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1.
Phytomedicine ; 135: 156067, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39326137

RESUMO

BACKGROUND: Renal fibrosis is a hallmark of chronic kidney disease (CKD). Smad3 serves as the principal transcription factor mediating the pro-fibrosis effects of TGF-ß signaling in renal fibrosis. Biochanin A (BCA), a natural isoflavone, has been shown to attenuate renal fibrosis by inhibiting TGF-ß signaling but the detailed mechanisms remain unresolved. This study aimed to elucidate the specific mechanisms by which BCA modulates TGF-ß signaling. METHODS: Renal fibrosis models were established both in vitro, using TGF-ß1-stimulated mouse renal tubular TCMK1 cells, and in vivo, employing mice with unilateral ureter obstruction (UUO). RNA-seq was conducted to identify BCA-regulated genes. The AnimalTFDB4.0 database was utilized to predict transcription factors with potential binding to Smad3 promoter. The activities of TGF-ß signaling and the cloned mouse Smad3 promoter were assessed using luciferase reporter assays. Plasmid transfection was performed using polyethylenimine in TCMK1 cells or ultrasound microbubbles in UUO kidneys. Gene expression was analyzed by RT-PCR, western blot, and immunohistochemistry assays. RESULTS: BCA significantly inhibited TGF-ß signaling activity and suppressed TGF-ß1-induced fibrotic gene expression in TCMK1 cells. RNA-seq and in silico analyses identified Smad3 as the key gene downregulated by BCA, while leaving Smad2 unaffected. This selective transcriptional suppression of Smad3 by BCA was validated by luciferase reporter assays using the cloned Smad3 promoter. Furthermore, transcription factor binding prediction identified that Klf6, a transcription factor downregulated by BCA, has binding potential to the Smad3 promoter and promotes Smad3 transcription. Klf6 expression was induced in TGF-ß1-stimulated TCMK1 cells and UUO kidneys, but this induction was abolished upon BCA treatment. Importantly, Klf6 overexpression restored Smad3 expression and counteracted the anti-fibrosis effects of BCA in both TGF-ß1-stimulated TCMK1 cells and UUO kidneys. CONCLUSION: TGF-ß-responsive Klf6 transcriptionally transactivates Smad3 expression. BCA exerts anti-renal fibrosis effects by inhibiting the Klf6-Smad3 signaling axis, underscoring its therapeutic potential in the treatment of CKD.

2.
Heliyon ; 10(16): e35728, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39220918

RESUMO

Renal fibrosis represents a pivotal characteristic of chronic kidney disease (CKD), for which effective interventions are currently lacking. The Src kinase activates the phosphatidylinositol-3 kinases (PI3K)/Akt1 pathway to promote renal fibrosis, casting a promising target for anti-fibrosis treatment. Chaihuang-Yishen formula (CHYS), a traditional Chinese medicinal prescription, has a validated efficacy in the treatment of CKD, however, with the underlying mechanism unresolved. This study aimed to uncover the pharmacological mechanisms mediating the effect of CHYS in treating renal fibrosis using network pharmacology followed by experimental validation. The chemical compounds of CHYS were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database or published literature, followed by the prediction of their targets using SwissTargetPrediction software. Disease (CKD/renal fibrosis)-related targets were retrieved from the Genecards database. Protein-protein interaction (PPI) network was generated using the drug-disease common targets and visualized in Cytoscape software. The drug-disease targets were further subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses by Metascape software. Additionally, the compound-target-pathway network was established in Cytosape to identify key compounds, targets, and pathways. Network pharmacology analysis screened out 96 active compounds and 837 potential targets within the 7 herbal/animal medicines of CHYS, among which 237 drug-disease common targets were identified. GO and KEGG analysis revealed the enrichment of fibrosis-related biological processes and pathways among the 237 common targets. Compound-target-pathway network analysis highlighted protein kinases Src and Akt1 as the top two targets associated with the anti-renal fibrosis effects of CHYS. In UUO mice, treatment with CHYS attenuates renal fibrosis, accompanied by suppressed expression and phosphorylation activation of Src. Unlike Src, CHYS reduced Akt1 phosphorylation without affecting its expression. In summary, network pharmacology and in vivo evidence suggest that CHYS exerts its anti-renal fibrosis effects, at least in part, by inhibiting the Src/Akt1 signaling axis.

3.
Front Biosci (Landmark Ed) ; 29(9): 336, 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39344310

RESUMO

BACKGROUND: Partial bladder outlet obstruction (pBOO) causes deposition of extracellular matrix (ECM), promotes bladder fibrosis, and decreases bladder compliance. METHODS: To investigate the effect of ß-adrenoceptor (ADRB) on the ECM deposition of pBOO rat model and explore its underlying mechanism, human bladder smooth muscle cells (hBSMCs) were exposed to the pathological hydrostatic pressure (100 cm H2O) for 6 h, reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were employed. Then the rats of sham operation and pBOO model were treated with vehicle or ADRB agonists for 3 weeks, and the alterations of the bladder were observed via Masson staining and immunohistochemical analysis. RESULTS: 100 cm H2O hydrostatic pressure significantly upregulated the expression of collagen I (COL1), collagen III (COL3) and fibronectin (FN), and downregulated the expression of ADRB2 and ADRB3 of hBSMCs at 6 h. The agonists of ADRB2 and ADRB3, Formoterol and BRL 37344, decreased COL1 and FN expression of hBSMCs under 100 cm H2O for 6 h compared with the cells exposed to hydrostatic pressure only. As the classic downstream pathways of ADRB, the EPAC pathway inhibited COL1 and FN expression of hBSMCs via regulating SMAD3 and SMAD2 activities, respectively. In pBOO rats, Procaterol (ADRB2 agonist), and Mirabegron (ADRB3 agonist) inhibited the formation of collagen and decreased the expression of FN and COL1 in the bladders of pBOO rats. CONCLUSIONS: The bladder fibrosis of pBOO and deposition of hBSMCs ECM under hydrostatic pressure were regulated by ADRB2, and ADRB3 via EPAC/SMAD2/FN and EPAC/SMAD3/COL1 pathways, these findings pave an avenue for effective treatment of pBOO.


Assuntos
Matriz Extracelular , Fibrose , Transdução de Sinais , Obstrução do Colo da Bexiga Urinária , Bexiga Urinária , Obstrução do Colo da Bexiga Urinária/metabolismo , Obstrução do Colo da Bexiga Urinária/patologia , Animais , Matriz Extracelular/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/efeitos dos fármacos , Ratos , Humanos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/metabolismo , Miócitos de Músculo Liso/metabolismo , Tiazóis/farmacologia , Fumarato de Formoterol/farmacologia , Acetanilidas/farmacologia , Etanolaminas/farmacologia , Etanolaminas/metabolismo , Fibronectinas/metabolismo , Fibronectinas/genética , Feminino , Agonistas Adrenérgicos beta/farmacologia
4.
Ren Fail ; 46(2): 2375033, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38967135

RESUMO

The Astragalus mongholicus Bunge and Panax notoginseng formula (A&P) has been clinically shown to effectively slow down the progression of chronic kidney disease (CKD) and has demonstrated significant anti-fibrosis effects in experimental CKD model. However, the specific active ingredients and underlying mechanism are still unclear. The active ingredients of A&P were analyzed by Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-HR-MS). A mouse model of CKD was constructed by 5/6 nephrectomy. Renal function was assessed by creatinine and urea nitrogen. Real-time PCR and Western Blot were performed to detect the mRNA and protein changes in kidney and cells. An in vitro fibrotic cell model was constructed by TGF-ß induction in TCMK-1 cells. The results showed that thirteen active ingredients of A&P were identified by UPLC-HR-MS, nine of which were identified by analysis with standards, among which the relative percentage of NOB was high. We found that NOB treatment significantly improved renal function, pathological damage and reduced the expression level of fibrotic factors in CKD mice. The results also demonstrated that Lgals1 was overexpressed in the interstitial kidney of CKD mice, and NOB treatment significantly reduced its expression level, while inhibiting PI3K and AKT phosphorylation. Interestingly, overexpression of Lgals1 significantly increased fibrosis in TCMK1 cells and upregulated the activity of PI3K and AKT, which were strongly inhibited by NOB treatment. NOB is one of the main active components of A&P. The molecular mechanism by which NOB ameliorates renal fibrosis in CKD may be through the inhibition of Lgals1/PI3K/AKT signaling pathway.


Assuntos
Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Fibrose , Flavonas , Rim , Panax notoginseng , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Insuficiência Renal Crônica , Transdução de Sinais , Animais , Camundongos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Masculino , Panax notoginseng/química , Flavonas/farmacologia , Flavonas/uso terapêutico , Rim/patologia , Rim/efeitos dos fármacos , Astrágalo/química , Camundongos Endogâmicos C57BL , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão
5.
BMC Complement Med Ther ; 24(1): 273, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39030535

RESUMO

BACKGROUND: Chronic kidney disease (CKD) and its associated end-stage renal disease (ESRD) are significant health problems that pose a threat to human well-being. Renal fibrosis is a common feature and ultimate pathological outcome of various CKD leading to ESRD. The Astragalus mongholicus Bunge and Panax notoginseng formula (A&P) is a refined compound formulated by our research group, which has been clinically administered for over a decade and has demonstrated the ability to improve the inflammatory state of various acute or chronic kidney diseases. However, the underlying mechanism by which A&P ameliorates renal fibrosis remains unclear. METHODS: We established a mouse model by surgically ligating the unilateral ureter to induce renal injury in vivo. And we utilized renal in situ electroporation of a plasmid with low LncRNA A33 expression to establish the unilateral ureteral obstruction(UUO)mouse model. In vitro, we stimulated primary tubular epithelial cells(pTEC) injury using TGF-ß1, siRNA-A33, and pcDNA3.1-A33 plasmids were transfected into pTECs to respectively knockdown and overexpress LncRNA A33, and both in vitro and in vivo models were intervened with A&P. RESULTS: The results demonstrated that A&P effectively alleviated renal fibrosis in mice. Subsequent findings indicated high expression of LncRNA A33 in the kidneys of UUO mice and TGF-ß1-induced renal tubular cells. In situ, renal electroporation of a plasmid with reduced LncRNA A33 expression revealed that inhibiting LncRNA A33 significantly improved renal fibrosis in UUO mice. Moreover, A&P effectively suppressed LncRNA A33 expression both in vitro and in vivo. Subsequent downregulation of LncRNA A33 in renal tubular epithelial cells resulted in the downregulation of numerous fibrotic markers, a significant inhibition of LncRNA A33, and a notable reduction in downstream ferroptosis signaling. Cell experiments demonstrated that A&P improved renal fibrosis in UUO mice by inhibiting LncRNA A33 and downregulating ferroptosis signaling. CONCLUSION: Through the inhibition of LncRNA A33 and subsequent downregulation of ferroptosis signaling, A&P showed potential as a therapeutic approach for improving renal fibrosis in UUO mice, providing a potential treatment avenue for CKD.


Assuntos
Modelos Animais de Doenças , Regulação para Baixo , Medicamentos de Ervas Chinesas , Ferroptose , Fibrose , Panax notoginseng , RNA Longo não Codificante , Animais , RNA Longo não Codificante/genética , Camundongos , Medicamentos de Ervas Chinesas/farmacologia , Ferroptose/efeitos dos fármacos , Masculino , Regulação para Baixo/efeitos dos fármacos , Astrágalo , Transdução de Sinais/efeitos dos fármacos , Obstrução Ureteral/tratamento farmacológico , Camundongos Endogâmicos C57BL , Rim/efeitos dos fármacos , Rim/patologia
6.
Neurourol Urodyn ; 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38979835

RESUMO

AIMS: This study aimed to determine the preventive effects of emodin on cyclophosphamide (CYP)-induced cystitis and to explore the molecular mechanism. METHODS: In vivo, mice were modeled by CYP. Before a half hour of CYP treatment, Jumonji domain-containing protein-3 (JMJD3) inhibitors (GSK-J4) and emodin were used to treat CYP model mice. Bladder samples were stained for hematoxylin-eosin and toluidine blue. Next, JMJD3 was quantified by immunofluorescence staining, RT-PCR, and Western blot. CXCR3 was quantified by Western blot and ELISA. In vitro, before stimulated by lipopolysaccharide (LPS), human bladder smooth muscle cells (hBSMCs) were transfected with pcDNA3.1-JMJD3 plasmids, shRNA-JMJD3 plasmids or pretreated with emodin. Collected cells to detect JMJD3 and CXCR3 ligands again; collected supernatant of culture for Transwell assay. Finally, as the JAK2 inhibitor, AG490 was used to pretreat LPS-induced hBSMCs. Western blot was performed to quantify proteins. RESULTS: Emodin inhibited mast cell migration and suppressed the expression of JMJD3, CXCR3, and CXCR3 ligands, not only in vivo but also in vitro. The pharmacological effects of emodin were similar to GSK-J4 or JMJD3 inhibition. In addition, emodin significantly downregulated the phosphorylation of JAK2 and STAT3, and inhibited JMJD3/CXCR3 axis transduction like AG490. CONCLUSION: Emodin has a preventive effect on cystitis by inhibiting mast cell migration through inhibition of the JAK2/STAT3/JMJD3/CXCR3 signaling pathway.

7.
Mol Med Rep ; 30(2)2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38904198

RESUMO

The TGF­ß/Smad signaling pathway plays a pivotal role in the onset of glomerular and tubulointerstitial fibrosis in chronic kidney disease (CKD). The present review delves into the intricate post­translational modulation of this pathway and its implications in CKD. Specifically, the impact of the TGF­ß/Smad pathway on various biological processes was investigated, encompassing not only renal tubular epithelial cell apoptosis, inflammation, myofibroblast activation and cellular aging, but also its role in autophagy. Various post­translational modifications (PTMs), including phosphorylation and ubiquitination, play a crucial role in modulating the intensity and persistence of the TGF­ß/Smad signaling pathway. They also dictate the functionality, stability and interactions of the TGF­ß/Smad components. The present review sheds light on recent findings regarding the impact of PTMs on TGF­ß receptors and Smads within the CKD landscape. In summary, a deeper insight into the post­translational intricacies of TGF­ß/Smad signaling offers avenues for innovative therapeutic interventions to mitigate CKD progression. Ongoing research in this domain holds the potential to unveil powerful antifibrotic treatments, aiming to preserve renal integrity and function in patients with CKD.


Assuntos
Processamento de Proteína Pós-Traducional , Insuficiência Renal Crônica , Transdução de Sinais , Proteínas Smad , Fator de Crescimento Transformador beta , Humanos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Fator de Crescimento Transformador beta/metabolismo , Proteínas Smad/metabolismo , Animais , Fosforilação , Fibrose , Ubiquitinação , Autofagia
8.
Ren Fail ; 46(1): 2338484, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38832469

RESUMO

Critically ill COVID-19 patients may exhibit various clinical symptoms of renal dysfunction including severe Acute Kidney Injury (AKI). Currently, there is a lack of bibliometric analyses on COVID-19-related AKI. The aim of this study is to provide an overview of the current research status and hot topics regarding COVID-19 AKI. The literature was retrieved from the Web of Science Core Collection (WoSCC) database. Subsequently, we utilized Microsoft Excel, VOSviewer, Citespace, and Pajek software to revealed the current research status, emerging topics, and developmental trends pertaining to COVID-19 AKI. This study encompassed a total of 1507 studies on COVID-19 AKI. The United States, China, and Italy emerged as the leading three countries in terms of publication numbers, contributing 498 (33.05%), 229 (15.20%), and 140 (9.29%) studies, respectively. The three most active and influential institutions include Huazhong University of Science and Technology, Wuhan University and Harvard Medical School. Ronco C from Italy, holds the record for the highest number of publications, with a total of 15 papers authored. Cheng YC's work from China has garnered the highest number of citations, totaling 470 citations. The co-occurrence analysis of author keywords reveals that 'mortality', 'intensive care units', 'chronic kidney disease', 'nephrology', 'renal transplantation', 'acute respiratory distress syndrome', and 'risk factors' emerge as the primary areas of focus within the realm of COVID-19 AKI. In summary, this study analyzes the research trends in the field of COVID-19 AKI, providing a reference for further exploration and research on COVID-19 AKI mechanisms and treatment.


Assuntos
Injúria Renal Aguda , Bibliometria , COVID-19 , Pandemias , SARS-CoV-2 , Humanos , COVID-19/complicações , COVID-19/epidemiologia , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/complicações , Itália/epidemiologia , Betacoronavirus , China/epidemiologia , Saúde Global
9.
Inflamm Res ; 73(8): 1267-1282, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38844677

RESUMO

BACKGROUND: Inflammatory macrophage infiltration plays a critical role in acute kidney disease induced by ischemia-reperfusion (IRI-AKI). Calycosin is a natural flavone with multiple bioactivities. This study aimed to investigate the therapeutic role of calycosin in IRI-AKI and its underlying mechanism. METHODS: The renoprotective and anti-inflammatory effects of calycosin were analyzed in C57BL/6 mice with IRI-AKI and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. RNA-seq was used for mechanism investigation. The molecular target of calycosin was screened by in silico methods and validated by surface plasmon resonance (SPR). Macrophage chemotaxis was analyzed using Transwell and agarose gel spot assays. RESULTS: Calycosin treatment significantly reduced serum creatinine and urea nitrogen and attenuated tubular destruction in IRI-AKI mice. Additionally, calycosin markedly suppressed NF-κB signaling activation and the expression of inflammatory mediators IL-1ß and TNF-α in IRI-AKI kidneys and LPS-stimulated RAW 264.7 cells. Interestingly, RNA-seq revealed calycosin remarkably downregulated chemotaxis-related pathways in RAW 264.7 cells. Among the differentially expressed genes, Ccl2/MCP-1, a critical chemokine mediating macrophage inflammatory chemotaxis, was downregulated in both LPS-stimulated RAW 264.7 cells and IRI-AKI kidneys. Consistently, calycosin treatment attenuated macrophage infiltration in the IRI-AKI kidneys. Importantly, in silico target prediction, molecular docking, and SPR assay demonstrated that calycosin directly binds to macrophage migration inhibitory factor (MIF). Functionally, calycosin abrogated MIF-stimulated NF-κB signaling activation and Ccl2 expression and MIF-mediated chemotaxis in RAW 264.7 cells. CONCLUSIONS: In summary, calycosin attenuates IRI-AKI by inhibiting MIF-mediated macrophage inflammatory chemotaxis, suggesting it could be a promising therapeutic agent for the treatment of IRI-AKI.


Assuntos
Injúria Renal Aguda , Quimiotaxia , Isoflavonas , Fatores Inibidores da Migração de Macrófagos , Macrófagos , Traumatismo por Reperfusão , Animais , Masculino , Camundongos , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Quimiotaxia/efeitos dos fármacos , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/genética , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Rim/efeitos dos fármacos , Rim/patologia , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Células RAW 264.7 , Traumatismo por Reperfusão/tratamento farmacológico
10.
Int Immunopharmacol ; 135: 112303, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38776855

RESUMO

Diabetic nephropathy (DN) is a common complication of diabetes, characterized by renal fibrosis and poor patient prognosis. Hederagenin (HDG) has shown promising improvement in chronic kidney disease (CKD) kidney fibrosis, but its mechanism in DN-induced kidney fibrosis remains unclear. In this study, a model of diabetic nephropathy (DN) in mice was induced by intraperitoneal injection of streptozocin (50 mg/kg), while in vitro, high glucose (25 mM) was used to induce HK2 cell damage, simulating tubular injury in DN kidneys. The improvement of HDG treatment intervention was evaluated by observing changes in renal function, pathological structural damage, and the expression of fibrosis-related proteins in renal tubular cells. The results demonstrate that HDG intervention alleviates renal dysfunction and pathological damage in DN mice, accompanied by reduced expression of fibrotic markers α-smooth muscle actin (α-SMA), fibronectin (FN) and Collagen-I. Mechanistically, this study found that HDG can inhibit ferroptosis and fibrosis induced by the ferroptosis inducer Erastin (1 µM) in renal tubular cells. Phosphorylation of Smad3 promotes ferroptosis in renal tubular cells. After using its specific inhibitor SIS3 (4 µM), the expression of downstream target protein NADPH oxidase 4 (NOX4) significantly decreases, while the level of glutathione peroxidase 4 (GPX4) is notably restored, mitigating ferroptosis. Smad3 overexpression attenuates the therapeutic effect of HDG on tubular cell fibrosis induced by high glucose. These results demonstrate HDG inhibits Smad3 phosphorylation, thereby reducing the expression of NOX4 and enhancing the expression of GPX4, ultimately attenuating ferroptosis induced renal fibrosis. These findings suggest that HDG offer therapeutic potential for DN renal fibrosis by targeting Smad3-mediated ferroptosis in renal tubular cells.


Assuntos
Nefropatias Diabéticas , Ferroptose , Fibrose , Camundongos Endogâmicos C57BL , NADPH Oxidase 4 , Ácido Oleanólico , Transdução de Sinais , Proteína Smad3 , Animais , Ferroptose/efeitos dos fármacos , Proteína Smad3/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/metabolismo , NADPH Oxidase 4/metabolismo , NADPH Oxidase 4/genética , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Masculino , Linhagem Celular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Túbulos Renais/patologia , Túbulos Renais/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo
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