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1.
Nat Methods ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965442

RESUMO

Dynamic imaging of genomic loci is key for understanding gene regulation, but methods for imaging genomes, in particular non-repetitive DNAs, are limited. We developed CRISPRdelight, a DNA-labeling system based on endonuclease-deficient CRISPR-Cas12a (dCas12a), with an engineered CRISPR array to track DNA location and motion. CRISPRdelight enables robust imaging of all examined 12 non-repetitive genomic loci in different cell lines. We revealed the confined movement of the CCAT1 locus (chr8q24) at the nuclear periphery for repressed expression and active motion in the interior nucleus for transcription. We uncovered the selective repositioning of HSP gene loci to nuclear speckles, including a remarkable relocation of HSPH1 (chr13q12) for elevated transcription during stresses. Combining CRISPR-dCas12a and RNA aptamers allowed multiplex imaging of four types of satellite DNA loci with a single array, revealing their spatial proximity to the nucleolus-associated domain. CRISPRdelight is a user-friendly and robust system for imaging and tracking genomic dynamics and regulation.

2.
Acta Pharmacol Sin ; 45(2): 366-377, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37770579

RESUMO

Diabetic nephropathy (DN) is characterized by chronic low-grade renal inflammatory responses, which greatly contribute to disease progression. Abnormal glucose metabolism disrupts renal lipid metabolism, leading to lipid accumulation, nephrotoxicity, and subsequent aseptic renal interstitial inflammation. In this study, we investigated the mechanisms underlying the renal inflammation in diabetes, driven by glucose-lipid metabolic rearrangement with a focus on the role of acetyl-CoA synthetase 2 (ACSS2) in lipid accumulation and renal tubular injury. Diabetic models were established in mice by the injection of streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high glucose (HG, 30 mmol/L) condition. We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells (RTECs) from the diabetic mice and human diabetic kidney biopsy samples, and ACSS2 was co-localized with the pro-inflammatory cytokine IL-1ß in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/L) in HK-2 cells significantly ameliorated HG-induced inflammation, mitochondrial stress, and fatty acid synthesis. Molecular docking revealed that ACSS2 interacted with Sirtuin 1 (SIRT1). In HG-treated HK-2 cells, we demonstrated that ACSS2 suppressed SIRT1 expression and activated fatty acid synthesis by modulating SIRT1-carbohydrate responsive element binding protein (ChREBP) activity, leading to mitochondrial oxidative stress and inflammation. We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular inflammation in DN by regulating the SIRT1-ChREBP pathway. This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal inflammation and dysregulation of fatty acid metabolic homeostasis in DN. Metabolic inflammation in the renal region, driven by lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Humanos , Camundongos , Animais , Sirtuína 1/metabolismo , Nefropatias Diabéticas/patologia , Acetilcoenzima A/metabolismo , Acetilcoenzima A/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Simulação de Acoplamento Molecular , Rim/patologia , Fatores de Transcrição/metabolismo , Metabolismo dos Lipídeos , Glucose/metabolismo , Ácidos Graxos/metabolismo , Inflamação/metabolismo , Ligases/metabolismo , Lipídeos
3.
Clin Nephrol ; 101(3): 101-108, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38126194

RESUMO

BACKGROUND: Systemic inflammatory indicators are important in the prognoses of various diseases. Such indicators, including the neutrophil-to-lymphocyte ratio (NLR), can be meaningful in predicting the clinical outcome in patients diagnosed with idiopathic membranous nephropathy (IMN). MATERIALS AND METHODS: 112 IMN patients diagnosed by renal biopsy were recruited retrospectively. The endpoint was defined as a combination of partial and complete remission. Statistical analysis determined the independent factors associated with clinical remission and the predictive utility of NLR. RESULTS: Within the 12-month follow-up period, 72 patients achieved clinical remission after treatment. Univariate analysis identified significant differences in serum albumin, estimated glomerular filtration rate (eGFR), proteinuria, neutrophil count, and NLR between the remission group and the non-remission group (all p < 0.05). Cox proportional hazards indicated that elevated eGFR (HR 1.022, 95% CI (1.009 - 1.035), p = 0.001), lower NLR (HR 0.345, 95% CI (0.237 - 0.501), p = 0.0001), and decreased proteinuria (HR 0.826, 95% CI (0.693 - 0.984), p = 0.032) were protective elements for remission. With an optimal cut-off value of 2.61, the pre-treatment NLR had an excellent ability to identify the remission (area under the curve (AUC), 0.785). Participants were separated into low- and high-NLR groups by using 2.61. Kaplan-Meier survival curves revealed significantly higher remission rates in the lower group (p < 0.0001). CONCLUSION: The NLR is an effective indicator for predicting clinical remission in patients with IMN.


Assuntos
Glomerulonefrite Membranosa , Humanos , Glomerulonefrite Membranosa/tratamento farmacológico , Neutrófilos , Estudos Retrospectivos , Linfócitos/patologia , Prognóstico , Proteinúria
4.
Int J Med Sci ; 21(4): 703-713, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38464833

RESUMO

Background: Renal anaemia and left ventricular hypertrophy are the main complications of chronic kidney disease and are shared among dialysis patients. This retrospective study aimed to compare the efficacies of the hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat and recombinant human erythropoietin in reversing ventricular remodeling in dialysis patients with renal anaemia. Methods: A total of 204 participants underwent baseline examinations, including echocardiograms and laboratory tests, before being administered either treatment for at least 24 weeks from January 2018 to October 2021, after which follow-up examinations were conducted at 6 months. Propensity score matching based on key variables included age, gender, cardiovascular diseases, cardiovascular medications, dialysis course and the vascular access at baseline was performed to include populations with similar characteristics between groups. Results: In total, 136 patients were included with roxadustat or recombinant human erythropoietin. The left ventricular mass index after treatment with roxadustat and recombinant human erythropoietin both significantly decreased after 6 months, but there was no significant difference in the change in left ventricular mass index between the two groups. In addition, the left ventricular end-diastolic diameters and left ventricular wall thickness, systolic blood pressure, and diastolic blood pressure significantly decreased in the roxadustat group. Roxadustat and recombinant human erythropoietin also increased haemoglobin significantly, but there was no significant difference in the change in haemoglobin between the two groups. The results of multiple linear regression showed that the change in haemoglobin was independent factor affecting the improvement of left ventricular mass index. Conclusions: The increase of haemoglobin was associated with improving left ventricular hypertrophy in dialysis patients. However, the beneficial effects between roxadustat and recombinant human erythropoietin on left ventricular mass index did not show clear superiority or inferiority in six months.


Assuntos
Anemia , Eritropoetina , Insuficiência Renal Crônica , Humanos , Anemia/tratamento farmacológico , Anemia/etiologia , Eritropoetina/uso terapêutico , Glicina/uso terapêutico , Hemoglobinas/análise , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Isoquinolinas/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Estudos Retrospectivos , Remodelação Ventricular
5.
BMC Nephrol ; 25(1): 72, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38413872

RESUMO

BACKGROUND: Diabetic nephropathy (DN) and atherosclerosis (AS) are prevalent and severe complications associated with diabetes, exhibiting lesions in the basement membrane, an essential component found within the glomerulus, tubules, and arteries. These lesions contribute significantly to the progression of both diseases, however, the precise underlying mechanisms, as well as any potential shared pathogenic processes between them, remain elusive. METHODS: Our study analyzed transcriptomic profiles from DN and AS patients, sourced from the Gene Expression Omnibus database. A combination of integrated bioinformatics approaches and machine learning models were deployed to identify crucial genes connected to basement membrane lesions in both conditions. The role of integrin subunit alpha M (ITGAM) was further explored using immune infiltration analysis and genetic correlation studies. Single-cell sequencing analysis was employed to delineate the expression of ITGAM across different cell types within DN and AS tissues. RESULTS: Our analyses identified ITGAM as a key gene involved in basement membrane alterations and revealed its primary expression within macrophages in both DN and AS. ITGAM was significantly correlated with tissue immune infiltration within these diseases. Furthermore, the expression of genes encoding core components of the basement membrane was influenced by the expression level of ITGAM. CONCLUSION: Our findings suggest that macrophages may contribute to basement membrane lesions in DN and AS through the action of ITGAM. Moreover, therapeutic strategies that target ITGAM may offer potential avenues to mitigate basement membrane lesions in these two diabetes-related complications.


Assuntos
Aterosclerose , Diabetes Mellitus , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/patologia , Membrana Basal/metabolismo , Glomérulos Renais/patologia , Aterosclerose/complicações , Macrófagos/metabolismo , Diabetes Mellitus/metabolismo , Antígeno CD11b/metabolismo
6.
J Transl Med ; 21(1): 34, 2023 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-36670462

RESUMO

BACKGROUND: The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer's disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD. METHODS: Aß1-42-treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APPswe/PSdE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aß deposition respectively. RESULTS: Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells. CONCLUSION: Tan IIA could promote Aß transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 mice.


Assuntos
Doença de Alzheimer , Células Endoteliais , Camundongos , Animais , Células Endoteliais/metabolismo , Sirtuína 1/metabolismo , Simulação de Acoplamento Molecular , Estresse do Retículo Endoplasmático , Doença de Alzheimer/tratamento farmacológico , Modelos Animais de Doenças
7.
Heart Fail Rev ; 26(5): 1119-1130, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-32405811

RESUMO

The objective of this study was to evaluate the pharmacoeconomic value of sacubitril-valsartan for the treatment of heart failure (HF). PubMed, Embase, Cochrane Library, ScienceDirect, Scopus, CNKI, Wanfang, and VIP databases were searched systematically and the retrieval time ended in August 2019. According to the criteria of inclusion and exclusion, the quality of studies included was evaluated as per the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) scale, and the results were extracted and analyzed systematically. The total of 11 cost-effectiveness studies was identified, 10 were performed in the developed countries and 1 in Thailand. All the patients in the studies had chronic heart failure with reduced ejection fraction (HFrEF). Totally, the quality of all the 11 studies was reported to be of an average score of 20.5. Study perspective and time horizons were described in the 11 studies. All included studies discounted the cost or effectiveness. Only 1 study estimated direct and indirect costs; 10 studies evaluated direct cost. The incremental cost-effectiveness ratio (ICER) of sacubitril-valsartan treating HFrEF was $13,150 per quality-adjusted life-years (QALY) in Thailand and $86,735 in Singapore. In European countries, the ICER was from $21,786 to $34,576 per QALY and mean value was $25,410.6 per QALY. In the USA, ICER values ranged from $47,099 to $143,891 per QALY, and mean value was $73,383.5 per QALY; ICER was $30,090 per QALY in Colombia. With the exception of Thailand and Singapore, the ICER of other countries in the included literature was below the implemented country-specific thresholds. Based on existing literatures, with the exception of Thailand and Singapore, sacubitril-valsartan for the treatment of HFrEF is a better cost-effective therapy with ICER basically below the implemented country-specific thresholds. Sacubitril-valsartan was not considered a cost-effective treatment for heart failure with reduced ejection fraction in Thailand and Singapore with the current economic evaluation evidences, but with the willingness-to-pay (WTP) of other counties, sacubitril-valsartan was found to be a cost-effective treatment compared with comparator. Drug cost, time horizon, and hospitalization were the most influential variables across studies. Four studies indicated that with the longer time horizon, the lower ICER value would gain. Further studies are warranted to better evaluate comprehensive utility value of sacubitril-valsartan on heart failure.


Assuntos
Insuficiência Cardíaca , Aminobutiratos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo , Análise Custo-Benefício , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Volume Sistólico , Tetrazóis/uso terapêutico , Valsartana
8.
Acta Pharmacol Sin ; 42(9): 1401-1408, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33277592

RESUMO

We previously reported that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, significantly ameliorated Alzheimer's disease (AD)-associated cognitive defects in APP/PS1 and SAMP8 mice by inhibiting Aß aggregation and tau hyperphosphorylation, suggesting a potential therapeutic effect of PF11 in the treatment of AD. In the present study we further evaluated the therapeutic effects of PF11 on relieving cognitive impairment in a rat model of sporadic AD (SAD). SAD was induced in rats by bilateral icv infusion of streptozotocin (STZ, 3 mg/kg). The rats were treated with PF11 (2, 4, 8 mg·kg-1·d-1, ig) or a positive control drug donepezil (5 mg·kg-1·d-1, ig) for 4 weeks. Their cognitive function was assessed in the nest building, Y-maze, and Morris water maze tests. We showed that STZ icv infusion significantly affected the cognitive function, tau phosphorylation, and insulin signaling pathway in the hippocampus. Furthermore, STZ icv infusion resulted in significant upregulation of the calpain I/cyclin-dependent protein kinase 5 (CDK5) signaling pathway in the hippocampus. Oral administration of PF11 dose-dependently ameliorated STZ-induced learning and memory defects. In addition, PF11 treatment markedly reduced the neuronal loss, protected the synapse structure, and modulated STZ-induced expression of tau phosphorylation by regulating the insulin signaling pathway and calpain I/CDK5 signaling pathway in the hippocampus. Donepezil treatment exerted similar beneficial effects in STZ-infused rats as the high dose of PF11 did. This study highlights the excellent therapeutic potential of PF11 in managing AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Ginsenosídeos/farmacologia , Proteínas tau/metabolismo , Doença de Alzheimer/induzido quimicamente , Animais , Calpaína/metabolismo , Pareamento Cromossômico , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/ultraestrutura , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Estreptozocina
9.
J Cell Mol Med ; 24(6): 3449-3459, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32000299

RESUMO

Epidemiological studies have found that diabetes and cognitive dysfunction are closely related. Quercetin has been certified with the effect on improving diabetes mellitus (DM) and cognitive impairment. However, the effect and related mechanism of quercetin on diabetic encephalopathy (DE) are still ambiguous. In this study, we used the db/db mice (diabetic model) to discover whether quercetin could improve DE through the Sirtuin1/NLRP3 (NOD-, LRR- and pyrin domain-containing 3) pathway. Behavioural results (Morris water maze and new object recognition tests) showed that quercetin (70 mg/kg) improved the learning and memory. Furthermore, quercetin alleviated insulin resistance and the level of fasting blood glucose. Besides, Western blot analysis also showed that quercetin increased the protein expressions of nerve- and synapse-related protein, including postsynapticdensity 93 (PSD93), postsynapticdensity 95 (PSD95), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brain of db/db mice. Quercetin also increased the protein expression of SIRT1 and decreased the expression of NLRP3 inflammation-related proteins, including NLRP3, the adaptor protein ASC and cleaved Caspase-1, the pro-inflammatory cytokines IL-1ß and IL-18. In conclusion, the present results indicate that the SIRT1/NLRP3 pathway may be a crucial mechanism for the neuroprotective effect of quercetin against DE.


Assuntos
Antioxidantes/farmacologia , Encefalopatias/patologia , Diabetes Mellitus/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Quercetina/farmacologia , Sirtuína 1/metabolismo , Animais , Glicemia/efeitos dos fármacos , Encefalopatias/prevenção & controle , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/prevenção & controle , Proteína 4 Homóloga a Disks-Large/metabolismo , Feminino , Resistência à Insulina/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Fator de Crescimento Neural/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos
10.
Clin Exp Nephrol ; 23(7): 969-981, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31049747

RESUMO

BACKGROUND: Contrast-induced nephropathy (CIN) is a common complication in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) and associated with poor outcome. Some previous studies have already set up models to predict CIN, but there is no model for patients with diabetes mellitus (DM) especially. Therefore, we aim to develop and validate a simple risk score for predicting the risk of CIN in patients with DM undergoing CAG/PCI. METHODS: A total of 1157 consecutive patients with DM undergoing CAG/PCI were randomly assigned to a development cohort (n = 771) and a validation cohort (n = 386). The primary endpoint was CIN, which was defined as an absolute increase in serum creatinine (SCr) by 0.5 mg/dL from the baseline within 48-72 h after contrast exposure. The independent predictors for CIN were identified by multivariate logistic regression, and the discrimination and calibration of the risk score were assessed by ROC curve and Hosmer-Lemeshow test, respectively. RESULTS: The overall incidence of CIN was 45 (3.9%). The new simple risk score (Chen score), which included four independent variables (age > 75 years, acute myocardial infarction, SCr > 1.5 mg/dL, the use of intra-aortic balloon pump), exhibited a similar discrimination and predictive ability on CIN (AUC 0.813, 0.843, 0.796, P > 0.05, respectively), mortality (AUC 0.735, 0.771, 0.826, respectively) and MACEs when being compared with the classical Mehran or ACEF risk score. CONCLUSION: Our data suggest that the new simple risk score might be a good tool for predicting CIN in patients with DM undergoing CAG/PCI.


Assuntos
Meios de Contraste/efeitos adversos , Angiografia Coronária/efeitos adversos , Doença da Artéria Coronariana/diagnóstico por imagem , Técnicas de Apoio para a Decisão , Diabetes Mellitus/epidemiologia , Nefropatias/induzido quimicamente , Intervenção Coronária Percutânea/efeitos adversos , Fatores Etários , Idoso , Biomarcadores/sangue , Meios de Contraste/administração & dosagem , Angiografia Coronária/mortalidade , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/terapia , Creatinina/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/mortalidade , Feminino , Humanos , Incidência , Balão Intra-Aórtico/efeitos adversos , Nefropatias/sangue , Nefropatias/diagnóstico , Nefropatias/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Intervenção Coronária Percutânea/mortalidade , Valor Preditivo dos Testes , Distribuição Aleatória , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Regulação para Cima
11.
Int J Biol Macromol ; 254(Pt 2): 127923, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37944734

RESUMO

In Alzheimer's disease (AD), amyloid-beta (Aß) plays a crucial role in pathogenesis. Clearing Aß from the brain is considered as a key therapeutic strategy. Previous studies indicated that Salvia miltiorrhiza (Danshen) could protect against AD. However, the main anti-AD components in Danshen and their specific mechanisms are not clear. In this study, pharmacological network analysis indicated that Tanshinone IIA (Tan IIA) was identified as the key active compound in Danshen contributing to protect against AD. Then, APP/PS1 double transgenic mice were employed to examine the neuroprotective effect of Tan IIA. APP/PS1 mice (age, 6 months) were administered (10 and 20 mg/kg) for 8 weeks. Tan IIA improved learning and anxiety behaviors in APP/PS1 mice. Furthermore, Tan IIA reduced oxidative stress, inhibited neuronal apoptosis, improved cholinergic nervous system and decreased endoplasmic reticulum stress in the brain of APP/PS1 mice. Moreover, Tan IIA treatment reduced the level of Aß. Molecular docking result showed that Tan IIA might block AD by upregulating Aß-degrading enzymes. Western blot results confirmed that the expressions of insulin degrading enzymes (IDE) and neprilysin (NEP) were significantly increased after Tan IIA treatment, which demonstrated that Tan IIA improved AD by increasing Aß-degrading enzymes.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Salvia miltiorrhiza , Camundongos , Animais , Simulação de Acoplamento Molecular , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Camundongos Transgênicos , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças
12.
Am Heart J ; 165(4): 600-8, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23537978

RESUMO

BACKGROUND: Few studies have assessed the predictive value of the ratio of the contrast media volume or grams of iodine to the creatinine clearance (V/CrCl or g-I/CrCl, respectively) for the risk of contrast-induced nephropathy (CIN) and mortality after percutaneous coronary intervention (PCI). METHODS: The association between V/CrCl and mortality was prospectively evaluated in 1,135 consecutive patients undergoing PCI. Cox regression models were used to adjust for the V/CrCl ratio and other confounding factors for risk of death within 1 year. RESULTS: Fifty-five patients (4.84%) developed CIN. The 1-year mortality was higher in patients with a V/CrCl ratio >2.62 (g-I/CrCl >0.97) than in others (4.44% vs 0.40%; P < .001). After adjusting for other risk factors, the 1-year mortality risk remained associated with increased V/CrCl ratio. The risk of death was significant for V/CrCl >2.62 (adjusted risk ratio [RR] for death 2.605, 95% CI 1.040-6.529, P = .041), V/CrCl >3.0 (g-I/CrCl >1.11) (adjusted RR 4.338, 95% CI 1.689-11.142, P = .002), and V/CrCl >3.7 (g-I/CrCl >1.37) (adjusted RR 2.557, 95% CI 1.162-5.627, P = .002). CONCLUSION: The data further support the prognostic significance of calculating the V/CrCl ratio to predict the relative maximum contrast volume during PCI. Use of a contrast dose determined based on the estimated renal function with a planned V/CrCl ratio <3.7 (g-I/CrCl <1.37) and preferably <2.62 (g-I/CrCl <0.97) might be valuable in reducing the risks of CIN and even death after PCI.


Assuntos
Angioplastia Coronária com Balão , Meios de Contraste/administração & dosagem , Meios de Contraste/efeitos adversos , Nefropatias/induzido quimicamente , Idoso , Angioplastia Coronária com Balão/métodos , Creatinina/sangue , Feminino , Humanos , Iodo/administração & dosagem , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
13.
J Clin Pathol ; 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38123970

RESUMO

BACKGROUND: Machine learning (ML) models can help assisting diagnosis by rapidly localising and classifying regions of interest (ROIs) within whole slide images (WSIs). Effective ML models for clinical decision support require a substantial dataset of 'real' data, and in reality, it should be robust, user-friendly and universally applicable. METHODS: WSIs of primary IgAN were collected and annotated. The H-AI-L algorithm which could facilitate direct WSI viewing and potential ROI detection for clinicians was built on the cloud server of matpool, a shared internet-based service platform. Model performance was evaluated using F1-score, precision, recall and Matthew's correlation coefficient (MCC). RESULTS: The F1-score of glomerular localisation in WSIs was 0.85 and 0.89 for the initial and pretrained models, respectively, with corresponding recall values of 0.79 and 0.83, and precision scores of 0.92 and 0.97. Dichotomous differentiation between global sclerotic (GS) and other glomeruli revealed F1-scores of 0.70 and 0.91, and MCC values of 0.55 and 0.87, for the initial and pretrained models, respectively. The overall F1-score of multiclassification was 0.81 for the pretrained models. The total glomerular recall rate was 0.96, with F1-scores of 0.68, 0.56 and 0.26 for GS, segmental glomerulosclerosis and crescent (C), respectively. Interstitial fibrosis/tubular atrophy lesion similarity between the true label and model predictions was 0.75. CONCLUSIONS: Our results underscore the efficacy of the ML integration algorithm in segmenting ROIs in IgAN WSIs, and the internet-based model deployment is in favour of widespread adoption and utilisation across multiple centres and increased volumes of WSIs.

14.
JCI Insight ; 8(20)2023 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-37870960

RESUMO

Albuminuria and podocyte injury are the key cellular events in the progression of diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is a nucleocytosolic enzyme responsible for the regulation of metabolic homeostasis in mammalian cells. This study aimed to investigate the possible roles of ACSS2 in kidney injury in DN. We constructed an ACSS2-deleted mouse model to investigate the role of ACSS2 in podocyte dysfunction and kidney injury in diabetic mouse models. In vitro, podocytes were chosen and transfected with ACSS2 siRNA and ACSS2 inhibitor and treated with high glucose. We found that ACSS2 expression was significantly elevated in the podocytes of patients with DN and diabetic mice. ACSS2 upregulation promoted phenotype transformation and inflammatory cytokine expression while inhibiting podocytes' autophagy. Conversely, ACSS2 inhibition improved autophagy and alleviated podocyte injury. Furthermore, ACSS2 epigenetically activated raptor expression by histone H3K9 acetylation, promoting activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Pharmacological inhibition or genetic depletion of ACSS2 in the streptozotocin-induced diabetic mouse model greatly ameliorated kidney injury and podocyte dysfunction. To conclude, ACSS2 activation promoted podocyte injury in DN by raptor/mTORC1-mediated autophagy inhibition.


Assuntos
Acetato-CoA Ligase , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Humanos , Camundongos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Rim/metabolismo , Ligases , Mamíferos , Alvo Mecanístico do Complexo 1 de Rapamicina , Acetato-CoA Ligase/metabolismo
15.
Int Urol Nephrol ; 55(2): 355-366, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35931920

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the developed world. Podocyte injury is a critical cellular event involved in the progression of DN. Our previous studies demonstrated that platelet-derived microparticles (PMPs) mediated endothelial injury in diabetic rats. This study aimed to investigate whether PMPs are deposited in podocytes and to assess their potential effects on podocyte injury in DN. METHODS: The deposition of PMPs in podocytes was assessed by immunofluorescent staining and electron microscopy. The changes in renal pathology and ultra-microstructure were assessed by periodic acid-Schiff staining and electron microscopy, respectively. The expression of inflammatory cytokines and extracellular matrix proteins was measured by immuno-histochemical staining and western blot. RESULTS: PMPs were widely deposited in podocytes of glomeruli in diabetic patients and animal models and closely associated with DN progression. Interestingly, aspirin treatment significantly inhibited the accumulation of PMPs in the glomeruli of diabetic rats, alleviated mesangial matrix expansion and fusion of foot processes, and decreased the protein expression of inflammatory cytokines and extracellular matrix secretion. An in vitro study further confirmed the deposition of PMPs in podocytes. Moreover, PMP stimulation induced the phenotypic transition of podocytes through decreased podocin protein expression and increased protein expression of α-SMA and fibronectin, which was correlated with increased production of inflammatory cytokines. CONCLUSION: Our findings demonstrated for the first time that the deposition of PMPs in podocytes contributed to the development of DN.


Assuntos
Micropartículas Derivadas de Células , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Podócitos , Ratos , Animais , Nefropatias Diabéticas/complicações , Podócitos/metabolismo , Diabetes Mellitus Experimental/metabolismo , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/patologia , Citocinas/metabolismo
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 29(5): 570-2, 2012 Oct.
Artigo em Zh | MEDLINE | ID: mdl-23042396

RESUMO

OBJECTIVE: A R1210C mutation of complement factor H (CFH) gene has been associated with age-related macular degeneration (AMD) in Caucasian population. This study was to verify above association in Han Chinese population. METHODS: The mutation was detected by direct sequencing in 258 patients with wet AMD and 426 matched controls. RESULTS: The R1210C mutation has not been identified in either sample. CONCLUSION: The R1210C mutation in CFH gene is not associated with AMD in Han Chinese population.


Assuntos
Fator H do Complemento/genética , Degeneração Macular/genética , Mutação , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Front Cardiovasc Med ; 9: 911987, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36176988

RESUMO

Background: Heart failure (HF) is a life-threatening complication of cardiovascular disease. HF patients are more likely to progress to acute kidney injury (AKI) with a poor prognosis. However, it is difficult for doctors to distinguish which patients will develop AKI accurately. This study aimed to construct a machine learning (ML) model to predict AKI occurrence in HF patients. Materials and methods: The data of HF patients from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database was retrospectively analyzed. A ML model was established to predict AKI development using decision tree, random forest (RF), support vector machine (SVM), K-nearest neighbor (KNN), and logistic regression (LR) algorithms. Thirty-nine demographic, clinical, and treatment features were used for model establishment. Accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curve (AUROC) were used to evaluate the performance of the ML algorithms. Results: A total of 2,678 HF patients were engaged in this study, of whom 919 developed AKI. Among 5 ML algorithms, the RF algorithm exhibited the highest performance with the AUROC of 0.96. In addition, the Gini index showed that the sequential organ function assessment (SOFA) score, partial pressure of oxygen (PaO2), and estimated glomerular filtration rate (eGFR) were highly relevant to AKI development. Finally, to facilitate clinical application, a simple model was constructed using the 10 features screened by the Gini index. The RF algorithm also exhibited the highest performance with the AUROC of 0.95. Conclusion: Using the ML model could accurately predict the development of AKI in HF patients.

18.
Curr Med Sci ; 42(3): 561-568, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35678917

RESUMO

OBJECTIVE: To evaluate the impact of hypertension on the clinical outcome of COVID-19 patients aged 60 years old and older. METHODS: This single-center retrospective cohort study enrolled consecutive COVID-19 patients aged 60 years old and older, who were admitted to Liyuan Hospital from January 1, 2020 to April 25, 2020. All included patients were divided into two groups: hypertension and nonhypertension group. The baseline demographic characteristics, laboratory test results, chest computed tomography (CT) images and clinical outcomes were collected and analyzed. The prognostic value of hypertension was determined using binary logistic regression. RESULTS: Among the 232 patients included in the analysis, 105 (45.3%) patients had comorbid hypertension. Compared to the nonhypertension group, patients in the hypertension group had higher neutrophil-to-lymphocyte ratios, red cell distribution widths, lactate dehydrogenase, high-sensitivity C-reactive protein, D-dimer and severity of lung lesion, and lower lymphocyte counts (all P<0.05). Furthermore, the hypertension group had a higher proportion of intensive care unit admissions [24 (22.9%) vs. 14 (11.0%), P=0.02) and deaths [16 (15.2%) vs. 3 (2.4%), P<0.001] and a significantly lower probability of survival (P<0.001) than the nonhypertension group. Hypertension (OR: 4.540, 95% CI: 1.203-17.129, P=0.026) was independently correlated with all-cause in-hospital death in elderly patients with COVID-19. CONCLUSION: The elderly COVID-19 patients with hypertension tend to have worse conditions at baseline than those without hypertension. Hypertension may be an independent prognostic factor of poor clinical outcome in elderly COVID-19 patients.


Assuntos
COVID-19 , Hipertensão , Idoso , COVID-19/complicações , Mortalidade Hospitalar , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2
19.
Int J Biol Sci ; 18(1): 96-111, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34975320

RESUMO

Background: G-protein-coupled receptor 43 (GPR43) is a posttranscriptional regulator involved in cholesterol metabolism. This study aimed to investigate the possible roles of GPR43 activation in podocyte lipotoxicity in diabetic nephropathy (DN) and explore the potential mechanisms. Methods: The experiments were conducted by using diabetic GPR43-knockout mice and a podocyte cell culture model. Lipid deposition and free cholesterol levels in kidney tissues were measured by BODIPY staining and quantitative cholesterol assays, respectively. The protein expression of GPR43, LC3II, p62, beclin1, low-density lipoprotein receptor (LDLR) and early growth response protein 1 (EGR1) in kidney tissues and podocytes was measured by real-time PCR, immunofluorescent staining and Western blotting. Results: There were increased LDL cholesterol levels in plasma and cholesterol accumulation in the kidneys of diabetic mice. However, GPR43 gene knockout inhibited these changes. An in vitro study further demonstrated that acetate treatment induced cholesterol accumulation in high glucose-stimulated podocytes, which was correlated with increased cholesterol uptake mediated by LDLR and reduced cholesterol autophagic degradation, as characterized by the inhibition of LC3 maturation, p62 degradation and autophagosome formation. Gene knockdown or pharmacological inhibition of GPR43 prevented these effects on podocytes. Furthermore, GPR43 activation increased extracellular regulated protein kinases 1/2 (ERK1/2) activity and EGR1 expression in podocytes, which resulted in an increase in cholesterol influx and autophagy inhibition. In contrast, after GPR43 deletion, these changes in podocytes were improved, as shown by the in vivo and in vitro results. Conclusion: GPR43 activation-mediated lipotoxicity contributes to podocyte injury in DN by modulating the ERK/EGR1 pathway.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Metabolismo dos Lipídeos , Sistema de Sinalização das MAP Quinases , Podócitos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Receptores de LDL/metabolismo
20.
Front Immunol ; 12: 796383, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35082785

RESUMO

Background: Lipid metabolism disorder, as one major complication in patients with chronic kidney disease (CKD), is tied to an increased risk for cardiovascular disease (CVD). Traditional lipid-lowering statins have been found to have limited benefit for the final CVD outcome of CKD patients. Therefore, the purpose of this study was to investigate the effect of microinflammation on CVD in statin-treated CKD patients. Methods: We retrospectively analysed statin-treated CKD patients from January 2013 to September 2020. Machine learning algorithms were employed to develop models of low-density lipoprotein (LDL) levels and CVD indices. A fivefold cross-validation method was employed against the problem of overfitting. The accuracy and area under the receiver operating characteristic (ROC) curve (AUC) were acquired for evaluation. The Gini impurity index of the predictors for the random forest (RF) model was ranked to perform an analysis of importance. Results: The RF algorithm performed best for both the LDL and CVD models, with accuracies of 82.27% and 74.15%, respectively, and is therefore the most suitable method for clinical data processing. The Gini impurity ranking of the LDL model revealed that hypersensitive C-reactive protein (hs-CRP) was highly relevant, whereas statin use and sex had the least important effects on the outcomes of both the LDL and CVD models. hs-CRP was the strongest predictor of CVD events. Conclusion: Microinflammation is closely associated with potential CVD events in CKD patients, suggesting that therapeutic strategies against microinflammation should be implemented to prevent CVD events in CKD patients treated by statin.


Assuntos
Doenças Cardiovasculares/imunologia , Inflamação/imunologia , Aprendizado de Máquina , Insuficiência Renal Crônica/imunologia , Idoso , Proteína C-Reativa/análise , Doenças Cardiovasculares/complicações , Colesterol/metabolismo , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/complicações , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco
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