Mahmoud El Safadi , Muhammad Faisal Hayat , Ali Akbar , Abdullah Nisar , Fuad M. Alzahrani , Khalid J. Alzahrani
{"title":"比洛贝汀通过调节 TLR-4、Nrf-2/Keap-1、JAK1/STAT3 和 NF-κB 通路对抗铬诱导的肝毒性的药疗潜力:药代动力学和分子动力学方法","authors":"Mahmoud El Safadi , Muhammad Faisal Hayat , Ali Akbar , Abdullah Nisar , Fuad M. Alzahrani , Khalid J. Alzahrani","doi":"10.1016/j.jtemb.2024.127567","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Chromium (Cr) is one of the top-notch noxious heavy metals that is documented to exert deleterious effects on various body organs including the liver. Bilobetin (BLB) is a natural flavonoid which exhibits a wide range of medicinal properties.</div></div><div><h3>Aim</h3><div>This trial was executed to investigate the pharmacotherapeutic potential of BLB to avert Cr instigated hepatotoxicity via modulating TLR4, JAK1/STAT3, Nrf-2/Keap-1 and NF-κB pathway.</div></div><div><h3>Research layout</h3><div>Our trial was executed on thirty-six male albino rats that were segregated into four equal groups including the control, Cr (10 mg/kg), Cr (10 mg/kg) + BLB (12 mg/kg) and BLB (12 mg/kg) alone treated group. Various biochemical parameters were assessed by using qRT-PCR, molecular docking, molecular dynamic simulation and histological approaches.</div></div><div><h3>Findings</h3><div>Our results revealed that Cr administration significantly impaired the health of hepatic tissues by reducing the gene expression of Nrf-2 and its downregulating genes while promoting the levels of oxidative stress markers (ROS and MDA). Moreover, Cr administration upregulated the hepatic enzymes including ALT, GGT, AST, and ALP while concurrently decreasing the levels of total protein and albumin. Cr exposure also elevated the gene expression of pro-inflammatory cytokines including toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1) nuclear factor kappa B (NF-κB), Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor alpha (TNF-α), C-reactive proteins, interferon-gamma inducible protein-10 (IP-10), Interleukin beta-1(IL-1β), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). Hepatic apoptosis was observed to be elevated following the Cr intoxication. Nonetheless, BLB treatment remarkably alleviated the hepatic damages via regulating the biochemical as well as histological profile of liver. Our findings are further endorsed by molecular docking analysis that demonstrated that BLB exhibit strong binding affinity to Keap-1 and STAT3 thus supporting its efficient hepatoprotective potential.</div></div><div><h3>Conclusion</h3><div>BLB protected the hepatic tissues via regulating Cr induced impairments. These findings were confirmed by molecular docking and molecular dynamic simulation analysis.</div></div>","PeriodicalId":49970,"journal":{"name":"Journal of Trace Elements in Medicine and Biology","volume":"86 ","pages":"Article 127567"},"PeriodicalIF":3.6000,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacotherapeutic potential of bilobetin to combat chromium induced hepatotoxicity via regulating TLR-4, Nrf-2/Keap-1, JAK1/STAT3 and NF-κB pathway: A pharmacokinetic and molecular dynamic approach\",\"authors\":\"Mahmoud El Safadi , Muhammad Faisal Hayat , Ali Akbar , Abdullah Nisar , Fuad M. Alzahrani , Khalid J. Alzahrani\",\"doi\":\"10.1016/j.jtemb.2024.127567\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Chromium (Cr) is one of the top-notch noxious heavy metals that is documented to exert deleterious effects on various body organs including the liver. Bilobetin (BLB) is a natural flavonoid which exhibits a wide range of medicinal properties.</div></div><div><h3>Aim</h3><div>This trial was executed to investigate the pharmacotherapeutic potential of BLB to avert Cr instigated hepatotoxicity via modulating TLR4, JAK1/STAT3, Nrf-2/Keap-1 and NF-κB pathway.</div></div><div><h3>Research layout</h3><div>Our trial was executed on thirty-six male albino rats that were segregated into four equal groups including the control, Cr (10 mg/kg), Cr (10 mg/kg) + BLB (12 mg/kg) and BLB (12 mg/kg) alone treated group. Various biochemical parameters were assessed by using qRT-PCR, molecular docking, molecular dynamic simulation and histological approaches.</div></div><div><h3>Findings</h3><div>Our results revealed that Cr administration significantly impaired the health of hepatic tissues by reducing the gene expression of Nrf-2 and its downregulating genes while promoting the levels of oxidative stress markers (ROS and MDA). Moreover, Cr administration upregulated the hepatic enzymes including ALT, GGT, AST, and ALP while concurrently decreasing the levels of total protein and albumin. Cr exposure also elevated the gene expression of pro-inflammatory cytokines including toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1) nuclear factor kappa B (NF-κB), Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor alpha (TNF-α), C-reactive proteins, interferon-gamma inducible protein-10 (IP-10), Interleukin beta-1(IL-1β), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). Hepatic apoptosis was observed to be elevated following the Cr intoxication. Nonetheless, BLB treatment remarkably alleviated the hepatic damages via regulating the biochemical as well as histological profile of liver. Our findings are further endorsed by molecular docking analysis that demonstrated that BLB exhibit strong binding affinity to Keap-1 and STAT3 thus supporting its efficient hepatoprotective potential.</div></div><div><h3>Conclusion</h3><div>BLB protected the hepatic tissues via regulating Cr induced impairments. 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Pharmacotherapeutic potential of bilobetin to combat chromium induced hepatotoxicity via regulating TLR-4, Nrf-2/Keap-1, JAK1/STAT3 and NF-κB pathway: A pharmacokinetic and molecular dynamic approach
Background
Chromium (Cr) is one of the top-notch noxious heavy metals that is documented to exert deleterious effects on various body organs including the liver. Bilobetin (BLB) is a natural flavonoid which exhibits a wide range of medicinal properties.
Aim
This trial was executed to investigate the pharmacotherapeutic potential of BLB to avert Cr instigated hepatotoxicity via modulating TLR4, JAK1/STAT3, Nrf-2/Keap-1 and NF-κB pathway.
Research layout
Our trial was executed on thirty-six male albino rats that were segregated into four equal groups including the control, Cr (10 mg/kg), Cr (10 mg/kg) + BLB (12 mg/kg) and BLB (12 mg/kg) alone treated group. Various biochemical parameters were assessed by using qRT-PCR, molecular docking, molecular dynamic simulation and histological approaches.
Findings
Our results revealed that Cr administration significantly impaired the health of hepatic tissues by reducing the gene expression of Nrf-2 and its downregulating genes while promoting the levels of oxidative stress markers (ROS and MDA). Moreover, Cr administration upregulated the hepatic enzymes including ALT, GGT, AST, and ALP while concurrently decreasing the levels of total protein and albumin. Cr exposure also elevated the gene expression of pro-inflammatory cytokines including toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1) nuclear factor kappa B (NF-κB), Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor alpha (TNF-α), C-reactive proteins, interferon-gamma inducible protein-10 (IP-10), Interleukin beta-1(IL-1β), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). Hepatic apoptosis was observed to be elevated following the Cr intoxication. Nonetheless, BLB treatment remarkably alleviated the hepatic damages via regulating the biochemical as well as histological profile of liver. Our findings are further endorsed by molecular docking analysis that demonstrated that BLB exhibit strong binding affinity to Keap-1 and STAT3 thus supporting its efficient hepatoprotective potential.
Conclusion
BLB protected the hepatic tissues via regulating Cr induced impairments. These findings were confirmed by molecular docking and molecular dynamic simulation analysis.
期刊介绍:
The journal provides the reader with a thorough description of theoretical and applied aspects of trace elements in medicine and biology and is devoted to the advancement of scientific knowledge about trace elements and trace element species. Trace elements play essential roles in the maintenance of physiological processes. During the last decades there has been a great deal of scientific investigation about the function and binding of trace elements. The Journal of Trace Elements in Medicine and Biology focuses on the description and dissemination of scientific results concerning the role of trace elements with respect to their mode of action in health and disease and nutritional importance. Progress in the knowledge of the biological role of trace elements depends, however, on advances in trace elements chemistry. Thus the Journal of Trace Elements in Medicine and Biology will include only those papers that base their results on proven analytical methods.
Also, we only publish those articles in which the quality assurance regarding the execution of experiments and achievement of results is guaranteed.