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The Potential Effects of Quercetin-Loaded Nanoliposomes on Amoxicillin/Clavulanate-Induced Hepatic Damage: Targeting the SIRT1/Nrf2/NF-κB Signaling Pathway and Microbiota Modulation.

ABSTRACT: Amoxicillin/clavulanate (Co-Amox), a commonly used antibiotic for the treatment of bacterial infections, has been associated with drug-induced liver damage. Quercetin (QR), a naturally occurring flavonoid with pleiotropic biological activities, has poor water solubility and low bioavailability. The objective of this work was to produce a more bioavailable formulation of QR (liposomes) and to determine the effect of its intraperitoneal pretreatment on the amelioration of Co-Amox-induced liver damage in male rats. Four groups of rats were defined: control, QR liposomes (QR-lipo), Co-Amox, and Co-Amox and QR-lipo. Liver injury severity in rats was evaluated for all groups through measurement of serum liver enzymes, liver antioxidant status, proinflammatory mediators, and microbiota modulation. The results revealed that QR-lipo reduced the severity of Co-Amox-induced hepatic damage in rats, as indicated by a reduction in serum liver enzymes and total liver antioxidant capacity. In addition, QR-lipo upregulated antioxidant transcription factors SIRT1 and Nrf2 and downregulated liver proinflammatory signatures, including IL-6, IL-1β, TNF-α, NF-κB, and iNOS, with upregulation in the anti-inflammatory one, IL10. QR-lipo also prevented Co-Amox-induced gut dysbiosis by favoring the colonization of Lactobacillus, Bifidobacterium, and Bacteroides over Clostridium and Enterobacteriaceae. These results suggested that QR-lipo ameliorates Co-Amox-induced liver damage by targeting SIRT1/Nrf2/NF-κB and modulating the microbiota.

SUBMITTER: Abd El-Emam MM

PROVIDER: S-EPMC10451903 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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The Potential Effects of Quercetin-Loaded Nanoliposomes on Amoxicillin/Clavulanate-Induced Hepatic Damage: Targeting the SIRT1/Nrf2/NF-κB Signaling Pathway and Microbiota Modulation.

Abd El-Emam Mahran Mohamed MM Mostafa Mahmoud M Farag Amina A AA Youssef Heba S HS El-Demerdash Azza S AS Bayoumi Heba H Gebba Mohammed A MA El-Halawani Sawsan M SM Saleh Abdulrahman M AM Badr Amira M AM El Sayed Shorouk S

Antioxidants (Basel, Switzerland) 20230725 8

Amoxicillin/clavulanate (Co-Amox), a commonly used antibiotic for the treatment of bacterial infections, has been associated with drug-induced liver damage. Quercetin (QR), a naturally occurring flavonoid with pleiotropic biological activities, has poor water solubility and low bioavailability. The objective of this work was to produce a more bioavailable formulation of QR (liposomes) and to determine the effect of its intraperitoneal pretreatment on the amelioration of Co-Amox-induced liver dam ...[more]

PMID: 37627483

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Project description:Mycoplasma gallisepticum (MG) is recognized as a principal causative agent of avian chronic respiratory disease, inflicting substantial economic losses upon the poultry industry. However, the extensive use of conventional antibiotics has resulted in the emergence of drug resistance and various challenges in their clinical application. Consequently, there is an urgent need to identify effective therapeutic agents for the prevention and treatment of mycoplasma-induced respiratory disease in avian species. AMP-activated protein kinase (AMPK) holds significant importance as a regulator of cellular energy metabolism and possesses the capacity to exert an anti-inflammatory effect by virtue of its downstream protein, SIRT1. This pathway has shown promise in counteracting the inflammatory responses triggered by pathogenic infections, thus providing a novel target for studying infectious inflammation. Quercetin possesses anti-inflammatory activity and has garnered attention as a potential alternative to antibiotics. However, there exists a gap in knowledge concerning the impact of this activation on MG-induced inflammatory damage. To address this knowledge gap, we employed AlphaFold2 prediction, molecular docking, and kinetic simulation methods to perform a systematic analysis. As expected, we found that both quercetin and the AMPK activator AICAR activate the chicken AMPKγ1 subunit in a similar manner, which was further validated at the cellular level. Our project aims to unravel the underlying mechanisms of quercetin's action as an agonist of AMPK against the inflammatory damage induced by MG infection. Accordingly, we evaluated the effects of quercetin on the prevention and treatment of air sac injury, lung morphology, immunohistochemistry, AMPK/SIRT1/NF-κB pathway activity, and inflammatory factors in MG-infected chickens. The results confirmed that quercetin effectively inhibits the secretion of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, leading to improved respiratory inflammation injury. Furthermore, quercetin was shown to enhance the levels of phosphorylated AMPK and SIRT1 while reducing the levels of phosphorylated P65 and pro-inflammatory factors. In conclusion, our study identifies the AMPK cascade signaling pathway as a novel cellular mediator responsible for quercetin's ability to counter MG-induced inflammatory damage. This finding highlights the potential significance of this pathway as an important target for anti-inflammatory drug research in the context of avian respiratory diseases.

Project description:ImportanceAcute sinusitis is one of the most common indications for antibiotic prescribing in children, with an estimated 4.9 million such prescriptions in the US annually. Consensus does not exist regarding the optimal empirical antibiotic.ObjectiveTo compare amoxicillin-clavulanate vs amoxicillin for the treatment of acute sinusitis in outpatient children.Design, setting, and participantsCohort study of children and adolescents aged 17 years or younger with a new outpatient diagnosis of acute sinusitis and a same-day new prescription dispensation of amoxicillin-clavulanate or amoxicillin in a nationwide health care utilization database. Propensity score matching was used to mitigate confounding.ExposureA new prescription dispensation of amoxicillin-clavulanate or amoxicillin.Main outcomes and measuresTreatment failure, defined as an aggregate of a new antibiotic dispensation, emergency department or inpatient encounter for acute sinusitis, or inpatient encounter for a sinusitis complication, was assessed 1 to 14 days after cohort enrollment. Adverse events were evaluated, including gastrointestinal symptoms, hypersensitivity and skin reactions, acute kidney injury, and secondary infections.ResultsThe cohort included 320 141 patients. After propensity score matching, there were 198 942 patients (99 471 patients per group), including 100 340 (50.4%) who were female, 101 726 (51.1%) adolescents aged 12 to 17 years, 52 149 (26.2%) children aged 6 to 11 years, and 45 067 (22.7%) children aged 0 to 5 years. Treatment failure occurred in 1.7% overall; 0.01% had serious failure (an emergency department or inpatient encounter). There was no difference in the risk of treatment failure between the amoxicillin-clavulanate and amoxicillin groups (relative risk [RR], 0.98 [95% CI, 0.92-1.05]). The risk of gastrointestinal symptoms (RR, 1.15 [95% CI, 1.05-1.25]) and yeast infections (RR, 1.33 [95% CI, 1.16-1.54]) was higher with amoxicillin-clavulanate. After patients were stratified by age, the risk of treatment failure after amoxicillin-clavulanate was an RR of 0.98 (95% CI, 0.86-1.12) for ages 0 to 5 years; RR was 1.06 (95% CI, 0.92-1.21) for 6 to 11 years; and RR was 0.87 (95% CI, 0.79-0.95) for 12 to 17 years. The age-stratified risk of adverse events after amoxicillin-clavulanate was an RR of 1.23 (95% CI, 1.10-1.37) for ages 0 to 5 years; RR was 1.19 (95% CI, 1.04-1.35) for 6 to 11 years; and RR was 1.04 (95% CI, 0.95-1.14) for 12 to 17 years.Conclusions and relevanceIn children with acute sinusitis who were treated as outpatients, there was no difference in the risk of treatment failure between those who received amoxicillin-clavulanate compared with amoxicillin, but amoxicillin-clavulanate was associated with a higher risk of gastrointestinal symptoms and yeast infections. These findings may help inform decisions for empirical antibiotic selection in acute sinusitis.

Project description:Manganese (Mn) is an essential trace element required for the development of human body and acts as an enzyme co-factor or activator for various reactions of metabolism. While essential in trace amounts, excessive Mn exposure can result in toxic accumulations in human brain tissue and resulting extrapyramidal symptoms called manganism similar to idiopathic Parkinson's disease (PD). Quercetin (QCT) has been demonstrated to play an important role in altering the progression of neurodegenerative diseases by protecting against oxidative stress. This study aimed to investigate the protective effect of QCT on Mn-induced neurotoxicity and the underlying mechanism in SK-N-MC human neuroblastoma cell line and Sprague-Dawley (SD) male rat brain. The results showed that Mn treatment significantly decreased the cell viability of SK-N-MC cell and increased the release of lactate dehydrogenase (LDH), which was attenuated by QCT pretreatment at 10 and 20 µg/mL. Compared to the Mn alone group, QCT pretreatment significantly attenuated Mn-induced oxidative stress, mitochondrial dysfunction and apoptosis. Meanwhile, QCT pretreatment markedly downregulated the NF-κB but upregulated the heme oxygenase-1 (HO-1) and Nrf2 proteins, compared to the Mn alone group. Our result showed the beneficial effect of QCT on hematological parameters against Mn in rat brain. QCT decrease reactive oxygen species (ROS) and protein carbonyl levels and increased Cu/Zn-superoxide dismutase (SOD) activity induced in Mn-treated rats. QCT administration caused a significant reduction in the Mn-induced neuroinflammation by inhibiting the expression of inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). QCT lowered the Mn elevated levels of various downstream apoptotic markers, including Bax, cytochrome c, cleaved caspase-3 and polymerase-1 (PARP-1), while QCT treatment upregulated anti-apoptotic Bcl-2 proteins and prevented Mn-induced neurodegeneration. Furthermore, administration of QCT (25 and 50 mg/kg) to Mn-exposed rats showed improvement of histopathological alteration in comparison to Mn-treated rats. Moreover, administration of QCT to Mn-exposed rats showed significant reduction of 8-hydroxy-2'-deoxyguanosine (8-OHdG), Bax, activated caspase-3 and PARP-1 immunoreactivity. These results indicate that QCT could effectively inhibit Mn induced apoptosis and inflammatory response in SK-N-MC cells and SD rats, which may involve the activation of HO-1/Nrf2 and inhibition of NF-κB pathway.

Dataset Information

The Potential Effects of Quercetin-Loaded Nanoliposomes on Amoxicillin/Clavulanate-Induced Hepatic Damage: Targeting the SIRT1/Nrf2/NF-κB Signaling Pathway and Microbiota Modulation.

Publications

The Potential Effects of Quercetin-Loaded Nanoliposomes on Amoxicillin/Clavulanate-Induced Hepatic Damage: Targeting the SIRT1/Nrf2/NF-κB Signaling Pathway and Microbiota Modulation.

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