Evaluation of naproxen-induced oxidative stress, hepatotoxicity and in-vivo genotoxicity in male Wistar rats

Ahmad, Mir Hilal; Fatima, Mahino; Hossain, Mobarak; Mondal, Amal Chandra

doi:10.1016/j.jpha.2018.04.002

Cited by 51 publications

(20 citation statements)

References 33 publications

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“…For example in humans, ibuprofen enhances oxidative stress in plasma during extreme exercise [ 77 ], and induces prolonged stress in a rat model [ 78 ]. Naproxen can induce oxidative stress and genotoxicity in male Wistar rats [ 79 ]. In addition, it has been documented that these non-antibiotic pharmaceuticals can have antimicrobial effects in vivo.…”

Section: Discussionmentioning

confidence: 99%

Non-antibiotic pharmaceuticals promote the transmission of multidrug resistance plasmids through intra- and intergenera conjugation

et al. 2021

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Antibiotic resistance is a global threat to public health. The use of antibiotics at sub-inhibitory concentrations has been recognized as an important factor in disseminating antibiotic resistance via horizontal gene transfer. Although non-antibiotic, human-targeted pharmaceuticals are widely used by society (95% of the pharmaceuticals market), the potential contribution to the spread of antibiotic resistance is not clear. Here, we report that commonly consumed, non-antibiotic pharmaceuticals, including nonsteroidal anti-inflammatories (ibuprofen, naproxen, diclofenac), a lipid-lowering drug (gemfibrozil), and a β-blocker (propranolol), at clinically and environmentally relevant concentrations, significantly accelerated the dissemination of antibiotic resistance via plasmid-borne bacterial conjugation. Various indicators were used to study the bacterial response to these drugs, including monitoring reactive oxygen species (ROS) and cell membrane permeability by flow cytometry, cell arrangement, and whole-genome RNA and protein sequencing. Enhanced conjugation correlated well with increased production of ROS and cell membrane permeability. Additionally, these non-antibiotic pharmaceuticals induced responses similar to those detected when bacteria are exposed to antibiotics, such as inducing the SOS response and enhancing efflux pumps. The findings advance understanding of the transfer of antibiotic resistance genes, emphasizing the concern that non-antibiotic, human-targeted pharmaceuticals enhance the spread of antibiotic resistance among bacterial populations.

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Section: Discussionmentioning

confidence: 99%

Non-antibiotic pharmaceuticals promote the transmission of multidrug resistance plasmids through intra- and intergenera conjugation

et al. 2021

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“…In the same study, naproxen also induced an adaptive response to ROS by increasing SOD and catalase. Interestingly, this increased ROS was supposed to be the underlying cause for significant genotoxic effect and fall of liver function exerted by naproxen [201]. Although, less frequent, coxibs may also cause liver damage via PG-dependent pathway.…”

Section: Risk Of Hepatotoxicitymentioning

confidence: 99%

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective

Bindu

Mazumder

Bandyopadhyay

2020

Biochemical Pharmacology

1,065

519

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Owing to the efficacy in reducing pain and inflammation, non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most popularly used medicines confirming their position in the WHO's Model List of Essential Medicines. With escalating musculoskeletal complications, as evident from 2016 Global Burden of Disease data, NSAID usage is evidently unavoidable. Apart from analgesic, anti-inflammatory and antipyretic efficacies, NSAIDs are further documented to offer protection against diverse critical disorders including cancer and heart attacks. However, data from multiple placebo-controlled trials and meta-analyses studies alarmingly signify the adverse effects of NSAIDs in gastrointestinal, cardiovascular, hepatic, renal, cerebral and pulmonary complications. Although extensive research has elucidated the mechanisms underlying the clinical hazards of NSAIDs, no review has extensively collated the outcomes on various multiorgan toxicities of these drugs together. In this regard, the present review provides a comprehensive insight of the existing knowledge and recent developments on NSAID-induced organ damage. It precisely encompasses the current understanding of structure, classification and mode of action of NSAIDs while reiterating on the emerging instances of NSAID drug repurposing along with pharmacophore modification aimed at safer usage of NSAIDs where toxic effects are tamed without compromising the clinical benefits. The review does not intend to vilify these 'wonder drugs'; rather provides a careful understanding of their side-effects which would be beneficial in evaluating the risk-benefit threshold while rationally using NSAIDs at safer dose and duration.

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“…For example in humans, ibuprofen could enhance oxidative stress in plasma during extreme exercise 53 and induce prolonged stress in a rat model 54 . Naproxen can induce oxidative stress and genotoxicity in male Wistar rats 55 . Diclofenac is also demonstrated to possess a broad antimicrobial activity in vitro 56 .…”

Section: Discussionmentioning

confidence: 97%

Non-antibiotic pharmaceuticals can enhance the spread of antibiotic resistance via conjugation

Wang

Zhang

et al. 2019

Preprint

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9Antibiotic resistance is a global threat for public health. It is widely acknowledged that 10 antibiotics at sub-inhibitory concentrations are important in disseminating antibiotic 11 resistance via horizontal gene transfer. While there is high use of non-antibiotic human-12 targeted pharmaceuticals in our societies, the potential contribution of these on the spread of 13 antibiotic resistance has been overlooked so far. Here, we report that commonly consumed 14 non-antibiotic pharmaceuticals, including nonsteroidal anti-inflammatories (ibuprofen, 15 naproxen, diclofenac), a lipid-lowering drug (gemfibrozil), and a β-blocker (propanolol), at 16 clinically and environmentally relevant concentrations, significantly accelerated the 17 conjugation of plasmid-borne antibiotic resistance genes. We looked at the response to these 18 drugs by the bacteria involved in the gene transfer through various analyses that included 19 monitoring reactive oxygen species (ROS) and cell membrane permeability by flow 20 cytometry, cell arrangement, and whole-genome RNA and protein sequencing. We found the 21 enhanced conjugation correlated well with increased production of ROS and cell membrane 22 permeability. We also detected closer cell-to-cell contact and upregulated conjugal genes. 23Additionally, these non-antibiotic pharmaceuticals caused the bacteria to have responses 24 similar to those detected when exposed to antibiotics, such as inducing the SOS response, and 25 enhancing efflux pumps. The findings advance our understanding of the bacterial transfer of 26 antibiotic resistance genes, and importantly emphasize concerns of non-antibiotic human-27 targeted pharmaceuticals for enhancing the spread of antibiotic resistance. 28 29 Key Words: antibiotic resistance; non-antibiotic pharmaceuticals; horizontal gene transfer; 30 conjugation; reactive oxygen species; cell membrane 31 approximately 95% of the drug market 9,10 , the role of non-antibiotic pharmaceuticals in the 51 emergence and spread of antibiotic resistance has received relatively little attention. Recently, 52Maier et al. 11 screened more than 1 000 marketed drugs against 40 representative gut 53 bacterial strains, and reported that more than 200 non-antibiotic pharmaceuticals could 54 exhibit antibiotic-like effects on the bacteria. They found these non-antibiotic 55 pharmaceuticals contributed to the emergence of antibiotic resistance through mutation or 56 increased expression of efflux pump genes 11 . However, they did not investigate if these non-57 4 antibiotic pharmaceuticals can facilitate HGT 11 . If non-antibiotic pharmaceuticals have 58 effects on the spread of antibiotic resistance, there may be features and properties of the non-59 antibiotic pharmaceuticals, or shared mechanisms, that promote the horizontal transfer of 60 ARGs. 61 62In this study, we investigated the potential of different types of commonly consumed non-63 antibiotic human-targeted pharmaceuticals for promoting conjugative transfer of plasmid 64 borne ARGs. We also explored the un...

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Evaluation of naproxen-induced oxidative stress, hepatotoxicity and in-vivo genotoxicity in male Wistar rats

Cited by 51 publications

References 33 publications

Non-antibiotic pharmaceuticals promote the transmission of multidrug resistance plasmids through intra- and intergenera conjugation

Non-antibiotic pharmaceuticals promote the transmission of multidrug resistance plasmids through intra- and intergenera conjugation

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective

Non-antibiotic pharmaceuticals can enhance the spread of antibiotic resistance via conjugation

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