A Wilms tumor is a childhood kidney tumor. In high-income countries, 90% of patients with this tumor survive. However, the tumor recurs in 15% of patients. It is important to identify the patients at risk of recurrence in order to adjust treatment in such a way that recurrence may potentially be prevented. However, we are currently unable to determine precisely which patients are at risk of recurrence. Therefore, we present an overview of factors that influence the risk of recurrence, also known as prognostic factors. These factors range from patient-, tumor- and treatment-related characteristics to geographic and socioeconomic factors. In addition to these factors, biological markers, such as genetic alterations, should be studied more intensively as these markers may be able to better identify patients at risk of tumor recurrence.In high-income countries, the overall survival of children with Wilms tumors (WT) is ~90%. However, overall, 15% of patients experience tumor recurrence. The adverse prognostic factors currently used for risk stratification  are present in only one third of these cases, and the significance of these factors is prone to change with advancing knowledge and improved treatment regimens. Therefore, we present a comprehensive, updated overview of the published prognostic variables for WT recurrence, ranging from patient-, tumor- and treatment-related characteristics to geographic and socioeconomic factors. Improved first-line treatment regimens based on clinicopathological characteristics and advancing knowledge on copy number variations unveil the importance of further investigating the significance of biological markers for WT recurrence in international collaborations. In high-income countries, children with Wilms tumors (WT) have an overall survival (OS) rate of ~90% when adopting recent protocols of co-operative groups in pediatric oncology ,3,4,5,6.PubMed, Embase, Web of Science and the Cochrane library were searched for relevant articles. The search terms are presented in As a consequence of the difference in upfront treatment approach between the COG RTC and SIOP-RTSG, the co-operative groups have developed different tumor staging and histological classification systems . The staAdvanced age at diagnosis ) is associated with higher tumor stage at diagnosis, higher frequency of high risk (HR) histology subtypes, especially diffuse anaplasia (DA), higher incidence of adverse loss of heterozygosity (LOH) patterns, and larger tumor volumes ,21,22. TThe prognostic significance of patient’s sex was studied in UKCCLG, COG and SIOP-initiated studies, all of which confirmed the lack of association between sex and tumor recurrence ,22,23,25Stage is one of the standard factors for primary treatment stratification. Patients with advanced-stage disease are treated with more intensive chemotherapy and additional radiotherapy , and patients with stage II intermediate risk (IR) tumors were randomized between AVD and treatment without doxorubicin (VA) . DetailsTumors that extend beyond the kidney are considered at least stage II in both the SIOP and COG staging system  and residual intravascular extension or piecemeal resection (COG and SIOP)). In neither SIOP (SIOP-1 and SIOP-2) nor COG (NWTS-3) studies was capsular penetration found to be a prognostic factor for recurrence, probably because this was already accounted for by adjusting treatment ,39. SimiThe criteria for stage III are different for COG and SIOP, and are listed in Invasion of abdominal lymph nodes, including the renal hilum and periaortic chain, which classifies patients as stage III, appears to be a prominent risk factor for recurrence in COG patients with upfront stage III disease ,49,50. ISIOP also considers invasion of lymph nodes as a criterion for stage III classification, including the presence of viable tumor cells, chemotherapy-induced changes or necrosis in lymph nodes . In the Omission of lymph node sampling likely results in understaging and subsequent undertreatment of patients with occult positive lymph nodes. Patients who had no lymph nodes sampled had worse EFS than those with positive lymph nodes during the NWTS-4 . Kieran From the NWTS-3 onwards, intra-operative tumor spill had been defined by the NWTSG as either local (stage II), when spill was confined to the flank, or diffuse (stage III) when the entire peritoneal cavity was contaminated. Patients with any type of intra-operative spill during surgery in the NWTS-4 study had an almost three-fold increased risk of recurrence . Closer n = 56, 12%), did not identify an association between intra-operative tumor spill  and RFS in multivariable analysis ,,35,30,35Anaplasia, currently diagnosed based on tumor cell morphology, is found in approximately 5 to 10% of WTs. In the first NWTS study, Beckwith et al. already demonstrated the association of anaplasia and adverse outcome when compared to non-anaplastic histology . SubsequMYCN mutations [TP53 mutations [TP53 mutational status in 40 DA WT samples. Estimates of 5-year EFS rates were 80% in patient with wild type TP53 and 44% for patients with mutated TP53. The corresponding hazard ratio for an event was 3.89 (95% CI: 1.26–16.9) for patients with mutated TP53 [TP53 have an increased risk of recurrence [TP53 mutations in fatal WT cases irrespective of tumor histology, reported that mutated TP53 was closely associated with anaplasia, although similar mutation rates were found in non-fatal anaplastic cases. Mutated TP53 was also observed in non-anaplastic fatal cases, including 7/17 blastemal-type tumors, suggesting that the molecular diagnosis of TP53 mutations may detect additional high-risk WT cases. Future studies should explore the prognostic significance of TP53 mutations for recurrence in apparent histology-based non-anaplastic WT.Anaplasia has previously been associated with utations , and TP5utations ,80. SIOPted TP53 . This stcurrence . Wegert Blastemal-type WT, defined as tumor comprised of at least ≥66% viable blastema after pre-operative chemotherapy , can, bySince none of the patients with completely necrotic tumors in two studies relapsed, and also OS was excellent (5-year OS in SIOP-9: 98% (95% CI: 91–100%) and 6.5-year OS in SIOP-9/GPOH: 96% 95% CI: 88.3–100%), these tumors are considered low-risk (LR) tumors ,24,86,88.3–100%, WT1 mutations do not show volume reduction after chemotherapy, which is thought to be due to chemotherapy-induced skeletal muscle cell differentiation rather than apoptotic cell death [WT1 mutations are not independently associated with an increased risk of tumor recurrence. Tumor volume at diagnosis was not associated with recurrence in the SIOP 93-01 and 2001 studies [Change in tumor volume, another measure of tumor response to chemotherapy, is associated with histological risk group . In the ll death ,91. Howe studies ,83.Nephrectomy specimen weight may be a surrogate marker of tumor volume. Combined analysis of NWTS-1, 2 and 3 confirmed earlier reports that tumor weight (<550 g vs. ≥550 g) was of prognostic value in patients <2 years of age with stage I, FHWT ,93. ThesWT1 deletion), Denys-Drash syndrome (WT1 mutation) and Beckwith-Wiedemann Syndrome (LOH or loss of imprinting (LOI) of 11p15). Excluding metachronous tumors, both COG and SIOP studies did not observe a higher relapse rate in WAGR patients than in non-syndromic WT patients [ARID1A, EP300, CHEK2, REST and PALB2 [PALB2 was additionally found to be associated with DA [TRIM28 have been found to predispose to familial and non-familial WT [TRIM28 mutations were primarily associated with epithelial histology and patients, both treated according to SIOP and COG guidelines, showed excellent RFS rates , and none of the 13 patients for which follow-up data was available relapsed) [TRIM28 mutations may thus have prognostic value. Whether the prognostic value persists independently of epithelial histology remains to be determined [Up to 15% of WT patients present with a WT predisposition syndrome, a malformation syndrome, or germline (epi)mutation ,94,95. Wpatients ,100. Simpatients . Germlinnd PALB2 . The lat with DA ,102. Larilial WT ,104. WTselapsed) ,106. TRItermined ,108.MYCN and TP53, as previously described in WT1, IGF2 (located at chromosome region 11p15), CTNNB1, WTX, SIX1/SIX2 and microRNA processing genes (miRNAPGs). Somatic WT1 mutations are observed in 10–20% of WT cases, and, in general, do not appear to have independent prognostic value [WT1 mutations, however, were found associated with recurrence in VLRWT patients specifically. This finding could not be reproduced in the AREN0532 study. The AREN0532 did confirm that VLRWT patients with LOH or LOI of 11p15 were more likely to experience tumor recurrence than patients with retention of imprinting [H19 (thought to result from LOI of 11p15 and leading to IGF2 overexpression [β-catenin (encoded by CTNNB1) and WTX (encoded by WTX) play a key role in the Wnt signaling pathway, in which wild type β-catenin co-activates transcription, and WTX is suggested to suppress Wnt signaling [SIX1 or SIX2 and a miRNAPG (including DROSHA or DGCR8) resulted in a decrease in EFS in a study by the COG [SIX1/SIX2 and miRNAPG mutations were associated with blastemal-type WT, which is an adverse prognostic factor for recurrence [SIX1 and miRNAPG mutations may be involved in driving tumor recurrence, suggesting potential prognostic value that must be confirmed in future studies [The review by Treger et al. provides a comprehensive overview of common somatic mutations in WTs and their clinical relevance . The mosic value ,109,110.printing . In a copression ,113) waspression . β-catenignaling . Alteredignaling ,109. Fin the COG . This ascurrence ,117. The studies ,119. RatGain of chromosome arm 1q is an independent prognostic marker for recurrence in WT patients, both in NWTSG/COG and SIOP-treated patients ,28,29,47n = 11). The prognostic effect of neither LOH 1p nor LOH 16q could be reproduced in adjusted analyses of SIOP, one of which also included UKW2-3 patients [The NWTS-5 study prospectively analyzed LOH of 1p only (LOH 1p) and 16q only (LOH 16q), as well as combined LOH of 1p and 16q (LOH 1p/16q) in WT patients ,29. The patients ,47.An updated analysis of NWTS-5 patients with longer follow-up showed that LOH 1p and LOH 16q, as well as LOH 1p/16q were associated with EFS in univariable survival analysis. When adjusted for 1q gain in multivariable analysis, the prognostic significance of LOH of 1p and/or 16q was lost, whereas the significance of 1q gain remained. However, LOH 1p and LOH 16q appeared significantly associated with 1q gain. When patients with and without 1q gain were analyzed separately, LOH of 1p and/or 16q was of independent prognostic value specifically in patients without 1q gain . The finTreatment of WT is multimodal, and the prognostic effect of treatment-related factors on patient outcome should be carefully deliberated. Rationally, inadequate treatment leads to worse prognosis, as we will further discuss in the context of resource constraints in low- and lower-middle-income countries. Nonetheless, therapeutic considerations in high-income countries may also potentially influence prognosis. The factors that will be discussed here include the two upfront treatment approaches, chemotherapeutic regimens, radiotherapy, surgical elements focused on lymph node sampling, the performance of NSS, minimally invasive surgery (MIS), and the importance of centralized expertise through international collaboration.In a randomized controlled trial, pre-operative chemotherapy, when compared to immediate nephrectomy, resulted in a reduction of tumor volume, which tended to reduce the risk of gross tumor spill, and a more favorable stage distribution among WT patients ,121,122.2 for patients with FH (rather than 300 mg/m2 prescribed during the SIOP 2001) did not negatively affect relapse-free and overall survival [Currently, SIOP treats roughly two–thirds of all patients with VA only. The other third is prescribed additional doxorubicin in case of stage II/III tumors with intermediate-risk non-stromal or non-epithelial histology and a tumor volume of ≥500 mL after pre-operative chemotherapy, stage IV tumors and tumors with HR histology ,124. Doxsurvival .n = 3/112) were seen only in patients with DA WT [https://clinicaltrials.gov/ct2/show/NCT04322318 (accessed on 21 June 2021)).The current COG and SIOP guidelines for radiotherapy treatment are presented in th DA WT . SIOP stth DA WT . Hence, th DA WT . Thirdlyth DA WT . The COGth DA WT . More inth DA WT ,64. Finath DA WT . COG stup-value: <0.001)) [In case of unilateral disease, the standard approach to surgery of WTs is total nephrectomy during open surgery. However nephrectomy in combination with radiation therapy and use of nephrotoxic chemotherapy can lead to loss of renal function . The ris<0.001)) ,131. The<0.001)) . Lymph n<0.001)) . Strict <0.001)) . In addi<0.001)) . These f<0.001)) . HoweverTherapy resistance is an important cause of failure of initial treatment, especially in patients who present with very-high risk relapse . Howeverhttps://paedcan.ern-net.eu/, accessed on 21 June 2021).Childhood cancer patients are more likely to survive when treated at high, compared to low volume centers, as high volume centers are more experienced in the treatment of (rare) childhood cancers, and as a result, can provide more (Wilms) tumor specific expertise ,137,138.An extensive discussion of all geographic and socioeconomic factors is beyond the scope of this review. However, whereas survival in high-income countries is excellent, outcomes of patients in low- and lower-middle-income countries leave much to be desired . TherefoCurrent negative prognostic factors used for patient stratification are present in only one third of WT patients who subsequently relapse. To potentially improve relapse prediction, we have provided an overview of the prognostic value of currently applied and novel factors. Tumor stage and histological subtype clearly remain relevant prognosticators, notwithstanding that the current staging system may deserve adjustments . Since both tumor stage definition and histologic classification are easily achievable in settings with limited resources, they remain valid prognostic classifiers in low- and middle-income countries. Patient age at diagnosis and biological markers such as 1q gain and LOH 1p/16q represent additional prognostic factors to validate or use in prospective larger experiences. It is noteworthy that access to multidisciplinary care and expertise also seem to significantly influence EFS rates of children with WT. Finally, international harmonization of definitions, diagnosis, treatment and radiology and pathology review in combination with identification of novel adverse genetic signatures may provide the opportunity to further develop the array of prognostic factors for WT recurrence.


Water deficit and rehydration frequently occur during wheat cultivation. Previous investigations focused on the water deficit and many drought-responsive genes have been identified in winter wheat. However, the hormone-related metabolic responses and de-peroxidative activities associated with rehydration are largely unknown. In this study, leaves of two winter wheat cultivars, “Hengguan35”  and “Shinong086” , were used to investigate water deficit and the post-rehydration process. Rehydration significantly promoted wheat growth and postponed spike development. Quantifications of antioxidant enzymes, osmotic stress-related substances, and phytohormones revealed that rehydration alleviated the peroxidation and osmotic stress caused by water deficit in both cultivars. The wheat cultivar HG showed a better rehydration-compensation phenotype than SN. Phytohormones, including abscisic acid, gibberellin (GA), jasmonic acid (JA), and salicylic acid (SA), were detected using high-performance liquid chromatography and shown to be responsible for the rehydration process. A transcriptome analysis showed that differentially expressed genes related to rehydration were enriched in hormone metabolism- and de-peroxidative stress-related pathways. Suppression of genes associated with abscisic acid signaling transduction were much stronger in HG than in SN upon rehydration treatment. HG also kept a more balanced expression of genes involved in reactive oxygen species pathway than SN. In conclusion, we clarified the hormonal changes and transcriptional profiles of drought-resistant and -sensitive winter wheat cultivars in response to drought and rehydration, and we provided insights into the molecular processes involved in rehydration compensation. Wheat is an important global staple crop vulnerable to climate conditions and its yield is associated with water supply during the cultivation season . Winter Arabidopsis C-repeat-binding factor gene (AtCBF4) is another key component in producing soluble sugars and enhancing the drought tolerance of plants (Oryza sativa Abscisic Stress-ripening 5 (OsASR5) gene plays an essential role in responses to drought stress by regulating ABA biosynthesis, promoting stomatal closure, and preventing drought stress-related protein inactivation (Gossypium hirsutum) WUSCHEL-like homeobox 4 (GhWOX4) gene results in severely impaired vascular growth and drought tolerance. Several phytohormones, including auxin (AUX), indoleacetic acid (IAA), ABA and ethylene, are significantly induced in Arabidopsis GhWOX4-overexpression lines . On November 28, 2018, 3 m3 water was irrigated for each plot, as to ensure safety of overwinter. All wheat plants were subjected to continuous drought stress until the fourth-leaf stage in spring of 2019. A Trimer Pico 64 portable soil moisture meter  was used to measure the 0–200 cm layer soil moisture content (v/v) at every 20 cm soil depth. At the four-leaf stage of wheat plant [168 days after seed sowing (DAS)], and the soil water content of 0–60 cm layer was about 20%, two treatments were set up (3 water for irrigation until the water content of the 0–60 cm soil layer reached 80% of the field water-holding capacity. For Treatment 2 (continuous drought stress treatment), no irrigation was applied. Each treatment includes three plots. Wheat leaf samples were collected in triplicate from both rehydrated and continuous-drought-stressed seedlings at 1 (169 DAS), 8 (176 DAS), 15 (183 DAS) days after irrigation. Leaf samples collected 1 day before the rehydration served as control . The soil water content of 0–60 cm layer in the rehydrated field was greater than 25% at 15 dpr, indicating a sufficient water supply for wheat growth. Soil water content of 0–60 cm layer in the continuous-drought-stressed field was consistently lower than 20%  and drought-sensitive variety Shinong086  were used in this study . The seee set up . For Trethan 20% .Plant height was determined by measuring the main tiller at 15 dpr (183 days after sowing). To monitor the development of the wheat embryos, developing spikes were collected at 1, 8, and 15 dpr with awns and rachis removed. The isolated embryos were observed using anatomic microscope. For evaluation of physiological activities, quantification of phytohormone content, RNA sequencing, and qRT-PCR assay, samples were collected from the fully expanded fourth leaves of wheat plants at 1, 8, and 15 dpr . Leaf sa2O2  method. Briefly, 2 g fresh wheat leaves were weighed and ground into a slurry with 10 ml pre-cooled 80% methanol in an ice bath. This slurry was sealed in plastic wrap and kept overnight at 4°C. The supernatant was obtained by centrifugation at 8,000 g at 4°C for 10 min. The residue was re-suspended in 8 ml pre-cooled 80% methanol, and the supernatant was collected again by centrifugation. The filtrate was concentrated under reduced pressure at 40°C to one-third of the original volume. Samples were extracted and decolorized using 30 ml petroleum ether three times, with the ether phase discarded each time. The aqueous phase was extracted using 20 ml ethyl acetate three times, and the ester phases were combined. Samples were then dried by evaporation under reduced pressure at 40°C. Samples were mixed with 2 ml acetic acid solution (pH 3.5), purified using a Sep-Pak C18 cartridge, eluted with methanol, and concentrated to dry powders under reduced pressure at 40°C. Before high-performance liquid chromatography (HPLC), samples were dissolved, diluted to a total volume of 2 ml in a mobile phase, and filtered through a 0.45 μm microporous membrane. An Agilent 1260 High Performance Liquid Chromatograph was employed. The chromatographic column used was an Eclipse XDB-C18 . Mobile phase A was methanol, and phase B was an aqueous acetic acid solution (pH 3.5). Five endogenous phytohormones in wheat leaves were separated at the same time by gradient elution. The gradient conditions were set as 0–7 min, 20% A; 7–10 min, 20–28% A; 0–17 min, 28% A; 17–19 min, 28–40% A; and 19–35 min, 40% A. The flow rate was 1 mL/min, and the injection volume was 10 μL. The detector wavelengths were set to 254 and 240 nm, and the detection temperature was room temperature .® Ultra™ RNA Library Prep Kit for Illumina ®  following the manufacturer’s recommendations. First-strand cDNA was synthesized using a random hexamer primer and M-MuLV Reverse Transcriptase (RNase H-). Second-strand cDNA synthesis was subsequently performed using DNA Polymerase I and RNase H. PCR products were purified (AMPure XP system), and library quality was assessed on the Agilent Bioanalyzer 2100 system. Q20, Q30, and the GC content of the clean data were calculated. Clean reads were aligned to wheat reference genome sequences released by the International Wheat Genome Sequencing Consortium using HISAT2  in accordance with the manufacturer’s instructions. Sequencing libraries were generated using NEBNext g HISAT2 .p-value  < 0.05 and |log2FoldChange| ≥ 1 were set as the criteria for determining DEGs and classified into clusters using k-means clustering. Heatmaps were visualized using the R package Complex Heatmap v2.5.5  were randomly selected from DEGs for the qRT-PCR assay to evaluate the reliability of the expression levels determined by RNA-seq. Primers for these DEGs were designed . The first-strand cDNA was synthesized using the EasyScript First-Strand cDNA reagent . The wheat designed . Three bt method . The FPKt-tests were used to compare treatment means at the 5% level.All of the statistical analyses were performed using SPSS Statistics 22.0 . Data are presented as means ± standard error (SE) values. A one-way ANOVA was conducted, and Student’s To investigate whether there is an association between rehydration compensation and drought tolerance, we compared the growth of drought-tolerant cultivar “HG” and the drought-sensitive cultivar “SN” under rehydration and drought-stress conditions . Plants To characterize the physiological changes of wheat leaves after being rehydrated, we further measured the SOD, POD, catalase (CAT), and ascorbate peroxidase (APX) activity levels in both HG and SN at 0, 1, 8, and 15 dpr . The oveTo determine the key phytohormones involved in the rehydration process, we quantified the concentrations of ABA, IAA, GA, JA, and SA using HPLC in both HG and SN leaves at 0, 1, 8, and 15 dpr . We obseTriticum aestivum reference genome (IWGSCV1.1 version) from Ensembl Genomes was used to assemble the transcriptome (R2 > 0.92) of correlation in the overall gene expression levels among biological replicates  were identified using DESeq2. All the raw data for the transcriptome assembly have been deposited in NCBI under BioProject PRJNA774165.RNA samples were collected from leaves of HG and SN at 0, 1, 8, and 15 dpr. Each sample included three biological replicates. In general, 42 RNA samples were prepared and sent for 12-Gb Illumina sequencing . The Tricriptome . In totaplicates . Samplesplicates . The fraCompared with the control group before rehydration (0 dpr), we identified 12,073, 13,927, and 14,250 DEGs in rehydrated HG at 1, 8, and 15 dpr, respectively. A total of 12,908, 12,079, and 14,169 DEGs were found in rehydrated SN at 1, 8, and 15 dpr, respectively. Compared with samples from HG at 0 dpr, there were 12,592, 6,117 and 11,039 DEGs in the non-watered HG (continuous drought stress) at 1, 8, and 15 dpr, respectively. There were 5,224, 8,151 and 11,478 DEGs in the non-watered SN at 1, 8, and 15 dpr, respectively. Interestingly, a large number of these identified DEGs (approximately 40%) encoded transcription factors (TFs), indicating a dynamic transcriptional change was triggered by the rehydration treatment .To further explore the core DEGs associated with rehydration or continuous drought stress, we checked the co-regulated DEGs between HG and SN at each time point. We identified 3,969, 6,964, and 6,230 co-regulated DEGs in both rehydrated HG and SN at 1, 8, and 15 dpr, respectively . We combA GO enrichment analysis was conducted on these rehydration-drought shared, rehydration-specific and drought-specific DEGs . RehydraKEGG annotations of these rehydration-drought shared, rehydration-specific and drought-specific DEGs were summarized to illustrate the regulatory pathways . We founTriticum aestivum sucrose non-fermenting-1-related protein kinase 2 genes  were significantly suppressed in HG at all three rehydration time points. A pyraclostrobin (PYR) or pyrabactin-resistance1-like (PYL) transcription factor gene (TraesCS2B02G105300) was upregulated at 8 dpr in both HG and SN, with a longer duration of induction in HG at 15 dpr. Three protein phosphatase type 2C genes  and two ABA-responsive element-binding factor genes (TraesCS6B02G364000 and TraesCS3D02G371900) were downregulated upon rehydration, with a more dramatic decrease in HG than SN. Moreover, the expression levels of several genes involved in the IAA, JA, and SA signaling pathways were also significantly altered.To reveal the molecular mechanisms controlling rehydration compensation in HG, we analyzed the expression levels of genes enriched in the “plant hormone signal transduction” KEGG pathway . Two TriPXMP2, TraesCS5B02G139100, TraesCS5A02G140800, and TraesCS5D02G151700) were downregulated upon rehydration, and had lower expression levels in HG compared with SN. The mean platelet volume gene  controlling ROS metabolism had accumulated transcripts in SN but was suppressed in HG. One of the Long-chain acyl-CoA synthetases genes  was constantly downregulated in HG after the rehydration treatment, whereas it was only downregulated at 8 dpr in SN. Three SOD related genes  were significantly upregulated at the early stage of rehydration. Most of the CAT related genes were induced at the late stage of rehydration. Interestingly, the overall expression level of one CAT related gene, TraesCS7B02G473400, in HG was significantly lower than that in SN, whereas the other CAT related gene, TraesCS7A02G549900, showed an opposite expression pattern. Based on the expression profiles of these genes involved in the ROS network, we speculated that HG might utilize a more balanced ROS pathway to achieve a greater rehydration compensation level.We further analyzed DEGs involved in the ROS network to interpret their associations with oxidation reduction and acclimation during rehydration compensation . The oveTraesCS3A02G535300), leaf type ferredoxin-NADP and oxidoreductase , Chlorophyll a/b binding protein , alpha-D-phosphohexomutase superfamily , Mitochondrial inner membrane protease ATP23 , and Pyruvate dehydrogenase E1 component subunit alpha  were randomly selected from DEGs for a quantitative real-time PCR (qRT-PCR) analysis (TaActin gene (GenBank accession AB181991.1) was used as an internal control. A high correlation (R2>0.9373) between overall expression levels from RNA-seq and qRT-PCR assays was observed  and PP2C, were differentially expressed after rehydration treatment as evidenced in the RNA-seq database , redox-sensitive transcription factors, or phosphatases. Serine/threonine-protein kinases are involved in ROS induction, including the activation of mitogen-activated protein kinase, which further regulates the ROS-signaling network  family genes significantly improved the scavenging activity of ROS under drought stress  BioProject database under accession number WZ conceived the project and set the scientific objectives. XL, XW, PL, XB, and XH contributed to the preparation of equipment and acquisition of data. XL, MY, and XW wrote the manuscript. All authors have read and approved the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We aimed to describe SARS-CoV-2 (COVID-19) infections among employees in a large, academic institution.Table 1. COVID-19 Attribution DefinitionsTable 2. Description of 3,140 COVID 19 Infections in Employees from 3/2020 to 4/2021We prospectively tracked and traced COVID-19 infections among employees across our health system and university. Each employee with a confirmed positive test and 3 presumed positive cases were interviewed with a standard contact tracing template that included descriptive variables such as high-risk behaviors and contacts, dates worked while infectious, and initial symptoms. Using this information, the most likely location of infection acquisition was adjudicated (Table 1). We compared behavior frequency between community and unknown, likely community and community and unknown cases using descriptive statistics. Table 3. Risk Factors for Community, Likely Community, and Unknown CasesNumber of SARS-CoV-2 cases among employees between 3/2020 and 4/2021 by month and stratified according to clinical employee working in the healthcare system, non-clinical employee employed by the healthcare system, and university employeeFrom 3/2020 to 4/2021 we identified 3,140 COVID-19 infections in 3,119 employees out of a total of 34,562 employees (9.0%) . Of those 3,119 employees 1,685 (54.0%) were clinical employees working in the health system, 916 (29.4%) were non-clinical employees working in the health system, and 518 (16.6%) were university employees. Descriptive characteristics for the COVID-19 infections and adjudications are outlined in Table 2. Severe disease among employees was significantly less frequent compared to patients in the health system . The frequency of travel within 14 days, masked gatherings and unmasked gatherings/activities was not significantly different between the community and unknown, likely community groups or the community and unknown groups (Table 3).The majority of COVID-19 infections were linked to acquisition in the community, and few were attributed to workplace exposures. Employees with unknown sources of COVID-19 participated in higher-risk activities at approximately the same frequency as employees with community sources of COVID-19. The most frequently reported initial symptoms were mild and non-specific and rarely included fever. Despite a comprehensive testing and benefit program, a large proportion of COVID-positive employees worked with symptoms, highlighting ongoing challenges with presenteeism in healthcare.Rebekah W. Moehring, MD, MPH, UpToDate, Inc.


For example, quercetin arrests human cervical cancer cell growth by blocking the G2/M phase cell cycle and inducing mitochondrial apoptosis through a p53-dependent mechanism. Other polyphenols such as resveratrol upregulate p53 expression in several cancer cell lines by promoting p53 stability, which in colon cancer cells results in the activation of p53-mediated apoptosis. Finally, among vitamins, folic acid seems to play an important role in the chemoprevention of gastric carcinogenesis by enhancing gastric epithelial apoptosis in patients with premalignant lesions by significantly increased expression of p53. In this review, we discuss the role of these and other dietary antioxidants in p53-mediated cell signaling in relation to cancer chemoprevention and tumor suppression in normal and cancer cells.Cancer arises through a complex interplay between genetic, behavioral, metabolic, and environmental factors that combined trigger cellular changes that over time promote malignancy. In terms of cancer prevention, behavioral interventions such as diet can promote genetic programs that may facilitate tumor suppression; and one of the key tumor suppressors responsible for initiating such programs is p53. The p53 protein is activated by various cellular events such as DNA damage, hypoxia, heat shock, and overexpression of oncogenes. Due to its role in cell fate decisions after DNA damage, regulatory pathways controlled by p53 help to maintain genome stability and thus “guard the genome” against mutations that cause cancer. Dietary intake of flavonoids, a C Cancer is a leading cause of mortality in the world, reporting 18.1 million new cases and 9.6 million deaths in 2018 , 4. HowePlants produce various defensive secondary metabolites such as polyphenols, isoprenoids, alkaloids, sulforaphanes, and certain vitamins and their precursors –11. MostIn 1979, p53 protein was identified. SDS-PAGE analysis indicated that the protein has 53 kDa molecular mass, thus named p53 , 23. In The main role of p53 is to control cell cycle progression, DNA repair, and apoptosis. In vertebrates, p53 has the ability to temporarily block the cell cycle and promote DNA repair. Under certain conditions, p53 can also induce senescence or promote apoptosis, thus providing mechanisms against the accumulation of potentially malignant or defective cells .Apoptosis is the cellular terminal process in the prevention of the proliferation of cells with anomalous DNA. In mammalian cells, p53 mediates apoptosis through transcriptional activation of proapoptotic target genes by two major apoptotic pathways: extrinsic pathway, mediated by death domain proteins belonging to the tumor necrosis factor receptor (TNF-R), and intrinsic pathway that monitors the B-cell lymphoma 2 (Bcl-2) family of proteins, which lead to cell death through the expression of caspases , 29. TheThe irreversible cell cycle arrest will lead to cellular senescence that can limit the expansion of mutations in cells . Therefo2/M phase during DNA damage, which prevents the propagation of mutagenic lesions to the daughter cells, and these transitions are monitored by p53 downregulatory p21 during the DNA damage [Cyclins and cyclin-dependent kinases (CDKs) are the two major proteins that control cell cycle progression. The cell cycle is arrested at the GA damage . The firA damage . DNA damA damage , 45.α, GADD45β, and GADD45γ nuclear proteins, G1 arrest by p21, and also results in apoptosis by apoptotic genes. p53 can also induce GADD45, enhancing nucleotide excision repair (NER) to reduce DNA damage and UV photoproducts [The endpoint of the DDR cascade is DNA repair. Various internal factors that cause DNA damage are ROS, free radicals, certain cellular metabolites, and various external factors such as UV light, certain drugs, and heavy metals. All these factors lead to the moderation of nucleotide bases of DNA, resulting in DNA strand breakage , 46. p53products . p53 alsproducts . p53 alsproducts –54.Excessive activity of p53 is highly harmful to cell survival and normal growth conditions; thus, the p53 protein level is regulated by ubiquitination and degradation, which is mediated mainly by the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2) . Cells aThe p53 protein is very low in normal cells due to continuous ubiquitination by MDM2 and MDMX . p53 is The p53 gene is classified as a wild type and mutant type. It has been suggested that more than 50% of all malignant tumors have mutations in the p53 gene . The mutκBp65), nuclear factor NF-kappa B p50 (NF-κBp50), sterol regulatory element-binding protein (SREBP), Yes-associated protein (YAP), vitamin D receptor (VDR), and nuclear factor erythroid 2-related factor 2 (Nrf2), which modulates the expression of diverse sets of genes. Mutant p53 proteins lose their ability to activate p53 target genes, and some mutants exert transdominant repression over the wild type [Mutant p53 protein interacts with several transcription factors, such as nuclear factor Y (NF-Y), E2F transcription factors (E2Fs), nuclear factor NF-kappa B p65 , tumor suppressor, to inhibit the expression of MDM2 and MDMX , 92. RecγH2AX histone mark in the MRN complex itself, and the downstream effector kinase Chk2 [ATM monomers are then recruited to DSBs with the MRN sensor complex stimulating the activation on multiple substrates at the site of damage . Substraase Chk2 . ATM phoase Chk2 , 103. Chase Chk2 . Chk2 suase Chk2  and its ase Chk2 . Other sase Chk2 . ATM plaase Chk2 .ATR-Chk1 signaling is activated strongly when DNA replication is impeded. DNA polymerases become uncoupled from the replicative helicase, generating tracts of ssDNA that rapidly become coated with the trimeric ssDNA-binding protein complex replication protein A (RPA) . ATR is ATR-Chk1 and ATM-Chk2 signaling are known for the stabilization and phosphorylation of p53. Chk1 and Chk2 activities are required for p53 phosphorylation . p53 exep53 is modulated by a few fundamental processes: acetylation, phosphorylation, ubiquitination, sumoylation, neddylation, and methylation . p53 undPhosphorylation responses to DNA damage and other stresses are controlled by regulators, subcellular localization, stability, and transcriptional activation of target genes, which prompts the biological effects , 117. SeAcetylation of p53 is another mechanism to stabilize the p53 protein that reduces ubiquitination and degradation. SIRT1 plays an important role by deacetylating p53 protein . AcetylaAutophagy is the mechanism of cells for eliminating unnecessary or dysfunctional cellular components. p53 signaling regulates autophagy, and p53 is an autophagy target protein. Under nutrient starvation and various stressful conditions, such as hypoxia, both the wild-type and mutant p53 can be degraded through autophagy –132. As p53 can also mediate functional responses between apoptosis and autophagy when it is subcellularly localized. p53 can localize to mitochondria, where it interacts with antiapoptotic B-cell lymphoma (Bcl) family proteins, allowing proapoptotic factors like Bcl-2-associated X protein (Bax) and Bcl-2-antagonist/killer (BAK) to oligomerize, facilitating mitochondrial outer membrane permeabilization and driving activation of the intrinsic apoptotic cell death pathway , 142. Bein vitro and in vivo studies have demonstrated that dietary biologically active (bioactive) compounds can modulate immunity to delay cancer development and progression through decreased cell proliferation, inactivation of carcinogens, inhibition of angiogenesis, induction of cell cycle arrest, apoptosis, and regulation of various signaling pathways [Numerous pathways , 149–152In vitro experiments have shown that vitamin C (ascorbic acid) can reduce cell proliferation and induce apoptosis through upregulation of p53, p21, and Bax and downregulation of Bcl-2 in T-cell colonies [6 activates the p53 pathway, which is responsible for controlling p21 mRNA transcription in HT29, Caco2, LoVo, HEK293T, and HepG2 cancer cells. p21 mRNA levels were higher in the colon of mice fed a diet with adequate vitamin B6 than those fed a vitamin B6-deficient diet, and this may help to understand the antitumor effect of vitamin B6 via the activation of p53 and elevation of p21 mRNA [α(OH)ase−/− mouse model [9) might play an important role in the chemoprevention of gastric carcinogenesis. In humans, the tumor suppressor p53 expression in the gastric mucosa was significantly increased, while the expression of Bcl-2 oncogene protein decreased after folic acid supplementation [α-mediated induction of p53 and reduction of p65 protein expression and unveils a novel mechanism by which NAC in combination with the PPARα ligand inhibits the growth of non-small-cell lung carcinoma (NSCLC) cells [β-Carotene, ascorbic acid, and vitamin E (α-tocopherol) protect against oxidative stress but reveal no direct influence on p53 expression in rats subjected to stress [β-carotene exacerbates DNA oxidative damage and modifies p53-related pathways of cell proliferation and apoptosis in cultured RAT-1 fibroblasts exposed to tobacco smoke condensate (tar) [colonies . Furthercolonies . Vitamincolonies . Vitaminp21 mRNA . A previse model . Folic aentation . FurtherC) cells . Water-sC) cells . β-Caroto stress . In contte (tar) .2/M phase and apoptosis induction through the disruption of mitochondrial membrane potential and activation of the intrinsic apoptotic pathway through p53 induction [γ) and reduced AKT activity in liver cancer cell lines [κB) pathway in a rat bladder carcinogenesis model has been documented, which is a safe and efficacious agent and promising therapeutic approach for bladder cancer [2/M arrest by modulating the expression of various proteins, which are involved in signaling. Moreover, theaflavins via p53 signaling inhibited Bcl-2 and interfered phagocytes via modulation of I-κB/NF-κB, as well as the expression of VEGF, and the phosphorylation of VEGFR was reduced in LNCaP cells [κB-dependent Bcl-2 that results in growth arrest and apoptosis in LNCaP cells [Flavonoids are suggested to reduce p53-mediated chronic inflammation leading to cancer progression . Quercetnduction . Furthernduction . Furthernduction . Anotherll lines . It was ll lines . The inhr cancer . Furtherr cancer . TheaflaaP cells . FurtheraP cells . Our preaP cells . Apple faP cells . FurtheraP cells .1 arrest and cell death, leading to inhibition of tumor cell proliferation and induction of cell death by ellagic acid, which supports as a chemopreventive agent [Caffeic acid increases p53 protein expression in a concentration-dependent manner and induces apoptosis by inhibiting Bcl-2 activity, leading to the release of Cyt c and subsequent activation of caspase-3 in HeLa cells . Pretreave agent .2/M phase arrest through the p53/p21Cip1/WAF1 pathway [Curcumin increases levels of p53, which provides an appropriate cellular environment for p53 and NAD(P)H quinone oxidoreductase (NQO1) to interact in HeLa, SiHa, and CaSki tumor-derived cell lines. At the same time, this interaction promotes the loss of interaction of p53 with its negative regulator E6AP ubiquitin-protein ligase (E6AP) when human papillomavirus E6 (HPV E6) oncoproteins are present . Another pathway . A previ pathway . Another pathway .γ and UV radiation-induced phosphorylation of p53 and Ser15, which may be modified directly mediated by ATM [γ irradiation as resistant to caffeine. Evidence indicated that harmine treatment induced apoptosis in MCF-7 cells through the upregulation of p53 expression and reported that harmine is able to upregulate p53 gene expression in breast cancer cell lines. Furthermore, harmine induced apoptosis in breast cancer cells in a time-dependent manner and real-time PCR outcomes on breast cancer cells showed that apoptosis induction in MCF-7 cells by harmine requires the activation of p53 gene expression [in vitro antiproliferative activity against HPV 16/18-positive human cervical cancer cell lines, which was achieved by HPV E6/E7 inhibition and subsequently p53-dependent intrinsic apoptosis [Caffeine suppresses the ATM/p53 signaling pathway in human T-lymphocyte leukemia MOLT-4 cells. Caffeine suppressed p21 upregulation and inhibited p53 phosphorylation on Ser15 and Ser392, which is ATM-independent, suggesting that caffeine might have another cellular target . Caffeind by ATM . Furtherd by ATM , in theipression . Colchicpoptosis .Dietary antioxidants, including polyphenols and vitamins, have been investigated for their prospective benefits such as antioxidant, antiproliferative, antiangiogenic, anticancer, immunomodulatory, and hypoglycemic properties, which increases their applications in the pharmaceutical, functional food, and cosmetic industries , 188. Th0/G1 and G2/M phase arrests, which may be due to rapid p53 accumulation [in vitro and in vivo models of research, the synergistic effects of the green tea extract EGCG and tisane herbal infusion in the eradication of malignant human prostate tumors were investigated. Apoptotic genes such as p53, p73, p21, and caspase-3 were all upregulated as a result of the antioxidant combination [κB pathway. It has been proposed that intravesical fisetin is a novel and promising therapeutic solution for bladder cancer because it is a safe and effective therapeutic agent [Anticancer effects of dietary antioxidants targeting the p53 signaling pathway have been identified using several cell-based and experimental animal models . In humamulation . Quercetmulation . A preclmulation . Using ibination . Intraveic agent .in vitro models, preclinical experimental animal models, and human studies.Cancer is one of the most common causes of disease worldwide. Currently, chemotherapy and radiotherapy are two major cancer treatments, although both are associated with prominent side effects. It is necessary to identify efficacious alternative pharmaceuticals with selective cytotoxicity to cancer cells with the aim of reducing the side effects. Also, novel approaches need to be investigated to reduce the risk of various cancers. Diets rich in polyphenols are implicated in protecting against oxidative stress and inflammation-mediated chronic diseases such as cardiovascular diseases, neurodegenerative disorders, and certain cancers. The cancer chemopreventive effects of dietary polyphenols and other antioxidants are well documented. Dietary polyphenols are able to modulate multiple cellular pathways, which are involved in the initiation and progression of cancer. Polyphenols found in fruits, vegetables, herbs, wine, and teas are safe for consumption. Thus, dietary polyphenols offer multitargeted therapeutic effects than a single drug. The chemopreventive effects of polyphenols have been shown through the modulation of various signaling pathways, including the p53 pathway. p53 signaling activates transcription factors in response to oxidative stresses. In this review, we have shown that certain polyphenols can stabilize p53 protein via phosphorylation and acetylation, contributing to oxidative homeostasis. p53 binds within the DNA and regulates transcriptional genes involved in DNA repair, metabolism, senescence, apoptosis, autophagy, and angiogenesis. Future studies need to be aimed at investigating the efficacy of specific dietary polyphenols and other natural antioxidants and their mixtures against various carcinogen-induced DNA damage through the activation of p53 in healthy cells using


BCOR, DDX3X and TP53. This review aims to provide a comprehensive overview about the role of EBV infection and a comparison of the EBV strains and LMP1 variants among different populations. Moreover, a brief summary of the ENKTCL genetic landscape is presented, highlighting the main therapeutically targetable pathways in ENKTCL oncogenesis: the JAK-STAT signaling pathway, the immune response evasion, MYC overexpression, as well as epigenetic alterations. Extranodal NK/T cell lymphoma (ENKTCL) is an aggressive lymphoma associated with Epstein-Barr virus (EBV) infection that occurs mainly in Asian and Latin American populations. In the last decade, the genetic landscape of ENKTCL has been characterized comprehensively using next-generation sequencing (NGS). This and similar high-throughput approaches revealed that these lymphomas are distinguished by frequent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as BCOR, DDX3X and TP53. The genomic landscape in ENKTCL highlights mechanisms of lymphomagenesis, such as immune response evasion, secondary to alterations in signaling pathways or epigenetics that directly or indirectly interfere with oncogenes or tumor suppressor genes. This overview discusses the most important findings of EBV pathogenesis and genetics in ENKTCL.Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus with tropism for B cells. EBV is linked to the pathogenesis of B cell, T cell and NK cell lymphoproliferations, with extranodal NK/T cell lymphoma, nasal type (ENKTCL) being the prototype of an EBV-driven lymphoma. ENKTCL is an aggressive neoplasm, particularly widespread in East Asia and the native population of Latin America, which suggests a strong genetic predisposition. The link between ENKTCL and different populations has been partially explored. EBV genome sequencing analysis recognized two types of strains and identified variants of the latent membrane protein 1 (LMP1), which revealed different oncogenic potential. In general, most ENKTCL patients carry EBV type A with LMP1 wild type, although the LMP1 variant with a 30 base pair deletion is also common, especially in the EBV type B, where it is necessary for oncogenic transformation. Contemporary high-throughput mutational analyses have discovered recurrent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as  There are some clinical and morphological overlapping features among these entities, therefore differential diagnosis is not always easy [Extranodal NK/T cell lymphoma, nasal type (ENKTCL) is considered the prototype of EBV-driven T and NK cell lymphoproliferative disorder (LPD). It has a predilection for extranodal involvement, including the nasopharyngeal region, skin, gastrointestinal tract, testis, and central nervous system (CNS). Morphologically, ENKTCL is characterized by angioinvasion and angiodestruction with prominent coagulative necrosis and karyorrhexis . Its patays easy ,11,12,13The contribution of EBV to the development of benign and malignant LPD has been extensively investigated since the discovery of the virus over the last 60 years. The importance of EBV in ENKTCL lymphomagenesis was first recognized in 1990, and since then has been confirmed in various studies ,15. To ibona-fide T cell cytotoxic phenotype characterized by CD8+, cytotoxic granules+, CD3+, CD5+, CD56−/+ and TCRγδ+ or TCRαβ+ [ENKTCL typically appears as ulceration in the mucosa of the upper aero-digestive tract . This ulceration is triggered by a neoplastic lymphoid infiltration associated with variable degrees of inflammation; some cases are advanced, showing large amounts of coagulative necrosis and destruction of the adjacent epithelial structures ,25,26. Tr TCRαβ+ ,30. In ar TCRαβ+ . CD30 anr TCRαβ+ ,33. Other TCRαβ+ ,35. The geographic distribution of ENKTCL is characteristic with higher incidence among Native Americans, Hispanic and Asian ethnic groups . In EuroAn ENKTCL case series from Guatemala described the association of this lymphoma with ethnicity and reported that 90% of the patients in the study were of Mayan origin and low socioeconomic status . In the RASGRPI, leading to defective activation of the MAPK pathway and impaired immune response to EBV, is also documented as an inherited susceptibility to EBV infection and EBV-driven LPD such as ENKTCL [A bias in these studies is that Hispanic population comprises all Latin-American immigrants, mainly Mexicans, which do not necessarily belong to the native indigenous population, where the incidence of this neoplasia seems to be higher ,52. The s ENKTCL . In addis ENKTCL .Although the universal association of EBV and ENKTCL is well recognized, the exact role of EBV in ENKTCL remains elusive . EBV is BZLF1, BRLF1, BALF5 and BCRF1 are expressed, resulting in the shedding of infectious virus into the oral cavity [EBV expresses various “latent genes”, comprising six Epstein-Barr nuclear antigens , three latent membrane proteins , two EBV-encoded noncoding RNAs (EBER 1 and 2), and many miRNAs from two regions of the EBV genome: BART and BHRF, so-called BHRF1- and BART-miR . Accordil cavity ,76. Infel cavity ,73,74. Tl cavity ,78. Thesl cavity ,74,79; ll cavity , and latl cavity . During l cavity ,78.The close association of EBV with oncogenesis in ENKTCL has been established by demonstrating the presence of EBV in clonal and episomal forms in tumor cells , as well as various EBV-encoded proteins. Infection by EBV induces the expression of several “latent genes”, which may lead to malignant transformation of lymphoblastoid cells, including EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C and 3 LMP1, 2A, 2B . AccordiSequencing studies have shown a 54% identity in amino acid sequence and 79% at gene level between EBV strains type A and B. In addition, a single amino acid change (S442D) in EBV type A seems to enhance the oncogenic ability of LMP1 , highligInterestingly, studies in Mexican population have revealed the presence of EBV type B with the 30 bp LMP1 deletion in about 9% of ENKTCL, 38% in diffuse large B cell lymphoma (DLBCL), 50% of CHL, and 53% in healthy carriers in reactive lymph nodes ,94,95. TBNLF1, a gene located within the BamHI-N region of the virus genome [The latent membrane protein 1 (LMP1) is a viral protein that is able to induce a malignant transformation not only in B cells but also in epithelial cells ,102,103.s genome . The pros genome ,108. Vars genome ,110,111.s genome . The 30 s genome ,114. LMPs genome ,116,117.BZLF1 and BRLF1 [Next-generation sequencing technology has also led to greater insights into EBV classification and the increased recognition of new strains and sequence variations ,90. EBV nd BRLF1 .The latest genomic and transcriptomic studies in ENKTCL demonstrated focal EBV genome deletions and integration of EBV fragments to the host genome. In addition, gene expression profiling described a higher number of T cell epitope abnormalities but lower activation of latent and lytic viral genes, in comparison to other EBV-associated cancers . LikewisAlthough EBV plays an essential role in the pathogenesis of ENKTCL, other factors might be equally important. During the last decade, several sequencing studies based on various platforms  have been published, analyzing different populations. This has led to a better understanding of the molecular pathogenesis of this entity, the discovery of new targeted therapies, and more recently, to the proposal of a classification according to the molecular changes associated with clinical prognosis. In POPDC3, PREP, PRDM1, ATG5, AIM1 and HACE1 [The most common recurrent cytogenetic alteration in ENKTCL is the loss of 6q21 in about 20 to 43% of cases, resulting in the loss of genes related to tumor suppression such as nd HACE1 ,127,128.nd HACE1 ,130.primary EBV-positive nodal T/NK cell lymphoma, a provisional entity in the WHO classification, is a distinct entity characterized by the loss of 14q11, where the TCR alfa locus is located and is indirect evidence of TCR rearrangement; therefore, it is a lymphoma of T cell origin. These lymphomas present in older patients and lack nasal or extranodal involvement [Further analyses have shown important differences between ENKTCL and ANKL, such as the gain of 2q and the losses in chromosomes 6q16-q27, 11q22-q23, 5p14-p14, 5q34-q35, 1p36-p36, 2p16, 4q12, and 4q31-q32 characteristic in ENKTCL ,132. Stuolvement . STAT3 , followed by epigenetic modifiers , tumor suppressor genes  and the RNA helicase gene DDX3X [STAT3 was the most frequently mutated gene similar to the Korean cohorts. [TP53 were reported with relatively high frequencies in ENKTCL from Latin America [TP53 mutations in the Chinese [DDX3X, another tumor suppressor, is also frequently mutated in the Chinese population and strongly associated with poor outcome [The mutational landscape of ENKTCL was first described in different cohorts from China, Korea and Japan, showing the same mutational profile but with different frequencies. The most recurrently mutated genes include members of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, mainly ne DDX3X ,24,135. ne DDX3X . STAT3 wcohorts. ,125,135. America  and in A America ,157, , DAPK1, PTPN6 (SHP1), TET2, SOCS6, and ASNS [CDKN2A, CDKN2B, and CDKN1A [EZH2 is a histone methyltransferase, a member of the polycomb repressor complex 2 (PCR2) which controls the DNA methylation of oncogenes and tumor suppressor genes acting as a transcriptional repressor. In ENKTCL, EZH2 not only acts as a repressor, but also acts as an oncogene, promoting proliferation, invasion and survival through the NF-kB signaling pathway [TRAF6, resulting in repressed cell proliferation, induced apoptosis, and enhanced chemosensitivity [Epigenetic alterations such as methylation in cell cycle regulators, histone modifications, and de-regulated miRNAs are also described. Aberrant promoter methylation is a common oncogenic mechanism in ENKTCL, which induces the silencing of various tumor suppressor genes such as and ASNS , as welld CDKN1A . EZH2 is pathway ,143,144. pathway ,159,160. pathway , whereas pathway ,146. On sitivity . The prositivity . In the sitivity ,162,163.BIRC5 encoding for survivin, MYC, PD-L1, RUNX3, AURKA, and PDGFRA. MYC is a well-known oncogene related to aggressive clinical behavior in mature B cell lymphomas [NOTCH1 mutations in T cell lymphomas [MGA mutations and 1p22.1 loss of heterozygosity are similarly related to MYC expression promoting the disturbance of the MAPK signaling pathway [Gene expression profiling has also enabled the distinguishing of upregulated genes, with an important role in the pathogenesis of ENKTCL including ymphomas , and is ymphomas . Overexpymphomas . Interes pathway .Tumor Suppressors and Immune Modulators)—consists of cases with JAK-STAT signaling pathway activation, TP53 mutations, del6q21, and mechanisms associated with the immune response such as antigen presentation, NK cell-mediated cytotoxicity, immune surveillance, PD-L1 overexpression, and genomic instability. This group predominates and presents higher NK cell gene expression than the other groups (MGA mutations and LOH at the BRDT locus)—is characterized by MGA mutations, a tumor suppressor gene, related to MYC overexpression and associated with MAPK, NOTCH3/4 and WNT signaling pathway activation —is linked to epigenetic changes, mainly aberrant histone acetylation leading to activation of the NF-kB and TCR signaling pathways  . The HEA subtype was characterized by increased lytic gene BNFR1, a partner of the histone chaperon complex, which interacts with DAXX to promote viral latency and cellular immortalization.Based on molecular integrated analysis of ENKTCL, a new molecular classification has been proposed, distinguishing three different ENKCTL subtypes defined according to their genetic characteristics . The firr groups . The sectivation . BRDT en VAV2/3) . These cThe contemporary understanding of ENKTCL pathogenesis has been enhanced. The use of high-throughput technologies has allowed the genetic analysis of large series of ENKTCL in different populations around the world. These studies have been conducted to investigate the pathogenesis of ENKTCL and the role of EBV in its oncogenesis. EBV strain distribution in ENKTCL shows EBV type A in Asian and Latin American population, whereas type B is identified in Latin American only in Peru and Mexico in comparison to other Western countries. Interestingly, LMP1 30 bp del variant, which promotes EBV oncogenic mechanisms, has been frequently demonstrated in the Chinese population and less commonly in Latin American countries, where its detection is mostly restricted to patients carrying EBV strain type B. As has been proposed in diffuse large B cell lymphoma, the integration of genomic structural alterations in ENKTCL has identified three molecular subgroups related to the cell of origin (NK vs T cell), pathogenic alterations, EBV sequences and clinical outcome. The model suggests that EBV infection is the earliest event, leading to the susceptibility of NK and T cells to genomic alterations that together will result in the pathogenesis of ENKTCL. Consequently, these alterations will influence the prognosis and therapy response. The understanding of the genetic alterations and their altered mechanisms should guide novel therapeutic interventions such as immune checkpoint inhibitors, MYC inhibitors, and histone deacetylase inhibitors. Nevertheless, these studies have only been conducted in Chinese populations, and new comprehensive genomics studies are needed to confirm these results.


Nowadays, emerging evidence has shown adverse pregnancy outcomes, including preterm birth, preeclampsia, cesarean, and perinatal death, occurring in pregnant women after getting infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the underlying mechanisms remain elusive. Thyroid hormone disturbance has been unveiled consistently in various studies. As commonly known, thyroid hormone is vital for promoting pregnancy and optimal fetal growth and development. Even mild thyroid dysfunction can cause adverse pregnancy outcomes. We explored and summarized possible mechanisms of thyroid hormone abnormality in pregnant women after coronavirus disease 2019 (COVID-19) infection and made a scientific thypothesis that adverse pregnancy outcomes can be the result of thyroid hormone disorder during COVID-19. In which case, we accentuate the importance of thyroid hormone surveillance for COVID-19-infected pregnant women. SARS-CoV-2, a novel enveloped RNA beta-coronavirus, infects host through angiotensin II-converting enzyme 2 (ACE2), a membrane-bound aminopeptidase that functions as its putative receptor predominantly expressed within type II alveolar cells of the lung. In addition to ACE2, SARS-CoV-2 requires the cellular protease, TMPRSS2, to cleave viral spike protein and facilitate fusion of viral and cellular membranes (The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) causes coronavirus disease 2019 (COVID-19) and an ongoing severe pandemic. As of May 16, 2021, confirmed infections have amounted to 162,177,376, with casualties reaching an alarming number of 3,364,178  during the first trimester, then changes to Th2 (anti-inflammatory response) by the second trimester, and again alters toward a Th1 phenotype at the end of third trimester concomitant with initiation of parturition . Break oVirtually all organs and biological systems possibly suffer from this new coronavirus infection by either direct virus-targeted damage or indirect effects. As the pandemic rapidly spread, thyroid dysfunction associated with COVID-19 has been gradually reported . HoweverIn the first and early part of the second trimester, fetuses entirely rely on maternal supply of TH . While f22.1Assessment of thyroid function for COVID-19 is not recommended by the World Health Organization clinical management guidelines . So far,On the other hand, a study indicated that ACE2 expression in the thyroid gland was among the top 10 in all body tissues . More st2.2As we all know, SARS-CoV-2 infection appears to induce an acute inflammatory status combined with a mixture storm of cytokines and chemokines, including IL-1α/β, IL-2, IL-6, IL-8, IL-17, IL-10, TNF-α, interferon (IFN)-γ, macrophage colony-stimulating factor (M-CSF), and granulocyte colony-stimulating factor (G-CSF) . Those c2.2.1NTIS is characterized by reduced circulating levels of T3, increased levels of rT3, normal or low serum total concentrations of T4, increased or decreased free T4 (FT4) level, unaltered or inappropriately low serum thyroid-stimulating hormone (TSH), indicating impaired TH conversion, and profoundly altered negative feedback in the pituitary and hypothalamus . It occuNotably, 2.2.2Afterward, the experimental induction of NTIS in rodents resulted in synchronous changes in hypothalamic, pituitary, and peripheral TH metabolism , arguingIL-1α and IL-1β inhibit the TSH-induced thyroglobulin (Tg) mRNA expression and Tg release in human cultured thyrocytes . On the It is demonstrated that IL-6 was found to be negatively correlated with serum T3 concentrations in hospitalized patients . Such maIFN-γ, as one of the cytokines mainly involved in antiviral and antibacterial responses, poses multiple threats on human thyrocytes. It inhibits TSH-induced TH and Tg secretion  and Tg m2.2.3Apart from the systemic deficiency of THs as a result of central depression and decreased TH synthesis, local regulation and conversion of THs also encounter alteration in the context of inflammation.Cellular entry of TH is necessary before intracellular conversion of TH by deiodinases and binding to the nuclear thyroid hormone receptor (TR) can take place. TH transporters, monocarboxylate transporter-10 (MCT10), and organic anion transporting polypeptide-4C1 have been presented to be altered in illness or acute inflammation, but the underlying function is still elusive . WhetherAnother pathogenesis for inflammation causing TH derangement is through influence on deiodinases, leading to TH production and degradation imbalance. There are three types of deiodinases, D1 and D2 are T3-producing enzymes while D3 inactivates T4 and T3. The expression and activity levels of all three deiodinases are likely to be altered during illness or inflammation, in divergent ways, depending on their locations in specific tissues or organs and the severity of illness . NotablyTo sum up, inflammation, together with cytokines triggered by SARS-CoV-2 infection, can negatively impact the maternal TH in the manner of disrupting central feedback loop, suppressing TH synthesis and inhibiting TH transport and conversion, ultimately leading to decreased secretion of T4 and T3.33.1Via this receptor, T4 and T3 can activate both the extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol 3-kinase (PI3K) pathways , matrix metalloproteinases 3 (MMP3), and fetal fibronectin , which a3.2.3L-thyroxine induces the gene expression of placental growth factor (PGF) and vascular endothelial growth factor (VEGF) , which, 3.2.4As mentioned above, a successful pregnancy requires comparatively suppressive modulation of the immune system to ensure the coexistence of mother and fetus. And maternal immune status fluctuates as the gestation advances. Decidua is responsible for releasing inflammatory mediators during pregnancy , and abn4TH enters and exit the placental cells through six TH membrane transporters: large amino acid transporter-1 (LAT1), LAT2, organic anion transporting polypeptide-1A2 (OATP1A2), OATP4A1, monocarboxylate transporter-8 (MCT8), and MCT10 . As mentWithin the placenta, TH is mostly acted on by D2 and D3. As clarified above, during inflammation, cytokines are able to suppress D2 activation, thus inhibiting T3 generation. That means inflammation caused by SARS-CoV-2 can become a risk factor for pregnancy, leading to lack of T3 in placenta and fetus. Furthermore, the main regulator of TH homeostasis in the placenta is D3 , which p5Significant physiological changes in the THs of pregnant women occur during pregnancy . Around Vaccines are currently one of the most promising preventive measures against COVID-19 . Vaccina6We provide a plausible overview relating to COVID-19, TH, and pregnancy, elucidating the possible mechanism that COVID-19 would give rise to adverse pregnancy outcomes. SARS-CoV-2 causes an overactivation of the immune response and culminates in a “cytokine storm,” which, on one hand, leads to a disturbance in maternal TH, and on the other hand, causes dysfunction of TH transporter and deiodinase in placenta. The overall TH disturbance in pregnant women eventually induces placenta dysfunction, including disturbance of EVT invasiveness and angiogenesis, and alteration of immune status. Therefore, physicians should raise alertness on TH abnormality when treating pregnant COVID-19 patients.Conceptualization: PH and SC. Resources: QS, PC, MW, and BW. Data curation: PC, MW, and BW. Writing: QS, MW, and PH. Supervision: PH and SC. Funding acquisition: PH and SC. TH’s contribution to this article is in the manuscript writing. All authors contributed to the article and approved the submitted version.This work was supported by grants from the National Natural Science Foundation of China , the Key Research and Development Programme of Hunan Province of China (2019SK2031), the Natural Science Foundation of Hunan Province (2020JJ5904), and China Postdoctoral Science Foundation .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Bardet–Biedl Syndrome is a rare non-motile primary ciliopathy with multisystem involvement and autosomal recessive inheritance. The clinical picture is extremely polymorphic. The main clinical features are retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, hypogonadism and genitourinary abnormalities, and kidney disease. It is caused by various types of mutations, mainly in genes encoding BBSome proteins, chaperonins, and IFT complex. Variable expressivity and pleiotropy are correlated with the existence of multiple genes and variants modifiers. This review is focused on the phenomena of heterogeneity  in Bardet–Biedl Syndrome, its mechanisms, and importance in early diagnosis and proper management. Ciliopathies are diseases caused by the dysfunction of motile and non-motile primary cilium . PrimaryCilia are microtubule-based organelles. They are anchored to the cytoskeleton and protrude at the cell surface . They haCiliopathies are characterized by a high clinical and molecular heterogeneity and a large clinical overlap between entities . The cliBardet–Biedl syndrome  is a rare autosomal recessive multisystem non-motile ciliopathy primarily characterized by heterogeneous clinical manifestations. The prevalence of BBS is high in inbred/consanguineous populations. In the general population, BBS has a prevalence of 0.7/100,000 and a prevalence at birth of 0.5/100,000 . HoweverBBS is characterized by a high genetic heterogeneity , variable expressivity and pleiotropy. There are 24 loci involved and the mutational profile is diverse. There are modifying variants and numerous interactions between the BBS proteins (interactions disease protein—disease protein) or between the BBS protein and another protein (interactions disease protein—non disease protein). These explain the extremely polymorphic clinical picture that includes both major and minor features .This pleiotropic disorder has a constellation of features, which are divided into major features  and minor features . Early onset childhood obesity and common adult morbid obesity was associated with BBS4 (rs7178130) and BBS6 (rs6108572 and rs221667) changes [Obesity is a frequent feature (89%), it affects the thorax and abdomen and has an early onset (from the age of 2–3 years) . Obesity changes .BBS17, which is a negative regulator for the ciliary trafficking mediated by BBSome and the Shh (Sonic hedgehog) signaling, was associated with mesoaxial polydactyly [Postaxial polydactyly is frequently reported in 79% of patients, with polydactyly of toes being more common than the polydactyly of fingers . The genydactyly .Cognitive impairment is present in 66% cases with BBS . PatientHypogonadism and genitourinary malformations have an incidence of 59% . HypogonKidney disease is present in 52% of BBS patients . The speMinor features are represented by various anomalies in different systems and organs: the nervous system, sensorial changes, cardiovascular system, gastrointestinal changes, different endocrine glands, and cutaneous or musculoskeletal changes .Neurodevelopmental abnormalities observed in patients with BBS include ataxia and poor coordination with mild hypertonia of all four extremities, seizures, speech abnormalities, behavioral, and psychiatric abnormalities .The dysmorphism in BBS is not specific, and the most frequent reported features are: a narrow forehead, brachycephaly or macrocephaly, large ears, short, narrow, and downslanted palpebral fissures, deep and widely set eyes, malar flattening, depressed nasal bridge, long and smooth philtrum, retrognathia .Anosmia/hyposmia are related to defects in olfactory cilia or the olfactory bulb . Oral/deCardiovascular anomalies are relatively frequent  and are represented by atrioventricular septal defects, bilateral persistent superior vena cava, interrupted inferior vena cava, and hemiazygos vein continuation. Moreover, there are reports of laterality defects, such as situs inversus totalis, midline abdominal organs, asplenia, or polysplenia .Gastrointestinal abnormalities can range from Hirschsprung disease, anatomic anomalies of the gastrointestinal tract  to inflammatory bowel disease, celiac disease, and liver disease .Endocrine/metabolic abnormalities include metabolic syndrome (54.3%), obesity, hyperlipidemia , insulin resistance, and elevated fasting plasma glucose with or without type 2 diabetes mellitus (15.8%), polycystic ovarian syndrome (14.7%), and subclinical hypothyroidism (19.4%). Subclinical hypothyroidism is a mild form of hypothyroidism characterized by peripheral thyroid hormone levels within normal reference laboratory range but serum thyroid-stimulating hormone (TSH) levels are mildly elevated. Hashimoto’s thyroiditis is the most common form of subclinical hypothyroidism and is more prevalent in BBS patients compared to the general population ,32,33.In addition other features were reported: cutaneous dermatoses , subclinical sensorineural hearing loss, musculoskeletal abnormalities  ,32.The clinical diagnosis of BBS is made in the presence of either four major features or three major features and two minor features . To deteIn There are three categories of gene effects: primary effect (at the molecular level—protein), secondary effect (at the cellular level), and multiple tertiary effects (pleiotropic)—at the phenotypic level of organ/organism (signs and symptoms) . Genes aLZTFL1 gene is mainly expressed in lymphoid tissue while the BBIP1 gene is specific to testis and the NPHP1 gene has an expression in skeletal muscle , rod photoreceptor cells , cone photoreceptor cells , spermatocytes , early spermatids , late spermatids (BBIP1), alveolar cells type 1 (WDPCP), alveolar cells type 2 (WDPCP), club cells (WDPCP) [The majority of genes involved in BBS presents a low tissue specificity. However, the l muscle . For sin (WDPCP) .BBS10), higher prevalence of primary diagnostic signs and some borderline signs with other ciliopathies, such as McKusick–Kaufman syndrome (MKKS) and Alström syndrome [Some BBS forms are considered chaperonopathies because three genes involved in BBS encode chaperon-like proteins. The three chaperonins-like proteins—MKKS, BBS12, BBS7—are involved in assembling BBSome, a multistep process ,39,40. Csyndrome . This insyndrome .MKKS are found in 3–5% of families in which there are disease-causing mutations (Bardet–Biedl Syndrome or McKusick-Kaufman syndrome) [BBS10 represent about 20% of all cases of BBS with certain ethnic variations: 43% in a Danish group and 8.3% in a Spanish cohort [Chaperonin-like BBS genes are characterized by a small number of coding exons (one to four) and, thus, a mutational screening of these genes be applied before a more complex analysis . Mutatioyndrome) ,43. Mutah cohort ,45.®) 2020.1 database (accessed in April 2021), 647 pathogenic variants are described. Mutational heterogeneity is important because testing strategies are consistent with mutation types. According to the Human Gene Mutation Database Professional  and BBS10 (identified in 20% of patients with BBS) [BBS1 and C91fsX95 in BBS10 [MKKS is required for BBSome assembly, and TTC8 is required for ciliary trafficking [BBS1 and BBS10 genes are the most common mutated genes in Europe and North America [BBSome is a multisubunit complex with eight proteins coding by the genes nd BBIP1 ,35. The in BBS10 . MKKS isfficking ,51,52. Mfficking . The BBS America .TMEM67, MKS1, MKKS, CCDC28B-coiled-coil domain containing 28B, C8orf37, BBS1). Modifying genes influence expressivity or pleiotropy [MKS1 gene: MKS1:c.1112_1114del (p.Phe371del), MKS1:c.1476T>G (p.Cys492Trp), MKS1:c.248A>G (p.Asp83Gly), MKS1:c.368G>A (p.Arg123Gln), MKS1:p.Ile450Thr in association with mutations in BBS1 and BBS10 genes [The phenotype of BBS can be changed by modifier genes. The PhenoModifier database contains 12 modifying variants described in 6 genes , HSCB (Iron-sulfur cluster co-chaperone protein HscB) , ACY1 (Aminoacylase-1) , EXOC7 (Exocyst complex component 7) , RAB3IP (Rab-3A-interacting protein) , FHOD1 (FH1/FH2 domain-containing protein 1) , PCM1  in interaction with genes products BBS1, BBS2, BBS4, BBIP1), CCDC28B (Coiled-coil domain-containing protein 28B)  [In an analysis conducted by Keith et al. in 2014, the authors showed the existence of multiple interconnectivity networks . These r1, BBS5) .Keith postulated that there is an interconnectivity between proteins in the case of locus heterogeneity. Thus, the BBS proteins in the vicinity of proteins involved in locus heterogeneity could be involved in the pathogenesis of similar diseases or may themselves be causes of disease .The cellular signaling pathways involved in BBS are: hedgehog, Wnt (wingless-related integration site), GPCR (G protein-coupled receptors), mTOR  ,6.The primary cilium is involved in Hedgehog signaling pathway and can act as both positive and negative regulator of this pathway . DefectsSeveral BBS-associated proteins intervene in the Wnt signaling pathway and play a role in regulating Wnt signaling by degrading Wnt effectors ,63. DishG-protein coupled receptors (GPCRs) are important for cilia structures and function. Neuronal cilia integrity is required for brain development and the adequate interaction in the adult brain . NeuronaMammalian target of rapamycin is also involved in BBS. CCDC28B interacts with the SN1 subunit of the mammalian target of rapamycin complex 2 (mTORC2). In this way it regulates the length of the cilia by affecting its assembly/stability [The eight subunits of BBSome are assembled in two parts: head and body. The head is formed by BBS2 which interacts with BBS7. The body is formed by the others proteins . The BBIP1 is the central part of the BBSome core ,69. BBIPARL6, TRIM32, WDPCP) six epistatic interaction effects were identified: BBS10-BBS5; BBS10-BBS12; BBS10-BBS1; BBS10-MKKS; BBS10-BBS4; BBS12-MKKS. Moreover, 12 additive interaction effects were found between the main complexes  and 1 between proteins of transition zone and others gene BBS1-BBS5, BBS1-BBS2, BBS1-NPHP1, BBS10-NPHP1, BBS2-NPHP1, BBS9-NPHP1, BBS7-NPHP1, BBS2-BBS4, BBS2-MKKS, BBS4-MKKS, BBS4-BBS9, BBS4-BBS7. On the other hand, no interaction effect was demonstrated in the following genes (nor additive or epistatic effect): TRIM32, WDPCP, CEP290, MKS1 [In a study that analyzed the effects of the proteome of the three modules  and three more genes that are not yet included in a module (90, MKS1 .Bardet–Biedl Syndrome is a rare ciliopathy characterized by a high degree of clinical heterogeneity. The mechanisms of heterogeneity are complex and explained by multiple loci, ubiquitous expression of genes, and multiple interaction of proteins coding by genes implicated in BBS. However, the deciphering of the entire mechanism implied in Bardet–Biedl Syndrome is a complex process that will require further research in the future.


The reduction-oxidation (redox) system consists of the coupling and coordination of various electron gradients that are generated thanks to serial reduction-oxidation enzymatic reactions. These reactions happen in every cell and produce radical oxidants that can be mainly classified into reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS modulate cell-signaling pathways and cellular processes fundamental to normal cell function. However, overproduction of oxidative species can lead to oxidative stress (OS) that is pathological. Oxidative stress is a main contributor to diabetic kidney disease (DKD) onset. In the kidney, the proximal tubular cells require a high energy supply to reabsorb proteins, metabolites, ions, and water. In a diabetic milieu, glucose-induced toxicity promotes oxidative stress and mitochondrial dysfunction, impairing tubular function. Increased glucose level in urine and ROS enhance the activity of sodium/glucose co-transporter type 2 (SGLT2), which in turn exacerbates OS. SGLT2 inhibitors have demonstrated clear cardiovascular benefits in DKD which may be in part ascribed to the generation of a beneficial equilibrium between oxidant and antioxidant mechanisms. In general terms, the reduction-oxidation (redox) system consists of the coupling and coordination of various electron gradients that are generated by serial reduction-oxidation enzymatic reactions. These reduction-oxidation reactions happen in fundamental biological processes in every cell  and lead2 consumed in the mitochondria is incompletely metabolized [The redox system is especially important during energy metabolism to generate adenosine triphosphate (ATP). The most important source of energy is glucose which is transformed into pyruvate via glycolysis. Pyruvate enters the tricarboxylic acid or Krebs cycle and reduces nicotinamide adenine dinucleotide (NAD) to NADH. Further, fatty acids (FA) can undergo β-oxidation to generate acetyl-CoA which then enters the Krebs cycle ,6. The Nabolized . Here, tabolized . Additioabolized . In vitrabolized ,15. The abolized ,17 , dinitrogen trioxide (N2O3), dinitrogen tetraoxide (N2O4), nitrogen dioxide (NO2), or S-nitrosothiols (RSNO) [2−. O2− is highly reactive and may combine with NO, leading to the formation of peroxynitrite (ONOO−). ONOO− is a powerful RNS that can irreversibly inhibit electron transport, which is pathological [Regarding RNS, these comprise nitric oxide (NO) and its derivatives, such as peroxynitrite (ONOOs (RSNO) ,19 (Tabls (RSNO) . The enzs (RSNO) . In mitoological ,22,23,242O2 into water and oxygen, and glutathione peroxidases reduce H2O2 to water [Both ROS and RNS are necessary for normal cell function as they modulate cell-signaling pathways and cellular processes. However, overproduction of any of them is pathological since it can damage macromolecules like proteins, lipids, or DNA . DNA damto water . Glutathto water . Furtherto water ,39.In this review, we will focus on oxidative stress-mediated mechanisms of kidney tubular dysfunction. Further, the contribution of the sodium/glucose co-transporter type 2 (SGLT2) in diabetic kidney disease (DKD) onset and the antioxidant potential of the SGLT2 inhibitors will be discussed.The tubular system has a very precise and highly regulated transport capacity between the tubule lumen and the bloodstream. A broad range of tubular transporters contribute to ion, amino acid, glucose, and other solute reabsorption. Therefore, tubular cells require a sufficient energy supply to sustain the high rate of exchange within the two compartments. Tubular cells are the most energy-demanding cells of the body after cardiac cells . Their m2O2) [2O2 mediates several cell functions, but excessive levels can induce inflammation, apoptosis, fibrosis, and cell damage. NOX4 has constitutive activity, hence, the amount of H2O2 depends on the expression level. As a result, it can be damaging or beneficial depending on its abundance at the given time [2O2 generated by NOX4 enhances nuclear factor erythroid 2-related factor 2 (Nrf2) stability, a regulator of antioxidant activity [As mentioned above, mitochondrial metabolism is a source of ROS that directly modulates cell-signaling pathways, protein function through post-translational modifications, and influences cell survival, proliferation, and apoptosis . However2O2) . Aragno 2O2) . Beyond ven time . Normallven time . Upregulven time ,53,54,55ven time ,56,57. Tven time . This coactivity .Excessive ROS production can damage mitochondria . Mitocho+/Glucose, 1:1) and it accounts for 5.7% of total renal Na+ reabsorption in healthy individuals [+/H+ Exchanger-3 (NHE3). Interestingly, NHE3 and SGLT2 have been shown to be interdependent [+ gradient created by the sodium-potassium pump (Na+/K+-ATPase), located in the basolateral membrane of PTC, is harnessed by SGLT2 to transport glucose and sodium across the plasma membrane down-gradient [Albeit glucose consumption is low in the proximal tubule (except for segment S3 ), PTCs aividuals . Althougependent . Therefogradient . At the gradient .+/H+ Exchanger-1 (NHE1) in the heart and vasculature and NHE3—the kidney isoform—are upregulated in heart failure and type 2 diabetes mellitus (T2DM) [+/K+-ATPase activity increases to restore the sodium gradient. As this transporter is ATP-dependent, its overactivation implies an increase in energy demand and oxygen consumption. It is worth mentioning that under normal conditions, 60% of kidney ATP consumption is intended for sodium uptake which is mostly attributed to basal Na+/K+-ATPase activity [SGLT2 plays a crucial role in glucose transport and intrarenal osmolarity. For that reason, the dysfunction of this co-transporter, which happens in diabetes, has a direct effect on intrarenal glucose metabolism and also on the redox environment. In diabetic patients, SGLT2 is overactivated, leading to increased glucose and sodium reabsorption . The dels (T2DM) . Additioactivity . Therefoactivity , which sactivity . Focusinactivity . The autactivity . Mitochoactivity . In addiactivity . Peroxynactivity . NOX4 isactivity . For thiactivity ,79. Induactivity . In addiactivity . The Kreactivity . Accordiactivity . Paradoxactivity . They practivity . In concactivity . Their gactivity . Interesactivity . mtDNA cactivity . In thisactivity  and in hactivity , which cactivity . ROS deractivity   are hypoglycemic drugs that target SGLT2 producing glycosuria. Consequently, SGLT2is decrease blood glucose in an insulin-independent manner, improving insulin resistance in diabetes ,91. To dIn diabetic experimental models, similar results have been found . The admThe beneficial antioxidant effects of SGLT2is observed in DKD can in part be attributed to improvement of glycemia and blood pressure control, as other hypoglycemic drugs also reduce oxidative stress . HoweverIt has also been demonstrated that targeting SGLT2 with canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex I-mediated respiration . In the In conclusion, oxidative stress has an important role in DKD onset. High levels of glucose together with increased ROS production overactivate the SGLT2 transporter in tubular cells, which, in turn, exacerbates oxidative stress. The use of SGLT2is has demonstrated clear cardiovascular benefits which may be in part ascribed by a beneficial balance between oxidant and antioxidant pathways.