Pub Date : 2024-09-04DOI: 10.1016/j.biopha.2024.117280
Acetaminophen (APAP) overdose is a prevalent cause of clinical pharmacological liver injury worldwide. Artemether (ART), a first-line antimalarial drug, has demonstrated hepatoprotective activity. However, its effect on APAP-induced acute liver injury (AILI) remains unclear. In this study, we investigated whether ART can protect against AILI and examined its underlying mechanisms. In vivo, ART mitigated APAP-induced liver histological changes, including mitochondrial damage, hepatocyte necrosis, hepatocyte apoptosis, and inflammatory infiltration. Additionally, ART reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in APAP-induced mice. ART also activated the Nrf2-HO-1/GPX4 signaling pathway, exerting antioxidant effects in both in vitro and in vivo models of AILI. To confirm Nrf2 as a target of ART in vivo, we pretreated C57BL/6 mice with the Nrf2 inhibitor, ML385. The results indicated that inhibiting Nrf2 diminishes the protective effect of ART against AILI. Overall, our findings suggest that ART's protective effect against AILI is mediated through the Nrf2-related antioxidant pathway.
{"title":"Artemether ameliorates acetaminophen-induced liver injury through Nrf2 pathway","authors":"","doi":"10.1016/j.biopha.2024.117280","DOIUrl":"10.1016/j.biopha.2024.117280","url":null,"abstract":"<div><p>Acetaminophen (APAP) overdose is a prevalent cause of clinical pharmacological liver injury worldwide. Artemether (ART), a first-line antimalarial drug, has demonstrated hepatoprotective activity. However, its effect on APAP-induced acute liver injury (AILI) remains unclear. In this study, we investigated whether ART can protect against AILI and examined its underlying mechanisms. In vivo, ART mitigated APAP-induced liver histological changes, including mitochondrial damage, hepatocyte necrosis, hepatocyte apoptosis, and inflammatory infiltration. Additionally, ART reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in APAP-induced mice. ART also activated the Nrf2-HO-1/GPX4 signaling pathway, exerting antioxidant effects in both <em>in vitro</em> and <em>in vivo</em> models of AILI. To confirm Nrf2 as a target of ART in vivo, we pretreated C57BL/6 mice with the Nrf2 inhibitor, ML385. The results indicated that inhibiting Nrf2 diminishes the protective effect of ART against AILI. Overall, our findings suggest that ART's protective effect against AILI is mediated through the Nrf2-related antioxidant pathway.</p></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0753332224011648/pdfft?md5=64d63e0721744d0268ed6175e19a9c94&pid=1-s2.0-S0753332224011648-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142142044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.biopha.2024.117346
Oxidative damage contributes to age-related macular degeneration. Irigenin possesses diverse pharmacologic properties, including antioxidative and antiapoptotic effects. Our in vivo experiments indicated that irigenin mitigates UVB-induced histopathologic changes and oxidative DNA damage. Histologic analyses and TUNEL staining revealed that this compound dose-dependently ameliorated UVB-induced retinal damage and apoptosis. Furthermore, irigenin substantially reduced the level of 8-hydroxyguanosine, a biomarker of UVB-induced oxidative DNA damage. We further explored the molecular mechanisms that mediate the protective effects of irigenin. Our findings suggested that UVB-induced generation of ROS disrupts the stability of the mitochondrial membrane, activating intrinsic apoptotic pathways; the underlying mechanisms include the release of cytochrome c, activation of caspase-9 and caspase-3, and subsequent degradation of PARP-1. Notably, irigenin reversed mitochondrial disruption and apoptosis. It also modulated the Bax and Bcl-2 expression but influenced the mitochondrial apoptotic pathways. Our study highlights the role of the Nrf2 pathway in mitigating the effects of oxidative stress. We found that UVB exposure downregulated, but irigenin treatment upregulated the expression of Nrf2 and antioxidant enzymes. Therefore, irigenin activates the Nrf2 pathway to address oxidative stress. In conclusion, irigenin exhibits protective effects against UVB-induced ocular damage, evidenced by the diminution of histological alterations. It mitigates oxidative DNA damage and apoptosis in the retinal tissues by modulating the intrinsic apoptotic pathways and the AIF mechanisms. Furthermore, irigenin effectively reduces lipid peroxidation, enhancing the activity of antioxidant enzymes by stimulating the Nrf2 pathway. This protective mechanism underscores the potential benefit of irigenin in combating UVB-mediated ocular damage.
氧化损伤是老年性黄斑变性的原因之一。鸢尾素具有多种药理特性,包括抗氧化和抗细胞凋亡作用。我们的体内实验表明,鸢尾素能减轻紫外线诱导的组织病理学变化和 DNA 氧化损伤。组织学分析和 TUNEL 染色显示,该化合物剂量依赖性地改善了紫外线诱导的视网膜损伤和凋亡。此外,鸢尾素还大大降低了 8-羟基鸟苷的水平,而 8-羟基鸟苷是紫外线诱导氧化 DNA 损伤的生物标志物。我们进一步探索了介导鸢尾素保护作用的分子机制。我们的研究结果表明,UVB 诱导的 ROS 会破坏线粒体膜的稳定性,激活内在凋亡途径;其基本机制包括细胞色素 c 的释放、caspase-9 和 caspase-3 的激活以及随后 PARP-1 的降解。值得注意的是,鸢尾素能逆转线粒体破坏和细胞凋亡。它还调节了 Bax 和 Bcl-2 的表达,但影响了线粒体凋亡途径。我们的研究强调了 Nrf2 通路在减轻氧化应激影响方面的作用。我们发现,紫外线照射会下调 Nrf2 和抗氧化酶的表达,但鸢尾素处理会上调 Nrf2 和抗氧化酶的表达。因此,鸢尾素能激活 Nrf2 通路以应对氧化应激。总之,鸢尾素对紫外线诱导的眼部损伤具有保护作用,组织学改变的减少就是证明。它通过调节固有的细胞凋亡途径和 AIF 机制,减轻了氧化 DNA 损伤和视网膜组织的细胞凋亡。此外,鸢尾素还能有效降低脂质过氧化,通过刺激 Nrf2 途径提高抗氧化酶的活性。这种保护机制凸显了鸢尾素在对抗紫外线介导的眼部损伤方面的潜在益处。
{"title":"Enhancing ocular protection against UVB: The role of irigenin in modulating oxidative stress and apoptotic pathways In Vivo","authors":"","doi":"10.1016/j.biopha.2024.117346","DOIUrl":"10.1016/j.biopha.2024.117346","url":null,"abstract":"<div><p>Oxidative damage contributes to age-related macular degeneration. Irigenin possesses diverse pharmacologic properties, including antioxidative and antiapoptotic effects. Our in vivo experiments indicated that irigenin mitigates UVB-induced histopathologic changes and oxidative DNA damage. Histologic analyses and TUNEL staining revealed that this compound dose-dependently ameliorated UVB-induced retinal damage and apoptosis. Furthermore, irigenin substantially reduced the level of 8-hydroxyguanosine, a biomarker of UVB-induced oxidative DNA damage. We further explored the molecular mechanisms that mediate the protective effects of irigenin. Our findings suggested that UVB-induced generation of ROS disrupts the stability of the mitochondrial membrane, activating intrinsic apoptotic pathways; the underlying mechanisms include the release of cytochrome c, activation of caspase-9 and caspase-3, and subsequent degradation of PARP-1. Notably, irigenin reversed mitochondrial disruption and apoptosis. It also modulated the Bax and Bcl-2 expression but influenced the mitochondrial apoptotic pathways. Our study highlights the role of the Nrf2 pathway in mitigating the effects of oxidative stress. We found that UVB exposure downregulated, but irigenin treatment upregulated the expression of Nrf2 and antioxidant enzymes. Therefore, irigenin activates the Nrf2 pathway to address oxidative stress. In conclusion, irigenin exhibits protective effects against UVB-induced ocular damage, evidenced by the diminution of histological alterations. It mitigates oxidative DNA damage and apoptosis in the retinal tissues by modulating the intrinsic apoptotic pathways and the AIF mechanisms. Furthermore, irigenin effectively reduces lipid peroxidation, enhancing the activity of antioxidant enzymes by stimulating the Nrf2 pathway. This protective mechanism underscores the potential benefit of irigenin in combating UVB-mediated ocular damage.</p></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0753332224012319/pdfft?md5=31cca55d45d78b7c92e131af832d6e77&pid=1-s2.0-S0753332224012319-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.biopha.2024.117357
Introduction
Obesity is a chronic noncommunicable disease characterized by excessive body fat that can have negative health consequences. Obesity is a complex disease caused by a combination of genetic, environmental, and lifestyle factors. It is characterized by a discrepancy between caloric intake and expenditure. Obesity increases the risk of acquiring major chronic diseases, including heart disease, stroke, cancer, and Type 2 diabetes mellitus (T2DM). Currently, the inhibition of pancreatic lipases (PL) is a promising pharmacological therapy for obesity and weight management. In this study, the inhibition of pancreatic lipase by Cannabis sativa (C. sativa) plant extract and cannabinoids was investigated.
Methods
The inhibitory effect was assessed using p-nitrophenyl butyrate (pNPB), and the results were obtained by calculating the percentage relative activity and assessed using one-way analysis of variance (ANOVA). Kinetic studies and spectroscopy techniques were used to evaluate the mode of inhibition. Diet-induced; and diabetic rat models were studied to evaluate the direct effects of C. sativa extract on PL activity.
Results
Kinetic analyses showed that the plant extracts inhibited pancreatic lipase, with tetrahydrocannabinol (THC) and cannabinol (CBN) being the potential cause of the inhibition noted for the C. sativa plant extract. CBN and THC inhibited the pancreatic lipase activity in a competitive manner, with the lowest residual enzyme activity of 52 % observed at a 10 μg/mL concentration of CBN and 39 % inhibition at a 25 μg/mL concentration of THC. Circular dichroism (CD) spectroscopy revealed that the inhibitors caused a change in the enzyme's secondary structure. At low concentrations, THC showed potential for synergistic inhibition with orlistat. C.sativa treatment in an in vivo rat model confirmed its inhibitory effects on pancreatic lipase activity.
Conclusion
The findings in this study provided insight into the use of cannabinoids as pancreatic lipase inhibitors and the possibility of using these compounds to develop new pharmacological treatments for obesity.
{"title":"The effects of Cannabis sativa and cannabinoids on the inhibition of pancreatic lipase – An enzyme involved in obesity","authors":"","doi":"10.1016/j.biopha.2024.117357","DOIUrl":"10.1016/j.biopha.2024.117357","url":null,"abstract":"<div><h3>Introduction</h3><p>Obesity is a chronic noncommunicable disease characterized by excessive body fat that can have negative health consequences. Obesity is a complex disease caused by a combination of genetic, environmental, and lifestyle factors. It is characterized by a discrepancy between caloric intake and expenditure. Obesity increases the risk of acquiring major chronic diseases, including heart disease, stroke, cancer, and Type 2 diabetes mellitus (T2DM). Currently, the inhibition of pancreatic lipases (PL) is a promising pharmacological therapy for obesity and weight management. In this study, the inhibition of pancreatic lipase by <em>Cannabis sativa</em> (<em>C. sativa</em>) plant extract and cannabinoids was investigated.</p></div><div><h3>Methods</h3><p>The inhibitory effect was assessed using p-nitrophenyl butyrate (<em>p</em>NPB), and the results were obtained by calculating the percentage relative activity and assessed using one-way analysis of variance (ANOVA). Kinetic studies and spectroscopy techniques were used to evaluate the mode of inhibition. Diet-induced; and diabetic rat models were studied to evaluate the direct effects of <em>C. sativa</em> extract on PL activity.</p></div><div><h3>Results</h3><p>Kinetic analyses showed that the plant extracts inhibited pancreatic lipase, with tetrahydrocannabinol (THC) and cannabinol (CBN) being the potential cause of the inhibition noted for the <em>C. sativa</em> plant extract. CBN and THC inhibited the pancreatic lipase activity in a competitive manner, with the lowest residual enzyme activity of 52 % observed at a 10 μg/mL concentration of CBN and 39 % inhibition at a 25 μg/mL concentration of THC. Circular dichroism (CD) spectroscopy revealed that the inhibitors caused a change in the enzyme's secondary structure. At low concentrations, THC showed potential for synergistic inhibition with orlistat. <em>C.sativa</em> treatment in an <em>in vivo</em> rat model confirmed its inhibitory effects on pancreatic lipase activity.</p></div><div><h3>Conclusion</h3><p>The findings in this study provided insight into the use of cannabinoids as pancreatic lipase inhibitors and the possibility of using these compounds to develop new pharmacological treatments for obesity.</p></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0753332224012423/pdfft?md5=4dca1f6cca4c85f2b5f0ec91e8798052&pid=1-s2.0-S0753332224012423-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.biopha.2024.117360
Macrophages undergo activation in response to multiple stimuli, including pathogens, growth factors and natural products. The inflammatory response and oxidative stress play critical roles in such macrophage activation. Some natural products reportedly promote immunoregulatory effects and the control of macrophage activation. Caryocar villosum (Cv), a native amazon plant, contains compounds that are an important source of molecules capable of macrophage activation. Herein, we demonstrate the immunomodulatory effects of oil obtained from Caryocar villosum (CvO) on macrophages. Macrophages were treated with varying concentrations of CvO, and resulting cellular morphological and functional changes were evaluated, including the production of nitric oxide (NO), reactive oxygen species (ROS), cytokines and phagocytic activity. Treatment of cells with 50 and 100 μg/mL CvO induced morphological and physiological alterations in the macrophages, such as increased cell surface and phagocytic activity. Additionally, treatment increased the productions of inflammatory cytokines (INF-γ, TNF-α, IL-6) and anti-inflammatory cytokines (IL-17 and IL-10) by macrophages, and significantly decreased ROS levels. In conclusion, these data suggest that, due to molecular diversity, CvO promoted an immunomodulatory effect on macrophages, mediated by an increased production of cytokines, and inhibition of ROS generation and phagocytic activity. Thus, CvO presents potential as a therapeutic agent for the treatment of inflammatory and non-inflammatory diseases.
{"title":"In vitro immunomodulatory effects of Caryocar villosum oil on murine macrophages","authors":"","doi":"10.1016/j.biopha.2024.117360","DOIUrl":"10.1016/j.biopha.2024.117360","url":null,"abstract":"<div><p>Macrophages undergo activation in response to multiple stimuli, including pathogens, growth factors and natural products. The inflammatory response and oxidative stress play critical roles in such macrophage activation. Some natural products reportedly promote immunoregulatory effects and the control of macrophage activation. <em>Caryocar villosum</em> (Cv), a native amazon plant, contains compounds that are an important source of molecules capable of macrophage activation. Herein, we demonstrate the immunomodulatory effects of oil obtained from <em>Caryocar villosum</em> (CvO) on macrophages. Macrophages were treated with varying concentrations of CvO, and resulting cellular morphological and functional changes were evaluated, including the production of nitric oxide (NO), reactive oxygen species (ROS), cytokines and phagocytic activity. Treatment of cells with 50 and 100 μg/mL CvO induced morphological and physiological alterations in the macrophages, such as increased cell surface and phagocytic activity. Additionally, treatment increased the productions of inflammatory cytokines (INF-γ, TNF-α, IL-6) and anti-inflammatory cytokines (IL-17 and IL-10) by macrophages, and significantly decreased ROS levels. In conclusion, these data suggest that, due to molecular diversity, CvO promoted an immunomodulatory effect on macrophages, mediated by an increased production of cytokines, and inhibition of ROS generation and phagocytic activity. Thus, CvO presents potential as a therapeutic agent for the treatment of inflammatory and non-inflammatory diseases.</p></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0753332224012459/pdfft?md5=44848787aa56f6024316f84a15685a0b&pid=1-s2.0-S0753332224012459-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.biopha.2024.117366
The RNA N6-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness in vitro. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models in vivo. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both in vitro and in vivo. All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.
{"title":"METTL3 inhibitor suppresses the progression of prostate cancer via IGFBP3/AKT pathway and synergizes with PARP inhibitor","authors":"","doi":"10.1016/j.biopha.2024.117366","DOIUrl":"10.1016/j.biopha.2024.117366","url":null,"abstract":"<div><p>The RNA N<sup>6</sup>-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness <em>in vitro</em>. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models <em>in vivo</em>. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both <em>in vitro</em> and <em>in vivo.</em> All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.</p></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0753332224012514/pdfft?md5=e57de27073e23877c6d23d11a29ff1bc&pid=1-s2.0-S0753332224012514-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.biopha.2024.117383
Ischemic heart disease (IHD) is a significant global health concern, resulting in high rates of mortality and disability among patients. Although coronary blood flow reperfusion is a key treatment for IHD, it often leads to acute myocardial ischemia-reperfusion injury (IRI). Current intervention strategies have limitations in providing adequate protection for the ischemic myocardium. DJ-1, originally known as a Parkinson's disease related protein, is a highly conserved cytoprotective protein. It is involved in enhancing mitochondrial function, scavenging reactive oxygen species (ROS), regulating autophagy, inhibiting apoptosis, modulating anaerobic metabolism, and exerting anti-inflammatory effects. DJ-1 is also required for protective strategies, such as ischemic preconditioning, ischemic postconditioning, remote ischemic preconditioning and pharmacological conditioning. Therefore, DJ-1 emerges as a potential target for the treatment of myocardial IRI. Our comprehensive review delves into its protective mechanisms in myocardial IRI and the structural foundations underlying its functions.
{"title":"DJ-1: Potential target for treatment of myocardial ischemia-reperfusion injury","authors":"","doi":"10.1016/j.biopha.2024.117383","DOIUrl":"10.1016/j.biopha.2024.117383","url":null,"abstract":"<div><p>Ischemic heart disease (IHD) is a significant global health concern, resulting in high rates of mortality and disability among patients. Although coronary blood flow reperfusion is a key treatment for IHD, it often leads to acute myocardial ischemia-reperfusion injury (IRI). Current intervention strategies have limitations in providing adequate protection for the ischemic myocardium. DJ-1, originally known as a Parkinson's disease related protein, is a highly conserved cytoprotective protein. It is involved in enhancing mitochondrial function, scavenging reactive oxygen species (ROS), regulating autophagy, inhibiting apoptosis, modulating anaerobic metabolism, and exerting anti-inflammatory effects. DJ-1 is also required for protective strategies, such as ischemic preconditioning, ischemic postconditioning, remote ischemic preconditioning and pharmacological conditioning. Therefore, DJ-1 emerges as a potential target for the treatment of myocardial IRI. Our comprehensive review delves into its protective mechanisms in myocardial IRI and the structural foundations underlying its functions.</p></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S075333222401268X/pdfft?md5=f3fade8af2463d136b07b1afa59b1ba2&pid=1-s2.0-S075333222401268X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.biopha.2024.117392
Sensorineural hearing loss is one of the most prevalent sensory deficits. Spiral ganglion neurons (SGNs) exhibit very limited regeneration capacity and their degeneration leads to profound hearing loss. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have been demonstrated to repair tissue damage in various degenerative diseases. However, the effects of MSC-sEV on SGN degeneration remain unclear. In this study, we investigated the efficacy of MSC-sEV for protection against ouabain-induced SGN degeneration. MSC-sEV were derived from rat bone marrow and their components related to neuron growth were determined by proteomic analysis. In primary culture SGNs, MSC-sEV significantly promoted neurite growth and growth cone development. The RNA-Seq analysis of SGNs showed that enriched pathways include neuron development and axon regeneration, consistent with proteomics. In ouabain induced SGN degeneration rat model, MSC-sEV administration via intratympanic injection significantly enhanced SGN survival and mitigated hearing loss. Furthermore, after ouabain treatment, SGNs displayed evident signs of apoptosis, including nuclei condensation and fragmentation, with numerous cells exhibiting TUNEL-positive. However, administration of MSC-sEV effectively decreased the number of TUNEL-positive cells and reduced caspase-3 activation. In conclusion, our findings demonstrate the potential of MSC-sEV in preventing SGN degeneration and promoting neural growth, suggesting intratympanic injection of MSC-sEV is a specific and efficient strategy for neural hearing loss.
{"title":"Intratympanic injection of MSC-derived small extracellular vesicles protects spiral ganglion neurons from degeneration","authors":"","doi":"10.1016/j.biopha.2024.117392","DOIUrl":"10.1016/j.biopha.2024.117392","url":null,"abstract":"<div><p>Sensorineural hearing loss is one of the most prevalent sensory deficits. Spiral ganglion neurons (SGNs) exhibit very limited regeneration capacity and their degeneration leads to profound hearing loss. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have been demonstrated to repair tissue damage in various degenerative diseases. However, the effects of MSC-sEV on SGN degeneration remain unclear. In this study, we investigated the efficacy of MSC-sEV for protection against ouabain-induced SGN degeneration. MSC-sEV were derived from rat bone marrow and their components related to neuron growth were determined by proteomic analysis. In primary culture SGNs, MSC-sEV significantly promoted neurite growth and growth cone development. The RNA-Seq analysis of SGNs showed that enriched pathways include neuron development and axon regeneration, consistent with proteomics. In ouabain induced SGN degeneration rat model, MSC-sEV administration via intratympanic injection significantly enhanced SGN survival and mitigated hearing loss. Furthermore, after ouabain treatment, SGNs displayed evident signs of apoptosis, including nuclei condensation and fragmentation, with numerous cells exhibiting TUNEL-positive. However, administration of MSC-sEV effectively decreased the number of TUNEL-positive cells and reduced caspase-3 activation. In conclusion, our findings demonstrate the potential of MSC-sEV in preventing SGN degeneration and promoting neural growth, suggesting intratympanic injection of MSC-sEV is a specific and efficient strategy for neural hearing loss.</p></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0753332224012770/pdfft?md5=925ea71905463f1983f18e580c650d83&pid=1-s2.0-S0753332224012770-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1016/j.biopha.2024.117397
Celastrol, the primary constituent of Tripterygium wilfordii, has demonstrated neuroprotective properties in rats with dementia by reducing inflammation. A high-fat diet and streptozotocin injection were utilized to establish a diabetic rat model, which was then employed to investigate the possible protective effect of celastrol against the development of diabetes-induced learning and memory deficits. Afterwards, the experimental animals received a dose of celastrol by gavage (4 mg/kg/d). An animal study showed that celastrol enhanced insulin sensitivity and glucose tolerance in diabetic rats. In the Morris water maze test, rats with diabetes performed poorly in terms of spatial learning and memory; treatment with celastrol improved these outcomes. Additionally, administration of celastrol downregulated the expression of inflammatory-related proteins (NF-κB, IKKα, TNF-α, IL-1β, and IL-6) and greatly reduced the generation of Aβ in the diabetic hippocampus tissue. Moreover, the insulin signaling pathway-related proteins PI3K, AKT, and GSK-3β were significantly upregulated in diabetic rats after celastrol was administered. Also, celastrol prevented damage to the brain structures and increased the synthesis of synaptic proteins like PSD-95 and SYT1. In conclusion, celastrol exerts a neuroprotective effect by modulating the insulin signaling system and reducing inflammatory responses, which helps to ameliorate the cognitive impairment associated with diabetes.
{"title":"The neuroprotective role of celastrol on hippocampus in diabetic rats by inflammation restraint, insulin signaling adjustment, Aβ reduction and synaptic plasticity alternation","authors":"","doi":"10.1016/j.biopha.2024.117397","DOIUrl":"10.1016/j.biopha.2024.117397","url":null,"abstract":"<div><p>Celastrol, the primary constituent of <em>Tripterygium wilfordii</em>, has demonstrated neuroprotective properties in rats with dementia by reducing inflammation. A high-fat diet and streptozotocin injection were utilized to establish a diabetic rat model, which was then employed to investigate the possible protective effect of celastrol against the development of diabetes-induced learning and memory deficits. Afterwards, the experimental animals received a dose of celastrol by gavage (4 mg/kg/d). An animal study showed that celastrol enhanced insulin sensitivity and glucose tolerance in diabetic rats. In the Morris water maze test, rats with diabetes performed poorly in terms of spatial learning and memory; treatment with celastrol improved these outcomes. Additionally, administration of celastrol downregulated the expression of inflammatory-related proteins (NF-κB, IKKα, TNF-α, IL-1β, and IL-6) and greatly reduced the generation of Aβ in the diabetic hippocampus tissue. Moreover, the insulin signaling pathway-related proteins PI3K, AKT, and GSK-3β were significantly upregulated in diabetic rats after celastrol was administered. Also, celastrol prevented damage to the brain structures and increased the synthesis of synaptic proteins like PSD-95 and SYT1. In conclusion, celastrol exerts a neuroprotective effect by modulating the insulin signaling system and reducing inflammatory responses, which helps to ameliorate the cognitive impairment associated with diabetes.</p></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0753332224012824/pdfft?md5=a8e553a4cb2041a33c195ae55194105b&pid=1-s2.0-S0753332224012824-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1016/j.biopha.2024.117325
Direct-acting antivirals ledipasvir (LDV) and daclatasvir (DCV) are widely used as part of combination therapies to treat Hepatitis C infections. Here we show that these compounds inhibit the proliferation, invasion, and colony formation of triple-negative MDA-MB-231 breast cancer cells, SRC-transduced SW620 colon cancer cells and SRC- transduced NIH3T3 fibroblasts. DCV also inhibits the expression of PDL-1, which is responsible for resistance to immunotherapy in breast cancer cells. The demonstrated low toxicity in many Hepatitis C patients suggests LDV and DCV could be used in combination therapies for cancer patients. At the molecular level, these direct-acting antivirals inhibit the phosphorylation of Akt and the ephrin type A receptor 2 (EPHA2) by destabilizing a Src-EPHA2 complex, although they do not affect the general kinase activity of Src. Thus, LDV and DCV could be effective drugs for Src-associated cancers without the inherent toxicity of classical Src inhibitors.
{"title":"FDA-approved antivirals ledipasvir and daclatasvir downregulate the Src-EPHA2-Akt oncogenic pathway in colorectal and triple-negative breast cancer cells","authors":"","doi":"10.1016/j.biopha.2024.117325","DOIUrl":"10.1016/j.biopha.2024.117325","url":null,"abstract":"<div><p>Direct-acting antivirals ledipasvir (LDV) and daclatasvir (DCV) are widely used as part of combination therapies to treat Hepatitis C infections. Here we show that these compounds inhibit the proliferation, invasion, and colony formation of triple-negative MDA-MB-231 breast cancer cells, SRC-transduced SW620 colon cancer cells and SRC- transduced NIH3T3 fibroblasts. DCV also inhibits the expression of PDL-1, which is responsible for resistance to immunotherapy in breast cancer cells. The demonstrated low toxicity in many Hepatitis C patients suggests LDV and DCV could be used in combination therapies for cancer patients. At the molecular level, these direct-acting antivirals inhibit the phosphorylation of Akt and the ephrin type A receptor 2 (EPHA2) by destabilizing a Src-EPHA2 complex, although they do not affect the general kinase activity of Src. Thus, LDV and DCV could be effective drugs for Src-associated cancers without the inherent toxicity of classical Src inhibitors.</p></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0753332224012101/pdfft?md5=717cc15d7597fd1ba333f631e974ec0f&pid=1-s2.0-S0753332224012101-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1016/j.biopha.2024.117362
Numerous studies have highlighted the role of translationally controlled tumor protein (TCTP) as a key inflammatory mediator of asthma and allergies. Our previous study revealed that blocking the cytokine-like activity of TCTP using JEW-M449, an anti-TCTP monoclonal antibody (mAb), alleviated allergic inflammation in asthmatic mice. This study aimed to determine whether directly delivering JEW-M449 into the respiratory tract is a more effective way of mitigating airway inflammation in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation than delivering this antibody via the intraperitoneal (IP) route. OVA-sensitized mice were intranasally administered JEW-M449 to enable its direct delivery to the respiratory tract before OVA challenge. We evaluated the changes in the levels of bronchoalveolar lavage fluid (BALF) cells, T helper type 2 (Th2) cytokines, OVA-specific immunoglobulin E (IgE), and histopathological alterations in the lung tissues. Intranasal (IN) administration of JEW-M449 significantly ameliorated the pathological changes associated with OVA-induced lung injury, including reduced inflammatory cell infiltration and mucus hypersecretion. Mice IN administered JEW-M449 also showed decreased OVA-mediated induction of Th2 cytokines in BALF and lung homogenates. Importantly, JEW-M449 delivered via the IN route reached the lung tissue more effectively and exerted superior anti-inflammatory effects in OVA-challenged mice than the IP-delivered JEW-M449. This study is the first to demonstrate the efficacy of directly delivering JEW-M449 anti-TCTP mAb into the respiratory tract to alleviate the asthma phenotype in a mouse model, thereby highlighting a potential delivery strategy for novel inhaled mAb therapeutics for human asthma.
许多研究都强调了翻译控制肿瘤蛋白(TCTP)作为哮喘和过敏症关键炎症介质的作用。我们之前的研究发现,使用抗TCTP单克隆抗体(mAb)JEW-M449阻断TCTP的细胞因子样活性,可以缓解哮喘小鼠的过敏性炎症。本研究旨在确定,在卵清蛋白(OVA)诱导的过敏性气道炎症小鼠模型中,直接将 JEW-M449 注入呼吸道是否比通过腹腔注射(IP)途径更有效地减轻气道炎症。给对 OVA 过敏的小鼠鼻内注射 JEW-M449,使其能在 OVA 挑战前直接进入呼吸道。我们评估了支气管肺泡灌洗液(BALF)细胞、T辅助2型(Th2)细胞因子、OVA特异性免疫球蛋白E(IgE)水平的变化以及肺组织的组织病理学改变。鼻内注射(IN)JEW-M449 能明显改善与 OVA 诱导的肺损伤相关的病理变化,包括减少炎症细胞浸润和粘液分泌过多。小鼠 IN 给药 JEW-M449 还能减少 OVA 介导的 BALF 和肺匀浆中 Th2 细胞因子的诱导。重要的是,与 IP 给药的 JEW-M449 相比,通过 IN 途径给药的 JEW-M449 能更有效地到达肺组织,并在 OVA 攻击的小鼠中发挥更佳的抗炎效果。这项研究首次证明了直接将JEW-M449抗TCTP mAb递送到呼吸道对缓解小鼠模型的哮喘表型具有疗效,从而突出了新型吸入式mAb疗法治疗人类哮喘的潜在递送策略。
{"title":"Therapeutic efficacy of JEW-M449, an anti-TCTP monoclonal antibody, administered via the nasal route in a BALB/c mouse model of ovalbumin-induced acute asthma","authors":"","doi":"10.1016/j.biopha.2024.117362","DOIUrl":"10.1016/j.biopha.2024.117362","url":null,"abstract":"<div><p>Numerous studies have highlighted the role of translationally controlled tumor protein (TCTP) as a key inflammatory mediator of asthma and allergies. Our previous study revealed that blocking the cytokine-like activity of TCTP using JEW-M449, an anti-TCTP monoclonal antibody (mAb), alleviated allergic inflammation in asthmatic mice. This study aimed to determine whether directly delivering JEW-M449 into the respiratory tract is a more effective way of mitigating airway inflammation in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation than delivering this antibody via the intraperitoneal (IP) route. OVA-sensitized mice were intranasally administered JEW-M449 to enable its direct delivery to the respiratory tract before OVA challenge. We evaluated the changes in the levels of bronchoalveolar lavage fluid (BALF) cells, T helper type 2 (Th2) cytokines, OVA-specific immunoglobulin E (IgE), and histopathological alterations in the lung tissues. Intranasal (IN) administration of JEW-M449 significantly ameliorated the pathological changes associated with OVA-induced lung injury, including reduced inflammatory cell infiltration and mucus hypersecretion. Mice IN administered JEW-M449 also showed decreased OVA-mediated induction of Th2 cytokines in BALF and lung homogenates. Importantly, JEW-M449 delivered via the IN route reached the lung tissue more effectively and exerted superior anti-inflammatory effects in OVA-challenged mice than the IP-delivered JEW-M449. This study is the first to demonstrate the efficacy of directly delivering JEW-M449 anti-TCTP mAb into the respiratory tract to alleviate the asthma phenotype in a mouse model, thereby highlighting a potential delivery strategy for novel inhaled mAb therapeutics for human asthma.</p></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0753332224012472/pdfft?md5=dfb4db4b8266d5b926278fc0cc844c87&pid=1-s2.0-S0753332224012472-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}