@article { author = {Akbari, Abolfazl}, title = {Reply to Letter to Editor by Elumalai et al. re : "Ginger (Zingiber officinale roscoe) extract could upregulate the renal expression of NRF2 and TNFα and prevents ethanol-induced toxicity in rat kidney"}, journal = {Avicenna Journal of Phytomedicine}, volume = {13}, number = {1}, pages = {3-6}, year = {2023}, publisher = {Mashhad University of Medical Sciences}, issn = {2228-7930}, eissn = {2228-7949}, doi = {10.22038/ajp.2022.66674.3146}, abstract = {Thanks for your valuable commenton the article entitled: “Ginger(Zingiber officinale roscoe) extractcould upregulate the renal expressionof NRF2 and TNFα and preventsethanol-induced toxicity in rat kidney”.We reviewed your comment. In thebeginning, I think it is necessary tofirst give an overview of NRF2 and itsexpression.Nuclear factor erythroid 2–relatedfactor 2 (Nrf2) is a transcription factorthat regulates important antioxidantand phase II detoxification genesagainst oxidative stress (Tonelli et al.,2017). Nrf2 is involved in theregulation of (1) production,utilization, and regeneration ofglutathione (GSH) and thioredoxin (TXN),(2) nicotinamide adenine dinucleotidephosphate (NADPH) regeneration, (3) hemeand iron metabolism, (4) reactive oxygenspecies (ROS) and xenobiotic detoxification(Tonelli et al., 2017). Nrf2 activity issubjected to regulation at various levelsincluding protein stability, transcription, andpost-transcription (Tonelli et al., 2017; Li etal., 2019). Regulation of Nrf2 proteinstability level occurs mainly by keap-1-dependent and keap-1-independentpathways. In addition to the modulation ofNrf2 protein stability, regulation of Nrf2signaling occurs at the transcriptional level.The transcriptional factors involved includethe aryl hydrocarbon receptor (AhR), NFκB, and Nrf2 itself (Li et al., 2019). Thetranscription of the Nrf2 gene is found to beactivated by AhR (Li et al., 2019), and theexpression of AhR may be decreased byethanol (Zhang et al., 2012). Nrf2 genepromoter also contains a binding site for NFκB, and NF-κB subunits p50 and p65 inducetransactivation of the Nrf2 gene (Rushworthet al., 2012). This explains the activation ofNrf2 by NF-κB-activating inflammatorycytokines. Although NF-κB activates Nrf2,Nrf2 activation attenuates NF-κB signaling,suggesting a cross-talk between Nrf2 andNF-κB (Cuadrado et al., 2014). Inhibition ofNF-κB signaling by Nrf2 may contribute, atleast partly, to the anti-inflammatoryfunction of Nrf2 activators, such assulforaphane (Sun et al., 2015). How Nrf2suppresses NF-κB signaling remainsAkbari AJP, Vol. 13, No. 1, Jan-Feb 2023 4unknown. It is suggested that Nrf2activation may shift the cellular redoxstatus to a more reducing state due toincreased expression of antioxidants(Li et al., 2019), and we know thatethanol or its metabolic products maydisrupt these conditions by producingdifferent species of free radicals(Comporti et al., 2010). Nrf2autoregulation is another mechanismthat regulates the transcription of thisgene. Due to the presence of ARE-likesequences in the promoter region ofthe Nrf2 gene, Nrf2 may activate itsown gene expression, leading toincreased production of Nrf2 protein(Kwak et al., 2002). This represents apositive feedback mechanism. On theother hand, Nrf2 may stimulate Keap1gene expression for its owndegradation (Lee et al., 2007). Thisnegative feedback is a mechanism tocontrol the undue expression of Nrf2and uncontrolled Nrf2 signaling (Leeet al., 2007). In fact, these descriptionsshow that the expression of this genecan be controlled by different andinterconnected cellular mechanismsthat are involved in variouspathophysiological events (Tebay etal., 2015; Wu et al., 2012). In vivo andin vitro studies showed thatinterventions such as ethanolconsumption (Wu et al., 2012, Gongand Cederbaum, 2006a, Dong et al.,2008), smoking (Knörr-Wittmann etal., 2005), or exposure to heavy metals(He et al., 2007; Korashy and El-Kadi,2006) have led to different changes inthe expression of this gene. Theexamination of each of these studiesshows contradictory results regardingthe expression of this gene, similar toour study. In addition, we were aware,based on studies by other researchersand previous studies on the expressionof this gene that the results presentedin our article may have occurredcontrary to what has been expected sofar. Nevertheless, we reported what weachieved. In addition, it should be noted thatdespite the results of all in vivo and in vivostudies, we face a complex and dynamicbiological system in the face of harmfulinterventions that can individually produceadaptations and compensatory responses,and conflicting results that justify manyunexpected data. Therefore, reporting aresult in a study that is different from otherstudies is not far from the mind and isusually seen in many studies in differentfields.To answer to the question “why theexpression of this gene is increased in thepresence of ethanol? Despite the hypothesesthat exist in this field”, we have not yetencountered a study that has been conductedspecifically for this purpose. However, Gonget al. (2006) reported that the induction ofCYP2E1 by ethanol is one pathway throughwhich, ethanol generates oxidative stress.They also suggested that the levels of proteinand mRNA Nrf2 are increased whenCYP2E1 is elevated, and Nrf2 plays a keyrole in the adaptive response againstincreased oxidative stress caused byCYP2E1 (Gong and Cederbaum, 2006a).Dong et al. (2008) also reported thatmaternal ethanol treatment increased bothNrf2 protein levels and Nrf2-ARE binding inmouse embryos. It has also resulted in amoderate increase in the mRNA expressionof Nrf2 downstream target genes (Dong etal., 2008). Because exposure to ethanolresults in the generation of ROS which areknown to activate Nrf2 (Kensler et al.,2007), the observed Nrf2 activation wasexpected. This response is not unique toethanol-exposed embryos. Similar effectshave been observed in cells treated with anumber of other toxic chemicals, includingheavy metals (He et al., 2007; Korashy andEl-Kadi, 2006), cigarette smoke (KnörrWittmann et al., 2005), and arachidonic acid(Gong and Cederbaum, 2006b). Of particularinterest to this study is that an increase inNrf2 protein has also been observed in liversand hepatocytes of alcohol-fed mice and rats(Gong and Cederbaum, 2006a).Ginger, ethanol and renal NRF2 expressionAJP, Vol. 13, No. 1, Jan-Feb 2023 5However, another contradiction thatcan be seen in the results of this studyis the decrease in the activity ofantioxidant enzymes despite the highlevel of expression of the Nrf2 gene.These results can be easily describedand interpreted. A decrease in theactivity of antioxidant enzymes isactually due to their use to scavenge freeradicals produced due to incomplete ethanolmetabolism and the increase in theexpression of the Nrf2s gene actuallyindicates a compensatory response toimprove the response capacity of theantioxidant system and increase the activityof these enzymes}, keywords = {ginger,Ethanol,Kidney}, url = {https://ajp.mums.ac.ir/article_21188.html}, eprint = {https://ajp.mums.ac.ir/article_21188_0e313edabb96dd4c6997c9520a0f932a.pdf} }