animais , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose , Ácido Fólico/toxicidade , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: AarF domain-containing kinase 4 (ADCK4)-associated glomerulopathy is a mitochondrial nephropathy caused by mutations in the ADCK4 gene, which disrupt coenzyme Q10 biosynthesis. CASE PRESENTATION: We report the case of a 25-year-old female patient with ADCK4-associated glomerulopathy presenting with proteinuria (and with no additional systemic symptoms). A known missense substitution c.737G > A (p.S246N) and a novel frameshift c.577-600del (p.193-200del) mutation were found. We followed the patient for 24 months during supplementation with coenzyme Q10 (20 mg/kg/d - 30 mg/kg/d) and describe the clinical course. In addition, we measured serum and urine coenzyme Q10 levels before and after coenzyme Q10 supplementation and compared them with those of healthy control subjects. The patient's urinary coenzyme Q10 to creatinine ratio was higher than that of healthy controls before coenzyme Q10 supplementation, but decreased consistently with proteinuria after coenzyme Q10 supplementation. CONCLUSIONS: Although the use of urinary coenzyme Q10 as a diagnostic biomarker and predictor of clinical remission in patients with ADCK4-associated glomerulopathy should be confirmed by larger studies, we recommend measuring urinary coenzyme Q10 in patients with isolated proteinuria of unknown cause, since it may provide a diagnostic clue to mitochondrial nephropathy.
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Nefropatias/urina , Glomérulos Renais , Proteínas Quinases , Ubiquinona/análogos & derivados , Adulto , Biomarcadores/urina , Feminino , Humanos , Nefropatias/diagnóstico , Nefropatias/genética , Mutação , Valor Preditivo dos Testes , Prognóstico , Proteínas Quinases/genética , Ubiquinona/urinaRESUMO
Clusters of patients with novel coronavirus disease 2019 (COVID-19) have been successively reported globally. Studies show clear person-to-person transmission. The average incubation period is 2-14 days, and mostly 3-7 days. However, in some patients, this period may be longer. Here, we report a familial cluster of COVID-19 where a 47-year-old woman with long-term use of glucocorticoids did not develop any symptoms within the 14-day quarantine period but was confirmed with COVID-19 by tested positive of antibody on day 40 after she left Wuhan. Almost at the same time, her father and sister were diagnosed with COVID-19. The results suggest that the long-term use of glucocorticoids might cause atypical infections, a long incubation period, and extra transmission of COVID-19.
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Infecções por Coronavirus/tratamento farmacológico , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Período de Incubação de Doenças Infecciosas , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso de 80 Anos ou mais , Betacoronavirus , COVID-19 , China , Feminino , Humanos , Pulmão/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Eliminação de Partículas ViraisRESUMO
Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP-induced AKI in vivo and in vitro. Compared with the model group, treatment with AKFPD effectively ameliorated kidney damages. In order to elucidate the mechanisms, we discovered that AKFPD treatment notably alleviated generation of reactive oxygen species, reduced the phosphorylation levels of MAPKs (ERK1 and 2, JNKs, and p38), suppressed inflammatory response, inhibited apoptosis, and abated the expression of CP transporters (organic cation transporter 2 and copper transport protein 1) compared with the model group. Moreover, because renal ischemia reperfusion injury (IRI)-induced AKI and LPS-induced AKI are the major models representative of renal transplantation-correlated AKI and sepsis-related AKI, which are also the main causes of AKI, we have also proved the effectiveness of AKFPD on these models. In conclusion, these findings suggest that AKFPD is a potent drug for CP-, IRI-, and LPS-caused AKI and elucidate the underlying mechanism.-Jiang, Y., Quan, J., Chen, Y., Liao, X., Dai, Q., Lu, R., Yu, Y., Hu, G., Li, Q., Meng, J., Xie, Y., Peng, Z., Tao, L. Fluorofenidone protects against acute kidney injury.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Cisplatino/toxicidade , Piridonas/farmacologia , Animais , Antineoplásicos/toxicidade , Linhagem Celular , Transportador de Cobre 1/genética , Transportador de Cobre 1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Rim/citologia , Rim/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Transportador 2 de Cátion Orgânico/genética , Transportador 2 de Cátion Orgânico/metabolismo , Peroxidase/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Traumatismo por ReperfusãoRESUMO
OBJECTIVE: Previous studies have suggested that blood pressure variability (BPV) is associated with an increased risk of mortality and cardiovascular events in patients on dialysis. However, the results are inconsistent. A comprehensive literature review was conducted to analyze the association between BPV and outcomes in patients on dialysis. METHODS: Articles in Embase, Medline, and Web of Science from the date of inception through January 1, 2020, were identified. The outcomes were all-cause and cardiovascular mortality and cardiovascular events. The risk of bias was assessed using the Newcastle-Ottawa scale tool. Random effects models were used to pool the overall effect sizes. Two reviewers extracted the data independently. Meta-regression and subgroup analyses were performed to explore potential heterogeneity. RESULTS: Fifteen eligible studies were included, and all enrolled hemodialysis recipients only. The overall risk of bias for the included studies was low. A 1-SD increase in systolic BPV was associated with higher risks of all-cause mortality (HR = 1.18; 95% CI 1.11-1.26, I2 = 53.8%), cardiovascular mortality (HR = 1.23; 95% CI 1.10-1.37, I2 = 57.2%), and cardiovascular events (HR = 1.27; 95% CI 1.07-1.51, I2 = 69.3%). Likewise, a 1-SD increase in diastolic BPV was associated with higher HR for all-cause and cardiovascular mortality (HR = 1.14; 95% CI 1.05-1.23, I2 = 0.0%, and HR = 1.14; 95% CI 0.94-1.38, I2 = 0.0%, respectively). CONCLUSIONS: A greater BPV is associated with higher risks of cardiovascular and mortality outcomes in patients on hemodialysis. Further research is required to determine whether BPV may be useful either as a marker enabling individualized treatment of cardiovascular risk or as a treatment target in its own right.
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Pressão Sanguínea , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Diálise Renal , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Diálise Renal/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND: High- and low-flux hemodialysis (HFHD and LFHD, respectively) are dialysis procedures designed to eliminate blood toxins that accumulate in end-stage renal disease. HFHD may reduce vascular calcification by removing serum fibroblast growth factor 23 (FGF-23). However, whether HFHD is better than LFHD is still under debate. We therefore compared the efficacy of HFHD and LFHD in controlling FGF-23 and vascular calcification. MATERIAL AND METHODS: Fifty hemodialysis patients were recruited and randomly treated with either HFHD or LFHD. Fasting venous blood was collected at baseline, six months, and twelve months after the treatment. We then measured levels of FGF-23, calcium, phosphorus, parathyroid hormone, and alkaline phosphatase. Further, abdominal lateral radiographs were taken to calculate aorta abdominalis calcification scores (AACs). RESULTS: Compared to the LFHD group, FGF-23 and AACs in the HFHD group significantly decreased after 12 months treatment (p=0.049 and p=0.002, respectively). AACs were positively correlated with FGF-23 in all patients (p=0.004), the HFHD group alone (p=0.040), and the LFHD group alone (p=0.037). We also found that older patients, patients with higher blood phosphorus levels, and higher FGF-23 levels had an increased risk of aorta abdominalis calcification (p=0.048, p=0.003, p=0.001, respectively). HFHD was more able to reduce the risk of aorta abdominalis calcification than LFHD (p=0.003). CONCLUSIONS: FGF-23 is an independent risk factor for the development of vascular calcification. HFHD may benefit hemodialysis patients by reducing serum FGF-23 levels and controlling vascular calcification.
Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Regulação da Expressão Gênica , Falência Renal Crônica/sangue , Insuficiência Renal Crônica/sangue , Calcificação Vascular/sangue , Adulto , Idoso , Fosfatase Alcalina/sangue , Fosfatase Alcalina/metabolismo , Aorta Abdominal/patologia , Cálcio/sangue , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fósforo/sangue , Radiografia Abdominal , Análise de Regressão , Diálise Renal , Insuficiência Renal Crônica/terapia , Fatores de RiscoRESUMO
OBJECTIVES: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a serious threat to public health due to its limited treatment options and high mortality rate. This study aims to identify the risk factors of carbapenem resistance in patients with K. pneumoniae isolates and develop CRKP prediction models using logistic regression (LR) and artificial neural network (ANN) methods. METHODS: We retrospectively analysed the data of 49,774 patients with Klebsiella pneumoniae isolates from a regional nosocomial infection surveillance system (RNSS) between 2018 and 2021. We performed logistic regression analyses to determine the independent predictors for CRKP. We then built and evaluated LR and ANN models based on these predictors using calibration curves, ROC curves, and decision curve analysis (DCA). We also applied the Synthetic Minority Over-Sampling Technique (SMOTE) to balance the data of CRKP and non-CRKP groups. RESULTS: The LR model showed good discrimination and calibration in both training and validation sets, with areas under the ROC curve (AUROC) of 0.824 and 0.825, respectively. The DCA indicated that the LR model had clinical usefulness for decision making. The ANN model outperformed the LR model both in the training set and validation set. The SMOTE technique improved the performance of both models for CRKP detection in training set, but not in the validation set. CONCLUSION: We developed and validated LR and ANN models for predicting CRKP based on RNSS data. Both models were feasible and reliable for CRKP inference and could potentially assist clinicians in selecting appropriate empirical antibiotics and reducing unnecessary medical resource utilization.
Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , Infecção Hospitalar , Infecções por Klebsiella , Humanos , Klebsiella pneumoniae , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Estudos Retrospectivos , Modelos Logísticos , Infecções por Klebsiella/tratamento farmacológico , Infecção Hospitalar/tratamento farmacológico , China/epidemiologiaRESUMO
Human embryonic stem cells (hESCs) can proliferate infinitely (self-renewal) and give rise to almost all types of somatic cells (pluripotency). Hence, understanding the molecular mechanism of pluripotency regulation is important for applications of hESCs in regenerative medicine. Here we report that PATZ1 is a key factor that regulates pluripotency and metabolism in hESCs. We found that depletion of PATZ1 is associated with rapid downregulation of master pluripotency genes and prominent deceleration of cell growth. We also revealed that PATZ1 regulates hESC pluripotency though binding the regulatory regions of OCT4 and NANOG. In addition, we demonstrated PATZ1 is a key node in the OCT4/NANOG transcriptional network. We further revealed that PATZ1 is essential for cell growth in hESCs. Importantly, we discovered that depletion of PATZ1 drives hESCs to exploit glycolysis which energetically compensates for the mitochondrial dysfunction. Overall, our study establishes the fundamental role of PATZ1 in regulating pluripotency in hESCs. Moreover, PATZ1 is essential for maintaining a steady metabolic homeostasis to refine the stemness of hESCs.
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Células-Tronco Embrionárias Humanas , Células-Tronco Pluripotentes , Humanos , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Pluripotentes/metabolismo , Zinco , Motivos AT-Hook , Diferenciação Celular/genética , Fatores de Transcrição/metabolismo , Dedos de Zinco , Proteínas Repressoras/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismoRESUMO
[This corrects the article DOI: 10.3389/fphar.2022.1043945.].
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(1) Background: Wharton's Jelly stem cells (WJ-MSCs) are multipotent mesenchymal stem cells that can proliferate rapidly and have low immunogenicity. Therefore, WJ-MSCs have gained considerable attention in the fields of immunomodulation and disease treatment and have entered clinical trials for the treatment of various diseases. Therefore, it is crucial to study the underlying mechanisms of WJ-MSCs proliferation, immune regulation, and disease treatment. Nuclear Receptor Subfamily 2 Group F Member 2 (NR2F2) is a transcription factor that is involved in the regulation of many different genes. However, it remains unknown how NR2F2 regulates stem cell identity in WJ-MSCs. (2) Methods: We used RNAi technology to knock down NR2F2 in WJ-MSCs, and studied the regulatory role of NR2F2 in WJ-MSCs by MTT, flow cytometry, RNA-seq, and other methods. We also utilized a co-culture system in which NR2F2-depleted WJ-MSCs with MH7A and HCT116/HepG2 were used to investigate the role of NR2F2 in immunomodulation and the inhibition of cancer cell growth. (3) Results: NR2F2 knockdown resulted in decreased expressions of Cyclin D1 and CDK4, slower cell proliferation, and increased expressions of IL6 and IL8. Furthermore, Cyclin D1, CDK4, and inflammatory factors were increased in human rheumatoid fibroblast-like synoviocyte line MH7A if co-cultured with NR2F2 depleted WJ-MSCs. In addition, we observed increased p53, decreased BCL-2, and increased cell apoptosis in liver cancer cell line HepG2 if co-cultured with NR2F2-depleted WJ-MSCs. (4) Conclusions: NR2F2 not only plays an important role in the cell cycle and immune regulation of WJ-MSCs but also has potential effects on the WJ-MSCs treatment of related diseases.
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Ciclina D1 , Células-Tronco Mesenquimais , Fator II de Transcrição COUP/metabolismo , Proliferação de Células/genética , Ciclina D1/metabolismo , Humanos , Imunomodulação/genética , Cordão Umbilical/metabolismoRESUMO
Renal ischemia-reperfusion injury (IRI) is one of the most common causes of acute kidney injury (AKI). It poses a significant threat to public health, and effective therapeutic drugs are lacking. Mefunidone (MFD) is a new pyridinone drug that exerts a significant protective effect on diabetic nephropathy and the unilateral ureteral obstruction (UUO) model in our previous study. However, the effects of mefunidone on ischemia-reperfusion injury-induced acute kidney injury remain unknown. In this study, we investigated the protective effect of mefunidone against ischemia-reperfusion injury-induced acute kidney injury and explored the underlying mechanism. These results revealed that mefunidone exerted a protective effect against ischemia-reperfusion injury-induced acute kidney injury. In an ischemia-reperfusion injury-induced acute kidney injury model, treatment with mefunidone significantly protected the kidney by relieving kidney tubular injury, suppressing oxidative stress, and inhibiting kidney tubular epithelial cell apoptosis. Furthermore, we found that mefunidone reduced mitochondrial damage, regulated mitochondrial-related Bax/bcl2/cleaved-caspase3 apoptotic protein expression, and protected mitochondrial electron transport chain complexes III and V levels both in vivo and in vitro, along with a protective effect on mitochondrial membrane potential in vitro. Given that folic acid (FA)-induced acute kidney injury is a classic model, we used this model to further validate the efficacy of mefunidone in acute kidney injury and obtained the same conclusion. Based on the above results, we conclude that mefunidone has potential protective and therapeutic effects in both ischemia-reperfusion injury- and folic acid-induced acute kidney injury.
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Objective: Mitochondrial damage contributes to extracellular matrix (ECM) deposition and renal fibrosis. In this study, we aimed (1) to investigate whether fluorofenidone (AKF-PD) can attenuate mitochondrial damage in two renal fibrosis models: unilateral ureteral obstruction (UUO) and renal ischemia-reperfusion injury (IRI), and (2) to explore the underlying mechanism. Method: Mitochondrial damage and renal lesions were analyzed in the UUO and IRI models. Mitochondrial energy metabolism, mitochondrial biogenesis, and oxidative stress were measured to assess the effect of AKF-PD on mitochondrial damage and to explore the underlying mechanism. In addition, HK-2 cells were stimulated with TGF-ß with and without AKF-PD. The mitochondrial morphology, mtROS, ATP contents, and redox-related proteins were then examined. Results: In both UUO and IRI models, AKF-PD relieved renal fibrosis, maintained mitochondrial structure, and increased mitochondrial DNA copy numbers. The protection was associated with (1) sustaining mitochondrial energy metabolism, evident by elevations of tricarboxylic acid (TCA) cycle enzymes and mitochondrial respiratory chain complexes; (2) improving mitochondrial biogenesis with increases of TFAM, NRF1, PGC-1α, and SIRT1; and (3) reducing mitochondrial oxidative stress likely via regulating SOD2, SIRT3, and NOX4 expressions. In HK-2 cells treated with TGF-ß, AKF-PD protected mitochondria along with improving mitochondrial morphology, enhancing ATP production, reducing mtROS, and regulating SOD2, SIRT3, and NOX4 expression. Conclusion: We demonstrate that AKF-PD inhibited renal fibrosis at least in part via protecting mitochondria from damages developed in the UUO and IRI models. The mitochondrial protection was associated with sustaining mitochondrial energy metabolism, improving mitochondrial biogenesis, and reducing mitochondrial oxidative stress. This research verified the protective effect of AKF-PD on mitochondria in the UUO and IRI models and elaborated the underlying mechanism.
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Nefropatias , Obstrução Ureteral , Fibrose , Humanos , Nefropatias/tratamento farmacológico , Piridonas/farmacologia , Piridonas/uso terapêuticoRESUMO
To analyze the change of optical property of PWS skin during photodynamic therapy, the reflection spectra and fluorescence spectra of PWS skin during PDT treatment were measured using mini-optical fiber spectrograph. The change of reflection spectra and fluorescence spectra were analyzed according to the histological structure of PWS skin and the absorption spectra of the main chromophores in skin (melanin and hemoglobin). The result showed that the spectra changed significantly at the wavelength at which melanin and hemoglobin have high absorption, or at which obvious difference existed in the absorption between HbO2 and Hb. The monitoring of reflection spectra and fluorescence spectra during PDT can provide information about the dynamic change of the optical property of PWS tissue.
Assuntos
Mancha Vinho do Porto/diagnóstico , Espectrometria de Fluorescência , Fluorescência , Hemoglobinas/análise , Humanos , Melaninas/análise , Fibras Ópticas , Fotoquimioterapia , Pele/patologiaRESUMO
Background: A large number of people contracted moderate-type COVID-19 around the world. However, to our knowledge no studies have covered the clinical course of patients with moderate-type COVID-19. This study describes the clinical course of moderate-type patients with COVID-19 from Wuhan City and Yiyang City, and explores factors relevant to the length of hospitalization and symptoms relief. Methods: The study analyzed the clinical course of 107 moderate-type patients with COVID-19 from the outbreak area (Wuhan) and the imported area (Yiyang), and used automatic linear modeling and multivariate linear regression analysis to explore the factors relevant to the length of hospitalization and symptoms relief. Furthermore, we created a scoring system to value the length of hospitalization and symptoms relief. Results: Lymphopenia, elevated C-reactive protein, increased LDH, bilateral lung GGO (ground glass opacity), and lung consolidation were more likely to appear in ordinary inpatients with moderate-type COVID-19 from Wuhan (P < 0.05), compared to infected medical staff from Wuhan and ordinary inpatients with moderate-type COVID-19 from Yiyang. Meanwhile, the length of hospitalization and symptoms relief was longer in ordinary patients with moderate-type COVID-19 from Wuhan (P < 0.05). Onset of symptoms to admission, ESR, leucocytes count, and bilateral lung GGO were linearly related to the length of hospitalization (P < 0.05); onset of symptoms to admission, leucocytes count, bilateral lung GGO, and lung consolidation were linearly related to the length of symptoms relief (P < 0.05). By using the scoring system, we found that the time of hospitalization and symptoms relief lengthened as the scores increased. Conclusions: This study described the clinical course of patients with moderate-type COVID-19, and found that ordinary patients with moderate-type COVID-19 in outbreak areas were more serious and needed stronger treatment and longer treatment time. Onset of symptoms to admission, ESR, leucocytes count, and bilateral lung GGO can be effective predictors of the length of hospitalization. And onset of symptoms to admission, leucocytes count, bilateral lung GGO, and lung consolidation can be effective predictors of the amount of time until symptoms relief. Most importantly, we have created a scoring system, which could contribute to the diagnosis and treatment of COVID-19.
Assuntos
COVID-19 , Humanos , Pulmão/diagnóstico por imagem , Estudos Retrospectivos , SARS-CoV-2 , Tomografia Computadorizada por Raios XRESUMO
Idiopathic pulmonary fibrosis (IPF) is one of the most common and devastating interstitial lung diseases with poor prognosis. Currently, few effective drugs are available for IPF. Hence, we sought to explore the role of mefunidone (MFD), a newly synthesized drug developed by our team, in lung fibrosis. In this study, MFD was found to attenuate bleomycin (BLM) -induced lung fibrosis and inflammation in mice according to Ashcroft and alveolitis scoring. The protein contents and total cell counts in bronchoalveolar lavage fluids of BLM-treated mice were also lowered by MFD. Moreover, the elevation of TGF-ß/Smad2 and phosphorylation of MAPK pathways was repressed by MFD. Additionally, MFD attenuated the swelling and vacuolization of mitochondria, lowered the ratio of apoptotic cells, restored the mitochondrial membrane potential, and reversed the expression of cleaved-caspase 3, Bcl-2 and Bax. Meanwhile, the level of epithelial marker, E-cadherin, was restored by MFD, while the levels of mesenchymal markers such as Snail and vimentin were down-regulated by MFD. Besides, MFD inhibited the expression of fibronectin and α-smooth muscle actin in TGF-ß treated normal human lung fibroblasts. Thus, our findings suggested that MFD could ameliorate lung fibrosis, cell apoptosis and EMT potentially via suppression of TGF-ß/Smad2 and MAPK pathways.