{"title":"ATP synthase as a negative regulator versus a functional-structural component of the high conductance state of mitochondrial permeability transition pore","authors":"Salvatore Nesci","doi":"10.1002/jbt.23821","DOIUrl":"10.1002/jbt.23821","url":null,"abstract":"","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lin Wu, Yingying Cheng, Runfeng Wang, Shukai Sun, Bo Ma, Zhiguo Zhang
{"title":"NDRG2 regulates glucose metabolism and ferroptosis of OGD/R-treated astrocytes by the Wnt/β-catenin signaling","authors":"Lin Wu, Yingying Cheng, Runfeng Wang, Shukai Sun, Bo Ma, Zhiguo Zhang","doi":"10.1002/jbt.23827","DOIUrl":"10.1002/jbt.23827","url":null,"abstract":"<p>Ischemic stroke is one main type of cerebrovascular disorders with leading cause of death and disability worldwide. Astrocytes are the only nerve cell type storing glycogen in the brain, which regulate the glucose metabolism and handle the energy supply and survive of neurons. Astrocyte ferroptosis contributes to neuron injury in brain disorders. N-myc downstream-regulated gene 2 (NDRG2) has been implicated in the progression of brain diseases, including ischemic stroke. However, whether NDRG2 could affect the glucose metabolism and ferroptosis of astrocytes during ischemic stroke remains largely unknown. Mouse astrocytes were treated with oxygen-glucose deprivation/reoxygenation (OGD/R) to establish the in vitro model. Glial fibrillary acidic protein, NDRG2, Wnt3a and β-catenin expression levels were detected by immunofluorescence staining and western blot analyses. Glucose metabolism was investigated by glucose uptake, lactate production, nicotinamide adenine dinucleotide phosphate hydrogen/nicotinamide adenine dinucleotide phosphate (NADPH/NADP<sup>+</sup>), ATP and glycolysis enzymes (HK2, PKM2 and lactate dehydrogenase A [LDHA]) levels. Ferroptosis was assessed via reactive oxygen species (ROS), glutathione (GSH), iron and ferroptosis-related markers (GPX4 and PTGS2) contents. Glycolysis enzymes and ferroptosis-related markers levels were measured via western blot. NDRG2 expression was elevated in OGD/R-induced astrocytes. NDRG2 overexpression aggravated OGD/R-induced loss of glucose metabolism through reducing glucose uptake, lactate production, NADPH/NADP<sup>+</sup> and ATP levels. NDRG2 upregulation exacerbated OGD/R-caused reduction of glycolysis enzymes (HK2, PKM2 and LDHA) levels. NDRG2 promoted OGD/R-induced ferroptosis of astrocytes by increasing ROS, iron and PTGS2 levels and decreasing GSH and GPX4 levels. NDRG2 overexpression enhanced OGD/R-induced decrease of Wnt/β-catenin signaling activation by reducing Wnt3a and β-catenin expression. NDRG2 silencing played an opposite effect. Inhibition of Wnt/β-catenin signaling activation by IWR-1 attenuated the influences of NDRG2 knockdown on glucose metabolism, glycolysis enzymes levels and ferroptosis. These findings demonstrated that NDRG2 contributes to OGD/R-induced inhibition of glucose metabolism and promotion of ferroptosis in astrocytes through inhibiting Wnt/β-catenin signaling activation, which might be associated with ischemic stroke progression.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yinying Xu, Yuting Xia, Jie Zhao, Hao Yu, Yanli Zhang, Dagan Mao
{"title":"p38MAPK/HSPB1 is involved in the regulatory effects of selenomethionine on the apoptosis, viability and testosterone secretion of sheep Leydig cells exposed to heat","authors":"Yinying Xu, Yuting Xia, Jie Zhao, Hao Yu, Yanli Zhang, Dagan Mao","doi":"10.1002/jbt.23826","DOIUrl":"10.1002/jbt.23826","url":null,"abstract":"<p>Testosterone derived from testicular Leydig cells (LCs) is important for male sheep, and the testis is susceptible to external temperature. The present study aimed to explore the alleviating effect of selenomethionine (Se-Met) on heat-induced injury in Hu sheep LCs. Isolated LCs were exposed to heat (41.5°C, heat exposure, HE) or not (37°C, nonheat exposure, NE), and cells in NE and HE were treated with 0 (C) or 8 μmol/L (S) Se-Met for 6 h. Cell viability, testosterone level, and the expression of <i>GPX1</i>, <i>HSD3B</i>, apoptosis-related genes and p38 mitogen-activated protein kinase (p38MAPK)/heat shock protein beta-1 (HSPB1) pathway were examined. The results showed that Se-Met increased <i>GPX1</i> expression (NE-S vs. NE-C: 2.28-fold; HE-S vs. HE-C: 2.36-fold, <i>p</i> < 0.05) and alleviated heat-induced decrease in cell viability (HE-S vs. HE-C: 1.41-fold; HE-C vs. NE-C: 0.61-fold, <i>p</i> < 0.01), although the viability was still lower than that in the NE-C cells (HE-S vs. NE-C: 0.85-fold) and Se-Met-treated cells (HE-S vs. NE-S: 0.81-fold). Se-Met relieved heat-induced decrease in testosterone level (HE-S vs. HE-C: 1.84-fold, <i>p</i> < 0.05) and <i>HSD3B</i> expression (HE-S vs. HE-C: 1.67-fold, <i>p</i> < 0.05). Se-Met alleviated heat-induced increase in Bcl2-associated protein X (BAX) expression (HE-C vs. HE-S: 2.4-fold, <i>p</i> < 0.05), and decrease in B-cell lymphoma-2 (BCL2) expression (HE-S vs. HE-C: 2.62-fold, <i>p</i> < 0.05), resulting in increased <i>BCL2</i>/<i>BAX</i> ratio in the HE-S cells (HE-S vs. HE-C: 5.24-fold, <i>p</i> < 0.05). Furthermore, Se-Met alleviated heat-induced activation of p-p38MAPK/p38MAPK (HE-C vs. HE-S: 1.79-fold, <i>p</i> < 0.05) and p-HSPB1/HSPB1 (HE-C vs. HE-S: 2.72-fold, <i>p</i> < 0.05). In conclusion, p38MAPK/HSPB1 might be involved in Se-Met-mediated alleviation of heat-induced cell apoptosis, cell viability and testosterone secretion impairments in sheep LCs.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Why thiamine alone is inadequate and how essential fatty acids can augment recovery from sepsis?","authors":"Undurti N. Das","doi":"10.1002/jbt.23820","DOIUrl":"10.1002/jbt.23820","url":null,"abstract":"","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"KLF4-induced upregulation of SOCS1 ameliorates myocardial ischemia/reperfusion injury by attenuating AC16 cardiomyocyte damage and enhancing M2 macrophage polarization","authors":"Jiming Zhou, Wei Luo, Zhong Xie, Chunchen Xia, Junbi Zhao","doi":"10.1002/jbt.23816","DOIUrl":"10.1002/jbt.23816","url":null,"abstract":"<p>Reperfusion strategies, the standard therapy for acute myocardial infarction (AMI), may result in ischemia/reperfusion (I/R) damage. Suppressor of cytokine signaling1 (SOCS1) exerts a cardioprotective function in myocardial I/R damage. Here, we investigated epigenetic modulators that deregulate SOCS1 in cardiomyocytes under hypoxia/reoxygenation (H/R) conditions. Human AC16 cardiomyocytes were exposed to H/R conditions to generate a cell model of myocardial I/R damage. Expression of mRNA and protein was detected by quantitative PCR and western blot analysis, respectively. Cell migratory and invasive abilities were evaluated by transwell assay. Cell apoptosis and M2 macrophage polarization were assessed by flow cytometry. TNF-α, IL-1β, and IL-6 levels were examined by ELISA. The interaction of KLF4 with SOCS1 was verified by chromatin immunoprecipitation and luciferase assays. SOCS1 and transcription factor KLF4 protein levels were underexpressed by 75% and 57%, respectively, in H/R-exposed AC16 cardiomyocytes versus control cells. Under H/R conditions, forced SOCS1 expression (2.7 times) induced cell migration (2.2 times) and invasion (1.9 times) and hindered cell apoptosis (by 45%) of AC16 cardiomyocytes as well as enhanced M2 macrophage polarization (4.6 times). Mechanistically, KLF4 upregulation promoted SOCS1 transcription (2.6 times) and expression (2.6 times) by binding to the SOCS1 promoter. Decrease of SOCS1 (by 51%) reversed the effects of KLF4 upregulation on cardiomyocyte migration, invasion and apoptosis, and M2 macrophage polarization under H/R conditions. Additionally, SOCS1 and KLF4 were underexpressed by 56% and 63%, respectively, in AMI serum. Our study indicates that KLF4-induced upregulation of SOCS1 can attenuate H/R-triggered apoptosis of AC16 cardiomyocytes and enhance M2 macrophage polarization.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Anti-inflammatory, antiosteoporotic, and bone protective effect of hydroxysafflor yellow A against glucocorticoid-induced osteoporosis in rats","authors":"Jianbo Kuai, Jiachun Zheng, Ankit Kumar, Hongwei Gao","doi":"10.1002/jbt.23797","DOIUrl":"10.1002/jbt.23797","url":null,"abstract":"<p>Osteoporosis is a common condition worldwide, affecting millions of people. Women are more commonly affected than men, and the risk increases with age. Inflammatory reaction plays a crucial role in the expansion of osteoporosis. Osteoporosis is characterized by a gradual decline in bone density and bone tissue quality, which increases fragility and raises the risk of fractures. We scrutinized the anti-osteoporosis effect of hydroxysafflor yellow A (HYA) against glucocorticoid-induced osteoporosis (GIOP) in rats. In-silico study was carried out on EGFR receptor (PDBID: 1m17), Estrogen Alpha (PDB id: 2IOG), MTOR (PDB id: 4FA6), RANKL (PDB id: 1S55), and VEGFR2 (PDB id: 1YWN) protein. For this investigation, Sprague-Dawley (SD) rats were used, and they received an oral dose of HYA (5, 10, and 20 mg/kg, b.w.) along with a subcutaneous injection of dexamethasone (0.1 mg/kg/day) to induce osteoporosis. The biomechanical, bone parameters, antioxidant, cytokines, inflammatory, nutrients, hormones, and urine parameters were estimated. HYA treatment significantly suppressed the body weight and altered the organ weight. HYA treatment remarkably suppressed the level of alkaline phosphatase, acid phosphatase, and improved the level of bone mineral density (total, proximal, mild, and dis). HYA treatment restored the level of calcium (Ca), phosphorus (P), estradiol (E<sub>2</sub>), and parathyroid hormone near to the normal level. HYA treatment remarkably altered the level of biomechanical parameters, antioxidant, cytokines, urine, and inflammatory parameters. HYA treatment altered the level of osteoprotegerin (OPG), receptor activator of nuclear factor kappa beta (RANKL) and RANKL/OPG ratio. The result clearly showed the anti-osteoporosis effect of HYA against GIOP-induced osteoporosis in rats via alteration of antioxidant, cytokines, inflammatory, and bone protective parameters.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuting Pang, Boji Xie, Bingmei Feng, Guiling Xu, Qinglin Ye, Xuesong Chen, Liangping Ruan, Hong Chen, Shang-Ling Pan, Chao Xue, Wei Li
{"title":"miR-542-5p targets GREM1 to affect the progression of renal fibrosis","authors":"Shuting Pang, Boji Xie, Bingmei Feng, Guiling Xu, Qinglin Ye, Xuesong Chen, Liangping Ruan, Hong Chen, Shang-Ling Pan, Chao Xue, Wei Li","doi":"10.1002/jbt.23818","DOIUrl":"10.1002/jbt.23818","url":null,"abstract":"<p>Renal fibrosis (RF) is a typical pathological presentation of end-stage chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD). However, the precise regulatory mechanisms governing this re-expression process remain unclear. Differentially expressed microRNAs (miRNAs) associated with RF were screened by microarray analysis using the Gene Expression Omnibus (GEO) database. The miRNAs upstream of the genes in question were predicted using the miRWalk database. The miRNAs involved in the two GEO data sets were intersected to identify key miRNAs; their regulatory pathways were investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Subsequently, the effects and the underlying mechanisms of target miRNA on RF were examined in a unilateral ureteral obstruction (UUO)-induced mice renal fibrotic model and a transforming growth factor-β1 (TGF-β1)-induced tubular epithelium (HK-2) fibrotic cell model. In total, 109 and 32 differentially expressed miRNAs were identified in the GSE133530 and GSE80247 data sets, respectively. <i>GREM1</i> was identified as a hub gene, where its 2196 upstream miRNAs were predicted; miR-574-5p was found to be downregulated and closely related to fibrosis after data set intersection and enrichment analyses, thus was selected for further investigation. A differential expression heatmap (GSE162794) showed that miR-542-5p was downregulated. The expression of <i>GREM1</i> mRNA was upregulated, whereas that of miR-542-5p was downregulated in UUO mice and fibrotic HK-2 cells as compared with the relevant controls. The binding site of miR-542-5p was predicted at the 3'UTR region of <i>GREM1</i> and was confirmed by subsequent dual luciferase reporter gene assay. Western blot analysis showed that Gremlin-1 and Fibronectin were significantly upregulated after induction of TGF-β1; when miR-542-5p was overexpressed or <i>GREM1</i> mRNA was interfered, the upregulations of Gremlin-1 and Fibronectin were significantly reduced. Our research demonstrates that miR-542-5p plays a critical role in the progression of RF, and thus may be a promising therapeutic target for CKD and ADPKD.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbt.23818","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Exploring the anticancer potential of new 3-cyanopyridine derivatives bearing N-acylhydrazone motif: Synthesis, DFT calculations, cytotoxic evaluation, molecular modeling, and antioxidant properties","authors":"Ibtissem Kadi, Güldeniz Şekerci, Houssem Boulebd, Zineddine Zebbiche, Suat Tekin, Khedidja Benarous, Talia Serseg, Fatümetüzzehra Küçükbay, Hasan Küçükbay, Taoues Boumoud","doi":"10.1002/jbt.23819","DOIUrl":"10.1002/jbt.23819","url":null,"abstract":"<p>3-Cyanopyridine derivatives are known for exhibiting excellent anticancer activity due to their strong capability to inhibit various biological targets, including Pim-1 kinase, survivin, and tubulin polymerization. On the other hand, <i>N</i>-acylhydrazones (NAH) are known to be a very versatile motif in medicinal chemistry and drug design. Based on these data, we report in this paper, the synthesis of novel 3-cyanopyridines incorporating <i>N</i>-acyl hydrazine scaffold, the evaluation of their cytotoxicity on the breast (MCF-7) and ovarian (A-2780) cancer cell lines and their antioxidant properties. Excluding <b>4a</b> and <b>4d</b>, all tested molecules exhibited high cytotoxicity against A-2780, with IC<sub>50</sub> values ranging from 1.14 to 1.76 µM. Conversely, only four molecules <b>3d</b>, <b>4b</b>, <b>4c</b>, and <b>4d</b> demonstrated cytotoxicity against MCF-7, with IC<sub>50</sub> values ranging from 1.14 to 3.38 µM. On the other hand, all the tested molecules exhibited a moderate antioxidant capacity in both the DPPH and metal chelation assays. Docking and molecular dynamics studies revealed that <b>2d</b>, <b>3d</b>, and <b>4d</b> are potential inhibitors of tubulin and the œstrogen receptor, which may explain their high cytotoxicity. These results are promising to study these newly synthesized 3-cyanopyridine-N-acylhydrazones in depth for use as potential anticancer candidates.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Attenuation of chromium (VI) and arsenic (III)-induced oxidative stress and hepatic apoptosis by phloretin, biochanin-A, and coenzyme Q10 via activation of SIRT1/Nrf2/HO-1/NQO1 signaling","authors":"Swapnil Tripathi, Dharati Parmar, Samir Raval, Rajeev Mishra, Gyanendra Singh","doi":"10.1002/jbt.23817","DOIUrl":"10.1002/jbt.23817","url":null,"abstract":"<p>Heavy metal contamination is an alarming concern on a global scale, as drinking tainted water significantly increases human susceptibility to heavy metals. In a realistic scenario, humans are often exposed to a combination of harmful chemicals rather than a single toxicant. Phloretin (PHL), biochanin-A (BCA), and coenzyme Q10 (CoQ10) are bioactive compounds owning plentiful pharmacological properties. Henceforth, the current research explored the putative energizing effects of selected nutraceuticals in combined chromium (Cr) and arsenic (As) intoxicated <i>Swiss</i> albino mice. Potassium dichromate (75 ppm) and sodium meta-arsenite (100 ppm) were given in the drinking water to induce hepatotoxicity, conjugated with PHL and BCA (50 mg/kg each), and CoQ10 (10 mg/kg) intraperitoneally for 2 weeks. After the statistical evaluation, it was observed that the hepato-somatic index, metal load, and antioxidant activity (lipid peroxidation and protein carbonyl content) increased along with the concomitant decrease in the antioxidants (catalase, glutathione-S-transferase, superoxide dismutase, reduced glutathione, and total thiol) in the Cr and As intoxicated mice. Additionally, light microscopy observations, DNA breakages, decreased silent information regulator 1 (SIRT1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) gene expressions, together with stimulated apoptotic cell death manifested by the increased expressions of caspase 8 and caspase 3, thus, proved consistency with the aforementioned outcomes. Importantly, the treatment with nutraceuticals not only restored the antioxidant activity but also favorably altered the expressions of SIRT1, Nrf2, HO-1, and NQO1 signaling and apoptosis markers. These findings highlight the crucial role of the PHL, BCA, and CoQ10 combination in reducing Cr and As-induced hepatotoxicity in mice. By averting the triggered apoptosis in conjunction with oxidative stress, this combination increases the SIRT1, Nrf2, HO-1, and NQO1 signaling, thereby reassuringly maintaining the cellular equilibrium.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sherien M. El-Daly, Shaimaa A. Gouhar, Sahar S. Abdelrahman
{"title":"Inflammation alters the expression pattern of drug transporters during Caco-2 cell stimulation and azoxymethane-induced colon tumorigenesis","authors":"Sherien M. El-Daly, Shaimaa A. Gouhar, Sahar S. Abdelrahman","doi":"10.1002/jbt.23815","DOIUrl":"10.1002/jbt.23815","url":null,"abstract":"<p>Drug transporters play a pivotal role in modulating drug disposition and are subject to alterations under inflammatory conditions. This study aimed to elucidate the intricate expression patterns of drug transporters during both acute and chronic inflammation, which are closely linked to malignant transformation. To investigate acute inflammation, we employed an in vitro model by subjecting Caco-2 cells to various inflammatory stimuli (IL-1β, TNF-α, or LPS) individually or in combination. The successful induction of inflammation was confirmed by robust increases in IL-6 and NO production. Notably, inflamed Caco-2 cells exhibited significantly diminished levels of ABCB1 and ABCG2, while the expression of ABCC2 was upregulated. For chronic inflammation induction in vivo, we employed the well-established AOM/DSS mouse model known for its association with colitis-driven tumorigenesis. Persistent inflammation was effectively monitored throughout the experiment via elevated IL-6 and NO levels. The sequential stages of tumorigenesis were confirmed through Ki-67 immunohistochemistry. Intriguingly, we observed gradual alterations in the expression patterns of the studied drug transporters during stepwise induction, with ABCB1, ABCG2, and ABCC1 showing downregulation and ABCC2 exhibiting upregulation. Immunohistochemistry further revealed dynamic changes in the expression of ABCB1 and ABCC2 during the induction cycles, closely paralleling the gradual increase in Ki-67 expression observed during the development of precancerous lesions. Collectively, our findings underscore the significant impact of inflammation on drug transporter expression, potentially influencing the process of malignant transformation of the colon.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}