Isabel Atienza-Navarro, Angel Del Marco, Maria de Los Angeles Garcia-Perez, Alvaro Raya-Marin, Carmen Gil, Ana Martinez, Isabel Benavente-Fernandez, Simon Lubian-Lopez, Monica Garcia-Alloza
{"title":"VP3.15 reduces acute cerebellum damage after germinal matrix-intraventricular hemorrhage of the preterm newborn.","authors":"Isabel Atienza-Navarro, Angel Del Marco, Maria de Los Angeles Garcia-Perez, Alvaro Raya-Marin, Carmen Gil, Ana Martinez, Isabel Benavente-Fernandez, Simon Lubian-Lopez, Monica Garcia-Alloza","doi":"10.1016/j.biopha.2024.117586","DOIUrl":"10.1016/j.biopha.2024.117586","url":null,"abstract":"<p><p>Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most common complications of the preterm newborn. The pathology of the GM-IVH is not completely understood and even regions distant from the lesion area are severely affected. It has been suggested that cerebellar diaschisis may underlie the neurodevelopmental problems that many of these kids show, including cerebral palsy, attention deficit disorders or hyperactivity. Additionally, GM-IVH has no successful treatment. VP3.15 is a dual action phosphodiesterase 7 (PDE7) and glycogen synthase kinase-3β (GSK-3β) inhibitor that limits neuroinflammation and neuronal loss. Therefore, it might also provide a relevant tool to reduce complications associated with GM-IVH. We have used a murine model of GM-IVH to analyze the short and long-term effects of VP3.15 in brain pathology and behavioral complications. In our hands, the induction of unilateral GM-IVH to P7 CD1 mice results in a short-term (P14) compromise of the cerebellar neuronal population and Purkinje cells arborization, an increase of microglia burden in the nuclei and an overall increase of punctuate cerebellar hemorrhages. Whereas brain alterations are no longer observed in the long term (P110), these animals present overt hyperactivity when analyzed in the adulthood, supporting the long-term behavioral impairment. Also, hyperactivity significantly correlates with ipsi and contralateral cerebellar sizes, neuronal densities and myelin basic protein levels. Importantly, treatment with VP3.15 significantly reduces neuronal loss, Purkinje cells simplification, the presence of cerebellar hemorrhages, as well as hyperactivity. Altogether, our data support the neuroprotective effects of VP3.15 in GM-IVH of the PT.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117586"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Astragaloside IV alleviates heatstroke brain injury and neuroinflammation in male mice by regulating microglial polarization via the PI3K/Akt signaling pathway.","authors":"Zeze Wang, Zhen Luo, Yulong Tan, Genlin He, Ping Li, Xiaoqian Liu, Tingting Shen, Yishan Liu, Xuesen Yang, Xue Luo","doi":"10.1016/j.biopha.2024.117545","DOIUrl":"10.1016/j.biopha.2024.117545","url":null,"abstract":"<p><p>Heatstroke is a condition caused by overheating of the body that leads to severe central nervous system dysfunction. Although there have been numerous studies on the pathological process of heatstroke, effective treatment methods are lacking. Astragaloside IV can protect the brain from inflammation and brain damage in various inflammation-related diseases, but it has not yet been used clinically for the treatment of heatstroke. Therefore, the aim of this study was to explore the neuroprotective effect of Astragaloside IV on heatstroke-induced central nervous system damage and its mechanism. Brain injury model under heatstroke was established using artificial climate simulation cabin. By scoring neurological deficits, performing histological and immunofluorescence staining of microglia, and detecting cytokine levels, we determined that Astragaloside IV alleviated brain injury and neuroinflammation. To further explore the potential molecular mechanism, RNA sequencing was performed to investigate the differences in the brain. The results revealed that the PI3K/AKT pathway is involved. In vitro experiments further confirmed that Astragaloside IV can abrogate the phenotypic changes in microglia induced by heatstroke. Moreover, Astragaloside IV promotes the polarization of M2 microglia by activating the PI3K/AKT pathway. In summary, these results indicate that Astragaloside IV alleviates neuroinflammation and brain injury induced by heatstroke through the PI3K/AKT pathway. Astragaloside IV is a commonly used therapeutic agent in the clinic, but its use in the treatment of heatstroke-induced brain injury has not been explored. This study reveals that Astragaloside IV may be a new therapeutic agent for the treatment of heatstroke-induced brain injury.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117545"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A novel synthetic compound, deferiprone-resveratrol hybrid (DFP-RVT), promotes hepatoprotective effects and ameliorates iron-induced oxidative stress in iron-overloaded β-thalassemic mice.","authors":"Jin Li, Hataichanok Chuljerm, Kornvipa Settakorn, Honghong Xu, Yongmin Ma, Woranontee Korsieporn, Narisara Paradee, Somdet Srichairatanakool, Pimpisid Koonyosying","doi":"10.1016/j.biopha.2024.117570","DOIUrl":"10.1016/j.biopha.2024.117570","url":null,"abstract":"<p><p>A high amount of iron in β-thalassemia patients can lead to oxidative stress and organ dysfunction, especially liver, the main iron accumulated organ. Iron catabolism causes the generation of reactive oxygen species (ROS), triggering liver inflammation, fibrosis, and cirrhosis. Deferiprone-resveratrol hybrid (DFP-RVT) is chemically synthesized by combining deferiprone (DFP) and resveratrol (RVT) which shows an iron-chelating property along with antioxidant activity. This study explored the hepatoprotective effect of DFP-RVT in iron overloaded β-knockout (BKO) thalassemic mice. The results revealed that DFP-RVT treatment improved liver function in iron-overloaded BKO mice by reducing liver enzymes and increasing hepcidin levels compared to iron overload control mice. Both DFP alone and DFP-RVT treatment groups demonstrated iron chelation effects by decreasing liver iron content (LIC), iron profiles, and iron deposition in the liver. Moreover, DFP-RVT powerfully showed antioxidant properties by decreasing liver and plasma thiobarbituric acid reactive substances (TBARs) and increasing reduced glutathione (GSH) and superoxide dismutase (SOD). Interestingly, transforming growth factor β1 (TGFβ1), which can contribute to chronic liver disease through liver injury, inflammation, fibrosis, and cirrhosis, is highly expressed in iron-overloaded mice. However, both DFP and DFP-RVT treatment significantly reduced TGFβ1 levels compared to the iron-overloaded group. Therefore, DFP-RVT could be a potent hepatoprotective compound through the mobilization of iron, reduction of ROS, improvement of liver enzymes, and alleviation of liver damage, potentially relieving liver dysfunction in iron-overloaded BKO mice.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117570"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"L-NRB alleviates amyotrophic lateral sclerosis by regulating P11-Htr4 signaling pathway.","authors":"Yunfeng Pan, Xiao Sun, Yu Tian, Miao Yu, Yun Luo, Xiaobo Sun","doi":"10.1016/j.biopha.2024.117588","DOIUrl":"10.1016/j.biopha.2024.117588","url":null,"abstract":"<p><strong>Introduction: </strong>L-NRB is a compound formed as a ring cleavage product of butylphthalide and borneol in a molar ratio 1:2. This study aimed to explore the therapeutic effect of L-NRB on amyotrophic lateral sclerosis (ALS) and its possible mechanism.</p><p><strong>Methods: </strong>SOD1-G93A mice were used as an ALS model. Behavioral tests, histopathological staining, Nissl staining, immunohistochemistry, enzyme-linked immunosorbent assays, and Western blotting were used to analyze the therapeutic effect. The underlying mechanism of L-NRB in treating ALS was investigated using transcriptomic analyses.</p><p><strong>Results: </strong>It was found that L-NRB alleviated motor dysfunction, pathological changes in the gastrocnemius muscle, and motor neuron injuries. The results indicated that L-NRB had a neuroprotective function associated with the inhibition of neuroinflammation. The anti-apoptotic effect of L-NRB was found to be related to the regulation of the P11-Htr4 signaling pathway.</p><p><strong>Conclusion: </strong>In summary, the results demonstrated the therapeutic effect of L-NRB on ALS and suggest a promising new therapeutic candidate for ALS.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117588"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sana A Fadil, Dina A I Albadawi, Khalid Z Alshali, Hossam M Abdallah, Mona M Saber
{"title":"Modulation of inflammatory mediators underlies the antitumor effect of the combination of morusin and docetaxel on prostate cancer cells.","authors":"Sana A Fadil, Dina A I Albadawi, Khalid Z Alshali, Hossam M Abdallah, Mona M Saber","doi":"10.1016/j.biopha.2024.117572","DOIUrl":"10.1016/j.biopha.2024.117572","url":null,"abstract":"<p><p>Prostate cancer stands as a prominent contributor to male mortality in cancer cases. Docetaxel (Doc) is a commonly used treatment, but some patients do not respond well due to drug toxicity and resistance. Morusin, a prenylated flavonoid found in Morus alba, show strong anticancer properties. The aim of this study was to investigate the combined effect of morusin and docetaxel on prostate cancer cells, while exploring the underlying mechanisms. The IC<sub>50</sub> values of morusin, docetaxel, and their combination on PC3 cells were evaluated using the sulforhodamine-B (SRB) assay. In addition, various markers including glutathione (GSH), malondialdehyde (MDA), inflammatory mediators (IL-6, TNF-α, NF-κB, and IL-10), NQO1, NRF2, and apoptotic markers (Bax and Bcl2) were evaluated. Co-administration of morusin and Doc significantly reduced Doc IC<sub>50</sub> value, indicating enhanced cytotoxicity. The combination therapy affected inflammatory mediators by increasing IL-6 levels and reducing elevated TNF-α and NF-κB levels. Furthermore, the combination reduced GSH levels and augmented MDA, NQO1 and NRF2 levels, which have a crucial role in the cellular response to oxidative stress. Moreover, morusin enhanced apoptosis induced by Doc through increasing Bax levels and decreasing Bcl-2 expression. Molecular docking analyses confirmed morusins' activity against the target proteins studied. In conclusion, the combination of morusin and docetaxel showed enhanced efficacy at lower drug concentrations in treating prostate cancer. The combination therapy may reduce drug resistance by modulating inflammatory mediators and regulating antioxidant markers. The results of this study indicate the possibility of morusin in being a supplementary treatment option for prostate cancer.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117572"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Veronika Nemethova, Petra Babiakova, Michal Selc, Kristina Jakic, Lucia Uhelska, Boglarka Teglasova, Peter Makovicky, Andrea Babelova, Filip Razga
{"title":"Therapeutic oligonucleotide ASC1R shows excellent tolerability and remarkable efficacy in reducing SARS-CoV-2 mRNA levels in C57BL/6 mice.","authors":"Veronika Nemethova, Petra Babiakova, Michal Selc, Kristina Jakic, Lucia Uhelska, Boglarka Teglasova, Peter Makovicky, Andrea Babelova, Filip Razga","doi":"10.1016/j.biopha.2024.117587","DOIUrl":"10.1016/j.biopha.2024.117587","url":null,"abstract":"<p><p>The coronavirus pandemic has resulted in over 775 million cases and 7 million deaths worldwide, driving efforts to develop therapeutic strategies to control the viral infection. Therapeutic oligonucleotides have shown promise in treating many pathological conditions, including those of viral origin. The present study assessed the in vivo efficacy and safety of ASC1R, a novel therapeutic oligonucleotide of unconventional design targeting the conserved viral RdRp sequence essential for replication. In functional studies, ASC1R was administered to transfected C57BL/6 mice at doses of 1 and 10 mg/kg. Safety assessments included acute toxicity evaluations at doses ranging from 30 to 100 mg/kg, and subacute toxicity evaluations of repeated doses of 1 and 10 mg/kg. Evaluations included general clinical observations, findings at necropsy, measurements of organ weight, and histopathological examinations of the liver, lungs, spleen, and kidneys. ASC1R effectively reduced RdRp levels >94 % within 24 hours following a single 1 mg/kg dose, with no observed organ toxicity. Acute and subacute toxicity assessments found that mice receiving high (≥30 mg/kg) or repeated (10 mg/kg for 7 days) doses of ASC1R showed an increase in relative spleen weight, without histopathological changes. The marked ability of a single low dose of ASC1R (1 mg/kg) to reduce viral RNA suggests its potential for clinical applications, balancing therapeutic efficacy with minimal side effects. Our findings indicate that ASC1R has promise as a viable treatment option for patients with COVID-19.</p>","PeriodicalId":93904,"journal":{"name":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","volume":"180 ","pages":"117587"},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}