Pub Date : 2024-07-01Epub Date: 2024-02-29DOI: 10.1080/15376516.2024.2322675
Andreas F Lehner, Sharmie D Johnson, Levent Dirikolu, Margaret Johnson, John P Buchweitz
Invasive fungal aspergillosis is a leading cause of morbidity and mortality in many species including avian species such as common ravens (Corvus corax). Methods were developed for mass spectral determination of voriconazole in raven plasma as a means of determining pharmacokinetics of this antifungal agent. Without further development, GC/MS/MS (gas chromatography-tandem quadrupole mass spectrometry) proved to be inferior to LC/MS/MS (liquid chromatography-tandem quadrupole mass spectrometry) for measurement of voriconazole levels in treated raven plasma owing to numerous heat-induced breakdown products despite protection of voriconazole functional groups with trimethylsilyl moieties. LC/MS/MS measurement revealed in multi-dosing experiments that the ravens were capable of rapid or ultrarapid metabolism of voriconazole. This accounted for the animals' inability to raise the drug into the therapeutic range regardless of dosing regimen unless cytochrome P450 (CYP) inhibitors were included. Strategic selection of CYP inhibitors showed that of four selected compounds including cimetidine, enrofloxacin and omeprazole, only ciprofloxacin (Cipro) was able to maintain voriconazole levels in the therapeutic range until the end of the dosing period. The optimal method of administration involved maintenance doses of voriconazole at 6 mg/kg and ciprofloxacin at 20 mg/kg. Higher doses of voriconazole such as 18 mg/kg were also tenable without apparent induction of toxicity. Although most species employ CYP2C19 to metabolize voriconazole, it was necessary to speculate that voriconazole might be subject to metabolism by CYP1A2 in the ravens to explain the utility of ciprofloxacin, a previously unknown enzymatic route. Finally, despite its widespread catalog of CYP inhibitions including CYP1A2 and CYP2C19, cimetidine may be inadequate at enhancing voriconazole levels owing to its known effects on raising gastric pH, a result that may limit voriconazole solubility.
{"title":"Mass spectrometric methods for evaluation of voriconazole avian pharmacokinetics and the inhibition of its cytochrome P450-induced metabolism.","authors":"Andreas F Lehner, Sharmie D Johnson, Levent Dirikolu, Margaret Johnson, John P Buchweitz","doi":"10.1080/15376516.2024.2322675","DOIUrl":"10.1080/15376516.2024.2322675","url":null,"abstract":"<p><p>Invasive fungal aspergillosis is a leading cause of morbidity and mortality in many species including avian species such as common ravens (<i>Corvus corax</i>). Methods were developed for mass spectral determination of voriconazole in raven plasma as a means of determining pharmacokinetics of this antifungal agent. Without further development, GC/MS/MS (gas chromatography-tandem quadrupole mass spectrometry) proved to be inferior to LC/MS/MS (liquid chromatography-tandem quadrupole mass spectrometry) for measurement of voriconazole levels in treated raven plasma owing to numerous heat-induced breakdown products despite protection of voriconazole functional groups with trimethylsilyl moieties. LC/MS/MS measurement revealed in multi-dosing experiments that the ravens were capable of rapid or ultrarapid metabolism of voriconazole. This accounted for the animals' inability to raise the drug into the therapeutic range regardless of dosing regimen unless cytochrome P450 (CYP) inhibitors were included. Strategic selection of CYP inhibitors showed that of four selected compounds including cimetidine, enrofloxacin and omeprazole, only ciprofloxacin (Cipro) was able to maintain voriconazole levels in the therapeutic range until the end of the dosing period. The optimal method of administration involved maintenance doses of voriconazole at 6 mg/kg and ciprofloxacin at 20 mg/kg. Higher doses of voriconazole such as 18 mg/kg were also tenable without apparent induction of toxicity. Although most species employ CYP2C19 to metabolize voriconazole, it was necessary to speculate that voriconazole might be subject to metabolism by CYP1A2 in the ravens to explain the utility of ciprofloxacin, a previously unknown enzymatic route. Finally, despite its widespread catalog of CYP inhibitions including CYP1A2 and CYP2C19, cimetidine may be inadequate at enhancing voriconazole levels owing to its known effects on raising gastric pH, a result that may limit voriconazole solubility.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-03-27DOI: 10.1080/15376516.2024.2331768
Deema K Sabir, Abeer Al-Masri, Munirah F Aldayel, Abeer A Sharaf
The agricultural fumigant pesticide aluminum phosphide (AlP) is cardiotoxic. Water causes AlP to emit phosphine gas, a cardiac toxin that affects heart function and causes cardiogenic shock. AlP poisoning's high fatality rate is due to cardiotoxicity. This study examines how resveratrol reduces oxidative stress, mitochondrial activity, and apoptosis in human cardiac myocyte (HCM) cells. After determining the optimal doses of resveratrol using the MTT test, HCM cells were subjected to a 24-h treatment of resveratrol following exposure to AlP (2.36 μM). The levels of reactive oxygen species (ROS), superoxide dismutase (SOD) activity, mitochondrial swelling, mitochondrial cytochrome c release, and mitochondrial membrane potential (MMP) in HCM cells were investigated. Also, the expression of Bax and Bcl-2, caspace-3 activity, and apoptosis were assessed. The present investigation revealed that AlP substantially increased the level of ROS and decreased SOD activation, which were significantly modulated by resveratrol in a dose-dependent manner. Moreover, AlP induced an elevation of mitochondrial swelling, cytochrome c release, and MMP collapse. Co-administration of resveratrol significantly reduced above mitochondrial markers. AlP also significantly upregulated BAX and downregulated Bcl-2 expression, elevated caspace-3 activity, and apoptosis. Resveratrol co-administration was able to meaningfully modulate the mentioned parameters and finally reduce apoptosis. In conclusion, resveratrol, via its pleotropic properties, significantly demonstrated cytoprotective effects on HCM cytotoxicity induced by AlP.
{"title":"Modulating oxidative stress, apoptosis, and mitochondrial dysfunctions on cardiotoxicity induced by aluminum phosphide pesticide using resveratrol.","authors":"Deema K Sabir, Abeer Al-Masri, Munirah F Aldayel, Abeer A Sharaf","doi":"10.1080/15376516.2024.2331768","DOIUrl":"10.1080/15376516.2024.2331768","url":null,"abstract":"<p><p>The agricultural fumigant pesticide aluminum phosphide (AlP) is cardiotoxic. Water causes AlP to emit phosphine gas, a cardiac toxin that affects heart function and causes cardiogenic shock. AlP poisoning's high fatality rate is due to cardiotoxicity. This study examines how resveratrol reduces oxidative stress, mitochondrial activity, and apoptosis in human cardiac myocyte (HCM) cells. After determining the optimal doses of resveratrol using the MTT test, HCM cells were subjected to a 24-h treatment of resveratrol following exposure to AlP (2.36 μM). The levels of reactive oxygen species (ROS), superoxide dismutase (SOD) activity, mitochondrial swelling, mitochondrial cytochrome c release, and mitochondrial membrane potential (MMP) in HCM cells were investigated. Also, the expression of Bax and Bcl-2, caspace-3 activity, and apoptosis were assessed. The present investigation revealed that AlP substantially increased the level of ROS and decreased SOD activation, which were significantly modulated by resveratrol in a dose-dependent manner. Moreover, AlP induced an elevation of mitochondrial swelling, cytochrome c release, and MMP collapse. Co-administration of resveratrol significantly reduced above mitochondrial markers. AlP also significantly upregulated BAX and downregulated Bcl-2 expression, elevated caspace-3 activity, and apoptosis. Resveratrol co-administration was able to meaningfully modulate the mentioned parameters and finally reduce apoptosis. In conclusion, resveratrol, <i>via</i> its pleotropic properties, significantly demonstrated cytoprotective effects on HCM cytotoxicity induced by AlP.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140132586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-02-27DOI: 10.1080/15376516.2024.2322006
Esat Mahmut Kocaman, Onur Şenol, Serkan Yıldırım, Muhammed Atamanalp, Sinan Özcan, İsmail Bolat, Arzu Ucar, Metin Kiliçlioğlu, Veysel Parlak, Mehmet Takkac, Gonca Alak
This study focuses on the comparative metabolic profiling and effects of two steroid types: natural and synthetic, specifically 17α-methyl testosterone (17α-MT) at varying concentrations (1.5, 2, and 3 mg/kg) in rainbow trout (Oncorhynchus mykiss). Over a 75-day feeding trial, growth metrics, such as feed efficiency, daily specific growth, live weight gain, total weight gain, and survival rate were systematically monitored every 15 days. At the end of the feeding trial, histopathology, immunohistochemistry, and metabolome analyses were performed in the high-concentration groups (3 mg/kg natural and 3 mg/kg synthetic), in which the lowest survival rate was determined. Key findings reveal that the type of hormone significantly influences growth parameters. While some natural steroids enhanced certain growth aspects, synthetic variants often yielded better results. The metabolomic analysis highlighted significant shifts in the metabolism of tryptophan, purine, folate, primary bile acids, phosphonates, phosphinates, and xenobiotics via cytochrome P450 pathways. Histopathologically, the natural hormone groups showed similar testicular, hepatic, muscular, gill, cerebral, renal, and intestinal tissue structures to the control, with minor DNA damage and apoptosis observed through immunohistochemistry. Conversely, the synthetic hormone groups exhibited moderate DNA damage and mild degenerative and necrotic changes in histopathology.
本研究的重点是虹鳟(Oncorhynchus mykiss)体内两种类固醇(天然类固醇和合成类固醇,特别是不同浓度(1.5、2 和 3 毫克/千克)的 17α 甲基睾酮(17α-MT))的代谢谱分析及其影响的比较。在为期 75 天的喂养试验中,每隔 15 天对饲料效率、日特定生长量、活体增重、总增重和存活率等生长指标进行一次系统监测。在饲养试验结束时,对高浓度组(3 毫克/千克天然组和 3 毫克/千克合成组)进行了组织病理学、免疫组化和代谢组分析,其中高浓度组的存活率最低。主要研究结果表明,激素类型对生长参数有显著影响。虽然某些天然类固醇能提高某些生长指标,但合成变体往往能产生更好的结果。代谢组学分析凸显了色氨酸、嘌呤、叶酸、初级胆汁酸、膦酸盐、膦酸盐以及通过细胞色素 P450 途径代谢的异种生物的显著变化。从组织病理学角度看,天然激素组的睾丸、肝脏、肌肉、鳃、脑、肾和肠道组织结构与对照组相似,通过免疫组化可观察到轻微的 DNA 损伤和细胞凋亡。相反,合成激素组在组织病理学上表现出中度 DNA 损伤和轻度变性及坏死变化。
{"title":"Analyzing the impact of synthetic and natural steroids: a study of cytochrome P450 metabolism, morphological alterations through metabolomics, and histopathological Examination.","authors":"Esat Mahmut Kocaman, Onur Şenol, Serkan Yıldırım, Muhammed Atamanalp, Sinan Özcan, İsmail Bolat, Arzu Ucar, Metin Kiliçlioğlu, Veysel Parlak, Mehmet Takkac, Gonca Alak","doi":"10.1080/15376516.2024.2322006","DOIUrl":"10.1080/15376516.2024.2322006","url":null,"abstract":"<p><p>This study focuses on the comparative metabolic profiling and effects of two steroid types: natural and synthetic, specifically 17α-methyl testosterone (17α-MT) at varying concentrations (1.5, 2, and 3 mg/kg) in rainbow trout (<i>Oncorhynchus mykiss</i>). Over a 75-day feeding trial, growth metrics, such as feed efficiency, daily specific growth, live weight gain, total weight gain, and survival rate were systematically monitored every 15 days. At the end of the feeding trial, histopathology, immunohistochemistry, and metabolome analyses were performed in the high-concentration groups (3 mg/kg natural and 3 mg/kg synthetic), in which the lowest survival rate was determined. Key findings reveal that the type of hormone significantly influences growth parameters. While some natural steroids enhanced certain growth aspects, synthetic variants often yielded better results. The metabolomic analysis highlighted significant shifts in the metabolism of tryptophan, purine, folate, primary bile acids, phosphonates, phosphinates, and xenobiotics <i>via</i> cytochrome P450 pathways. Histopathologically, the natural hormone groups showed similar testicular, hepatic, muscular, gill, cerebral, renal, and intestinal tissue structures to the control, with minor DNA damage and apoptosis observed through immunohistochemistry. Conversely, the synthetic hormone groups exhibited moderate DNA damage and mild degenerative and necrotic changes in histopathology.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aluminum (Al) overexposure damages various organ systems, especially the nervous system. Regularly administered aluminum chloride (AlCl3) to rats causes dementia and pathophysiological alterations linked to Alzheimer's disease (AD). Taxifolin's neuroprotective effects against AlCl3-induced neurotoxicity in vitro and in vivo studies were studied. Taxifolin (0.1, 0.3, 1, 3, and 10 μM) was tested against AlCl3 (5 mM)-induced neurotoxicity in C6 and SH-SY5Y cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Additionally, neural morphology was examined by confocal microscopy. Additionally, taxifolin's mode of binding with the co-receptor of toll-like receptor 4 (TLR4), human myeloid differentiation-2 (hMD-2) was investigated. AlCl3 (25 mg/kg/d, i.p.) was administered to rats for 14 d, and from the eighth day, taxifolin (1, 2, and 5 mg/kg/d, i.p.) was given along with AlCl3. This study assessed memory impairment using the Morris water maze, plus maze, and pole tests. This study also performed measurement of oxidant (malondialdehyde [MDA] and nitrite), antioxidant (reduced glutathione), and inflammatory (myeloperoxidase [MPO] activity, TLR4 expression) parameters in rats' brain in addition to histopathology. The docking score for taxifolin with hMD-2 was found to be -4.38 kcal/mol. Taxifolin treatment reduced the neurotoxicity brought on by AlCl3 in both C6 and SH-SY5Y cells. Treatment with 10 μM taxifolin restored AlCl3-induced altered cell morphology. AlCl3 administration caused memory loss, oxidative stress, inflammation (increased MPO activity and TLR4 expression), and brain atrophy. Taxifolin treatment significantly improved the AlCl3-induced memory impairment. Taxifolin treatment also mitigated the histopathological and neurochemical consequences of repeated AlCl3 administration in rats. Thus, taxifolin may protect the brain against AD.
{"title":"Neuroprotective effect of taxifolin against aluminum chloride-induced dementia and pathological alterations in the brain of rats: possible involvement of toll-like receptor 4.","authors":"Bhagawati Saxena, Pragnesh Parmar, Heena Chauhan, Pooja Singh, Ashok Kumar Datusalia, Vivek Kumar Vyas, Nagja Tripathi, Jigna Shah","doi":"10.1080/15376516.2024.2329653","DOIUrl":"10.1080/15376516.2024.2329653","url":null,"abstract":"<p><p>Aluminum (Al) overexposure damages various organ systems, especially the nervous system. Regularly administered aluminum chloride (AlCl<sub>3</sub>) to rats causes dementia and pathophysiological alterations linked to Alzheimer's disease (AD). Taxifolin's neuroprotective effects against AlCl<sub>3</sub>-induced neurotoxicity <i>in vitro</i> and <i>in vivo</i> studies were studied. Taxifolin (0.1, 0.3, 1, 3, and 10 μM) was tested against AlCl<sub>3</sub> (5 mM)-induced neurotoxicity in C6 and SH-SY5Y cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Additionally, neural morphology was examined by confocal microscopy. Additionally, taxifolin's mode of binding with the co-receptor of toll-like receptor 4 (TLR4), human myeloid differentiation-2 (<i>h</i>MD-2) was investigated. AlCl<sub>3</sub> (25 mg/kg/d, <i>i.p.</i>) was administered to rats for 14 d, and from the eighth day, taxifolin (1, 2, and 5 mg/kg/d, <i>i.p.</i>) was given along with AlCl<sub>3</sub>. This study assessed memory impairment using the Morris water maze, plus maze, and pole tests. This study also performed measurement of oxidant (malondialdehyde [MDA] and nitrite), antioxidant (reduced glutathione), and inflammatory (myeloperoxidase [MPO] activity, TLR4 expression) parameters in rats' brain in addition to histopathology. The docking score for taxifolin with <i>h</i>MD-2 was found to be -4.38 kcal/mol. Taxifolin treatment reduced the neurotoxicity brought on by AlCl<sub>3</sub> in both C6 and SH-SY5Y cells. Treatment with 10 μM taxifolin restored AlCl<sub>3</sub>-induced altered cell morphology. AlCl<sub>3</sub> administration caused memory loss, oxidative stress, inflammation (increased MPO activity and TLR4 expression), and brain atrophy. Taxifolin treatment significantly improved the AlCl<sub>3</sub>-induced memory impairment. Taxifolin treatment also mitigated the histopathological and neurochemical consequences of repeated AlCl<sub>3</sub> administration in rats. Thus, taxifolin may protect the brain against AD.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140094625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-18DOI: 10.1080/15376516.2024.2364192
Amir Saamaan Fattahi, Azadeh Khalili, Seyed Ali Hashemi, Parvaneh Najafizadeh, Roham Mazloom, Sara Khodayar, Gholamreza Bayat
Valproic acid (VA) is a broad-spectrum anticonvulsant agent that acts through several molecular mechanisms to control different types of seizures. The main concern of the drug is its liver toxicity...
{"title":"A trend over time study of hepatic Farnesoid-X-activated receptor and its downstream targets modulation by valproic acid in mice","authors":"Amir Saamaan Fattahi, Azadeh Khalili, Seyed Ali Hashemi, Parvaneh Najafizadeh, Roham Mazloom, Sara Khodayar, Gholamreza Bayat","doi":"10.1080/15376516.2024.2364192","DOIUrl":"https://doi.org/10.1080/15376516.2024.2364192","url":null,"abstract":"Valproic acid (VA) is a broad-spectrum anticonvulsant agent that acts through several molecular mechanisms to control different types of seizures. The main concern of the drug is its liver toxicity...","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141551004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-01-31DOI: 10.1080/15376516.2024.2307975
Muhammad Luthfi, R B Pandey, Yong-Chao Su, Pornthep Sompornpisut
Recent studies have revealed a notable connection between pesticide exposure and Recurrent Pregnancy Loss (RPL), yet the precise molecular underpinning of this toxicity remains elusive. Through the alignment of Differentially Expressed Genes (DEGs) of healthy and RPL patients with the target genes of 9 pesticide components, we identified a set of 12 genes responsible for RPL etiology. Interestingly, biological process showed that besides RPL, those 12 genes also associated with preeclampsia and cardiovascular disease. Enrichment analysis showed the engagement of these genes associated with essential roles in the molecular transport of small molecules, as well as the aldosterone-regulated sodium reabsorption, endocrine and other factor-regulated calcium reabsorption, mineral absorption, ion homeostasis, and ion transport by P-type ATPases. Notably, the crosstalk targets between pesticide components played crucial roles in influencing RPL results, suggesting a role in attenuating pesticide agents that contribute to RPL. It is important to note that non-significant concentration of the pesticide components observed in both control and RPL samples should not prematurely undermine the potential for pesticides to induce RPL in humans. This study emphasizes the complexity of pesticide induced RPL and highlights avenues for further research and precautionary measures.
{"title":"Deciphering molecular basis of pesticide-induced recurrent pregnancy loss: insights from transcriptomics analysis.","authors":"Muhammad Luthfi, R B Pandey, Yong-Chao Su, Pornthep Sompornpisut","doi":"10.1080/15376516.2024.2307975","DOIUrl":"10.1080/15376516.2024.2307975","url":null,"abstract":"<p><p>Recent studies have revealed a notable connection between pesticide exposure and Recurrent Pregnancy Loss (RPL), yet the precise molecular underpinning of this toxicity remains elusive. Through the alignment of Differentially Expressed Genes (DEGs) of healthy and RPL patients with the target genes of 9 pesticide components, we identified a set of 12 genes responsible for RPL etiology. Interestingly, biological process showed that besides RPL, those 12 genes also associated with preeclampsia and cardiovascular disease. Enrichment analysis showed the engagement of these genes associated with essential roles in the molecular transport of small molecules, as well as the aldosterone-regulated sodium reabsorption, endocrine and other factor-regulated calcium reabsorption, mineral absorption, ion homeostasis, and ion transport by P-type ATPases. Notably, the crosstalk targets between pesticide components played crucial roles in influencing RPL results, suggesting a role in attenuating pesticide agents that contribute to RPL. It is important to note that non-significant concentration of the pesticide components observed in both control and RPL samples should not prematurely undermine the potential for pesticides to induce RPL in humans. This study emphasizes the complexity of pesticide induced RPL and highlights avenues for further research and precautionary measures.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-01-09DOI: 10.1080/15376516.2023.2301357
Heba Nageh Gad El-Hak, Safaa M Kishk, Heba M A Abdelrazek
The modulatory role of primrose oil (PO) supplementation enriched with γ-linolenic acid and D/L-alpha tocopherol acetate against a carbon tetrachloride (CCl4)-induced liver damage model was assessed in this study. Twenty male Albino rats were divided into four groups. The control group received corn oil orally. The PO group received 10 mg/kg P O orally. The CCl4 group received 2 mL/kg CCl4 orally and PO/CCl4 group; received PO and 2 mL/kg CCl4 orally. The relative liver weight was recorded. Serum liver enzymes, hepatic malondialdehyde (MDA), hepatic reduced glutathione (GSH) and the expression of hepatic tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) were assessed. The binding affinities of γ-linolenic acid and D/L-alpha tocopherol constituents with IL-1β, IL-6 and TNF-α were investigated using molecular docking simulations. Histopathological and electron microscopic examinations of the liver were performed. The results indicated that CCl4 elevated serum liver enzyme and hepatic MDA levels, whereas GSH levels were diminished. The upregulation of IL-1β, IL-6, and TNF-α gene expressions were induced by CCl4 treatment. The PO/CCl4-treated group showed amelioration of hepatic injury biomarkers and oxidative stress. Restoration of histopathological and ultrastructural alterations while downregulations the gene expressions of TNF-α, IL1-β and IL-6 were observed. In conclusion, evening primrose oil enriched with γ-linolenic acid and D/L-alpha tocopherol acetate elicited a potential amelioration of CCl4-induced hepatic toxicity.
{"title":"Evening primrose oil enriched with gamma linolenic acid and D/L-alpha tocopherol acetate attenuated carbon tetrachloride-induced hepatic injury model in male rats via TNF-α, IL-1β, and IL-6 pathway.","authors":"Heba Nageh Gad El-Hak, Safaa M Kishk, Heba M A Abdelrazek","doi":"10.1080/15376516.2023.2301357","DOIUrl":"10.1080/15376516.2023.2301357","url":null,"abstract":"<p><p>The modulatory role of primrose oil (PO) supplementation enriched with γ-linolenic acid and D/L-alpha tocopherol acetate against a carbon tetrachloride (CCl<sub>4</sub>)-induced liver damage model was assessed in this study. Twenty male Albino rats were divided into four groups. The control group received corn oil orally. The PO group received 10 mg/kg P O orally. The CCl<sub>4</sub> group received 2 mL/kg CCl<sub>4</sub> orally and PO/CCl<sub>4</sub> group; received PO and 2 mL/kg CCl<sub>4</sub> orally. The relative liver weight was recorded. Serum liver enzymes, hepatic malondialdehyde (MDA), hepatic reduced glutathione (GSH) and the expression of hepatic tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) were assessed. The binding affinities of γ-linolenic acid and D/L-alpha tocopherol constituents with IL-1β, IL-6 and TNF-α were investigated using molecular docking simulations. Histopathological and electron microscopic examinations of the liver were performed. The results indicated that CCl<sub>4</sub> elevated serum liver enzyme and hepatic MDA levels, whereas GSH levels were diminished. The upregulation of IL-1β, IL-6, and TNF-α gene expressions were induced by CCl<sub>4</sub> treatment. The PO/CCl4-treated group showed amelioration of hepatic injury biomarkers and oxidative stress. Restoration of histopathological and ultrastructural alterations while downregulations the gene expressions of TNF-α, IL1-β and IL-6 were observed. In conclusion, evening primrose oil enriched with γ-linolenic acid and D/L-alpha tocopherol acetate elicited a potential amelioration of CCl<sub>4</sub>-induced hepatic toxicity.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139080931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-01-25DOI: 10.1080/15376516.2024.2306375
Zi-Tan Peng, Rong Hu, Jing-Yu Fu
This study aimed to examine the expression and biological functions of ACTL6A in glioma cells (U251), the effects of sulforaphane on the growth of U251 cells and the involvement of the ACTL6A/PGK1 pathway in those effects. The U251 cell line was transfected with ACTL6A over-expression plasmids to upregulate the protein, or with ACTL6A inhibitor to underexpress it, then treated with different concentrations of sulforaphane. Cell viability, proliferation, and apoptosis were assessed using standard assays, and levels of mRNAs encoding ACTL6A, PGK1, cyclin D1, Myc, Bax or Bcl-2 were measured using quantitative real-time polymerase chain reaction (qRT-PCR). ACTL6A and PGK1 were expressed at higher levels in glioma cell lines than in normal HEB cells. ACTL6A overexpression upregulated PGK1, whereas ACTL6A inhibition had the opposite effect. ACTL6A overexpression induced proliferation, whereas its inhibition repressed proliferation, enhanced apoptosis, and halted the cell cycle. Moreover, sulforaphane suppressed the growth of U251 cells by inactivating the ACTL6A/PGK1 axis. ACTL6A acts via PGK1 to play a critical role in glioma cell survival and proliferation, and sulforaphane targets it to inhibit glioma.
{"title":"Sulforaphane suppresses cell proliferation and induces apoptosis in glioma via the ACTL6A/PGK1 axis.","authors":"Zi-Tan Peng, Rong Hu, Jing-Yu Fu","doi":"10.1080/15376516.2024.2306375","DOIUrl":"10.1080/15376516.2024.2306375","url":null,"abstract":"<p><p>This study aimed to examine the expression and biological functions of ACTL6A in glioma cells (U251), the effects of sulforaphane on the growth of U251 cells and the involvement of the ACTL6A/PGK1 pathway in those effects. The U251 cell line was transfected with ACTL6A over-expression plasmids to upregulate the protein, or with ACTL6A inhibitor to underexpress it, then treated with different concentrations of sulforaphane. Cell viability, proliferation, and apoptosis were assessed using standard assays, and levels of mRNAs encoding ACTL6A, PGK1, cyclin D1, Myc, Bax or Bcl-2 were measured using quantitative real-time polymerase chain reaction (qRT-PCR). ACTL6A and PGK1 were expressed at higher levels in glioma cell lines than in normal HEB cells. ACTL6A overexpression upregulated PGK1, whereas ACTL6A inhibition had the opposite effect. ACTL6A overexpression induced proliferation, whereas its inhibition repressed proliferation, enhanced apoptosis, and halted the cell cycle. Moreover, sulforaphane suppressed the growth of U251 cells by inactivating the ACTL6A/PGK1 axis. ACTL6A acts <i>via</i> PGK1 to play a critical role in glioma cell survival and proliferation, and sulforaphane targets it to inhibit glioma.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-02-23DOI: 10.1080/15376516.2024.2316003
Zicong Zheng, Ting Du, Song Gao, Taijun Yin, Li Li, Lijun Zhu, Rashim Singh, Rongjin Sun, Ming Hu
Irinotecan-induced severe diarrhea (IISD) not only limits irinotecan's application but also significantly affects patients' quality of life. However, existing animal models often inadequately represent the dynamics of IISD development, progression, and resolution across multiple chemotherapy cycles, yielding non-reproducible and highly variable response with limited clinical translation. Our studies aim to establish a reproducible and validated IISD model that better mimics the pathophysiology progression observed in patients, enhancing translational potential. We investigated the impact of dosing regimens (including different dose, infusion time, and two cycles of irinotecan administration), sex, age, tumor-bearing conditions, and irinotecan formulation on the IISD incidence and severity in mice and rats. Lastly, we investigated above factors' impact on pharmacokinetics of irinotecan, intestinal injury, and carboxylesterase activities. In summary, we successfully established a standard model establishment procedure for an optimized IISD model with highly reproducible severe diarrhea incidence rate (100%) and a low mortality rate (11%) in F344 rats. Additionally, the rats tolerated at least two cycles of irinotecan chemotherapy treatment. In contrast, the mouse model exhibited suboptimal IISD incidence rates (60%) and an extremely high mortality rate (100%). Notably, dosing regimen, age and tumor-bearing conditions of animals emerged as critical factors in IISD model establishment. In conclusion, our rat IISD model proves superior in mimicking pathophysiology progression and characteristics of IISD in patients, which stands as an effective tool for mechanism and efficacy studies in future chemotherapy-induced gut toxicity research.
{"title":"Optimized rat models better mimic patients with irinotecan-induced severe diarrhea.","authors":"Zicong Zheng, Ting Du, Song Gao, Taijun Yin, Li Li, Lijun Zhu, Rashim Singh, Rongjin Sun, Ming Hu","doi":"10.1080/15376516.2024.2316003","DOIUrl":"10.1080/15376516.2024.2316003","url":null,"abstract":"<p><p>Irinotecan-induced severe diarrhea (IISD) not only limits irinotecan's application but also significantly affects patients' quality of life. However, existing animal models often inadequately represent the dynamics of IISD development, progression, and resolution across multiple chemotherapy cycles, yielding non-reproducible and highly variable response with limited clinical translation. Our studies aim to establish a reproducible and validated IISD model that better mimics the pathophysiology progression observed in patients, enhancing translational potential. We investigated the impact of dosing regimens (including different dose, infusion time, and two cycles of irinotecan administration), sex, age, tumor-bearing conditions, and irinotecan formulation on the IISD incidence and severity in mice and rats. Lastly, we investigated above factors' impact on pharmacokinetics of irinotecan, intestinal injury, and carboxylesterase activities. In summary, we successfully established a standard model establishment procedure for an optimized IISD model with highly reproducible severe diarrhea incidence rate (100%) and a low mortality rate (11%) in F344 rats. Additionally, the rats tolerated at least two cycles of irinotecan chemotherapy treatment. In contrast, the mouse model exhibited suboptimal IISD incidence rates (60%) and an extremely high mortality rate (100%). Notably, dosing regimen, age and tumor-bearing conditions of animals emerged as critical factors in IISD model establishment. In conclusion, our rat IISD model proves superior in mimicking pathophysiology progression and characteristics of IISD in patients, which stands as an effective tool for mechanism and efficacy studies in future chemotherapy-induced gut toxicity research.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-02-12DOI: 10.1080/15376516.2024.2310012
Michael Oluwatoyin Daniyan, Nusrat Omotayo Omisore, Oluwole Isaac Adeyemi, Ayokunmi Stephen Olusa, Samuel Folarin Olaniran, Idris Ajayi Oyemitan, Moses Atanda Akanmu, Gbola Olayiwola
Toxicity profiling is an integral part of the drug discovery pipeline. The 3Rs principle-Replacement, Reduction, and Refinement, is considered a golden rule in determining the most appropriate approach for toxicity studies. The acute toxicity study with proper estimate of median lethal dose (LD50) is usually an initial procedure for the determination of most suitable test doses for preclinical toxicological and pharmacological profiling. Several methods, which have been devised to determine the LD50, are faced with the challenge of using a large number of animals and time constraints. Despite the inherent advantage of the newer OECD Test Guidelines, the increasing concerns among toxicologists, the regulatory authorities and the general public, on the need to adhere to 3Rs principle, necessitated the need for an improved approach. Such an approach should not only minimize the time and number of animals required, but also take into cognizance animal welfare, and give accurate, comparable, and reproducible results across laboratories. While taking advantage of the inherent merits of the existing methods, here is presented the mathematical basis and evaluation of an improved method for toxicity profiling of test substances and estimation of LD50. The method makes use of the generated Table of values for the selection of appropriate test doses. Our proposed method has capacities to optimize the time and number of animal use, ensure more reliable and reproducible results across laboratories, allow for easy selection of doses for subsequent toxicity profiling, and be adaptable to other biological screening beyond toxicity studies.
{"title":"An improved method for toxicological profiling of chemical substances.","authors":"Michael Oluwatoyin Daniyan, Nusrat Omotayo Omisore, Oluwole Isaac Adeyemi, Ayokunmi Stephen Olusa, Samuel Folarin Olaniran, Idris Ajayi Oyemitan, Moses Atanda Akanmu, Gbola Olayiwola","doi":"10.1080/15376516.2024.2310012","DOIUrl":"10.1080/15376516.2024.2310012","url":null,"abstract":"<p><p>Toxicity profiling is an integral part of the drug discovery pipeline. The 3Rs principle-Replacement, Reduction, and Refinement, is considered a golden rule in determining the most appropriate approach for toxicity studies. The acute toxicity study with proper estimate of median lethal dose (LD<sub>50</sub>) is usually an initial procedure for the determination of most suitable test doses for preclinical toxicological and pharmacological profiling. Several methods, which have been devised to determine the LD<sub>50</sub>, are faced with the challenge of using a large number of animals and time constraints. Despite the inherent advantage of the newer OECD Test Guidelines, the increasing concerns among toxicologists, the regulatory authorities and the general public, on the need to adhere to 3Rs principle, necessitated the need for an improved approach. Such an approach should not only minimize the time and number of animals required, but also take into cognizance animal welfare, and give accurate, comparable, and reproducible results across laboratories. While taking advantage of the inherent merits of the existing methods, here is presented the mathematical basis and evaluation of an improved method for toxicity profiling of test substances and estimation of LD<sub>50</sub>. The method makes use of the generated Table of values for the selection of appropriate test doses. Our proposed method has capacities to optimize the time and number of animal use, ensure more reliable and reproducible results across laboratories, allow for easy selection of doses for subsequent toxicity profiling, and be adaptable to other biological screening beyond toxicity studies.</p>","PeriodicalId":23177,"journal":{"name":"Toxicology Mechanisms and Methods","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139547371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}