Ceftriaxone Calcium Crystals Induce Acute Kidney Injury by NLRP3-Mediated Inflammation and Oxidative Stress Injury

Zhang, Yifan; Ning, Benxiang; Xu, Zheng; Xu, Luwei; Zhou, Lin; Ge, Yu‐Zheng; Jia, Ru

doi:10.1155/2020/6428498

Cited by 16 publications

(9 citation statements)

References 30 publications

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“…In addition, an abnormal increase in glucose (GLU) ( Figure 6 G) was presumably because liver damage prevented the degradation of GLU, which is mainly degraded in the liver [ 38 ]. A decreased urea nitrogen (BUN) and creatinine (Cre) and increase in serum calcium (Ca) and serum sodium (Na) ( Figure 6 K–N) indicate that ETX could damage the kidney of mice [ 39 , 40 , 41 , 42 , 43 ], consistent with previous reports that the kidney is one of the main target organs of ETX. However, after the treatment with ZA, these values tended toward normal; mice with the maximum ZA treatment time had blood biochemical parameters similar to the control group.…”

Section: Resultssupporting

confidence: 89%

Statins as Potential Preventative Treatment of ETX and Multiple Pore-Forming Toxin-Induced Diseases

Huang

Zhao

Liu

et al. 2023

IJMS

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Epsilon toxin (ETX), produced by type B and D strains of Clostridium perfringens, can cause fatal enterotoxaemia in ruminant animals, particularly sheep, cattle, and goats. Previous studies show that the cytotoxicity of ETX is dependent on the integrity of lipid rafts, the maintenance of which is ensured by cholesterol. Zaragozic acid (ZA) is a statin drug that reduces the synthesis of squalene, which is responsible for cholesterol synthesis. In this study, ZA significantly reduced the toxicity of ETX in Madin–Darby canine kidney (MDCK) cells. We show that ZA does not affect the binding of ETX to MDCK cells, but propidium iodide staining (PI) and Western blotting confirmed that ZA significantly disrupts the ability of ETX to form pores or oligomers in MDCK cells. Additionally, ZA decreased the phosphatidylserine exposure on the plasma membrane and increased the Ca2+ influx of the cells. Results of density gradient centrifugation suggest that ZA decreased the number of lipid rafts in MDCK membranes, which probably contributed to the attenuation of pore-formation. Moreover, ZA protected mice against ETX in vivo. All mice pre-treated with ZA for 48 h before exposure to an absolute lethal dose of ETX (6400 ng/kg) survived. In summary, these findings provide an innovative method to prevent ETX intoxication. Considering many pore-forming toxins require lipid rafts, we tested and found ZA also inhibited the toxicity of other toxins such as Clostridium perfringens Net B and β-toxin (CPB) and Staphylococcus aureus α-hemolysin (Hla). We expect ZA can thus be developed as a broad-spectrum medicine for the treatment of multiple toxins. In addition, other statins, such as lovastatin (LO), also reduced the toxicity of ETX. These findings indicate that statin medicines are potential candidates for preventing and treating multiple toxin-induced diseases.

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Section: Resultssupporting

confidence: 89%

Statins as Potential Preventative Treatment of ETX and Multiple Pore-Forming Toxin-Induced Diseases

Huang

Zhao

Liu

et al. 2023

IJMS

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“…12 Under various pathologic conditions, the strong correlation between oxidative stress injury and nuclear factor E2-related factor 2 (Nrf2) has been previously proved. [13][14][15] The preceding study has pointed out that Nrf2/HO-1 pathway is one of the most recognized signaling closely associated with oxidative and anti-oxidative balance. 16,17 Under normal circumstances, the cap "n" collar subfamily of basic region-leucine zipper transcription factor Nrf2 is restricted in the cytoplasm by binding to its ligand Kelch-like ECH associating protein 1 (Keap1).…”

Section: Introductionmentioning

confidence: 99%

Loganin Attenuates Septic Acute Renal Injury with the Participation of AKT and Nrf2/HO-1 Signaling Pathways

Zhang¹,

Wang²,

Kang³

et al. 2021

DDDT

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Purpose: Sepsis, a destructive inflammatory response syndrome, is the principal reason to induce death in the intensive care unit. Loganin has been proved to possess the property of anti-inflammation, antioxidant, neuroprotection, and sedation. The primary aim of this study was to evaluate whether Loganin could alleviate acute kidney injury (AKI) during sepsis and investigate the latent mechanisms. Methods: Septic AKI models were established by cecal ligation and puncture (CLP) surgery in mice and given Loganin (20, 40, 80 mg/kg) by gavage. Lipopolysaccharides (LPS)stimulated human kidney proximal tubular (HK2) cells incubated in Loganin (5, 10, 20 μ M) were used to explore the accurate mechanisms. Survival rate, renal function (creatinine and blood urea nitrogen), and renal pathological changes were detected in septic mice. Oxidative stress markers (SOD, GSH-Px, MDA, and SOD), mitochondrial membrane potential, mitochondrial calcium overload, and nuclear factor E2-related factor 2 (Nrf2)/hemeoxygenase 1 (HO-1) pathway activation in vivo and in vitro were determined by commercial kits and Western blot. Cell apoptosis, apoptotic-related protein (cleaved caspase-3, Bcl-2, and Bax) expression and protein kinase B (AKT) phosphorylation in vivo and in vitro were measured by TUNEL staining and Western blot. Finally, AKT blockage by 10 μM LY294002 or Nrf2 inhibition by10 μ M ML385 were utilized to prove the involvement of AKT and Nrf2/HO-1 pathway in AKI during sepsis. Results: We found Loganin treatment (20, 40, 80 mg/kg) mitigated septic AKI reflected by elevated renal function and palliative pathological changes. Oxidative stress and apoptosis in the kidney and LPS-treated HK2 cells were also inhibited by Loganin administration, which was accompanied by AKT and Nrf2/HO-1 pathway activation. Besides, the protective effects of Loganin could be diminished by AKT or Nrf2 blockage, indicating the involvement of AKT and Nrf2/HO-1 pathway. Conclusion: The results suggested that the protective effects of Loganin on AKI during sepsis might be mediated by AKT and Nrf2/HO-1 pathway signaling activation in kidney proximal tubular cells.

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“…Lactam antibiotics could also target inflammasomes. It was reported that Cf, a third-generation cephalosporin lactam, used after priming cells with high concentration of calcium, could activate NLRP3 [ 76 ]. However, it remained unclear whether the inflammasome activation was Cf associated, or if it was the result of calcium-sensing receptors stimulation which, by reducing intracellular cAMP levels, could also activate NLRP3 [ 77 ].…”

Section: Discussionmentioning

confidence: 99%

“…It appears that NLRP3 activation by Cf could require priming factors other than LPS. The high levels of calcium found in the tumor microenvironment [ 76 , 77 ] could be an alternative priming factor.…”

Section: Discussionmentioning

confidence: 99%

Azithromycin and Ceftriaxone Differentially Activate NLRP3 in LPS Primed Cancer Cells

Tezcan

Al-Saadi

Hamza

et al. 2022

IJMS

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Background: Cancer patients are prescribed antibiotics, such as macrolides and lactamides, for infection treatment. However, the effect of these antibiotics on NLRP3 activation remains largely unknown. Method: Lung cancer (A549) and prostate cancer (PC3) cell lines were primed with lipopolysaccharide (LPS) to activate NLRP3 transcription. Cells were then treated with azithromycin (Az) or ceftriaxone (Cf). NLRP3 activation was analyzed by qPCR, Western blot, and ELISA. Cell growth and viability were assessed by real-time cell analysis and Annexin V expression. Levels of 41 cytokines were also analyzed using a multiplex assay. Results: LPS-Az activated transcription of NLRP3, Pro-CASP-1, and Pro-IL-1β in A549 cells, while failing to upregulate NLRP3 and Pro-IL-1β in PC3 cells. LPS-Az decreased the secretion of pro-inflammatory cytokines while it induced the pro-angiogenic factors in A549 and PC3 cells. In contrast, LPS-Cf suppressed the expression of NLRP3-associated genes, NLRP3 protein expression, the inflammatory cytokine secretion in A549 and PC3 cells. LPS-Az and LPS-Cf had a limited effect on cell growth and viability. Discussion: Our data suggest that Cf could suppress LPS induced NLRP3 ,which should be considered when selecting antibiotics for cancer treatment. In contrast, the effect of Az on LPS primed NLRP3 and the inflammatory cytokines production appears to depend on the cancer cell origin. Therefore, these data indicate that considerations are required when selecting Az for the treatment of cancer patients.

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Ceftriaxone Calcium Crystals Induce Acute Kidney Injury by NLRP3-Mediated Inflammation and Oxidative Stress Injury

Cited by 16 publications

References 30 publications

Statins as Potential Preventative Treatment of ETX and Multiple Pore-Forming Toxin-Induced Diseases

Statins as Potential Preventative Treatment of ETX and Multiple Pore-Forming Toxin-Induced Diseases

Loganin Attenuates Septic Acute Renal Injury with the Participation of AKT and Nrf2/HO-1 Signaling Pathways

Azithromycin and Ceftriaxone Differentially Activate NLRP3 in LPS Primed Cancer Cells

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