scholarly journals RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 245
Author(s):  
So-Young Kim ◽  
Samel Park ◽  
Seong-Woo Lee ◽  
Ji-Hye Lee ◽  
Eun Soo Lee ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Kidney Injury ◽  
Ros Generation ◽  
Dependent Manner ◽  
Lysosomal Storage ◽  
Cellular Mechanisms ◽  
Cell Death Pathways ◽  
Fabry Nephropathy

Fabry disease is a lysosomal storage disease with an X-linked heritage caused by absent or decreased activity of lysosomal enzymes named alpha-galactosidase A (α-gal A). Among the various manifestations of Fabry disease, Fabry nephropathy significantly affects patients’ morbidity and mortality. The cellular mechanisms of kidney damage have not been elusively described. Necroptosis is one of the programmed necrotic cell death pathways and is known to play many important roles in kidney injury. We investigated whether RIPK3, a protein phosphokinase with an important role in necroptosis, played a crucial role in the pathogenesis of Fabry nephropathy both in vitro and in vivo. The cell viability of podocytes decreased after lyso-Gb3 treatment in a dose-dependent manner, with increasing RIPK3 expression. Increased reactive oxygen species (ROS) generation after lyso-Gb3 treatment, which was alleviated by GSK’872 (a RIPK3 inhibitor), suggested a role of oxidative stress via a RIPK3-dependent pathway. Cytoskeleton rearrangement induced by lyso-Gb3 was normalized by the RIPK3 inhibitor. When mice were injected with lyso-Gb3, increased urine albuminuria, decreased podocyte counts in the glomeruli, and effaced foot processes were observed. Our results showed that lyso-Gb3 initiated albuminuria, a clinical manifestation of Fabry nephropathy, by podocyte loss and subsequent foot process effacement. These findings suggest a novel pathway in Fabry nephropathy.

scholarly journals FGF1ΔHBS prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Dezhong Wang ◽  
Yuan Yin ◽  
Shuyi Wang ◽  
Tianyang Zhao ◽  
Fanghua Gong ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Metabolic Regulation ◽  
Cardiac Injury ◽  
Serum Levels ◽  
Ros Generation ◽  
Dependent Manner ◽  
Cardiac Tissues ◽  
Beneficial Effects

AbstractAs a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1∆HBS) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1∆HBS treatment. Both in vivo and in vitro studies indicate that FGF1∆HBS exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5’ AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1∆HBS testify to its promising potential for use in the treatment of DCM and other metabolic disorders.

scholarly journals Possible Role for Cellular Karyopherins in Regulating Polyomavirus and Papillomavirus Capsid Assembly

2008 ◽  
Vol 82 (20) ◽  
pp. 9848-9857 ◽  
Author(s):  
Gregory Bird ◽  
Malinda O'Donnell ◽  
Junona Moroianu ◽  
Robert L. Garcea
Keyword(s):  
Dna Binding ◽  
Capsid Assembly ◽  
Dependent Manner ◽  
Cellular Mechanisms ◽  
Virion Assembly ◽  
Localization Signal ◽  
Murine Polyomavirus ◽  
Cytoplasmic Assembly

ABSTRACT Polyomavirus and papillomavirus (papovavirus) capsids are composed of 72 capsomeres of their major capsid proteins, VP1 and L1, respectively. After translation in the cytoplasm, L1 and VP1 pentamerize into capsomeres and are then imported into the nucleus using the cellular α and β karyopherins. Virion assembly only occurs in the nucleus, and cellular mechanisms exist to prevent premature capsid assembly in the cytosol. We have identified the karyopherin family of nuclear import factors as possible “chaperones” in preventing the cytoplasmic assembly of papovavirus capsomeres. Recombinant murine polyomavirus (mPy) VP1 and human papillomavirus type 11 (HPV11) L1 capsomeres bound the karyopherin heterodimer α2β1 in vitro in a nuclear localization signal (NLS)-dependent manner. Because the amino acid sequence comprising the NLS of VP1 and L1 overlaps the previously identified DNA binding domain, we examined the relationship between karyopherin and DNA binding of both mPy VP1 and HPV11 L1. Capsomeres of L1, but not VP1, bound by karyopherin α2β1 or β1 alone were unable to bind DNA. VP1 and L1 capsomeres could bind both karyopherin α2 and DNA simultaneously. Both VP1 and L1 capsomeres bound by karyopherin α2β1 were unable to assemble into capsids, as shown by in vitro assembly reactions. These results support a role for karyopherins as chaperones in the in vivo regulation of viral capsid assembly.

scholarly journals Dendritic Cells Expressing MyD88 Molecule Are Necessary and Sufficient for CpG-Mediated Inhibition of IgE Production in Vivo

2019 ◽  
Author(s):  
Ricardo Wesley Alberca-Custódio ◽  
Luciana Mirotti ◽  
Eliane Gomes ◽  
Fernanda Peixoto Barbosa Nunes ◽  
Raquel Souza Vieira ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
Immunoglobulin E ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Cellular Mechanisms ◽  
Necessary And Sufficient ◽  
Myd88 Pathway

Elevated levels of immunoglobulin E (IgE) are associated with allergies and other immunological disorders. Experimentally, sensitization with alum adjuvant favors IgE production while CpG-ODN adjuvant, a synthetic toll-like receptor 9 (TLR9) agonist, inhibits it. The cellular mechanisms underlying TLR-regulation of immunoglobulin production are still controversial. Specifically, TLR-mediated IgE regulation in vivo is not yet known. We show that augmented levels of IgE induced by sensitizations to OVA with or without alum adjuvant or with OVA-pulsed dendritic cells (DCs) were inhibited when sensitization to OVA was performed in the presence of CpG. Notably, CpG-mediated suppression of IgE production required MyD88-expression on DCs but not on B-cells. This contrasts with previous reports of in vitro regulation IgE where CpG acted directly on B cells via MyD88 pathway. In addition, CpG also inhibited IgE production in a MyD88-dependent manner when sensitization was performed with OVA-pulsed DCs. Finally, CpG signaling through MyD88 pathway was also necessary and sufficient to prevent anaphylactic antibody production involved in active cutaneous anaphylaxis.

scholarly journals Macrophages-Derived, LRG1-Enriched Extracellular Vesicles Exacerbate Aristolochic Acid Nephropathy Via A TGFβR1-Dependent Manner

2021 ◽  
Author(s):  
Wenjuan Jiang ◽  
Jiahui Dong ◽  
Changlin Du ◽  
Chuanting Xu ◽  
Songbing Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Aristolochic Acid ◽  
Herbal Medicines ◽  
Kidney Injury ◽  
Dependent Manner ◽  
Aristolochic Acid Nephropathy ◽  
Injury Model ◽  
Culture Model

Abstract Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by some herbal medicines, but treatment remains ineffective. We previously found NADPH oxidases 4 (NOX4), which regulates oxidative stress, play an important role in kidney injury model. However, its regulatory mechanism of action in AAN is still obscure. In this study, we established AAN model in vivo, a co-culture system of macrophage and TEC, and macrophage/TEC conditioned media culture model in vitro respectively. We found macrophages infiltration promoted injury，oxidative stress and apoptosis of TEC. Furthermore, the role of macrophage in AAN was dependent on macrophages-derived EV. Importantly, we found that macrophages-derived, Leucine-rich α-2-glycoprotein 1(LRG1)-enriched EV induced TEC injury and apoptosis of via a TGFβR1-dependent process. Mechanistically, macrophages-derived, LRG1-enriched EV mediating TECs injury by upregulating NOX4 in AAN model. This study may help design a better therapeutic strategy to treat AAN patients.

scholarly journals Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury by Inhibiting Ferroptosis

2022 ◽  
Vol 2022 ◽  
pp. 1-14
Author(s):  
Lu Zhou ◽  
Peng Yu ◽  
Ting-ting Wang ◽  
Yi-wei Du ◽  
Yang Chen ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Inhibitory Effect ◽  
Ros Generation ◽  
Molecular Events ◽  
Mda Content ◽  
Effect Of Pd ◽  
In Cis

Cisplatin is widely used in the treatment of solid tumors, but its application is greatly limited due to its nephrotoxicity; thus, there is still no effective medicine for the treatment of cisplatin-induced acute kidney injury (Cis-AKI). We previously identified that polydatin (PD) exerts nephroprotective effects by antioxidative stress in AKI models. Recent evidence suggests that oxidative stress-induced molecular events overlap with the process of ferroptosis and that there are common molecular targets, such as glutathione (GSH) depletion and lipid peroxidation. Nevertheless, whether the nephroprotective effect of PD is related to anti-ferroptosis remains unclear. In this study, the inhibitory effect of PD on ferroptosis was observed in both cisplatin-treated HK-2 cells (20 μM) in vitro and a Cis-AKI mouse model (20 mg/kg, intraperitoneally) in vivo, characterized by the reversion of excessive intracellular free iron accumulation and reactive oxygen species (ROS) generation, a decrease in malondialdehyde (MDA) content and GSH depletion, and an increase in glutathione peroxidase-4 (GPx4) activity. Remarkably, PD dose-dependently alleviated cell death induced by the system Xc− inhibitor erastin (10 μM), and the effect of the 40 μM dose of PD was more obvious than that of ferrostatin-1 (1 μM) and deferoxamine (DFO, 100 μM), classical ferroptosis inhibitors. Our results provide insight into nephroprotection with PD in Cis-AKI by inhibiting ferroptosis via maintenance of the system Xc−-GSH-GPx4 axis and iron metabolism.

scholarly journals Involvement of S100A8/A9-TLR4-NLRP3 Inflammasome Pathway in Contrast-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (1) ◽  
pp. 209-222 ◽  
Author(s):  
Xuexian Tan ◽  
Xiaohe Zheng ◽  
Zena Huang ◽  
Jiaqiong Lin ◽  
Chuli Xie ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Nlrp3 Inflammasome ◽  
Tissue Injury ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Underlying Mechanism ◽  
Male Rats ◽  
Ros Generation

Background: Contrast-induced acute kidney injury (CIAKI) is a common cause of hospital-acquired acute kidney injury (AKI). S100A8/A9-TLR4-NLRP3 inflammasome pathway triggers inflammation, apoptosis and tissue injury in several AKI models. Nevertheless, the underlying mechanism of S100A8/A9-TLR4-NLRP3 inflammasome pathway in CIKAI is not clear. We aimed to investigate the possible role of S100A8/A9-TLR4-NLRP3 inflammasome in the pathophysiology of CIAKI. Methods: We treated male rats and NRK-52E cells by iopromide to establish in vivo and in vitro models of CIAKI. We collected serum and urine samples to detect renal function. We obtained kidney tissue for histological analysis and detection of protein concentration. We used inhibitor of TLR4 and NLRP3-siRNA to further testify their role in CIAKI in NRK-52E cells. Results: Iopromide caused elevation of SCr, BUN and NGAL level, decrease of endogenous creatinine clearance, morphological injury and tubular apoptosis, enhanced IL-1β and IL-18 expression, and increased expression of S100A8/A9, TLR4 and NLRP3 inflammsome. In NRK-52E cells, iopromide caused enhanced apoptotic rates and ROS generation, which could be ameliorated by inhibitor of TLR4 and NLRP3-siRNA. Moreover, inhibition of TLR4 dampened NLRP3 expression. Conclusion: S100A8/A9-TLR4-NLRP3 inflammasome pathway represented a key mechanism of CI-AKI, which provided a potential therapeutic target.

Lymphocytic microparticles inhibit angiogenesis by stimulating oxidative stress and negatively regulating VEGF-induced pathways

2008 ◽  
Vol 294 (2) ◽  
pp. R467-R476 ◽  
Author(s):  
Chun Yang ◽  
Bupe R. Mwaikambo ◽  
Tang Zhu ◽  
Carmen Gagnon ◽  
Josiane Lafleur ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
Umbilical Vein ◽  
Ros Generation ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Endothelial Cell Function

Recent studies have demonstrated that lymphocyte-derived microparticles (LMPs) impair endothelial cell function. However, no data currently exist regarding the contribution of LMPs in the regulation of angiogenesis. In the present study, we investigated the effects of LMPs on angiogenesis in vivo and in vitro and demonstrated that LMPs strongly suppressed aortic ring microvessel sprouting and in vivo corneal neovascularization. In vitro, LMPs considerably diminished human umbilical vein endothelial cell survival and proliferation in a concentration-dependent manner. Mechanistically, the antioxidants U-74389G and U-83836E were partially protective against the antiproliferative effects of LMPs, whereas the NADPH oxidase (NOX) inhibitors apocynin and diphenyleneiodonium significantly abrogated these effects. Moreover, LMPs increased not only the expression of the NOX subunits gp91phox, p22phox, and p47phox, but also the production of ROS and NOX-derived superoxide (O2−). Importantly, LMPs caused a pronounced augmentation in the protein expression of the CD36 antiangiogenic receptor while significantly downregulating the protein levels of VEGF receptor type 2 and its downstream signaling mediator, phosphorylated ERK1/2. In summary, LMPs potently suppress neovascularization in vivo and in vitro by augmenting ROS generation via NOX and interfering with the VEGF signaling pathway.

scholarly journals Tangshen Formula Attenuates Diabetic Kidney Injury by Imparting Anti-pyroptotic Effects via the TXNIP-NLRP3-GSDMD Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Nan Li ◽  
Tingting Zhao ◽  
Yongtong Cao ◽  
Haojun Zhang ◽  
Liang Peng ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Kidney Injury ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Protective Effects ◽  
Interacting Protein ◽  
Diabetic Kidney ◽  
Tangshen Formula

We previously reported that Tangshen formula (TSF), a Chinese herbal medicine for diabetic kidney disease (DKD) therapy, imparts renal protective effects. However, the underlying mechanisms of these effects remain unclear. Pyroptosis is a form of programmed cell death that can be triggered by the NLRP3 inflammasome. Recently, the association between the pyroptosis of renal resident cells and DKD was established, but with limited evidence. This study aimed to investigate whether the renal protective effects of TSF are related to its anti-pyroptotic effect. DKD rats established by right uninephrectomy plus a single intraperitoneal injection of STZ and HK-2 cells stimulated by AGEs were used. In vivo, TSF reduced the 24 h urine protein (24 h UP) of DKD rats and alleviated renal pathological changes. Meanwhile, the increased expression of pyroptotic executor (GSDMD) and NLRP3 inflammasome pathway molecules (NLRP3, caspase-1, and IL-1β) located in the tubules of DKD rats were downregulated with TSF treatment. In vitro, we confirmed the existence of pyroptosis in AGE-stimulated HK-2 cells and the activation of the NLRP3 inflammasome. TSF reduced pyroptosis and NLRP3 inflammasome activation in a dosage-dependent manner. Then, we used nigericin to determine that TSF imparts anti-pyroptotic effects by inhibiting the NLRP3 inflammasome. Finally, we found that TSF reduces reactive oxygen species (ROS) production and thioredoxin-interacting protein (TXNIP) expression in AGE-stimulated HK-2 cells. More importantly, TSF decreased the colocalization of TXNIP and NLRP3, indicating that ROS-TXNIP may be the target of TSF. In summary, the anti-pyroptotic effect via the TXNIP-NLRP3-GSDMD axis may be an important mechanism of TSF for DKD therapy.

scholarly journals Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Gang Wang ◽  
Yanan Wang ◽  
Qinzhi Yang ◽  
Chunrong Xu ◽  
Youkun Zheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Apoptosis ◽  
Vascular Complications ◽  
Tunel Staining ◽  
Ros Generation ◽  
Dependent Manner ◽  
Diabetic Vascular Complications ◽  
Induced Apoptosis

AbstractMethylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis of diabetic vascular complications, including endothelial cell apoptosis induced by oxidative stress. Metformin (MET), a widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation and limit cell apoptosis. However, the molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Protein expression and protein phosphorylation were investigated using western blotting, ELISA, and immunohistochemical staining, respectively. Cell viability and apoptosis were assessed by the MTT assay, TUNEL staining, and Annexin V-FITC and propidium iodide double staining. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results revealed that MET prevented MGO-induced HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3, and attenuated MGO-induced mitochondrial morphological alterations in a dose-dependent manner. MET pretreatment also significantly suppressed MGO-stimulated ROS production, increased signaling through the ROS-mediated PI3K/Akt and Nrf2/HO-1 pathways, and markedly elevated the levels of its downstream antioxidants. Finally, similar results were obtained in vivo, and we demonstrated that MET prevented MGO-induced oxidative damage, apoptosis, and inflammation. As expected, MET reversed MGO-induced downregulation of Nrf2 and p-Akt. In addition, a PI3K inhibitor (LY-294002) and a Nrf2 inhibitor (ML385) observably attenuated the protective effects of MET on MGO-induced apoptosis and ROS generation by inhibiting the Nrf2/HO-1 pathways, while a ROS scavenger (NAC) and a permeability transition pores inhibitor (CsA) completely reversed these effects. Collectively, these findings broaden our understanding of the mechanism by which MET regulates apoptosis induced by MGO under oxidative stress conditions, with important implications regarding the potential application of MET for the treatment of diabetic vascular complications.

scholarly journals Phorbol 12-Myristate 13-Acetate Induced Toxicity Study and the Role of Tangeretin in Abrogating HIF-1α-NF-κB Crosstalk In Vitro and In Vivo

2020 ◽  
Vol 21 (23) ◽  
pp. 9261
Author(s):  
Sukkum Ngullie Chang ◽  
Debasish Kumar Dey ◽  
Seong Taek Oh ◽  
Won Ho Kong ◽  
Kiu Hyung Cho ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Nuclear Translocation ◽  
Hypoxia Inducible Factor ◽  
Tumor Promoter ◽  
Root Tip ◽  
Ros Generation ◽  
Dependent Manner ◽  
Human Keratinocyte

Phorbol 12-myristate 13-acetate (PMA) is a potent tumor promoter and highly inflammatory in nature. Here, we investigated the toxic effects of PMA on different model system. PMA (10 μg) caused chromosomal aberrations on the Allium cepa root tip and induced mitotic dysfunction. Similarly, PMA caused embryonic and larval deformities and a plummeted survivability rate on zebrafish embryo in a dose-dependent manner. Persistently, PMA treatment on immortalized human keratinocyte human keratinocyte (HaCaT) cells caused massive inflammatory rush at 4 h and a drop in cell survivability at 24 h. Concomitantly, we replicated a cutaneous inflammation similar to human psoriasis induced by PMA. Herein, we used tangeretin (TAN), as an antagonist to counteract the inflammatory response. Results from an in vivo experiment indicated that TAN (10 and 30 mg/kg) significantly inhibited PMA stimulated epidermal hyperplasia and intra-epidermal neutrophilic abscesses. In addition, its treatment effectively neutralized PMA induced elevated reactive oxygen species (ROS) generation on in vitro and in vivo systems, promoting antioxidant response. The association of hypoxia-inducible factor 1-alpha (HIF-1α)-nuclear factor kappa-light-chain-enhancer of activated b cells (NF-κB) crosstalk triggered by PMA enhanced PKCα-ERK1/2-NF-κB pathway; its activation was also significantly counteracted after TAN treatment. Conclusively, we demonstrated TAN inhibited the nuclear translocation of HIF-1α and NF-κB p65. Collectively, TAN treatment ameliorated PMA incited malignant inflammatory response by remodeling the cutaneous microenvironment.

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