Chrysophanol Relieves Cisplatin-Induced Nephrotoxicity via Concomitant Inhibition of Oxidative Stress, Apoptosis, and Inflammation

Cisplatin (CDDP) is one of the most frequently prescribed chemotherapy medications. However, its nephrotoxicity which often leads to acute kidney injury (AKI), greatly limits its clinical application. Chrysophanol (CHR), a mainly active anthraquinone ingredient, possesses various biological and pharmacological activities. In this study, we aimed to investigate the underlying protective mechanisms of CHR against CDDP-induced AKI (CDDP-AKI) using C57BL/6 mouse and human proximal tubule epithelial cells. In vivo, we found that pre-treatment with CHR greatly relieved CDDP-AKI and improved the kidney function and morphology. The mechanistic studies indicated that it might alleviate CDDP-AKI by inhibiting oxidative stress, apoptosis, and IKKβ/IκBα/p65/transcription factor nuclear kappa B (NF-κB) inflammation signaling pathway induced by CDDP. Moreover, we found that the cell viability of HK2 cells reduced by CDDP was partially rescued by CHR pre-incubation. Flow cytometry results further indicated that CHR pre-incubation suppressed CDDP induced cellular reactive oxygen species (ROS) generation and inhibited cell apoptosis in a dose-dependent manner. In summary, our results suggested that CHR might be a novel therapy for CDDP-induced AKI.

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

10.21203/rs.3.rs-648122/v1 ◽

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.

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RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

Cells ◽

10.3390/cells10020245 ◽

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.

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

Cell Death and Disease ◽

10.1038/s41419-021-04478-x ◽

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.

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Hexagonal boron nitride nanoparticles trigger oxidative stress by modulating thiol/disulfide homeostasis

Human & Experimental Toxicology ◽

10.1177/09603271211002892 ◽

2021 ◽

pp. 096032712110028

Author(s):

F Kar ◽

İ Söğüt ◽

C Hacıoğlu ◽

Y Göncü ◽

H Şenturk ◽

...

Keyword(s):

Oxidative Stress ◽

Boron Nitride ◽

Hexagonal Boron Nitride ◽

Chemical Properties ◽

Heart Tissue ◽

Albino Rats ◽

Dependent Manner ◽

Tissue Samples ◽

Boron Nitride Nanoparticles

Background: Hexagonal boron nitride nanoparticles (hBN NPs) are encouraging nanomaterials with unique chemical properties in medicine and biomedical fields. Until now, the optimal hBN NP’s dosage and biochemical mechanism that can be used for in vivo systems has not been fully revealed. The main aim of this article is to reveal characteristics, serum and tissue interactions and any acute cytotoxic effect of different dose of hBN NPs for the first time. Methods: hBN NPs at concentrations varying between 50–3200 µg/kg was administered by intravenous injection to Wistar albino rats (n = 80) divided into seven dosage and control groups. Blood and tissue samples were taken after 24 hours. Results: Our findings suggested that higher doses hBN NPs caused oxidative stress on the serum of rats dose-dependently. However, hBN NPs did not affect thiol/disulfide homeostasis on kidney, liver, spleen, pancreas and heart tissue of rats. Furthermore, hBN NPs increased serum disulfide formation by disrupting the thiol/disulfide balance in rats. Also, LOOH and MPO levels increased at high doses, while CAT levels decreased statistically. Conclusion: The results revealed that hBN NPs induce oxidative stress in a dose-dependent manner by modulating thiol/disulfide homeostasis in rats at higher concentrations

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Protective Role of Nrf2 in Renal Disease

Antioxidants ◽

10.3390/antiox10010039 ◽

2020 ◽

Vol 10 (1) ◽

pp. 39

Author(s):

Melania Guerrero-Hue ◽

Sandra Rayego-Mateos ◽

Cristina Vázquez-Carballo ◽

Alejandra Palomino-Antolín ◽

Cristina García-Caballero ◽

...

Keyword(s):

Oxidative Stress ◽

Current Knowledge ◽

Unmet Need ◽

Kidney Injury ◽

Protective Role ◽

Renal Diseases ◽

Related Factor ◽

Ckd Progression ◽

Protective Mechanisms ◽

Novel Therapeutic Strategies

Chronic kidney disease (CKD) is one of the fastest-growing causes of death and is predicted to become by 2040 the fifth global cause of death. CKD is characterized by increased oxidative stress and chronic inflammation. However, therapies to slow or prevent CKD progression remain an unmet need. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that plays a key role in protection against oxidative stress and regulation of the inflammatory response. Consequently, the use of compounds targeting Nrf2 has generated growing interest for nephrologists. Pre-clinical and clinical studies have demonstrated that Nrf2-inducing strategies prevent CKD progression and protect from acute kidney injury (AKI). In this article, we review current knowledge on the protective mechanisms mediated by Nrf2 against kidney injury, novel therapeutic strategies to induce Nrf2 activation, and the status of ongoing clinical trials targeting Nrf2 in renal diseases.

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

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00542-2 ◽

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.

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The Antiinfective Effects of Velvet Antler of Formosan Sambar Deer (Cervus unicolor swinhoei) onStaphylococcus aureus-Infected Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2011/534069 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 16

Author(s):

Ting-Yeu Dai ◽

Chih-Hua Wang ◽

Kun-Nan Chen ◽

I-Nung Huang ◽

Wei-Sheng Hong ◽

...

Keyword(s):

Lipoteichoic Acid ◽

Lavage Fluid ◽

Dependent Manner ◽

Protective Mechanisms ◽

Velvet Antler ◽

Sambar Deer ◽

Dose Dependent ◽

Cervus Unicolor

We assayed the effects of velvet antler (VA) of Formosan sambar deer (Cervus unicolor swinhoei) and its extracts on the anti-infective activity against pathogenicStaphylococcus aureus in vitroandin vivoin this study.In vitrodata indicated that the VA extracts stimulated the proliferation of resting splenocytes and macrophages in a dose-dependent manner up to the highest concentration used (150 μg mL−1). The production of proinflammatory cytokines (TNF-α, IL-6, IL-12) by lipoteichoic acid was significantly suppressed after being cocultured with the VA extracts in a dose-dependent manner. Animal test inS. aureus-infected mice demonstrated that the numbers of bacteria determined in the kidneys and peritoneal lavage fluid ofS. aureus-infected mice were significantly higher than those found in the same organs of mice pretreated with the VA samples. Moreover, the highly enhanced phagocytic activity of macrophages was further verified afterin vitrotreatment with the VA samples. The protective mechanisms of the VA samples might include an immune enhancer and an inflammatory cytokine suppressor.

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7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z Notonipetranone Attenuates Neuropathic Pain by Suppressing Oxidative Stress, Inflammatory and Pro-Apoptotic Protein Expressions

Molecules ◽

10.3390/molecules26010181 ◽

2021 ◽

Vol 26 (1) ◽

pp. 181

Author(s):

Amna Khan ◽

Adnan Khan ◽

Sidra Khalid ◽

Bushra Shal ◽

Eunwoo Kang ◽

...

Keyword(s):

Oxidative Stress ◽

Neuropathic Pain ◽

Interleukin 1 ◽

Related Factor ◽

Dependent Manner ◽

Glutathione S Transferase ◽

Quinone Oxidoreductase ◽

Apoptotic Protein ◽

Apoptotic Proteins ◽

Apoptosis And Inflammation

7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid obtained from a natural source has proved to be effective in minimizing various side effects associated with opioids and nonsteroidal anti-inflammatory drugs. The current study focused on investigating the effects of ECN on neuropathic pain induced by partial sciatic nerve ligation (PSNL) by mainly focusing on oxidative stress, inflammatory and apoptotic proteins expression in mice. ECN (1 and 10 mg/kg, i.p.), was administered once daily for 11 days, starting from the third day after surgery. ECN post-treatment was found to reduce hyperalgesia and allodynia in a dose-dependent manner. ECN remarkably reversed the histopathological abnormalities associated with oxidative stress, apoptosis and inflammation. Furthermore, ECN prevented the suppression of antioxidants (glutathione, glutathione-S-transferase, catalase, superoxide dismutase, NF-E2-related factor-2 (Nrf2), hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase) by PSNL. Moreover, pro-inflammatory cytokines (tumor necrotic factor-alpha, interleukin 1 beta, interleukin 6, cyclooxygenase-2 and inducible nitric oxide synthase) expression was reduced by ECN administration. Treatment with ECN was successful in reducing the caspase-3 level consistent with the observed modulation of pro-apoptotic proteins. Additionally, ECN showed a protective effect on the lipid content of myelin sheath as evident from FTIR spectroscopy which showed the shift of lipid component bands to higher values. Thus, the anti-neuropathic potential of ECN might be due to the inhibition of oxidative stress, inflammatory mediators and pro-apoptotic proteins.

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Abstract 107: Apocynin Attenuates Isoproterenol-induced Myocardial Injury: Implications For Targeting Nadph Oxidase In Myocardial Fibrogenesis

Circulation Research ◽

10.1161/res.113.suppl_1.a107 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Yu Chen ◽

Jingang Cui ◽

Qinbo Yang ◽

Chenglin Jia ◽

Minqi Xiong ◽

...

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Myocardial Fibrosis ◽

Myocardial Injury ◽

Oxidase Inhibitor ◽

Ros Generation ◽

Dependent Manner ◽

Expression Of Genes ◽

Therapeutic Development ◽

Myocardial Injuries

Myocardial fibrosis results from cardiac injuries caused by various pathophysiological mechanisms including myocardial infarction, leading to destruction of myocardial architecture and progressive cardiac dysfunction. Oxidative stress is likely involved in myocardial ischemic injury and the subsequent tissue remodeling mediated by myocardial fibrogenesis. Our current study aimed to evaluate the implication of NADPH oxidase in overproduction of reactive oxygen species and its contribution to the pathogenesis of myocardial fibrogenesis after ischemic injuries. The effects of Apocynin, a selective NADPH oxidase inhibitor, were evaluated in the mouse model of isoproterenol-induced myocardial injury by histopathological approaches and whole-genome gene expression profiling. The results demonstrated that Apocynin was able to inhibit the development of ISO-induced myocardial necrotic lesions and fibrogenesis in a dose-dependent manner. Moreover, the preventive effects of Apocynin on myocardial injuries were associated with suppressed expression of genes implicated in inflammation responses and extracellular matrix, which were remarkably upregulated by isoproterenol administration. In summary, o ur study provides proof-of-concept for the involvement of NADPH oxidase-mediated ROS generation in myocardial ischemic injuries and fibrogenesis, which will benefit the mechanism-based therapeutic development targeting NADPH oxidase and oxidative stress in treating myocardial fibrosis and related disorders.

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miR-187 modulates cardiomyocyte apoptosis and oxidative stress in myocardial infarction mice via negatively regulating DYRK2

10.22514/sv.2021.137 ◽

2021 ◽

Keyword(s):

Oxidative Stress ◽

Myocardial Infarction ◽

Protective Effect ◽

Myocardial Infarct ◽

Annexin V ◽

Cardiomyocyte Apoptosis ◽

Ros Generation ◽

Downstream Target

Myocardial infarction is a serious representation of cardiovescular disease, MicroRNAs play a role in modifying I/R injury and myocardial infarct remodeling. The present study therefore examined the potential role of miR-187 in cardiac I/R injury and its underlying mechanisms. miR-187 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with miR-187 mimic or inhibitor to confirm the function of miR-187 in H/R. DYRK2 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with DYRK2 inhibitor. A myocardium I/R mouse model was established. Circulating levels of miR-187 or DYRK2 was detected by quantitative realtime PCR and protein expression was detected by western blotting. The cell viability in all groups was determined by MTT assay and the apoptosis ratio was detected by flow cytometry after staining with Annexin V-FITC. The effect of miR-187 on cellular ROS generation was examined by DCFH-DA. The level of lipid peroxidation and SOD expression were determined by MDA and SOD assay. The findings indicated that miR-187 may be a possible regulator in the protective effect of H/R-induced cardiomyocyte apoptosis, cellular oxidative stress and leaded to DYRK2 suppression at a posttranscriptional level. Moreover, the improvement of miR-187 on H/R-induced cardiomyocyte injury contributed to the obstruction of DYRK2 expression. In addition, these results identified DYRK2 as the functional downstream target of miR-187 regulated myocardial infarction and oxidative stress.These present work provided the first insight into the function of miR-187 in successfully protect cardiomyocyte both in vivo and in vitro, and such a protective effect were mediated through the regulation of DYRK2 expression.

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