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Objectives: The objective of this study is to investigate the indirect causalities between gut microbiota and sleep disorders. Methods: In stage 1, we utilized 196 gut microbiota as the exposure factor and conducted a two-sample univariable Mendelian randomization (MR) analysis on five sleep disorders: insomnia, excessive daytime sleepiness (EDS), sleep-wake rhythm disorders (SWRD), obstructive sleep apnea (OSA), and isolated REM sleep behavior disorder (iRBD). In stage 2, we validated the MR findings by comparing fecal microbiota abundance between patients and healthy controls through 16S rDNA sequencing. In stage 3, we explored the indirect pathways by which the microbiota affects sleep, using 205 gut microbiota metabolic pathways and 9 common risk factors for sleep disorders as candidate mediators in a network MR analysis. Results: In stage 1, the univariable MR analysis identified 14 microbiota potentially influencing five different sleep disorders. In stage 2, the results from our observational study validated four of these associations. In stage 3, the network MR analysis revealed that the Negativicutes class and Selenomonadales order might worsen insomnia by increasing pain [mediation: 12.43% (95% CI: 0.47, 24.39%)]. Oxalobacter could raise EDS by disrupting adenosine reuptake [25.39% (1.84, 48.95%)]. Allisonella may elevate OSA risk via obesity promotion [36.88% (17.23, 56.54%)], while the Eubacterium xylanophilum group may lower OSA risk by decreasing smoking behavior [7.70% (0.66, 14.74%)]. Conclusion: Triangulation of evidence from the MR and observational study revealed indirect causal relationships between the microbiota and sleep disorders, offering fresh perspectives on how gut microbiota modulate sleep.
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OBJECTIVES: To explore the causal relationships between sex hormone levels and incidence of isolated REM sleep behavior disorder (iRBD). METHODS: In our study, we utilized Genome-Wide Association Studies (GWAS) data for iRBD, including 9447 samples with 1061 cases of iRBD provided by the International RBD Study Group. Initially, we conducted a two-sample univariate MR analysis to explore the impact of sex hormone-related indicators on iRBD. This was followed by the application of multivariable MR methods to adjust for other hormone levels and potential confounders. Finally, we undertook a network MR analysis, employing brain structure Magnetic Resonance Imaging (MRI) characteristics as potential mediators, to examine whether sex hormones could indirectly influence the incidence of iRBD by affecting brain structure. RESULTS: Bioavailable testosterone (BioT) is an independent risk factor for iRBD (Odds Ratio [95 % Confidence Interval] = 2.437 [1.308, 4.539], P = 0.005, corrected-P = 0.020), a finding that remained consistent even after adjusting for other sex hormone levels and potential confounders. Additionally, BioT appears to indirectly increase the risk of iRBD by reducing axial diffusivity and increasing the orientation dispersion index in the left cingulum and cingulate gyrus. CONCLUSIONS: Our research reveals that elevated levels of BioT contribute to the development of iRBD. However, the specific impact of BioT on different sexes remains unclear. Furthermore, high BioT may indirectly lead to iRBD by impairing normal pathways in the left cingulum and cingulate gyrus and fostering abnormal pathway formation.
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Estudo de Associação Genômica Ampla , Imageamento por Ressonância Magnética , Análise da Randomização Mendeliana , Transtorno do Comportamento do Sono REM , Testosterona , Humanos , Testosterona/sangue , Transtorno do Comportamento do Sono REM/genética , Masculino , Feminino , Incidência , Fatores de Risco , Pessoa de Meia-Idade , Encéfalo/diagnóstico por imagem , IdosoRESUMO
OBJECTIVES: To explore the value of metagenomic next-generation sequencing (mNGS) technology in the etiological diagnosis of sepsis in preterm infants following antibiotic use. METHODS: A retrospective analysis of medical records for 45 preterm infants with sepsis who were treated at Henan Provincial People's Hospital. All patients received antibiotic treatment for ≥3 days and underwent both blood culture and mNGS testing. The detection rates of pathogens by blood culture and mNGS testing were compared. RESULTS: The positive detection rate of pathogens by blood mNGS was higher than that by blood culture (44% vs 4%; P<0.001). Blood mNGS detected 28 strains of pathogens, including 23 bacteria, 4 fungi, and 1 Ureaplasma parvum. Blood culture identified one case each of Rhodotorula mucilaginosa and Klebsiella pneumoniae. In the group treated with antibiotics for >10 days, the positive rate of blood mNGS testing was higher than that of blood culture (40% vs 3%; P<0.001); similarly, in the group treated with antibiotics for ≤10 days, the positive rate of blood mNGS testing was also higher than that of blood culture (53% vs 7%; P=0.020). Treatment plans were adjusted based on blood mNGS results for 13 patients, with an effectiveness rate of 85% (11/13). CONCLUSIONS: In preterm infants with sepsis following antibiotic use, the positive rate of pathogen detection by blood mNGS is higher than that by blood culture and is unaffected by the duration of antibiotic use. Therefore, mNGS testing can be considered for confirming pathogens when clinical suspicion of infection is high but blood culture fails to detect the pathogen.
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Antibacterianos , Sequenciamento de Nucleotídeos em Larga Escala , Recém-Nascido Prematuro , Metagenômica , Sepse , Humanos , Recém-Nascido , Antibacterianos/uso terapêutico , Sepse/microbiologia , Sepse/tratamento farmacológico , Masculino , Feminino , Estudos Retrospectivos , Metagenômica/métodosRESUMO
Morphology regulation of heterodimer nanoparticles and the use of their asymmetric features for further practical applications are crucial because of the rich optical properties and various combinations of heterodimers. This work used silicon to asymmetrically wrap half of a gold sphere and grew gold branches on the bare gold surface to form heterogeneous nano pineapples (NPPs) which can effectively improve Surface-enhanced Raman scattering (SERS) properties through chemical enhancement and lightning-rod effect respectively. The asymmetric structures of NPPs enabled them to self-assemble into the monolayer membrane with consistent branch orientation. The prepared substrate had high homogeneity and better SERS ability than disorganized substrates, and achieved reliable detection of malachite green (MG) in clams with a detection limit of 7.8 × 10-11 M. This work provided a guide to further revise the morphology of heterodimers and a new idea for the use of asymmetric dimers for practically photochemical and biomedical sensing.
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Ouro , Corantes de Rosanilina , Silício , Análise Espectral Raman , Corantes de Rosanilina/química , Análise Espectral Raman/métodos , Ouro/química , Silício/química , Animais , Ananas/química , Nanopartículas Metálicas/química , Bivalves/química , Limite de Detecção , Propriedades de SuperfícieRESUMO
Background: Acteoside, an active ingredient found in various medicinal herbs, is effective in the treatment of diabetic kidney disease (DKD); however, the intrinsic pharmacological mechanism of action of acteoside in the treatment of DKD remains unclear. This study utilizes a combined approach of network pharmacology and experimental validation to investigate the potential molecular mechanism systematically. Methods: First, acteoside potential targets and DKD-associated targets were aggregated from public databases. Subsequently, utilizing protein-protein interaction (PPI) networks, alongside GO and KEGG pathway enrichment analyses, we established target-pathway networks to identify core potential therapeutic targets and pathways. Further, molecular docking facilitated the confirmation of interactions between acteoside and central targets. Finally, the conjectured molecular mechanisms of acteoside against DKD were verified through experimentation on unilateral nephrectomy combined with streptozotocin (STZ) rat model. The underlying downstream mechanisms were further investigated. Results: Network pharmacology identified 129 potential intersected targets of acteoside for DKD treatment, including targets such as AKT1, TNF, Casp3, MMP9, SRC, IGF1, EGFR, HRAS, CASP8, and MAPK8. Enrichment analyses indicated the PI3K-Akt, MAPK, Metabolic, and Relaxin signaling pathways could be involved in this therapeutic context. Molecular docking revealed high-affinity binding of acteoside to PIK3R1, AKT1, and NF-κB1. In vivo studies validated the therapeutic efficacy of acteoside, demonstrating reduced blood glucose levels, improved serum Scr and BUN levels, decreased 24-hour urinary total protein (P<0.05), alongside mitigated podocyte injury (P<0.05) and ameliorated renal pathological lesions. Furthermore, this finding indicates that acteoside inhibits the expression of pyroptosis markers NLRP3, Caspase-1, IL-1ß, and IL-18 through the modulation of the PI3K/AKT/NF-κB pathway. Conclusion: Acteoside demonstrates renoprotective effects in DKD by regulating the PI3K/AKT/NF-κB signaling pathway and alleviating pyroptosis. This study explores the pharmacological mechanism underlying acteoside's efficacy in DKD treatment, providing a foundation for further basic and clinical research.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Glucosídeos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fenóis , Polifenóis , Estreptozocina , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Animais , Ratos , Glucosídeos/farmacologia , Glucosídeos/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Fenóis/farmacologia , Fenóis/química , Ratos Sprague-DawleyRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The JinChan YiShen TongLuo (JCYSTL) formula, a traditional Chinese medicine (TCM), has been used clinically for decades to treat diabetic nephropathy (DN). TCM believes that the core pathogenesis of DN is "kidney deficiency and collateral obstruction," and JCYSTL has the effect of "tonifying kidney and clearing collateral," thus alleviating the damage to kidney structure and function caused by diabetes. From the perspective of modern medicine, mitochondrial damage is an important factor in DN pathogenesis. Our study suggests that the regulation of mitophagy and mitochondrial function by JCYSTL may be one of the internal mechanisms underlying its good clinical efficacy. AIM OF THE STUDY: This study aimed to investigate the mechanisms underlying the renoprotective effects of JCYSTL. MATERIALS AND METHODS: Unilateral nephrectomy combined with low-dose streptozotocin intraperitoneally injected in a DN rat model and high glucose (HG) plus hypoxia-induced HK-2 cells were used to explore the effects of JCYSTL on the HIF-1α/mitophagy pathway, mitochondrial function and apoptosis. RESULTS: JCYSTL treatment significantly decreased albuminuria, serum creatinine, blood urea nitrogen, and uric acid levels and increased creatinine clearance levels in DN rats. In vitro, medicated serum containing JCYSTL formula increased mitochondrial membrane potential (MMP); improved activities of mitochondrial respiratory chain complexes I, III, and IV; decreased the apoptotic cell percentage and apoptotic protein Bax expression; and increased anti-apoptotic protein Bcl-2 expression in HG/hypoxia-induced HK-2 cells. The treatment group exhibited increased accumulation of PINK1, Parkin, and LC3-II and reduced P62 levels in HG/hypoxia-induced HK-2 cells, whereas in PINK1 knockdown HK-2 cells, JCYSTL did not improve the HG/hypoxia-induced changes in Parkin, LC3-II, and P62. When mitophagy was impaired by PINK1 knockdown, the inhibitory effect of JCYSTL on Bax and its promoting effect on MMP and Bcl-2 disappeared. The JCYSTL-treated group displayed significantly higher HIF-1α expression than the model group in vivo, which was comparable to the effects of FG-4592 in DN rats. PINK1 knockdown did not affect HIF-1α accumulation in JCYSTL-treated HK-2 cells exposed to HG/hypoxia. Both JCYSTL and FG-4592 ameliorated mitochondrial morphological abnormalities and reduced the mitochondrial respiratory chain complex activity in the renal tubules of DN rats. Mitochondrial apoptosis signals in DN rats, such as increased Bax and Caspase-3 expression and apoptosis ratio, were weakened by JCYSTL or FG-4592 administration. CONCLUSION: This study demonstrates that the JCYSTL formula activates PINK1/Parkin-mediated mitophagy by stabilizing HIF-1α to protect renal tubules from mitochondrial dysfunction and apoptosis in diabetic conditions, presenting a promising therapy for the treatment of DN.
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Diabetes Mellitus , Nefropatias Diabéticas , Medicamentos de Ervas Chinesas , Doenças Mitocondriais , Ratos , Animais , Nefropatias Diabéticas/patologia , Proteína X Associada a bcl-2 , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2 , Ubiquitina-Proteína Ligases/metabolismo , Hipóxia , Proteínas Quinases/metabolismoRESUMO
Background: Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), and there is growing evidence to support the role of immunity in the progression of DN to ESRD. Chemokines and chemokine receptors (CCRs) can recruit immune cells to sites of inflammation or injury. Currently, no studies have reported the effect of CCRs on the immune environment during the progression of DN to ESRD. Methods: Differentially expressed genes (DEGs) from the GEO database were identified in DN patients versus ESRD patients. GO and KEGG enrichment analyses were performed using DEGs. A protein-protein interaction (PPI) network was constructed to identify hub CCRs. Differentially expressed immune cells were screened by immune infiltration analysis, and the correlation between immune cells and hub CCRs was also calculated. Result: In this study, a total of 181 DEGs were identified. Enrichment analysis showed that chemokines, cytokines, and inflammation-related pathways were significantly enriched. Combining the PPI network and CCRs, four hub CCRs (CXCL2, CXCL8, CXCL10, and CCL20) were identified. These hub CCRs showed an upregulation trend in DN patients and a downregulation trend in ESRD patients. Immune infiltration analysis identified a variety of immune cells that underwent significant changes during disease progression. Among them, CD56bright natural killer cell, effector memory CD8 T cell, memory B cell, monocyte, regulatory T cell, and T follicular helper cell were significantly associated with all hub CCR correlation. Conclusion: The effect of CCRs on the immune environment may contribute to the progression of DN to ESRD.
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Diabetes Mellitus , Nefropatias Diabéticas , Falência Renal Crônica , Humanos , Citocinas , Monócitos , Inflamação , Biologia ComputacionalRESUMO
RATIONALE & OBJECTIVE: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel, orally administered agents for anemia management in chronic kidney disease (CKD). We evaluated the cardiac and kidney-related adverse effects of HIF-PHIs among patients with CKD and anemia. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). SETTING & STUDY POPULATIONS: Patients with anemia and CKD not receiving maintenance dialysis. SELECTION CRITERIA FOR STUDIES: RCTs comparing HIF-PHIs to placebo or an erythropoiesis-stimulating agent (ESA) with primary outcomes of cardiac and kidney-related adverse events (AEs). DATA EXTRACTION: Two independent reviewers evaluated RCTs for eligibility and extracted relevant data. ANALYTICAL APPROACH: Dichotomous variables were pooled using the Mantel-Haenszel method and presented as risk ratios (RRs). Subgroup analyses evaluated different intervention times and HIF-PHIs, as well as phase 2 versus phase 3 trials. The certainty of findings was rated according to GRADE criteria. RESULTS: Twenty-three studies with 15,144 participants were included. No significant difference in the risk of cardiac AEs was observed between the HIF-PHIs group and the placebo (RR, 1.02 [95% CI, 0.89-1.16]; moderate certainty) or ESA (RR, 1.06 [95% CI, 0.98-1.14]; low certainty) groups. No significant difference in the risk of kidney-related AEs was observed between the HIF-PHIs group and the placebo (RR, 1.09 [95% CI, 0.98-1.20]; moderate certainty) or ESA (RR, 1.00 [95% CI, 0.94-1.06]; low certainty) groups. The occurrence of hypertension and hyperkalemia was higher in the HIF-PHIs group than in the placebo group (RRs of 1.35 [95% CI, 1.14-1.60] and 1.25 [95% CI, 1.03-1.51], respectively; both findings had high certainty). The occurrence of hypertension was lower in the HIF-PHIs group than in the ESA group (RR, 0.89 [95% CI, 0.81-0.98]; moderate certainty). LIMITATIONS: The reporting criteria of cardiac and kidney-related AEs and dosage of HIF-PHIs were inconsistent across trials. CONCLUSIONS: The occurrence of cardiac or kidney-related AEs in the HIF-PHI groups were not different compared with placebo or ESA groups. REGISTRATION: Registered at PROSPERO with registration number CRD42021228243.
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Anemia , Hematínicos , Hipertensão , Inibidores de Prolil-Hidrolase , Insuficiência Renal Crônica , Humanos , Inibidores de Prolil-Hidrolase/efeitos adversos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/tratamento farmacológico , Anemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hematínicos/efeitos adversos , RimRESUMO
OBJECTIVE: To investigate the factors related to renal impairment in patients with diabetic kidney disease (DKD) from the perspective of integrated Chinese and Western medicine. METHODS: Totally 492 patients with DKD in 8 Chinese hospitals from October 2017 to July 2019 were included. According to Kidney Disease Improving Global Outcomes (KDIGO) staging guidelines, patients were divided into a chronic kidney disease (CKD) 1-3 group and a CKD 4-5 group. Clinical data were collected, and logistic regression was used to analyze the factors related to different CKD stages in DKD patients. RESULTS: Demographically, male was a factor related to increased CKD staging in patients with DKD (OR=3.100, P=0.002). In clinical characteristics, course of diabetes >60 months (OR=3.562, P=0.010), anemia (OR=4.176, P<0.001), hyperuricemia (OR=3.352, P<0.001), massive albuminuria (OR=4.058, P=0.002), atherosclerosis (OR=2.153, P=0.007) and blood deficiency syndrome (OR=1.945, P=0.020) were factors related to increased CKD staging in patients with DKD. CONCLUSIONS: Male, course of diabetes >60 months, anemia, hyperuricemia, massive proteinuria, atherosclerosis, and blood deficiency syndrome might indicate more severe degree of renal function damage in patients with DKD. (Registration No. NCT03865914).
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Hiperuricemia , Insuficiência Renal Crônica , Humanos , Masculino , Rim , Proteinúria , Insuficiência Renal Crônica/complicaçõesRESUMO
Background: Triptolide, a major active ingredient isolated from Tripterygium wilfordii Hook f., is effective in the treatment of membranous nephropathy (MN); however, its pharmacological mechanism of action has not yet been clarified. We applied an approach that integrated network pharmacology and experimental validation to systemically reveal the molecular mechanism of triptolide in the treatment of MN. Methods: First, potential targets of triptolide and the MN-related targets were collected from publicly available database. Then, based on a protein-protein interaction network as well as GO and KEGG pathway enrichment analyses, we constructed target-pathway networks to unravel therapeutic targets and pathways. Moreover, molecular docking was applied to validate the interactions between the triptolide and hub targets. Finally, we induced passive Heymann nephritis (PHN) rat models and validated the possible molecular mechanisms of triptolide against MN. Results: The network pharmacology results showed that 118 intersected targets were identified for triptolide against MN, including mTOR, STAT3, CASP3, EGFR and AKT1. Based on enrichment analysis, signaling pathways such as PI3K/AKT, MAKP, Ras and Rap1 were involved in triptolide treatment of MN. Furthermore, molecular docking confirmed that triptolide could bind with high affinity to the PIK3R1, AKT1 and mTOR, respectively. Then, in vivo experiments indicated that triptolide can reduce 24 h urine protein (P < 0.01) and protect against renal damage in PHN. Serum albumin level was significantly increased and total cholesterol, triglycerides, and low-density lipoprotein levels were decreased by triptolide (P < 0.05). Compared with PHN group, triptolide treatment regulated the PI3K/AKT/mTOR pathway according to Western blot analyses. Conclusion: Triptolide could exert antiproteinuric and renoprotective effects in PHN. The therapeutic mechanism of triptolide may be associated with the regulation of PI3K/AKT/mTOR signaling pathway. This study demonstrates the pharmacological mechanism of triptolide in the treatment of MN and provides scientific evidence for basic and clinical research.
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Glomerulonefrite Membranosa , Animais , Ratos , Glomerulonefrite Membranosa/tratamento farmacológico , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TORRESUMO
Diabetic nephropathy (DN) is a progressive microvascular diabetic complication. Growing evidence shows that persistent mitochondrial dysfunction contributes to the progression of renal diseases, including DN, as it alters mitochondrial homeostasis and, in turn, affects normal kidney function. Pharmacological regulation of mitochondrial networking is a promising therapeutic strategy for preventing and restoring renal function in DN. In this review, we have surveyed recent advances in elucidating the mitochondrial networking and signaling pathways in physiological and pathological contexts. Additionally, we have considered the contributions of nontraditional therapy that ameliorate mitochondrial dysfunction and discussed their molecular mechanism, highlighting the potential value of nontraditional therapies, such as herbal medicine and lifestyle interventions, in therapeutic interventions for DN. The generation of new insights using mitochondrial networking will facilitate further investigations on nontraditional therapies for DN.
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Antioxidantes/uso terapêutico , Nefropatias Diabéticas/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Rim/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Comportamento de Redução do Risco , Animais , Antioxidantes/efeitos adversos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Rim/metabolismo , Rim/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Resultado do TratamentoRESUMO
Background: Treatment for adult patients with refractory idiopathic membranous nephropathy (RIMN) by conventional immunosuppressive regimens is not satisfactory. This study aims to evaluate the effectiveness of Chinese herbal medicine, Shulifenxiao formula, as a promising regimen. Methods: A total of 31 RIMN patients resistant to corticosteroid or immunosuppressive agents were retrospectively analyzed. Shulifenxiao treatment lasted a minimum of 12°months in all patients and extended to 24°months in 11 patients. The primary outcomes [the complete remission (CR) and partial remission (PR)] and secondary outcomes (the serum creatinine and estimated glomerular filtration rate (eGFR) levels) were measured at 6, 12, 18, and 24°months. Results: The data provided an average follow-up of 21 ± 9.16°months from baseline. The remission was attained in 25/31 patients (80.7%: CR 29.0% and PR 51.6%) at 12°months and in 10/11 patients (90.9%: CR 54.6% and PR 36.4%) at 24°months, respectively. Proteinuria reduced from 6.02 g/d at baseline to 0.98 g/d at 12°months (p < 0.001) and to 0.27 g/d at 24°months (p = 0.003); serum albumin increased from 28 g/L to 37.2 g/L at 12°months (p < 0.001) and to 41.3 g/L at 24°months (p = 0.003); eGFR improved from 100.25 ml/min/1.73 m2 to 118.39 ml/min/1.73 m2 at 6°months (p < 0.001) and finally to 111.62 ml/min/1.73 m2at 24°months (p = 0.008). Only two patients developed subsequent relapse. Conclusion: Shulifenxiao formula as a clinical cocktail therapy serves as an alternative therapeutic option for steroid and immunosuppressant-resistant RIMN patients, with a favourable safety profile, though further studies are warranted. Clinical Trial registration: http://www.chictr.org.cn, Chinese Clinical Trials Registry [ChiCTR1800019351].
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Hypertensive renal injury is a complication of hypertension. Cordyceps cicadae (C. cicadae) is a traditional Chinese medicine used to treat chronic kidney diseases especially renal fibrosis. Autophagy is described as a cell self-renewal process that requires lysosomal degradation and is utilized for the maintenance of cellular energy homeostasis. The present study explores the mechanism underlying C. cicadae's renoprotection on hypertensive nephropathy (HN). First, HN rat models were established on spontaneously hypertensive rats (SHRs). The expression of fibrosis-related protein and autophagy-associated protein was detected in vivo. NRK-52E cells exposed to AngII were chosen to observe the potential health benefits of C. cicadae on renal damage. The level of extracellular matrix accumulation was detected using capillary electrophoresis immunoquantification and immunohistochemistry. After treatment with lysosomal inhibitors (chloroquine) or an autophagy activator (rapamycin), the expression of Beclin-1, LC3II, and SQSTM1/p62 was further investigated. The study also investigated the change in sirtuin1 (SIRT1), fork head box O3a (FOXO3a), and peroxidation (superoxide dismutase (SOD) and malondialdehyde (MDA)) expression when intervened by resveratrol. The changes in SIRT1 and FOXO3a were measured in patients and the SHRs. Here, we observed that C. cicadae significantly decreased damage to renal tubular epithelial cells and TGFß1, α-smooth muscle actin (α-SMA), collagen I (Col-1), and fibronectin expression. Meanwhile, autophagy defects were observed both in vivo and in vitro. C. cicadae intervention significantly downregulated Beclin-1 and LC3II and decreased SQSTM1/p62, showing an inhibition of autophagic vesicles and the alleviation of autophagy stress. These functions were suppressed by rapamycin, and the results were just as effective as the resveratrol treatment. HN patients and the SHRs exhibited decreased levels of SIRT1 and FOXO3a. We also observed a positive correlation between SIRT1/FOXO3a and antifibrotic effects. Similar to the resveratrol group, the expression of SIRT1/FOXO3a and oxidative stress were elevated by C. cicadae in vivo. Taken together, our findings show that C. cicadae ameliorates tubulointerstitial fibrosis and delays HN progression. Renoprotection was likely attributable to the regulation of autophagic stress mediated by the SIRT1 pathway and achieved by regulating FOXO3a and oxidative stress.
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Anemia , Eritropoetina , Inibidores de Prolil-Hidrolase , Insuficiência Renal Crônica , Anemia/tratamento farmacológico , Epoetina alfa , Eritropoetina/uso terapêutico , Humanos , Metanálise em Rede , Inibidores de Prolil-Hidrolase/uso terapêutico , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
BACKGROUND: Chronic kidney disease (CKD) is an increasing public health issue. Anemia, which is a complication of CKD, is associated with reduced quality of life and increased morbidity and mortality. Currently quite a few clinical studies have been conducted to compare roxadustat with epoetin alfa [all for dialysis-dependent (DD) patients] or placebo [all for nondialysis-dependent (NDD) patients]. Our meta-analysis aimed to investigate the efficacy and safety of roxadustat for anemia in patients with CKD. METHODS: We thoroughly searched eight electronic resource databases for randomized controlled trials (RCTs) comparing the efficacy and safety between roxadustat versus epoetin alfa or placebo for the treatment of anemia in patients with CKD. RESULTS: Four Phase 2 and two Phase 3 studies with 1010 participants were included. Hemoglobin (Hb) and transferrin levels were increased significantly in the roxadustat group versus those in the placebo {standard mean difference [SMD] 1.57 [95% confidence interval (CI) 1.17-1.98]; SMD 1.81 [95% CI 1.53-2.08]; respectively, both low-quality evidence} or epoetin alfa group [SMD 0.47 (95% CI 0.02-0.93), very low-quality evidence; SMD 1.05 (95% CI 0.81-1.29), low-quality evidence; respectively]. Hepcidin levels were reduced significantly in the roxadustat group versus those in the placebo [SMD -1.72 (95% CI -3.03 to -0.41), very low-quality evidence] or epoetin alfa group [SMD -0.23 (95% CI -0.43 to -0.02), low-quality evidence]. Ferritin and serum transferrin saturation (TSAT) levels were reduced significantly in the roxadustat group versus those in the placebo group [SMD -0.82 (95% CI -1.31 to -0.33); SMD -0.54 (95% CI -0.76 to -0.32), respectively; both low-quality evidence] and ferritin and TSAT levels in the roxadustat group were comparable to those in the epoetin alfa group [SMD 0.02 (95% CI -0.18-0.21); SMD 0.15 (95% CI -0.04-0.35), respectively, both low-quality evidence]. As for safety, the incidence of adverse events (AEs) in the roxadustat group was insignificantly different from that of the placebo group [risk ratio (RR) 0.99 (95% CI 0.83-1.18); P = 0.89, very low-quality evidence]. But the incidence of AEs in the roxadustat group was significantly higher than that in the epoetin alfa group [RR 1.25 (95% CI 1.01-1.54); P = 0.04, low-quality evidence]. There was no significant association between roxadustat and the incidence of serious AEs (SAEs) for both NDD and DD patients [RR 1.08 (95% CI 0.51-2.28) and RR 1.43 (95% CI 0.85-2.40), respectively, both very low-quality evidence]. CONCLUSION: In this meta-analysis of RCTs, we found evidence that after the oral administration of roxadustat, NDD patients' Hb levels were increased effectively and DD patients' Hb levels were maintained effectively. The risk of SAEs was not observed with the short-term use of roxadustat. These findings support roxadustat for the treatment of anemia in patients with CKD.
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Anemia , Glicina/uso terapêutico , Isoquinolinas/uso terapêutico , Insuficiência Renal Crônica , Anemia/tratamento farmacológico , Anemia/etiologia , Glicina/análogos & derivados , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Diálise Renal , Insuficiência Renal Crônica/complicaçõesRESUMO
OBJECTIVE: Understanding the multifactorial changes involved in the kidney and heart after acute myocardial infarction (AMI) is prerequisite for further mechanisms and early intervention, especially autophagy changes. Here, we discussed the role of adaptive autophagy in the heart and kidney of rats with AMI. METHODS: A rat model of AMI was established by ligating the left anterior descending branch of the coronary artery. Animals were sacrificed at 2 and 4 weeks after the operation to assess the morphological and functional changes of the heart and kidney, as well as the autophagy pathway. In vitro, HK-2 and AC16 cell injuries and the autophagy pathway were assayed after autophagy was inhibited by 3-methyladenine (3-MA) in a hypoxia incubator. RESULTS: We found that the left ventricular systolic pressure (LVSP) significantly decreased in the model group at weeks 2 and 4. At weeks 2 and 4, the level of urinary kidney injury molecule 1 (uKIM1) of the model group was significantly higher than the sham group. At week 4, urinary neutrophil gelatinase-associated lipocalcin (uNGAL) and urinary albumin also significantly increased. At week 2, microtubule-associated protein 1 light chain 3-II (LC3-II), ATG5, and Beclin1 were significantly elevated in the heart and kidney compared with the sham-operated rats, but there was no change in p62 levels. At week 4, LC3-II did not significantly increase and p62 levels significantly increased. In addition, 3-MA markedly increased KIM1, NGAL, and the activity of caspase-3 in the hypoxic HK-2 and AC16 cell. CONCLUSION: Autophagy will undergo adaptive changes and play a protective role in the heart and kidney of rats after AMI.
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Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of oral medicines being developed for the treatment of anemia in chronic kidney disease (CKD) patients. This study aimed to compare the efficacy and safety of HIF-PHI vs epoetin and darbepoetin in CKD patients with anemia not undergoing dialysis. The PubMed, Embase, Cochrane Library, Web of Science, and clinicaltrials.gov databases were searched from inception to October 2019 for randomized controlled trials investigating different agents (six HIF-PHIs, epoetin, darbepoetin, and placebo) for treating CKD patients with anemia that did not undergo dialysis. The outcomes included a change in hemoglobin (Hb) levels and all-cause mortality. A total of 19 studies were included. Compared with the placebo, except for vadadustat (mean differences: 1.12, 95 % confidence interval [CI]: â0.11-2.35), the other drugs significantly increased Hb levels, with mean differences of 2.46 (95 % CI: 0.93-3.99) for desidustat, 1.81 (0.87-2.75) for enarodustat, 1.68 (0.64-2.72) for molidustat, 1.66 (0.89-2.44) for epoetin, 1.63 (0.69-2.56) for darbepoetin, 1.61 (0.99-2.22) for roxadustat, and 1.55 (0.74-2.36) for daprodustat. No differences were found in the Hb level elevations among these eight drugs. Compared with the placebo, there also was no significant association between the drugs and all-cause mortality (molidustat of RR, 0.39 [95 % CI, 0.06-2.59]; roxadustat, 0.40 (0.06-2.84); enarodustat, 0.33 (0.01-16.25); desidustat, 0.34 (0.01-17.00); epoetin, 0.50 (0.18-1.42); daprodustat, 0.54 (0.09-3.31); darbepoetin, 1.03 (0.65-1.65); and vadadustat, 1.43 (0.15-13.27)). No differences were observed in the all-cause mortality among the drugs. In conclusion, these HIF-PHIs are effective and relatively tolerant for treating anemia patients with CKD not undergoing dialysis. Further research should consider the limitations of our study to evaluate the value of these HIF-PHIs in clinical settings.
Assuntos
Anemia/tratamento farmacológico , Darbepoetina alfa/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Epoetina alfa/uso terapêutico , Hematínicos/uso terapêutico , Hemoglobinas/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Insuficiência Renal Crônica/complicações , Idoso , Idoso de 80 Anos ou mais , Anemia/enzimologia , Anemia/etiologia , Anemia/mortalidade , Biomarcadores/sangue , Darbepoetina alfa/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Epoetina alfa/efeitos adversos , Feminino , Hematínicos/efeitos adversos , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Hypertensive renal injury is a primary etiology of end-stage renal disease, and satisfactory therapeutic strategies are urgently required. Cordyceps cicadae, a traditional Chinese herb, has potential renoprotective benefits and is widely used in the treatment of many kidney diseases. To investigate the mechanisms underlying the renoprotective effect of C. cicadae on hypertensive renal injury, we studied the effect of C. cicadae on tubular epithelial cells (TECs) in a spontaneously hypertensive rat (SHR) model and angiotensin II- (AngII-) cultured primary TECs. Our study showed that C. cicadae treatment could decrease 24-hour urine albumin, albumin-to-creatinine ratio (ACR), ß2-MG level, and kidney injury molecule-1 (kim-1) level in SHR urine, alleviate interstitial fibrosis, and reduce α-smooth muscle actin (α-SMA) expression in SHR kidney. In primary TECs, medicated serum containing C. cicadae (CSM) might significantly reduce the AngII-induced production of kim-1 and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, C. cicadae treatment could decrease TEC apoptosis in SHRs as assessed by the terminal transferase-mediated biotin dUTP nick-end labeling (TUNEL) assay. CSM could inhibit caspase-3 activity and enhance cellular viability as measured by methyl thiazolyl tetrazolium in AngII-cultured TECs, suggesting that CSM might reduce the apoptosis level in TECs induced by AngII. We found that the SIRT1 expression level was markedly lowered, while the protein level of acetylated-p53 was elevated in the TECs of patients with hypertensive renal injury and SHRs. C. cicadae presented the effect of regulating the SIRT1/p53 pathway. Further SIRT1 inhibition with EX527 reversed the effect of C. cicadae on AngII-induced apoptosis. Taken together, our results indicate that C. cicadae offers a protective effect on TECs under hypertensive conditions, which may be related to its antiapoptotic effect through regulation of the SIRT1/p53 pathway.
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Idiopathic membranous nephropathy (IMN) is one of the main types of chronic kidney disease in adults and one of the most common causes of endstage renal disease. In recent years, the morbidity of IMN among primary glomerular diseases has markedly increased, while the pathogenesis of the disease remains unclear. To address this, a number of experimental models, including Heymann nephritis, antithrombospondin type1 domaincontaining 7A antibodyinduced IMN, cationic bovine serum albumin, antihuman podocyte antibodies and zymosanactivated seruminduced C5b9, have been established. This review comprehensively summarized the available animal and cell models for IMN. The limitations and advantages of the current models were discussed and two improved models were introduced to facilitate the selection of an appropriate model for further studies on IMN.
Assuntos
Modelos Animais de Doenças , Glomerulonefrite Membranosa , Modelos Teóricos , Animais , Complexo de Ataque à Membrana do Sistema Complemento , Glomerulonefrite Membranosa/patologia , Humanos , Rim , Glomérulos Renais/patologia , Podócitos/imunologia , Receptores da Fosfolipase A2 , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/patologia , Trombospondinas/imunologia , Zimosan/farmacologiaRESUMO
OBJECTIVE: This study is aimed at investigating the efficacy of a very low-energy diet (VLED) in overweight and obese individuals with type 2 diabetes mellitus (T2DM). METHODS: We thoroughly searched eight electronic resource databases of controlled studies concerning the efficacy and acceptability of intermittent or continuous VLEDs in patients with T2DM compared with other energy restriction interventions. RESULTS: Eighteen studies (11 randomized and seven nonrandomized controlled trials) with 911 participants were included. The meta-analyses showed that compared with a low-energy diet (LED) and mild energy restriction (MER), VLED is superior in the reduction of body weight (mean difference (MD) MDLED = -2.77, 95% confidence interval (CI) CILED = -4.81 to - 0.72, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, I 2 = 0%) and TG level (MD = -0.25, 95%CI = -0.55 to 0.06, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, I 2 = 0%) and TG level (MD = -0.25, 95%CI = -0.55 to 0.06, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39, P LED = 0.008; MDMER = -6.72, 95%CIMER = -10.05 to - 3.39. CONCLUSION: Dietary intervention through VLEDs is an effective therapy for rapid weight loss, glycemic control, and improved lipid metabolism in overweight and obese individuals with T2DM. Thus, VLEDs should be encouraged in overweight and obese individuals with T2DM who urgently need weight loss and are unsuitable or unwilling to undergo surgery. As all outcome indicators have low or extremely low quality after GRADE evaluation, further clinical trials that focus on the remission effect of VLEDs on T2DM are needed.